European Association for the Study of Diabetes — 49th Annual Meeting Executive Highlights
In this final report, we provide our complete coverage of the 49th Annual Meeting of the European Association for the Study of Diabetes, held in Barcelona, Spain from September 22-27, 2013. This year’s estimated attendance totaled over 18,000 delegates, representing more than 100 countries. The conference featured 264 oral presentations, 30 symposia, 14 corporate symposia, and 1,095 posters – nearly identical to last year’s meeting in Berlin, with the exception of 90 more posters this year (which may be a proxy for better science, or more posters covering similar topics, or merely more poster spots given in an effort to heighten attendance). There were 76 exhibitors listed, down substantially from the 92 we saw in 2012.
To help you sort through all of the learnings, we’ve organized our commentary into nine sections: (1) Incretin Therapies; (2) SGLT-2 Inhibitors; (3) Insulin Therapy; (4) Cardiovascular and Other Major Outcomes Trials; (5) Diabetes Complications; (6) Diabetes Technology; (7) Obesity, Prediabetes, and Metabolic Surgery; (8) Novel Therapies, Basic Science, and Additional Topics; and (9) Exhibit Hall. For your convenience, each section is also available as a separate document. Titles highlighted in blue are new additions that were not initially included in our live daily updates from Barcelona. Additionally, titles highlighted in yellow represent our top ten favorite talks of the meeting — choosing this list was exceptionally difficult, given the large number of noteworthy talks we attended. For those who have limited time to read through this report, we’ve compiled these top ten highlights in a separate document, published concurrently with this full report.
Below we outline major themes we noticed at the meeting, followed by the table of contents.
DRUGS
-
On the drug front, EASD 2013 featured slightly more new data and discussion on SGLT-2 inhibitors (and SGLT-1/SGLT-2 dual inhibitors) than 2012’s meeting – as at ADA 2013, EASD 2013 had less focus on primary efficacy data and more focus on the drugs’ side effect and safety profiles and their use in special populations. An ADA poster on the use of BI/Lilly’s empagliflozin in type 1 diabetes was presented as an oral at EASD 2013: after eight weeks, patients experienced a 0.4% drop in A1c from an 8.0% baseline, 20% reduced their daily insulin requirement, and 33% saw reduced rates of symptomatic hypoglycemia – to us, these data further suggest that the insulin-independent mechanism of SGLT-2 inhibitors could provide greater glycemic control and improved quality of life for type 1 patients. However, this study raised several issues that require further examination – e.g., how to adjust insulin therapy when adding an SGLT-2 inhibitor, and why investigators observed a spontaneous increase in carbohydrate intake after SGLT-2 inhibitor therapy (we hadn’t heard this before; it sounded a bit random). Lexicon Pharmaceuticals’ Chief Medical Officer Dr. Pablo Lapuerta presented an oral on the robust gastrointestinal and genitourinary safety profile of Lexicon’s SGLT-1/SGLT-2 dual inhibitor LX4211 – while many KOLs have noted that SGLT-1 inhibition causes GI side effects, LX4211 therapy did not lead to an excess of GI side effects (nausea, diarrhea). Participants on LX4211 saw similar rates of UTIs compared to placebo, as well as a low incidence of vaginal infections that did not lead to treatment discontinuation. EASD also featured a poster (#953) on the use of canagliflozin (J&J’s Invokana) in people with stage 3 chronic kidney disease – as expected, canagliflozin was shown to be more effective in those with less severe kidney disease. We also saw the longest canagliflozin data presented to date – at 104 weeks, canagliflozin 100 mg and 300 mg provided significantly greater A1c reductions (~0.7% for both) compared to glimepiride (0.55%) from a baseline A1c of 7.8% (Oral presentation #182). Notably, new 52-week data on two lesser-known SGLT-2 inhibitors (Taisho’s luseogliflozin [submitted in Japan] and Roche/Chugai’s recently discontinued candidate, tofogliflozin) were also presented. Luseogliflozin, as an add on to glimepiride in Japanese patients with type 2 diabetes, conferred a 0.6% A1c reduction (baseline = 8.1%) and similar weight loss (2.2 kg placebo-adjusted weight loss at 52 weeks) compared to other SGLT-2 inhibitors. These are the first efficacy data for luseogliflozin that we have seen at a major meeting. Tofogliflozin’s 52-week data showed a fairly standard SGLT-2 inhibitor profile with regards to A1c reduction (0.7% reduction from a baseline of 7.8% as monotherapy), weight loss (3.4 kg), and blood pressure, and surprisingly, demonstrated a significant reduction in LDL cholesterol. The data did not provide much insight into why Roche/Chugai decided to terminate the program although we believe when a compound isn’t likely to be first (or second), the barriers to reach success do make it difficult for companies to continue to push compounds forward unless they have some very tangible differentiation.
- With CVOTs at the forefront of everyone’s minds at EASD, we heard murmurs throughout the conference of hope that SGLT-2 inhibitors might ultimately be CV-protective due to their favorable effects on weight and blood pressure (as a reminder, they also cause an increase in LDL cholesterol levels). We attended an oral presentation by Dr. David Sjöström (Global Brand Physician, AstraZeneca, Molndal, Sweden) that concluded that dapagliflozin-induced weight loss was a critical factor in much of the improvement in A1c and blood pressure seen with the candidate. While we will, of course, need to wait until SGLT-2 inhibitor CVOTs report results to draw firm conclusions, some characterized it as interesting that researchers have not lost hope that a diabetes therapy could prove CV-protective after SAVOR and EXAMINE’s neutral results. (On that note, we would say the lower efficacy and relatively short trial time are what drove those results.) Clearly the issues of trial design, study population, and interim data disclosure will also apply to SGLT-2 inhibitor trials, and we wonder if lessons learned from the older incretin CVOTs will help better inform the design and analysis of data from any SGLT-2 inhibitor trials. While discussing the evaluation of SGLT-2 inhibitor safety, Dr. Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) provided a truly valuable synthesis and overview on CVOTs, FDA policy, clinical trial design, and data interpretation. The clear theme of Dr. Kaul’s presentation was uncertainty – he emphasized a vast array of unanswered questions for the drug class, including cardiovascular and renal safety, bone health, risks of malignancy, and volume depletion.
- EASD 2013 featured rich discussion and commentary on the implications of the two DPP-4 inhibitor CVOTs, SAVOR and EXAMINE, now that the medical community has had a few weeks to digest the data. Overall, we believe that prescribing practices will generally remain the same (we do not think that most HCPs had very serious safety concerns, if any, about DPP-4 inhibitors to begin with), perhaps with slightly more reticence to prescribe DPP-4 inhibitors to patients at risk for heart failure and with slightly more reassurance on pancreatic safety risks. In our view, the question of whether BMS/AZ’s Onglyza (saxagliptin; SAVOR trial) or Takeda’s Nesina (alogliptin; EXAMINE trial) are cardioprotective has not been definitively answered – most speakers also appear to agree that the trial design and patient enrollment (extremely short trials enrolling high-risk patients) essentially precluded the possibility that the trials would turn out cardioprotective, and it is a shame that we may never know the truth about DPP-4 inhibitors and cardioprotection since no one has the financial incentive to fund a long-enough and large-enough trial in a newly-diagnosed patient population. The discussion on SAVOR and EXAMINE centered about the increased risk of hospitalization for heart failure found in SAVOR and the trend toward the same result observed in EXAMINE. Although there was broad recognition that the signals were not linked to an increase in mortality, a number of KOLs, including Drs. Mansoor Husain (University Health Network, Toronto, Ontario, Canada) and Naveed Sattar (University of Glasgow, Glasgow, UK) emphatically called for more analysis of the hospitalization data. Given that a study on Novartis’ Galvus (vildagliptin) found that the drug had an effect on ventricular size, Dr. Sattar noted that a class-wide effect cannot be ruled out.
Other important safety findings (pancreatitis, hypoglycemia, kidney function) were also discussed, but were overshadowed by the heart failure discussion. The SAVOR group went to great lengths to conduct subanalyses on hypoglycemia in response to the finding that saxagliptin caused a slight increase in both mild and severe hypoglycemia – overall, clinicians did not express much concern regarding DPP-4 inhibitors and hypoglycemia risk; however, it was instructive to learn that saxagliptin did not have a significant impact on the risk of overall hypoglycemia unless patients were on sulfonylureas, or if they had a baseline A1c below 7% and were on combination therapy involving insulin. Looking forward, we think time-dependent analyses will be helpful to examine the temporal relationship between hypoglycemia and cardiovascular outcomes, which could shed light on hypoglycemia’s contribution to CV risk. Finally, most speakers found the pancreatitis findings in EXAMINE and SAVOR reassuring; however, as expected, most KOLS noted that the CVOTs had too few pancreatitis cases from which to draw meaningful conclusions.
- We noticed less talk on the subject of incretin therapies and pancreatitis this year, and what we did hear was more reassuring than what has been heard at conferences earlier this year. The general consensus among most speakers at this year’s EASD was that current data is insufficient to support an increased risk of pancreatitis and pancreatic cancer. This was due, in large part, to better data on the issue. Neither SAVOR-TIMI 53 nor EXAMINE showed a statistically significant association between DPP-4 inhibitors and pancreatitis, a point that was brought up multiple times during the conference. Additionally, Dr. Peter Boyle (International Prevention Research Institute, Lyon, France) presented the results of a meta-analysis of 70 independent studies, which indicated no evidence of any increased risk of pancreatitis with incretin therapies (summary relative risk = 1.08; 95% CI: 0.87-1.34). This growing consensus among KOLs, along with recent statements from the ADA, EASD, and other high-profile organizations, indicate to us that the hysteria over the issue is beginning to subside (although there is widespread agreement on the need for more data).
- We were very excited to see more data on the use of incretin therapies and SGLT-2 inhibitors in type 1 diabetes. We feel that progress on this front is imperative, given that type 1 diabetes patients have relatively few options at their disposal when it comes to pharmacotherapy. Dr. Urd Kielgast (University of Copenhagen, Copenhagen, Denmark) delivered a terrific review of studies of GLP-1 agonists and DPP-4 inhibitors in this patient population. The studies he surveyed indicate that GLP-1 agonists have encouraging potential to improve A1c, reduce insulin dose, reduce glycemic variability, prevent weight gain, and (possibly) improve hypoglycemia in type 1 patients. Data on DPP-4 inhibitors is somewhat less consistent. Dr. Simon Heller (University of Sheffield, Sheffield, UK) and his research group featured an oral presentation and poster on the use of liraglutide (Novo Nordisk’s Victoza) in type 1 diabetes patients, which indicated that the drug is effective and (very importantly) does not impair patients’ counterregulatory response to hypoglycemia. Given the ability of both SGLT-2 inhibitors and incretin therapies to reduce postprandial glucose spikes, we hope that these options are studied further in type 1 diabetes patients, particularly as adjuncts to basal insulin.
- EASD had plenty of discussion on basal insulins, a reminder of all the innovation happening in this area. Novo Nordisk’s exhibit hall booth was dedicated entirely to Tresiba (insulin degludec) on the day of the hall’s opening – it was swarming with visitors eager to learn more about the ultra-long-acting basal insulin, which was recently launched (as of Novo Nordisk 2Q13, Tresiba had launched in the UK, Denmark, Switzerland, Mexico, and Japan). Meanwhile, Sanofi’s new glargine formulation also came up at EASD. Though the EDITION I trial was already presented at ADA 2013, hearing the results again from Dr. Matthew Riddle (Oregon Health and Science University, Portland, OR) reminded us of the product’s hypoglycemia benefits relative to Lantus (insulin glargine). On a broader level, we enjoyed a lively debate on the pros and cons of longer-acting basal insulins. Drs. Luigi Meneghini (University of Miami, Miami, FL) and Philip Home (Newcastle University, Newcastle upon Tyne, UK) both agreed that variability, consistency, and bioavailability are of great importance, and that the current “gold standard” for basal insulin needs is pump therapy. However, they diverged on many other topics, including the safety of once-weekly insulin. This is not a clear-cut debate that we expect to be resolved anytime soon – aside from safety, once-weekly drugs also have other important considerations like convenience (Is it hard to remember once-weekly?), ease of delivery device, titration, and side effects.
- There was unfortunately no notable new data on the ultra-rapid-acting insulin front; however, the HypoAna trial was a great reminder of why analog insulin truly makes a difference for patients. The two-year crossover trial included 159 type 1 patients with recurrent severe hypoglycemia (≥2 episodes in the past year). The patients were first randomized to either analog insulin (detemir and aspart) or to human insulin/NPH, and then crossed over to the other study arm. Significantly, treatment with analog insulin resulted in a 29% rate reduction (p<0.05) for severe hypoglycemia compared to human insulin. This corresponds to an absolute rate reduction of 0.5 severe hypoglycemia episodes per patient-year, meaning the number needed to treat with insulin analogs to avoid one episode of severe hypoglycemia is just two patients per year! What a victory for patients – our hope is that payers and governments see this data and realize the true value of reimbursing analog insulin. While many payers use the long-term nature of diabetes complications to justify older-generation treatments, this study shows a very short-term payoff to more expensive drugs. That’s something worth paying for.
- Combination therapies for type 2 diabetes received a substantial amount of attention this year. The star of the show, so to speak, was basal insulin/GLP-1 agonist co-therapy, a combination that Dr. John Buse (University of North Carolina, Chapel Hill, NC) characterized as potentially “unparalleled” in terms of efficacy and that Dr. Stephen Gough (University of Oxford, Oxford, UK) termed the “most exciting area of current development” in the future of GLP-1 agonists. Both KOLs specifically mentioned Novo Nordisk’s IDegLira, a fixed-ratio combination of Victoza (liraglutide) and Tresiba (insulin degludec). Dr. Gough re-presented the promising results of the DUAL-1 study on IDegLira, first shared at this year’s ADA (see page 4 of our ADA 2013 Incretins Report at http://www.closeconcerns.com/knowledgebase/r/6001b62d). As background, the study demonstrated a remarkable 1.9% A1c reduction (from a baseline of 8.3%) with IDegLira compared to drops of 1.3% and 1.4% with liraglutide and insulin degludec, respectively. A group led by Dr. Bernard Zinman (University of Toronto, Toronto, Canada) presented a poster comparing liraglutide and NovoLog (insulin aspart) as add-ons to insulin degludec; the liraglutide group saw a greater A1c change and more weight loss compared to the insulin aspart group. In a corporate symposium sponsored by Sanofi, Dr. Melanie Davies (University of Leicester, Leicester, UK) also highlighted that Sanofi’s once-daily GLP-1 agonist Lyxumia (lixisenatide; co-developed with Zealand Pharma) is being primarily marketed as an add-on to the company’s top-selling basal insulin Lantus (insulin glargine). Excitingly, SGLT-2 inhibitors were part of the combination therapy discussion this year — notably, Dr. Julio Rosenstock (University of Texas Southwest Medical Center, Dallas, TX) forecasted the combination of SGLT-2 inhibitors with either incretin therapies (as an early treatment option) or basal insulin (as a later-stage option). During a panel discussion during a BMS/AZ corporate symposium on GLP-1 agonists and SGLT-2 inhibitors, Dr. Tina Vilsbøll (University of Copenhagen, Copenhagen, Denmark) noted that triple-therapy fixed-dose combinations of DPP-4 inhibitors, metformin, and SGLT-2 inhibitors are being developed and studied.
- A series of retrospective database studies on the effect of insulin and sulfonylureas on all-cause mortality emphasized the safety concerns associated with sulfonylureas, but also drew attention to broader questions regarding data interpretation. In two studies sponsored by BMS/AZ, Dr. Craig Currie (Cardiff University, Cardiff, UK) and his associates mined the UK’s Clinical Practice Research Datalink, and found that all-cause mortality increased by 35% and 58% when SFUs were used with metformin or as monotherapy, respectively. We feel that these results warrant further investigation into the safety and long-term impacts of SFUs, and will be looking forward to the results of Lilly/BI’s CAROLINA CVOT for Tradjenta (linagliptin), which compares the DPP-4 inhibitor to glimepiride (estimated primary completion in 2018). A third study found a significant, dose-dependent increase in risk for all-cause mortality with insulin therapy, which we found slightly more surprising. These three studies, especially the one investigating insulin, demonstrate the potential pitfalls of putting too much stock in retrospective database analyses. Indication bias could have played a significant role in the insulin study, as a provider’s decision to place a patient on insulin likely reflected more poorly controlled diabetes. We believe that retrospective studies can generally only be seen as hypothesis-generating, especially when data from prospective studies are available.
DEVICES
- A major technology highlight of EASD came in Abbott’s corporate symposium, which introduced attendees to “Flash Glucose Monitoring.” Abbott has created a new device category designed as a “widely acceptable alternative” to traditional blood glucose monitoring, while at the same time collecting enough glucose data to allow generation of ambulatory glucose profile (AGP) reports. Specifically, the system involves use of a 14-day, factory-calibrated (!), subcutaneous sensor (MARD of 8.5% vs. YSI in an n=12 study) and a wireless touchscreen reader device. Abbott’s new product will not have CGM alarms on the receiver – instead, to see the real-time glucose value, glucose trend arrow, and eight-hour trend graph, the reader device is physically scanned over the sensor patch, which allows wireless collection (via RFID) and display of the glucose data on the reader’s color touchscreen. While it could give “CGM-like” data if someone “scanned” the reader over the sensor every five minutes, we believe this device is more likely to be used to get intermittent data quite easily (i.e., no fingerstick, no blood, and what sounds like little hassle). Abbott’s intention is that this new system will have the same indication as the FreeStyle Navigator CGM in Europe – a claim to dose insulin off the readings, except in cases of hypoglycemia or when glucose is changing rapidly. Pending a CE Mark, the product is expected to launch in 2H14 in Europe.
- We don’t expect to see many traditional CGM users switching to this new system, though we do think it will help expand the continuous glucose sensing market, especially to intensively managed patients and their HCPs that have not embraced CGM for whatever reason (e.g., cost, the need for fingerstick calibration, inaccuracy, perceived hassle factor regarding alarms, etc.). We also believe that several other patient groups may be drawn to this product: people who can’t afford CGM, pregnant patients, elderly patients, type 2 patients who need to monitor diabetes closely when making therapeutic changes, inpatients, and people with prediabetes and a high risk of “converting” to type 2 diabetes. The biggest question will relate to pricing, and we expect to see Abbott do cost effectiveness studies to help make this system attractive to payers.
- An entire session put the spotlight on the shortcomings of the European medical device regulatory process. We heard striking presentations from BMJ journalist Ms. Deborah Cohen and Drs. Lutz Heinemann (Profile Institute, Neuss, Germany) and John Pickup (King’s College London School of Medicine, UK) – all harshly criticized the numerous deficiencies in the European CE Mark process, problems that run the gamut from minimal requirements to get a device approved (often no clinical data is needed) to little transparency to shocking conflicts of interest. EASD President Dr. Andrew Boulton chaired this session and expressed his view that Europe should have a single agency for evaluating medical devices (similar to the European Medicines Agency for drugs). During the conference, a European Parliament committee voted on several potential improvements to the CE Mark system, with a final vote expected at the end of October. However, it remains to be seen if these improvements go far enough for diabetes devices like BGMs and insulin pumps – some suggested they do not. EASD is mounting a big push on the medical device regulation front, which started back in March with its press release, “Avoiding a medical device disaster in diabetes.” We think it’s valuable to fix deficiencies that would make patients safer, though the tradeoff is creating a process that slows down the regulatory system and delays patients from getting innovative devices. It’s a very tough balance to strike, though most would argue that the US system has been too restrictive over the past few years (e.g., the four-year delay in getting the Medtronic Veo/MiniMed 530G). This debate could have some big implications for the field going forward.
- EASD brought new data on two insulin delivery solutions designed to speed up insulin absorption: Insuline’s InsuPad and BD’s intradermal needles. Dr. Andreas Pfützner’s (IKFE, Mainz, Germany) presentation on the Barmer reimbursement study was the focus of Insuline’s corporate symposium. The 145-patient study evaluated the benefits of using Insuline’s wearable heated pad for MDI users. Notably, patients using the device experienced 45% less hypoglycemia and needed 28% less prandial insulin. In our visit to the company’s exhibit hall booth, we appreciated a full demonstration of the device, which seemed quite user friendly and unobtrusive. Notably, the InsuPad will be launching in October in Germany with full reimbursement (i.e., no out of pocket costs for patients). Also on the faster insulin delivery front, BD presented a poster on the feasibility of using intradermal needle technology in infusion sets. The study showed that 24-hour intradermal basal-bolus infusion “is feasible” in ambulatory people (n=50) without diabetes using a commercial insulin pump – rates of leakage and adhesion were similar between intradermal and subcutaneous delivery, while bleeding and edema were lower with intradermal delivery. Encouragingly, the poster concluded that “additional work with intradermal sets for insulin infusion is justified and three-day extended duration studies are underway.” We’re very glad to see work on speeding up insulin absorption, since there has not been any significant innovation in this space since currently available rapid-acting analogs came to market (starting with Humalog in 1996).
OBESITY & METABOLIC SURGERY
- EASD 2013 noticeably lacked significant discussion of pharmacotherapies for obesity – an embodiment of the difficult regulatory environment in the EU. We heard very little on Vivus’ Qsiva (the EU name for Qsymia; phentermine/topiramate ER), Arena/Eisai’s Belviq (lorcaserin), Orexigen’s Contrave (bupropion/naltrexone), and Novo Nordisk’s Victoza (liraglutide) for obesity. The dearth of discussion around these drugs reflects the challenging regulatory landscape, which has brought setbacks to several obesity drugs candidates: earlier this year, the EMA requested a pre-approval CVOT for Qsiva, and Arena withdrew its EU MAA for Belviq when it recognized that the CHMP was going to recommend against approval. The question remains what it will take for the EMA to approve an anti-obesity agent. The EMA’s decision on Contrave (expected in 2014) may provide some insight, especially since the EMA will look at the drug’s interim CVOT data when making its decision. Alternatively, at ECO, Dr. Nick Finer (University College Hospital, London, UK) hypothesized that Victoza might be next to market in the EU, since it is a gut hormone rather than a centrally acting compound like the other obesity candidates (for more details on his comments, please see page 18 of our ECO Day #2 report at http://www.closeconcerns.com/knowledgebase/r/f9de4ac7).
- Instead, the conversation on anti-obesity measures focused on bariatric surgery, particularly who should undergo these procedures. Dr. Lars Sjöström (University of Gothenburg, Gothenburg, Sweden), former primary investigator of the Swedish Obesity Subjects (SOS) study, and Dr. Ele Ferrannini (University of Pisa, Pisa, Italy) both strongly critiqued the current BMI-based eligibility criteria for bariatric surgery. They explained that BMI does not predict surgery’s impact on diabetes prevention or remission. In contrast, metabolic factors, particularly beta cell function (according to Dr. Ferrannini) offer a more accurate prediction of who will best respond to the procedure. In his discussion of bariatric surgery, Dr. Ferrannini also detailed how biliopancreatic diversion improves insulin resistance more so than roux-en-Y gastric bypass. Dr. Ferrannini referenced an ongoing trial that suggests that the positive effects of BPD could be due to its stimulation bile acids secretion; this result indicates that bile acids could be an potentially promising treatment approach.
EXHIBIT HALL
- The EASD 2013 exhibit hall had a device highlights from J&J, Medtronic, Sanofi, and YOFi Meter. J&J was showing off the new OneTouch Verio meter, which gives patients color coded indicators and automatic “progress” messages. The focus on enhanced on-meter features was also present in the Sanofi booth, where we saw the MyStarExtra meter (made by AgaMatrix) on display for the first time ever — it provides patients with a three-day fasting glucose average, a trend arrow, and even an A1c estimate! The product is launching in Spain and Italy this year, with more countries to follow in 2014. As we understand it, Sanofi also has meter updates coming for the newest iPhones along with an Android system. Our exhibit hall trip also brought us to the YOFi Meter exhibit – the “all-in-one” device is a single handheld that contains a 20-strip cassette (Infopia strips), a lancing cassette, a color touchscreen, a cellular chip that automatically sends data to the cloud (in partnership with Qualcomm), and a built-in pedometer. Launch is slated for “next September;” although the representative would not say where. This mHealth focus was also present in Medtronic’s booth, where we saw the new Connected Care pump/CGM remote monitoring device up close for the first time – great to see multiple companies on board with seamlessly sending device data to the cloud. Medtronic’s booth also brought an update on the Enhanced Enlite sensor (called “Enlite 2” on Medtronic’s F4Q13 earnings call), which received a CE Mark in September. It has two main innovations: an 80% reduction in implanted volume size over the Enlite and improved sensor-transmitter communication. The rep could not say if these improvements translate to better accuracy.
- On the drug side, companies marketed new products and highlighted CVOT data. On the first day of the hall, Novo Nordisk’s neon-green exhibit was dedicated entirely to Tresiba (insulin degludec) – visitors were swarming reps to learn more about the benefits of the new ultra-long-acting basal insulin. On the SGLT-2 front, BMS/AZ marketed Forxiga (dapagliflozin) in an expansive booth, while Janssen’s booth highlighted Invokana (canagliflozin). [As a reminder, Invokana received a positive opinion from the EMA's CHMP in late September, though has not been approved yet (read our coverage at http://www.closeconcerns.com/knowledgebase/r/749d39a5). Sanofi sported a much fuller booth than usual, a reflection of exciting new additions to its portfolio. The company prominently featured the new GLP-1 agonist Lyxumia (lixisenatide), and highlighted the ways it can complement treatment with Sanofi’s bestselling basal insulin Lantus (glargine). We noticed an increased focus on Januvia’s CV profile at the MSD (Merck) booth than we have seen in the past, with several prominent displays dedicated to the topic and MSD’s CVOT of the agent, TECOS. The cardiovascular focus was also present in Takeda’s booth, where signs highlighted the recently published alogliptin CVOT results from EXAMINE.
OTHER OBSERVATIONS
- Overall we felt that EASD 2013 had more of a basic-science bent than ADA 2013 – a difference we thought was particularly prominent when it came to research on how to cure type 1 diabetes and prevent its complications. At ADA, we attended numerous discouraging oral presentations on candidates, which failed to demonstrate significant efficacy in human trials (for more details, please see our ADA 2013 Report – Type 1 Diabetes Therapies [Cure Related] at http://www.closeconcerns.com/knowledgebase/r/ec380feb). In Barcelona, discussions on how to cure type 1 diabetes centered on new insights into the disease’s pathophysiology (e.g., B cell and T cell communication, epitopes on the IA-2 autoantigen, etc.) and agents (e.g., mesenchymal stem cells) that appear promising in early research. Indeed, Dr. Richard Insel (JDRF, New York, NY) pressed that if researchers do not understand the pathogenesis of type 1 diabetes, they will be unable to validate the biomarkers needed to detect type 1 diabetes and intervene in the disease’s progression. We did not cover many of EASD’s basic science sessions, since we focused our resources on topics that may have a greater impact on patients’ lives in the short-term; however, we look forward to hopefully seeing the benefits of this early research in the years to come.
- Social media was notably less present at EASD than at ADA 2013. Walking through Chicago’s McCormick Place lobbies and exhibit hall one frequently passed displays of ADA and diabetes related tweets. In contrast, we did not see tweets prominently displayed in the Fira Barcelona Gran Via. In line with this, EASD attendees were not as active on social media as were ADA’s. On twitter, the ADA (#2013ADA) hash tag was used 5,173 (conferring 21,686,477 impressions, i.e., people who saw tweets with this hash tag) times, whereas EASD’s (#2013EASD) was tweeted 3,560 times (conferring 8,346,284 impression). Similarly, at ADA 1,156 people tweeted on the conference and at EASD 970 people tweeted. We also observed that more tweeters at ADA were members of the diabetes online community, whereas tweets at EASD were dominated by companies and the media. Among the people who were tweeting, the five most productive twitter handles were: 1) @Medicalfacts, 2) @NovoNordiskLive, 3) @bhrw (an endocrinologist from the Netherlands), 4) @diaTribeNews, and 5) @diabetescounsel.
- Executive Highlights
- 1. Incretin Therapies
- Oral Presentations: Individualizing the Choice Among GLP-1 Receptor Agonists
- POSITIVE EFFECTS OF LIRAGLUTIDE AS ADJUNCT TO INSULIN IN TYPE 1 DIABETES: GLYCEMIC CONTROL AND SAFETY IN A RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED CROSSOVER TRIAL
- GLYCEMIC CONTROL AND HYPOGLYCEMIA IN METFORMIN-TREATED T2DM PATIENTS WITH EXENATIDE BID VS. INSULIN LISPRO TID ADDED TO TITRATED INSULIN GLARGINE QD: THE 4B TRIAL
- SUSTAINING HBA1C CONTROL OVER THREE YEARS DURING TREATMENT WITH EXENATIDE ONCE WEEKLY COMPARED WITH INSULIN GLARGINE
- EFFICACY AND SAFETY OF DULAGLUTIDE VS METFORMIN IN TYPE 2 DIABETES (AWARD-3)
- HARMONY 3: 104 WEEK EFFICACY OF ALBIGLUTIDE COMPARED TO SITAGLIPTIN AND GLIMEPIRIDE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS ON METFORMIN
- Oral Presentations: State of the Art of Inhibiting DPP-4
- CARDIOVASCULAR (CV) SAFETY OF LINAGLIPTIN IN PATIENTS WITH TYPE 2 DIABETES: A POOLED COMPREHENSIVE ANALYSIS OF PROSPECTIVELY ADJUDICATED CV EVENTS IN PHASE 3 STUDIES
- COMPARISON OF THE PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS SAXAGLIPTIN, SITAGLIPTIN, AND VILDAGLIPTIN
- IMPROVED GLUCAGON DYNAMICS DURING HYPOGLYCEMIA AND FOOD-RECHALLENGE BY DPP-4 INHIBITION BY VILDAGLIPTIN IN INSULIN-TREATED PATIENTS WITH TYPE 2 DIABETES
- DURABILITY OF THE EFFICACY AND SAFETY OF ALOGLIPTIN COMPARED TO GLIPIZIDE OVER 2 YEARS WHEN USED IN COMBINATION WITH METFORMIN
- GEMIGLIPTIN ADDED TO ONGOING METFORMIN THERAPY PROVIDES SUSTAINED GLYCEMIC CONTROL OVER 52 WEEKS AND WAS WELL TOLERATED IN PATIENTS WITH TYPE 2 DIABETES
- Oral Presentations: Impact of Treatment and Genetic Susceptibility to Comorbidities and Mortality
- Oral Presentations: Insulin in Type 2 Diabetes – Earlier? Dangerous? Stronger?
- Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
- Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
- Posters
- ADDITION OF LIRAGLUTIDE VS. ADDITION OF A SINGLE DOSE OF INSULIN ASPART TO INSULIN DEGLUDEC PLUS METFORMIN IN PATIENTS WITH TYPE 2 DIABETES (POSTER #1027)
- TREATMENT WITH LIRAGLUTIDE AS ADJUNCT TO INSULIN IN TYPE 1 DIABETS: EFFECTS ON COUNTERREGULATORY RESPONSE TO HYPOGLYCEMIA: A RANDOMIZED, DOUBLE BLIND, CROSSOVER TRIAL (POSTER #1007)
- EFFECTS OF SIX WEEKS TREATMENT WITH SITAGLIPTIN ON COUNTERREGULATORY AND INCRETIN HORMONES DURING ACUTE HYPOGLYCEMIA IN PATIENTS WITH TYPE 1 DIABETES (POSTER #599)
- Symposium: Risks and Benefits of Drugs
- Symposium: Incretin-based Medications – Areas of Active Research and Unanswered Questions
- Corporate Symposium: Glucose Lowering Approaches: Short Term and Long Term Safety Considerations (Sponsored by Sanofi)
- Corporate Symposium: Insights into Advancing the GLP-1 Experience (Sponsored by Lilly)
- Corporate Symposium: Pathophysiology and Glycemic Control in T2D: Focusing on the Underlying Defect to Improve Treatment Outcomes (Sponsored by Sanofi)
- Corporate Symposium: Catalysts for Change? How Can GLP-1 Receptor Agonists and SGLT-2 Inhibitors Help Us Reshape Individualized Diabetes Care? (Sponsored by BMS/AZ)
- Corporate Symposium: The Evolution of Diabetes Management in the 21st Century — The Role of Sitagliptin (Sponsored by Merck)
- Oral Presentations: Individualizing the Choice Among GLP-1 Receptor Agonists
- 2. SGLT-2 Inhibitors
- Oral Presentations: Glucose Down The Drain
- THE SODIUM GLUCOSE CO-TRANSPORTER-2 (SGLT2) INHIBITOR EMPAGLIFLOZIN IMPROVES GLYCEMIC CONTROL IN PATIENTS WITH TYPE 1 DIABETES: A SINGLE-ARM CLINICAL TRIAL
- CANAGLIFLOZIN DEMONSTRATES DURABLE GLYCEMIC IMPROVEMENTS OVER 104 WEEKS COMPARED WITH GLIMEPIRIDE IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS ON METFORMIN
- DAPAGLIFLOZIN-INDUCED WEIGHT LOSS IMPACTS 24 WEEK HBA1C AND BLOOD PRESSURE LEVELS
- LUSEOGLIFLOZIN, A SELECTIVE SGLT2 INHIBITOR, ADDED ON TO GLIMEPIRIDE FOR 52 WEEKS IMPROVES GLYCAEMIC CONTROL WITH NO MAJOR HYPOGLYCAEMIA IN JAPANESE TYPE 2 DIABETES PATIENTS
- EFFICACY AND SAFETY OF TOFOGLIFLOZIN ADMINISTERED FOR 52 WEEKS AS MONOTHERAPY OR COMBINED WITH OTHER ORAL HYPOGLYCEMIC AGENTS IN JAPANESE PATIENTS WITH TYPE 2 DIABETES
- FAVOURABLE GASTROINTESTINAL AND GENITOURINARY SAFETY PROFILE OF LX4211 ADDED-ON TO METFORMIN IN A PHASE 2B STUDY
- Posters
- Symposium: Risks and Benefits of Drugs
- Corporate Symposium: What is Important in T2D Management — Experts’ Perspectives (Sponsored by Lilly)
- Corporate Symposium: New Options and Opportunities in the Era of Individualized Therapy (Sponsored by Janssen Cilag)
- Oral Presentations: Glucose Down The Drain
- 3. Insulin Therapy
- Michael Berger Debate: New Basal Insulins – The Longer the Better?
- Oral Presentations: Hypoglycemia – Balancing Glucose Control
- THE EFFECT ON INSULIN ANALOGS ON THE RISK OF SEVERE HYPOGLYCAEMIA IN PATIENTS WITH TYPE 1 DIABETES AND RECURRENT SEVERE HYPOGLYCAEMIA: THE HYPOANA TRIAL
- LOWER RATES OF OVERALL, NOCTURNAL AND SEVERE HYPOGLYCAEMIA DURING MAINTENANCE TREATMENT WITH IDEGASP VS BIPHASIC INSULIN ASPART 30 IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: A META-ANALYSIS
- Oral Presentations: Insulin in Type 2 Diabetes – Earlier? Dangerous? Stronger?
- EXOGENOUS INSULIN AND RISK OF ALL-CAUSE MORTALITY IN TYPE 2 DIABETES: A DOSE-RESPONSE ASSOCIATION
- NEW INSULIN GLARGINE FORMULATION: GLUCOSE CONTROL AND HYPOGLYCAEMIA IN PEOPLE WITH TYPE 2 DIABETES USING BASAL AND MEALTIME INSULIN (EDITION I)
- THE EFFECT OF EARLY INTENSIVE DIABETES TREATMENT ON LONG-TERM GLYCEMIC CONTROL IN NEWLY DIAGNOSED TYPE 2 DIABETES: MULTICENTRE RANDOMISED PARALLEL TRIAL
- Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
- Corporate Symposium: Basal Insulin Therapy — Combining to Target (Sponsored by Novo Nordisk)
- Corporate Symposium: Pathophysiology and Glycemic Control in T2D: Focusing on the Underlying Defect to Improve Treatment Outcomes (Sponsored by Sanofi)
- 4. Cardiovascular and Other Major Outcomes Trials
- Oral Presentations: Clinical Interventions and Cardiovascular Outcomes
- Oral Presentations: Biomarkers and Risk Scores, Out with the Old, In with the New?
- Symposium: DPP-4 Inhibitors and CVD
- Symposium: UKPDS: 15 Years on from Barcelona
- Symposium: EASD/ADA Symposium: The DCCT/EDIC Study: 30 Years of Progress and Contributions
- Symposium: Rising Star
- Corporate Symposium: Cardiovascular Disease and Impaired Renal Function: Is there a Role for GLP-1? (Sponsored by Novo Nordisk)
- Private Corporate Symposium: Scientific Exchange and Expert Opinions on CV Outcomes in Diabetes (Sponsored by Sanofi)
- OPENING REMARKS
- THE CURRENT REGULATORY ENVIRONMENT IN DIABETES: WHAT NEEDS CHANGING? WHAT IS ABOUT TO CHANGE?
- CV OUTCOMES TRIALS WITH NEW GLUCOSE LOWERING AGENTS: WHAT ARE WE LEARNING?
- INSULIN AND CV OUTCOMES: ONGOING ANALYSES OF THE ORIGIN TRIAL
- BALANCING THE BENEFITS AND RISKS OF GLUCOSE LOWERING THERAPIES
- HIGHLIGHTS OF THE NEW 2013 ESC/EASD GUIDELINES FOR DIABETES AND CV RISK PREVENTION
- PANEL DISCUSSION
- WORKSHOP: HOW BAD IS HYPOGLYCEMIA?
- WORKSHOP: WHICH GLUCOSE-LOWERING AGENT DO I ADD NEXT?
- Corporate Symposium: Cardiovascular Risk Control: The Critical Aim of T2D Management (Sponsored by Lilly/BI)
- Corporate Symposium: SAVOR Trial: How May the Largest DPP-4 Inhibitor CV Safety Study Influence Day-To-Day Clinical Practice? (Sponsored by BMS/AZ)
- Corporate Symposium: Glucose Lowering Approaches: Short Term and Long Term Safety Considerations (Sponsored by Sanofi)
- Satellite Session: 6th CIBERDEM Annual Meeting
- 5. Diabetes Complications
- Debate: Dogmata in Diabetes: Albuminuria is a Surrogate Endpoint for Cardiorenal Disease
- Oral Presentations: Impact of Treatment and Genetic Susceptibility to Comorbidities and Mortality
- Oral Presentations: Retinopathy: Risk Stratification and Novel Therapies
- Oral Presentations: Clinical Nephropathy — Focus On Novel Biomarkers and Improving Outcomes
- Oral Presentations: Diabetes Prediction: Is Stratification the Solution?
- Corporate Symposium: Diabetes and Complications (Sponsored by the Danish Diabetes Academy and JDRF)
- 6. Diabetes Technology
- Oral Presentations: In-Patient Diabetes: Rights and Wrongs
- Oral Presentations: Technologies to Transform Diabetes
- Posters
- Symposium: Diabetes Technology – The Search for Quality
- Corporate Symposium: Ambulatory Glucose Profile (AGP) and New Sensor Technology – The Next Frontier in Diabetes Management (Sponsored by Abbott)
- Corporate Symposium: How New Technologies & Social Media Can Improve the Lives of People with Diabetes (Sponsored by IDF Europe)
- Corporate Symposium: Technology and Innovation in Type 1 and Type 2 Diabetes Care (Sponsored by Sanofi)
- Corporate Symposium: InsuPad – Improvement of Insulin Therapy – A New Option (Sponsored by InsuLine)
- Corporate Symposium: Personalized Diabetes Management – The Journey to More Efficient and Effective Solutions (Sponsored by Roche)
- Media Symposium: Personalized Diabetes Management – The Optimal Solution for Enhanced Confidence, Efficiencies and Outcomes? (Sponsored by Roche Diabetes Care)
- 7. Obesity, Prediabetes, and Metabolic Surgery
- 8. Novel Therapies, Basic Science, and Additional Topics
- Opening Ceremony: Presidential Address
- Award Lecture: 7th Albert Renold Lecture
- Award Lecture: 48th Minkowski Lecture
- Ceremonial Lecture: 45th Claude Bernard Lecture
- Oral Presentations: Novel Therapeutic Agents and Insights
- Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
- Oral Presentation: New Frontiers in Autoantibody Epidemiology
- Oral Presentation: FGF-21 Cures It All?
- GLUCAGON LIKE PEPTIDE 1 (GLP-1) IN COMBINATION WITH FIBROBLAST GROWTH FACTOR 21 (FGF-21) ENHANCES BROWNING OF WHITE ADIPOSE TISSUE
- BROWN ADIPOSE TISSUE, A SINK OF GLUCOSE DISPOSAL? EFFECTS OF FGF-21 ON GLUCOSE METABOLISM IN BROWN ADIPOSE CELLS
- FGF21 RESISTANCE RELEVANT TO INSULIN RESISTANCE IN SKELETAL MUSCLE OF PATIENTS WITH TYPE 2 DIABETES
- Oral Presentation: Health Economic Aspects of Diabetes: Happy, Healthy and Prosperous
- Symposium: Pathophysiological Phenotypes in Type 2 Diabetes
- Symposium: Psychosocial Issues in Diabetes
- Symposium: From Gene Loci to Function: What Have We Learnt?
- Corporate Symposium: Innovative Comprehensive Approaches to Addressing Diabetes Challenges (Sponsored by Sanofi)
- Satellite Session: DIRECT – Personalized Medicines in Type 2 Diabetes
- 9. Exhibit Hall
1. Incretin Therapies
Oral Presentations: Individualizing the Choice Among GLP-1 Receptor Agonists
POSITIVE EFFECTS OF LIRAGLUTIDE AS ADJUNCT TO INSULIN IN TYPE 1 DIABETES: GLYCEMIC CONTROL AND SAFETY IN A RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED CROSSOVER TRIAL
Simon Heller, MD (University of Sheffield, Sheffield, UK)
After noting that GLP-1 agonists have promising potential for use in type 1 diabetes because of their ability to suppress glucagon release, inhibit gastric emptying, and lower weight (relative to insulin), Dr. Simon Heller discussed secondary results from a randomized, single-center, placebo-controlled crossover trial investigating the effects of liraglutide (Novo Nordisk’s Victoza) on the counterregulatory response to hypoglycemia, when used as an adjunct to insulin. The study enrolled 45 participants with type 1 diabetes, and allocated them to either a 0.6, 1.2, or 1.8 mg daily dose of liraglutide, and placebo for four weeks of treatment (with a two-to-three week washout period in between). At baseline, participants had an average age of 35 years, weight of 74 kg (163 lbs), BMI of 24 kg/m2, and duration of diabetes of 17 years. Given the short duration of the trial, there were no significant differences in A1c between liraglutide and placebo. Other findings, however, were promising: the 1.2 and 1.8 mg doses of liraglutide significantly reduced daily insulin dose by 27% and 24%, respectively, versus placebo. The two top doses also reduced patients’ glucagon secretion. Even though treatment only lasted four weeks, liraglutide led to weight loss of up to 3.3 kg (7.2 lbs) (whether the investigators considered this a safety issue arose – they did not). There was no significant difference in hypoglycemia seen between the groups – this was a bit surprising. GI side effects were more common with liraglutide; none of these adverse events were severe. Dr. Heller mentioned that some patients in the study tested positive for C-peptide; during Q&A, a number of attendees suggested analyzing the data to see if these patients responded more positively to liraglutide. We are glad to see that Novo Nordisk is investigating this use of GLP-1 agonists — as a reminder, the phase 3a ADJUNCT ONE trial of liraglutide in type 1 diabetes is expected to begin this coming December.
Questions and Answers
Q: Did you measure the C-peptide levels at follow-up?
A: We did measure C-peptide in all patients at the start, and we found that a few tested positive.
Q: Do you have more data on the number of hypoglycemia episodes across the three liraglutide doses?
A: We measured the hypoglycemia in terms of percentages. About 18% had symptomatic hypoglycemia, but we didn’t see any major difference in terms of daytime episodes or nighttime episodes.
Q: Did baseline C-peptide levels discriminate between responders and non-responders?
A: It’s a good question. I think our numbers are too small, but that should be looked into.
Q: Might you elaborate on the last item in your slide that said that larger trials are needed to establish the clinical benefit? How large should the numbers be, and what would you define as enough of a clinical benefit?
A: That’s a challenging question for me to answer in this short period of time. I’d say it would need to be far longer than one month. In terms of numbers, I’d say we would need to treat a few hundred patients, and it would be interesting to see if people with C-peptide positivity would see a greater impact.
GLYCEMIC CONTROL AND HYPOGLYCEMIA IN METFORMIN-TREATED T2DM PATIENTS WITH EXENATIDE BID VS. INSULIN LISPRO TID ADDED TO TITRATED INSULIN GLARGINE QD: THE 4B TRIAL
Bruce Wolffenbuttel, MD, PhD (University of Groningen, Groningen, Netherlands)
Dr. Bruce Wolffenbuttel presented the results of a 30-week study comparing the efficacy and safety of exenatide BID versus insulin lispro TID as an add-on to insulin glargine therapy and metformin (with or without sulfonylurea). In the trial, participants were randomized to exenatide BID (per protocol n=247) or insulin lispro TID (n=263); respectively, 84% and 86% of participants completed the trial. At baseline, participants were on average 60 years old, had diabetes duration of 13 years, A1c of 8.2-8.3%, fasting glucose of 7.0-7.1 mmol/l (126-128 mg/dl), weight of 89-91 kg (196-200 lbs), and BMI of 32-33 kg/m2. After 30 weeks of treatment, there was no significant difference in A1c change (both treatments lowered A1c by an average of 1.1%); however, when looking at weight change, there was a significant difference (-2.5 kg [5.5 lbs] with exenatide, and +2.1 kg [4.6 lbs] with insulin lispro; p<0.0001). Though similar percentages of participants (~49-50%) achieved an A1c of ≤7% in both arms, a significantly higher percentage of participants on exenatide (44.6%) achieved the target with ≤1 kg (2.2 lbs) increase in body weight than those on insulin lispro (22.9%). In addition, patients on exenatide achieved a significant reduction in systolic blood pressure versus those on insulin lispro, as well as improvements in Diabetes Treatment Satisfaction Score (DTSQ) and Impact of Weight on Quality of Life (IWQoL). The incidence in minor hypoglycemia was significantly lower with exenatide versus insulin lispro (29.5% versus 40.7%; p=0.004), mainly attributed to a lower incidence of daytime hypoglycemia (15.2% versus 33.7%; p<0.001). A higher percentage of patients in the exenatide arm discontinued treatment (5.4% versus 2.6%), mainly due to nausea and vomiting at the beginning of the trial. Based on the results of the study, Dr. Wolffenbuttel concluded that the addition of a short-acting GLP-1 agonist instead of mealtime insulin is a novel and effective treatment strategy for patients for whom basal insulin does not provide optimal control.
Questions and Answers
Q: In the group of exenatide patients, did they continue with metformin, or did they stop metformin?
A: Both treatment arms continued on metformin, two grams daily. Sulfonylureas were stopped at the beginning of randomization.
Q: I think the GI symptoms that you mentioned probably were pertaining to metformin rather than exenatide. Do you think that was true, or do you think they were caused by exenatide?
A: I think that’s a good question. Most of all those patients were already on metformin. I think most of the side effects we saw were to the new treatment, exenatide; however, I don’t know how the combination may affect underlying small intolerances to metformin. We don’t have an answer to that.
Q: Do you have any data about glycemic variability?
A: We have some research on postprandial glucose. When you look at the blood glucose curve of a day, you see that during the day, postprandial glucose is similar. Only after lunch is it lower with lispro than exenatide, which has to do with the fact that those on lispro had a lunchtime injection.
SUSTAINING HBA1C CONTROL OVER THREE YEARS DURING TREATMENT WITH EXENATIDE ONCE WEEKLY COMPARED WITH INSULIN GLARGINE
Jaret Malloy, PhD (Bristol Myers Squibb, Princeton, NJ)
Dr. Jaret Malloy presented the final three-year results and an additional sub-analysis of the DURATION-3 trial, which compared once-weekly GLP-1 agonist Bydureon (exenatide once-weekly [EQW]) to insulin glargine (IG) in people with type 2 diabetes. Patients in the study were on background metformin or metformin + SFU (SFU was discontinued at the beginning of the study), had a mean baseline A1c of 8.3%, ~8 years diabetes duration, and a baseline BMI of 32 kg/m2. After three years, patients on EQW had better glycemic control (A1c reduction of 1.0% vs. 0.8% on IG) and weight loss (-2.5 kg [-5.5 lbs] vs. +2.0 kg [4.4lbs] on IG), whereas IG conferred better reductions in fasting plasma glucose (-2.7 mmol/L [-49 mg/dl] vs. -1.7 mmol/L [31 mg/dl] on EQW). For our full coverage of DURATION-3 three-year results at ADA 2013, please see our ADA 2013 Incretins report at http://www.closeconcerns.com/knowledgebase/r/6001b62d). The sub-analysis that Dr. Malloy presented today examined characteristics of people who were able to maintain glycemic control through all three years (A1c ≤7%) vs. those who did not maintain control (A1c >7% at two consecutive visits or A1c ≥9% at any one visit). A greater proportion of EQW patients achieved and maintained A1c control compared to IG patients (50% vs. 43% of the ITT population and 43% and 33% of the three-year completer population). This was despite a steady increase in mean insulin dose in the IG group throughout the three years. At baseline, for both the EQW and IG treatment groups, those who achieved and maintained glycemic control had a lower baseline A1c, lower FPG, and less SFU use than the group that lost glycemic control. Regardless of “goal achievement” status, EQW patients reported lower exposure-adjusted minor hypoglycemia events compared to IG patients.
Questions and Answers
Q: My experience with once-weekly exenatide is that the weight and A1c go down very nicely after one month. But after one year, despite the fact that weight goes up by two-to-three kg, the A1c is maintained and does not get worse. I think this suggests an improvement in beta cell function. What is your view?
A: We saw weight loss over the first 26 weeks to one year, which was maintained over the three year period such that you have a 2.5 kg decrease on exenatide after three years compared to a 2.0 kg increase with glargine, resulting in a 4.5 kg difference. Other long-term studies have shown maintenance of that weight loss out to five years, for example in the DURATION 1 trial. In relation to your question about beta cell function, at this point we don’t have any hard data in change in beta cell function with long-term treatment.
Q: Do you have any information about postprandial glucose profile after three years? Or is it all about FPG? What is the nature of the excellent glycemic control?
A: We don’t have postprandial measures out to three years. But what you see with insulin glargine is the maintenance of the FPG reduction and still you get gradual increases in A1c. So you could then speculate that it’s the deterioration in postprandial glucose control in that group, and at that those patients might be ones you would target with postprandial treatment. It’s similar to data you saw in the previous talk – looking at a short-acting GLP-1 agonist or mealtime insulin for those patients.
EFFICACY AND SAFETY OF DULAGLUTIDE VS METFORMIN IN TYPE 2 DIABETES (AWARD-3)
Santiago Tofe Povedano, MD (Clinica Juaneda, Palma de Mallora, Spain)
Dr. Santiago Tofe Provedano presented results of Lilly’s phase 3 AWARD-3 trial for its once-weekly GLP-1 agonist dulaglutide. The primary objective was to show non-inferiority compared to metformin in people with newly diagnosed type 2 diabetes (3 months – 5 years), with superiority as a secondary objective. The same results were also presented at ADA 2013 – please see page 7 of our ADA 2013 Incretins report at http://www.closeconcerns.com/knowledgebase/r/6001b62d for our full coverage. In short, both 1.5 mg and 0.75 mg doses of dulaglutide conferred superior A1c reductions after 26 weeks, and this advantage was maintained out to 52 weeks. The high dose conferred similar weight loss as metformin, while weight loss on the low dose was lower. GI side effects were comparable between the dulaglutide and metformin arms.
Questions and Answers
Q: I’m surprised to see is that the glycemic control is almost comparable in both dulaglutide doses, but in the 1.5 mg dose, there are more GI side effects. Can you comment on that?
A: It did not affect glycemic control because most of the GI symptoms were mild to moderate and transient – by week two or four, most patients were relieved of the symptoms.
Q: There is an analysis of metformin where they claim that the maximal effective dose is achieved with 3,000 mg/day, not 2,000. In your study maybe you did not use the highest level of metformin. So when you state that you have this comparison, I don’t know how valid that is.
A: This was the original design of the study. I don’t know if increasing to 3,000 mg/day could have achieved a further reduction in A1c level. I think there are studies that the optimal dose is 2,000 mg/day. So I don’t know. It could have been tested, but the original design of this study was 2,000 mg. I’m afraid I cannot answer this. There is one more thing. You might consider that a 0.5% reduction in A1c might be low for this metformin arm. You have to keep in mind that the patients had a pretty low baseline A1c of 7.6%. And the lower the A1c level is, the lower effect you can expect from any intervention. Secondly, 75% of patients were already treated with an oral antidiabetic agent, and as you can figure out, most were already treated with metformin. The washout period was fairly short (two weeks), so most of the patients randomized had been previously treated with metformin and likely had some effect of having already been treated by metformin.
HARMONY 3: 104 WEEK EFFICACY OF ALBIGLUTIDE COMPARED TO SITAGLIPTIN AND GLIMEPIRIDE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS ON METFORMIN
Murray Stewart, MD (GlaxoSmithKline, King of Prussia, PA)
HARMONY 3, part of GSK’s eight-part phase 3 program for albiglutide (the once weekly GLP-1 agonist Eperzan), assessed the safety and efficacy of 30 mg albiglutide versus 2 mg glimepiride and 100 mg sitagliptin (Merck’s Januvia). Dr. Murray Stewart presented the final study results, which were first presented as a poster at this year’s ADA. At baseline, participants had an average age of 55 years, BMI of 32.6 kg/m2, weight of 91 kg (200 lbs), A1c of 8.1%, and diabetes duration of six years. After 104 weeks, albiglutide demonstrated a 0.91% A1c reduction, a statistically significantly greater reduction than with sitagliptin (0.35%) or glimepiride (0.27%) treatment. The albiglutide group lost 1.2 kg (2.7 lbs) on average, similar to the weight loss seen with placebo (1.0 kg [2.2 lbs]) and sitagliptin (0.9 kg [2.0 lbs]), and significantly better than the weight gain with glimepiride. Notably, the incidence of nausea and vomiting seen in HARMONY 3 with albiglutide (10% and 6%, respectively) was lower than the rate seen with other GLP-1 agonists, especially during the early weeks of therapy — if this finding holds true in head-to-head trials or in clinical practice, it could be a most valuable differentiating factor for albiglutide. Albiglutide had a 17% incidence of injection site reactions (most of which were mild to moderate), compared to 8% with glimepiride, and 6% with sitagliptin. There were also two adjudicated cases of probable pancreatitis in the albiglutide group, one of which was “at least possibly related to the study drug” — we note that this number represents a very small percentage of the treatment group. As background, albiglutide is under regulatory review in the EU and US; this summer, the FDA decided to postpone the drug’s PDUFA date, likely to allow for more time to review recent HARMONY trial data.
Questions and Answers
Q: I wonder about the very small weight loss you saw with [albiglutide]. Did you ask if they were having any trouble eating, or if they were eating as much as before?
A: Other than general diet instructions in the beginning, we did not impose any restrictions or ask any questions about what they ate.
Q: You mentioned that injection site issues happened, which were mostly mild and moderate. How many were severe, and what problems did you see?
A: There was only one case where there was some swelling; there were not systemic reactions. Less than 1% withdrew due to reactions.
Q: In this trial, albiglutide’s efficacy was better than that of glimepiride. With other GLP-1 agonists we have had mixed results — there was a liraglutide trial that showed that the drug was as effective as glimepiride. Why do you think you saw the efficacy difference you saw?
A: I think it may be partly related to the titration regimens. We could have maybe pushed the titration for both glimepiride and albiglutide a bit further.
Oral Presentations: State of the Art of Inhibiting DPP-4
CARDIOVASCULAR (CV) SAFETY OF LINAGLIPTIN IN PATIENTS WITH TYPE 2 DIABETES: A POOLED COMPREHENSIVE ANALYSIS OF PROSPECTIVELY ADJUDICATED CV EVENTS IN PHASE 3 STUDIES
Odd Erik Johansen MD, PhD (Boehringer-Ingelheim, Ingelheim, Germany)
Dr. Odd Erik Johansen presented results of a prospectively defined pooled analysis of 19 randomized controlled trials (RCTs) between 12 weeks and 2 years in length to characterize the CV safety of linagliptin (Lilly/BI’s DPP-4 inhibitor Tradjenta). These results were first presented at ADA 2013 (see our ADA 2013 Incretin report at http://www.closeconcerns.com/knowledgebase/r/6001b62d for details of the presentation). The 19 trials encompassed 5,847 patients on linagliptin and 3,612 on placebo or active comparator. The HR for the primary outcome of four-point MACE (CV death, MI, stroke, and hospitalization for unstable angina), was 0.78 (95% CI 0.55-1.12), showing that linagliptin did not significantly increase or decrease CV events. Dr. Johansen also presented results of an analysis that included only trials that compared linagliptin to placebo (which included all but one of the trials included in the primary analysis, which was a two-year head-to-head comparison with glimepiride). In this 18-trial “placebo-cohort” analysis, the HR was 1.09 (95% CI=0.68-1.75) for the primary four-point MACE endpoint. In this cohort, the HR for hospitalization for heart failure was 1.04 (95% CI 0.43-2.47) – the wide confidence intervals reflect that very small number of events collected (21). Dr. Johansen concluded that in a diverse patient population ranging from low to high CV risk, linagliptin was not associated with increased risk for CV events or hospitalization for heart failure.
Questions and Answers
Q: On the reduced risk of nonfatal stroke and TIA with linagliptin, how do you interpret that mechanistically? There have been some studies suggesting linagliptin may be neuroprotective.
A: I think it is nice hypothesis generating data. There are far too few events to arrive at any conclusions, but you alluded also to some preclinical trials conducted in collaboration with researchers from Sweden where we saw that brain injury following stroke was reduced. It’s very interesting, and we’re obviously encouraged to see the hard outcomes.
COMPARISON OF THE PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS SAXAGLIPTIN, SITAGLIPTIN, AND VILDAGLIPTIN
Harvey Katzeff, MD (Merck, Rahway, NJ)
Dr. Harvey Katzeff presented results of a PK/PD analysis directly comparing the DPP-4 inhibitors saxagliptin (BMS/AZ’s Onglyza), sitagliptin (Merck’s Januvia), and vildagliptin (Novartis’ Galvus). Dr. Katzeff noted that there has never been a direct comparison of the DPP-4 inhibition provided by these agents using a single inhibition assay. The study sought to assess the difference in DPP-4 inhibition at 24 hours (trough levels) after the final dose following five days of administration in patients with type 2 diabetes. It was an open label, randomized, placebo-controlled, five-period cross over study (n=22; mean baseline A1c of 7.4%). Sitagliptin 100 mg once-daily (QD) and vildagliptin 50 mg twice-daily (BID) provided the best levels of inhibition 24 hours after the final dose (92% inhibition), followed by saxagliptin 5 mg QD (74%). Vildagliptin 50 mg once-daily provided the worst DPP-4 inhibition levels 24 hours after the final dose (29%) and placebo provided 4% inhibition. Looking at the time course of DPP-4 activity for 96 hours following the administration of each drug for five days, sitagliptin maintains its DPP-4 inhibition of ~92% over the course of 24 hours and then slowly declines. Vildagliptin 50 mg BID maintains ~90% inhibition over 24 hours but then falls rapidly from 24-48 hours to near zero levels. Saxagliptin maintains about 72% inhibition over 24 hours but also falls rapidly over the next 24 hours. Vildagliptin once-daily rises and falls rapidly such that by 24 hours it has very low inhibition levels. In summary, Dr. Katzeff concluded that the three DPP-4 inhibitors provided significantly different profiles of DPP-4 inhibition, with sitagliptin and vildagliptin BID providing the maximal levels of inhibition. However, as a couple audience members asked during Q&A, it is unclear if these PK data have clinical implications since the efficacy and safety of DPP-4 inhibitors appears to be largely similar.
Questions and Answers
Q: It would have been interesting to see if these differences in inhibition resulted in different GLP-1 levels.
A: That would be a nice start of a new study.
Q: Very clean data, but if you see these differences, why are there no clinical differences when you test these drugs? Does it matter?
A: For vildagliptin twice-daily, several small studies compared to it to sitagliptin and found virtually no difference in A1c, fasting glucose, or postprandial glucose. There is a one head-to-head trial for saxagliptin vs. sitagliptin. The A1c values are non-inferior, but the fasting glucose on saxagliptin was not as low as the fasting glucose on sitagliptin, numerically, and the 95% CIs did not match. So that might be considered a statistically significant difference, and that might be similar to what you see in the DPP-4 inhibition levels at 24 hrs.
Q: With Merck having done this study – is it prepared to do a clinical trial comparing the three prospectively?
A: That is certainly something to consider.
IMPROVED GLUCAGON DYNAMICS DURING HYPOGLYCEMIA AND FOOD-RECHALLENGE BY DPP-4 INHIBITION BY VILDAGLIPTIN IN INSULIN-TREATED PATIENTS WITH TYPE 2 DIABETES
Bo Ahrén, MD, PhD (Lund University, Lund, Sweden)
Dr. Bo Ahrén presented data on the effect of Novartis’ DPP-4 inhibitor Galvus (vildagliptin) on glucagon secretion during meal ingestion and subsequent clamp-induced hypoglycemia in type 2 diabetes patients on insulin. Dr. Ahrén noted that this study addresses an important research question since DPP-4 inhibitors are increasingly used with basal insulin. The single-center, double-blind, crossover, placebo-controlled hypoglycemia clamp study enrolled 29 type 2 diabetes patients (mean age of 58 years; mean diabetes duration of 15 years; mean A1c of 7.7%). All patients were on basal insulin, and (notably) all but three were also on rapid-acting insulin. Patients were placed on vildagliptin (50 mg twice daily) and placebo for four-week periods, with a four-week washout in between. At the end of each four-week period, all subjects were fed a meal, subjected to a hyperinsulinemic hypoglycemic clamp, and subsequently re-challenged with a second meal. The investigators found that glucagon secretion was significantly reduced during the initial and final meals (as expected), but that glucagon levels rebounded during hypoglycemia, indicating an intact counterregulatory response. Plasma levels of GLP-1 and GIP were elevated throughout the test, while other counterregulatory hormones responses were preserved during hypoglycemia. The results, Dr. Ahrén concluded, indicate that vildagliptin preserves “glucagon dynamics” — in other words, it suppresses glucagon secretion via increased GLP-1 levels during hyperglycemia, but does not inhibit the counterregulatory glucagon response during hypoglycemia. These and previous results from clamp studies serve to strengthen the DPP-4 inhibitors’ safety profile, which (in our minds) is one of the class’ greatest strengths.
Questions and Answers
Q: I want to challenge your conclusion that a DPP-4 inhibitor would actually enhance the counterregulatory response to hypoglycemia via glucagon. What is possible is that the plasma glucagon response was absolutely spontaneous due to the natural history of type 2 diabetes, and your model is a postprandial hypoglycemia model and not a fasting hypoglycemia model. That is important because amino acids levels have a big effect on glucagon secretion. I would propose that the increase in glucagon you saw was due to the amino acids from the meal.
A: My message was not that there would be an increase in the counterregulatory response; it was that it would be sustained. It’s important to be able to rely on a sustained glucagon response during hypoglycemia. Regarding the mechanism of counter-regulation, it could be the amino acids, the activation of autonomic nerves, or just the drop in glucose. The conclusion here is that DPP-4 inhibition does not impair this response.
Q: We know that GIP increases glucagon during hypoglycemia. Do you have data on GIP levels during the study?
A: That’s a very good point, because I think one of the protective elements of DPP-4 inhibition is the elevation in GIP. This study was not exactly designed to investigate a correlation between GIP and glucagon, but that would be interesting to investigate.
DURABILITY OF THE EFFICACY AND SAFETY OF ALOGLIPTIN COMPARED TO GLIPIZIDE OVER 2 YEARS WHEN USED IN COMBINATION WITH METFORMIN
Stefano Del Prato, MD (University of Pisa, Pisa, Italy)
Dr. Stefano Del Prato presented data from one of the longer studies we have seen on Takeda’s DPP-4 inhibitor Nesina (alogliptin). Previous studies of shorter duration have established alogliptin’s efficacy and safety — Dr. Del Prato’s research group investigated whether these effects would last over longer periods of time. The 104-week, multicenter, double-blind, randomized trial enrolled 2,639 type 2 diabetes patients on metformin monotherapy, and randomized them to alogliptin 12.5 mg once daily, alogliptin 25 mg once daily, or glipizide 5 mg once daily (with the potential to titrate up to a 20 mg dose). By week 25, all three treatment arms saw an A1c decrease of approximately 0.8%; from then until week 104, each group saw a slight increase (glipizide more so than the alogliptin arms). The final A1c reductions were 0.59% for the glipizide arm, 0.68% for the alogliptin 12.5 mg arm, and 0.72% for the 25 mg alogliptin arm (the latter being statistically superior to glipizide). Both alogliptin groups experienced a significantly greater reduction in fasting plasma glucose than the glipizide. The glipizide group gained an average of 1 kg (~2 lbs) by week 104, while both alogliptin groups lost slightly under 1 kg (~2 lbs) (p<0.001). Glipizide led to a ten-fold higher incidence of hypoglycemia than either of the alogliptin doses. No worrying pancreatitis or MACE signal was seen, and there was no difference in the incidence of overall adverse events. Overall, the results indicate that alogliptin’s glycemic efficacy is durable over two years in patients also on metformin (the very slight increase in A1c in the alogliptin groups between weeks 25 and 104 could of course be attributable to the natural progression of the disease).
Questions and Answers
Q: When you said you were monitoring pancreatitis, did you mean that you have been measuring amylase systematically?
A: No we have not been.
Q: Regarding the differences in fasting plasma glucose and postprandial glucose, do you think that the small A1c difference you saw was solely due to fasting plasma glucose?
A: I think it is a combination of both, although we don’t have any data on the contribution of each.
Q: If you look carefully at the design of all these studies comparing DPP-4 inhibitors and sulfonylureas, they are set up from the beginning to support the superiority of the DPP-4 inhibitors — all trials choose baseline A1cs that are low. If you want to be fair, you need to choose higher A1c, 8% to 9%, or test them as monotherapies.
A: These studies are meant to explore second-line options on top of metformin. Also they are not intended to investigate efficacy, but rather durability. The important thing is that the doses of both were fixed. This does not prove anything about efficacy.
Q: But the average dose for the sulfonylurea was only 5.2 mg, which isn’t a high dose at all.
A: That’s true, but if you have to continue up-titrating your dose of sulfonylurea, you are not getting at durability. The question is not how much sulfonylurea you need to add over time, it’s a question of the response over time on a constant dose.
GEMIGLIPTIN ADDED TO ONGOING METFORMIN THERAPY PROVIDES SUSTAINED GLYCEMIC CONTROL OVER 52 WEEKS AND WAS WELL TOLERATED IN PATIENTS WITH TYPE 2 DIABETES
Eun-Jung Rhee, MD, PhD (Kangbuk Samsung Medical Center, Seoul, Korea)
Dr. Rhee presented 52-week results of a study comparing the efficacy and safety of LG Life Science’s DPP-4 inhibitor gemigliptin to sitagliptin (Merck’s Januvia). In the multicenter, multinational (Korea and India), active-controlled, parallel group, double-blind trial, participants on metformin monotherapy were randomized to 50 mg gemigliptin QD (24-week completers n=124), 25 mg gemigliptin BID (n=127), or 100 mg sitagliptin QD (n=120) for 24 weeks of treatment, followed by a 28-week extension during which all participants were given 50 mg gemigliptin QD. At baseline, patients were on average 52-55 years of age, with diabetes duration of 6-7 years, BMI of 26 kg/m2, and A1c of 7.9-8.1%. All treatment arms brought about a significant reduction in A1c from baseline to the 24-week mark, with no significant differences between arms (DOM 2013); over 52 weeks, all three treatments demonstrated sustained efficacy (~1.1% A1c reduction). Efficacy was fairly consistent across subgroups when stratified by age, duration of diabetes, gender, and BMI. Dr. Rhee noted that patients originally on sitagliptin (through 24 weeks) had greater DPP-4 inhibition after switching to gemigliptin (when measured at the 52-week mark). There were no significant differences in weight and waist circumference change between treatment arms. Gemigliptin was well tolerated for 52 weeks, with a low risk of hypoglycemia and no weight gain.
Questions and Answers
Q: You mentioned that when looking at the extent of DPP-4 inhibition you saw a difference. Do you think the difference is genuine, or was it due to the way the assay was performed?
A: We actually did not expect the result, but we could just see the difference between gemigliptin and sitagliptin. We could also see the higher increase in GLP-1 levels when gemigliptin was prescribed instead of sitagliptin. There might be some differences between those two DPP-4 inhibitors, but more studies have to be performed.
Q: Did you measure any other parameters – blood pressure, lipids?
A: Yes. For lipids profiles from phase 2 and other phase 3 trials, all treatments of gemigliptin lowered total cholesterol, LDL, and triglycerides, consistent with other DPP-4s. I don’t exactly remember changes in blood pressure, but it at least did not increase, I think.
Oral Presentations: Impact of Treatment and Genetic Susceptibility to Comorbidities and Mortality
DIABETES, INCRETIN THERAPY, PANCREATITIS, AND PANCREATIC CANCER: META-ANALYSES
Peter Boyle, PhD (International Prevention Research Institute, Lyon, France)
Dr. Peter Boyle explored the potential associations between diabetes, incretin therapies, pancreatitis, and pancreatic cancer through a series of meta-analyses. His presentation was a condensed version of the talk he gave during Sanofi’s corporate symposium on Sunday; for our coverage of the Sunday event, please see page 20 of our EASD Day #2 Report at http://www.closeconcerns.com/knowledgebase/r/f517afa8. Pooling the results of randomized control trials and observational studies produced a strong correlation between diabetes and pancreatitis (an unsurprising finding). A separate meta-analysis of 70 independent studies (including RCTs and observational studies), however, showed no evidence of increased risk of pancreatitis with incretin therapies (summary relative risk=1.08; 95% CI, 0.87-1.34). Dr. Boyle took issue with the over reliance on databases such as the FDA-AERS, which cannot provide information on potential confounding factors and may be subject to significant reporting bias. Dr. Boyle concluded by noting that, at this time, poor data quality precludes the possibility of drawing definitive conclusions about pancreatitis risk with incretin therapy and that large prospective studies are urgently needed to provide satisfactory answers. Dr. Boyle, however, hypothesized that if any risk for pancreatitis exists with incretin mimetics, it probably is small.
Questions and Answers
Q: I had found the data from Peter Butler’s study convincing. Is it possible that there are some sort of subclinical changes caused by these agents that don’t immediately manifest as clinical symptoms?
A: What we are here to discuss is the risk of pancreatitis and pancreatic cancer. I don’t agree that the work of Peter Butler is very robust. I had a privilege to attend a NIDDK meeting in June on this issue [for our coverage of this meeting, please see http://www.closeconcerns.com/knowledgebase/r/8326d0dd and http://closeconcerns.com/knowledgebase/r/e90a832d], and there was strong criticism of Dr. Butler’s study. There is still lot of doubt about the reliability of that work, and it is based on a very small sample size.
Q: You mentioned that we need large population-based studies. Have you worked out what sample size and duration we would need to resolve the issue of pancreatitis and cancer?
A: We would love population studies of about 15 million people followed for four to five years, but we’re not going to get that. I think that a 3,000-4,000 patient trial lasting four to five years should suffice, assuming 100 events per 100,000 patients. Databases are inadequate; we need more direct, clinical information about the etiology of pancreatitis.
Q: Could you comment on the reporting system through which data makes its way into studies? Sometimes databases use passive reporting, and sometimes this data makes its way into scientific papers. As a scientific community, should we be limiting ourselves to randomized control trials and better observational studies?
A: We’ve got to be careful — these database studies are fraught with difficulties, and you have to pay attention to get them right. I think the FDA database has some problems. The databases in England, Denmark, and the Swedish registry are fairly rigorous. Generally, you have to be careful about where data come from.
Oral Presentations: Insulin in Type 2 Diabetes – Earlier? Dangerous? Stronger?
IDEGLIRA, A NOVEL FIXED-RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE, IS EFFICACIOUS AND SAFE IN SUBJECTS WITH TYPE 2 DIABETES: A LARGE, RANDOMIzED PHASE 3 TRIAL
Stephen Gough, MD (University of Oxford, Oxford, UK)
Dr. Stephen Gough presented and discussed the results of the phase 3 DUAL-1 study of Novo Nordisk’s IDegLira, a fixed-ratio combination of the company’s once-daily GLP-1 agonist Victoza (liraglutide) and ultra-long acting basal insulin Tresiba (insulin degludec). As a reminder, these very impressive data were first unveiled at this year’s ADA — read our coverage of the original presentation on page 4 of our ADA 2013 Incretins Report at http://www.closeconcerns.com/knowledgebase/r/6001b62d. The DUAL-1 study included 1,663 patients, randomized in a 2:1:1 ratio between IDegLira, insulin degludec, and liraglutide. IDegLira demonstrated a remarkable 1.9% A1c drop from a mean baseline of 8.3%, compared to drops of 1.3% and 1.4% (from the same baseline) for liraglutide and insulin degludec, respectively. The combination product also led to significantly less weight gain than insulin degludec (0.5 kg of weight loss compared to 1.5 kg of weight gain, respectively), and a 32% risk reduction for hypoglycemia compared to insulin degludec alone. IDegLira patients experienced significantly less nausea at trial onset than patients on liraglutide (3% compared to 10%), an effect that Dr. Gough partly attributed to the titration protocol in the IDegLira arm. During Q&A, Dr. Gough mentioned that there were a few small yet statistically significant differences between the treatment arms regarding lipid profiles, but did not elaborate on the subject — we would certainly be very interested in seeing that data.
Questions and Answers
Q: One would need to administer approximately 30 units of IDegLira to reach a meaningful dose range for liraglutide of 1 mg or more. Did the majority of patients use more than 30 units, and have you looked at patients who used fewer than 30 units to see whether a dose of liraglutide below 1 mg had a meaningful effect?
A: This here is the first data we have, and more data will be available once we do further analysis. I don’t think we need to hit a certain dose of liraglutide to see a certain benefit — the mean dose was 1.4 mg, but we’ll have to analyze this further.
Q: Did you look at lipid profiles before and after the trial?
A: We did — there were some small changes in terms of total cholesterol and triglycerides from the beginning to the end. There were some small statistically significant changes, but it’s hard to interpret those and disentangle them from the weight change.
Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
INITIATION OF NEW INJECTABLE TREATMENT INTRODUCED AFTER ANTI-DIABETIC THERAPY WITH ORAL-ONLY REGIMENS (INITIATOR) STUDY: AN INTERIM ANALYSIS
James Chu MD (Monterey Endocrine and Diabetes Institute, Monterey, CA)
This work presents the interim results of an observational study on the real-world effects of prescribing insulin glargine (Lantus, Sanofi) and liraglutide (Victoza, Novo Nordisk) for patients with type 2 diabetes who are failing oral therapy. The study was sponsored by Sanofi. Dr. Chu examined two large US healthcare databases (Optum and HealthCore) and found ~1,400 patients who had enough data available for analysis. At baseline, the patients who were prescribed glargine appeared to be sicker – they had a much higher A1c, tended to be older and had more comorbidities. On the other hand, the liraglutide group tended to be better controlled, on more oral agents and heavier – implying that the two drugs are prescribed for different things. Insulin glargine demonstrated a greater reduction in A1c, but baseline A1c was so different that a comparison is difficult. As might be expected, hypoglycemia was lower with liraglutide and patients lost rather than gained weight. Patients taking liraglutide discontinued more. The databases did not show a significant net drug cost increase with glargine (with no clear explanation), but there was an observed increase with liraglutide of $950-$1,150/patient year (causing Dr. Chu to call for cost-effectiveness studies). Finally, the average baseline A1c ranged from 8.6% to 9.8% across the four cohorts – definitely well past time to add insulin or GLP-1 agonists to oral agents. Next step for the investigators is to increase the number of subjects and to assess outcomes by accounting for differences in the patient groups.
- The purpose of the INITIATOR study is to compare outcomes in a real world setting for patients with type 2 diabetes insufficiently controlled on oral agents starting insulin glargine (Lantus, Sanofi) or liraglutide (Victoza, Novo Nordisk). This is an observational, longitudinal cohort study, using databases from commercial health insurers in the USA – Optum and HealthCore. The presentation represents interim data. The final analysis hopes to achieve n>4,000. Patients selected were previously taking OADs only with A1c >7%. They initiated glargine or liraglutide between 2010 and 2011, and had continuous health coverage 6 month before and 12 months after initiation. These criteria narrowed the set of subjects to 1,417 across both databases.
- Physicians appeared to prescribe glargine and liraglutide in different situations. Glargine patients tend to be older, with more comorbidities, higher A1c, on a lower number of OADs. On the other hand, liraglutide patients are younger, more are women, they have higher BMI and lower A1c. One interpretation is that glargine patients are sicker, and liraglutide patients are more concerned about losing weight. The database also tells us that more glargine patients persisted with their medicine refills compared with liraglutide.
- Both groups had decreases in A1c, although it is hard to compare differences because of differences in baseline A1c. Baseline A1c was roughly 8.6% for liraglutide patients versus (a massive) 9.8% for glargine patients. (Remember that they were already treated with oral agents). Patients taking glargine reduced their A1c by 1.3%-1.4% in the follow up period, compared to a reduction of 0.5%-0.6% in the liraglutide group. In the next phase of the study, the team will attempt to match patients to compare outcomes.
- As might be expected, weight increased (by about 1kg) for those taking glargine and decreased (by about 2kg-3kg) for those taking liraglutide. Hypoglycemia was also lower for the liraglutide cohort (with big differences in the data reported in each database).
- A cost analysis (of medical and pharmacy costs compared to baseline) yielded a non-significant and confusing result for glargine (one database had a large increase, the other a large decrease), and a statistically significant cost increase in the range $950-$1,150/patient year for liraglutide. Dr. Chu claimed that this result warranted further analysis of the cost-effectiveness of liraglutide.
Questions and Answers
Q: How could adding insulin not result in a cost increase? Was Lantus given for free?
A: I don’t know. The data represents different costs in many different situations.
Q: Since we went from 118,000 patients in the database to 755, is this really a real world study? I think there is a major impact of selection bias.
A: The selection attrition was related to data points we needed. With this data, there is a much broader range of clinical situations than in a randomized controlled trial, so we are trying to capture a real world situation.
Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
INITIAL TRIPLE COMBINATION THERAPY IS MORE EFFECTIVE AND SAFER THAN STEPWISE ADD ON CONVENTIONAL THERAPY IN NEWLY DIAGNOSED TYPE 2 DIABETES MELLITUS
Ralph DeFronzo, MD (University of Texas Health Sciences Center, San Antonio, TX)
Dr. Ralph DeFronzo re-presented the results of his group’s Triple Therapy study, which showed that metformin/pioglitazone/exenatide combination therapy led to significant improvements in glycemic control and lower rates of hypoglycemia versus conventional therapy in newly diagnosed type 2 diabetes patients. For our full coverage of the presentation, please see our ADA 2013 report at https://closeconcerns.app.box.com/s/xpjoerk8bam7mqqb5m9v.
Questions and Answers
Q: I have a question about the Kaplan-Meier survival curve on failure. It looks like the first occurrence of failure was around six months. But, in your study protocol, you start switching to sulfonylurea at month one and then insulin at month three. I seem a little confused about that difference.
A: You shouldn’t be confused. It’s exactly what you said. The point is that people fail very early, and metformin and sulfonylurea are not the end-all. Many ended on insulin glargine, which was titrated up to 60 units in the trial. When you get up to that point, you fail. After six months, there was a progressive failure rate. That’s what you can expect with metformin, sulfonylurea, and insulin. I can assure you that’s what Dr. Turner saw in UKPDS. Remember that at the end of 10 years, despite what Dr. Turner thought, that monotherapy would control everyone, he had to change the protocol to add metformin to sulfonylurea and vice versa, and some had to add insulin. People tend to forget that at the end of the study, people had an average A1c of 8.6%, and 65% were on insulin therapy. The data we see here in a much smaller group are really just reproducing what Dr. Turner showed 30 years ago. It’s exactly what you see in literature about sulfonylurea or metformin failure; I don’t think there’s anything inconsistent with the Kaplan-Meier plot.
Posters
ADDITION OF LIRAGLUTIDE VS. ADDITION OF A SINGLE DOSE OF INSULIN ASPART TO INSULIN DEGLUDEC PLUS METFORMIN IN PATIENTS WITH TYPE 2 DIABETES (POSTER #1027)
Chantal Mathieu, Helena Rodbard, Bertrand Cariou, Yehuda Handelsman, Athena Philis-Tsimikas, Ann Marie Ocampo Francisco, Azhar Rana, Bernard Zinman
Dr. Bernard Zinman’s group compared the use of the GLP-1 agonist Victoza (liraglutide) and Novolog (rapid-acting insulin aspart) in patients inadequately controlled with metformin and the basal insulin Tresiba (insulin degludec). As background, all the products studied in this trial are made by Novo Nordisk. The 26-week study was designed to simulate the likely progression of therapy for a patient on basal insulin who might need help improving postprandial glucose. The investigators screened patients who were on metformin/insulin degludec combination therapy; those with an A1c at or above 7.0% were randomized to additional treatment with either insulin aspart (n=89; administered only once daily, before the largest meal) or liraglutide once daily (n=88; 1.2-1.8 mg). The addition of liraglutide reduced A1c 0.74% by week 26 while insulin aspart led to a 0.39% reduction from a baseline of 7.7% (p=0.0024). Mean fasting plasma glucose levels were unchanged in both treatment groups. Liraglutide addition led to 3 kg (~7 lbs) of weight loss, while aspart addition led to 1 kg (~2 lbs) of weight gain (p<0.0001) from respective baselines of 95 kg (209 lbs) and 91 kg (200 lbs). The degludec/liraglutide arm experienced an 87% lower incidence of confirmed hypoglycemia (86% lower incidence of nocturnal hypoglycemia) than the degludec/aspart arm. Approximately half (49%) of the degludec/liraglutide group, but only 7% of the degludec/aspart arm, achieved an A1c below 7.0% without weight gain or confirmed hypoglycemia (some may characterize the composite as “artificial” – we think it is a great way to present the results given all the problems with adherence). As expected, the addition of liraglutide led to an elevated incidence of adverse events (mostly nausea), but most were mild and transient. Liraglutide emerged as the winner of this study – the hypoglycemia and weight data was certainly impressive – but given that insulin aspart was administered only once a day, we don’t think it was truly “real-world”. That said, had aspart been given before every meal, there could well have been more weight gain and more hypoglycemia.
TREATMENT WITH LIRAGLUTIDE AS ADJUNCT TO INSULIN IN TYPE 1 DIABETS: EFFECTS ON COUNTERREGULATORY RESPONSE TO HYPOGLYCEMIA: A RANDOMIZED, DOUBLE BLIND, CROSSOVER TRIAL (POSTER #1007)
Thomas Pieber, Sigrid Deller, Martina Brunner, Lene Jensen, Erik Christiansen, Fumiaki Kiyomi, Simon Heller
Incretin therapies have been shown to reduce glucagon levels in type 1 and type 2 diabetes — a desirable effect in most cases, as glucagon contributes to higher blood sugar levels. However, a potential concern for use in type 1 diabetes is whether impaired glucagon secretion could hinder recovery from hypoglycemia, a process that is already partially compromised in type 1 diabetes patients. Dr. Simon Heller’s research group designed a hypoglycemic clamp study to test whether Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) would affect the glucagon counter-regulatory response to hypoglycemia in 45 type 1 diabetes patients. In a plot of glucagon levels compared to plasma glucose level during the induced hypoglycemia sessions, liraglutide treatment downshifted the glucagon level curve compared to placebo (as would be expected), but patients in each liraglutide group responded to hypoglycemia with an increase in glucagon secretion. The poster also noted that baseline levels of glucagon were lower in the liraglutide treatment groups compared to the control. The secretion of adrenaline and cortisol in response to hypoglycemia (other counter-regulatory hormones for hypoglycemia) were also not impaired by any liraglutide dose. Significantly less insulin was needed in the three liraglutide groups during the hypoglycemic clamp than in the corresponding placebo groups, likely due to the overall repression of glucagon levels conferred by liraglutide. The investigators note that the potential benefit of this phenomenon merits further study. Overall, the results of this study were encouraging that liraglutide does not completely eliminate the glucagon counterregulatory response to hypoglycemia.
EFFECTS OF SIX WEEKS TREATMENT WITH SITAGLIPTIN ON COUNTERREGULATORY AND INCRETIN HORMONES DURING ACUTE HYPOGLYCEMIA IN PATIENTS WITH TYPE 1 DIABETES (POSTER #599)
JE Schopman, JBL Hoekstra, BM Frier, MT Ackermans, JJ de Sonnaville, AM Stades, R Zwertbroek, JJ Holst, FK Knop, F Holleman
Because the glucagon response to type 1 diabetes is diminished in people with type 1 diabetes, and because incretin-based therapies are known to repress glucagon secretion, this study investigated whether use of the DPP-4 inhibitor sitagliptin (Merck’s Januvia) would diminish the counter-regulatory glucagon response to hypoglycemia in people with type 1 diabetes. In this single-center, randomized double-blind, placebo-controlled, three-period cross-over study, 16 male patients with type 1 diabetes and intact hypoglycemia awareness received 100 mg/day sitagliptin or placebo for six weeks and were monitored during three acute hypoglycemic events (at baseline, after sitagliptin, and after placebo). Glucagon and adrenergic counterregulatory responses were not changed by sitagliptin treatment.
Symposium: Risks and Benefits of Drugs
GLP-1 BASED THERAPIES AND PANCREATIC DISEASE: WHAT’S THE CLINICAL EVIDENCE?
Juris Meier, MD (St. Josef Hospital, Bochum, Germany)
In a balanced manner, Dr. Juris Meier detailed the issue of incretin therapy and pancreatic disease, tracing it from its early beginnings to the most recent and cutting-edge data. Dr. Meier analyzed the main trials that gave birth to the controversy. He explained that Elashoff et al.’s FDA-AERS analysis was weakened by a potential over-reporting bias, a lack of validation, and a dearth of information on potential confounders. Dr. Robert Butler’s 2013 morphological study, Dr. Meier noted, had small and poorly matched groups. Singh et al.’s retrospective population-based case-control study faces the same limitations as any retrospective study, according to Dr. Meier (i.e., the potential for residual confounders, etc.). A meta-analysis of incretin therapy randomized control trials conducted by Drs. Meier and Michael Nauck (Diabeteszentrum Bad Lauterberg, Harz, Germany) showed no significant safety signal. Due to the low incidence of pancreatitis, Drs. Meier and Nauck estimated that only a study with 40,000 patients in each group would be powerful enough to elucidate a statistically significant 20% risk signal — a likely unrealistic prospective study size. Dr. Meier concluded with a series of practical recommendations. He pressed not to use GLP-1 agonists in patients with chronic pancreatitis, a history of acute pancreatitis, or a family history of pancreatic cancer. However, he sees their use being acceptable in patients with cholecystolithiasis or hypertriglyceridemia. Additionally, he recommended against routine surveillance of amylase or lipase levels unless symptoms of pancreatitis appear, because abnormal results may not be indicative of an adverse event.
- Dr. Meier opened his presentation by walking attendees through the incretin and pancreatitis controversy while offering his own commentary. He noted that Elashoff et al.’s FDA-AERS database study in 2011 has been heavily criticized for its likely over-reporting bias, lack of validation, and incomplete information about confounding factors. More reliable case-control studies have been performed since, according to Dr. Meier; however, they are still limited by their retrospective nature. Dr. Meier brought up Dr. Peter Butler’s (in)famous pancreatic morphological study, which has been criticized for its small, poorly matched groups and likely accidental inclusion of type 1 diabetes patients. SAVOR-TIMI 53 and EXAMINE, the respective cardiovascular outcomes trials for BMS/AZ’s Onglyza (saxagliptin) and Takeda’s Nesina (alogliptin), both had statistically insignificant numerical imbalances in the number of pancreatitis cases. While these numbers may illustrate trends, Dr. Meier stated, they cannot prove or disprove the association.
- To help clarify the issue, Dr. Meier and Dr. Nauck conducted a meta-analysis of data from trials of all incretin therapies currently available in Europe. Some individual trials trended towards an increased thought insignificant risk, and the pooled estimate was neutral.
- Dr. Meier next discussed mechanistic factors behind GLP-1 agonism, which in theory could impact the pancreas. For example, he pointed to the increase in lipase secretion seen during GLP-1 agonist therapy (Steinberg et al., Gastroenterology 2012) as a somewhat troubling phenomenon that merits further study. Dr. Meier worried that much of the data on lipase activity is not publicly available. Potential mechanistic explanations of the link between GLP-1 agonism and pancreatitis include the direct stimulation of pancreatic GLP-1 receptors in acinar tissue, the indirect effects of GLP-1 agonists on exocrine pancreatic function, and the activation of afferent neural pathways. These or other mechanisms could inhibit pancreatic outflow; inhibit bile motility; or lead to gallstones, which in turn could lead to pancreatitis. Dr. Meier discussed a smattering of early evidence from mechanistic studies that lend credence to these ideas. A study showed that exenatide reduced patients’ gallbladder ejection fraction, and radiolabeling data indicating that GLP-1 receptors are located near exocrine cells of the pancreas.
- Dr. Meier ended with a series of practical recommendations. He suggested against the use of GLP-1 agonists in patients with chronic pancreatitis, a history of acute pancreatitis, or a family history of pancreatic cancer. He advocated the immediate discontinuation of treatment if pancreatitis is suspected. However, patients with cholecystolithiasis and hypertriglyceridemia, he said, can continue using the drug class. Dr. Meier dissuaded providers from conducting routine surveillance of amylase and lipase levels unless clinical symptoms manifest themselves (a recommendation which received attention during Q&A). Finally, he said, any and all recommendations should be reviewed after the publication of the ongoing outcomes trials.
Questions and Answers
Q: I had a patient on Byetta [exenatide] with no symptoms, and I did an amylase test and found a nearly tenfold elevation. After discontinuing the drug, the results returned to normal. What would you say about those situations?
A: I think it is a very valid point. We don’t have a clear answer on how to proceed in such cases. I would concur that if a patient has a tenfold elevation, I would also withdraw treatment. I would probably not withdraw treatment if the elevation were below threefold.
Q: Why did you say that there is no use in screening for enzymes? I had two patients with an increase in those enzymes, and then I stopped the GLP-1 analog and they went back to normal. Chronic pancreatitis can have no symptoms.
A: I think the problem is that if you perform routine monitoring of amylase or lipase, you will see elevated levels in 20% to 30% of cases. If you have these abnormalities in the absence of clinical symptoms, what do you do? This may lead to ultrasounds, CTs, and even MRIs, which could be unnecessary in the absence of clinical symptoms. I would prefer performing lab studies only if we see symptoms.
Q: Just one point of clarification – I agree that we shouldn’t be measuring lipase and amylase in the clinical setting, but should we be measuring them in trials?
A: Definitely yes.
GLP-1 BASED THERAPIES AND PANCREATIC DISEASE: REVIEW OF POTENTIAL MECHANISMS
Fred Gorelick, MD (Yale University, New Haven, CT)
Dr. Fred Gorelick concluded the session with a discussion of potential mechanisms of the proposed link between incretin therapies and pancreatic disease. The majority of the talk was dedicated to a general discussion of pancreatitis and pancreatic cancer; although this information was enlightening, we wish that more of the presentation dealt with diabetes and diabetes drugs. In his conclusion, Dr. Gorelick noted that the mechanisms of drug-induced pancreatitis are largely unknown and that animal models are rarely useful for mechanistic investigations. He expressed agreement with the recommendations of previous speaker Dr. Juris Meier (St. Josef Hospital, Bochum, Germany; for details on his comments, please above) and added that HCPs should suggest avoidance of cigarette smoking and heavy alcohol consumption in patients taking GLP-1 agonists. He also noted that data on the timing of pancreatitis incidence would be informative in determining if incretins cause pancreatic disease.
Symposium: Incretin-based Medications – Areas of Active Research and Unanswered Questions
POTENTIAL USE OF DPP-4 INHIBITORS AND GLP-1 RECEPTOR AGONISTS IN TYPE 1 DIABETES?
Urd Kielgast, MD (University of Copenhagen, Denmark)
Dr. Urd Kielgast provided a terrific review of studies of GLP-1 agonists and DPP-4 inhibitors in type 1 diabetes (comprehensive tables below). Our takeaway from all the studies was that there is very encouraging potential to use GLP-1 agonists in type 1 diabetes to improve A1c, reduce insulin dose, reduce glycemic variability, improve hypoglycemia (potentially), and reduce body weight. Dr. Kielgast only covered three DPP-4 studies in type 1 diabetes, and the results were inconsistent – Garg et al. showed no benefit, two studies showed an A1c benefit, and one showed a benefit on insulin dose. Encouragingly, neither GLP-1s nor DPP-4s appear to impair the counterregulatory response to hypoglycemia in type 1 diabetes. Dr. Kielgast concluded that large-scale clinical trials are now justified to elucidate the potential long-term benefits of GLP-1 agonists in type 1 diabetes – we agree. As a reminder, Novo Nordisk’s phase 3a trial for liraglutide in type 1 diabetes is expected to begin in December 2013 (ADJUNCT ONE, ClinicalTrials.gov Identifier: NCT01836523).
- Dr. Kielgast reminded the audience of the potential benefits of GLP-1 based therapies in type 1 diabetes: reduced fasting glucose, reduced postprandial glucose, reduced insulin dose, reduced body weight, reduced risk of hypoglycemia, improved glycemic control, and potentially improved beta cell function (an open question).
- Lack of glucagon suppression contributes to postprandial hyperglycemia in type 1 diabetes and type 2 diabetes. Thus, Dr. Kielgast hypothesized that suppressing excess glucagon “should perhaps be considered as a future target in treating type 1 diabetes.” We completely agree.
- Dr. Kielgast covered six studies testing GLP-1 receptor agonists in type 1 diabetes – the clear theme was a reduction in insulin dose, an improvement in glucose control, and a reduction in body weight.
|
Study |
Drug/Size/ Length |
A1c/Glucose |
Insulin Dose |
Body Weight |
Notes |
|
Kuhadiya et al., Endocrine Practice 2013 |
Liraglutide |
A1c: -0.4% (Baseline: 7.9%) |
-18% |
-4.7 kg |
Obese patients with type 1 diabetes |
|
Harrison et al., J Investig Med 2013 |
20 weeks |
A1c -0.4 and |
-19% |
-4.2% |
Retrospective chart review; nausea caused four patients to discontinue |
|
Varanasi et al., Eur J Endocrinol 2011 |
Liraglutide |
A1c: -0.4% (Baseline: 6.5%) |
-34% |
-4.5 kg |
Pages 4-5 at http://www.closeconcerns.com/knowledgebase/r/5f9e5133 |
|
Kielgast Diabetes Care 2011 |
Liraglutide |
A1c: -0.3% and |
-18% and |
-2.3 kg |
Efficacy depended on baseline C-peptide |
|
Kielgast Diabetes 2011 |
Meal study |
Exogenous GLP-1 decreases peak postprandial glucose by 45% |
-50% (bolus insulin) |
NA |
Benefits occurred regardless of residual -cell function |
|
Rother et al, Diabetes Care 2009 |
Exenatide |
A1c: No difference |
-13% |
-4.1 kg |
Exenatide did not improve beta-cell function |
- Dr. Kielgast covered just a handful DPP-4 inhibitor studies in type 1 diabetes, which have shown inconclusive results. We hope there is still potential, since the once-daily oral administration would be warmly received.
|
Study/Size/ Length |
Drug |
A1c |
Insulin Dose |
Body Weight |
Notes |
|
Garg et al., Endocrine Practice 2013 |
Sitagliptin |
No Difference |
No Difference |
No Difference |
C-peptide positive patients had a non-significant trend towards decrease in A1c, mean glucose, and time spent in hyperglycemia |
|
Farngren et al., JCEM 2012 |
Vildagliptin |
A1c: -0.3% (Baseline: 7.5%) |
No Difference |
|
Inhibited glucagon secretion during hyperglycemia; did not compromise glucagon counterregulatory response during hypoglycemia |
|
Ellis et al., Diabet Med 2011 |
Sitagliptin |
A1c: -0.3% |
|
|
“Further investigation is warranted in patients with type 1 diabetes” |
Questions and Answers
Dr. Paolo Pozzilli (Universitario Campus Bio-Medico, Rome, Italy): Good presentation on what’s been done so far. But you are missing three abstracts presented at EASD last year. The data is quite encouraging with linagliptin and saxagliptin in patients with LADA. This data suggested increases in C-peptide in these patients. There’s a reduction of insulin dose that cannot be explained simply by the suppression of glucagon. Also, in measuring residual beta cell function in type 1 diabetes patients, the arginine test is not the best test. You need to either use a very specific test or a mixed meal test. Garg et al. is only one paper that showed no effect. In all other patients, there is an effect. This is quite encouraging for developing trials in this direction.
A: I completely agree that the reduction in insulin dose is not only due to glucagon suppression. There’s also suppression of gastric emptying and appetite. We asked our patients to eat the same and have the same level of physical activity to hopefully address the direct glucose lowering effects of liraglutide. That’s why the insulin dose parameter has to be interpreted very carefully.
Q: There is a theme emerging about the most consistent effect of incretin-based therapies in type 1 diabetes – a reduction in insulin dose. While obviously that's beneficial for type 2 diabetes, what is the benefit in type 1 diabetes? Is it worth pursuing if that’s the only benefit?
A: You are absolutely right. Patients were allowed to reduce their insulin dose as they felt was best. Perhaps they shouldn’t have been able to do that. Probably the glycemic effect may have been better.
Q: It’s a small tradeoff…
A: The beneficial effects of reducing the insulin dose may be in reducing hypoglycemia, but we have not shown that for sure.
Q: I’m wondering about the percentage of insulin dose reduction. In Poster #576 here, type 1 diabetes patients underwent a euglycemic clamp, and we gave them an oral glucagon receptor antagonist. They saw a 20% reduction in insulin dose. This is the effect of glucagon antagonism. What is the plus effect with gastric emptying?
A: I cannot go into the mechanisms in a four-week study. I think the combination of gastric emptying, glucagon suppression, and perhaps C-peptide levels is at work.
Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Harz, Germany): What is the main endpoint for a study of GLP-1 in type 1 diabetes patients? Would it be weight loss, hypoglycemia?
A: A1c. In the studies performed here, for four weeks, it’s very difficult to see A1c. But A1c and weight loss would be primary endpoint I would choose. And it would be obese patients.
Q: Regarding the mechanism of action of how we decrease glucagon levels in patients with type 1 diabetes – is that through the delta cell and somatostatin? And is there any electrophysiological improvement of the rest of the beta cells?
A: It does not seem that intra-islet insulin is necessary for glucagon. It’s likely to be mediated through somatostatin, but it’s a matter of some controversy.
TOWARDS A BETTER EXPLOITATION OF GLP-1’S POTENTIAL TO TREAT TYPE 2 DIABETES: WHERE DO CURRENT DEVELOPMENTS OF GLP-1 RECEPTORS AIM?
Stephen Gough, MD (University of Oxford, Oxford, UK)
Dr. Gough provided a rousing presentation on the future of the GLP-1 agonist class to begin the symposium. He laid out a wish list for future GLP-1 agonists, which included normoglycemia with no hypoglycemia, sustained weight loss, few to no side effects, and improved long-term outcomes. He told the story of the class’ success over the past decade, both in terms of proven efficacy and their resultant entry into treatment guidelines, and argued that they should be used earlier in the course of treatment. He then highlighted the differences between short and long-acting GLP-1 analogues, and argued that providers should take advantage of these differences to individualize treatment for patients. For example, a short-acting GLP-1 agonist would be best in a patient in need of postprandial glucose control, while a longer-acting agent would be more suited to control fasting plasma glucose. A significant portion of the presentation was given to a discussion of GLP-1 agonist/insulin combination therapy, which Dr. Gough considered the best way to derive extra benefit from the GLP-1 agonist class in the short term. He highlighted the two class’ complementary characteristics and expressed enthusiasm about the combination of the two classes within one device, citing data on Novo Nordisk’s IDegLira (a fixed-dose combination of insulin degludec and liraglutide). Looking further into the future, he postulated that a significant advance could involve finding ways to introduce GLP-1 agonists directly into the bloodstream rather than subcutaneously (where they have been shown to have greater efficacy and cause fewer GI side effects). He mentioned the possibility of oral or even inhaled (!) GLP-1 agonists, although he acknowledged that these alternate forms of delivery lie farther in the future. During Q&A, Dr. Gough stated that longer-acting GLP-1 agonists are not necessarily better for every patient, and affirmed the growing consensus that pancreatitis concerns are not backed up by convincing data at present.
- Dr. Gough began with a GLP-1 agonist wish list for the future, which included normoglycemia without hypoglycemia, better side effect profiles, and improved long term outcomes. He touched upon the growing interest in the scientific community in the extra-pancreatic effects of GLP-1 agonists (including their possible neuroprotective role), but explained that his presentation would keep its sights on the drug class’ metabolic effects.
- GLP-1 agonists have shown impressive clinical results during their relatively short career, and as a result have come to occupy important positions in most type 2 diabetes treatment algorithms. Dr. Gough expressed his belief that this position is deserved, given the great efficacy, low hypoglycemia, and (most uniquely among diabetes drug classes) consistent weight loss they confer. He then called for the use of GLP-1 agonists earlier in the time course of diabetes treatment, suggesting that early treatment could help improve patients’ “metabolic memory” and reduce complications later in life.
- Dr. Gough emphasized that the heterogeneity of the GLP-1 agonist class can help individualize therapy for patients. He noted that the class can roughly be divided into short-acting agents (exenatide BID, lixisenatide) and long-acting agents (exenatide QW, liraglutide, albiglutide). There are clinically relevant differences between the categories that prescribers should consider: for example, longer-acting agents are more effective at controlling fasting plasma glucose, while shorter-acting agents exert a greater effect on postprandial glucose and gastric emptying. Further contributing to efforts to more intelligently target GLP-1 therapy, some scientists are searching for biomarkers that may be able to predict which patients will respond most effectively to which agents.
- Dr. Gough was especially enthusiastic about the use of GLP-1 agonists alongside insulin therapy, terming it the “most exciting area of current development in this field.” Basal insulin/GLP-1 agonist combination therapy has been shown to preserve the benefits of each drug class while minimizing their respective side effect profiles. Dr. Gough explicitly mentioned Novo Nordisk’s IDegLira (a fixed-dose combination of insulin degludec and liraglutide), noting that the pen device allows the titration of both drugs together.
- Gazing further into the future, Dr. Gough discussed different delivery methods for GLP-1 agonists. He cited studies showing that subcutaneous delivery of a GLP-1 agonist yields less glycemic efficacy and more severe GI side effects than intravenous delivery. Dr. Gough suggested that activation of subcutaneous GLP-1 receptors may be activating the autonomic nervous system, or that the drugs are being modified in interstitial space. In either case, the development of more direct and convenient delivery methods for these drugs would (in his mind) be an immensely important development. He mentioned that proof-of-concept studies on oral and even inhaled GLP-1 agonists are being looked into — interestingly, we learned during Q&A that Dr. Gough believes that inhalable GLP-1 may be more attainable than an inhalable insulin.
Questions and Answers
Q: All the novel GLP-1 agonists that are under development right now aim at once-weekly injection. Is that something that represents a real advantage over once- or twice-daily agents?
A: I’m not sure — this is related to my earlier point about treatment individualization. Some people may prefer a once-weekly injection: you can take care of it once and forget about it the rest of the week. Some may prefer a once-daily option that allows you to stay focused on your diabetes. Also, if you have a problem with the agent that you’re on, it takes longer for a long-acting to clear from your system. I know some biweekly agents are being looked into, but I’m not sure there are any benefits to moving beyond once a week.
Q: Could you speak about pancreatic effects of the GLP-1 agonist class?
A: The easiest answer is that there is an excellent presentation tomorrow by Juris Meier on the current state of the pancreatitis debate. Currently, a number of high-profile organizations that have made it clear that there is nothing right now that should change our prescription behavior. The studies aren’t giving us a decisive answer one way or another.
Q: Do you think that we could see a combined inhalable insulin and GLP-1?
A: No, I think it’s most unlikely. It’s unlikely that we’ll see inhaled insulin for obvious reasons, and right now inhaled GLP-1 is at proof-of-concept stage.
UNDERSTANDING THE MODE OF ACTION OF DPP-4 INHIBITORS: RECENT INSIGHTS
Bo Ahrén, MD, PhD (Lund University, Lund, Sweden)
Dr. Bo Ahrén concluded the session with a discussion of recent mechanistic data on DPP-4 inhibitors. He pointed out that the DPP-4 enzyme is not distributed evenly throughout the body; rather, it is localized in high concentrations immediately adjacent to the intestinal L cells that produce GLP-1, leading to rapid deactivation of GLP-1 before it can enter the hepatic portal system. The significance of this mechanistic insight is that inhibition of DPP-4 has a particularly strong positive impact on GLP-1 levels in the portal system, and thereby an especially strong effect on the pancreas and liver (key target areas for the reduction of blood glucose). Dr. Ahrén also hypothesized that the increased level of GLP-1 in the portal circulation could activate autonomic nerves in the gut, which in turn stimulate the secretion of insulin in the pancreas. He next noted that GLP-1 enters the lymphatic system in addition to blood vessels, and that the hormone’s lymphatic effects deserve further study. Dr. Ahrén next addressed DPP-4’s effects on targets other than GLP-1. He cited evidence that DPP-4 inhibition increases plasma levels of GIP, which likely protects against hypoglycemia. He also brought up early evidence that DPP-4 inhibitors increase the secretion of neuropeptides such as PACAP that act at acetylcholine terminals to directly stimulate pancreatic insulin secretion. Another beneficial effect of DPP-4 inhibition being studied is its potential inhibition of the pancreatic islet inflammation seen in type 2 diabetes. Dr. Ahrén’s talk certainly broadened our understanding of the effects of DPP-4 inhibition, and we look forward to seeing data from future studies of DPP-4 inhibitors’ non-GLP-1-mediated effects.
Questions and Answers
Q: In my practice, we had a patient that had substantial hepatic adiposity that decreased after we prescribed a DPP-4 inhibitor. Is there evidence that DPP-4 inhibitors may have an effect on fat in the liver?
A: That would be an important mechanism, as the reduction of fat in the liver could reduce insulin resistance. There are studies right now investigating DPP-4 inhibitors in patients with fatty livers; it will be interesting to see the data that results from those studies.
Q: Would the PACAP neuropeptide explain the reduction in glucagon seen with DPP-4 inhibition?
A: No, we measured glucagon excretion and we did not see a change. The PACAP effect would explain the insulin effect.
Corporate Symposium: Glucose Lowering Approaches: Short Term and Long Term Safety Considerations (Sponsored by Sanofi)
DIABETES, INCRETIN THERAPY, PANCREATITIS, AND PANCREATIC CANCER
Peter Boyle, PhD (International Prevention Research Institute, Lyon, France)
Looking at available prospective trials (as well as several observational studies) and following the PRISMA guidelines for meta-analyses, Dr. Peter Boyle explored the potential associations between: 1) diabetes and pancreatic cancer; 2) diabetes and pancreatitis risk; 3) pancreatitis and pancreatic cancer risk; 4) the use of incretin therapies and pancreatitis risk; 5) the use of GLP-1 receptor agonists and pancreatitis risk; and 6) the use of DPP-4 inhibitors and pancreatitis risk. From his meta-analysis of 70 independent studies, Dr. Boyle concluded that there is no evidence of increased risk of pancreatitis with incretin therapies (overall summary relative risk [SRR]=1.08; 95% CI: 0.87-1.34). Dr. Boyle proceeded to discuss two analyses of the FDA Adverse Event Reporting System (AERS) database, cautioning the audience how such analyses could be misinterpreted or blown out of proportion by the media. Dr. Boyle noted that Raschi et al. highlighted the severe limitation of the FDA AERS database in drawing conclusions about the causal nature of any signal found, given various biases (the Weber effect, the ripple effect, and notoriety bias, described below), and he pointed out fact that 90% of those identified in the FDA AERS database had other risk factors for pancreatitis. After removing this analysis from Dr. Boyle’s meta-analyses, the point estimates of the SRRs for incretin therapies, GLP-1 agonists, and DPP-4 inhibitors all tended even closer to neutrality. Dr. Boyle commented that the poor quality of data available precludes drawing any definitive conclusions apart from observations that any potential increased risk of pancreatitis associated with incretin therapies is likely to be small. As such, carefully designed, large, prospective, population-based registries with good follow-up collecting key clinical and epidemiological information are urgently needed to answer these critical safety questions and provide reassurance to diabetes patients and their clinicians.
- Diabetes is associated with an increased risk of pancreatitis and pancreatic cancer. In a meta-analysis of a number of prospective studies, Dr. Boyle found an overall summary relative risk (SRR) of 1.68 (95% CI: 1.56-1.82) for pancreatic cancer for those with diabetes. Meanwhile, he found diabetes to have an SRR of 1.90 (95% CI: 1.56-2.33) for pancreatitis. Not surprisingly, Dr. Boyle found pancreatitis (all forms) to have an SRR of 10.52 (95% CI: 6.34-17.47) for pancreatic cancer in a meta-analysis of 27 independent studies. Chronic pancreatitis had an even higher SRR for pancreatic cancer – 13.24 (95% CI: 5.66-30.96).
- From his meta-analysis of 70 independent studies, Dr. Boyle concluded that there is no evidence of increased risk of pancreatitis with incretin therapies (overall summary relative risk [SRR]=1.08; 95% CI: 0.87-1.34). He noted that there is some evidence of publication bias based on the Egger and Macaskill tests, but that the overall risk of bias is quite low. Looking only at observational studies, incretin therapies had an SRR of 1.17 (95% CI: 0.87-1.57) for pancreatitis. In separate meta-analyses, Dr. Boyle found GLP-1 agonists (based on 28 independent studies) and DPP-4 inhibitors (based on 42 independent studies) to have SRRs of 1.09 (95% CI: 0.79-1.52) and 1.15 (95% CI: 0.85-1.54) for pancreatitis, respectively (both had some evidence of publication bias based on the Egger and Macaskill tests).
- Dr. Boyle called it “terrifying” that the BMJ stated that incretins had a 25-fold increased risk of pancreatitis (featuring the article on the front cover of an issue), based on the results of an analysis of the FDA Adverse Event Reporting System (AERS) database. He clarified that this 25-fold risk could not be used as an odds ratio, because the analysis conducted was a disproportionality analysis (as background, disproportionality analysis measures the rate of events between those on drug versus off drug). Based on his calculations, if there actually were a 25-fold increase in acute pancreatitis with incretin therapies, they would cause 68,250 cases of acute pancreatitis in the US in one year (a quarter of all cases). If this happened, Dr. Boyle commented, “Gastroenterologists would be banging on doors.” As such, Dr. Boyle cautioned members of the audience about this flawed interpretation.
- Dr. Boyle stated that he thought Raschi et al.’s analysis of the FDA AERS database provided a lot of great insight into what was going on regarding incretins and pancreatitis risk (Acta Diabetologia 2013). Raschi and colleagues used a case/non-case method, and reported an odds ratio with a corresponding confidence interval calculated as a measure of disproportionality between two groups. Looking at 2,625 cases and 156,601 non-cases, Raschi et al. found a significant association between exenatide and sitagliptin with pancreatitis. Specifically, there was disproportionality in pancreatitis risk in the first quarter of 2008 with exenatide soon after the FDA issued an alert (notoriety bias), and in the second quarter of 2008 with sitagliptin (the ripple effect). In addition, disproportionate numbers of adverse events were reported during the first two years the medications were on the market (the Weber effect). Dr. Boyle thought the authors of the paper drew a good conclusion, that “temporal analysis found a striking influence of relevant FDA warnings on reporting of pancreatitis (the so-called notoriety bias), and is, therefore, recommended to avoid a transforming pharmacovigilance signal of alert automatically into an alarm.”
PANEL DISCUSSION
Moderator: Vivian Fonseca, MD (Tulane University, New Orleans, LA); Hertzel Gerstein, MD (McMaster University, Hamilton, Canada); and Peter Boyle, PhD (International Prevention Research Institute, Lyon, France)
Dr. Fonseca: Hertzel, could you comment on a few things regarding the FDA? One was the controversy about rosiglitazone. Also, recently Sanofi withdrew their NDA for lixisenatide to await results from clinical trials. Could you explain the rationale there?
Dr. Gerstein: First of all, one can never understand what a regulatory agency does. It’s not a scientific agency. Regulators are there to regulate drugs, their audience is the public, and they will tend to make decisions based on all sorts of considerations, including politics, what is in the media, and the general public’s perceptions. They do consider the science, but they are there to regulate, which is an important principle. The rosiglitazone issue came up a few years ago, as there were allegations it caused cardiovascular and all sorts of other harms, based on problematic meta-analyses. There were politically charged discussions, including Congress and Senate hearings, and the decision was made several years ago to suspend large trials of rosiglitazone. Re-adjudication of the results vindicated the initial studies. As such, the FDA is now appropriately reconsidering its initial decision. But unfortunately, as a result, the TZD class is gone (pioglitazone for other reasons). Any other potential benefits that would have came out, we will never know. Regarding the second issue, the FDA wanted to review ongoing results from the trial. Large, international outcomes trials are designed so that data safety boards review emerging safety issues in confidence. The reason is because if anyone had an event and the whole world knew, people would make decisions and judgments based on very little data, and those judgments become entrenched, and before you know it, a drug would become haloed as a wonderful drug or damned as a bad drug on very little data That’s why safety is reviewed by the DSMB – their job is decide when safety signals emerge and to alert the world. When Sanofi submitted its file, the FDA wanted to review ongoing results of this large ELIXA outcomes trial. Initially, there was hope that they would do this confidentially, but when it became clear that confidentiality could not be guaranteed, I personally think Sanofi did the right thing to get the right results from this trial rather than risk poisoning the trial by having the results presented publicly. The investigators and the steering committee don’t know the result. People at Sanofi didn’t know the results. The decision [to withdraw the NDA] was made blind of the results. This is the right thing to do, to not expose the results of an ongoing trial until the DSMB says you do it or until a trial is finished. The best example is that canagliflozin made that mistake – its interim CV results were presented to the FDA, and it’s now universally viewed as crippling to their outcomes trial.
Dr. Fonseca: Why do people say drugs are causing cancer three months [after they start taking them]?
Dr. Boyle: I don’t think they understand what carcinogenesis is all about. In the majority of human cancer in adults, there are large delays. I do not know of a good example of a quick response to a carcinogen. Generally it takes years or decades.
Corporate Symposium: Insights into Advancing the GLP-1 Experience (Sponsored by Lilly)
LONG ACTING GLP-1 RECEPTOR AGONIST: CLINICAL IMPACT AND INDIVIDUALIZED CARE
Francesco Giorgino, MD, PhD (University of Bari Aldo Moro, Bari, Italy)
Dr. Francesco Giorgino reviewed the phase 3 AWARD program for Lilly’s GLP-1 receptor agonist dulaglutide. In particular he relayed results from the AWARD-1, AWARD-3, and AWARD-5, whose detailed results were presented at ADA 2013 (66-OR, 69-OR, and 71-OR, respectively). Reflecting on these trials’ results, he concluded that dulaglutide is associated with superior glycemic control (as measured by change in A1c or percent of users reaching A1c target) when compared to metformin, sitagliptin, or exenatide BID. In terms of weight, he remarked that dulaglutide causes more weight loss than sitagliptin, and similar weight loss to metformin and exenatide BID. He acknowledged, however, that only dulaglutide 1.5 mg (not 0.75 mg) caused comparable weight loss to metformin and exenatide BID. At the BMS/AZ Corporate Symposium, Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Harz, Germany) explained that dulaglutide 0.75 mg’s association with less weight loss than other GLP-1 receptor agonists could be because dulaglutide does not cross the blood-brain barrier as readily as other agents. Thus, it might not impact a patient’s appetite as significantly. Turning to dulaglutide’s safety, Dr. Girogino described its safety profile as determined by the overall AWARD program’s results to date. He underscored that safety signals have not been found for either pancreatitis or a new adverse event.
- In the AWARD program so far, as expected, the most common adverse events are GI related. Among the participants on dulaglutide, 11-28% have experienced nausea and 6-17% have vomited. Researchers have not identified a pancreatitis signal and the pancreatitis rate has been 1.4 cases per 1,000 patient years. Dr. Girogino, however, noted that it is very difficult to draw conclusions from the low number of pancreatic events. The rate of hypoglycemia has been one or fewer events per patient per year. Systolic blood pressure has dropped a mean of 1-3 mmHg and heart rate has increased 2-4 bpm. Less than 5% of dulaglutide users have experienced an injection site reaction, and no nodules have been observed.
- AWARD-1 compared dulaglutide at two doses (1.5 mg and 0.7 5mg) to exenatide twice daily (BMS/AZ’s Byetta) and placebo on a background of maximal doses of metformin and pioglitazone (Takeda’s Actos). After 26 weeks, dulaglutide 1.5 mg provided an A1c reduction of 1.5% from baseline (compared to a reduction of 1.0% with exenatide), which was roughly 1% lower than the placebo group. For more details on AWARD-1’s results, please see page 6 of our ADA 2013 Report – Incretin-Based Therapies at http://www.closeconcerns.com/knowledgebase/r/6001b62d. Dr. Carol Wysham (University of Washington, Spokane, WA), who presented AWARD-1’s results at ADA, also has a poster at EASD 2013 (919-P) on AWARD-1’s results.
- AWARD-3 compared dulaglutide monotherapy to metformin, for patients with an average type 2 diabetes duration of 2.6 years, and an A1c of 7.6%. The trial’s results indicate that dulaglutide had a superior A1c reduction at 26 weeks (around 0.2% better than metformin, but statistically significant), together with a higher percentage of patients reaching target. More details on AWARD-3’s results can be found on page 7 of our ADA 2013 Report – Incretin-Based Therapies at http://www.closeconcerns.com/knowledgebase/r/6001b62d. Dr. Santiago Tofé Povedano will be presenting the results at EASD 2013 in OP-004 on Tuesday at 11:30 AM in Bernard Hall.
- AWARD-5 compared dulaglutide 1.5 mg and 0.75 mg to sitagliptin and placebo in 1,098 type 2 patients. At 52 weeks, both dulaglutide doses provided superior A1c reductions compared to sitagliptin (1.11%, 0.86%, and 0.39%, respectively), as well as larger improvements in body weight (-3.22 kg [-7.1 lbs], -2.7 kg [-6.0 lbs], and -1.63 kg [-3.6], respectively). For more information on AWARD-5’s 52-week results, please see page 8 of our ADA 2013 Report – Incretin-Based Therapies at http://www.closeconcerns.com/knowledgebase/r/6001b62d. Dr. Giorgino noted that Dr. Nauck is presenting full 104-week results from AWARD-5 in a poster at EASD (921-P).
PANEL DISCUSSION
Moderator: Bruno Guerci MD, PhD (Hospital Jeanne d’Arc, Nancy, France)
Panelists: John Jendle, MD, PhD (Örebro University Hospital, Örebro, Sweden); Francesco Giorgino, MD, PhD (University of Bari Aldo Moro, Bari, Italy)
Q: How is dulaglutide excreted from the body?
Dr. Jendle: With a very large molecule like dulaglutide – 60,000 Daltons – the clearance from the kidneys will be very low, if any. It is believed that as far as liraglutide is concerned, the clearance is by proteolytic pathways with the molecular being degraded into amino acid components.
Q: Do you have concerns regarding the pancreatitis seen in animal studies?
Dr. Giorgino: This is a very hot topic in diabetes care. It does not only apply to dulaglutide but also other incretins as well. With regard to the AWARD program, the incidence comes out to be the same in all arms. There is also evidence of a very slight increase in amylase and lipase enzymes – this is a biochemically significant change but it does not appear to be clinically significant. It is not demonstrated that this change will lead to pancreatitis. We do not see a specific signal for the pancreatitis issue.
Q: Do you have information on AWARD-2 or AWARD-4?
Dr. Giorgino: The safety profile is maintained as we have seen on the other AWARD studies, particularly with regards to pancreatitis. In both studies, dulaglutide was found to be more efficacious than glargine.
Q: These two papers are not yet published?
Dr. Giorgino: No, only press releases.
Q: Does dulaglutide need to be refrigerated? When can we expect to use it?
Dr. Jendle: It is best to keep it in the refrigerator; however, there are investigations and discussions surrounding how long it can be kept at room temperature. Regarding when we can anticipate to use it – that is always a difficult question. Submission is on track and is expected to the FDA before the end of this year.
Q: What is the rate of antibody formation with dulaglutide?
Dr. Jendle: Throughout the program antibodies have been assessed. This molecule has very low immunogenicity – less than 0.5% of patients all together have developed antibodies.
Dr. Giorgino: In the design of the molecule there was one amino acid substitution to reduce the immunogenicity. Of course the structure is very similar to that of GLP-1 overall.
Q: Are you planning to conduct a study comparing liraglutide and dulaglutide?
Dr. Giorgino: I know this study has been planned and is developing. Clearly the comparison in the AWARD program that I have presented – AWARD-1 – was with exenatide BID, because at the time this was the GLP-1 that was available. Liraglutide came later.
Q: Are you planning to look at dulaglutide in people with renal impairment?
Dr. Giorgino: That is another topic that needs to be addressed. I am aware that there is a study being planned in people with impaired kidney function. I do not anticipate that status having much of an effect, since the drug is not excreted through the kidney.
Q: How many patients were included in all of the AWARD program?
Dr. Giorgino: It is about 5,000 patients. We have shown these data.
Q: Can you comment on the CV study? What is the objective of the study?
Dr. Jendle: The REWIND Study was commenced in 2011. It is an event driven study with 9,600 patients and 1,000 MACE events. It is anticipated to end in 2018.
Dr. Giorgino: After the publication of the SAVOR and EXAMINE studies, we know these agents had no effect on CV outcomes. I think we have seen in the dulaglutide program that there is an effect on body weight and SBP, and I think there is a very low rate of hypoglycemia. Also, GLP-1’s non-mimetic effects might potentially contribute to the CV outcomes.
Corporate Symposium: Pathophysiology and Glycemic Control in T2D: Focusing on the Underlying Defect to Improve Treatment Outcomes (Sponsored by Sanofi)
CONTRIBUTION OF NEW GLP-1 RECEPTOR AGONISTS IN TYPE 2 DIABETES
Francesco Giorgino, MD, PhD (University of Bari Aldo Moro, Bari, Italy)
After emphasizing the importance of factoring in patterns of glucose abnormalities (e.g., elevated fasting glucose versus elevated postprandial glucose) in therapy choice, Dr. Francesco Giorgino reviewed the differences between short-acting and longer-acting GLP-1 agonists and highlighted the stronger postprandial effect of the short-acting agents. In a 28-day, randomized, open-label, parallel group, multicenter phase 2 trial, lixisenatide brought about a greater reduction in postprandial glucose than liraglutide did (Kapitza et al., DOM 2013). Similarly, in a 30-week, randomized, non-inferiority study, exenatide BID brought about a greater reduction in postprandial glucose than exenatide once weekly did (Drucker et al., Lancet 2008). Dr. Giorgino also noted that short-acting agents have the ability to delay gastric emptying, which correlates with reductions in postprandial glucose levels – in one study, changes in postprandial glucose with lixisenatide were inversely correlated with the magnitude of gastric emptying inhibition (Lorenz et al., Regulatory Peptides 2013). In addition, Dr. Giorgino reviewed data from lixisenatide’s phase 3 GetGoal program, highlighting its ability to reduce postprandial hyperglycemia across a wide breadth of treatment regimens, and its lower incidence of hypoglycemia and nausea compared to exenatide in the GetGoal-X study.
TREATMENT INTENSIFICATION USING THE COMBINATION OF BASAL INSULIN AND GLP-1 RECEPTOR AGONISTS
Melanie Davies, MB ChB, MD (University of Leicester, Leicester, UK)
Dr. Melanie Davies discussed the rationale and evidence for the use of GLP-1 agonists in combination with basal insulin. She noted that adding basal insulin to a GLP-1 agonist and adding a GLP-1 agonist to basal insulin are both good options. Dr. Davies emphasized that a short-acting GLP-1 agonist should be used in combination with basal insulin, given their stronger effect on postprandial hyperglycemia compared to longer-acting GLP-1 agonists (Kapitza et al., DOM 2012). Looking within the short-acting GLP-1 agonist category, Dr. Davies highlighted that lixisenatide had reduced rates of nausea and hypoglycemia compared to exenatide in the head-to-head GetGoal-X trial. In addition, Dr. Davies stressed the importance of optimizing basal insulin dosing, noting that in a post hoc analysis from GetGoal-L, the therapeutic effect of lixisenatide when used in combination with basal insulin is greater when fasting glucose is well controlled (Vidal et al., to be presented at EASD).
PANEL DISCUSSION
Moderator: Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX); Anthony Barnett, MD (University of Birmingham, Birmingham, United Kingdom); Matthew Riddle, MD (Oregon Health Sciences University, Portland, OR); Melanie Davies, MB ChB, MD (University of Leicester, Leicester, United Kingdom)
Dr. Rosenstock: We dealt a lot with early intervention, and discussing time of intervention. Is there any way to define phenotypes of who should go first with basal insulin or with a GLP-1 agonist?
Dr. Davies: I think it would be fantastic if there was an easy answer to that. Some data suggests that if a patient is more obese and has a higher A1c, it may drive you one way or another. I think the predictors have been a little disappointing. If you look at some of the GLP-1 data, you would think they would work better early, but some people who have had diabetes for decades also respond. It hasn’t been as easy as we would like to pick out clear predictors of who would respond and who won’t. We have to look at the overall profile of the patient, and look at them in terms of their priorities and what treatments are acceptable to them.
Dr. Riddle: I agree with what Melanie said, that we don’t have very good predictors for the right first injectable. At least in the US, it’s strongly influenced by ease of access to one or the other. The barriers are greater to injectable GLP-1 drugs. Health insurance plans are less willing to pay for it. In addition, there is an evidence base of long experience of insulin. We know the benefit/risk profile better for insulin. So, people are more often beginning with insulin. It’s true that we need to know who will have a better response, and we will have to discover that.
Q: How much should we consider family history of cancer before initiating any patient on a GLP-1 agonist?
Dr. Barnett: If you look at recently published studies – SAVOR, and EXAMINE – which included a large number of high-risk patients, there was no signal whatsoever for pancreatic cancer or pancreatitis. If you look at large meta-analyses, you do not see any evidence of increased risk of pancreatic cancer. There are some concerns about histological studies and animal data. In general, it’s not something that would mitigate my use of GLP-1 agonists or DPP-4 inhibitors. Others may disagree.
Q: What is the decision-making process of selecting a GLP-1 agonist when you combine it with basal insulin? Which one would you use?
Dr. Davies: I think that for adding a GLP-1 agonist to basal insulin, a short-acting GLP-1 agonist – exenatide or lixisenatide – should be used. If you look, there are more studies with lixisenatide. In a head-to-head of lixisenatide with exenatide, lixisenatide showed equivalent A1c lowering, but less nausea and less hypoglycemia than exenatide. In the UK, the cost of lixisenatide is cheaper than exenatide, which is another consideration. For many patients, they may want to limit the number of injections, and take a drug that is once daily compared to twice daily.
Q: With all the different treatment options, how much do you keep adding, rather than switching [therapies]?
Dr. Barnett: The trouble is, if we wait until patients achieve an A1c of 9-10%, we’ve missed the boat. For most these patients, I really think the emphasis should be on early treatment appropriate for each individual patient. I don’t think it’s good enough that GPs target an A1c of 7.5%. For those, we need to be getting down to 6.5% and maintaining it as long as possible. The earlier you do it, the longer you’ll have good glycemic control. We should stop drugs that are clearly not working. And, with new drugs, the rule of thirds seems to hold true – with GLP-1 agonists, a third do brilliantly, a third do well, and for the last third they don’t seem to make a difference. We need to have stopping rules in place in addition to starting rules.
Corporate Symposium: Catalysts for Change? How Can GLP-1 Receptor Agonists and SGLT-2 Inhibitors Help Us Reshape Individualized Diabetes Care? (Sponsored by BMS/AZ)
The symposium opened with a short video on “transformational thinking” and change, quoting world leaders in transformational thinking such as Aristotle, Heraclites, Martin Luther King, Jr., John F. Kennedy, and Steve Jobs. Panelists overviewed clinical trial data and clinical experience with GLP-1 receptor agonists and SGLT-2 inhibitors. Full coverage of the symposium will come in our EASD 2013 full report.
CLINICAL EXPERIENCE: HOW CAN GLP-1 RECEPTOR AGONISTS IMPROVE DAILY LIFE FOR PATIENTS?
Tina Vilsboll, MD (University of Copenhagen, Copenhagen, Denmark)
Dr. Tina Vilsboll discussed clinical considerations for using GLP-1 receptor agonists. She shaped her argument around the three major factors she considers when facing a diabetes patient: A1c-lowering efficacy, effect on body weight, and risk of hypoglycemia. She noted that GLP-1 receptor agonists were the only agent in the ADA/EASD 2012 position statement that had a positive effect on all three factors. She emphasized that weight and hypoglycemia effects have a large bearing on adherence, which in turn impacts effectiveness. She relayed that a minority of patients adhere fully to insulin treatment, according to a prescription re-fill study (Donnelly et al, Q J Med 2007) that found that only 33% of patients take ≥80% of the insulin prescribed by their physicians. Finally, Dr. Vilsboll addressed pancreatitis, stating that it has been well established that type 2 diabetes increases the risk of pancreatitis by two-to-three fold. She suggested that GLP-1 receptor agonists do not change this risk, as the odds ratio for pancreatitis on GLP-1 receptor agonists compared to other glucose-lowering agents has consistently been found to be around 1.0 (though she cautioned that the CIs were quite wide).
- Notably, in her discussion of DURATION-6 results (a head-to-head of BMS/AZ’s Bydureon and Novo Nordisk’s Victoza), while Victoza slightly edged out Bydureon in A1c-reducing efficacy (1.5% vs. 1.3% reduction) and body weight, Victoza resulted in substantially more nausea and vomiting. With regard to patients achieving an A1c <7.0% with no weight gain and no hypoglycemia, she presented results from two separate posters presented at EASD 2012 and EASD 2013 with one showing that 46% of patients achieve this composite endpoint on Bydureon vs. the other poster that showed only 34% of patients achieving this composite endpoint on Victoza (Aroda, EASD 2013 Poster #893 and Ratner, EASD 2013 2012 Poster #806).
PANEL DISCUSSION
Michael Nauck, MD, PhD (Diabetes Zentrum Bad Lauterberg, Harz, Germany); Tina Vilsboll, MD (University of Copenhagen, Copenhagen, Denmark); Peter Rossing, MD (Aarhus University and University of Copenhagen, Copenhagen, Denmark); Samy Hadjadj, MD (Poitiers Medical University Hospital, Poitiers, France)
Q: Why does the efficacy of dapagliflozin depend on renal function, and where is a meaningful cutoff where you should not use SGLT-2 inhibitors anymore?
Dr. Rossing: It seems that the lower the filtration rate, the lower the effect, because you need a filtration of glucose in order for this mechanism to be active. Based on the data that Samy showed, if your estimated glomerular filtration rate (eGFR) is below 60 ml/min/1.73 m2 then the effect is so small that, actually, it’s advised against. I think to some extent it depends on the studies. For canagliflozin, the data are in a larger trial, and it found that if you have GFR between 45-60 ml/min/1.73 m2 there might be a meaningful effect.
Q: What proportion of the type 2 diabetes population falls under these criteria? Sixty ml/min/1.73 m2 doesn’t seem to be too low.
Dr. Rossing: The prevalence of patients with GFR in the range of 30-60 ml/min/1.73 m2 depends very much on age group. In the elderly, it is a considerable population – I would think around 15-20% that are below this eGFR of 60. The older you are, the higher the fraction of low GFR. It is not a trivial problem, and it’s also relevant for other classes of drugs.
Q: Do we know the exact mechanisms that cause the genitourinary infections? And more importantly, do we know the risk factors for these infections so that we can sort patients at especially high risk and better treat them with other agents?
Dr. Hadjadj: The mechanism is probably due to the glycosuria – more glucose is good fuel for bacteria in general. Females have twice or three times greater risk than men. Females who are sexually active also have more risk than when not sexually active. This has been proven in studies with nuns. One very simple and effective thing is to tell female patients to go to the toilet after sexual intercourse.
Q: For dapagliflozin, is any patient profile considered high risk for tumors? And why is dapagliflozin contraindicated for use with pioglitazone?
Dr. Rossing: I would say, as Samy has showed you, the concern was whether this increases bladder tumors. The experimental data did not show increased risk of bladder or other tumor types. But we would all be a little concerned with a drug that acts on the kidney and increases outflow of urine that then shows potential signs of bladder cancer. On the other hand, when you go into the data, you will find that many were early cases, making it unlikely that it was the drug causing it. I think at this moment we have to be open-minded and consider it carefully. These are very small numbers – there are no experimental data to suggest caution related to cancers. So maybe for a patient with a history of bladder cancer, this drug would not be my choice but I don’t have any data to support that. Regarding pioglitazone, I think that it’s just that there are no studies demonstrating the effect. People say basically that SGLT-2 inhibition is a way of lowering glucose that should work in any patient.
Q: Even for type 1 diabetes?
Dr. Rossing: Even for type 1 diabetes. I’ve seen some studies initiated, but I haven’t seen the data. I think it’s exciting that this could be of value even in type 1 patients. We don’t have the data so it’s not something I’m recommending, but theoretically yes.
Q: I’m a bit surprised no one has mentioned this so far – this is the first class of oral glucose-lowering agents that lowers body weight. We have never had that. My question is: how much of this weight loss is negative fluid balance, and how much is loss of adipose tissue?
Dr. Hadjadj: There were some body composition studies performed before and after dapagliflozin treatment. After six months you have a decrease in fat mass – so you don’t lose that much water. In addition, you can initially lose some water, but at certain point you reset your body fluid at another level. Otherwise you would completely run out of fluids! I tried to show in the weight loss data that you have some great stability. So you have reset everything at another level. This reset is associated with a decrease in fat mass and particularly visceral fat mass. There is a preferential loss of visceral fat. We don’t know why.
Dr. Rossing: I think initially it was debated because the weight loss is quite a quick response, so some suspected that there might be some fluid loss initially. You can calculate that you’re losing about 300 calories per day due to glucose you’re excreting so you could consider the continuous negative energy balance. However, patients also compensate for the energy balance when weight stabilizes.
Dr. Nauck: But your energy expenditure is lower when body mass is reduced, and usually you lose a little muscle mass when you lose fat mass, leading to a new balance.
Q: I am curious about the triple combination of metformin, DPP-4, and SGLT-2 inhibitors. Besides in the US, where triple combinations have been popular, could this be attractive to Europeans?
Dr. Vilsboll: Absolutely, which is why companies developing SGLT-2s are working on these combinations. Some companies are even working on combining it in one pill.
Q: Are there studies telling us whether there will be weight loss with that combination, and what kind of glycemic control it confers?
Dr. Vilsboll: I haven’t seen the data, but I think they’re very close to being final. There are trials that have been ongoing for a while. Another interesting approach would also be the combination of metformin, GLP-1 and an SGLT-2 inhibitor. It might not be as convenient as one tablet, but combining GLP-1 with SGLT-2 would also be an interesting approach. What you see in body weight with this combo would be interesting in the future.
Q: What is the predicted reduction in insulin dose if you add dapagliflozin to insulin?
Dr. Hadjadj: the answer is a little hard to give. In the trials we ran, you were not expected to modify insulin dose. You could modify it if you had hypoglycemia or bad glucose control. In the study with add-on to insulin, the point was to have no change in insulin dosage (and baseline dose was 70-something units per day) and still show an A1c decrease of about 1%. I’m not sure you can expect any clear decrease in insulin dose. To the best of my knowledge, I don’t know any study performed that used SGLT-2 inhibitors as insulin sparing agents. Everything was done in another way, so I cannot answer this question properly.
Q: Which is the best option among the GLP-1 agonists? Is there one best option?
Dr. Vilsbøll: It is a question that we are often asked. Right now, in Denmark, I can prescribe five different DPP-4 inhibitors; I don't really need to have five to prescribe but it is nice to have because then the companies compete on price. For GLP-1 agonists there are also a couple options. There are long acting and short acting options. The two compounds that are mainly used are liraglutide as a once-daily injection and exenatide as a once-weekly. There are benefits to a one-daily; the efficacy is slightly more pronounced but the patients have more nausea. In contrast, you could say that with the once-weekly approach only one-third of patients do what they are told and take it as prescribed.
Dr. Nauck: So you tell them to take it on Sunday on the way back from church?
Dr. Vilsbøll: [Laughter] That is a good idea. It also looks like GLP-1s in the future might be even better.
Q: Why are some people responding to GLP-1s and others do not respond?
Dr. Nauck: I think Tina gave us some idea why weight reduction is induced. It has to do with your sense of satiety. This is something that is regulated by the hypothalamus. GLP-1 has a chance even when infused into the greater circulation to cross the blood-brain barrier and interact with these regions. One thought for why dulaglutide does not generally cause as much weight loss as other GLP-1s because it does not cross the blood-brain barrier as readily. There is some question of whether slowed stomach emptying might also contribute, and I don't think that is it. Between the different long-acting agents there is no difference in body weight despite them having different impacts on gastric emptying.
Dr. Vilsbøll: Some doctors say that they have 25% non-responders. That has not been my experience. There are some, maybe 5-7%. Remember that patients may not be doing what you believe they are doing.
Dr. Nauck: I think this very much depends on how you define a non-responder. Usually we define non-responders by looking at clinical trials lasting 26 weeks or longer and seeing who got to a certain A1c target. I think when you look at type 2 diabetes, GLP-1 studies in general have a lot of non-responders. But that is true for SFUs, metformin, TZDS; they sum up to 30-40% in most of the studies. I think this is important to learn from. You might need to be more sensitive to whether or not a person is a responder. To your question of what is behind it, I find it interesting that there might be some mechanistic nonresponse. We know that there are polymorphisms of the GLP-1 receptor that are highly prevalent in the Caucasian population, and if you do GLP-1 studies they do not respond as well as those with the wild type receptor. I think that genotype testing could be helpful at some point on this.
Dr. Vilsbøll: Some people have a lot of impact on body weight but not A1c, or A1c but not body weight. It is not a cure for type 2 diabetes.
Corporate Symposium: The Evolution of Diabetes Management in the 21st Century — The Role of Sitagliptin (Sponsored by Merck)
DPP-4 INHIBITORS AND INCRETIN BASED THERAPY DIFFERENTIATION
Carolyn Deacon, PhD (University of Copenhagen, Copenhagen, Denmark)
Dr. Carolyn Deacon provided a detailed comparison of several DPP-4 inhibitors: Merck’s Januvia (sitagliptin), Novartis’ Galvus (vildagliptin), BMS/AZ’s Onglyza (saxagliptin), Takeda’s Nesina (alogliptin), and BI/Lilly’s Tradjenta (linagliptin) [LG Life Science’s gemigliptin, Daiichi Sankyo’s tenegliptin, and Kowa’s anagliptin were among the agents mentioned but not included in the analysis due to their limited geographic availability.] Dr. Deacon acknowledged that most DPP-4 inhibitors have similar mechanistic efficacy (i.e., DPP-4 enzyme inhibition above 80%) and low hypoglycemia incidence – the differentiating factors are largely their PK/PD profiles, drug interactions, and metabolism pathways. Sitagliptin, alogliptin, and linagliptin have relatively long half lives (upwards of 12 hours), while vildagliptin and saxagliptin have shorter half lives (2-3 hours), although saxagliptin’s primary metabolite also has DPP-4 inhibitory activity. Linagliptin is the only major DPP-4 inhibitor not cleared via the kidneys, allowing it to be used without dose adjustment in patients with end-stage renal disease. Given the prevalence of kidney disease in people with diabetes, we think this is an underappreciated advantage. Vildagliptin has been shown to lead to small increases in liver transaminases, requiring dose changes and liver function tests in the hepatically impaired. Dr. Deacon characterized the DPP-4 inhibitor class as safe, and noted that there has not been convincing data connecting the class to increased CV risk or pancreatitis.
Questions and Answers
Q: Which drugs do you use or adjust in terms of renal impairment? Also is one better than the other in terms of reducing albuminuria?
A: The reduction in dose in patients with renal impairment isn’t for renal safety; it is just to keep the blood levels of the drug constant. In terms of the effect on albuminuria, it seems to be a class effect. We haven’t had much data on this, but we’ve seen it with sitagliptin, linagliptin, and vildagliptin, so I think it’s a class effect. We don’t know, however, whether this is just an outcome of glycemic control, or an effect on endothelial function or blood pressure.
Q: You mentioned the potential effect of linagliptin on arrhythmias. Based on the registration trials, do you think it is because of its Xanthine-based structure?
A: Well yes, linagliptin is related to caffeine, so it’s a good question. The arrhythmias are generally being seen at doses higher than the normal dose. I don’t think it translates into cardiovascular risk. It would be interesting to know the actual mechanism behind that.
Q: Can you compare the addition of a DPP-4 inhibitor or a sulfonylurea to metformin?
A: We see similar efficacy in terms of glycemic control with sulfonylureas and DPP-4 inhibitors, but there is a definite hypoglycemia advantage with the latter.
Q: Do you have any thoughts on the potential differences in activity of the DPP-4 inhibitor class in Asians versus other ethnic groups?
A: I have seen two studies showing that we’re seeing slightly greater A1c reductions in Asian populations compared to Caucasians. Perhaps it is due to the etiology of the disease – in Asians, diabetes is due more to beta cell deficit than insulin resistance, which could be behind it.
Q: Do you know if there is any difference in DPP-4 activity at different sites that could be therapeutically beneficial?
A: The data here is very confusing, and it largely comes down to the way that we measure DPP-4 activity. As far as I’m aware, we haven’t really looked to see if there are different sites of enzyme activity. I don’t think it would be a useful thing to measure in clinical practice.
POTENTIAL CARDIOVASCULAR EFFECTS OF DPP-4 INHIBITORS
Mansoor Husain, MD (University Health Network, Toronto, Ontario, Canada)
Dr. Mansoor Husain spoke on the hot topic of DPP-4 inhibitors and cardiovascular risk, which heated up even further this month with the presentation of SAVOR-TIMI 53 (BMS/AZ’s CVOT for Onglyza [saxagliptin]) and EXAMINE (Takeda’s CVOT for Nesina [alogliptin]) at ESC’s annual meeting — read about the presentations in our ESC 2013 Day #1 Report for at http://www.closeconcerns.com/knowledgebase/r/2a8925c5. Regarding EXAMINE, Dr. Husain noted that the investigation team decided not to pursue superiority, as the incidence of cardiovascular outcomes was nearly identical in the treatment and comparator arms. He pointed out that the enrolled patients in both arms were “well taken care of” (the vast majority were on aspirin and statins, among other medications), and postulated that this may have blunted any potential cardioprotective effect Nesina might have had. Turning to SAVOR-TIMI 53, Dr. Husain highlighted the 27% increase in hospitalization for heart failure seen in the saxagliptin arm, and emphasized the need for further investigation of the issue. On the bright side for the two CVOTs, he noted, neither of the trials showed a significant pancreatitis signal. To conclude, he believes that DPP-4 inhibitors are safe based on the vast majority of RCT data, and could potentially have cardioprotective effects based on early data.
- Dr. Husain provided appreciable background on the issue of DPP-4 inhibitors and cardiovascular disease. He began with the basics, citing a preclinical study that demonstrated that DPP-4 knockout mice had significantly better survival rates after an induced myocardial infarction. Turning to small, mechanistic studies of incretin therapies, he highlighted evidence that DPP-4 inhibitors might have cardioprotective potential. He did mention evidence (Pratley et al., Lancet 2010) showing that sitagliptin slightly elevated patients’ heart rate, but stated that the clinical significance of this phenomenon is likely low.
- The “heart” of Dr. Husain’s presentation was a discussion of the results of EXAMINE and SAVOR-TIMI 53. Regarding EXAMINE, he highlighted that nearly all the enrolled patients were on aspirin and statins, and many were on other cardioprotective medications (Editor’s Note: almost all patients in SAVOR were also on statins by the end of the trial). He used this fact to explain the lack of cardiovascular benefit seen in the alogliptin arm — tightening glycemic control in patients that otherwise are so well taken care of, he said, may not have been able to cause a measurable CV benefit in 18 months (the mean patient follow-up in the study). He did not believe that the data on pancreatitis indicated any safety issues.
- Turning to SAVOR-TIMI 53, Dr. Husain stated emphatically that the 27% increase in hospitalization for heart failure seen in the Onglyza group deserves further attention. The fact that the outcome was pre-defined and adjudicated, in his mind, likely means that the signal is real rather than the result of random chance. He expressed a desire for the study data to be re-analyzed in order to better explain the troubling signal — we heard at another session today that subgroup and baseline risk analyses may be ready to present at AHA in November. As with EXAMINE there was no significant pancreatitis signal seen in SAVOR. To conclude, Dr. Husain expressed his confidence in the DPP-4 inhibitor class, reminding the audience that a plethora for RCT data has suggested that the class is safe.
Questions and Answers
Q: Regarding the DPP-4 knockout mouse experiment, in which a lack of DPP-4 reduced infarct size and improved survival, aren’t there no GLP-1 receptors in the myocardium?
A: There are GLP-1 receptors in the atria. And in Dan Drucker’s beautiful Nature Medicine paper, these receptors were shown to be important for GLP-1-mediated release of ANP, which is released by the heart in conditions of increased pressure. I would imagine that after an MI, anything that promotes the release of ANP would be beneficial.
Q: Does the result of SAVOR-TIMI change your recommendations about Onglyza?
A: It’s a very unexpected and very unexplained result. I can think of three or four mechanisms that would have explained the opposite, but this I am truly at a loss to explain mechanistically. One always has the hazard, even in a large study, of having an outlier emerge. If we are to believe the early presentations, it may be occurring in patients at risk of heart failure. The only caveat may be to avoid Saxagliptin in patients at risk for heart failure.
Q: Ultimately, would you recommend the use of DPP-4 inhibitors in patients with cardiovascular disease?
A: I think the takeaway message is that if you need to use a blood-sugar-lowering drug in patients with either recent acute cardiac syndrome or who are at high risk for cardiovascular events, these drugs are safe. How many drugs classes have the same level of data as DPP-4 inhibitors are getting?
2. SGLT-2 Inhibitors
Oral Presentations: Glucose Down The Drain
THE SODIUM GLUCOSE CO-TRANSPORTER-2 (SGLT2) INHIBITOR EMPAGLIFLOZIN IMPROVES GLYCEMIC CONTROL IN PATIENTS WITH TYPE 1 DIABETES: A SINGLE-ARM CLINICAL TRIAL
Bruce Perkins, MD (Toronto General Research Institute, Ontario, Canada)
This single-arm, open-label, proof of concept, eight-week study explored use of BI/Lilly’s SGLT-2 inhibitor empagliflozin in 42 patients with type 1 diabetes (mean age: 24 years; mean BMI: 25 kg/m2). We first covered results of this study in a poster in our ADA 2013 Full Report; see page 139 at http://www.closeconcerns.com/knowledgebase/r/94f937d8. Results of the treatment period were compared to a two-week placebo run-in period. Mean A1c levels decreased by 0.4% from an 8% baseline, and a stratified analysis found a more pronounced decline in those with the highest baseline A1c (>8.0%). Frequency of symptomatic hypoglycemia was reduced by 33% (0.12 to 0.04 events/day) A range of non-hypoglycemia adverse events were reported by the sample, including two cases of diabetes ketoacidosis that forced the two participants to drop out of the study (though Dr. Perkins attributed these occurrences to the effect of aggressive insulin reductions and not empagliflozin itself – a reminder that more defined insulin protocols may be needed in future studies). Two interesting and currently inexplicable findings are: 1) the 20% drop in total daily insulin needs was explained primarily by reductions in basal insulin (not bolus as might be expected); and 2) the amount of carbohydrate intake in subjects increased dramatically, shooting up from 177 grams per day at baseline to 229 grams per day at week eight (we would guess this has to do with patients’ feeling more freedom to eat less strictly). CGM parameters were also measured but are still undergoing analysis and will be presented at a later date. The data on SGLT-2s continues to look encouraging in type 1 diabetes, and we hope companies aggressively move this class into trials for type 1 diabetes.
Questions and Answers
Q: With regards to the increased intake of carbohydrates, was this suggested by doctors or done spontaneously by patients?
A: There is no question that this was a spontaneous compensation to this therapy. It was a substantial increase. Unfortunately, we didn't expect this and don't have a way to reveal the mechanism. Of course, there substantial glycemic mass is lost through the mechanism of action of this drug.
Q: Could the altered renal dynamic change the excretion of ketones?
A: I do not know, but further studies are going to have to look at blood and urinary ketones, although I do not see a mechanism for their loss.
CANAGLIFLOZIN DEMONSTRATES DURABLE GLYCEMIC IMPROVEMENTS OVER 104 WEEKS COMPARED WITH GLIMEPIRIDE IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS ON METFORMIN
Gisle Langslet, MD (Oslo University Hospital, Oslo, Norway)
Dr. Gisle Langslet presented the results of a 104-week study of the efficacy and safety of J&J’s SGLT-2 inhibitor Invokana (canagliflozin). According to the abstract, these results represented the longest follow-up of canagliflozin treatment presented to date. People (n=1,450) on stable background metformin were randomized them to one of three therapy groups: canagliflozin 100 mg, canagliflozin 300 mg, or the sulfonylurea glimepiride. Both canagliflozin doses led to a significantly greater reduction in A1c (from an average of 7.8%) than glimepiride (-0.74% with canagliflozin 300 mg, -0.65% with canagliflozin 100 mg, -0.55% with glimepiride, p=0.04). Furthermore, the glycemic improvement seen in both canagliflozin groups was significantly more durable over 104 weeks than that seen with glimepiride Regarding safety, the incidence of adverse events (AEs) was similar across all groups, with more serious AEs seen with glimepiride. Most serious AEs were severe hypoglycemic events, which were more common with glimepiride (41% incidence with glimepiride compared to 7% and 8% in the canagliflozin 100 mg and 300 mg doses, respectively). Genitourinary infections were seen more frequently with both doses of canagliflozin (15% of female canagliflozin patients experienced them), but these effects were generally mild and few led to discontinuation of treatment. Although previous studies have demonstrated the safety and efficacy of canagliflozin, this study was valuable in that it demonstrated the durability of earlier results over nearly two years.
- The double-blind, phase 3 trial (n=1,450 people on stable background metformin) randomized people to one of three therapy groups: canagliflozin 100 mg, canagliflozin 300 mg, or the sulfonylurea glimepiride (dose titrated as needed up to 8 mg; mean dose 5.6 mg).
- At baseline, patients had an average age of 56 years, average A1c of 7.8%, average BMI of 31, and average disease duration of 6.6 years.
- Fasting plasma glucose, body weight, and systolic blood pressure were also significantly decreased in both canagliflozin cohorts compared to the glimepiride group. Both canagliflozin doses led to a 10% increase in HDL cholesterol, and the 300 mg canagliflozin group saw a 14% increase in LDL cholesterol (11% increase for 100 mg dose) — these changes occurred during the first 26 weeks, and were stable from then until the end of the trial.
Questions and Answers
Q: It seems that the difference in fasting plasma glucose was greater than the difference in A1c — is that correct?
A: Yes, at the end of the 104-week period, that is what we saw.
Q: It has been suggested that the changes in cholesterol may be a measure of hemoconcentration. Do you have any data on this from earlier in the therapy?
A: I don’t think we have lipid measurements from early in the study. These changes in cholesterol are seen with most SGLT-2 inhibitors.
Comment: Regarding the LDL rise, which was seen only in the first 26 weeks, the question is whether it is a direct or indirect effect. The fact that this increase is not seen in patients with renal impairment, for whom the drug is less effective, tells me that it is a direct effect.
Q: What is nice about this protocol is that glimepiride could be titrated; this is more clinically realistic. My question is, did you see that the glimepiride dose was increased during the study?
A: During our study, glimepiride could be up and down titrated, and as I said, the mean maximum dose of glimepiride was 5.6 mg.
DAPAGLIFLOZIN-INDUCED WEIGHT LOSS IMPACTS 24 WEEK HBA1C AND BLOOD PRESSURE LEVELS
David Sjöström, MD, PhD (Global Brand Physician, AstraZeneca, Molndal, Sweden)
Dr. David Sjöström presented an analysis to determine how much of the A1c and blood pressure improvements dapagliflozin was associated with in a 24-week study were due to the concomitant weight loss. He framed this research question by explaining that it is not clear whether relatively small amounts of weight loss (<5%) lead to significant improvements in CV risk factors like A1c and blood pressure. The baseline characteristics of the study cohort mirror the populations of the six phase 3 studies from which data for this analysis were pooled. The average baseline BMI was ~32 kg/m2 and the mean A1c was 8.3%. In total, 1,066 patients were randomized to receive either 10 mg dapagliflozin or placebo. Treatment with dapagliflozin resulted in significantly greater reductions in A1c, weight, and blood pressure than placebo. Estimating the contribution of dapagliflozin-induced weight loss to the improvements observed in A1c, SBP, and DBP found a significant association between change in body weight and the three dependent variables. Each kilogram of body weight lost was associated with a 0.028 percentage point reduction in A1c, a 0.606 mmHg reduction in SBP, and a 0.253 mmHg drop in DBP. The researchers found that, in a dapagliflozin treated patient, 3 kg of weight loss drove an 8% relative decline in A1c from baseline, a 37% decline in SBP, and a 32% reduction in DBP. Purifying the effect of weight loss independent of dapagliflozin treatment demonstrated that the modest reductions in body weight achievable through SGLT-2 inhibition produce notable improvements in CV risk factors.
Questions and Answers
Q: Why don’t patients disappear if they are continuously excreting calories?
A: The large majority of patients do lose weight on dapa. However, the response is variable. You have a number of different regulatory layers, such as appetite, which would be more individualized, giving us a more varied response. However, overall there does consistently seem to be weight loss of some magnitude. The reason people do not disappear when they keep excreting calories – say you lose approximately 240 calories/day via urine, and if you have a typical intake of 2,400 calories, you are losing 10% of your calories. If you retain the same intake over time, you would lose the part of your body weight that needed the 10% of calories you excreted to be supported. If you put that into thermodynamic equations, it would take one-to-two years to equalize. However, what we have noticed is that patients have a propensity to increase their food intake. There is no threat of disappearing from use of SGLT-2 inhibitors.
Q: Don’t you think that it is difficult to fully disentangle weight loss and changes in blood pressure? How do you differentiate between glucose loss and sodium loss?
A: In our studies, we saw a transient increase in sodium excretion, but over time there was no change in sodium levels. I agree there are some aspects this presentation could not fully answer.
Q: What do you think about SGLT-2 in type 1 diabetes patients?
A: I think that the other speaker in this session will have a nice presentation on this topic.
LUSEOGLIFLOZIN, A SELECTIVE SGLT2 INHIBITOR, ADDED ON TO GLIMEPIRIDE FOR 52 WEEKS IMPROVES GLYCAEMIC CONTROL WITH NO MAJOR HYPOGLYCAEMIA IN JAPANESE TYPE 2 DIABETES PATIENTS
Nobuya Inagaki, MD, PhD (Kyoto Graduate School of Medicine, Kyoto, Japan)
Luseogliflozin is an SGLT-2 inhibitor being developed in Japan by Taisho Pharmaceuticals. It is reported to be more specific for SGLT-2 (over SGLT-1) compared to dapagliflozin or canagliflozin. This phase 3 study assessed the performance of luseogliflozin 2.5 mg versus placebo on top of stable glimepiride (GLIM) in 221 patients over 24 weeks and then with an open label extension for all patients to 52 weeks (during which dose could be increased to 5 mg). A1c reduction was 0.5% from the baseline (8.1%) and 0.9% with respect to placebo at 24 weeks, and was maintained to a 0.6% reduction out to 52 weeks. Weight reduction for luseogliflozin was 2.2 kg from baseline at 52 weeks, and 1.5 kg at 24 weeks relative to the placebo group. As expected, there was an excess of genitourinary adverse events in the luseogliflozin group (2.7%) but no resultant discontinuations, and there was also double the hypoglycemia in the luseogliflozin group, which Dr. Inagaki implied was because glimepiride doses were not decreased when luseogliflozin was added.
-
Luseogliflozin is a phase 3 SGLT-2 inhibitor being developed by Taisho Pharmaceutical that is highly selective for SGLT-2 (versus SGLT-1). This study assessed the efficacy and safety of luseogliflozin added to glimepiride (GLIM) over 52 weeks, since sulfonylureas represent the majority treatment in Japan.
-
The study was a double blind randomized controlled trial of luseogliflozin 2.5 mg versus placebo on top of GLIM for 24 weeks in 221 patients. There was an open label extension to 52 weeks, in which all patients took luseogliflozin, but those with insufficient control could increase the dose to 5 mg. Baseline A1c was 8.1%, participants were 75% male, average BMI was 25 kg/m2 and average diabetes duration was about 7 years.
-
At week 24, the luseogliflozin arm exhibited an A1c reduction of 0.5% from the baseline (8.1%) and 0.9% with respect to the placebo arm. This was maintained out to 52 weeks with a 0.6% reduction from baseline. Weight reduction for luseogliflozin was 2.2 kg from baseline at 52 weeks, and 1.5 kg at 24 weeks relative to the placebo group. Fasting glucose in the luseogliflozin group was 34 mg/dl lower than the placebo arm at 24 weeks. Other parameters showed slight improvement, including insulin resistance, blood pressure and lipids.
-
As might have been expected, there was an excess of genitourinary adverse events in the luseogliflozin group (2.7%) but no resultant withdrawals. There was also 8.7% hypoglycemia in the luseogliflozin group, compared to 4.2% in the placebo arm. It seems that glimepiride doses were not decreased when luseogliflozin was added, leading to the excess hypoglycemia.
Questions and Answers
Q: Are there any differences with luseogliflozin compared to dapagliflozin or canagliflozin?
A: This drug has a very high affinity for SGLT-2 and so the dose is very small compared to other drugs. This drug is metabolized in the liver via several pathways, which may lead to differences to the other drugs.
EFFICACY AND SAFETY OF TOFOGLIFLOZIN ADMINISTERED FOR 52 WEEKS AS MONOTHERAPY OR COMBINED WITH OTHER ORAL HYPOGLYCEMIC AGENTS IN JAPANESE PATIENTS WITH TYPE 2 DIABETES
Yukio Tanizawa, MD, PhD (Yamaguchi University, Yamaguchi Prefecture, Japan)
Dr. Yukio Tanizawa presented data on the use of tofogliflozin (Chugai’s SGLT-2 inhibitor) as a monotherapy and in combination with other oral therapies for 52 weeks. Dr. Tanizawa concluded that tofogliflozin positively reduced A1c (~0.7-0.9%) and body weight in both mono- and combination therapy. In monotherapy, participants were randomized to either 20 mg (n=63) or 40 mg (n=127) of tofogliflozin, and in the combination therapy, participants were randomized to use of either sulfonylureas (n=171), glinide (n=22), “BG” (n=105; this was not defined), TZD (n=102), a-glucosidase inhibitor (n=99), and DPP-4 inhibitor (n=103), with either a 20 mg (n=178) or 40 mg (n=424) dose of tofogliflozin. In the monotherapy group, A1c levels dropped 0.7% (baseline of 7.8%) and body weight dropped 3.0 and 3.4 kg for 20 mg and 40 mg of tofogliflozin, respectively. A1c dropped an average of 0.8% for all combination therapies for 20 mg tofogliflozin, and dropped 0.9% for 40 mg of tofogliflozin (baseline range from 7.7% to 8.4%). Body weight dropped an average of 2.5 kg for all combination therapies with 20 mg tofogliflozin, and 3 kg with 40 mg of tofogliflozin. Interestingly, Dr. Tanizawa remarked that tofogliflozin in addition to “BG” and an a-glucosidase inhibitor increased weight loss to 3.9 kg on average, but only when used with 40 mg of tofogliflozin. Dr. Tanizawa highlighted that the use of tofogliflozin as a monotherapy may significantly reduce waist circumference, adiponectin, blood pressure, and HDL and LDL, relative to baseline.
-
Both the monotherapy and combination studies were 52-week randomized, open-label, parallel-group comparison. There were 194 participants in the monotherapy trial and 602 in the combination therapy trial.
-
The baseline A1c for patients on monotherapy was 7.8%, and patients had an average BMI of 25-26 kg/m2. Additionally, the average age was 58-59 years in the tofogliflozin groups. For patients on combination therapy, the baseline A1c ranged from 7.7-8.4% and BMI ranged from 24-28 kg/m2. The average age of patients ranged from 56 years to 60 years for both doses.
-
Patients in monotherapy experienced a significant decrease in weight circumference (p <0.001), adiponectin (p <0.001), blood pressure (SBP: p <0.01 and p <0.05, 20 mg and 40 mg, respectively), and HDL (p <0.01 and p <0.001, 20 mg and 40 mg, respectively) for both the 20 mg and 40 mg groups. Additionally, patients taking 40 mg of tofogliflozin had a significant reduction in triglyceride levels (p <0.01). Surprisingly, Dr. Tanizawa noted, patients on 20 mg, but not 40 mg, of tofogliflozin experienced significant reductions in both DBP (p <0.01) and LDL (p<0.05) levels.
-
There were low levels of cystitis, urinary tract infection, genital infection, and hypoglycemia reported across all groups. There was a particularly low rate of urinary and genital infections – 1-3% in those on tofogliflozin – prompting someone in Q&A to suggest cultural biases. There was no significant difference between groups, and no more than 5% of patients in any group experienced any one adverse events (except for 6% of participants taking a 20 mg dose experiencing mild hypoglycemia). Dr. Tanizawa noted that the three moderate hypoglycemic events all occurred when tofogliflozin was used in conjunction with sulfonylureas.
-
Nasopharyngitis and upper respiratory tract infection were the most common adverse event. Dr. Tanizawa noted that 70% of patients experienced an adverse event, however, these were likely not due to the medications. There were other changes in safety parameters in the monotherapy group, such as an increase in uric acid levels.
Questions and Answers
Q: This was an interesting presentation, thank you. I am wondering why you are doing this open label? Is it ok for regulations to do this without a placebo control? I am also surprised that there were close to zero genital infections. Could it be that something else is going on? Maybe it is just cultural for women not to complain?
A: We had done a separate, placebo, double-blinded trial.
Q: Do you think it is conceivable that there are cultural differences that cause women not to report their genital infections?
A: I don’t know if this is cultural difference. In fact, genital infections are very rare in Japanese populations.
Comment: If that is the case, then maybe we will start to have country-specific drugs.
Q: Are you examining triple therapy?
A: No, not at this moment.
FAVOURABLE GASTROINTESTINAL AND GENITOURINARY SAFETY PROFILE OF LX4211 ADDED-ON TO METFORMIN IN A PHASE 2B STUDY
Pablo Lapuerta, MD (Chief Medical Officer, Lexicon Pharmaceuticals, The Woodlands, TX)
LX4211 is Lexicon Pharmaceutical’s dual SGLT-1/SGLT-2 inhibitor. SGLT-2 is the major glucose transporter in the kidney, and SGLT-1 primarily influences glucose and galactose absorption in the gut, although it has a lesser role in the kidney. In this phase 2b 12-week study of 299 patients on top of metformin, LX4211 didn’t show an excess of GI side effects (nausea, diarrhea) or urinary tract infections over placebo. Vaginal infections were only seen with LX4211, but their incidence was reasonably low and no patients discontinued as a result.
- LX4211 is an interesting dual SGLT-1/SGLT-2 inhibitor under development by Lexicon Pharmaceuticals and is currently undergoing phase 2b studies. SGLT-1 is the primary glucose and galactose transporter in the gastrointestinal tract, although it has a minor role in the kidney, where SGLT-2 is the primary transporter. SGLT-2 inhibition has been associated with an increase in genitourinary infections, and it is thought that the incidence may relate to the degree of glycosuria. Lexicon believes that the SGLT-1 inhibition of LX4211 might lead to lower glycosuria and therefore a better safety profile. On the other hand, SGLT-1 inhibition is often linked with GI side effects such as diarrhea, although studies of people with natural SGLT-1 mutations do not support this.
- Accordingly, this study seeks to investigate the safety profile of LX4211 added to metformin, over a 12-week period. At baseline, 299 subjects inadequately controlled on metformin were randomized to four doses (from 75 mg to 400 mg) and placebo. BMI was 33 kg/m2 and baseline A1c was 8.0%.
- After 12 weeks, the highest dose of LX4211 (400 mg) showed a 0.9% A1c reduction from baseline, and the lowest dose (75 mg) reached 0.5% reduction. There was a nice dose response effect. However, higher doses of LX4211 didn’t increase glucose excretion in the urine above that of the 200 mg dose
- Genital tract infections were observed in 7%-10% of women at the three higher doses, with none occurring in men or in the placebo group. There wasn’t a strong trend with dose, and there were no discontinuations as a result. Urinary tract infections were the same as placebo. Diarrhea ranged from 4%-10%, compared to 7% in the placebo group. Nausea, vomiting and constipation were also comparable with placebo. LX4211 also exhibited no changes in hypoglycemia, orthostatic blood pressure, LDL or urine electrolytes.
- Dr. Lapuerta concluded that the favorable GI profile of LX4211 suggests that there is a therapeutic window for SGLT-1 inhibition, and that the dual inhibition approach is promising. Longer duration studies will be forthcoming.
Questions and Answers
Q: Is there an increase in GLP-1?
A: We didn’t measure it in this study, but we have documented sustained GLP-1 elevation for several hours in other studies.
Q: What was the impact on body weight?
A: There was an approximately 2% reduction in body weight. So we see similar weight loss to other members of the class despite less glycosuria.
Q: What was the change in blood pressure?
A: There was a 6mm Hg decline in systolic blood pressure.
Q: Isn’t SGLT-2 blocking better, because of SGLT-1’s effect on the kidney?
A: Looking at the pharmacokinetic profile, we don’t think systemic SGLT-1 inhibition is likely. If it was, there would be more glycosuria. We believe that the inhibition is in the GI tract.
Q: How much was water weight loss? Did you check serum electrolytes?
A: There was no change in serum sodium and potassium. We didn’t check weight loss via DEXA or waist circumference. But the weight change was gradual and did not plateau. A diuretic effect would have been more dramatic, and we didn’t observe this.
Posters
CANAGLIFLOZIN IS EFFECTIVE AND GENERALLY WELL TOLERATED IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS AND STAGE 3 CHRONIC KIDNEY DISEASE (POSTER #953)
Vincent Woo, Melanie Davies, Dick de Zeeuw, George Bakris, Vlado Perkovic, Cristiana Mayer, Ujwala Vijapurkar, Keith Usiskin, and Gary Meininger
Treatment with antihyperglycemic agents is often contraindicated in patients with type 2 diabetes and compromised renal function. The present poster detailed the results of an analysis assessing the efficacy and safety of the SGLT-2 inhibitor canagliflozin (CANA) compared to placebo in patients with suboptimal type 2 diabetes control and stage 3 chronic kidney disease (CKD). This analysis pooled data from subjects (n=1,085) enrolled in four randomized, double-blind, placebo-controlled, phase 3 studies. The total study sample (eGFR ³30 and <60 ml/min/1.73 m2) was further divided into two eGFR subgroups of subjects with: 1) eGFR ³45 and <60 ml/min/1.73 m2 (n=721), and 2) eGFR ≥30 and <45 ml/min/1.73 m2 (n=364). CANA 100 mg and CANA 300 mg lowered A1c an average 0.52% and 0.62%, respectively, from baseline compared to an average 0.14% decrease with placebo. Furthermore, treatment with CANA resulted in significantly more body weight loss than placebo (2.0 kg [4.4 lbs] and 2.4 kg [5.3 lbs] with CANA 100 and 300, respectively, vs. 0.5 kg [1.1 lbs] with placebo). Comparing the two subgroups, reductions in A1c and body weight with CANA were more pronounced in patients with eGFR ³45 ml/min/1.73m2 than in patients with eGFR <45 mL/min/1.73 m2. For the overall population, the two CANA doses were significantly more effective than placebo in lowering systolic blood pressure (CANA 100: 4.4 mmHg; CANA 300: 6.0 mmHg; placebo: 1.6 mmHg), which was a trend observed in both eGFR subgroups. Most importantly, CANA was well tolerated among patients with CKD, with the incidence of overall adverse events being only marginally higher in treatment groups. These positive results attesting to the tolerability and efficacy of CANA in patients with renal impairment are much welcomed, especially given hesitations regarding the safety of this class of agents in high-risk populations.
- Baseline characteristics for the overall population included a mean age of 67.1 years, BMI of 32.5 kg/m2, A1c of 8.1%, and duration of diabetes of 15.1 years. The study was primarily comprised of white males.
- In terms of the safety of CANA in the overall population, the incidence of overall adverse events was slightly higher in the CANA 100 and 300 mg groups than in the control arm (74% and 75.3%, respectively, vs. 70.4% in placebo). Serious adverse events, however, were more commonly reported with placebo group than with CANA (13.3% and 14.8% in the CANA 100 and 300 mg groups, respectively, vs. 19.6% in placebo). Treatment with CANA was associated with a higher rate of adverse events related to reduced intravascular volume and renal function. Furthermore, among the 88.2% of subjects on background insulin or a sulfonylurea, the proportion that had documented episodes of hypoglycemia was higher in the CANA 100 and 300 mg-treated arms (41.9% and 43.8%, respectively) than in placebo (29.2%). In subjects not on insulin or a sulfonylurea, the reported rates of hypoglycemia were low across all groups, with no incidences of severe hypoglycemia.
Symposium: Risks and Benefits of Drugs
UPDATE ON THE EVALUATION OF SGLT-2 INHIBITORS
Sanjay Kaul, MD (Cedars-Sinai Medical Center, Los Angeles, CA)
Dr. Sanjay Kaul gave a truly outstanding, opinion-filled talk on SGLT-2 inhibitors, cardiovascular outcomes trials, FDA policy, clinical trial design, and data interpretation. Regarding SGLT-2s, the clear theme of Dr. Kaul’s presentation was uncertainty – he emphasized a vast array of unanswered questions for the drug class, including cardiovascular and renal safety, bone health, risks of malignancy, and volume depletion. He specifically reviewed the cardiovascular profiles of dapagliflozin and canagliflozin, outlining more concerns with canagliflozin based on the data. As he did at the canagliflozin advisory committee, Dr. Kaul came out against the release of interim CVOT data, though he also proposed a number of valuable ways to ensure trial integrity. Speaking more broadly, Dr. Kaul commented that the 2008 cardiovascular risk assessment guidance has hardly stifled innovation, a comment we found reasonable when he compared it to blood pressure medications – but not in diabetes, our major concern. Dr. Kaul spoke out against the FDA’s use of fixed hazard ratios for cardiovascular safety (1.8 and 1.3) – instead, he advocated for flexible assessments based on risk/benefit profiles (i.e., to accept a higher level of risk for a higher level of benefit). This was great to hear from a patient perspective. We appreciated his discussion of rosiglitazone as well, a drug that, in his view, still has insufficient high-quality evidence to incriminate or exonerate it on the cardiovascular safety front. Dr. Kaul highlighted the scary duality implicit in that drug’s story: it became a blockbuster without an established outcome benefit though was virtually killed on insufficient evidence and entrenched opinions. We thought this was one of the best talks at EASD 2013 – more of Dr. Kaul’s opinions and nuanced discussion is below.
-
Regarding rosiglitazone, the catalyst for the development of 2008 cardiovascular guidance for drug development, Dr. Kaul noted that a lingering uncertainty remains regarding its safety. In his opinion, there is insufficient high-quality evidence to incriminate or exonerate the drug’s effect on cardiovascular safety. The fact that the drug became a blockbuster without an established outcome benefit does not reflect well on drug development; however, it is equally lamentable that the drug was virtually killed on insufficient evidence and entrenched opinions.
-
Dr. Kaul commented that he thought the 2008 cardiovascular risk assessment guidance has hardly stifled innovation, noting that there are 15 cardiovascular outcomes trials, with two completed (SAVOR and EXAMINE) and many underway. He said there is “quite a rich landscape” in diabetes drug development right now; for comparison, only one new blood pressure medication has been approved by the FDA in the last 15 years.
-
-
Dr. Kaul summarized the current benefits of SGLT-2 inhibitors. He noted that SGLT-2 inhibitors have been shown to have “modest” glycemic control (an ~0.7% reduction from a baseline of ~8%), relatively low frequency of hypoglycemia, “modest” weight loss (~1.8 kg [4.0 lbs]), and a blood-pressure-lowering effect on the order of approximately 4.5 mmHg, which could potentially be clinically beneficial. To this regard, he commented that we don’t know whether non-physiologic reductions in blood pressure yield cardioprotective effects.
- He also addressed risks of the class: mycotic genital infection (odds ratio=5.0); urinary tract infections (odds ratio=1.4), but not pyelonephritis; polyuria, nocturia, and dysuria; volume depletion, thirst, and increased hematocrit; and increased LDL (benefits and risks were adapted from Vasilakou et al., Ann Intern Med 2013). Dr. Kaul commented that he did not know what the clinical relevance of increased LDL observed with SGLT-2 inhibitor treatment might be.
- Dr. Kaul noted that in terms of cardiovascular safety, canagliflozin had an imbalance in stroke as well as uncertainty around an early increase in MACE. Additionally, an increased LDL was observed with canagliflozin and empagliflozin.
- In Dr. Kaul’s opinion, the issue of volume depletion with SGLT-2 inhibitors is likely underestimated, noting that in CANVAS’ study protocol design, the earliest assessments of volume depletion were conducted at six weeks. He emphasized that the potential effects of volume depletion on the RAAS system activation should be explored, since the CETP inhibitor torcetrapib (a lipid drug to increase HDL) that increased aldosterone was also associated with a significant increase in cardiovascular events.
- Dr. Kaul commented that we have no idea what the effects of SGLT-2 inhibitors are on bone health, given that at present, most evaluations have only been conducted out to one or two years at most. As for malignancy, it remains uncertain what the implications the observed imbalances in bladder and breast cancer with dapagliflozin treatment are. He did not think tumor induction was the likely mechanism, but tumor promotion might be (though, to date, little is known about tumor-promoting agents). During Q&A, Dr. Kaul commented that he believed the imbalances were likely due to detection/ascertainment bias.
- In Dr. Kaul’s review of the cardiovascular profiles of SGLT-2 inhibitors, he expressed more comfort with dapagliflozin’s profile than with canagliflozin’s profile. He noted that in the meta-analysis of cardiovascular risk with dapagliflozin treatment: 1) the observed population in trials for dapagliflozin were representative of the intended treatment population; 2) excess cardiovascular risk (HR of 1.8) was ruled out; and 3) numerical imbalances in cardiovascular endpoints consistently favored dapagliflozin versus control. As for canagliflozin, Dr. Kaul pointed out a number of concerns he had with the conducted meta-analysis, including that: 1) there was an early increased MACE risk (whether it is a true risk or a “random high” remains uncertain); 2) the sponsors’ claim of a “lack of association with volume depletion-related AEs” might not have painted the whole picture, since early (less than six week) volume and blood pressure changes were not captured due to protocol; 3) there was limited patient exposure (~1.1 years), that is, the number of events was driven by a high number of patients as opposed to duration of exposure; 4) the impact of imbalance in rescue therapy use remains unclear; and 5) the public release of interim results may have compromised trial integrity.
- With the public release of interim results for the cardiovascular outcomes trial for canagliflozin (CANVAS) in mind, Dr. Kaul emphasized that partial unblinding threatens trial integrity and reliability, and proposed a solution to the issue. He noted that disclosure of interim analyses slows enrollment; reduces adherence in the experimental arm (for HR >1.2); encourages cross-ins in the control arm (HR <0.8); and minimizes retention. To use interim analysis results and maintain trial integrity, Dr. Kaul suggested that data access be restricted to an unblinded “firewalled group” formed with input from the regulator, DMC, and steering committee; discussions should occur in a “closed” session to preserve data integrity; and regulators should only disclose publicly if a hazard ratio of 1.8 has been ruled out (implying a point estimate of <1.26 without loss of equipoise).
- There are a number of remaining unanswered questions about SGLT-2 inhibitors. Regarding durability, it remains to be seen whether the efficacy of drugs in the class will wane with normalized glucose levels. As for safety and tolerability, SGLT-2 inhibitors have unproven long-term safety (especially in the elderly [>75 years], those with renal impairment [GFR <45-60 ml/min/1.73 m2], and those on loop diuretics). He emphasized that the use of SGLT-2 inhibitors should be further investigated in patients with renal impairment, in particular with regards to nephropathy and increased volume depletion. Finally, he also commented that SGLT-2 inhibitors have not been substantially evaluated in minority populations.
- Reflecting on cardiovascular safety assessments performed to date and their limitations, Dr. Kaul proposed a number of ways to enhance the integrity of non-inferiority safety trials. Dr. Kaul emphasized the need for such trials to: reduce the ineligibility rate; optimize adherence in the experimental arm (to decrease bias to the null); avoid cross-ins in the control arm (to decrease bias to the null); maximize retention and avoid protocol deviation and drop out (to decrease bias to the null); enroll, capture data, and adjudicate events in a timely manner; minimize exposure of the control arm to treatments that increase cardiovascular risk (to decrease bias to the null); restrict the primary endpoint to stringent MACE – cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (to decrease ascertainment error and misclassification); adjust for multiplicity if interim data is used for the final analysis (to reduce type 1 error); not publicly disclose results of interim analyses (to increase trial integrity). Dr. Kaul also noted that placebo-controlled trials should be preferred over active-controlled trials (as one would not necessarily know the safety profile of the active comparator). In addition, extension phases of trials add noise (given that they are often unblinded); as such Dr. Kaul advocated for extensions to be blinded.
- Dr. Kaul questioned whether we should continue to allow disease-oriented surrogate endpoints to be the standard for regulatory approval, or demand patient-oriented health outcomes benefit for both microvascular and macrovascular complications. He commented that he is not persuaded by the statement that microvascular benefits are unequivocally demonstrated with oral agents for type 2 diabetes, deeming laserphotocoagulation and reduced albuminuria as examples of unvalidated surrogate endpoints. Instead, he would like to see studies with concrete patient outcome benefits – for example, in renal failure, amputations, and blindness.
- Dr. Kaul argued against the FDA’s use of fixed hazard ratios (1.8 and 1.3) with regards to cardiovascular safety. Instead of fixed margins, Dr. Kaul proposed that allowable risk should be determined based on the amount of benefit, as opposed to trial feasibility. For example, he would be willing to accept a greater potential increase in harm for a therapy that lowered A1c by 1.5-2.0%, whereas for a therapy that lowered A1c by 0.5%, he might not even be willing to accept a hazard ratio of 1.3. Furthermore, he advocated for benefit/risk assessment to incorporate the patient’s view of acceptable or tolerable risk, and for it to evolve from the mindset to “ensure drug safety” to ensure “favorable risk/benefit.” Finally, he emphasized the need to develop more tools for communication of benefit/risk not only to patients, but also to the scientific community, academia, and regulators.
- Dr. Kaul explained that an asymmetry exists in how drug efficacy and safety are evaluated – RCTs vs. non-clinical data/PK-PD studies/retrospective review. Efficacy is assessed in randomized controlled trials, in which endpoints are anticipated and prespecified. These trials are designed with adequate power to assess the endpoint, and the endpoints have clear adjudication, and are precisely measured/quantified. In contrast, safety is typically assessed using a combination of non-clinical data, pharmacokinetic/pharmacodynamic studies, meta-analyses, observation databases, and monitoring programs (e.g., FDA AERS and Sentinel). This stems from a major limitation in randomized controlled trials: there is limited exposure to treatment and narrow study populations, so safety issues cannot be fully captured. In contrast to efficacy assessments, safety issues are often unanticipated, and as such are not prespecified for measurement, or adjudicated proactively (O’Neill, Drug Information Journal 2008).
Questions and Answers
Q: Surely when we prescribe to patients, they are exposed to risks other than cardiovascular risk. What do you think of things like bladder cancer or breast cancer?
A: As I mentioned fleetingly, there was an imbalance in one of the drugs. I believe it’s probably related to ascertainment bias. In order for sponsors to clearly adjudicate this uncertainty, it would require a 30,000-patient trial, which in my opinion, and probably the majority of yours, is not possible to do pre-approval. That should be evaluated in a post-approval, phase 4 type of study.
Corporate Symposium: What is Important in T2D Management — Experts’ Perspectives (Sponsored by Lilly)
THE ROLE OF SGLT-2 INHIBITORS AND EMPAGLIFLOZIN
Bernard Zinman, MD (Leadership Sinai Centre for Diabetes, Toronto, Canada)
Dr. Bernard Zinman delivered a comprehensive talk on Lilly/BI’s SGLT-2 inhibitor candidate empagliflozin, which is currently under regulatory review in the US and EU — read our coverage of the drug’s submission at http://www.closeconcerns.com/knowledgebase/r/5ad420ec. Dr. Zinman began by comparing pooled phase 3 data on empagliflozin, J&J’s Invokana (canagliflozin) and BMS/AZ’s Forxiga (dapagliflozin). Empagliflozin appears to be slightly more effective than dapagliflozin in terms of A1c reduction, but slightly less effective than canagliflozin. Of course, it is important to keep in mind that these comparisons are not drawn from head-to-head studies. Dr. Zinman next discussed a 78-week phase 3 study comparing empagliflozin to placebo in patients on basal insulin, in which empagliflozin demonstrated a 0.6% placebo-adjusted A1c reduction from a baseline of 8.2%. Additionally, empagliflozin led to an average of 4 lbs of weight loss and a reduction in patients’ daily insulin needs by six units (although no difference in hypoglycemia was seen despite this reduction). Another phase 3 study showed that the drug’s A1c-lowering efficacy and weight loss benefits were largely preserved in patients with mild renal impairment; a less robust but still clinically meaningful change in A1c and weight loss was seen in patients with moderate renal impairment. With regard to the increase in genitourinary infections seen in the trials, Dr. Zinman noted that patients with a past history of such infections were overrepresented in empagliflozin’s phase 3 program.
- Dr. Zinman shared pooled data from pivotal phase 3 trials of empagliflozin, canagliflozin, and dapagliflozin. On average, empagliflozin demonstrated a 0.6% A1c reduction. Dapagliflozin demonstrated slightly lower efficacy, while results with canagliflozin appeared stronger than either dapagliflozin or empagliflozin. However, Dr. Zinman pointed out, canagliflozin’s efficacy is substantially diminished in patients with renal impairment.
- The beauty of the SGLT-2 inhibitor class, Dr. Zinman stated, is that the A1c reductions seen with SGLT-2 inhibitors do not seem to depend on background therapy, due in large part to the class’ insulin-independent mechanism of action. With this in mind, it will be interesting to see how SGLT-2 inhibitors are incorporated into the treatment algorithm in the coming years – Will they emerge as the most common third line option after metformin and DPP-4 inhibitors? Will they increase the time before patients go on injectable therapy?
- Dr. Zinman discussed the results of a 78-week, phase 3 trial comparing empagliflozin 10 and 25 mg vs. placebo as an add-on to basal insulin in type 2 diabetes patients (n=494). The data was first presented at this year’s ADA. At week 78, the higher dose of empagliflozin led to a 0.6% placebo-adjusted reduction in A1c from a baseline of 8.3%, a six-unit reduction in patients’ daily insulin requirements, and 2 kg (~4 lbs) average weight loss. There was no significant difference in hypoglycemia (despite the reduction in insulin dose), and a slight increase in drug-related adverse events with empagliflozin (largely attributable to genitourinary infections).
- Dr. Zinman also discussed the findings of a phase 3 trial investigating empagliflozin in patients with stage 2-4 renal disease. The study (also first presented at ADA) ran for 52 weeks and enrolled 741 patients with mild and moderate renal impairment (eGFRs from 60-90 and 30-60 ml/min/1.73 m2, respectively). Empagliflozin 25 mg led to an average A1c reduction of approximately 0.6% vs. placebo at 52 weeks in patients with mild renal impairment from a baseline of 8.0% – the improvement was similar in magnitude to the reduction seen in patients with normal renal function. Reductions in weight (~5 lbs or 2 kg) and systolic blood pressure (~5 mmHg) were also largely preserved in patients with mild renal impairment. The sustained A1c reduction in those with moderate renal impairment (0.4% from a baseline of 8.0%) was slightly less robust though still clinically meaningful. Dr. Zinman noted that empagliflozin seemed to temporarily reduce eGFR slightly, but that deficit recovered almost immediately once the medicine was stopped, indicating that the change was likely due to hemodynamics rather than tissue changes.
- A tolerability analysis of empagliflozin shows that the candidate led to an increase in the incidence of genitourinary infections. This is not altogether surprising, as the same side effect has been seen with other SGLT-2 inhibitors. However, Dr. Zinman noted that patients with a past history of genitourinary effects were overrepresented in empagliflozin’s phase 3 study pool, and that infections were generally mild and rarely led to a discontinuation of treatment.
- For Dr. Sanjay Kaul’s outstanding review of the SGLT-2 inhibitor class and outstanding safety concerns, please see pages three through six of our EASD report at http://www.closeconcerns.com/knowledgebase/r/a436c2c2.
Corporate Symposium: New Options and Opportunities in the Era of Individualized Therapy (Sponsored by Janssen Cilag)
SGLT-2 INHIBITION – THE CLINICAL PERSPECTIVE
Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX)
Dr. Julio Rosenstock reviewed clinical data for SGLT-2 inhibitors (specifically dapagliflozin, canagliflozin, and empagliflozin), highlighting their: 1) ability to lower A1c consistently across various therapy regimens (by ~0.6-0.9% from a baseline of 8%); 2) consistent and persistent ~2 kg (4 lb) weight loss; 3) low risk of hypoglycemia; 4) ability to lower and sustain a loss of ~5 mmHg in systolic blood pressure; and 5) elevated risk of urinary tract and genital infections. Regarding canagliflozin, Dr. Rosenstock noted that when added on to metformin, canagliflozin 300 mg provided slightly greater A1c reduction than sitagliptin, and brought about significantly greater weight loss (Diabetologia 2013). He also commented that he thinks SGLT-2 inhibitor in combination with insulin is an important combination, given the difficult nature of control for many on insulin. Dr. Rosenstock commented that he sees metformin in combination with a DPP-4 inhibitor or GLP-1 agonist as an early combination treatment on the horizon, followed by the addition of an SGLT-2 inhibitor or basal insulin (assuming patients can afford and tolerate such therapies).
- Dr. Rosenstock listed the potential benefits of SGLT-2 inhibitors: once-daily dosing; their ability to reduce both fasting and postprandial glucose; their ability to lower A1c in a predictable and consistent manner; blood-pressure-lowering effects; a mechanism independent from insulin secretion; their ability to complement any other drug; and their potential for use in type 1 diabetes.
- Subsequently, he commented on a number of concerns that have arisen with the class. Dr. Rosenstock does not believe that weight loss with SGLT-2 inhibitors will wane over time (they’ve been shown to have a persistent effect out to two years). He believes the effects are minimal regarding polyuria, that electrolyte disturbances aren’t really an issue, and that there isn’t currently enough data to comment on the potential of hypotension/dehydration. Although there is indeed an increased risk of urinary tract infections with SGLT-2 inhibitors, Dr. Rosenstock pointed out that, reassuringly, there was no increased risk of pyelonephritis. As fungal genital infections are a real concern of these drugs, Dr. Rosenstock explained that those who have recurrent episodes should not be on the medications. In addition, he pointed out that SGLT-2 inhibitors are indeed less effective in patients with renal impairment. Meanwhile, the jury remains out on unexpected side effects and long-term safety.
INDIVIDUALIZING TREATMENT APPROACHES FOR YOUR PATIENTS
David Matthews, PhD (University of Oxford, Oxford, United Kingdom)
Dr. David Matthews argued that individualizing treatment approaches for patients is imperative, delineating mathematical, statistical, and pragmatic considerations. In terms of mathematics, Dr. Matthews noted with 12 drug classes now available for type 2 diabetes, the number of permutations of therapies (as monotherapy or in combination) that could be used would be in the millions, so it would be nearly impossible to have an evidence base for every combination therapy before trying them. Regarding statistics, Dr. Matthews explained that even though one drug may on average be more effective than another, each has a distribution of efficacy; that is, even though a drug may be worse on average, some individuals still benefit. In terms of practical considerations, healthcare providers must consider factors such as resources, patient engagement, needle phobia, and work imperatives, to name a few, when individualizing therapy. He commented that obviously, treatment individualization should take into account what the best option would be for the patient, and that it should aim to be minimally disruptive. Given the fact that the evidence base will never come close to completely characterizing all possible therapy regimens, Dr. Matthews proposed for doctors to conduct “trials of one” with their patients – to test out one drug for a period, see how they’re responding, and then consider switching to a different medication if appropriate. To further engage patients in tailoring treatment for their diabetes, Dr. Matthews suggested the use of topic cards, getting patient involvement in research, and advocacy as several options. In conclusion, Dr. Matthews quoted William Osler, who stated, “Medicine is a science of uncertainty and an art of probability.”
MEET THE EXPERT SESSION
Manuel Puig Domingo, MD (Universitat Autònoma de Barcelona, Barcelona, Spain); David Matthews, DPhil (Oxford, England, UK); Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX); Guntram Schernthaner, MD (University of Vienna, Vienna, Austria); John Wilding, MD (University of Liverpool, Liverpool, UK)
Dr. Schernthaner: Can SGLT-2 inhibitors be used in patients with type 1 diabetes?
Dr. Wilding: It is certainly an area to watch for in the future, though it would always be complimentary to insulin.
Dr. Schernthaner: I have some friends who are doctors and also have type 1 diabetes. They have taken SGLT-2 inhibitors and have had an enormous decrease in postprandial glucose levels and far fewer hypoglycemic events. They are experts and have been using insulin for 30 years, so in some cases it could be helpful. Some of the doctors were obese and lost weight, but many people with type 1 are slim and further weight reduction would not be a good option. There was a paper that showed change in intestinal absorption of glucose. What is your comment on this observation?
Dr. Wilding: Canagliflozin is selective for SGLT-2, but it will have a small and transient effect to inhibit SGLT-1. In that situation, what it may be doing at the initial dose is delaying the absorption of glucose from the gut, reducing post-prandial glucose levels. The mechanism is speculative, and it’s still very clear that about 90% of canagliflozin’s effect is due to its effect on the kidney, though the modest gut effect is scientifically interesting and may contribute in a small way to the therapeutic effect of canagliflozin.
Dr. Schernthaner: The comparison with sitagliptin is not the best. If canagliflozin was compared to something more potent, would it show similar results?
Dr. Matthews: You need to do the trial, so I don't know. All of the head-to-head trials are quite interesting, but drug companies tend to select something they think they will win against. Traditionally, if you have something that works weakly, you try against placebo because you’re sure you’ll win against that. They try against the worst agent around. The industry is skewing what you’re going to get out of trials, so take them with a pinch of salt. They’ve been chosen to give some sort of gloss. Having said that, the reality is that all these data, because drug companies have so many people involved, are absolutely correct. The realty is that pharmaceutical companies give you truth, but only the truth about what it is they have done. Why haven’t we done another trial with metformin? Nobody is doing trials on metformin now to see if it has CVD protection because no one will fund that stuff! With trials, you can come up with any question, and all I would say is, go and talk to Novartis and I’m sure you could persuade them to do the trial.
Dr. Wilding: Everyone has a good response to glimepiride initially – how long do you have to go for before you know who the right people are?
Dr. Matthews: Once you start on the principle of individualized treatments, then it behooves us to think about pharmacokinetics and indicators. Rob Ratner has done some interesting work looking at who did well in what trials. There are huge problems with doing that. If you’re not careful, you will get some chance findings, but at least you can start thinking about whether those people had certain characteristics. As soon as we start to focus on that, we’ll get more useful information on to whom to administer the drug.
Dr. Schernthaner: There is a weight loss of 3 kg [6.6 lbs.] associated with the use of SGLT-2 inhibitors. Patients are not shrinking. What is the stabilizing mechanism so that weight is not continuously going down with SGLT-2 inhibitors?
Dr. Domingo: We have some mechanistic explanations. They lose calories and water, but the initial effects are overcome by adaptive mechanisms that might tend to avoid or prevent additional weight loss. We are focusing on this particular new treatment, but if you look at any treatments currently available, all show this stabilizing effect. This is case with GLP-1 related treatments, as well. They lose weight but at the end they tend to stabilize and not lose additional weight. Patients treated with bariatric surgery lose weight, and after 1-2 years it is maintained, or recovered, but in most cases it is stabilized. We think an adaptive mechanism is playing a huge role.
Dr. Matthews: You’re going to defend your weight. This is central to the whole of your genetic makeup – the whole of your genome is designed to do that. You can’t just say why didn’t you lose weight? This doesn’t work. You do defend your weight in all sorts of ways, and that is built directly into homeostatic mechanisms. You’ll defend your body size.
Dr. Wilding: As your weight falls, your metabolic rate falls. That’s why all weight interventions result in a plateau. In dapagliflozin and canagliflozin, if you look at what type of tissue if being lost, two-thirds is fat and one-third is lean tissue. It’s about the same proportion if you go on diet or take canagliflozin. The majority is fat, and that’s an important thing to make clear.
Q: Can you comment on the CANVAS trials?
Dr. Matthews: CVOTs are always complex. You need to take patients and study them for a long time for cardiovascular effects to be apparent. Rosiglitazone is a classic example. Pharmaceuticals get completely locked into the 1.3 upper limit of confidence intervals for CV protection. CVOTs are expensive things to do. If you look at EXAMINE and SAVOR, they saw zero changes, which satisfies regulators, and the 1.3 margin hasn’t been exceeded. CANVAS trials are an absolute nightmare, with J&J and investigators of CANVAS trials trying to defend it from people trying to look into it too early. You have to give stuff to regulators to get canagliflozin on books, so they can start to make return on investments, and then you can start a longer CVOT. The reason UKPDS chose what it chose is that it ran for 10 years. Robert Turner thought the whole thing would be over in three years, and at 10 years we finally produced results. It’s tough to do those things, but if you take the right people for long enough, then you get effects and you can bank that. With CANVAS, we hope to get results that are we are proud to show you.
Dr. Schernthaner: Julio, are there any differences between SGLT-2 inhibitors? What proportion of canagliflozin’s action is due to SGLT-1 inhibition?
Dr. Rosenstock: There is a little bit of SGLT-1 inhibition. There is a nice study that shows a reduction in GI absorption with canagliflozin. I’m not sure if the SGLT-1 effect is that important.
Dr. Schernthaner: We have experienced dapagliflozin in a number of different countries. We also have full reimbursement. But we don’t have any experience with canagliflozin, so how is the situation in the States with that?
Dr. Rosenstock: It’s hard to tell, but from what we hear from the sponsor, they say take-up is going very well, especially with general practitioners. There were concerns because the class is counterintuitive – all of a sudden we’re telling them glycosuria is a good thing – but they say uptake is good. I’m told in Germany dapagliflozin is doing very well. The thing is with this type of drug is that you can tell from day one that it works. It’s predictable and consistent.
Dr. Schernthaner: When will SGLT-2 inhibitors officially be added to ADA/EASD guidelines?
Dr. Matthews: We said in the position statement last year that we would think about revising this in three years. The EASD will probably set up a process next year. We did write it with the idea that it is a flexible document. That’s why we didn’t call it “guidelines”– it's a position statement. I think SGLT-2 will be another box on the options you get. There’s no plan to reconvene at the moment. The process is you get together a collection of people appointed by EASD and ADA and get lots of reviewers before it reaches the public domain. It requires multiple stages, rather than algorithmic guidelines that no one reads.
Dr. Rosenstock: The class look good, but I have concerns about the elderly, about the frail, about the people on diuretics, about the people with good blood pressures of 110/70 who might have hypotensive episodes. Those things need to be discussed. I still have concerns about people with borderline compromised renal function, though there doesn't seem to be an indication with that. The jury is still out about the long-term safety of these compounds.
Dr. Schernthaner: I’m always really concerned about new compounds. In my opinion, no drug is the drug for anyone. Individual use if very important.
Dr. Wilding: In the UK, dapagliflozin has been positioned in same way as DPP-inhibitors; it is also reimbursed. You are then down to having an individual discussion with the patient to see which is the most appropriate option for that patient. For a patient who is obese and on insulin and metformin, I would recommend a SGLT-2 because there is good chance that they would lose weight and see an improvement in control. But if they have problems with genital infections, that might push me to recommend a DPP-4 inhibitors. You have to take into account the individual patient.
Dr. Rosenstock: Both are valid options. You have to take everything into consideration. The advantage with SGLT-2 inhibitors is that you get an immediate effect. The patient can feel it, whereas DPP-4 inhibitors are not satisfying expectations for a sustained effect.
3. Insulin Therapy
Michael Berger Debate: New Basal Insulins – The Longer the Better?
PRO
Luigi Meneghini, MD, MBA (University of Miami, Miami, FL)
After highlighting some of the current limitations of insulin therapy and describing the evolution of basal insulin analogs, Dr. Luigi Meneghini made the case for longer-acting basal insulins. Reviewing clinical data for insulin degludec, U-300 insulin glargine, and PEGylated insulin lispro, Dr. Meneghini noted that these longer-acting agents provide: 1) more consistent biologic activity over a 24-hour period (e.g., insulin degludec has a half life of 24.5 hours, versus 12.5 hours with insulin glargine [Heise et al., Diabetes 2011; Heise et al., Diabetologia 2011]); 2) comparable efficacy with current long-acting agents; 3) no increased risk of overall hypoglycemia, and reduced risk of nocturnal hypoglycemia (e.g., significantly lower rates with insulin degludec versus insulin glargine); and 4) no specific issues regarding exercise or recovery from hypoglycemia.
CONTRA
Philip Home, MD, PhD (Newcastle University, Newcastle upon Tyne, United Kingdom)
Dr. Philip Home deemed Dr. Meneghini’s predominant focus on duration of action to be “unsophisticated thinking,” arguing that other properties and circumstances matter, and matter a lot. Specifically: 1) variability of subcutaneous absorption matters; 2) bioavailability can become a problem; 3) longer duration of action could preclude fast dose adjustments required in some circumstances; 4) weekly insulin dosing could be dangerous; and 5) rapid-acting insulins in pumps will be better than short-acting insulins even for basal insulin delivery, particularly for closed-loop control. Dr. Home drew upon numerous examples, some from insulin’s earlier days. For example, even though insulin detemir has a shorter duration of action than insulin glargine, it has been documented to have lower variability. In addition, he pointed out that bovine ultralente insulin never caught on even though it had a duration of action of ~36 hours, explaining how the formulation had low bioavailability and was thus difficult to titrate to get good control. On a final note, Dr. Home emphasized that the metabolic properties of insulin matter – in a 12-week study comparing the liver-selective PEGylated insulin lispro with insulin glargine in patients with type 2 diabetes, those who received PEGylated lispro had elevated triglycerides and ALT levels, suggesting the insulin could contribute to the development of fatty liver (Bergenstal et al., Diabetes Care 2012).
PANEL DISCUSSION
Luigi Meneghini, MD, MBA (University of Miami, Miami, FL) and Philip Home, MD, PhD (Newcastle University, Newcastle upon Tyne, United Kingdom)
[In a poll of the audience, more people voted for Dr. Meneghini than Dr. Home.]
Q: Is there anything you could say to one another to challenge one another directly?
Dr. Meneghini: [Jokingly] First of all, I thought it was a clinical debate, and not a political English type of exercise. I appreciate the weak arguments that you proposed, which although very enthusiastic, they are delusional. I think one thing we agree on is that “longer-acting” may not be the right word for new basal insulins. I think you and I referred to it in terms of consistent action. A lot of evidence shows that these newer insulins have a more consistent biological effect. You mentioned that using rapid-acting insulin in a pump is the ideal way; on that point, we do agree. I think maybe we should have named the debate something else, like longer acting is almost always better.
Dr. Home: Thank you for agreeing with me that variability and consistency are important. Ultimately, Luigi explained very nicely why longer-acting insulins at least up to 24 hours are advantageous, but as I said, other properties do matter. What I’d like to do is just ask my penultimate point, and say, what about weekly insulins? A yearly insulin? Would you be happy?
Dr. Meneghini: Yes. Let me qualify that. We’re talking about basal insulin. I don’t think the beta cell ever goes on vacation, except obviously if blood sugar goes low. But that is unpredictable with exogenous insulin. I think there is a place for weekly insulin for patients. If we’re able to optimize basal insulin replacement [in terms of daily amount], then I think it will be a safe option [in terms of daily distribution]. What I’m going to agree with you now is that a lot of individuals put on basal insulin are over-basalized. They get too much basal for their needs, and when they do exercise or skip a meal, excessive basal insulin drives hypoglycemia.
Dr. Home: I would like to suggest there is more of a problem with weekly insulin. I can’t always predict how active I am going to be later in the week. Whether I’m enjoying myself in my garden when I get home depends on the weather in Newcastle. I have no idea what it will be.
Dr. Meneghini: Are you telling me you don’t know how to use basal insulin?
Dr. Home: Fortunately, I don’t have to take it. The beta cell is a lovely example of basal insulin – it has a duration of action of five minutes. That tells us something else, doesn’t it? Unless you have a smart insulin in the system, it is certainly better to inject more frequently.
Q: I do not believe you have to say that for all patients with type 1 or type 2 diabetes, longer-acting agents are better. For clinicians whose patients regularly say they have nocturnal hypoglycemia, I think this is an option. I think that at a certain time for certain patients, going on long-acting insulin is probably good, but putting them all on these treatments is probably not right.
Dr. Meneghini: I think you bring up an absolutely correct point. We’re looking at options – the more options we have in the armamentarium, the better. For example, for patients with strong dawn phenomenon, a longer-acting insulin might be less effective than NPH.
Dr. Home: Other things come into play if you want to give insulin in the morning, and some patients don’t want to do that. You really do need a 24-hour insulin to cope with the end of the night.
Q: Is there a difference between using long-acting insulin for type 1 versus type 2 diabetes?
Dr. Meneghini: The evidence [available] shows less risk of hypoglycemia, and that relates to more consistent biologic activity. Obviously you have to individualize treatment. Would I use them [longer-acting basal analogs] for type 1 and type 2? Absolutely. The best test tube is type 1 diabetes – it is the most insulin-deficient environment. Historically, whatever worked for type 1 [diabetes] worked for type 2, whether it was multiple daily injections or some other therapy.
Dr. Home: But it is the case that people with type 1 diabetes are more sensitive to differences in pharmacokinetics and pharmacodynamics. People with type 2 diabetes produce a lot of insulin on their own, which buffers some of the issues. It makes my argument about variability less important.
Q: I was a little puzzled, Philip, by your comments on liver-preferential insulin. All my life I learned that subcutaneous insulin was wrong, and insulin going first to the liver would be expected to be beneficial. Of course no one wants too much and fatty liver. But, do we know if we don’t want one at all, or want some degree [of liver selectivity]?
Dr. Home: I don’t know, but for truly insulin-deficient, thin individuals with type 1 diabetes, or people with pancreatic diabetes, I suspect having hepato-preferential insulin will be a good thing. But in type 2 diabetes, the problem is different. I suggested to the EASD we ought to have a debate on liver-preferential insulin, whether it’s good or bad. My suspicion is that by driving more insulin at the liver, it would worsen the problem of calorie toxicity at the liver in type 2 diabetes. This, I would expect, needs a lot more study. My point here is that the metabolic properties of insulin matter, and not necessarily that that particular insulin has a problem.
Q: I think the most exciting thing is the lack of variability. I’m worried that our colleagues in industry will just develop long-acting insulins with this very useful quality. In type 1 diabetes, we have some quite good evidence against long-acting basals. In a structured education program, only twice-daily basal produced better control with the currently available basals. The advantage of pumps is that you can vary basal replacement over 24 hours. The focus is shifting away from shorter-acting, twice-daily basal insulin to long-acting basals, but what do you tell your patients when they want to go skiing?
Dr. Home: Thanks for the support. You present an even more sophisticated argument. But yes, we vary basal insulin during the night in pumps, don’t we? Don’t we need to find some way to do this with injected insulin?
Dr. Meneghini: I think it’s a good point; I think the gold standard in terms of basal insulin delivery is still fast-acting insulin in a pump because of the flexibility it affords. In terms of going skiing, plenty of exercise literature says you can reduce basal insulin doses, which might have some impact in reducing hypoglycemia; however, supplementing physical activity with carbohydrate [intake] would be a better option.
Q: Après skiing and drinking, what do you do with your basal insulin?
Dr. Meneghini: Didn’t anyone tell you not to drink after you ski?
Dr. Home: They don’t ski a lot in Miami.
Q: Could you comment about intra- versus inter-individual variability? I wonder if its low intra-individual variability that is important for patients, and low inter-individual variability that is important for prescribing physicians?
Dr. Home: Yes is the answer to that, in a way. When we talk about variability, some manufacturers have tried intentionally to confuse us about the different kinds of variability. As a prescribing physician, what you want to know is what does approximately the same thing in everyone, and to understand what you’re going to get – predictability, you might call it. Whereas, a person on insulin with titrated dosage wants the same effect every day. You’re probably right that for individuals, it’s intra-individual variability that matters, and that for physicians, it’s certainly helpful to have some predictability. But of course, if your patients have a lot of erratic insulin absorption from day to day, they would come back to you and report hypoglycemia, and you don’t want that either.
Q: Philip’s main argument is that it’s not a matter of duration, but a matter of variability. Luigi’s argument is that the newer insulins produced less hypoglycemia and more flexibility, with the same rate of hypoglycemia during exercise. Philip, what are your counterpoints to these?
Dr. Home: Don’t get me wrong, I think that insulins which give better duration of action are important. All I’m saying is that there’s more than one property that is important. I’ve worked with manufacturers to develop insulins for 33 years now. I know that if you don’t go to a sophisticated company like Novo Nordisk or Lilly, who have been in insulin for a long time, the first idea is that we must extend action. You must point out that other properties are just as important. Variability and bioavailability are the most important.
Q: From a practical perspective, how do you titrate longer-acting and very long-acting insulin?
Dr. Meneghini: There are quite a few titration algorithms, ranging anywhere from adjustments on a daily basis, to three days a week, to weekly. Given the nature of the longer-acting basals that we’ve talked about (it takes about three to four days to reach steady state), I would not advise any changes more than once every three to four days to stay on the safe side, looking at the studies done where weekly titration is made.
[Dr. Meneghini and Dr. Home gave each other a friendly embrace at the end of the session.]
Oral Presentations: Hypoglycemia – Balancing Glucose Control
THE EFFECT ON INSULIN ANALOGS ON THE RISK OF SEVERE HYPOGLYCAEMIA IN PATIENTS WITH TYPE 1 DIABETES AND RECURRENT SEVERE HYPOGLYCAEMIA: THE HYPOANA TRIAL
Ulrik Pedersen-Bjergaard, MD (Hillerød Hospital, Hilleroed, Denmark)
Dr. Pedersen-Bjergaard presented notable results from the HypoAna study – the two-year crossover trial included 159 type 1 patients with recurrent severe hypoglycemia (>2 episodes in the past year). Patients were randomized to a basal-bolus regimen using analog insulins (detemir and aspart) or human insulin/NPH. Each patient underwent a three-month run-in period, nine months of treatment in one of the arms, a three-month washout period, and then nine months in the other arm. Significantly, treatment with analog insulin resulted in a 29% rate reduction (p<0.05) in severe hypoglycemia (intention-to-treat analysis), which rose to 34% when adjusted for A1c. This corresponds to an absolute rate reduction of 0.5 severe hypoglycemia episodes per patient-year, meaning the number needed to treat with insulin analogs to avoid one episode of severe hypoglycemia is just two patients per year. Striking and victorious results to say the least, and notably, the reduction in hypoglycemia in the analog arm still translated to a 0.13% A1c advantage over human insulin (p<0.05; baseline A1c: 8%). Dr. Pedersen-Bjergaard showed an interesting graph of severe hypoglycemia by time of day – the advantage of analogs only showed up in the nocturnal period. Overall, we were extremely glad to see the real-world ambition of this study and the inclusion of patients with recurrent severe hypoglycemia, those who arguably need analogs the most. We hope this data can be taken to governments and payers who do not cover analog insulin for type 1 diabetes – we think the study clearly supports cost savings with analog insulin.
- The HypoAna trial was a two-year, crossover, seven-center study. The protocol randomized 159 patients to treatment with basal-bolus therapy with insulin aspart/detemir or regular human insulin/NPH. Patients had a three-month run-in period with the insulins, followed by nine months of maintenance. There was then a three-month washout period, followed by crossover to the other therapy for nine months. The glycemic target was the maintenance of baseline A1c (8%), as these patients had a high frequency of severe hypoglycemia. The number of daily doses and adjustment of insulin was at the discretion of the local investigator.
- Dr. Pedersen-Bjergaard emphasized the key inclusion criterion: patients had to have had two or more episodes of severe hypoglycemia in the previous year. The study’s primary endpoint compared severe hypoglycemia between analogs and human insulin in the nine-month maintenance periods. Severe hypoglycemia was defined strictly as requiring third party assistance. Secondary endpoints included hypoglycemia as measured via CGM. The CGM data was not shown in this presentation. A blinded adjudication of endpoints according to Whipple’s triad and severity was applied.
- Fifty-three percent (53%) of the 159 patients were classified as hypoglycemia unaware and 41% had impaired hypoglycemia awareness (based on a Danish questionnaire). Patients had a mean duration of diabetes of 30 years and a baseline A1c of 8%.
- While 159 patients were randomized, there were 49 dropouts (36 while on human insulin and 13 while on an insulin analog). While that reflects a fairly high 31% dropout rate, it disproportionately occurred in the human insulin arm. We wonder if the dropout reflects patients seeing worse clinical outcomes with human insulin. We suspect if the dropout rate had been lower, the data would have been even more compelling.
- Overall, 64% of participants had an episode of severe hypoglycemia during the study. The mean rate during the maintenance periods was 1.3 episodes per patient per year. A striking 34% of these episodes resulted in a coma.
- The prevalence of severe hypoglycemia was 55% with human insulin vs. 39% with analog insulin – this translates to a 29% rate reduction, which rises to 34% when adjusted for A1c.
- The baseline A1c of 8% was maintained throughout the study in both groups – the slide showed no noticeable improvement or decrement in either group over the two-year trial. A1c was a very slight 0.13% better during analog treatment (p<0.05), though this was not a point of emphasis.
- To us, this study provides clear proof for why A1c does not tell the full story – anyone looking at this study would say patients were miles better off with analog insulin (and far less costly), though that improvement was not at all reflected in A1c. We hope that payers are governments will be very receptive to this type of severe hypoglycemia data, since it is so directly tied with economic data.
- Dr. Pedersen-Bjergaard highlighted a Swedish survey that found patients experience more than one episode of severe hypoglycemia per patient-year (Kristensen et al., Diabetes Res Clinc Pract 2012). Further, the survey discovered a disproportionate distribution of events: only 20% of patients had recurrent severe hypoglycemia, though they accounted for up to 90% of all events.
- To date, insulin analogs have shown a less clear impact on severe hypoglycemia for three main reasons: 1) high risk patients are excluded from studies; 2) studies are thereby deflated from statistical power; and 3) hypoglycemia events are mainly safety endpoints. These limitations were the rationale for conducting this study in patients with recurrent severe hypoglycemia.
Questions and Answers
Q: Did you think about the ethics of the study? Many of us would use analogs in people who have these problems already.
A: Of course, we all have used analog insulins in high-risk subjects. We have personal experiences indicating that it may be beneficial. Still, we felt that this study was needed, because there are no scientific data to support these experiences.
Q: Very nice paper. You had 50% of your population with hypoglycemia unawareness. How was that diagnosed – a questionnaire? And what did you do during the run-in period and the crossover period – did patients go back to their previous regimen?
A: Hypoglycemia unawareness was classified according to a Danish developed questionnaire, and it was classified in three groups: normal, impaired, and unawareness. This was not an inclusion criteria; it was only a description of the subject. 95% of patients had some degree of impaired awareness. During run-in and crossover, there was no insulin algorithm supplied. It was all at the discretion of the local investigator. Subjects came into the study with a certain insulin treatment, and the investigator shifted to the trial treatment based on their own experience.
Q: Congratulations on this study. Did you recommend a different carb distribution in the different treatment arms?
A: We did no other interventions other than the treatment.
Q: This was a real-world study, so you left it to the people and investigators. Did you collect data on how people used the insulin – twice-daily NPH and so on?
A: I did not show the distribution of insulin regimens for sake of time. We saw the same difference between the treatment arms regardless of how many basal injections they got in the study.
Q: There is a difference in PK and PD in the human insulin regimen. Did you give different instructions on one insulin regimen vs. another?
A: There were no standardized instructions given to the patients. They just followed usual care.
LOWER RATES OF OVERALL, NOCTURNAL AND SEVERE HYPOGLYCAEMIA DURING MAINTENANCE TREATMENT WITH IDEGASP VS BIPHASIC INSULIN ASPART 30 IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: A META-ANALYSIS
Allan Vaag, MD (Rigshospitalet, Copenhagen, Denmark)
Dr. Allan Vaag presented a post-hoc meta-analysis of two 26-week phase 3 trials comparing Novo Nordisk’s IDegAsp (a premix of 70% insulin degludec/30% insulin aspart) to biphasic insulin aspart (NovoMix: 70% insulin aspart protamine/30% insulin aspart). IDegAsp had a significant advantage over NovoMix in all measures of hypoglycemia: a 19% lower rate of overall confirmed hypoglycemia (p=0.03); a 57% lower rate of nocturnal confirmed hypoglycemia (p=0.0001); and a 39% lower rate of severe hypoglycemia (not statistically significant, as there were only 29 episodes). Dr. Vaag mentioned that in the FDA’s review of insulin degludec, the agency also requested hypoglycemia outcomes during the maintenance period (“when patients had been used to using these novel insulins”). When narrowing the IDegAsp vs. NovoMix data to the maintenance period, the hypoglycemia data looked even stronger – IDegAsp had a 31% lower rate of overall confirmed hypoglycemia (p<0.05), a striking 84% lower rate of severe hypoglycemia (P<0.05), and 62% lower rate of nocturnal confirmed hypoglycemia (p<0.0001). He emphasized that the these definitions of hypoglycemia were “discussed and challenged by the FDA,” but they were prespecified for insulin degludec, and thus, used in this meta-analysis.
Oral Presentations: Insulin in Type 2 Diabetes – Earlier? Dangerous? Stronger?
EXOGENOUS INSULIN AND RISK OF ALL-CAUSE MORTALITY IN TYPE 2 DIABETES: A DOSE-RESPONSE ASSOCIATION
Craig Currie, PhD (Cardiff University, Cardiff, UK)
Following his presentation on Day #5 of EASD on increased all-cause mortality seen with sulfonylureas compared to DPP-4 inhibitors (which you can read at http://www.closeconcerns.com/knowledgebase/r/a436c2c2), Dr. Craig Currie presented results of another study from his series of retrospective database studies drawn from the UK Clinical Practice Research Datalink (CPRD) showing an increased risk of all-cause mortality and other endpoints with high-dose insulin use. Dr. Currie began by noting that there has been longstanding uncertainty over the safety profile of insulins, citing an editorial published in Lancet this past June (Nolan et al., Lancet 2013). He discussed potential pathological mechanisms that could explain insulin’s hypothetical risk, including weight gain, hypoglycemia, dysrhythmia, and increases in insulin resistance. His group hypothesized that, if there was in fact an increased risk of death or adverse events with insulin, they would see a dose-dependent increase in such outcomes. They mined the CPRD (which covers over 10 million UK patients) for type 2 diabetes patients who had initiated insulin treatment between 2000 and 2012 (n=8,414), and used a Cox model to examine the effect of dosage on all-cause mortality, MACE, cancer, and a composite endpoint of all three factors. They found a dose-dependent increase in risk of all-cause mortality and the composite endpoint with insulin treatment; patients on a high daily dose (>1.5 U/kg/day) had an adjusted hazard ratio of 2.15 for all-cause mortality compared with the low daily dose group (<0.5 U/kg/day). A subgroup analysis showed that the risk was highest in patients with low baseline A1c and advanced age. MACE and cancer also showed borderline-significant increases at higher insulin doses. Interestingly, patients on combination therapy with insulin and metformin had only half the risk of all-cause mortality as those patients on insulin alone. Overall, we find it hard to put much stock in these results. Dr. Currie himself noted that indication bias could have affected the results — the decision to put a patient on a higher insulin dose likely reflected more poorly controlled diabetes, which in turn could indicate a higher risk of complications. Furthermore, the study lumped all forms of insulin together, which we feel may be an over-generalization of a heterogeneous class of drugs. Lastly, the limitations of retrospective database studies are well-known — they cannot be seen as more than hypothesis-generating, especially when we have data on the safety profile of insulin from large, prospective randomized control trials such as ORIGIN.
Questions and Answers
Q: Is it better to use less insulin or more metformin?
A: Both. I’m not a physician, I’m an epidemiologist. There’s clearly quite a complex issue here. Insulin isn’t necessarily safe in type 2 diabetes, and now the randomized trial guys have got to sort this out once and for all.
Q: I saw you had a few sub-analyses but I never saw renal function. We usually don’t put patients with renal failure on metformin, so that could be a major confounder, and that could be why ORIGIN didn’t see an increased risk.
A: We did look at that, but there was no change in risk for patients with renal problems.
Q: Which insulin was used in the study, human or analog?
A: This was a population data, so it’s a mixed bag of everything that was used in the past ten years.
NEW INSULIN GLARGINE FORMULATION: GLUCOSE CONTROL AND HYPOGLYCAEMIA IN PEOPLE WITH TYPE 2 DIABETES USING BASAL AND MEALTIME INSULIN (EDITION I)
Matthew Riddle, MD (Oregon Health and Science University, Portland, OR)
Dr. Matthew Riddle presented the results of EDITION I, a six-month phase 3a study comparing the efficacy and safety of a new long-acting U-300 (300 U/ml) insulin glargine formulation to U-100 insulin glargine (100 U/ml) in very obese patients with type 2 diabetes (BMI: 37 kg/m2, baseline A1c: 8.2%). The data was first presented at ADA 2013 as a late-breaking poster (43-LB). Following six months of treatment, U-300 was non-inferior to U-100 in A1c-lowering efficacy (both groups dropped A1c by an average of 0.8% from baseline). However, patients receiving U-300 showed a significant 21% reduction in severe/nocturnal confirmed hypoglycemia from month three to month six (36% with U-300 vs. 46% with U-100; p=0.004). Furthermore, the occurrence of any hypoglycemic event was numerically lower, but not statistically significant, in patients receiving U-300 vs. U-100. The U-300 arm required a 10% higher insulin dose by the end of the trial (0.97 U/kg vs. 0.88 U/kg). Weight change were similar in both study arms: a gain of 0.9 kg. There were no differences in safety or adverse events between U-300 and U-100. We look forward to seeing results from other EDITION studies, which will test the new glargine in a variety other populations – topline results from EDITION III (n=800 type 2s on orals) and EDITION IV (n=500 type 1s) are expected in 2H13, and FDA submission is expected in 1H14.
Questions and Answers
Q: To what extent did this study deal with the massive obesity epidemic that one finds in the United States? What about much lower body weight patients? And from the economic perspective, can the company reduce the price of insulin?
A: On the economic one, I have no helpful information. We all hope insulins can be provided at reasonable cost. Regarding the first question, these were large patients with high doses, and we see them particularly in the US, but all over the world. We chose this study population in part because we know this is a growing problem, and we wanted to determine if the new insulin might have some clinical benefits. It does seem to, particularly for hypoglycemia. We will look at other populations in the EDITION program.
Q: Was there a cutoff for eGFR in the inclusion criteria?
A: There was. I cannot quote it, but they could not have renal failure. They had to have renal function at least adequate enough to permit metformin use.
Q: Patients were nearly morbidly obese people. Is there comparable data in lower BMI patients? What about those patients with a BMI of 30 kg/m2 or lower?
A: The other EDITION studies will look at different populations.
THE EFFECT OF EARLY INTENSIVE DIABETES TREATMENT ON LONG-TERM GLYCEMIC CONTROL IN NEWLY DIAGNOSED TYPE 2 DIABETES: MULTICENTRE RANDOMISED PARALLEL TRIAL
JT Woo, MD, PhD (Kyung Hee University Hospital, Seoul, South Korea)
This interesting study randomized patients to 12 weeks of early intensive insulin treatment (glargine and glulisine) or initial oral combination therapy (metformin and glimepiride). The 97 patients were newly diagnosed with type 2 diabetes, had a very high baseline A1c of 10%, and were followed over a two-year period (after the short-term 12-week intensive period, treatment switched to either diet/exercise [A1c <8%] or oral drug therapy [A1c>8%]). After early intensive treatment, A1c decreased significantly in both groups but was not statistically different: -3.3% (insulin) vs. -3.5% (orals). Throughout the 104 weeks of the follow-up period, both groups maintained an A1c around 7%, though those who had undergone intensive insulin treatment were more likely to be at an A1c <7%: 68%-89% vs. 41-65% with orals. The most notable data of the presentation was the comparison of diabetes remission rates (A1c <7% without medication) at 104 weeks – 46% of the intensive insulin therapy group had diabetes remission vs. just 18% of those in the orals group (p=0.02). This data seemed to confirm a number of previous studies out of Asia showing a benefit of short-term intensive insulin treatment. However, we thought some of the Q&A criticism was spot on regarding the study’s protocol – metformin plus sulfonylurea was likely under-treatment, as the baseline A1c was 10%. That said, we continue to be intrigued by the use of early insulin and hope to see a wider array of studies in the future.
- This trial took place at eight university hospitals in Korea in 97 patients newly diagnosed with type 2 diabetes (<1 year duration; baseline A1c: 10%). After screening, patients were randomized to 12 weeks of intensive insulin therapy (insulin glargine and glulisine) or combination oral drugs (glimepiride and metformin). Intensive treatment was stopped after 12 weeks if A1c <7% or total inulin requirement <10 units/day. Following the intensive period, patients underwent a short four-week period of lifestyle intervention. If A1c <8%, they continued on with lifestyle intervention. If A1c >8%, they went on “rescue drug therapy” (unspecified). Patients were followed up every one to three months for two years.
Questions and Answers
Q: I assume the remission rate at 12 weeks as very good predictor of long-term remission?
A: Yes.
Q: I think it was problematic to use glimepiride and metformin for patients with an A1c around 10%. The ADA/EASD suggest insulin in this situation. It was absolutely clear why you had a high failing rate in that group – they had a very high A1c. Starting from these very high levels, you should use three drugs as Dr. DeFronzo did.
A: I don’t think they were initially at a very high A1c level – it was about 10% at the time of diagnosis. As I mentioned before, they had no symptoms of hypoglycemia.
Q: Why did you do an oral glucose tolerance test during the study? Did you measure C-peptide levels or insulin levels?
A: Yes, we checked insulin sensitivity and secretion parameters. Insulin secretion dramatically increased from baseline, but there was no difference between the two groups. The one difference was in disposition index, which was much higher in the IIT group compared to the orals group. We’re analyzing this very finely to confirm this result.
Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
THE EFFICACY OF METFORMIN-BASED OAD IS NOT INFERIOR TO INSULIN GLARGINE IN NEWLY DIAGNOSED TYPE 2 DIABETES MELLITUS PATIENTS WITH SEVERE HYPERGLYCEMIA AFTER SHORT-TERM INTENSIVE INSULIN THERAPY
Shumin Yang, MD (Chongqing Medical University, Chongqing, China)
Dr. Shumin Yang presented the results of a study investigating the efficacy of metformin-based oral antidiabetic (OAD) therapy versus insulin glargine in newly diagnosed patients with type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy (IIT). After a 10-14 day run-in phase of IIT, participants in the trial were randomized to receive metformin-based OAD therapy (n=24 completers at 48 weeks) or insulin glargine (n=20) for 24 weeks, followed by a 24-week extension on metformin-based OAD therapy. To be included in the study, patients must have been newly diagnosed with type 2 diabetes, drug naïve, and had fasting plasma glucose above 11.1 mmol/l (200 mg/dl), or postprandial glucose above 16.7 mmol/l (300 mg/dl). Metformin was initiated at 425 mg BID, and titrated to a maximum of 2,500 mg/day. If patients failed to achieve a target fasting plasma glucose of 4.4-8.0 mmol/l (79-144 mg/dl), gliclazide or glimepiride was added. Insulin glargine was initiated at 6-8 U per night, and titrated every three days to achieve target. At baseline, there were no significant differences between treatment arms – participants had an average age of 56-58 years, BMI of 24 kg/m2, A1c of 11.7-11.8%, and fasting plasma glucose of 16-18 mmol/l (288-324 mg/dl) before IIT. Following IIT, OAD therapy showed similar efficacy in sustaining both fasting and postprandial glucose control as insulin glargine, as well as reductions in A1c over 24 weeks. From baseline, the insulinogenic index increased significantly in both groups, and HOMA-B also increased, suggesting that beta cell function improved in both groups. No differences in hypoglycemia were observed between arms, and there were no cases of severe hypoglycemia during the trial. OAD therapy lowered weight an average of ~1.2 kg (2.6 lbs), compared to a ~0.4 kg (0.9 lb) gain with insulin glargine treatment.
Questions and Answers
Comment: Somehow I feel that you received a mixed message from your very important trial, because you allowed patients in the oral treatment group to add sulfonylurea, which really is the cause of the increase in hypoglycemia and also potentially the reason weight changes were not significantly different.
Corporate Symposium: Basal Insulin Therapy — Combining to Target (Sponsored by Novo Nordisk)
SYNERGIES OF COMPLEMENTARY DRUGS
John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)
Dr. John Buse’s presentation, which focused on the combined use of basal insulins and GLP-1 agonists, was somewhat more narrow in scope than the ambitious talk title might have suggested but definitely worth attending. He began by providing broad background on the pathology of type 2 diabetes, beginning with Dr. Ralph DeFronzo’s study on the natural history of beta cell dysfunction, and subsequently covering the pleiotropic effects of basal insulin and GLP-1 agonists in type 2 diabetes patients. He characterized long-acting basal insulin as the most effective treatment option currently available for reducing fasting plasma glucose, and compared the magnitude of the advance from Sanofi’s Lantus (insulin glargine) to Tresiba (insulin degludec) to the previous leap from NPH to Lantus. Turning to the GLP-1 agonists, Dr. Buse remarked that the class is the most effective currently available tool for the reduction of postprandial glucose levels. He noted that Novo Nordisk’s Victoza (liraglutide) has generally proven to be more effective than the other GLP-1 agonists it has been compared to in clinical trials. Bringing the two halves of his presentation together, he expressed great enthusiasm about basal insulin/GLP-1 agonist co-therapies, stating that the combination could provide “unparalleled” efficacy in terms of both postprandial and fasting plasma glucose levels. He also noted that the combination would help mitigate the side effects seen with Tresiba monotherapy (hypoglycemia, weight gain) and Victoza monotherapy (nausea). For more background on Tresiba and its fixed-dose combinations
INSULIN-INCRETIN COMBINATION THERAPY
Stephen Gough, MD (University of Oxford, Oxford, UK)
Dr. Stephen Gough spoke on the subject of insulin/incretin co-therapies, focusing on Novo Nordisk’s IDegLira (a fixed-dose combination of the GLP-1 agonist Victoza [liraglutide] and the basal insulin Tresiba [insulin degludec]) – he suggested this product could have powerful antihyperglycemic effects and better safety profiles than other currently available therapies. He highlighted IDegLira’s simplicity — it is a once-daily injection that comes pre-mixed at a fixed dose. The majority of the presentation was given to an overview of the DUAL 1 study, which compared IDegLira to use of its individual constituent parts, Tresiba (insulin degludec) and Victoza (liraglutide) — for our coverage of the initial DUAL 1 presentation at this year’s ADA, see page four of our ADA 2013 Incretins Report at http://www.closeconcerns.com/knowledgebase/r/6001b62d. In the trial, over 80% of patients on IDegLira achieved an A1c target of <7.0% — Dr. Gough called the A1c levels in this treatment arm “some of the lowest we’ve seen.” Furthermore, IDegLira mitigated the side effects seen with Victoza monotherapy (nausea) and Tresiba monotherapy (hypoglycemia and weight gain). Despite his apparent strong belief in the potential of IDegLira, during Q&A Dr. Gough cautioned against the “knee-jerk response” of switching all type 2 diabetes patients to insulin/incretin therapy; rather, he recommended that providers view products like IDegLira within the scope of currently available treatment algorithms and continue to consider all options within the framework of individualized diabetes therapy.
PANEL DISCUSSION
Peter Kurtzhals, PhD (Novo Nordisk, Bagsvaerd, Denmark); Thomas Pieber, MD (University Hospital of Graz, Graz, Austria); Athena Philis-Tsimikas, MD (Scripps Health, La Jolla, CA); Luigi Meneghini, MD, MBA (University of Miami, Miami, FL); John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC); Stephen Bain, MD (Abertawe Bro Morgannwg University NHS Trust, Swansea, UK); Stephen Gough, MD (University of Oxford, Oxford, UK)
Q: What is the effect of warming the injection site or of exercise if you inject degludec into a limb.
Dr. Kurtzhals: That was not studied directly, but the absorption would be subject to factors like blood flow to the same extent as other injections. Changes in blood flow would likely affect absorptions, but no more than it would for other insulins.
fixed format.
Q: Does degludec’s flexible dosing translate to a better quality of life?
Dr. Meneghini: In theory it should, but remember that these are forced flexible dosing studies, in which we took patients and forced them to take the insulin at different times. Perhaps a good opportunity would be to give patients a free-flex option when they could take the dose whenever they wanted.
Dr. Pieber: Some patients want to sleep in and don’t want to have to wake up at six in the morning, and some patients may want to go out at night and not have to take their insulin then. So I think there will definitely be an improvement in quality of life.
Dr. Gough: I don’t think the trial setting is the best way to pick up quality of life issues. We will learn about those things in the real world setting.
Q: Would you consider administering GLP-1 agonists earlier, even in prediabetes?
Dr. Buse: The health economics of using metformin right now are hard to deny, but with more time and greater assurance on safety, I think these GLP-1 therapies will progressively be used earlier and earlier. I do hope that the obesity program, which includes patients with prediabetes in those trials, will give us some indication of the benefits in the prediabetic period.
Q: The issue around pancreatitis — what is the current status of that debate regarding DPP-4 inhibitors and GLP-1 agonists? I’m afraid people are still talking about the Butler paper.
Dr. Buse: The way I would characterize it – there are now more opinion pieces on the issue than actual data studies – but if you look carefully at the data studies that do exist, the stronger the study design, the lesser the risk demonstrated for pancreatitis. But right now we cannot exclude the possibility of a slight increased risk of pancreatitis with these agents. Regarding pancreatic cancer, we can look at the current data from autopsy studies and animal models as hypothesis-generating, but there is not a shred of clinical evidence. Getting a definitive answer will take time. For now, if there is a risk (and there may be no risk), it is quite small and over intermediate periods of time.
Q: Are you encouraged by the results from SAVOR and EXAMINE, which showed no signal of pancreatitis, albeit up to only two years?
Dr. Buse: That’s the problem – we don’t have any five-year studies yet. For now, the safety looks good over at least two years.
Dr. Bain: For drugs in the incretin class, it is safe to say that we will have more safety data than we have ever had on most other classes.
Dr. Meneghini: I have been using these agents since 2005, and I have yet to see a case of pancreatitis or pancreatic cancer. I wouldn’t use them in patients that have pancreatic disease, but overall I’m pretty confident in their safety.
Dr. Philis-Tsimikas: I have one concern, that when topics like this reach the media like this one has, that even if you acquire data afterwards confirming the drugs’ safety, it is hard to overcome the huge media surge. I wish we could moderate some of the media pieces, although I know that cannot be done.
Dr. Buse: Recognize that we are going to have a lot of data in a couple years. LEADER will tell us about many thousands of patients over five years. We’ll have long term studies conducted on GLP-1 agonists and DPP-4 inhibitors. We’ll begin to understand the 5 year timeline in the coming few years, and the 10 year timeline in the next decade.
Q: What is the clinical paradigm for how we could use insulin/incretin therapy?
Dr. Gough: I think that it is important to follow existing guidelines, such as the ones released by ADA and EASD. I think there is a knee-jerk response to say that everyone should go onto insulin/incretin therapy, but I think we should still prescribe on an individual basis.
Corporate Symposium: Pathophysiology and Glycemic Control in T2D: Focusing on the Underlying Defect to Improve Treatment Outcomes (Sponsored by Sanofi)
BASAL INSULIN THERAPY: TIMELY INITIATION AND EFFECTIVE MANAGEMENT
Matthew Riddle, MD (Oregon Health Sciences University, Portland, OR)
Dr. Matthew Riddle discussed the rationale for timely initiation of basal insulin, noting that: 1) the treat-to-target concept can safely be used in clinical practice; 2) basal hyperglycemia is the main problem when oral anti-diabetics fail (Riddle et al., Diabetes Care 2011); 3) timely initiation of basal insulin is especially effective; 4) the risk of hypoglycemia can be further reduced; and 5) further intensification is possible for many patients. With regards to titration, Dr. Riddle commented that there is no single scheme that works better than any other; he emphasized that what is most important is to involve the patient early on in treatment decisions so they can better self manage their diabetes going forward. As for timely initiation, Dr. Riddle noted that individuals with lower A1c have a higher likelihood of achieving an A1c ≤7%. In a pooled analysis (n=2,193), ~56% of individuals with a baseline A1c of 8% and ~75% of those with a baseline A1c of 7.5-7.6% achieved an A1c of ≤7% over six months (Riddle et al., DOM 2013). Dr. Riddle highlighted that the risk of hypoglycemia with insulin glargine is already relatively low (~2%), but this risk can be further reduced with better patient education and new insulins. Specifically, he pointed out that both insulin degludec and Gla-300 (a new, higher concentration of insulin glargine) had reductions in hypoglycemia versus insulin glargine (Zinman et al., Diabetes Care 2012; Riddle et al., ADA 2013). He emphasized basal insulin as a platform from which further intensification is possible – with basal/bolus therapy, prandial insulin with the main meal, or the addition of a short-to-intermediate-acting GLP-1 agonist. In closing, Dr. Riddle stated that basal insulin can be part of a lifetime strategy of timely intensification of therapy, and that we should consider a “treat-to-defend-the-ceiling approach” in which an A1c of 7% is the upper limit.
4. Cardiovascular and Other Major Outcomes Trials
Oral Presentations: Clinical Interventions and Cardiovascular Outcomes
BASELINE CHARACTERISTICS OF PARTICIPANTS ENROLLED IN THE CARDIOVASCULAR OUTCOME STUDY OF LINAGLIPTIN VERSUS GLIMEPIRIDE IN EARLY TYPE 2 DIABETES (CAROLINA)
Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)
Dr. Julio Rosenstock spoke on the ongoing CAROLINA cardiovascular outcome trial for BI/Lilly’s Tradjenta (linagliptin), which he discussed recently during a Sanofi symposium on cardiovascular considerations in diabetes — read our coverage of his full talk on CVOTs on page 4 of our EASD 2013 Day #1 Report at http://closeconcerns.us1.list-manage1.com/track/click?u=8855a320a24ebfbc0280ac3e1&id=5479bdd23f&e=7af8859490. Dr. Rosenstock spoke favorably about CVOTs during his introduction, stating that the current FDA regulatory approval process provides the opportunity to better assess long-term efficacy, durability, and safety of new agents. After discussing the design of the study (n=6,103, event-driven, with a glimepiride comparator group and estimated run time of six to seven years), he highlighted the exceptional differences between CAROLINA and other CVOTs for DPP-4 inhibitors, especially SAVOR-TIMI 53 (for BMS/AZ’s Onglyza [saxagliptin]) and EXAMINE (for Takeda’s Nesina [alogliptin]. The most important difference he outlined was that CAROLINA was the only trial of the three to use an active comparator, which (in his mind) makes for a more fair comparison. He also noted that the patients in CAROLINA have earlier-stage diabetes than the populations in SAVOR and EXAMINE (average baseline A1c of 7.2% in CAROLINA compared to 8.0% in SAVOR and EXAMINE). He noted that this demographic difference may give CAROLINA a better chance to demonstrate CV safety and perhaps even cardioprotection.
- As background for his presentation, Dr. Rosenstock briefly discussed the need for more cardiovascular outcomes data for specific diabetes therapies. He stated that the current FDA regulatory approval requirements provide an excellent opportunity to better assess the long-term efficacy, durability, and safety of new agents. While FDA-mandated cardiovascular outcomes trials (CVOTs) will help provide that information for more recently developed pharmacotherapies, Dr. Rosenstock mentioned that we lack convincing data on the safety profile of sulfonylureas (SFUs), a much older drug class.
- The CAROLINA CVOT, currently ongoing, is investigating the cardiovascular safety profile of linagliptin compared to that of glimepiride. The study will follow approximately 6,000 patients until 631 documented cardiovascular events occur; Dr. Rosenstock estimated that this will take approximately six to seven years total, but acknowledged that an extension is possible if the event rate is lower than expected. CAROLINA’s enrolled patients had a mean type 2 diabetes duration of six years at baseline; only 35% had established CV disease, and most were on at least one therapy for cardiovascular risk reduction. According to Dr. Rosenstock, the study is appropriately powered to demonstrate non-inferiority and (possibly) superiority.
- Dr. Rosenstock highlighted the exceptional characteristics of CAROLINA, especially the ways in which it differs from other DPP-4 inhibitor CVOTs. CAROLINA is the only CVOT for a major DPP-4 inhibitor that includes an active comparator group. Dr. Rosenstock dedicated a slide of his presentation to an in-depth comparison of CAROLINA with SAVOR-TIMI 53 (the CVOT for BMS/AZ’s Onglyza) and EXAMINE (the CVOT for Takeda’s Nesina). CAROLINA generally enrolled patients with less advanced diabetes (roughly six years since diagnosis, on average) compared to SAVOR and EXAMINE (whose patients averaged 12 and seven years since diagnosis, respectively). The average A1c of CAROLINA patients at baseline was 7.2%, compared to 8.0% in the other two trials. CAROLINA is also the only one of the three studies which did not enroll any patients on insulin therapy. Dr. Rosenstock commented that CAROLINA’s slightly healthier patient population make it more likely to demonstrate a cardioprotective effect than other DPP-4 inhibitor CVOTs.
Questions and Answers
Q: So one thing that strikes me is your prediction of a 2%-per-annum MACE rate in the comparator group, which is pretty high given the profile of your patients. If your study ends up being underpowered, or if your MACE rate estimate was too optimistic, what does that do to your chances of demonstrating non-inferiority?
A: You’re right that patients that don’t have cardiovascular risk factors will have a lower event rate, but that will be balanced out by patients who have established cardiovascular disease who will have a higher event rate of 2% to 3% per year. We’ve put a lot of thought into that estimate, and based on what we’ve seen in previous studies, I think that if anything our event rate expectation is conservative, but your concern is valid. Another important thing is that this is an event-driven trial – we will sit and wait until we get a certain number of events, which could possibly require an extension of the trial if the event rate is low.
Q: Why did you choose glimepiride as the comparator?
A: We want to have the most fair trial we can get, so we wouldn’t choose the worst sulfonylurea – we want the one that is the most widely used, the one that is most widely accepted, the one that gives you less hypoglycemia. We’re not going to force the study in one direction to benefit linagliptin.
Q: Since you have no placebo control, how would you discriminate whether you are doing better with the DPP-4 inhibitor or sulfonylurea?
A: We’re getting an opportunity to examine the natural history of diabetes. The ideal, you’re right, would have been to have three arms, including a placebo control. In CARMELINA, we’ll be comparing linagliptin versus placebo, due to regulatory requirements. However, I think CAROLINA is a more scientifically correct study.
LIRAGLUTIDE EFFECT AND ACTION IN DIABETES: EVALUATION OF CARDIOVASCULAR OUTCOME AND RESULTS (LEADER) TRIAL DESIGN AND METHODS
Steven Marso, MD (Saint Luke’s Health System, Kansas City, MO)
Dr. Stephen Marso provided an overview of the design, methods, and baseline characteristics of the LEADER trial, the cardiovascular outcomes trial for liraglutide (Novo Nordisk’s Victoza). In the trial, patients have been randomized to liraglutide 0.6-1.8 mg or placebo in addition to standard of care, with anticipated treatment duration of 3.5-5 years. The primary endpoint will be time from randomization to the first occurrence of the composite cardiovascular outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Dr. Marso highlighted that a wide array of secondary endpoints will be measured, including an expanded composite cardiovascular outcome, death, acute coronary syndrome, cerebrovascular events, heart failure, coronary revascularization, nephropathy, retinopathy, pancreatitis, neoplasms, and thyroid disease. In terms of study design, all participants had a two-week-plus placebo run-in period to demonstrate that they could have at least 50% adherence to the regimen and the willingness to continue with the injection protocol for the duration of the trial. Study investigators estimate that the primary event rate would be 1.8% in both arms, and that up to 10% of patients would permanently stop treatment. Based on these assumptions, they calculated they would need a minimum of 8,754 subjects with a minimum follow-up of 42 months after randomization of the last subject to test non-inferiority of liraglutide versus placebo, and superiority (only if non-inferiority is met).
- LEADER includes patients in two cardiovascular risk cohorts: those with prior cardiovascular disease (CVD), and those without CVD. Those in the prior CVD cohort were ≥50 years of age at enrollment, and have at least one of the following: cardiovascular disease, cerebrovascular disease, peripheral vascular disease, chronic renal failure, or heart failure. Those in the no prior CVD cohort were ≥60 years of age at enrollment, and have at least one of the following: microalbuminuria or macroalbuminuria, hypertension and left ventricular hypertrophy by ECG or imaging, left ventricular systolic or diastolic dysfunction by imaging, or an ankle-brachial index <0.9.
- Of the 9,340 patients randomized, 7,592 (81%) have prior CVD, and 1,748 (19%) did not have prior CVD. At baseline, participants had an average age of 65 years, BMI of 32.5 kg/m2, A1c of 8.7%, and diabetes duration of 12.7 years. In terms of existing therapy: 5% were treatment naïve; 21%, 29%, and 4% were taking one, two, and three oral antidiabetics (OAD), respectively; and 42% were prior insulin users. Approximately 90% had hypertension, 77% had dyslipidemia, 57% had coronary artery disease, 17% had congestive heart failure, 18% had peripheral vascular disease, and 2% had eGFR <30 ml/min/1.73 m2 at baseline.
Questions and Answers
Q: Do you think the distribution of eGFR in your achieved sample of study entrants is typical of the background population with type 2 diabetes, given that 80% of them have cardiovascular disease? Or do you think you’ve managed to oversample people with worse renal function in this trial?
A: When the trial started, we thought we would need to oversample those with an eGFR of less than 30, but we didn’t have to oversample. We fell just short of the intended target of around 200. The short answer is that the profile of those with low eGFR is similar to the background CV risk of patients we enrolled; I don’t believe we overscreened or oversampled to get enough patients with eGFR less than 30. As background, the FDA recommended enrolling patients with eGFR less than 30, so the point was to oversample that population.
Q: Could you say something about the dosage estimate of insulin and rescue therapy you have? You have quite a high A1c to start with, so I could imagine there needing to be some handling of high glucose levels when injecting placebo for four years.
A: Being one of two cardiologists on the steering committee, my fear was that people would have a hard time injecting placebo for five years. The operational approach to the trial is a rather pragmatic one, as a global clinical trial. The way diabetes is managed around the globe is quite different. Our recommendations for rescue therapy and insulin treatment are highly regionalized, so we try to follow national guidelines and standards.
Q: Could you comment on your power calculations, and what your assumptions were with the withdrawal rate?
A: The initial assumption was that we would have less than 10% permanent dropouts. I think the trial is meeting or exceeding those expectations. We estimated an event rate of 1.8%. Given the high-risk nature of the population, prior epidemiological data, and prior studies, I suspect it will be higher than that.
Oral Presentations: Biomarkers and Risk Scores, Out with the Old, In with the New?
INVESTIGATING THE VALIDITY OF THE UKPDS OUTCOMES EQUATIONS IN CURRENT CLINICAL PRACTICE
Phil McEwan, PhD (Swansea University, Swansea, United Kingdom)
Dr. Phil McEwan discussed the results of a study that recalibrated the UKPDS 68 risk equations to contemporary UK patient data and investigated the implications of using such recalibrated equations in health-economic evaluation. In the study, Dr. McEwan and colleagues used retrospective UK cohort data extracted from The Health Improvement Network (THIN) database, which includes ~6% of the UK population. Using this data, he and his team recalibrated risk equations from UKPDS 68 for myocardial infarction (MI), congestive heart failure (CHF), ischemic heart disease (IHD), stroke, end-stage renal disease (ESRD), blindness, and amputations. These equations were calibrated to two cohort profiles – a low-risk cohort (n=54,169; newly diagnosed type 2 diabetes, ages 25-65, BMI <45 kg/m2, no diagnosis of cancer), and an intermediate-risk cohort (n=68,990; at least 55 years of age with one cardiovascular risk factor in the year prior to their index date, diabetes duration of at least 10 years, age of 65 years or older, or A1c ≥7.5%). Comparing the original UKPDS 68 risk equations with the new THIN-calibrated equations, the UKPDS 68 risk equations appeared to significantly overestimate the risk of MI, and underestimated the risk of CHF, IHD, ESRD, and amputations. Applying both the UKPDS 68 and THIN-calibrated risk equations to a health-economic model, Dr. McEwan concluded that economic evaluations utilizing the UKPDS 68 risk equations are robust, and can be calibrated for specific groups.
Questions and Answers
Q: I was a statistician who worked on the UKPDS study. One thing that is very different is the care of the patients. I am not surprised that the rate of amputation is lower, because patients were seen every three to four months, and had their feet looked at by someone trained to look at feet problems. As such, they were much less likely to have had ulcers which progress. Some of these things might be explained by differences in clinical care.
A: That’s a great point. I think it’s helpful to try to provide insight into how much of a difference it’s likely to make.
Symposium: DPP-4 Inhibitors and CVD
RESULTS FROM EXAMINE
William White, MD (University of Connecticut, Farmington, CT) and Simon Heller, MD (University of Sheffield, Sheffield, United Kingdom)
Dr. William White and Dr. Simon Heller presented results from EXAMINE, the cardiovascular outcomes trial for alogliptin (Takeda’s Nesina). The main findings from the study were initially presented at the European Society of Cardiology’s annual conference earlier this month – see our ESC 2013 Day #1 Report at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for our full coverage. In light of SAVOR’s finding that saxagliptin increased hospitalization for heart failure, EXAMINE investigators performed a post-hoc analysis of heart failure hospitalization in EXAMINE, which did not pre-specify hospitalization for heart failure as an endpoint (the pre-specified heart failure endpoint in was a composite of CV death plus hospitalization for heart failure, which EXAMINE investigators have noted is the standard in heart failure trials). EXAMINE’s pre-specified CV mortality and hospitalization for heart failure analysis found that the HR was 0.98 (95% CI: 0.82-1.21) with alogliptin treatment. The new post-hoc analysis showed that the HR for hospitalization for heart failure alone was 1.19 (95% CI: 0.90-1.58), while CV mortality alone was 0.84 (0.64-1.10). Although the hospitalization for heart failure result was not statistically significant, it trends in the same direction of SAVOR’s result.
Questions and Answers
Q: I have some problems with the numbers on heart failure. In Table 1 in the publication on September 2nd, you state that 28% of all patients in EXAMINE had preexisting congestive heart failure, amounting to some 750 patients with heart failure in each arm. Now you report a history of heart failure only in 400-some patients in each arm. Did you change the definition for this new analysis?
Dr. White: The number in the paper was at the time of randomization, so that could have included post-ACS heart failure. What we are reporting now is before the primary ACS event. That’s why the numbers are higher in the paper. We thought that from the standpoint of evaluating morbidity, it made more sense.
Q: Did you do a post hoc exploratory analysis to look at patients using sulfonylurea?
Dr. White: We did a subgroup analysis looking at those who were taking or not taking sulfonylurea, and there was no heterogeneity.
Q: Did you look at microalbuminuria between groups?
Dr. Heller: We did not measure microalbuminuria.
Comment: The only concern I have is with pancreatitis. I don’t think it’s appropriate to do statistics when you have 12 and five cases. The only thing we can say is that there is an imbalance, consistent with the concerns we have had. It is an imbalance that we need to take into consideration.
Dr. Heller: Alternative etiologies seemed to explain some of those cases. I agree that the numbers are small, but I think we could still conclude that these events were relatively unusual, which is reassuring, and that’s probably as far as we can go.
Q: Were investigators allowed to combine multiple medications, including insulin, on top of alogliptin? If so, why is it that such a low percentage of patients achieve an A1c of less than 7%?
Dr. Heller: The investigators were free to use whatever antidiabetic medications they so chose, and medications increased more in the placebo group, but you’re right, they didn’t match the A1c levels in both groups. I can’t speak for many investigators around the world, but clearly it is an issue, of inertia I presume.
Q: Do you think the percentage of patients who achieved an A1c of less than 7% may have affected the outcome?
Dr. Heller: Of course it’s worth remembering that the patients in the trial were at very high risk. Other intensive control trials suggest very aggressive and low A1c may have adverse consequences, so I’m sure that would be in the investigators’ minds when trying to improve A1c in this group. We don’t have data to conclude whether this affected the outcome.
SAXAGLIPTIN AND CARDIOVASCULAR OUTCOMES IN PATIENTS WITH TYPE 2 DIABETES
Deepak Bhatt, MD (Harvard University, Cambridge, MA)
Dr. Deepak Bhatt took the stage to present the main results of the SAVOR-TIMI 53 trial, which investigated the cardiovascular effects of BMS/AZ’s DPP-4 inhibitor Onglyza (saxagliptin). This data was first presented at the European Society of Cardiology’s annual conference earlier this month along with the results of EXAMINE — see our ESC 2013 Day #1 Report at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for our full coverage of those presentations. The investigators designed a trial powerful enough to potentially demonstrate cardiovascular superiority, given that earlier studies had hinted at a slight cardioprotective effect. However, after two years of treatment, saxagliptin showed no significant effect on the composite primary composite outcome of cardiovascular death, myocardial infarction, and ischemic stroke. The DPP-4 inhibitor led to a somewhat modest A1c improvement of 0.5% (0.3% placebo-adjusted) from a baseline of 8%, although Dr. Bhatt noted that the modest difference was largely due to the escalation of treatment in the placebo cohort. He mentioned that there was a statistically significant increase in hospitalization for heart failure (a much-discussed signal during the weeks since ESC), but noted that the increase was relatively small in an absolute sense (0.7%), that it was not associated with an increase in mortality, and that most cases of hospitalizations were in patients with high levels of BNP (a protein associated with heart failure risk). No significant differences were seen between saxagliptin and placebo in subgroup analyses by age, baseline A1c, pre-existing CVD, or concomitant therapy, among other criteria. He ended by noting that further analyses of SAVOR data are ongoing, and will be presented at the American Heart Association’s annual conference on November 16-20 in Dallas.
A DIABETOLOGIST’S INTERPRETATION OF A CARDIOVASCULAR STUDY
Itamar Raz, MD (Hadassah Medical Center, Jerusalem, Israel)
Next, Dr. Itamar Raz discussed interesting secondary analyses of SAVOR-TIMI 53 data. In patients with A1c >7.0% at baseline, saxagliptin was significantly more effective at lowering A1c in patients also on metformin, insulin (alone or in combination), or sulfonylureas (the improvement was non-significant for saxagliptin monotherapy). Dr. Raz next provided an expanded analysis of patient renal function. Significantly more patients in the treatment arm progressed to a better category of renal function (defined by albumin/creatinine ratio) than in the control arm (11% vs. 9%), and significantly fewer patients from the treatment arm saw their renal function category worsen (13% vs. 16% with placebo), indicating that saxagliptin may prevent the deterioration of (or even improve) renal function. The first round of SAVOR data had shown that saxagliptin modestly but significantly increased the incidence of both minor and major hypoglycemia. The investigators conducted a thorough examination of hypoglycemia occurrence, and found that there was no risk increase for most patients, but a significant increase in patients on sulfonylureas (which are known to cause hypoglycemia) and/or those with a baseline A1c below 7%. Turning to pancreatitis, study adjudicators found 26 definite or possible acute pancreatitis events in the saxagliptin group compared to 25 in the placebo group (17 vs. nine cases of “definite pancreatitis”). However, the mean event duration was shorter in the saxagliptin group, and patients continued with saxagliptin treatment in 60% of cases. A scatterplot of the data shows that there was no temporal clustering of cases, as would be expected if the drug was directly causing pancreatitis.
- Dr. Raz began by presenting more detailed data on saxagliptin’s glycemic efficacy. Significantly fewer patients on the drug received new or increased doses of other diabetes drugs during the trial than in the placebo group, regardless of baseline A1c. Next, we saw data on the mean change in A1c segmented by concomitant therapy — patients on saxagliptin combination therapy with metformin, insulin, or sulfonylurea saw significantly greater drops in A1c than saxagliptin placebo patients on the same concomitant antidiabetic drugs. The difference in A1c change between the saxagliptin and placebo cohorts was not significant but trended towards an effect. Notably, this combination therapy analysis was limited to patients with baseline A1cs above 7% — we imagine that the investigators used this cutoff because patients with lower baseline A1c likely had smaller change, making it difficult to demonstrate statistical significance.
- Saxagliptin had a modest but statistically significant beneficial effect on renal function. Prior to the trial, the investigators pre-determined a series of categories based on albumin/creatinine ratio (<30, 30-300, and >300 mg/G). Patients underwent urinary albumin excretion tests yearly and at the end of the trial. Only 13% of patients in the saxagliptin arm shifted to a worse category, compared to 16% of the placebo group (p<0.001). Around 11% of saxagliptin patients saw an improvement in their renal function category, compared to 9% of placebo patients (p<0.001).
- The SAVOR study group conducted in in-depth analysis of hypoglycemia, perhaps in response to the finding of a significant increase in both mild and severe hypoglycemia in the saxagliptin arm. The study used a fairly broad definition of minor hypoglycemia: in addition to glucose measurements below 54 mg/dl, the definition included episodes with symptoms that were resolved after carbohydrate consumption with no blood glucose data. Severe hypoglycemia was defined as any event that required the assistance of another person (regardless of blood glucose). This analysis demonstrated that saxagliptin did not have a significant impact on overall hypoglycemia unless the patient was on sulfonylureas, or if they had a baseline A1c below 7% and were on combination therapy involving insulin. The only significant increase in major hypoglycemia was in saxagliptin patients who were treated with sulfonylureas and had a baseline A1c below 7%. This analysis should somewhat assuage fears about the early hypoglycemia data, as sulfonylureas’ impact on hypoglycemia is well known, and most patients with low baseline A1c had less of margin of error during treatment.
- Dr. Raz concluded by presenting a more in-depth analysis of the pancreatitis seen during SAVOR. As with some other incretin safety trials, the overall incidence of pancreatitis was low (making statistically significant differences unlikely) but there was a slight numerical imbalance. Adjudicators found 24 cases of any pancreatitis event and 17 cases of definite pancreatitis (compared to 21 and nine cases in the placebo group, respectively). However, Dr. Raz noted that the mean duration of pancreatitis cases was far less in the saxagliptin group compared to the placebo group (14 and 44 days, respectively), and that 60% of pancreatitis patients in the treatment arm continued uninterrupted on saxagliptin, suggesting that patients and providers did not see the drug as a causal factor. Dr. Raz also displayed a scatterplot of pancreatitis cases graphed against time (cases were fairly evenly distributed along the entire study time course) — he argued that if saxagliptin was causing pancreatitis, cases would be clustered towards the beginning of the trial. While this study was neither large nor long enough to definitely disprove the possibility of a pancreatitis effect, we found Dr. Raz’s arguments in this section convincing.
Questions and Answers
Q: Regarding the hypoglycemia you saw in the group on sulfonylurea with low A1c, could that have been a protocol problem?
A: As you saw, we recruited patients with A1cs below 6.5% — they comprised 8% of our patient total. We discussed the issue, and at the end of day we decided not to change the protocol. But this is something that will be discussed.
Q: Did most of the hypoglycemia cases happen early in the trial?
A: That is a good question – I don’t have the answer yet. Most probably happened during the earlier stages of the trial.
Q: I have a question about the increase in hospitalization for heart failure. The background treatment was different than in EXAMINE: fewer patients were on beta blockers and ACE inhibitors. Did you analyze the data by baseline cardiovascular medications? Also, did you see if there was an increase in BNP with sitagliptin compared to placebo?
A: We do have BNP data, more specifically pro-BNP levels, since BNP can be affected by DPP-4 inhibitors. We hope to have that data analyzed by AHA. It is important to keep in mind that the overall hazard ratio for the secondary endpoints was 1.02, so no sign of harm. The p-value for hospitalization was significant, but it is hard to interpret the significance of one item like that when the overall hazard ratio is neutral. An analysis looking for differences in sub-characteristics, including cardiovascular medications, is being done. We showed the preliminary BNP data here because we were looking for the group at highest risk, but in terms of clinical descriptors, the biggest risk factor for the development of heart failure was previous heart failure, and that was true in both arms. EXAMINE did not find a significant excess in heart failure – I commend the investigators for doing a lot of analyses. It takes a lot of effort. There are two explanations I can think of: one is that finding in our trial in spurious; the other is that the same effect exists in EXAMINE but the trial was not powerful enough to pick it up, and that if it was as powerful as SAVOR, the finding would have been significant there as well. But overall the data is reassuring to some extent, as the hospitalization for heart failure was isolated and did not lead to an increase in other cardiovascular outcomes.
Q: Did you analyze whether the occurrence of hypoglycemia was in any way related to the occurrence of the primary cardiovascular endpoint?
A: We’re in the process of evaluating the relationship between hypoglycemia and the primary and secondary endpoints. It’s tricky to do those analyses though, because as previous analyses have shown, hypoglycemia is associated with a number of things, from cardiovascular death, to non-cardiovascular death, to cancer. What is necessary is to do time-dependent analyses, to examine the temporal relationships.
Q: Does the expertise of providers at the different sites have an effect in hypoglycemia – to be up-front, was there more hypoglycemia with cardiologists than with endocrinologists?
A: We don’t have the answer for that, as we didn’t do these analyses yet. One thing we can learn from SAVOR is that for patients who have A1c less than 7%, you shouldn’t add saxagliptin to a sulfonylurea. Most patients who had established cardiovascular disease came to us through cardiologists, and most of those people had an A1c between 7% and 8%. I believe we will find that most hypoglycemia was related to multiple risk factors.
COMMENTARY
Naveed Sattar, MD, PhD (University of Glasgow, Glasgow, UK)
Dr. Naveed Sattar ended the session with an energetic, no-holds-barred interpretation of SAVOR and EXAMINE results. He noted that the FDA’s new guidelines “force” study designs that may be less than ideal (i.e., they enroll higher risk patient populations to promote expediency), but that this is a reality of the times. He brought up the apparent paradox between the results of earlier DPP-4 inhibitor trials, which (when meta-analyzed) showed promise of a cardioprotective effect, and the results of SAVOR and EXAMINE, which were neutral. Dr. Sattar stated emphatically that we should not be surprised by this result, as A1c reductions as modest as those seen in SAVOR and EXAMINE (0.3 – 0.35%) couldn’t have an appreciable effect on cardiovascular risk in a mere two years. To be successful in such a time period, he argued that DPP-4 inhibitors would need to have pleiotropic effects on blood pressure or lipids. Overall, he argued, CV management is more effective when pursued through agents such as statins and blood pressure medications than through glucose lowering. In his view, statin use in SAVOR was suboptimal at 78%. He found the pancreatitis data from both trials reassuring, although he acknowledged that they are not enough to disprove a possible effect. The hypoglycemia results of SAVOR, in his mind, indicate that A1c targets should be relaxed in patients with cardiovascular disease. He found the reduction of progression to albuminuria seen with saxagliptin modest and generally unsurprising. He emphatically stated that the medical community must take the hospitalization signal in SAVOR seriously — given the similar but non-significant trend seen in EXAMINE, as well as data showing that the DPP-4 inhibitor Galvus (vildagliptin) had a slight effect on ventricular size, Dr. Sattar argued that we cannot rule out a class-wide effect.
Symposium: UKPDS: 15 Years on from Barcelona
HISTORICAL PERSPECTIVE
Rury Holman, FMedSci (University of Oxford, Oxford, UK)
Fifteen years after primary results from the UKPDS were first presented at EASD in Barcelona, Dr. Rury Holman regaled the audience with a historical perspective of the study, reviewing its conception, execution, and (early, primary, and post-trial) results. He began by giving thanks to everyone involved in the trial, in particular paying respect to his mentor Dr. Robert Turner, who conceived of the UKPDS (jotting down the basic design on the back of an envelope in 1976) and saw the study through to the end. Providing an interesting anecdote, Dr. Holman noted that Dr. Turner didn’t get everything right in his initial brainstorm – on his back-of-the-envelope calculations, he estimated the study to cost to be ~£37,000 per year (which would have cost just over a quarter million pounds over seven years), while the actual costs reached ~£23 million by 1998. After reviewing results from the UKPDS, Dr. Holman summarized key lessons: 1) the study confirmed beyond a doubt that better glucose control reduced the risk of microvascular complications for those with type 2 diabetes; 2) there was a borderline significant finding that better glucose control may reduce the risk of macrovascular complications, confirmed by subsequent UKPDS post-trial monitoring (“the legacy effect”); 3) sulfonylurea is as effective as insulin in the prevention of late complications and cardiovascular events, with no evidence of excess cardiovascular mortality as suggested by the UGDP; 4) primary randomization to metformin showed significant reductions in cardiovascular and all-cause mortality; and 5) antihypertensive treatment is highly effective in delaying progression of diabetic retinopathy and nephropathy.
GLOBAL IMPACT OF UKPDS FINDINGS
David Matthews, MD (Oxford Centre for Diabetes, Oxford, UK)
Dr. David Matthews took the stage to discuss the lasting impact of the UKPDS study on diabetes care. He noted that there are now 82 numbered UKPDS publications, which have garnered over 37,000 academic citations. In his view, the UKPDS was the first study to provide definitive evidence that improved glycemic control reduces complications. He directly addressed the controversy over the almost-but-not-quite statistically significant (p=0.052) 16% risk reduction for cardiovascular complications seen in the original study results. He felt that the finding was very noteworthy even though it fell slightly short of the p=0.05 boundary, and made the claim that the effect size was more important than the statistical significance (or lack thereof). Dr. Matthews reminded the audience that the UKPDS played a large role in establishing metformin’s primacy in type 2 diabetes treatment, and is the basis of many type 2 diabetes care guideline documents. UKPDS also changed the way the diabetology community thought of diabetes, largely by introducing the concept of ‘beta cell failure’ to replace the idea of treatment failure. Dr. Matthews touched upon the much-discussed UKPDS finding that metformin reduced patients’ risk for cardiovascular outcomes — the result was statistically significant, but weakened somewhat by the fact that there were only 342 patients in the metformin arm. “Because of the UKPDS,” he concluded, “millions of people will have better outcomes and better lives – that is impact.”
POST TRIAL MONITORING RESULT OF THE UKPDS SULFONYLUREA PLUS METFORMIN STUDY
Rury Holman, FMedSci (University of Oxford, Oxford, UK)
After describing the potential safety concerns of sulfonylurea (SFU) in combination with metformin brought to light in the initial findings of the UKPDS SFU+metformin sub-study, Dr. Rury Holman presented unpublished follow-up results, which alleviated such worries. In the initial sub-study, after a median seven years on SFU, participants in that arm were randomized to continue on SFU monotherapy (n=269), or to add metformin (n=268). After an additional median follow-up of 6.6 years, those on SFU+metformin had an increased rate of diabetes-related deaths (RR=1.96; 95% CI: 1.02-3.75; p=0.039) and all-cause mortality (RR=1.60; p=0.041) compared to those on SFU alone (Lancet 1998). Dr. Holman explained that these initial findings could have been anomalous for a number of reasons, including the fact that the major effect appeared to be fewer deaths in the SFU alone group, not more deaths with SFU+metformin. Looking at 10-year post-monitoring results, neither safety signal remained – with SFU+metformin therapy, the relative risk of diabetes-related deaths was 1.18 (95% CI: 0.82-1.69), and the relative risk of all-cause mortality was 1.24 (95% CI: 0.95-1.60). Dr. Holman stated that these post-trial results suggested “the evil play of chance” in the original sub-study, as the number of events evened out over time. Though he found these results to be comforting, he nonetheless advocated for further studies to better characterize SFU+metformin and other combination therapies.
- Dr. Holman provided an overview of the Glucose Lowering in Non-Diabetic Hyperglycemia Trial (GLINT), which will further investigate the use of metformin as first-line therapy. The UK-based multicenter cardiovascular primary prevention trial will include men and women ≥40 years of age with A1c ≥5.5% and <6.5% and 10-year Framingham risk of ≥20%. Participants will be randomized to metformin XR (1,500 mg/day) or placebo. The study’s primary endpoint will be time to the composite cardiovascular outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. In addition, cancer incidence will be examined as a secondary endpoint. In the five-year trial, a total of 11,834 patients will be enrolled (500 in the feasibility phase; the first patient and first visit will occur in September 2013).
Symposium: EASD/ADA Symposium: The DCCT/EDIC Study: 30 Years of Progress and Contributions
INTRODUCTION AND OVERVIEW
Bernard Zinman, MD (University of Toronto, Toronto, Canada)
Dr. Bernard Zinman provided a thorough overview of the design and results of the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC), highlighting the beneficial effects of intensive therapy on microvascular and neurologic complications. DCCT was designed to evaluate how intensive glycemic control can prevent or reduce the progress of long-term complications, measured mainly through the incidence of retinopathy. Dr. Zinman reviewed the results of the study, highlighting the 2% drop in A1c in the intensive arm. Turning to EDIC, Dr. Zinman highlighted the “metabolic memory” phenomenon that allowed patients in the intensive group to experience the continued benefit of risk reduction past the end of DCCT. Dr. Zinman specifically noted the importance of this data collection for evaluating cardiovascular outcomes, since patients with type 1 diabetes provide a “pure glucose model” for examining the role glycemia plays in CVD (implying that patients with type 2 diabetes are NOT a good model to test this hypothesis). Dr. Zinman expressed his continued gratitude to the participants of the study and emphasized the incredible 95% retention of the surviving participants. For more information on DCCT and EDIC, please see page 226 of our ADA 2013 full report at http://www.closeconcerns.com/knowledgebase/r/94f937d8.
- Dr. Zinman also reminded the audience that the difference in A1c levels between the two groups could explain over 96% of risk reduction for all complications in the intensive control group. These complications included: sustained 3-step progression, severe non-proliferative diabetic retinopathy (SNPDR), laser treatment, CSME, albumin excretion rate (AER) >39 mg per 24 hours, and AER >300 mg per 24 hours.
- DCCT had a massive impact on diabetes public health for diabetes. Dr. Zinman noted that after DCCT, intensive therapy was advocated as the standard of care for people with type 1 diabetes. Additionally, government and public health agencies advertised DCCT as a way to lower barriers to intensive control, and in many areas, insurance coverage of intensive therapy supplies became mandatory.
MICROVASCULAR UPDATE
William Tamborlane, MD (Yale University, New Haven, CT)
Dr. William Tamborlane gave the microvascular update from DCCT/EDIC, noting that the results have been “incredibly remarkable.” Indeed, the data was clear, consistent, and compelling for the three areas he covered: retinopathy, nephropathy, and neuropathy – it never got old to see slide after slide after slide demonstrating the benefits of intensive therapy on microvascular complications. Dr. Tamborlane’s summary said it all in a few bullet points: 1) intensive therapy reduces all microvascular disease substantially and consistently (it’s rare one can make such an absolute claim in medicine, though in this case, it’s justified!); 2) the benefits of intensive therapy are closely associated with reductions in A1c; 3) the early reduction in microvascular complications during the DCCT has translated to salutary effects on more advanced disease; and 4) metabolic memory applies to all microvascular complications. We note that his presentation condensed the three separate talks we saw in a similarly titled symposium at ADA 2013 – see pages 226-232 at http://www.closeconcerns.com/knowledgebase/r/94f937d8.
CARDIOVASCULAR UPDATE
Trevor Orchard, MD (University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA)
Dr. Trevor Orchard reviewed the cardiovascular benefits of the DCCT/EDIC trial and highlighted that the benefits of intensive glycemic control have only increased as EDIC continues. He emphasized the risk reduction for cardiovascular events that patients from the intensive control group experienced, such as the reduction in atherosclerosis and clinically important outcomes of cardiovascular death, myocardial infarction, or stroke (57% reduction after 11 years!). Dr. Orchard also noted that they are not done with the full mediation model, and they plan do finish after there are 100 cardiovascular deaths, likely within the next few years. Additionally, there is currently a manuscript in progress on the analysis of mortality from DCCT/EDIC, now that there have been 50 deaths – however, all the data is embargoed until publication. For more information on DCCT and the cardiovascular disease update, please see page 227 of our ADA 2013 full report at http://www.closeconcerns.com/knowledgebase/r/94f937d8.
THE FUTURE
Gayle Lorenzi, RN, CDE (UCSD, San Diego, CA)
Ms. Gayle Lorenzi closed the session with a look at what’s next in DCCT/EDIC. She highlighted areas of continued exploration/redefinition along with future ancillary studies of gastric emptying, C-peptide, and hearing impairment.
- Areas of continued exploration and redefinition include: metabolic memory; triopathy; evidence-based guidelines for the frequency of retinopathy and nephropathy screening; glycemic variability; non-glycemic risk factors and outcomes; cognitive function; and health economics.
- Ms. Lorenzi shared details on three future ancillary DCCT/EDIC studies: gastric emptying, residual C-peptide secretion, and hearing in long-standing type 1 diabetes.
- Gastric emptying: This pilot study will occur at seven EDIC centers and include 80 participants. A C-spirulina gastric emptying breath test will be administered. The study is tasked with answering two main questions: “What is the prevalence of disturbances in gastric emptying?” and “How do they impact glycemic control?” The results will determine whether to expand the investigation and evaluate the full cohort
- Residual C-peptide: In a pilot study presented at ADA 2013, researchers found demonstrable C-peptide in 17% of 58 DCCT/EDIC patients. This upcoming study will examine the full DCCT/EDIC cohort and perform mixed-meal tolerance tests and measured C-peptide using three ultrasensitive assays. Outcomes include A1c over time/insulin dose, hypoglycemia, mediators/risk factors, and long-term complications. The trial will also permit a comparison of the three ultrasensitive assays.
- Hearing impairment: A study will examine the incidence and impact of hearing impairment in the DCCT/EDIC cohort. Researchers will examine its relationship to glycemic control.
PANEL DISCUSSION
Bernard Zinman, MD (University of Toronto, Toronto, Canada); William Tamborlane, MD (Yale University, New Haven, CT); Trevor Orchard, MD (University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA); and Gayle Lorenzi, RN, CDE (UCSD, San Diego, CA)
Q: Because there is a scarcity of data on limited joint mobility, I was wondering if you acquired any data on that from your studies?
Ms. Lorenzi: We completed a study looking at limited shoulder mobility as well as joint problems and function limitations within hands and fingers. We presented results at the ADA meeting in June, and the publication is pending [Editor’s note: For more information, please see page 230 of our ADA 2013 Full Report at http://www.closeconcerns.com/knowledgebase/r/94f937d8]. What I will tell you is that it was an evaluation that got such an enthusiastic response from participants because we were giving a voice to what many had been experiencing over the course of time.
Q: Are you planning to study incidence of cancer?
Dr. Zinman: Obviously as the study population ages, they develop diseases associated with their age group. With 1,441 patients, there are not enough incidences of cancer to show differences. Nonetheless, we are characterizing cancers and outcomes the best we can. We are definitely looking at it, but we are not sure if what we see will be clinically relevant.
Q: I have a question concerning the rate of severe end-stage complications. Renal impairment was low in both the intensive group and the conventional group compared to the historical data that Dr. Zinman showed. I wondered what you thought about that in terms of metabolic memory – in the DCCT, participants’ A1c levels were 9% on average. You also didn’t mention blood pressure in your model for CVD. I was wondering if you tried to unpack these things at all.
A: The one slide I left out was the one that shows predictors of metabolic memory. Your baseline A1c levels at entry also indicated risks of developing complications. I think old data shows that some of these patients were under horrible control. The conventional control may have been better than the treatment 10 years previously, and having an A1c of 8% for years before the study may provide benefits. We were seeing hardly any retinopathy in the adolescent population (those older than 10 who had diabetes more than three years); their A1c levels were under 8% for decades.
Dr. Orchard: We were only controlling for baseline. We excluded with hypertension. I agree that hypertension is a major risk factor, and we discuss hypertension in a separate paper.
Comment: Is CVD related to incidence of hypertension?
Dr. Orchard: We are going to look at that, but we are going hold off until we have 100 cases.
Q: Do you have any data on continuing or not-continuing problems with hypoglycemia in the intensive group? Do they continue to have an excess of hypoglycemia in EDIC?
Dr. Zinman: No one in the study is going back to conventional treatment; the A1c targets achieved are just not nearly as low as they were for the intensive group in the DCCT. Disappointingly, I think there are still significant rates of hypoglycemia. They are less, but not significantly less.
Dr. Orchard: It is more apparent than real because we collect data annually and extrapolate for the year; there is a bias of ascertainment. The DCCT period up to EDIC is problematic, however, now the difference between two groups is all gone.
A: In the Type 1 Diabetes Exchange, A1c levels are a huge risk factor for severe hypoglycemia. For CGM trials and new analogs, we are certainly seeing that we are able to lower A1c without increasing the risk for hypoglycemia.
Symposium: Rising Star
THE CAMERA STUDY: INVESTIGATING THE EFFECTS OF METFORMIN IN NON-DIABETIC PATIENTS WITH CORONARY HEART DISEASE
David Preiss, MD (University of Glasgow, Glasgow, Scotland)
The CAMERA (Carotid Atherosclerosis: Metformin for Insulin Resistance) study was a randomized control trial investigating metformin use in patients without diabetes but with established coronary heart disease (n=173). The primary endpoint was change in progression in carotid intima-media thickness (IMT), while secondary endpoints included carotid plaque score progression and change in several metabolic parameters. Baseline characteristics were comparable across metformin and placebo groups, with an average age of 63.5 years and BMI of 30 kg/m2. Participants were drawn from an already high-risk population of individuals on stains for an average of 6.5 years. After 18 months, researchers found no effect on all measures of CV risk, including cIMT (p=0.29), carotid plaque (p=0.89), and cholesterol levels (both non-HDL and HDL). Significant changes were only observed in markers of diabetes risk, as weight, BMI, triglyceride, HOMA-IR and GGT levels were appreciably lowered. Such results verify the efficacy of metformin in reducing risk of progression to type 2 diabetes, though the drug’s potential to mitigate CV risk was not substantiated by this study.
- There are indications that metformin imparts CV benefit. This was suggested specifically by the overweight subset of UKPDS, in which those on metformin did markedly better in terms of CV outcomes than those on lifestyle modifications alone, and researchers speculated that this finding was independent of glycemic improvement.
Questions and Answers
Q: Is 18 months long enough to see an effect?
A: There should be longer and multi-center trials, but the majority of IMT studies have been 1-2 years long. That’s pretty typical for this type of study, so certainly we could speculate that if it was longer with more patients we could have showed some sort of benefit.
Q: What was the change in systolic blood pressure?
A: Essentially no change in metformin versus placebo.
Q: Given the weight loss you saw, and all these patients were obese, how would you characterize using metformin as a weight loss option?
A: We’ve had a bit of discussion of this. We have a safe, CV useful drug. Maybe we should consider using it in bigger numbers than we do now.
Corporate Symposium: Cardiovascular Disease and Impaired Renal Function: Is there a Role for GLP-1? (Sponsored by Novo Nordisk)
THE HISTORY OF CARDIOVASCULAR DISEASE TRIALS IN DIABETES AND OVERVIEW OF ONGOING TRIALS
Steven Nissen, MD (Cleveland Clinic, Cleveland, OH)
In front of an audience of several thousand people, Dr. Steven Nissen, the mastermind behind the FDA’s 2008 CV requirement for type 2 diabetes drugs, reviewed the history of cardiovascular trials in diabetes and emphasized the importance of characterizing drugs beyond their effects on glucose. He cited examples of when a gluco-centric view of diabetes failed to bring to light either positive or negative CV outcomes of a drug (e.g., negative effects of muraglitazar and rosiglitazone and positive CV effects of pioglitazone). This prompted him to recommend a procedure to the FDA that he thought represented a balanced way of bringing new drugs to market in a timely fashion while allowing us to be more informed about these drugs’ effects on clinically relevant outcomes. Notably, he remarked that the FDA’s implementation of the CV guidance has not always been “as thoughtful as we would like.” He was “completely puzzled” by the FDA’s recent decision to require a pre-approval CVOT for Novo Nordisk’s long-acting insulin analog Tresiba (insulin degludec), especially because the 2008 FDA Advisory Panel that convened to discuss the diabetes CV requirements explicitly exempted insulins from the requirement, and because and the Advisory Panel that convened to discuss Tresiba voted 8-4 to approve it. “If you torture the data enough,” he remarked, “eventually it will confess,” implying that the FDA had gone looking for trouble in the degludec submission package and eventually convinced themselves of a CV risk. Overall, we think Dr. Nissen was quite cardio-centric; during the presentation he downplayed the importance of glycemic control for the prevention of microvascular complications such as blindness, neuropathy, and kidney failure. On the other hand, he very rationally argued that it is in patients’ and prescribers’ best interests to gain as much knowledge about a drug’s effects as possible in a way that minimally delays bringing new therapies to market – if only the idea were so simple to implement in practice.
A ROLE FOR GLP-1 IN CARDIOPROTECTION?: EFFECTS ON CARDIOVASCULAR REMODELLING AND ACUTE MYOCARDIAL INFARCTION
Thomas Engstrøm, MD (Rigshospitalet, Copenhagen, Denmark)
Dr. Thomas Engstrøm presented compelling evidence of the possible cardioprotective effects of GLP-1 receptor agonists. His talk centered on the agent’s application in pharmacological conditioning, an experimental technique used to reduce reperfusion injury following an ischemic insult. Data indicate that the duration of occlusion determines the relative contributions of reperfusion and ischemic injury to the final myocardial damage. While preconditioning is an established means of modifying infarct size, recently postconditioning has also gained medical acclaim as a powerful means of attenuating myocardial damage. In fact, mechanical postconditioning, which uses balloon inflations and deflations, was shown to increase the salvage index by 32%. Turning to the possibility of pharmacological postconditioning, Dr. Engstrøm explored the use of GLP-1 analogs, which he believes acts as a cardioprotective ligand by stimulating the salvage pathway. When low concentrations of exenatide were administered to rats during the postconditioning process, infarct size was reduced by 42-50%. Repeating this experiment with a GLP-1 antagonist or inactive GLP-1 abolished the protective effect. Over the last five years, this finding has been reproduced in many species – in the human setting, the salvage index increased by 15% overall. Because no reflow [impeded blood flow to ischemic tissue after relieving the occlusion] is associated with poor clinical outcomes, GLP-1 analogs may be a promising candidate to protect against ischemia-reperfusion injury and limit infarct size.
- Postconditioning entails administering short episodes of ischemia during reperfusion, after a prolonged insult. The talk focused on the novel use of GLP-1 analogs in this technique, which Dr. Engstrøm differentiated from ischemic preconditioning. This latter procedure differs from postconditioning in that the myocardium is subjected to short periods of ischemia to build resistance to a subsequent insult.
- During ischemia, mitochondria explode from an influx of water through the mPTP pores, irreversibly killing the cell. GLP-analogs, which are resistant to DPP-4 degradation, stimulate the salvage pathway by keeping the mPTP pores in a closed state. Dr. Engstrøm proposed this as a mechanism of GLP-analog activity in postconditioning, though he mentioned that other plausible explanations also exist.
PANEL DISCUSSION
Moderator: Eduard Montanya, MD (University of Barcelona, Barcelona, Spain)
Panelists: Zachary Bloomgarden, MD (The Mount Sinai Hospital, New York, NY); Thomas Engstrøm, MD (University of Copenhagen, Copenhagen, Denmark); Steven Nissen, MD (Cleveland Clinic, Cleveland, Ohio); Jorge Plutzky, MD (Brigham and Women’s Hospital, Boston, MA)
Dr. Montanya: Steve, your presentation on SFUs was challenging. If a company were to request FDA approval now for a SFU, would they be approved?
Dr. Nissen: They would have to perform a two stage trial, first to rule out an upper confidence interval of 1.8, and then 1.3. Unless the SFU had a truly unique feature, I don't think any pharmaceutical company would spend the money to bring it to market because we have so many generic drugs. They would have to do an outcome trial, and I don’t know what result of that would be.
Dr. Montanya: How can you submit interim analysis of a cardiovascular trial without the risk of the FDA devaluating the remaining part of trial?
Dr. Nissen: Excellent question. What do you do when you have completed a trial to rule out the 1.8 but not the 1.3? We submitted a request that would require the FDA to hold confidential results of interim analysis until the full trial is completed. This went through a whole series of legal reviews. We went up and down the highest levels of the FDA, and the FDA has now developed this as a policy, so that if a new drug is brought to market and rules out 1.8 – and this I think would apply to insulin degludec – then that data can be submitted but it cannot be publically released because that would undermine the ultimate trial to rule out 1.3. The FDA has agreed to keep confidential interim results.
Dr. Montanya: What is the effect of weight reduction as provided by some of the GLP-1 agonists? When you think about the results of the Look AHEAD study, there was weight reduction but no impact on CV outcomes. What are your thoughts on the outcome on CV disease with weight reduction?
Dr. Plutzky: This is a very interesting issue. We need to think in a more integrated way about the relationship between adiposity and how it changes to caloric excess. Adiposity plays an important functional, physiological role. As we try to expand our fat depots, that’s where we see pathologic deposition of fat in pathologic locations, (visceral fat, liver, skeleton muscle). As patients begin to experience significant weight loss, you see a reversal of excess fat in those abnormal locations. You lose it first in visceral fat, the liver, and skeleton muscles, as opposed to subcutaneous fat. As a result, it’s reflecting shifts in how fatty acids are being handled. It also seems to reverse inflammatory pathways. Those will continue to hold up as we have more evidence for weight loss. Certainly the most gratifying thing in the clinic is how metabolic parameters improve with even modest weight loss. We remain hopeful that weight loss will help reverse some of the pathologic pathways.
Dr. Montanya: What about adverse events in elderly populations using liraglutide? You think they would benefit from adjustments such as a slow titration compared to the younger population or some differences in administration?
Dr. Bloomgarden: Slow titration is clearly appropriate for all individuals treated with liraglutide developing GI intolerance. That’s really the way we all use the drug clinically. We explain to them that they can stay at lower doses and adjust it, in consultation with us. We don’t see a substantially higher likelihood of adverse effects in this group, but we need to emphasize with them, like anyone else, the need to be in communication.
Dr. Montanya: The populations chosen for these cardiovascular outcome trials are those that are already at high risk. How can the trials be translated to the general population?
Dr. Nissen: It’s a huge problem. Companies want to study very high-risk patients so that they can get to 122 events quickly and get the drug on the market. But it is different population, and may be a population more resistant to seeing benefits. I would like to see some companies do longer trials in lower risk populations where there may be greater potential for benefit. The economics drive us to use high-risk populations because getting 620 events from low-risk groups could take a sample size of 20,000 or more, and that is costly and takes a long time. But looking at the legacy of UKPDS, I wonder if seven to eight year studies might be a way we would be able to better understand the potential to reduce CV outcomes.
Dr. Bloomgarden: A further caveat of the difficulty of undertaking this type of study: there was a study that looked at the prevalence of cardiovascular disease in healthy people with diabetes, and they came up with a shocking finding that the likelihood of CV disease, let alone events, was on the order of 0.6% of the populations, so that their hope to see evaluate noninvasive measures of CV disease failed utterly. What if we took a population of 3,000 people with an event rate of 0.6%? At one year, assuming those receiving and not receiving drug had the same number of events, it would be 18 in each group, if you look at the shape of the bell curve, it would exceed 1.8 by a little bit. So a drug that had absolutely no effect in a moderately large number of individuals would then be dinged as having a signal. These studies can only be undertaken by the government in collaboration with industry. I went though the numbers once – you would need 50,000 persons studied for a decade. As much as some people like to think that the pharmaceutical industry is guilty of trying to save all the money they can, we can’t ask the industry to undertake a study of that magnitude. Yet we have a world in which millions of people are developing diabetes and those studies are of critical importance.
Dr. Plutzky: There are a number of subtle clinical variables to consider. When do you begin your statin? Or did you initiate later? To what extent are these subtle variables, or other variables like degree of liver fat, inflammation, visceral fat, etc. coming into play and potentially changing results? We’re not yet able to separate patients that we assume are part of a homogenous population but may not be in terms of these slight variations.
Dr. Engstrøm: Some people think that we now have treatments that are so good with event rates that are so low that we can’t improve them anymore – we can do better. If you look at studies with big cohorts of patients, there are some subsets of populations that have high rates. We need to define those cohorts and be more aggressive in our development of drugs to treat those cohorts.
Dr. Montanya: Can we consider that there is a class effect between the different GLP-1 agonists? What are you thoughts on incretin therapies?
Dr. Plutzky: There are core aspects to their action, but we have to look at evidence to see if there are differences among the various insulin modulators. It’ll be challenging to assume that they’re the same. Some aspects will be similar among them, but we really need to look at signals in data to understand them.
Dr. Nissen: Every time we think we understand something, we get a surprise. When the TZDs were introduced, it seemed like they have similar glucose lowering effects. Why shouldn’t pioglitazone and rosiglitazone be similar? Looking beneath the surface we certainly saw lipid differences, but that’s a little bit of a different, more complex model. What I’ve learnt is that you can trust, but you must also verify. We may believe there is commonality, but we have to verify first. That’s why each of the GLP-1 analogs is doing a clinical trial. If they all show the same benefits, then six to seven years from now somebody can say I told you so, but until then I'm going to keep my eyes and ears open.
Dr. Montanya: Why are the potential dangers of insulin not taken into account? What is the basis for that?
Dr. Nissen: Endogenous human insulin is indistinguishable from that administered exogenously. Once has to argue that it’s the same molecule, same receptor, doing the same thing. When you change the root of delivery, all you change are the pharmacokinetics. With these subtle differences, there isn’t much of a reason to believe that they would have differences in outcomes. Insulin is insulin, and I would be shocked if we didn’t find that at the end of the day. If it is human insulin, it's the same drug given in different forms. If we want to go this route, where every new formulation undergoes a CV trial, I’m just not sure if that’s in society’s best interest.
Private Corporate Symposium: Scientific Exchange and Expert Opinions on CV Outcomes in Diabetes (Sponsored by Sanofi)
OPENING REMARKS
Riccardo Perfetti, MD, PhD (VP Global Medical Affairs, Sanofi Diabetes, Paris, France)
Dr. Riccardo Perfetti opened the symposium by remarking upon the relevance of the topic at hand, specifically commenting on Sanofi’s recent decision to withdraw its US submission for the GLP-1 agonist Lyxumia (lixisenatide). As Sanofi stated in its announcement earlier this month (see details at http://www.closeconcerns.com/knowledgebase/r/c7496472), Dr. Perfetti remarked that unblinding investigators to the interim results of Lyxumia’s CVOT, ELIXA, would have “gigantic negative consequences” on the continuation and interpretation of the study. He cited two past examples that informed the decision to remain blinded to the trial results: first, the FDA once previously refused to update a drug’s label to reflect new CVOT data showing CV benefit for a drug whose interim data been publicly disclosed because the interim data disclosure compromised the trial’s final results. One of these was for sulfinpyrazone (for gout). As we understand it, the FDA felt that the disclosure of the interim analysis had compromised the conduct of the study and did not accept to include the study results (or altered the product indication) once the study was completed. More recently, Dr. Perfetti said that J&J’s Invokana (canagliflozin) also went through a dramatic change of plans for its CVOT, CANVAS, after the disclosure of interim results at its FDA Advisory Committee meeting. The original plan for CANVAS had originally allowed for a trial expansion after the interim analysis, but the investigators felt that the rigorousness of such an expansion would have been compromised by the public disclosure of data, and so they canceled that part of the study. Dr. Perfetti noted that this resulted in a delay for full trial results.
THE CURRENT REGULATORY ENVIRONMENT IN DIABETES: WHAT NEEDS CHANGING? WHAT IS ABOUT TO CHANGE?
Philip Home, DPhil, DM (Newcastle University, Newcastle Upon Tyne, UK)
Dr. Philip Home reviewed some of the regulatory challenges and historical examples that have shaped today’s regulatory environment. Dr. Home criticized regulatory agencies’ historical tendency to over-react to safety scares by subsequently focusing great attention to specific safety issues rather than focusing on overall safety profile (e.g., liver failure with troglitazone, CV risk with rosiglitazone, and pancreatitis risk with incretin-based therapies). One challenge that regulators face is the uncertainty that noisy data generate both for very infrequent events (e.g., the five-fold greater bladder and breast cancer imbalance found in dapagliflozin studies) or very frequent events (e.g., would one treat a numerical imbalance of 56 vs. 40 myocardial infarctions in a group of 2,500 people after one year a 40% increase or a chance difference?). He noted that regulatory agencies, subject to political pressure and external fright, react conservatively to such noise. As such, he finds large randomized-controlled trials (RCTs) very valuable (e.g., the ongoing diabetes cardiovascular outcomes trials) for shedding light on all possible adverse outcomes, no matter what the pre-specified primary outcome is. He would like to see large RCTs mandated for all newly licensed diabetes medications to assess a wide range of possible safety issues (not only focusing on CV safety). While he does not think it is not practical to try to apprehend all unexpected safety issues at the time of drug approval, he remarked that such issues will always crop up at some point and that such RCTs are the most rigorous way of finding them. Dr. Home emphasized that no medication is truly “safe” and that regulators must continue to consider the balance between risk and benefit.
- Dr. Home made a few additional notable comments regarding regulators’ concerns over recent drugs such as Novo Nordisk’s Tresiba (insulin degludec) and J&J’s Invokana (canagliflozin). He remarked that the FDA’s concern over the excess CV risk (numerically, a 13-fold increase in events) seen in the first 30 days of CANVAS was “really pure nonsense” since the placebo group clearly had an artificially low level of events during that time and the curves eventually crossed. With regard to insulin degludec’s submission package, Dr. Home highlighted the FDA’s acknowledgement that no causation or plausible mechanism has been elucidated. Nonetheless, he also pointed out that when the FDA called for an extended dataset that provided data over a longer exposure period, the CV result was exacerbated rather than tending back toward the mean (which is what one would expect if an early fluke had produced the original result of concern).
- As another notable piece of advice, Dr. Home warned that when interpreting composite analyses and meta-analyses based on fewer than 50 events, “beware!” And with <100 events, “be cautious!” And for meta-analyses based on studies with diverse findings, “be skeptical!”
Questions and Answers
Q: According to all the results you showed in the table for degludec, what were the differences between original and updated data?
A: Essentially, the HRs were all worse in the updated data. The updated data were simply the data collected for patients following the original intended end of the studies. My only point was that those HRs were jumping around … if you see HRs in meta-analyses jumping around, you know they’re unreliable.
Dr. Julio Rosenstock (University of Texas Southwestern, Dallas, TX): There are some issues I will discuss in my talk, but the thing I think is important to emphasize is the difference between the EMA and the FDA. The EMA does not conduct their own independent evaluation, and they don’t have the same thoroughness as FDA.
A: EMA goes through the dossier closely but doesn’t run the analysis again. That is very true. I would also criticize the EMA; I think it is too closed and secretive. I would like to see a more open reporting. Having said that, having worked with the internal people, they are very good. They are sharp people who know their stuff.
CV OUTCOMES TRIALS WITH NEW GLUCOSE LOWERING AGENTS: WHAT ARE WE LEARNING?
Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)
Dr. Julio Rosenstock began his presentation by noting that the currently available data on diabetes therapies and cardiovascular risk, while suggestive of benefit, is far from conclusive. Additionally, he pointed out that most past studies examined treatment regimens rather than specific therapies, and cited ORIGIN as the only major trial so far that has had enough power to analyze a single drug and come out with a decisive, convincing result. The FDA’s more stringent CV safety requirements for diabetes drugs are somewhat unfair to industry, in Dr. Rosenstock’s mind, but at the end of the day, he is very much in favor of the CV safety requirement since it provides the opportunity to obtain valuable new data on drug safety. Much of the presentation was dedicated to an overview of ongoing and recently completed CVOTs. He came down harshly against the use of interim data from CANVAS (the CVOT for J&J’s Invokana [canagliflozin]), which he said compromised the integrity of the trial. By the same logic, he applauded Sanofi’s move to withdraw its NDA for Lyxumia (lixisenatide) in order to prevent biasing the result of its ELIXA CVOT. He expressed concern for the MACE signal seen in the initial Tresiba (insulin degludec) data, especially the fact that the initial signal was confirmed by an updated analysis of an extended dataset. Moving on to the recently disclosed results of SAVOR-TIMI 53 and EXAMINE (the completed CVOTs for BMS/AZ’s Onglyza [saxagliptin] and Takeda’s Nesina [alogliptin], respectively), he noted with concern that there was a numerical imbalance in pancreatitis cases in both studies, even though the difference was not statistically significant. Looking to the future, Dr. Rosenstock called for more trials to be conducted in patients without established CV disease, using active controls rather than placebo comparators.
- Dr. Rosenstock began by noting that the majority of data that we have on diabetes therapies and CVD is on the effect of treatment intensity rather than on specific drugs. The limited data available on specific therapies, he stated, is insufficient to draw convincing conclusions. As an example, he cited a secondary analysis of metformin therapy from UKPDS — while metformin did seem to reduce patients’ risk of CVD, Dr. Rosenstock pointed out that the sub-study was insufficiently powered (342 patients on metformin). He cited ORIGIN as a rare example of a study sufficiently powered to convincingly analyze a specific drug.
- The FDA’s requirement of cardiovascular safety data on all diabetes drug candidates is unfair for industry, in Dr. Rosenstock’s mind, but presents the opportunity to obtain valuable data. After a discussion of the FDA policy, Dr. Rosenstock discussed recent and ongoing cardiovascular outcomes trials for diabetes drugs.
- Dr. Rosenstock expressed misgivings over using interim CVOT data in the approval process, as such data disclosure can compromise the integrity and validity of study data. He cited J&J’s Invokana (canagliflozin) as an example. He applauded the decision on the part of Sanofi to withdraw the NDA for Lyxumia (lixisenatide) in order to preserve the integrity of the ELIXA CVOT — read our coverage of that recent news at http://www.closeconcerns.com/knowledgebase/r/c7496472.
- Dr. Rosenstock briefly expressed concern about the current cardiovascular data on Novo Nordisk’s Tresiba (insulin degludec), noting that the original data had a worrying signal for CV events that was confirmed (and amplified somewhat) by subsequent analysis. We hope that the results of Novo Nordisk’s planned CVOT will help clear up this uncertainty — it is scheduled to begin later this year (see our Novo Nordisk 2Q13 update at http://www.closeconcerns.com/knowledgebase/r/006471af for more details).
- Dr. Rosenstock next moved onto SAVOR-TIMI 53, BMS/AZ’s CVOT for Onglyza (saxagliptin). He noted that while the study’s primary outcome was non-inferiority, it was powered to show superiority — we interpreted his view as slightly disappointed, though the safety results are certainly a positive in our view, especially given how hard it is to design a trial that will show safety and also superiority. The increase in hospitalization for heart failure and significantly higher incidence of hypoglycemia seen in the treatment arm must be analyzed, he stated emphatically – he did not mention that the heart failure risk was not accompanied by a concomitant increase in any CV outcomes including overall or CV mortality; we imagine that the increased hypoglycemia was limited to patients who were also on insulin or SFU therapy (no DPP-4s have ever been linked to significant hypoglycemia caused by the DPP-4 inhibitor, of which we’re aware). He also broke out the pancreatitis results, highlighting the numerical increase in acute pancreatitis seen in the saxagliptin group, even though the difference was not statistically significant due to the very small numbers. The same concern applied to the results of EXAMINE, Takeda’s CVOT for Nesina (alogliptin), in which the treatment arm had a numerically greater number of acute pancreatitis cases than the comparator arm. See our ESC 2013 Day #1 Report at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for our initial coverage of the EXAMINE and SAVOR-TIMI 53 data presentations.
- To conclude, Dr. Rosenstock questioned whether CVOTs are investigating the right kind of patients. He pointed out that most current CVOTs enroll patients with established cardiovascular disease, and many utilize placebo comparators. In the future, he proposed, trials should enroll patients without significant longstanding CVD, and consider using active comparators — he cited CAROLINA (the CVOT for BI/Lilly’s Tradjenta [linagliptin]) as an example of progress in the right direction in this regard, as it compares Tradjenta to the sulfonylurea glimepiride. We are extremely eager for this analysis and salute BI/Lilly for taking it on; on the other hand, we know that BI/Lilly also are doing a more typical CVOT to satisfy FDA. We also wonder whether this is the right population although given the vastly improved standard of care, we believe it would be challenging for trial execution to choose a different group.
INSULIN AND CV OUTCOMES: ONGOING ANALYSES OF THE ORIGIN TRIAL
Hertzel Gerstein, MD, MSc (McMaster University, Hamilton, Ontario, Canada)
Dr. Hertzel Gerstein began by characterizing insulin as a “miracle drug” due to its effect in type 1 diabetes, but noted that the insulin therapy for type 2 diabetes has been dogged by controversy over feared cardiovascular and cancer risks for decades. After providing an overview of ORIGIN’s design and central results, he shared and interpreted results from more recent analyses of ORIGIN data. To address concerns regarding insulin glargine’s potential atherogenicity, an ORIGIN substudy compared changes in carotid intima media thickness (CIMT) during the trial in patients from the insulin glargine and comparator arm — the data indicated that glargine treatment had no effect on plaque formation and may in fact have slowed progression of atherosclerosis. Dr. Gerstein spent a great deal of time discussing data recently presented at ESC on the association between hypoglycemia and CV risk in ORIGIN (see page 7 of our ESC 2013 Day #1 report at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for our coverage of that presentation). While severe and non-severe hypoglycemia was indeed higher for patients in the glargine arm, the effect of severe hypoglycemia on MACE and all-cause mortality was greater in the standard care group than in the insulin glargine group. Speakers that have commented on this result have remarked that this may be due to widespread sulfonylurea use in the standard care arm. He postulated that severe hypoglycemia may in fact be a marker rather than a direct cause of most cardiovascular events — we think this is a critical area of investigation and would love to gain more clarity on this front.
BALANCING THE BENEFITS AND RISKS OF GLUCOSE LOWERING THERAPIES
Matthew Riddle, MD (Oregon Health and Science University, Portland, OR)
Dr. Matthew Riddle discussed data from landmark studies to demonstrate that the risk:benefit ratio for diabetes treatment is optimized by treating patients early and that, contrary to conventional wisdom, there is no reason to withhold early use of insulin. In contrast, he noted that people for whom the risk:benefit ratio is poorer include people with high baseline A1c, clinical evidence of CV risk, poor response to treatment (<0.5% A1c reduction), and severe hypoglycemia or hypoglycemia unawareness. With regard to treatment modalities, he noted that metabolic surgery does not yet have a well-defined place in the treatment arsenal given that prospective studies are not designed well enough. He reviewed the benefits and risks of GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors, providing harsh criticism of the Butler et al. pancreatic morphology study. He noted that SAVOR and EXAMINE’s neutral outcomes just goes to show how much hazard is needed to interpret pooled analyses (since previous pooled analyses had suggested the CVOTs might come out positive), and that SGLT-2 inhibitors should be very low in the treatment paradigm since we do not yet know much about the risk:benefit ratio.
- Dr. Riddle presented a risk matrix plotting patient populations from landmark trials on a grid with diabetes duration on the x-axis, and CV risk on the y-axis. ACCORD enrolled a population with both long diabetes duration and established CVD, and it demonstrated potential “trouble” with intensive therapy (i.e., increased mortality). In comparison, UKPDS was in a newly diagnosed population with low CV risk, and it demonstrated long-term CV benefit with low risks. ORIGIN enrolled people with short diabetes duration but previous CVD. Dr. Riddle argued that ORIGIN showed low short-term risk of early glargine use (CV neutrality, increased risk of hypoglycemia but lower risk of mortality compared to standard care) with the benefits of decreasing progression from pre-diabetes to diabetes and potential improvements in microvascular outcomes down the road. Finally, he stated that there were no studies of people with long diabetes duration and no CV risk. Thus, he concluded that the available evidence supported earlier intervention for maximizing benefit and reducing risk.
HIGHLIGHTS OF THE NEW 2013 ESC/EASD GUIDELINES FOR DIABETES AND CV RISK PREVENTION
Peter Grant, MD (University of Leeds, Leeds, UK)
Dr. Peter Grant, co-chair of the newly released ESC/EASD 2013 guidelines on diabetes, presented the highlights and rationale behind the new guidelines. Compared to the previous 2007 guidelines, the 2013 version simplifies diabetes diagnosis, simplifies CV risk assessment, reverses the suggestion for aspirin use in people free from CVD, individualizes glycemic targets, individualizes blood pressure targets, and raises method of revascularization as an important issue. With regard to diabetes diagnosis, the 2013 guidelines now recommend use of A1c and FPG with an OGTT if still in doubt. This brings the ESC/EASD in line with the ADA and WHO on diagnostic guidelines. With regard to CV risk assessment, the new guidelines recommend simply assigning all people with diabetes a “high risk” CV status, with the presence of any additional risk factors raising the status to “very high risk.” Dr. Grant said that this was one recommendation he slightly disagreed with since he believes there is still a “low risk” group of people with diabetes that have comprehensive risk factor control. Finally, Dr. Grant reminded the audience that guidelines are not rules, so clinical judgment should ultimately inform when to violate the guidelines. Please see page 8 of our ESC Day #1 Highlights at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for more comments from the co-chairs Dr. Grant and Dr. Lars Ryden.
PANEL DISCUSSION
Peter Grant, MD (University of Leeds, Leeds, UK); Matthew Riddle, MD (Oregon Health and Science University, Portland, OR); Jeffrey Probstfield, MD (University of Washington Health Sciences Center, Seattle, WA); Julio Rosenstock, MD (University of Texas Southwestern, Dallas, TX)
Questions and Answers
Q: Does insulin have a better cardioprotective effect than GLP-1 analogs?
Dr. Rosenstock: Neither of the two has shown to be cardioprotective.
Q: Does the panel think that CVOTs are needed for glucose lowering drugs?
Dr. Gerstein: I think that’s a really interesting question. I think we have glucose lowering drugs for a lot of reasons – for one, they improve patients’ quality of life. Also these drugs definitely improve microvascular complications like nerve disease and eye disease in the short term. Third, people have diabetes for the rest of their lives, and people are living longer. It very well may be that many of the drugs in development will have remarkable cardioprotective effects. We didn’t know that lipid lowering had remarkable cardioprotective effect until statins. But yes, I believe in the future, and I do think that some of these drugs will have a cardioprotective effect.
Dr. Riddle: It’s a good question because I think there are two separate related issues. One is that yes, we do need RCTs – big ones, long ones, early in the natural history of drug. Whether to demonstrate superiority or the best way to use the drug, yes we do need them. We always learn things we didn’t know we would learn. The other issue is the safety issue. That is not always so reliable addressed with RCTs. We need prospective, well-structured data collection registries to collect that data as well.
Q: Any thoughts on the increase in hospitalization for heart failure with saxagliptin?
Dr. Rosenstock: No. It’s an interesting thing — I think that it will be critical to see the data from EXAMINE. Twelve percent of patients in SAVOR had previous CHF, in EXAMINE it was much higher. And we’re talking real CHF. I think that they need to go back and look at those patients.
Dr. Riddle: I have nothing to add – it’s unknown.
Dr. Probstfield: I think there’s a good chance it’s by chance alone. Even if you use a conventional correction for it, it doesn’t reach statistical significance.
Q: Peter, you should have considered this extensively when you were looking at all of the issues related to setting the guidelines. Are the CV trials adequate to assess the non-safety issues?
Dr. Grant: We’ve got ourselves in a bit of a mess – it’s incredible difficult to judge what they actually mean. Even hearing experts talking about it, they give contradictory views on what these trials are telling us. Really, I feel that as diabetologists we’ve become victims of our own success in this area. The cardiologists are driving the agenda, but they don’t think diabetes is a complex disease, and we’re getting ourselves to a place where the tail is wagging the dog a bit. We need to come to a consensus on how to manage this.
Q: Are the CV studies adequate to generalize results to most other patients with type 2 diabetes?
Dr. Grant: I don’t think they are, because so much of what we’re seeing is contradictory and difficult to interpret. All you can really say is that if you lower blood glucose, you will get short-term benefits in terms of microvascular disease, and potentially long-term benefits.
Dr. Gerstein: I think it’s ridiculous to make CV conclusions based on two-year trials. If you looked at the effects of gastric bypass on death for 1.5 years, you would see no effect, even in people with triple vessel disease. You need time for intervention to bear fruit. For blood pressure lowering, it’s fast. For statin use, it’s pretty fast, but at two years you get a better effect than at one or three years. For glucose, you need four-to-five years to see metabolic effects. So I think short trials will never tell you the answer for CV effects.
Dr. Rosenstock: I second what Hertzel said, and I would add that I think we’re looking at the wrong patients. I think it’s hard to believe that we’re going to reverse cardiovascular disease when it’s already well established. Type 2 diabetes patients are in it for the long run – these studies should not be stopped when they do the primary analysis; they should continue to see if there is an effect. That’s why I’m interested in the CAROLINA trial.
Dr. Riddle: I support the idea that this is a long-term problem. We should think of heart disease as a 20-year complication of poor metabolic control. Most heart control is the result of some metabolic disturbance that was not treated long before. What I want to emphasize is I think we’re barking up the wrong tree. We’re taking the wrong approach to find the most severely affected patients in an attempt to turn back the clock. You don’t improve ESRD by trying to improve glucose control or improve stroke by blood pressure control.
Q: I think chronic disease like diabetes should be looked at in terms of quality of life along with cardiovascular metrics. Do you agree that quality of life outcomes are important?
Dr. Gerstein: Yes.
Dr. Riddle: Well, sure. I think it’s very important. I would add to that that patient-reported outcomes and other behavioral measures should be linked to behavioral observations like retention in a trial and keeping appointments with study investigators or a doctor. There are ways to assess the behavioral side of a management problem better than we have, and we need to do that to improve the design of trials.
WORKSHOP: HOW BAD IS HYPOGLYCEMIA?
Pratik Choudhary, MD (King’s College Hospital, London, UK); Stephen Davis, MBBS (University of Maryland School of Medicine, Baltimore, MD)
Drs. Pratik Choudhary and Stephen Davis discussed the consequences of hypoglycemia, focusing on cardiovascular safety and quality of life. Notably, Dr. Choudhary noted that of UK hospital admissions for hypoglycemia, 10% are for people with type 1 diabetes, and 90% are for people with type 2 diabetes (which is perhaps a greater proportion than most might expect). Of the people with type 2 diabetes, 50% were SFU-treated and 50% were insulin-treated. Dr. Davis remarked that a blood glucose of 50 mg/dl for two hours activates the same (or worse) proinflammatory, athrothrombotic, and endothelial dysfunction factors as two hours of hyperglycemia. In the discussion following the presentation, the group came to the consensus that all hypoglycemia, even non-severe hypoglycemia, is serious and influences therapy despite the fact that non-severe hypoglycemia has not been associated with increased CV risk or death (e.g., in ORIGIN) and was not associated with increased automobile accidents in the UK in a study conducted by Dr. Choudhary. The presenters also suggested that non-severe hypoglycemia was a predictor of severe hypoglycemia, which is a marker for CV risk and death. The group agreed that for someone with a previous myocardial infarction, one should be cautious about intensifying glucose control for fear of hypoglycemia. With regard to whether hypoglycemia was a risk marker for CVD or a causal factor, the group was split. Some thought it was only a marker, while others, including the sole cardiologist in the room, thought that there were causal mechanisms. Finally, the group agreed that nocturnal hypoglycemia is worse than daytime hypoglycemia due to the inability to treat quickly that can result in much higher costs as well as the worry that it causes patients and families.
WORKSHOP: WHICH GLUCOSE-LOWERING AGENT DO I ADD NEXT?
Vivian Fonseca, MD (Tulane University, New Orleans, LA) and Angelo Avogaro, MD, PhD (University of Padova, Padova, Italy)
In this case-based workshop, Drs. Vivian Fonseca and Angelo Avogaro prompted attendees to select the most appropriate second-line treatment. The session benefitted from a remarkably diverse group of attendees — the providers in the room shared background and treatment guidelines from their respective countries, and at times jokingly referred to each other by their home countries (almost giving the room the aura of a United Nations conference). Attendees from Eastern Europe and Latin America seemed somewhat more eager to utilize basal insulin, whereas those from Western Europe and the United States seemed to favor incretin therapies slightly more. Dr. Fonseca recommended waiting for more data on the SGLT-2 inhibitor class before prescribing them early as a second-line therapy for most patients. He also expressed optimism about the 5,000-patient GRADE study (ClinicalTrials.gov Identifier: NCT01794143), which will provide much-needed head-to-head data on the use of four different diabetes therapies (glimepiride, sitagliptin, liraglutide, and insulin glargine) when added to metformin. An attendee from Mexico hypothesized that the largely neutral results from both the SAVOR and EXAMINE CVOTs might detract from Onglyza and Nesina’s popularity, but another attendee quickly countered that these two studies’ major aim was to establish the drugs’ basic safety (which they successfully did), and thus should have the potential to only help the DPP-4 inhibitor class.
Corporate Symposium: Cardiovascular Risk Control: The Critical Aim of T2D Management (Sponsored by Lilly/BI)
THE IMPORTANCE OF CV OUTCOME TRIALS
Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)
Building off his presentation “CV Outcomes Trials with New Glucose Lowering Agents: What are We Learning?” at the previous day’s Sanofi event, Dr. Julio Rosenstock underscored the importance of CVOT, in his view. He began by noting that the “best that we can say” about currently available data on diabetes therapies and cardiovascular risk protection “is that it is suggestive but clearly is not conclusive.” Turning to SAVOR-TIMI 53, BMS/AZ’s CVOT for Onglyza (saxagliptin), Dr. Rosenstock expressed surprise and some concern at the agent’s association with higher rates of hospitalization due to congestive heart failure. Notably, he also implied that the numerical imbalance against saxagliptin in pancreatitis events could be indicative of a broader pancreatitis risk among incretin mimetics, remarking that pooled analysis of the CVOTs “may find something interesting” in terms of pancreatic events. More broadly, Dr. Rosenstock voiced strong support for the safety trials the FDA has required, cataloguing the many research questions it enables investigators to pursue.
- Dr. Rosenstock voiced strong support for the safety trials the FDA has required of late. He acknowledged that “industry may not like it” but that he sees the CVOTs are a great research opportunity to 1) learn more about the natural history of type 2 diabetes, 2) test drug effectiveness rather than just efficacy, 3) assess long-term durability, and 4) better define a drug’s cost:benefit profile.
- The ideal situation, Dr. Rosenstock believes, would be for CVOTs to continue beyond their primary outcome so that researchers can see a drug’s legacy effects. Also due to his curiosity in legacy effects, Dr. Rosenstock hopes to see more people with CV risk factors but not CVD enrolled in CVOTs. He thinks a greater representation of this population would give trials a better chance of demonstrating CV protection, since people will not enter with negative metabolic memory. We suspect that companies have tended to avoid enrolling this healthier population in large numbers, because trials would likely have to be larger, longer, and therefore more expensive to ascertain the needed number of CV events.
- On SAVOR-TIMI 53, Dr. Rosenstock remarked that it was “surprising” saxagliptin was associated with a higher rates of hospitalization due to congestive heart failure (CHF). We note, however, the heart failure risk was not accompanied by an increase in any CV outcomes, including overall or CV mortality. Dr. Rosenstock remarked that “[the CHF trend] raises a number of questions.” He noted that this finding could be by chance or that it could be real. During the subsequent panel discussion, Dr. Bernard Zinman (University of Toronto, Toronto, Canada), hypothesized that DPP-4 inhibitors could cause CHF by preventing the degradation of peptides other than GLP-1 or GIP (Dr. Rosenstock had left for another symposium he was speaking at, so we was unable to answer questions on SAVOR-TIMI or CVOTs). One of the peptides, circulating at a higher level, due to its breakdown being inhibited, could have a deleterious effect on the CV system. Dr. Zinman pressed that providers should be careful not to believe that the CHF association is a class effect, since they are metabolized differently and have varied impacts on different peptides.
- Dr. Rosenstock stated that the SAVOR-TIMI 53 “authors claim that there was no difference in pancreatitis.” He noted, however, that while there was no statistical difference in the rate of pancreatitis, there was a numerical difference. He continued to suggest that when the CVOT results are pooled “we may find something interesting there.”
- Dr. Rosenstock was “a bit disappointed” that SAVOR did not find a greater difference in A1c improvement between saxagliptin and placebo. Physicians were asked to treat both the saxagliptin and the placebo arms to an A1c target; however, Dr. Rosenstock does not believe the placebo group received an intensive glycemic intervention when the subjects were seen every 6 months for study visits and no specific directions were given to the physicians taken care of their diabetes. He explained this was, in part, due to cardiologists providing much of the care.
- Similar to his comments at the Sanofi event on Sunday (we are finalizing these notes), Dr. Julio Rosenstock pressed that while the data “very, very clearly” demonstrate that good control reduces microvascular complications, they are not conclusive on macrovascular complications. Regarding macrovascular risk, Dr. Rosenstock remarked that “UKPDS gave us a little reassurance [about glucose control’s impact on CV outcomes] but not enough.”
- Additionally, he noted that the majority of data that we have on diabetes therapies and CVD are on combination therapies rather than on specific drugs. The limited data available on specific therapies, he thinks, are insufficient to draw convincing conclusions. As an example, he told attendees that many people’s belief that metformin is certainly CV protective is largely unfounded. He explained that in the study often cited, a secondary analysis of metformin therapy from UKPDS, metformin did seem to reduce patients’ risk of CVD; however, it was insufficiently powered to draw definitive conclusions (n=342 people on metformin).
- Overall, Dr. Rosenstock believes that among the ongoing CVOTs, the one with the better chances of finding CV protection is CAROLINA because it has enrolled type 2 patients with earlier diabetes as suggested by lower A1C levels (and the fact that none are on insulin), contrasting with the study populations in the other CVOTs. Furthermore, CAROLINA also has less percentage of subjects with established CVD and more subjects with only CV risk factors and it is the only CVOT with an active comparator (linagliptin vs glimepiride). We look especially forward to seeing the results of a CVOT with an SFU.
IS EARLY INTERVENTION THE BEST INTERVENTION?
Stephen Gough, MD (University of Oxford, Oxford, UK)
Dr. Stephen Gough artfully described the molecular biology underpinning landmark trial demonstrations of metabolic memory in people with type 1 and type 2 diabetes. He opened by reminding attendees how large-scale trials like UKPDS and DCCT/EDIC showed that achieving metabolic control early in the course of diabetes reduce a person’s progression through the disease’s natural history and his/her development of complications. Dr. Gough proceeded to explain that atherogenic and inflammatory mediators are elevated even prior to the onset of diabetes, and that they contribute to the development of microvascular complications, even if glycemic control is later achieved. One explanation could be that poor glycemic control leads to elevated oxidative stress and the non-enzymatic glycation of cellular proteins and lipids, resulting in an increased risk of tissue and organ damage. In his view, epigenetic mechanisms likely also play a central role in this metabolic memory. Dr. Gough concluded that early intervention is needed to establish a positive metabolic memory, slow a person’s disease progression, and risk for complications. Reflecting on this, we are encouraged by the growing number of technologies and therapies that can empower the average patient to pursue tight glycemic control beginning at diagnosis. For example, Abbott’s newly introduced Flash Glucose Monitoring System might remove several barriers (e.g., hassle, poor strip reimbursement, etc.) previously deterring patients from checking their blood glucose more often.
- A potential pathway for the epigenetic “regulation” of metabolic memory is that hyperglycemia leads to excess oxygen and nitrogen free radicals. These free radicals, in particular, originate at the level of glycated-mitochondrial proteins. The presence of these free radicals can result in an increased risk of mitochondrial DNA damage. As a result, proteins encoded by the damaged mitochondrial DNA also become abnormal. Preclinical studies, according to Dr. Gough, suggest that the hyperglycemia-induced abnormalities in mitochondria continue even when euglycemia is restored.
SGLT2 INHIBITION: POTENTIAL IMPACT ON CV RISK FACTORS
Bernard Zinman, MD (University of Toronto, Toronto, Canada)
Dr. Bernard Zinman detailed the impact of SGLT-2 inhibitors on cardiovascular risk factors, which provide hints to the class’ potential impact on cardiovascular outcomes. With the exception of LDL cholesterol, these CV risk factors improve. Dr. Zinman noted that some variation in the magnitude of improvements appears to exist between agents; however, he view these disparities as small and, due to no head-to-head trials being preformed, not robust. Delving into the increase seen in LDL, Dr. Zinman described the effect as small but potentially a dose response, increasing the odds that it results from the SGLT-2 inhibitor given. He sighed, this is “not what we want to see,” but did not express great concern over its clinical significance, pressing, “the consequence remains to be demonstrated.” Dr. Zinman concluded that the field needs well-powered, long-term studies in which CV events are adjudicated. Thus, he believes results from the SGLT-2 inhibitors’ CV outcome trials (i.e., empagliflozin’s EMPA-REG OUTCOME, canagliflozin’s CANVAS, ad dapagliflozin’s DECLARE) will define the CV effects of SGLT-2 inhibitors.
- During Q&A, Dr. Zinman remarked that empagliflozin’s greater specificity for SGLT-2 than other SGLT-2 inhibitors does not appear to be clinically significant.
- Dr. Zinman noted that SGLT-2 inhibitors might improve beta cell function by reducing glucotoxicity. He explained that such an effect has been seen in preclinical studies; however, it is unclear if it also occurs in humans – Dr. Zinman hypothesized that it does.
Questions and Answers
Q: Can you explain the change in body composition or is it only water variations?
A: These compounds inhibit SGLT-2 so you actually have an excretion of glucose and of sodium – it basically acts as a diuretic in terms of lowering blood pressure. Patients do not experience excessive urination except for early on.
Q: Can you please comment on the effects of SGLT2s on improving beta cell function?
A: It was Ralph DeFronzo and his trainees. At the time they wanted to have a mechanism of reducing glucose independent of metformin. When you independently reduce glucose by in essence having a glucose sink, you get an improvement in beta cell function and insulin action. That was a seminal observation to prove the idea of glucose toxicity. Now, does that happen in people? I think it does but we will see.
Q: Can you comment on the increase in hospitalizations for heart failure seen in SAVOR?
A: The fact is that DPP-4 inhibitors inhibit the breakdown of compounds other than GLP-1 and GIP. One can postulate that there are some peptides that are circulating at a higher level because their breakdown was inhibited, and that could have a deleterious effect. We should be careful not to ascribe that response to all DPP-4 inhibitors. They are metabolized differently and have different side effects. We don't know if it is a class effect or unique to saxagliptin.
Q: Why don't you continue to lose weight when you are on an SGLT-2 inhibitor?
A: I think that there is a compensation effect and you eat more. The good thing is that the weight comes down and stays down.
Q: If you compare the three available SGLT-2 inhibitors, empagliflozin is the most specific for SGLT-2 of the three. Now it is not clear that we want that specific of inhibition. Can you comment on this?
A: I think that the reductions in A1c are pretty similar. It would be very interesting to do a head-to-head comparison between empagliflozin and one that is less selective. There may be some differences. Are they clinically meaningful? Doesn't seem to be.
PANEL DISCUSSION
Moderator: Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)
Panelists: Stephen Gough, MD (University of Oxford, Oxford, UK); Bernard Zinman, MD (University of Toronto, Toronto, Canada)
Q: Where do you see SGLT-2 inhibitors fitting in the current treatment paradigm?
Dr. Zinman: It can be used along the entire spectrum of diabetes. I think we are now entering the age where we should be using drugs that are not associated with weight gain or increased risk of hypoglycemia. We have enough options to do this. I would use these drugs early. As I mentioned, you can use them in type 1 diabetes, though that certainly is not a labeled indication.
Q: What do you make of SGLT-2 inhibitors’ cancer risk?
Dr. Zinman: With dapagliflozin there was a suggestion of a small number of additional bladder tumors. I don't think this has been demonstrated with the other agents. I don't think there is any evidence to suggest a risk.
Q: You think SGLT-2 inhibitors can be used in type 1 diabetes?
Dr. Zinman: Studies are ongoing that look at that. Bruce Perkins will report a very preliminary POC on SGLT-2 inhibitors for type 1 diabetes. This is a several week experience looking at A1c, renal function, and hypoglycemia.
Q: Do SGLT-2 inhibitors increase people’s heart rate?
Dr. Zinman: There is no increase in heart rate; don't ask me why. They are unlike the GLP-1 RAs, which are associated with an increase in heart rate.
Q: Regarding the elevation in LDL; what kind of isoforms are increased?
Dr. Zinman: I don't think there is enough data to talk about that at this stage.
Q: At the end of the day, is good glycemic control important for preventing macrovascular outcomes?
Dr. Rosenstock: I think it is not a question of whether good glycemic control is resulting in health benefits. In people with renal failure, at any stage, an improvement in glycemic control is transmitted into health benefits. Of course, don't over treat.
Dr. Gough: I am going to speak on the concept of metabolic memory and I am going to say that if you want to be able to see CV benefits, you have to start early.
Q: What is the mechanism of the cardioprotective effect in earlier stage patients?
Dr. Zinman: I think that when you look at DPP-4 inhibitors, you see that obviously GLP-1 is increasing and so is GIP. GLP-1 has all kind of effects on endothelial tissue. We don't really know what the logic would be. CAROLINA is a unique study, not so much because it has an active comparator, but because it answers a clinically meaningful question: you are on metformin and are starting to fail it, should you go on an SFU or a DPP-4 inhibitor?
Q: Why in CAROLINA was glimepiride used instead of glipizide?
Dr. Rosenstock: I don't think we should answer this question. The SFUs have a mode of action such that at any stage it would work. However, if you don't have the breaks you will get problems. With all SFUs there will be a risk of severe hypoglycemia.
Corporate Symposium: SAVOR Trial: How May the Largest DPP-4 Inhibitor CV Safety Study Influence Day-To-Day Clinical Practice? (Sponsored by BMS/AZ)
THE POTENTIAL IMPACT OF SAVOR ON CLINICAL PRACTICE
Chantal Mathieu, MD (Katholieke Universiteit Leuven, Leuven, Belgium)
Dr. Chantal Mathieu provided her interpretation of SAVOR results from a clinical perspective. As a reminder, SAVOR is the CVOT for BMS/AZ’s DPP-4 inhibitor Onglyza (saxagliptin), whose results were released earlier this month at ESC 2013. The trial confirmed the CV safety of Onglyza with a HR of 1.00 for MACE compared to placebo and did not achieve its secondary CV superiority endpoint – please see http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for full results, including evidence that potentially supports its pancreatic safety. Dr. Mathieu had a glass half full perspective on SAVOR results – she remarked that we already know that glucose control prevents microvascular disease, and now we can also conclude that Onglyza is safe on the cardiovascular side. She stated that it was, of course, disappointing that the superiority endpoint was not met and explained why this may have been the case despite the suggestions from animal studies and pooled analyses of phase 2 and 3 trials that the drug might show benefit. First, compared to the phase 2/3 clinical trial program, the population studied in SAVOR had much more advanced diabetes and CVD risk (80% already had CVD present). Second, any effects of the 0.3% A1c difference between the treatment and placebo groups would almost certainly take more than 2 years to emerge (based on previous experience from UKPDS and STENO-2). She highlighted the fact that even though investigators were told to titrate the two arms of the trial equally, the Onglyza arm still performed 0.3% better in A1c reductions. Finally, she remarked that the safety findings for pancreatitis and pancreatic cancer were another big takeaway – while two years may have been too short a time to see any difference of pancreatic cancer due to the drug, she still thought the data showing no difference between the groups were reassuring.
Corporate Symposium: Glucose Lowering Approaches: Short Term and Long Term Safety Considerations (Sponsored by Sanofi)
GLUCOSE LOWERING DRUGS AND CV OUTCOMES: THE EVIDENCE
Hertzel Gerstein, MD (McMaster University, Hamilton, Canada)
Dr. Hertzel Gerstein provided a whirlwind overview of the currently available evidence regarding glucose-lowering and cardiovascular outcomes. He noted that in a meta-analysis of the UKPDS, ACCORD, ADVANCE, and VADT trials, intensive glycemic control showed a marginally significant 9% reduction in MACE beyond placebo, driven by a 15+% reduction in myocardial infarction for those who were intensively controlled (CONTROL Group, Diabetologia 2009). Subsequently, Dr. Gerstein stated that based on the results of the BARI-2D trial, the means by which glucose is lowered does not appear to have an effect on cardiovascular outcomes – insulin-sensitizing (e.g., rosiglitazone or metformin) and insulin-supplying (e.g., sulfonylureas, insulin) agents had comparable effects on mortality and cardiovascular outcomes (NEJM 2009). Dr. Gerstein then reviewed the available evidence on cardiovascular outcomes for individual type 2 diabetes medications, and displayed a comprehensive list of the ongoing cardiovascular outcomes trials, noting that there are approximately 115,000 people(!) who are being followed in such trials (Gerstein et al., Circulation 2013).
- Dr. Gerstein reviewed the available evidence on cardiovascular outcomes for individual drug classes. Though no one can say for sure what metformin’s pleiotropic effects on cardiovascular outcomes might be, the data to date suggest a potential cardioprotective effect. As for meglitinides, there was absolutely no effect on cardiovascular outcomes for patients with impaired glucose tolerance in NAVIGATOR. For TZDs, rosiglitazone had a neutral effect in RECORD, and pioglitazone suggested cardioprotective benefit in PROACTIVE. Meanwhile, ORIGIN showed that insulin glargine had a long-term neutral effect on cardiovascular outcomes. In addition, an exploratory analysis of the STOP-NIDDM trial suggested cardiovascular benefit for acarbose. Most recently, two cardiovascular outcomes trials for DPP-4 inhibitors reported. EXAMINE showed no effect on MACE or death from cardiovascular causes for alogliptin, while SAVOR-TIMI showed no effect on MACE or MACE+. However, Dr. Gerstein noted that there was an intriguing heart failure signal in the SAVOR-TIMI trial, which remains to be explained (he commented that it could potentially just be a chance finding).
PANEL DISCUSSION
Moderator: Vivian Fonseca, MD (Tulane University, New Orleans, LA); Hertzel Gerstein, MD (McMaster University, Hamilton, Canada); and Peter Boyle, PhD (International Prevention Research Institute, Lyon, France)
Dr. Fonseca: Hertzel, could you comment on a few things regarding the FDA? One was the controversy about rosiglitazone. Also, recently Sanofi withdrew their NDA for lixisenatide to await results from clinical trials. Could you explain the rationale there?
Dr. Gerstein: First of all, one can never understand what a regulatory agency does. It’s not a scientific agency. Regulators are there to regulate drugs, their audience is the public, and they will tend to make decisions based on all sorts of considerations, including politics, what is in the media, and the general public’s perceptions. They do consider the science, but they are there to regulate, which is an important principle. The rosiglitazone issue came up a few years ago, as there were allegations it caused cardiovascular and all sorts of other harms, based on problematic meta-analyses. There were politically charged discussions, including Congress and Senate hearings, and the decision was made several years ago to suspend large trials of rosiglitazone. Re-adjudication of the results vindicated the initial studies. As such, the FDA is now appropriately reconsidering its initial decision. But unfortunately, as a result, the TZD class is gone (pioglitazone for other reasons). Any other potential benefits that would have came out, we will never know. Regarding the second issue, the FDA wanted to review ongoing results from the trial. Large, international outcomes trials are designed so that data safety boards review emerging safety issues in confidence. The reason is because if anyone had an event and the whole world knew, people would make decisions and judgments based on very little data, and those judgments become entrenched, and before you know it, a drug would become haloed as a wonderful drug or damned as a bad drug on very little data That’s why safety is reviewed by the DSMB – their job is decide when safety signals emerge and to alert the world. When Sanofi submitted its file, the FDA wanted to review ongoing results of this large ELIXA outcomes trial. Initially, there was hope that they would do this confidentially, but when it became clear that confidentiality could not be guaranteed, I personally think Sanofi did the right thing to get the right results from this trial rather than risk poisoning the trial by having the results presented publicly. The investigators and the steering committee don’t know the result. People at Sanofi didn’t know the results. The decision [to withdraw the NDA] was made blind of the results. This is the right thing to do, to not expose the results of an ongoing trial until the DSMB says you do it or until a trial is finished. The best example is that canagliflozin made that mistake – its interim CV results were presented to the FDA, and it’s now universally viewed as crippling to their outcomes trial.
Dr. Fonseca: Why do people say drugs are causing cancer three months [after they start taking them]?
Dr. Boyle: I don’t think they understand what carcinogenesis is all about. In the majority of human cancer in adults, there are large delays. I do not know of a good example of a quick response to a carcinogen. Generally it takes years or decades.
Satellite Session: 6th CIBERDEM Annual Meeting
SUMMARY OF THE RESULTS OF THE LOOK AHEAD TRIAL
F. Xavier Pi-Sunyer, MD, PhD (Columbia University College of Physicians and Surgeons, New York City, NY)
Dr. Xavier Pi-Sunyer provided insightful commentary on the Look AHEAD study’s primary results, which were originally presented at ADA. As a reminder, the primary results are based on almost 12 years of data on the impact of an intensive lifestyle intervention program on cardiovascular morbidity and mortality in obese or overweight individuals with type 2 diabetes. Dr. Pi-Sunyer reminded attendees that the lifestyle intervention did not significantly improve cardiovascular outcomes relative to standard of care, resulting in the intervention being terminated early. Dr. Pi-Sunyer’s take away from the Look AHEAD trial was that overweight and obese people with type 2 diabetes can improve their cardiovascular outcomes in one of two ways: 1) by being more physically active and improving their diet or 2) by increasing the number of drugs they take. As a reminder, on average people in the intervention arm used significantly fewer medications per year compared to those receiving standard care, and specifically reduced the number of diabetes, lipid-lowering, and anti-hypertensive medications. Dr. Pi-Sunyer noted, however, that people receiving the lifestyle intervention arm experienced significant improvement in some measures, including sleep apnea, cardiovascular risk factors (except LDL cholesterol), urinary incontinence, and overall quality of life. For more details on the Look AHEAD trial, as well as its primary results, please see pg. 20 of our ADA 2013 Report – Healthcare Delivery, Cost-Effectiveness, Lifestyle, Prevention, and Epidemiology at http://www.closeconcerns.com/knowledgebase/r/0691a23e.
Questions and Answers
Q: There appears to be a link between type 2 diabetes and Alzheimer’s disease. Did you take into account this situation in your group? Did the person with diabetes and Alzheimer’s disease have a different result than those without?
A: At first we did not do cognitive assessments. The reason is because we did not have enough money. We also enrolled some people who only spoke Spanish and had a lot of American Indians enrolled, who are not particularly literate. So we did not do it at the beginning. However, we are doing it now. We just put in a request to follow people for another five years. Based on what we have seen for other factors, we think that it is likely that cognitive assessments of the two groups would have been similar. Still, we will see if we get a differential over the next five years. It is a very good question.
Q: You have stated that patients in Look AHEAD on the lifestyle intervention had a significantly reduced use of drugs. So at the end, is this intervention cost effective?
A: This study was finished just the end of last year. We are doing all of the cost analysis. I do not have that for you now. The way we did this intervention was quite expensive. We did track all the medications so we can get the medication costs for the two groups. It has not been published yet, because it is still being done. My suspicion is that it will come out to be similar cost effectiveness.
Q: How do you know that those in the intervention arm worked out more?
A: We don't know. Many of them are health conscious people – they volunteered for a 13-year trial. Some of them got quite upset when they were randomized to the control group. Many of them went and did other things; some went to weight watchers, some used meal replacements. We do know that those in the control were not as fit and that they did not lose as much weight. Could they have done something else? Sure.
Q: The results are a little bit depressing. I have seen that in the intervention group all the risk factors improved but LDL cholesterol. Can you extend a little bit on the lack of efficacy of reducing LDL in not reducing outcomes?
A: We have known that LDL cholesterol is extremely important for CV risk. We also know that weight loss is not particularly good at lowering LDL. This trial confirmed that. If I did a similar trial again, I would also put in strong anti-LDL medications in order to try and get their LDL below 70 mg/dl. Most of the intervention group had an LDL above 70 mg/dl. We did not impact LDL overall and that might have made a huge difference.
Q: Do you have any data on people’s smoking habits?
A: We did not allow smokers in. The reason we didn't was because we felt it would not be ok to go 13.5 years to not tell a smoker to not smoke and we were concerned that a big anti-smoking campaign would compound the results. However, at least in our country, very few obese diabetic patients smoke. Maybe they are addicted to food and not smoke. Certainly type 2 diabetes patients already are told not to smoke very strongly by their doctors.
Q: What I saw was that in the first year the results are splendid, then in the follow up the weight is increasing. What happened? Have you looked at adherence?
A: We have self-reported data on physical activity. They did their physical activity at or near home; they did not do it at the center. We do not know how accurate their results are and clearly the physical activity went down over time. Whether that is a function of age, fatigue, boredom, I do not know. We assume that the compliance with the diet also changed over time. The only measures of that are the weight and the waist circumference. But the risk factors all went down and stayed down pretty well.
5. Diabetes Complications
Debate: Dogmata in Diabetes: Albuminuria is a Surrogate Endpoint for Cardiorenal Disease
PRO
Dick de Zeeuw, MD, PhD (University Medical Center Gronigen, Gronigen, The Netherlands)
Dr. Dick de Zeeuw framed the question of whether albuminuria is a surrogate endpoint for cardiorenal disease by stating that a valid surrogate 1) has a plausible mechanism for elevating risk of the outcome (i.e., renal and CV risk) and 2) is an independent predictor of risk for the outcome. Additionally, reducing the factor’s level must be an independent predictor of risk reduction. In Dr. de Zeeuw’s opinion albuminuria meets these three criteria. First, he detailed a mechanism by which albuminuria could be tied to elevated CV and renal risk. An albuminuria leak could cause inflammatory responses in both the kidney and capillary beds, according to Dr. de Zeeuw, thereby damaging the kidneys and CV system. Indeed, the more vessels within a vascular bed are exposed to albuminuria, the greater the renal and CV risk. Regarding the second requirement – that albuminuria be an independent predictor of CV/renal risk – Dr. de Zeeuw pressed that it is “not a debatable issue” that albuminuria is a strong predictor of risk. Finally, he presented data suggesting that interventions that lower albuminuria are independently associated with renal and CV protection. Thus, he sees albuminuria as a valid surrogate for a meaningful CV and renal outcome in diabetes.
- Dr. de Zeeuw preempted Dr. Giancarlo Vierti’s (King’s College London School of Medicine, London, UK) citations of the ONTARGET, ACCOMPLISH, and ALTITIUDE trials in Dr. Vierti’s argument against albuminuria being a valid surrogate. For background, these trials showed a reduction in blood pressure and albuminuria without further renal and CV protection. However, Dr. de Zeeuw underscored that these trials are not robust counterexamples to albuminuria’s validity. Participants in ONTARGET, Dr. de Zeeuw explained, had low levels of albuminuria to begin with, making it difficult to discern a benefit from further reducing albuminuria. Few participants in ACCOMPLISH had micro- (~25%) or macroalbuminuria (~5%), so these subpopulations were small. In ALTITUDE albuminuria levels did not decrease to a large extent, leading Dr. de Zeeuw to question if one should have even expected to see an improvement in CV or renal risk. Additionally, during the subsequent panel discussion, he explained that these trials were intended to test the safety and efficacy of novel agents. Thus, it could be the experimental treatments negatively impacted renal or CV risk, confounding the impact of albuminuria on these outcomes.
- More specifically, ONTARGET was a randomized control trial comparing three arms: telmisartan (an angiotensin II inhibitor), ramipril (an ACE inhibitor), and a combination of the two. The trial failed to show any differences between the groups and even showed additional renal risk with the combined therapy.
- ACCOMPLISH was a study to determine if high-dose fixed combination of benazepril-amlodipine would be more effective than benazepril-hydrochlorothiazide in reducing CV morbidity and mortality. The trial was terminated early because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide.
- ALTITUDE was a phase 3 trial for Novartis’ aliskiren (a renin inhibitor). ALTITUDE was terminated in December 2011 after the seventh interim analysis due to futility or a slight increase in the primary endpoint with aliskiren; the primary endpoint was defined as a composite of time to CV death or first occurrence of cardiac arrest with resuscitation, nonfatal MI, stroke, hospitalization for heart failure, ESRD, death attributable to renal failure, need for renal-replacement therapy, doubling of baseline serum creatinine.
CONTRA
Giancarlo Viberti, MD (King’s College London School of Medicine, London, UK)
Dr. Giancarlo Viberti countered that current evidence does not substantiate an argument for the use of albuminuria as a surrogate for renal or CV outcomes in treatment decisions. Dr. Viberti underscored the need to look at prospective studies, which pre-specify looking at the albuminuria and renal/CV risk. According to Dr. Viberti, such prospective studies do not demonstrate that treatment-associated differences in attained levels of albuminuria translate into a reduction of renal and CV outcomes in diabetes. For example, Dr. Viberti detailed the ALTITUDE study (a phase 3 trial for Novartis’ aliskiren [renin inhibitor]), which found that reducing albuminuria did not impact either CV or renal outcomes. Furthermore, Dr. Viberti thinks studies that rely on albuminuria reduction as a proof of concept for designing randomized control trials could be misleading. Indeed, he concluded by asserting that if he were to design a large trial today he would not base his hypothesis on a drug’s impact on CV or renal outcomes the albuminuria reductions it produces.
PANEL DISCUSSION
Giancarlo Viberti, MD (King’s College London School of Medicine, London, UK); Dick de Zeeuw, MD, PhD (University Medical Center Gronigen, Gronigen, The Netherlands)
Q: In clinical practice today, is there any reason to measure albuminuria outside a study?
Dr. Viberti: Yes, because you can identify people with cardiovascular disease. It is a beautiful biomarker. It is a strong predictor of the outcome – one of the strongest. However, that does not mean that it is a surrogate to the outcome.
Dr. de Zeeuw: You can use it in practice. Whether it is a mechanistic connection is something totally different. The question is whether the FDA is right or wrong to say it is not a surrogate. We debate with the FDA all the time. ALTITUDE was not set up to test the impact of reducing albuminuria. It was designed to test an anti-hypertensive treatment. It was not designed to test the surrogacy of albuminuria. Is it a surrogate? I agree with you that it is not. But then the question is whether blood pressure is a surrogate, since it also decline in ALTITUDE and a benefit was not seen.
Comment: I would like to support this idea of being critical of post-hoc analyses. They are hypothesis generating and should not be used for drawing conclusions.
Q: I wonder about the durability of effect – if we remove some of the albuminuria treatments the albuminuria goes back up. Is albuminuria a sign of the plasticity of the condition and not a causative path?
Dr. de Zeeuw: For me that is an argument that it is a causative path – that is the case with blood pressure and hear rate. When you stop taking medications for those conditions the markers go up again. That is why I think that it is a causative pathway. Albuminuria was an abnormally low reduction in ALTITUDE. The fact that albuminuria could be lowered and you could still have a negative outcome does not mean that albuminuria is not connected to the outcome. It could be that the drug did something of harm.
Q: If reaching surrogacy is such a tall order, is it really possible? If it is not attainable should we be trying to do it in a different manner?
Dr. Viberti: I agree that it is a tall order. What else do we have? A1c is not a surrogate. Nowadays companies that develop a new drug need to also prove that there is no renal or CV harm; glucose is not enough anymore.
Oral Presentations: Impact of Treatment and Genetic Susceptibility to Comorbidities and Mortality
COMBINATION THERAPY WITH METFORMIN PLUS SULFONYLUREAS VERSUS METFORMIN PLUS DPP-4 INHIBITORS AND RISK OF ALL-CAUSE MORTALITY
Craig Currie, PhD (Cardiff University, Cardiff, UK)
Dr. Craig Currie presented one of two BMS/AZ-supported, retrospective analyses his research team performed on the safety of sulfonylureas (SFUs) as either a first line agent or as an add-on to metformin. The researchers looked at the Clinical Practice Research Datalink, a retrospective UK dataset that includes roughly 10% (~10 million) of all patients treated in primary care in the UK. The analysis looking specifically at SFUs in combination with metformin found that being on a SFU plus metformin (n=33,983) was associated with an adjusted hazard ratio of 1.357 (95% CI, 1.076-1.710; p=0.010) for all-cause mortality compared with combination therapy with a DPP-4 inhibitor and metformin (n=7,864). For context, 84 people on a DPP-4 inhibitor and metformin died and 1,133 people on an SFU and metformin died. All of the subgroup analyses found a numerical imbalance in the favor of DPP-4 inhibitors with regards to all-cause mortality, and a few were statistically significant (females, older than 63 years, and having a Charlson index of at least two). Dr. Currie’s group also conducted two sensitivity analyses: 1) a matched-cohort study using age, gender, year of index exposure, diabetes duration, BMI, serum creatinine, and A1c, and 2) a matched-cohort using a propensity score predicted by a “wide range of candidate co-variables” The adjusted hazards ratio significantly disfavored the SFU plus metformin arm for both the directly matched analysis (aHR=1.85; 95% CI, 1.40-2.45) and the propensity matched analysis (aHR=1.50; 95% CI, 1.09-2.05).
- The researchers looked at the Clinical Practice Research Datalink: a retrospective UK dataset, which comprises ~10% (n=10 million) of all patients treated in primary care in the UK. From this dataset, the researchers extracted people with type 2 diabetes who initiated treatment between 2007 (when DPP-4 inhibitors were introduced in the country) and 2013. They criteria required a six-month wash-in period to ensure people had not previously received the studied treatment. The index date was defined as the first prescription date and the end date was when a person died or 90 days after her last prescription.
- The main comparative analysis utilized a Cox proportional hazards model to compare time to death. The covariates included were age, gender, diabetes duration, A1c, SBP, HDL, LDL, triglycerides, serum creatinine, BMI, smoking status, and baseline morbidity as measured by contacts with their general practitioner and a Charlson index (which stratifies comorbidity). We were disappointed that Dr. Currie’s group did not use a more robust measure of renal failure than creatinine.
- Dr. Currie also conducted two sensitivity analyses. One was a matched-cohort study using the following criteria: age (±2 years), gender, year of index exposure, diabetes duration (±1 year), BMI (±3 kg/m2), serum creatinine (±10 μmol/l), and A1c (±1%). The second analysis was a matched-cohort using a propensity score predicted by a “wide range of candidate co-variables” (Dr. Currie did not specify these).
- The baseline characteristics between the SFU plus metformin group and the DPP-4 inhibitor plus metformin group varied significantly for several covariates. The average age was 62.3 years in the SFU and metformin arm vs. 59.6 years in the DPP-4 inhibitor and metformin arm (p <0.001). The baseline A1c was 9.1% in the SFU and metformin arm and 8.5% in the DPP-4 inhibitor plus metformin arm (p <0.001). The mean diabetes duration was 5.1 years in the SFU plus metformin arm and 5.5 years (p=0.010) in the DPP-4 inhibitor and metformin arm. The mean follow-up for each treatment was not reported.
- Being a retrospective analysis, this study had several important weaknesses, the magnitude of whose impact attendees sharply questioned during Q&A. As noted above, large differences existed in the baseline characteristics between the two groups. Though Dr. Currie worked to control for these differences, due to the dataset’s limitations, he was not able to control for several key covariates, including race/ethnicity and income. Additionally, it is possible that confounding by indication could have impacted the results – a patient characteristic might cause a physician to prescribe a SFU inhibitor instead of a DPP-4 inhibitor, and make a person more likely to die independent of taking a SFU (though the matched-cohort using a propensity score might have been able to account for both of these variations). Furthermore, the DPP-4 inhibitor and metformin arm had relatively few events (n=84), raising the question of whether the result could have been skewed by chance. We also note that Dr. Currie’s analysis included many different SFUs. It could be that earlier generation SFUs drove mortality risk, while later generation options (i.e., gliclazide) were less harmful. We would be interested in the results of a subanalysis looking at each SFU’s risk independently.
Questions and Answers
Q: One of the problems with these analyses is that you are looking at relatively new drugs and we have not accumulated enough numbers. In terms of mortality the numbers were relatively small.
A: We don't have any control over these data. We get the data and we periodically analyze the data to independently determine if there are any signals. All we can do is wait.
Q: Can you tell us what drugs did you mostly see?
A: The primary DPP-4 inhibitor in this study was Januvia.
Q: I am interested in the cause of the deaths. Do you have data on that, and on hypoglycemia?
A: We tend not to look at hypoglycemia since it is fairly unreliably reported. Similarly, the death report does not come with the primary cause of death. All cause mortality, however, uses all CV, cancer, etc. deaths.
Q: We know there are significant differences between SFUs in terms of CV risk and mortality. So under this view, which are the SFUs you have in your study?
A: That is true. We do have that information. It is possible for us to break it up further.
Q: The current recommendations in the UK are to introduce patients on metformin and then later SFUs. What are the criteria to introduce a person onto a DPP-4 inhibitor and metformin?
A: It guides for physicians doing so when a patient is contraindicated for a SFU. However, nobody takes care of the guidelines anyways. So… [Laughter]
Q: You started your study when gliptins were introduced, so there is a calendar year bias. Did you adjust for that?
A: We did look at calendar year.
Q: You said that we should be taking this to the regulatory authorities. Would you like to comment on the limitations of your study? Including the varied baseline characteristics.
A: This is just one part of the puzzle. I think that the majority of population scientists think that there is a reason to look at SFUs and when I’m on it insulins as well.
ASSOCIATION BETWEEN FIRST-LINE MONOTHERAPY WITH SULFONYLUREA VERSUS METFORMIN AND RISK OF ALL-CAUSE MORTALITY
Christopher Morgan, MSc (Pharmatelligence, Cardiff, UK)
Dr. Christopher Morgan presented the second of two BMS/AZ-supported, retrospective analyses his and Dr. Craig Currie’s (Cardiff University, Cardiff, UK) research team performed on the safety of sulfonylureas (SFUs). In both studies, the researchers looked at the Clinical Practice Research Datalink, a retrospective UK dataset, which comprises ~10% (n=10 million) of all patients treated in primary care in the UK. The analysis looking specifically at SFUs as a first-line monotherapy, found that being on a SFU (n=15,687), instead of metformin (n=76,811) was associated with an adjusted hazard ratio of 1.580 (95% CI, 1.483-1.684; p<0.001). All of the subgroup analyses found a statistically significant imbalance in the favor of metformin. Like the first trial, the research group also conducted two sensitivity analyses: 1) a matched-cohort study using age, gender, year of index exposure, diabetes duration, BMI, serum creatinine, and A1c, and 2) a matched-cohort using a propensity score predicted by a “wide range of candidate co-variables” The adjusted hazards ratio significantly disfavored the SFU arm for both the directly matched analysis (aHR=1.38; 95% CI, 1.05-1.70) and the propensity matched analysis (aHR=1.90; 95% CI, 1.73-2.09).
- The researchers looked at the Clinical Practice Research Datalink, a retrospective UK dataset, which comprises ~10% (n=10 million) of all patients treated in primary care in the UK. From this dataset, the researchers extracted people with type 2 diabetes who initiated treatment between 2000 and 2013. They required a six months wash-in period to ensure people had not previously received the studied treatment. The index date was defined as the first prescription date and the end date was when a person died or 90 days after her last prescription.
- As with the first study, the main comparative analysis utilized a Cox proportional hazards model to compare time to death. The covariates included were age, gender, diabetes duration, A1c, SBP, HDL, LDL, triglycerides, serum creatinine, BMI, smoking status, and their baseline morbidity as measured by contacts with their general practitioner and a Charlson index (which stratifies comorbidity). We were disappointed that the group did not use a more robust measure of renal impairment than creatinine.
- Dr. Morgan also conducted two sensitivity analyses. One analysis was a matched-cohort study using the following criteria: age (±2 years), gender, year of index exposure, diabetes duration (±1 year), BMI (±3 kg/m2), serum creatinine (±10 μmol/l), and A1c (±1%). The second analysis was a matched-cohort using a propensity score predicted by a “wide range of candidate co-variables” (Dr. Morgan did not specify these).
- The baseline characteristics between the SFU plus metformin group and the DPP-4 inhibitor plus metformin group significantly varied for several covariates. The average age was 61 years in the metformin arm vs. 68 years in the SFU arm (p <0.001). Baseline creatinine was 85 in the metformin arm and 98 in the SFU arm (p<0.001). The Charlson index was 1.9 in the metformin arm and 2.2 in the SFU arm, indicating that people receiving SFU monotherapy were significantly more ill at treatment initiation (p<0.001). The mean A1c was 8.6% in the metformin arm and 9.1% in the SFU arm (p<0.001). The mean follow up for each treatment was 3.1 years.
- Being a retrospective analysis, this study had several important weaknesses — their magnitude was sharply questioned during Q&A. As with the first study, while the research group worked to control for differences in baseline characteristics between the two groups, due to the dataset’s limitations, they were unable to control for several key covariates, including race/ethnicity and income. Additionally, it is possible that confounding by indication could have impacted the results – a patient characteristic might cause a physician to prescribe a SFU instead of metformin, and make a person more likely to die independent of taking a SFU. Though the matched-cohort using a propensity score might have been able to account for both of these variations. Furthermore, as one attendee noted, “A physician prescribing a SFU first line in this day in age is not the same as a physician prescribing metformin.” Thus, there could have been uncontrolled physician level covariates. We also note that Dr. Currie’s analysis included many different SFUs. It could be that earlier generation SFUs drove mortality risk, while later generation options (i.e., gliclazide) were less harmful. We would be interested in the results of a subanalysis looking at each SFU’s risk independently.
Questions and Answers
Q: Could it be metformin intolerance that biases people to die?
A: These were all patients whose first ever script was for either a SFU or metformin.
Q: Did you control for ethnicity?
A: Ethnicity could not go into the model because it is poorly coded in the dataset.
Comment: You can imagine that a physician prescribing a SFU first line in this day in age is not the same as a physician prescribing metformin.
A: That is true, but it used to be that people were prescribed SFUs over metformin in general.
Comment: The variations seen in the subgroup analyses make me concerned that there were unmeasured confounding factors.
A: All of the adjusted hazard ratios are within one another’s confidence intervals, except for the younger than 63 years group, which was even more likely to die on an SFU. Potentially there are residual confounders. We adjusted as much as we could. We cannot deal with what is unknown. The fact that all three of our analyses came up with a significant difference indicates that there is something in this finding.
Q: Did you control for renal function?
A: We used creatinine as a proxy.
Q: Did you take into account the differences between SFUs?
A: Everybody bar 300 patients was prescribed a second generation SFU. Gliclazide was the most common. I think 12,000 of the patients were on gliclazide.
Q [Dr. Ele Ferrannini (University of Pisa, Pisa, Italy)]: The results of this and the previous study suggest that SFUs will kill more people than DPP-4 inhibitors and metformin. How do you reconcile this finding with trial evidence? In ORIGIN, SFUs did not kill an excess number of people. If I remember correctly, SFUs in the UKPDS were not associated with excess mortality.
A: In UKPDS they were at an increased risk when on an SFU in combination with metformin.
Dr. Ferrannini: That analysis was on only 320 people.
Q: Have you factored in a time dependent analysis? I am interested in if there is an SFU dose effect. That would be one way to get around there being an indication bias in these analyses.
A: That is something we could do.
Oral Presentations: Retinopathy: Risk Stratification and Novel Therapies
PIOGLITAZONE INCREASES THE RISK OF DIABETIC MACULAR EDEMA IN PATIENTS WITH TYPE 2 DIABETES
Kanta Fujimoto, MD (Tazuke Kofukai Kitano Hospital, Osaka, Japan)
Dr. Kanta Fujimoto presented the results of a retrospective cohort study that investigated whether the use of pioglitazone increases the risk of diabetic macular edema (DME) in patients with type 2 diabetes. The study included 22,115 patients in the Kitano Hospital database with type 2 diabetes who did not have a history of DME – 953 who had used pioglitazone at some point in time, and 21,162 who had not. In the analysis, Dr. Fujimoto and colleagues adjusted for potential confounds, including age, sex, A1c, renal failure, congestive heart failure, insulin use, antiplatelet use, and renin-angiotensin inhibitor use. After adjusting for such confounds, the incidence of DME among pioglitazone non-users was found to be 0.45%, compared to 1.15% in pioglitazone users, at 12 years of follow-up. The two-year follow-up hazard ratio for pioglitazone and DME was 5.28 (95% CI: 1.55-17.92), while the 12-year follow-up hazard ratio was 5.06 (95% CI: 2.59-9.91). Pioglitazone use in combination with insulin was found to carry an even higher risk, with a 12-year follow-up hazard ratio of 11.86 (95% CI: 4.70-29.93). Dr. Fujimoto noted that the study had some limitations, including that it did not account for covariates such as duration of diabetes, blood pressure, and lipid profiles.
Questions and Answers:
Q: As you know, pioglitazone is an insulin-sensitizing drug that is usually only used after failure of metformin, and in particular, in obese patients who have more insulin resistance. The question is, why have you not been taking into account variables such as BMI in your adjustments?
A: That’s a good point. Unfortunately we do not have [the adjusted hazard ratio taking BMI/weight into account]. That is an important factor.
Q: What dose of pioglitazone did you use in the study? The max dose of 45 mg, or a lower dose?
A: We do not have data on the specific doses of pioglitazone used. Many doctors used 15 mg.
36-MONTH SAFETY AND EFFICACY OF RANIBIZUMAB IN DIABETIC MACULAR EDEMA: THE RESTORE EXTENSION STUDY (FINAL ANALYSIS)
Anna Boixadera, MD (Hospital Vall D’Hebron, Barcelona, Spain)
Dr. Anna Boixadera discussed the 36-month results of the RESTORE study, which examined the efficacy and safety of ranibizumab (Novartis’ Lucentis) in patients with diabetic macular edema (DME). In the study, patients with visual impairment due to DME were randomized to 0.5 mg ranibizumab + sham laser (n=83 who entered the 24-month extension following the 12-month core study), 0.5 mg ranibizumab + active laser (n=83), or sham injection + active laser (n=73). In months 0, 1, and 2 of the study, participants were administered three injections of ranibizumab/placebo monthly and had one sham/active laser treatment; in months 3-11, they were administered one injection and had one laser treatment; and in month 12, they were only administered one injection. In the 24-month extension, participants in all arms were treated with ranibizumab as necessary, based on their visual acuity levels. By the final year of the study, the mean number of treatments declined to an average of less than three injections per year; across all treatment arms, 19-25% of patients did not need any ranibizumab during the 24-month extension. Mean improvements in best corrected visual acuity (BCVA) and central retinal thickness (CRT) with ranibizumab treatment at 12 months were maintained through the 36-month mark, and these measures improved in patients initially treated with laser therapy only in the first 12 months during the subsequent extension period. During the extension period, no new ocular or non-ocular safety findings emerged (during the trial, the most frequent adverse events were nasopharyngitis [23.3%], cataracts [16.3%], eye pain [15.4%], and hypertension [13.3%]).
Questions and Answers:
Q: I keep criticizing that Novartis doesn’t publish its kidney data [for ranibizumab]. You showed some proteinuria data. What was the actual number of proteinuria cases in patients?
A. It’s low. [Editor’s note: Dr. Boixadera returned to the slide, which showed that one patient in the ranibizumab + sham laser and one patient in the ranibizumab + laser treatment arms had proteinuria.]
Oral Presentations: Clinical Nephropathy — Focus On Novel Biomarkers and Improving Outcomes
PREDICTORS OF RAPID DECLINE IN RENAL FUNCTION IN TYPE 2 DIABETES
Helen Looker, MBBS (University of Dundee, Dundee, UK)
The aim of this case-controlled SUMMIT study was to identify serum biomarkers beyond eGFR that predict which patients with established renal impairment would have the most rapid subsequent decline in renal function. Using a large cohort of patients with type 2 diabetes, cases (n=154) were defined as those who had lost ³40% of their baseline eGFR over a follow up of £42 months, while controls (n=155) had a <5% drop in eGFR at a follow up of £42 months. Individual biomarkers were adjusted for age, sex, diabetes duration, and all clinical covariates. Of the 24 biomarkers measured, 14 were significantly associated with progression to renal disease. Many of these, including Cystatin C, ADMA, SDMA, and VCAM, have previously been linked to compromised renal function. As expected, the strongest and most reliable predictor was Cystatin C; however, biomarkers of particular interest that contributed to a modest improvement in prediction of progression to renal dysfunction include: 1) NT-ProBNP, which has principally been an indicator of heart failure and CVD but was found to be a predictor of renal impairment independent of eGFR; 2) N-Acetyl Beta D Glucosaminidase (NAG), a marker of lysosomal enzyme release in serum; 3) SDMA:ADMA ratio, a measure of ADMA catabolism; and 3) Soluble Tumor Necrosis Factor Receptor 2 (STNFR2), a receptor for TNF alpha and a pro-inflammatory mediator of glomerulonephritis. Future studies should seek to replicate these findings and develop risk scores in broader populations.
Questions and Answers
Q: Your population in this study was rather special.
A: The causes behind the renal decline are probably many and varied. Yes, these are polarized and extreme cases and controls. Part of the next step is to test this in a wider, more general renal population without such limited starting points.
Q: Once you identify reliable markers of progression of renal disease, how do you envision applying that to patient management?
A: We haven’t quite got the master plan worked out. We want to try to stratify our populations for clinical trials, meaning that we intend to provide them with biomarkers so they can select patients with the greatest risk and thereby enrich their study samples. Then, we want to decide which biomarkers can be identified cheaply and easily.
Q: Essentially, you found that the lower your eGFR is to start with, the faster you are to decline?
A: Yes, but we are also showing that other biomarkers may have additional importance as well.
LONG-TERM RENAL OUTCOME IN THE STENO 2 STUDY
Peter Gaede, MD (Copenhagen University Hospital, Slagelse, Denmark)
The aims of this study were to evaluate the long-term mortality and progressive decline of renal function in patients with type 2 diabetes and microalbuminuria. The entirety of the sample was originally enrolled in the Steno 2 Study, in which 160 patients with type 2 diabetes and microalbuminuria were randomized to either conventional or intensified, multiple risk factor treatment for an average of eight years (1993-2001), following which point all patients were offered the intervention. Compared to the control, multifactorial treatment was found to: 1) decrease a composite of death by any cause and end stage renal disease by 49% (primary endpoint); 2) lower all-cause mortality, end stage renal disease, or doubling of baseline creatinine by 45% (secondary endpoint); and 3) diminish the risk of progression to microalbuminuria by 66% (tertiary endpoint). Notably, intervention reduced the mean time to dialysis by 6.6 years, meaning that it succeeded in postponing initiation of renal replacement therapy. There was no difference in renal function between the treatment and control arm after 19 years of follow-up, but Dr. Gaede attributed this to competing risk from CV death in the control group and interpreted the general results of the study as support for early, intensive treatment.
Questions and Answers
Q: For both the primary and secondary endpoints, your curves diverge after eight years. How did you interpret this?
A: It seems that mortality starts to rise around year eight, but when you look at the curves as a whole, it doesn’t really matter. This could be due to chance. One of the important messages we drew at year eight was that the sooner you start treatment, the more effective it is. This is another argument for early intervention, in my mind.
Comment: One interpretation could be that it takes time. For the microvascular side of complications, you need a period of shorter time. If you aim for hard endpoints or death, you need more. I think that is the explanation.
Q: What happened with HbA1c?
A: We have data up to year 13; it’s the same, and has been the same for the follow-up period. It’s around 7.8% in both groups.
Oral Presentations: Diabetes Prediction: Is Stratification the Solution?
BIOMARKERS OF CARDIAC STRESS AND RISK OF MICROVASCULAR EVENTS IN PATIENTS WITH TYPE 2 DIABETES: RESULTS FROM THE ADVANCE TRIAL
Paul Welsh, PhD (University of Glasgow, Glasgow, Scotland)
Dr. Paul Welsh presented results on the ability of two cardiac biomarkers, hsTNT and NT-proBNP, to predict microvascular events (particularly nephropathy) in 439 type 2 patients from the ADVANCE trial. Dr. Welsh and his colleagues created two models around the cohort, and found that, for both models, there was a moderate independent risk association between microvascular events and hsTnT; microvascular events and NT-proBNP; nephropathy and hsTnT; and nephropathy and NT-proBNP (all associations: p <0.001). It’s valuable to see evidence that biomarkers can predict microvascular events, even when numerous factors are controlled for. Complications are responsible for much of the healthcare cost burden related to diabetes, and we are hopeful that better biomarkers can help HCPs catch complications earlier or prevent them entirely.
- The researchers used two models in their analysis. Model one adjusted for age, sex, and randomized treatment allocations. Model two included the same three factors, and additionally controlled for diabetes duration, smoking, systolic blood pressure, resting heart rate, BMI, albumin/creatinine ratio, eGFR, A1c, glucose, lipids, C-reactive protein, and history of CVD. Dr. Welsh was especially proud of the fact that the aforementioned association values remained significant even after controlling for all of the factors in model two.
- There was moderate improvement in risk classification for all microvascular events, nephropathy, and retinopathy when using either hsTnT, NT-proBNP, or hsTnt and NT-proBNP together. Dr. Welsh and his group analyzed the data both categorically and continuously, and he noted that the continuous model is more appropriate for statistics, although less valuable for clinical practice. However, Dr. Welsh did find a great improvement in risk classification using the continuous model, with values for all markers in both all microvascular and nephropathy with p <0.001. Additionally, the risk was improved in retinopathy, with p <0.05 for all groups.
- Researchers randomly selected a sample of 3,862 participants from ADVANCE that were over the age of 55, diagnosed with type 2 diabetes over the age of 30, and at risk for CVD and all microvascular events (at five-year follow-up). Each participant’s hsTnT and NT-proBNP plasma levels were taken, and this study used data from 439 patients that had new and worsening cases of microvascular events.
- The average A1c of participants was 7.8%, the average BMI was 30 kg/m2, and the average age of participants was 67 years.
Questions and Answers
Q: If I remember correctly, your definition of nephropathy is to renal death. Would making a narrower definition lower the predictability of your model?
A: That is a valid question, and that is something we could look at. What you want to avoid is renal death and other interventions, and I don’t know of any study that is powered to do that. That is a difficult question.
Q: I have a question about your base model for the prediction analysis. How did you choose variables?
A: There are not many models. It’s been through revisions. This is updated data compared to what is in the abstracts because we have had reviewer input since we submitted. We put in everything we think would be important for CV models – that’s our approach. We thought about putting in CRP for the prediction model, but the CRP probably isn’t going to be used in risk prediction anytime soon.
Corporate Symposium: Diabetes and Complications (Sponsored by the Danish Diabetes Academy and JDRF)
CLOSING REMARKS
Richard Insel, MD (Chief Scientific Officer, JDRF, New York, NY)
Dr. Richard Insel concluded the joint JDRF and Danish Diabetes Academy session by giving his top themes and takeaways from the morning discussion on diabetes complications. Dr. Insel highlighted the need for more basic research into complications, particularly to understand the pathogenesis of complications. Down the road, the goal would be to target the specific pathways and physiology that cause complications to develop. Use of the human model, particularly patients who experience spontaneous remission or a halt in the progression of a disease, may help determine the pathogenesis. Not understanding the pathogenesis of complications, Dr. Insel warned, eliminates the possibility for us to validate biomarkers – an area he remarked is also crucial for detecting disease and intervening early. Dr. Insel also called for better staging and risk scores to determine who will likely get a complication and how quickly the individual will progress. Shorter trials with intermediate endpoints can help accomplish this. Turning to current medical treatment, Dr. Insel highlighted the necessity of using drugs efficiently, calling for more effective screening of complications, particularly in the eyes. Drugs, he remarked, should be used as the right time and in the right patients; one example Dr. Insel gave was VEGF inhibitors that work very successfully for only about 50% of patients. Concluding the session, Dr. Insel urged the youth in the room (specifically, the two post-docs from Denmark) to continue to create novel partnerships between academia, funding institutes, and industry in order to keep research moving forward.
6. Diabetes Technology
Oral Presentations: In-Patient Diabetes: Rights and Wrongs
THE SAFETY AND EFFICACY OF A SUBCUTANEOUS CONTINUOUS GLUCOSE MONITORING SYSTEM COMPARED TO POINT OF CARE MEASUREMENT IN CRITICALLY ILL PATIENTS: A RANDOMISED CONTROLLED TRIAL
Daphne Bloom (Medical Student, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands)
This trial compared the efficacy and safety of CGM (FreeStyle Navigator; n=87) vs. point-of-care testing (Accu-Chek Inform II; n=90) to guide insulin dosing in ICU patients. Data from the FreeStyle Navigator CGM or Accu-Chek BGM was inputted into a computerized insulin titration program, which nurses then used to obtain an insulin dose. The study was somewhat biased against CGM, as the program was only designed to use single glucose values (i.e., not continuous data or trends). Overall, there was no significant difference between the two groups in terms of hypoglycemia or time spent in target range – this was not that surprising given the algorithm’s limitations. However, the big difference came in the average number of blood samples that were required per patient per 24 hours: just two in the CGM group vs. 12 in the point-of-care testing group (p<0.01). We thought this was fairly compelling – both technologies offered similar glucose control, though CGM did so with significantly less effort. Given the subsequent presentation on nursing burden and cost-effectiveness (see below), we viewed this as a net positive study for in-hospital CGM.
Questions and Answers
Dr. Silvio Inzucchi (Yale University, New Haven, CT): I’m confused about the way the CGM data was plugged into the computer algorithm. You got continuous CGM data every 10 minutes. Point-of-care testing was less often. It sounds like you had much more information with CGM. Was each CGM data point entered into the computerized algorithm?
A: The glucose values were only entered whenever the protocol asked for it. The FreeStyle Navigator was also entered into the algorithm when it had alarms. But there was a disadvantage. If the FreeStyle Navigator alarmed, the blood glucose was entered into the system, and the system then gave advice. If after 15 minutes the blood glucose level was still not in the target range, the CGM alarmed again, and the value was entered into the protocol. But the more frequently you enter values, the advice is not adjusted from these frequent values. So you see higher doses of insulin and faster drops in glucose.
Q: So you may have found a better result with a different protocol?
A: We think if the protocol was adjusted it would have been more in favor of CGM.
Q: What is your experience with the reliability of CGM in this specific subgroup of patients? How good does this match patients in the ICU? For these patients, is subcutaneous measurement equally reliable?
A: Yes, it is. In a previous study, we compared different types of CGM. We compared values with arterial blood glucose using a blood gas analyzer. The study showed that this device was reliable and had accurate glucose values.
CONTINUOUS GLUCOSE MONITORING AT THE INTENSIVE CARE UNIT: NURSING WORKLOAD REDUCTION AND COST-BENEFIT ANALYSIS
Marjolein Sechterberger, MD (Academic Medical Center, Amsterdam, Netherlands)
This study was an economic sub-analysis of that discussed above, which compared use of CGM (FreeStyle Navigator) to point-of-care testing (Accu-Chek Inform II) in the ICU setting. Overall, the researchers found that use of CGM reduced nursing workload by 63%, saving nurses 22 minutes per patient per day over point-of-care testing (“This is clinically meaningful in a busy ICU setting”). Additionally, CGM also reduced costs by 12 euros per patient per day (41 vs. 53 euros) – see below for the specifics of what costs were included. We were quite glad to see this positive data, as the need for better inpatient glycemic control is profound, and CGM has the power to help. We note that this cost-benefit data did not look at clinical outcomes, since the study duration was quite short – we continue to hope that someone conducts a large, long-term hospital study comparing CGM vs. point-of-care testing. If done properly, we are optimistic that CGM would not only improve outcomes, but would demonstrate striking cost-effectiveness.
- The researchers documented the average time it took to complete CGM and point-of-care testing tasks – on average, point-of-care measurements took three minutes, sensor placement took 3.5 minutes (presumably done only ones), sensor calibration took 2.5 minutes, and obtaining a CGM value and entering it into the glucose algorithm took 0.3 minutes.
- The cost-benefit analysis demonstrated a 12 euro per day advantage for CGM – this analysis included a broad array of estimates. Personnel costs were estimated at 38 euros per hour. Device costs included: the FreeStyle Navigator receiver 1,009 euros (1.38 euros per day), 61 euros per sensor (24.40 euros per day), and 892 euros for the Accu-Chek Inform II meter (1.22 euros per day). Ongoing material costs were estimated at: 0.7 euros for point-of-care measurement and 1.19 euros for the FreeStyle Navigator calibration strip (we’re not sure why the latter was more than double the price of the former). Finally, laboratory costs for point-of-care glucose measurement were estimated at 1.66 euros (it was not specified what this included and whether it was per day, per patient, or per test).
Questions and Answers
Q: Say I want to convince the person who manages the budget of my hospital, “I need CGM in my unit.” What comes first – time burden? Euros? Both?
A: Yes, of course. Nursing time in the ICU setting is very diverse and glucose control is only a part of the daily tasks of nurses. However, it’s important to keep in mind that it takes substantial time for glycemic control. You could maybe diminish the costs by use of a CGM system.
Q: Did the protocol require confirmation of any of the CGM data with point-of-care testing prior to action being taken. If the CGM alarmed, were the nurses able to act directly on the CGM data, or did they have to perform a fingerstick test to confirm?
A: It depends. Normally during the study, the values of the CGM system were used for the glucose control algorithm.
Q: I’m a physician from Denmark. I want to ask about the priority of this data. I’m concerned about the workload for nurses. I’d imagine better quality, less hypoglycemia, better outcomes, and shorter patient stays. I’m just curious why you prefer to focus on workload for nurses.
A: We were limited by the amount of data generated by the randomized controlled trial. This was only powered to detect a difference in hypoglycemia or hyperglycemia events. There was no long term data that we could use for the economic analysis. It was a sub analysis, and we were limited by the data. Maybe just focusing on nursing workload can be extended when you have more available data.
Dr. Silvio Inzucchi (Yale University, New Haven, CT): Nice study, and I understand the importance. But the value added of 22 minutes per day is only cost savings if the nurse can do something else productive during that time. It’s unlikely they could take another patient on. In that small savings of time, unless the minutes can be apportioned to something else of value, it’s not really cost savings.
A: Nursing personnel costs was only part of the economic analysis. There were diminished laboratory costs as well – that was substantial.
Oral Presentations: Technologies to Transform Diabetes
THE PHARMACOLOGIC PROFILE OF RAPID-ACTING INSULIN ADMINISTERED BY JET-INJECTION IN PATIENTS WITH DIABETES
Elsemiek Engwerda, MD (Radboud University, Nijmegen, The Netherlands)
Dr. Elsemiek Engwerda detailed a 24-patient study comparing postprandial glucose levels following needle-free jet-injected insulin (via air pressure) and conventional needle-injected insulin. Patients with type 1 and type 2 diabetes were tested on two separate days after eating a standardized large carbohydrate (108 grams) meal, with glucose and insulin measured for the subsequent six hours. On the pharmacokinetic front, jet-injection had a clear advantage – it led to a 44% reduction in the time to peak insulin concentration vs. needle injection, translating to a 40 minute advantage (51 minutes vs. 91 minutes; p =0.003). The faster absorption led to a slight 12 mg/dl advantage for jet injection in terms of maximal blood glucose (227 mg/dl vs. 239 mg/dl), though the result was not statistically significant (p=0.36). It was somewhat surprising to us not to see a larger improvement in glycemia, given the 40-minute advantage in time to peak insulin levels. There was also a non-significant trend towards higher discomfort with the jet injector as measured on a 0-10 point visual analog scale (~2 vs. ~1.1; p =0.14). We found this study interesting and hypothesis-generating, though by no means a slam dunk for jet injection – the needleless infusion is certainly attractive, though the trend towards higher pain was concerning. Nevertheless, it was encouraging to see EASD bringing news on new insulin delivery technologies – we also saw new data on Insuline’s InsuPad and BD’s intradermal needles (see our coverage elsewhere in this report).
- Jet injected insulin is a needle free alternative for insulin administration that uses high velocity air pressure (>100 m/s). Insulin delivery by jet injection has a larger subcutaneous dispersion pattern than insulin delivery by a conventional pen, which may enable more rapid insulin uptake.
- This study was a placebo-controlled, randomized, double-dummy crossover study, with participants tested after two standardized meals, two weeks apart. Each participant received his or her personalized insulin aspart dose one minute before a standardized meal (108 g carbohydrate, 7 g fat, and 11 g protein). Blood glucose was tested every five minutes for the first three hours, and every 10 minutes for the remaining three hours. Blood insulin levels were tested every five minutes for the first hour, every 15 minutes for the second hour, and then once every half hour for the last four hours of the study.
- Patients with both type 1 (n=12) and type 2 diabetes (n=12) participated, with an average A1c of 7.5%. The average age of participants was 39 years for participants with type 1 diabetes and 61 years for participants with type 2 diabetes. The average BMI was 26 kg/m2 for participants with type 1 diabetes and 27 kg/m2 for type 2 diabetes. Eight participants with type 2 diabetes were using metformin, and the majority of participants with both type 1 diabetes and type 2 diabetes were using a basal-bolus insulin regimen. It was valuable to see the small study recruit patients with both type 1 and type 2 diabetes.
Questions and Answers
Q: If you look at the time it takes for the insulin to peak when using the jet injection vs. conventional pen, it seems as though the time for the jet injector is similar to values for subcutaneous injections, which seem delayed. Do you have any explanation for the greater absorption times?
A: No, I do not. In the first study we did in healthy participants, the time to maximum plasma insulin levels was reached faster. I’m not sure if the delay was due to the diabetes or if it was due to something else.
Q: Did you find a difference between patients with type 1 diabetes and type 2 diabetes?
A: There was not a significant difference between patients with type 1 diabetes and patients with type 2 diabetes; however, we did use a small sample size, with 12 participants in each group.
Q: Are you going to try doing additional tests using more balanced meals – for example, meals with fewer carbohydrates that we could recommend to our patients?
A: We are going to do a third test to look at reducing hyperglycemia. However, I am not sure if we are going to test this with a more balanced meal. You are right that the meal we are currently using is very high in carbohydrates (about 100 g), so perhaps this is not representative of real life.
Q: Are you aware if the insulin is injected subcutaneously or dermally when you use the jet-injected insulin? I ask because there is a difference in absorption between subcutaneous and dermal.
A: It is absorbed in the subcutaneous tissue.
Q: I am wondering about the injection size given the difference in absorption between the different body sizes. Where was the insulin injected?
A: The insulin was injected in the abdomen, about five centimeters from the belly button.
CLINICAL EVALUATION OF THE IMPERIAL COLLEGE BIO-INSPIRED ARTIFICIAL PANCREAS OVERNIGHT AND AFTER BREAKFAST IN ADULTS WITH TYPE 1 DIABETES
Monika Reddy, MD (Imperial College London, London, UK)
Dr. Monika Reddy presented the results from a 13-hour closed-loop study (n=17) evaluating Imperial College’s closed-loop system (Medtronic Enlite CGM, Accu-Chek Spirit Combo pump, laptop driven control – certainly a research platform at this stage). Overall, participants spent an average of 68% of the time in target (70-180 mg/dl), no time in hypoglycemia, and 32% of the time above 180 mg/dl. Data looked less solid in the tighter euglycemic range of 70-140 mg/dl, with participants in range only 39% of the time. When considering nocturnal values, participants spent a perfect 100% of the time between 70 and 180 mg/dl and 59% of the time between 70 and 140 mg/dl. In highlighting the challenges of controlling blood glucose after meals, Dr. Reddy remarked that “the peak was higher than [we] would have ideally liked.” Indeed, this was to be expected given that the study did not use an ultra-fast insulin or add glucagon (which allows a system to dose more aggressively). We’d note this study also hardly tested the robustness of the system, as it was in-clinic, of short duration (13 hours), used laptop-driven control, included only one small meal (40-grams of carbohydrate), used a 70% pre-meal bolus, and had no exercise.
- This was a non-randomized, open-label study with 20 participants (17 completed the study) with type 1 diabetes. The average A1c level was 7.4%, the average age was 44 years, the average duration of diabetes was 22 years, and the average BMI was 25 kg/m2. Fifty-five percent of participants were Male.
- The study lasted 13 hours, including overnight and one breakfast period. Participants came in the evening at six, inserted two Enlite sensors, and at eight, participants connected to the closed-loop circuit running their basal rate. At 10 pm, closed-loop control started, and at 6 am, participants were given a standard 40 g breakfast with 70% pre-meal bolus; the study ended at 11 AM.
- The next step is a 24-hour, randomized, cross-over, controlled, closed-loop study. We hope the investigators include a more robust test of the system with larger meals and exercise.
- While EASD 2013 has little on the closed-loop front, you can find the most recently reported studies in our ADA 2013 report: http://www.closeconcerns.com/knowledgebase/r/94f937d8.
Questions and Answers
Q: Do you think there is room for improvement in the postprandial period?
A: The peak was higher than we would have ideally liked, and it was more prolonged than we would have ideally liked. We have to be cautious because this is the first time the algorithm has been tested. We need more experience in order to be more aggressive in our tuning.
Q: I have a question about the premeal bolus: did you give it immediately before the meal or did you delay?
A: We gave the bolus immediately before breakfast.
Q: When you were discussing the design of controller, you mentioned that it was 70% basal insulin. Is basal insulin given consistently irrespective of the controller?
A: Yes. The only time that would change is if we were reducing or suspending insulin. However, the basal was independent. We would only withdraw insulin if we were below the 70 mg/dl threshold.
Posters
PROOF OF RELIABILITY OF INTRADERMAL DEVICES UNDER EXTENDED WEAR BASAL/BOLUS INFUSION CONDITIONS (POSTER #1088)
EA McVey, SC Keith, DE Sutter, K Judge, J Herr, RJ Pettis (BD, Franklin Lakes, NJ)
This study tested use of BD’s intradermal microneedle technology in infusion sets in 50 people without diabetes over 24 hours. Diluent was infused (via Animas OneTouch Ping or Medtronic MiniMed Paradigm 723) at a basal rate of one unit per hour with three 10-unit boluses at meals and one before bed. Each participant simultaneously wore either four intradermal (34 gauge, 1.5 mm with two different proprietary geometries) or four subcutaneous sets (steel: 28 gauge, 6 mm; Teflon: 24 gauge, 6mm). First and foremost, the study showed that 24-hour intradermal basal-bolus infusion “is feasible” in ambulatory people without diabetes using a commercial insulin pump – rates of leakage and adhesion were similar between intradermal and subcutaneous delivery, while bleeding and edema were lower with intradermal delivery. Mean pain scores did not exceed one (on a 0-10 visual analog scale) for any device, delivery route, or time point. We were somewhat surprised to see that intradermal delivery didn’t have an edge on this measure, though perhaps the score wasn’t sensitive enough. The researchers also used a proprietary algorithm to measure pressure and flow – the data suggested that one of the intradermal set designs (“B”) performed similarly to the subcutaneous set, while set design “A” appeared to be worse. Encouragingly, the poster concluded that “additional work with intradermal sets for insulin infusion is justified and three-day extended duration studies are underway.” We look forward to seeing longer-term data, especially with PK/PD results.
- The poster shared few details on the design of the two intradermal microneedle infusion sets, only noting their size (34 gauge, 1.5 mm) and “two different proprietary geometries.” We wonder if this has to do with the shape of the needle, or perhaps needle arrangement (i.e., in the case of multiple microneedles on the set) or the insertion angle.
- Interestingly, it was clear from the flow data that intradermal set design matters quite a bit. Set design A was clearly worse than set design B. Mean number of flow interruptions per infusion for set A was 1.8 (Animas) and 2.9 (Medtronic) vs. 1.1 and 1.0 for set B (lower is better). Set B also lasted much longer before a flow interruption (321-391 minutes vs. 80-164 minutes), had a shorter mean duration of flow interruption (23-28 minutes vs. 32-38 minutes), had fewer silent occlusions lasting more than one hour (2-4 vs. 4-6), and had a lower percentage of infusion time interrupted (2-3% vs. 6-16%).
- The study suggested that existing infusion sets exhibit flow problems undetected by pump occlusion alarms – 5-10% of commercial infusion sets experienced a flow interruption of over one hour in length, and this study was just 24 hours long! In the case of one of the subcutaneous Teflon sets, there was a mean duration of flow interruption of 74 minutes, two silent occlusions lasting more than one hour, and 11% of infusion time interrupted – again, we would underscore that this study was only 24 hours.
- Flow interruptions were more likely to happen shortly after insertion. In the case of the subcutaneous steel needle set (Animas pump), the mean time to the first flow interruption was just six minutes.
- This data underscores how critically important it is to improve infusion sets, a very under researched and underdeveloped area in our view. However, we believe it is one with lots of promise to improve patient outcomes.
- For intradermal infusion, the Medtronic pump had more alarms than the Animas pump (30% vs. 0%; p<0.001). This is explained by product differences – the Medtronic pump has a lower occlusion alarm threshold than the Animas pump.
SIX-MONTH DATA FROM A CLINICAL STUDY OF AN IMPLANTABLE FLUORESCENCE-BASED GLUCOSE SENSOR (POSTER #1084)
T Whitehurst, J Emken, P Huffstetler, S Tankiewicz, X Wang, S Rajaraman, M Mortellaro, R Rastogi, O Chen, C Mdingi, K Lechleiter, A Dehennis (Senseonics, Germantown, MD)
This poster presented six-month data from a small pilot study (n=4) of Senseonics’ implantable CGM. A sensor was implanted in each patient’s upper arm and its performance was assessed in clinic visits every 14-28 days following implantation. During the clinic visits, blood samples were taken every 15 minutes and compared to a YSI measurement. The data was analyzed prospectively with calibration updates twice per day using SMBG measurements – it was not clear to us if patients were actually calibrating the system in real-time every day using the product’s associated iPhone/iPod touch user interface. Overall MARD was a solid 11.9% and consistent across all four patients (11.2%-12.8%). A Clarke Error Grid Analysis (vs. YSI) showed 81% of points in the A-Zone, 17% in the B-Zone, and 2% in the D-Zone. The percentage of remaining sensor fluorescence (relative to baseline) remained high after 180 days, “suggesting that the sensor may last for more than six months after implant.” The graph of signal responsivity did show a very slight decline over six months in all patients, though without longer-term data, it’s hard to say how the trend would continue. Overall, we found these results quite encouraging, as the accuracy looks comparable to Dexcom’s G4 Platinum. That said, manufacturing with precision and accuracy at scale is a whole different ballgame, and we look forward to larger studies of the company’s product. We think many patients would be interested in this six-month implantable CGM product concept, assuming it is accurate and the on-body transmitter is not cumbersome (it looked to be the size of the second-gen OmniPod in the picture).
- Senseonics’ system includes an implantable subcutaneous CGM sensor (3 mm x 16 mm), a body-worn transmitter (power and data), and an iPhone/iPod touch app. The implanted sensor communicates with the on-body transmitter via 13.56 Mhz RFID, and the transmitter communicates with the iPhone/iPod touch app via Bluetooth LE. The transmitter can be downloaded to a PC, and notably, also includes a vibration motor to alert patients to out-of-range glucose values.
Close Concerns Questions
- Were patients wearing the on-body transmitter and using the iPhone/iPod app as pictured in the poster? In essence, was this real-world use of the product as patients would use the commercialized version?
- Were the twice-daily SMBG calibration values entered by patients in real-time, prospectively?
- Could patients view glucose values in real-time?
Symposium: Diabetes Technology – The Search for Quality
FROM THE PAST TO THE PRESENT
John Pickup, MD (King’s College London School of Medicine, London, UK)
“High-quality healthcare is difficult to define,” said Dr. John Pickup, “but like a dead parrot, we know it when we see it.” This opening framed Dr. Pickup’s talk on the historic and current safety of CGM and insulin pumps. After running through previously published data on insulin pump quality and CGMs, Dr. Pickup pressed that the current level of pre-market clinical evaluation of devices in Europe is inadequate. These evaluations may not be based on robust clinical trial data, he noted, and are almost always centered on manufacturer rather than independent data (a problem in the US as well!). Further, Dr. Pickup asserts that the whole process itself lacks transparency and post-market surveillance of quality is “poor.” He urged that such surveillance should be proactive, organized, and systematic. Instead of the current system, Dr. Pickup believes assessment and regulation of quality needs systematic and independent organization by some quality institute. As more complex devices come to market in the coming years, Dr. Pickup warned that quality regulation will only become increasingly complex, demanding, and expensive.
- Dr. Pickup listed five key characteristics of high-quality healthcare: 1) safe; 2) clinically effective; 3) cost-efficient (i.e., the best use of resources); 4) patient-centered (i.e., meets patient needs, expectations, and preferences; and does not adversely affect quality of life); and 5) equitable (i.e., available with equal quality to all without respect to gender, ethnicity, geographic location, or socioeconomic status). Dr. Pickup honed in on safety in this presentation, noting that other areas are important but a whole other topic of discussion.
Questions and Answers
Q: We are seeing more and more apps for phones. Where does the pump start and the phone end?
A: That is quite right. I am pretty sure mHealth is going to be a big thing in the future and will introduce all sort of regulatory problems of its own.
Q: How can we retrieve data regarding misuse of the pump when it is used improperly? I do believe that many pumps are robust, however, they can be extensively misused as a hammer or whatever.
A: I agree with you about the problem of misuse of pumps. One has to factor in proper training – that to has to be regulated and controlled. I don't think that manufacturers should just issue devices, put them on the market, and give them to patients without any kind of feeling on the training that needs to be done and the checking of patient education. I think that needs to come under regulation and standardization too. I think post-market surveillance needs to get some handle on patient adherence.
DO EU REGULATIONS FOR MEDICAL DEVICES PROTECT PATIENTS' SAFETY?
Deborah Cohen (Investigative Reporter, British Medical Journal, London, UK)
Ms. Deborah Cohen, a reporter at the BMJ, provided an “investigative journalist” view on the status of medical device regulation in Europe (“It’s cowboy territory”). Her presentation focused outside of diabetes (e.g., metal-on-metal hip replacements); we had a hard time making connections between orthopedic surgery and diabetes. She made a strong case for inadequacies in the current CE Mark process: no requirement to show that a device has good clinical utility; a non-existent safety net to identify poor device performance; a lack of transparency and data collection (her team literally could not do a systematic evaluation of the system); over 70 different organizations around the EU and elsewhere; and no data on which notified body even CE marked a device. Most shocking was her discussion of BMJ’s undercover attempt to get a fake metal-on-metal hip replacement approved in the EU. In short, the team uncovered some shocking conflicts of interest, unqualified regulators, little/non-existent data requirements (only a literature review was needed!), and surprising post-market surveillance requirements (putting cards in the box would be enough). She concluded her presentation with an outline of the European parliament’s proposal to change the system (a committee vote is apparently taking place shortly or may have taken place).
- According to Ms. Cohen, a European Parliament committee is voting today on a proposal to change the EU medical device system. She noted that some political groups vetoed a single FDA/EMA-type of regulatory body (“allegedly” after lobbying). The changes include: 1) formation of a publically accessible databank, Eudamed, to log devices that are on and removed from the market; 2) data in Eudamed that contains certificates and details on clinical investigations and post-marketing surveillance; 3) review of clinical studies by a third party or external expert under the principles of highest scientific principles; 4) patients harmed will be compensated for any damage and associated treatment as result of a faulty medical device; 5) implanted devices will have a card to be given to patients and recorded in HCP notes; 6) notified bodies will have in house staff with medical, technical, and pharma knowledge to assess/challenge evidence; 7) the names of those in charge of assessment and their conflicts of interests will be published; 8) unannounced inspections by notified bodies; and 9) fees proportionate and consistent with national standards. Most of these changes have less to do with gaining approval as they do with monitoring devices post-approval, though overall, gaining approval will certainly be more work.
- The BMJ went undercover to get its own fake metal-on-metal hip implant on the EU market – the results were published in a 2012 article, “How a fake hip showed up failings in European device regulation” (Cohen, BMJ). The device was called “TMH” (“total metal hip”) and the team created a fake Chinese company with a website. This set the bar on the lower side, as these hip replacement are widely recognized as unsafe and subject to legal action all over the world. The team visited 14 notified bodies in five different European countries (including Turkey) and one in South Korea to see who would grant the Total Metal Hip a CE Mark certificate. The fake 80-page scientific dossier as put together with the help of an orthopedic surgeon, and there was no clinical data in the dossier. However, it was clear from the bench tests that this implant failed and produced high levels of metal debris.
- According to Ms. Cohen, one of the Notified Bodies in the Czech Republic told them, “We are on the side of manufacturers and their products, not on the side of patients.” She explained that notified bodies make money on giving a CE Mark; her team was told to essentially shop around and “ask different notified bodies that is the best for you.” Costs for processing all the documents to obtain a CE certificate varied from €2750 ($3590) to €50 000 ($65,272), depending on the notified body. According to Ms. Cohen, the “shopping around” is evidence that manufacturers are looking for the notified body that will ask the least demanding questions and provide the easiest route to approval.
- A South Korean office of the Czech notified body had a serious conflict of interest – their “one-stop-shop” service brought three separate companies together under one organization. One of the companies performs notified body duties across Asia and has certified over 1,000 products for access to the European market. The other two offer consultation services for manufacturers hoping to gain market access to the European Union and the US.
- Some notified bodies were prepared to assess the product without any experience of assessing hip implants. One consulting firm advised putting a European stamp on the fake hip, even though it was made in China. Another notified body had a chemical engineer prepared to assess the data on the hip implant.
- “There is an inherent conflict of interest – an annual sum of money is paid to the notified body. There is no incentive to take a CE mark away, because the notified body is making money on it every year.”
- Ms. Cohen has published a number stories in the BMJ on deficiencies in EU medical device regulation, including: “How a fake hip showed up failings in European device regulation” (Cohen, BMJ 2012); “EU approval system leaves door open for dangerous devices” (Cohen BMJ 2012); “Europeans are left to their own devices” (Cohen et al., BMJ 2011); “Notified bodies: are they fit for purpose? (Cohen BMJ 2012); ”“Out of joint: the story of the ASR” (Cohen, BMJ 2011).
- As an investigative journalist, Ms. Cohen also has articles on GLP-1 safety, insulin, rosiglitazone, and other topics: “European drugs agency clashes with scientists over safety of GLP-1 drugs” and “Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?” (BMJ 2013); “How small changes led to big profits for insulin manufacturers” (BMJ 2010); and “Rosiglitazone: what went wrong?” (BMJ 2010).
Questions and Answers
Dr. Andrew Boulton (President, EASD): Thank you. It’s frightening, but confirming our worse fears.
Q: You should be a detective. You listed some items up for review. Do you agree with those recommendations?
A: I would much rather see a single body like the FDA and follow that model. The reasons given for not doing that are flawed. People say the process is slicker, quicker, and cheaper with lots of different bodies. The logic doesn't seem there. At FDA, you know someone has expertise and can answer queries. The recommendations are an improvement, but to be fair, I don’t think it could have become much worse.
Q: Are they going to penalize companies?
A: I don’t know.
Dr. Boulton: Do you agree with us that we should have a single European agency for medical devices?
A: Absolutely, I totally agree.
THE EUROPEAN PERSPECTIVE: SAFETY EVALUATION OF DIABETES DEVICES
Lutz Heinemann, PhD (Science & Co, Düsseldorf, Germany)
Dr. Lutz Heinemann’s 45-minute presentation provided a clear call to action: the EU needs to establish a sound evaluation of the performance of diabetes devices before approval and some level of quality control post-approval. Fortunately, he thinks that positive improvements (details below) to the CE Mark procedure are in development that will provide better medical devices to patients in the EU. Indeed, he echoed Ms. Cohen’s comments that the European Parliament is voting shortly on a set of proposals to modify the EU medical device regulatory system. Framing the current problem, Dr. Heinemann reprised data from the two DTS meetings this year suggesting that many glucose meters are falling short of the previous and new ISO standards. On the research side (both industry and academia), he thinks a change of mindset is needed for increased communication of safety and regulatory concerns. It was particularly disconcerting to hear him mention members of industry pressing investigators to exclude unfavorable data (he characterized them as “outraged”). To boot, and very surprisingly, he has found that European diabetes journals are not willing to accept articles focused on device safety. Dr. Heinemann offered several strategies to improve device safety in Europe: 1) embed an independent research institute into the regulatory framework (he believes this should be funded by manufacturers); 2) found a European diabetes journal to communicate safety findings; 3) facilitate conversation between stakeholders via roundtable discussions; and 4) perform large long-term clinical studies and develop registries to increase evidence on the use of devices. Dr. Heinemann thinks that the EASD in particular has an important role to play in improving the status of diabetes technology regulation in the EU (notably, a transatlantic panel on insulin pumps is writing a statement, to be published in 2014).
- The EU Commission has proposed a new legislative act, impacting the regulation of meters and medical devices. The main changes proposed by the Commission are 1) stronger supervision of notified bodies by national authorities; 2) more power for notified bodies vis-à-vis the manufacturers; 3) clearer rights and responsibilities for manufacturers; 4) an extended database of medical devices (Eudamed) – he noted that the FDA initiated a similar database last week (Global Unique Device Identification Database, or GUDID); 5) better traceability of devices; 6) reinforced rules for clinical investigations; and 7) adaptation of the health and safety requirements.
- The EU Commission delayed voting on the medical device proposals from July 10, 2013 to today, according to Dr. Heinemann. Members of the European Parliament’s Environment, Public Health, and Food Safety Committee (ENVI) offered over 900 changes to the proposal. The vote was postponed to today to give lawmakers more time to work on compromise amendments. Following the outcome, the EU Parliament’s will vote on whether to adopt the proposal and any of the ENVI Committee’s amendments. Dr. Heinemann was uncertain when this vote would happen; it is our understanding that it is scheduled for this November.
- Dr. Heinemann proposed to the audience that an independent research institute should be embedded into the regulatory framework. Currently, no independent research institute focused on diabetes devices exits in Europe with the exception of Switzerland’s. He argued that embedding an independent research institute into the regulatory system would support notified bodies with specific knowledge and could perform highly specialized evaluations. Additionally, it could check a device’s standards in the laboratory.
- Dr. Heinemann believes such an institute could be funded by manufacturers and insurance companies. He expressed bewilderment that funding does not currently exist for such an institute, despite the presence of a €2-3 billion (~$2.7-4.1 billion) market for SMBG and other diabetes technologies. We think this will be a challenging proposition given the declining profitability in the SMBG industry and upcoming competitive bidding for insulin pumps (we have found this landscape challenging to follow, but it sounds like non integrated pump/CGM devices will be under competitive bidding in the US soon – that said, unlike SMBG, many fewer companies will likely “bid” to supply reliable pumps and this time around, we imagine consumer feedback will be widespread, unlike during the initial competitive bidding process with SMBG)..
- Dr. Heinemann requested the formation of a technology or clinically oriented, European diabetes journal to better discuss safety issues. He rhetorically asked, “If you encounter a safety issue with a medical device, what do you do? Who do you approach?” Typically, researchers disseminate information via journals. In Dr. Heinemann’s experience it is difficult to get a manuscript about safety issues published in a European diabetes journal. He pressed that although academics and journal editors might not view safety issues as a scientific topic, it is very important for patients.
- Also to improve communication, Dr. Heinemann was in favor of round tables with various diabetes technology stakeholders. He proposed that an EU round table on SMBG should include EASD; regulators; the European Commission; industry; notified bodies; the Institute for Diabetes Technology, Ulm; Radbound University Nijmegen Medical Center; IDF Europe; and IFCC. We felt that including patients at the recent DTS meeting was a positive addition.
- Notably, the EASD is forming a transatlantic panel to develop a proposal on how insulin pumps should be evaluated. The statement is to be published by the EASD in the summer of 2014. The aim of this initiative is to strengthen the quality management of diabetes devices. EASD’s Executive Committee asked two experts from the US and three from the EU to put the initial document together. A draft of the statement will be presented at the EASD-Diabetes Technology Meeting in February 2014 (details below).
- The EASD has also organized two Diabetes Technology meetings and is hosting a third in February 2014 in Düsseldorf, Germany. Dr. Heinemann pressed that an EASD-Diabetes Technology meeting is necessary, despite the growing number of conferences. In his view, neither the EASD nor the ADA annual meeting is “focused” on diabetes technology, and ATTD and the Diabetes Technology Meeting (DTM) take a different approach to the topic. Dr. Heinemann promised that device regulation will be a major topic at EASD-DT. More information on EASD-DT is to become available on www.easd.org later this month.
- Additionally, EASD has supported the development of a registry for insulin pumps in Sweden. Dr. Heinemann is uncertain that registries are “the” way to determine the benefit of diabetes devices in daily life; however, he thinks they are a good idea in principle, since they can provide more information on the usage of devices. His concern is who will pay for the additional work registries require of HCPs. We couldn’t agree more with his assessment.
- Dr. Heinemann mentioned that the EASD is also in “intensive” communication with the ADA, to improve the safety of diabetes devices.
- Upon attending the September 9 DTS meeting with the FDA on SMBG, Dr. Heinemann expressed mild outrage: “Why is there not such an activity in the EU?!” For more details on the Diabetes Technology Society’s BGM surveillance meeting, please see our report at http://www.closeconcerns.com/knowledgebase/r/2fae6348. (We would note that this is a fairly new occurrence in the US.)
- Dr. Heinemann was frustrated to see European authorities failing to respond to inaccurate blood glucose meters. As evidence, he pointed to BfArM, Germany’s regulatory authority. In this case, only 71.5% of a currently marketed blood glucose meter’s readings were within 15 mg/dl/20% of the true value, far below the 95% required in the 2003 ISO Standards. Hypoglycemia accuracy was also particularly poor with this meter. Despite this data, BfArM opted refused to take action and pull the meter off the market, since the “distributor’s testing of retained samples with control solution showed no abnormality, […] the manufacturer’s testing results at the time of production were ok, […and] there was no increase of customer complaints.” This is completely unacceptable from our view and very surprising that such devices would be able to gain approval. Once they are approved, of course, this gives reimbursement bodies the cover to hide under – “well, these are approved!” Meanwhile, patients are forced to use devices that do not work optimally.
- Dr. Heinemann recently co-authored an editorial with Dr. David Klonoff (Mills-Peninsula Health Services, San Mateo, CA) in JDST entitled “Freedom of Speech and Science: Can Companies Force Us to Withdraw Data They Don't Like?” (2013). We were surprised and disappointed that companies would even dream of trying to cover up disappointing scientific results discovered in an academic journal. To us, this really speaks to the need for independent testing.
- Dr. Heinemann posed several important questions on current European post-market surveillance, which is conducted by the manufacturer.
- Though manufacturers have medical device vigilance systems in place, it sounds like there is a lot of variance. Dr. Heinemann astutely asked: 1) “How good are these systems?”; 2) “When will issues be detected?”; 3) “How much has to happen until a physician reports an issue?”; and 4) “Is it a causal relationship between a safety issue and a device?”
- Similarly, he questioned manufacturers’ quality management systems. He noted that while these systems can be inspected by authorities, it is unclear how often and how seriously authorities monitor these systems. Similarly, he was uncertain if all manufacturers have comparable quality management systems and what impact such systems have inside a company. Dr. Heinemann also expressed frustration that the evaluations of these systems are not made publically available.
- Regular manufacturer inspections are conducted; however, the quality of these inspectors is not clear. At the Diabetes Technology Society’s May 2013 meeting – “Do Currently Available Blood Glucose Meters Meet Regulatory Standards?” – an FDA representative (according to Dr. Heinemann) noted that small manufacturers, especially those abroad, might be inspected less often, if they are inspected at all. For more details on this meeting, please see our coverage at http://www.closeconcerns.com/knowledgebase/r/2e03af3f.
- Regarding withdrawals, Dr. Heinemann called for companies to be less hesitant about removing potentially dangerous products from the market. He acknowledged that withdrawals are cost and labor intensive, bad for the company’s reputation, and that competitors try to take advantage of such events (a strategy Dr. Heinemann characterized as a “stupid move” though not one likely to disappear). However, he pressed providers to support companies in this process and avoid delayed reactions, which might impose safety risks to patients.
THE US PERSPECTIVE: THE GOVERNMENT AND DEVICES IN DIABETES CARE
David Sacks, MD (Senior Scientist, NIH, Bethesda, MD)
Dr. David Sacks concluded the session with the US/FDA perspective on medical device regulation. His presentation was very straightforward and focused entirely on explaining the FDA’s scope, structure, the device approval process, post-marketing surveillance, and adverse event reporting systems/statistics. It was devoid of opinion and did not suggest specific improvements to the US or EU systems; rather, it was clearly intended to serve as an informative backdrop against the current EU system (described in prior presentations). His talk did just that – it was abundantly clear that the FDA’s system is more robust, better at ensuring patient safety, and stronger in enforcement power than the EU’s system (“FDA, despite their nice leafy green campus, is not to be trifled with…You can’t argue with the FDA…The FDA wields more than just a big stick”). His background information served as a refresher, though we wish he had given his thoughts on whether the current FDA process and scope is adequate for patient safety, especially regarding post-market surveillance. Based on problems raised at DTS, such as manufacturers like Prodigy still having devices on the market, we were surprised to hear the US held up as such a beacon; on the other hand, all things are relative.
- For all medical devices, the number of serious adverse events grew 17% from 2001-2009. There was a particularly noticeable increase in life-threatening and fatal adverse events. This increase could reflect many things, including lower quality products, better reporting, more patients on medical devices, or some other factor. Dr. Sacks did not hypothesize on why; we would be cautious in over-interpretation of the adverse event reporting, since this is also uncontrolled.
- There were over 14,000 adverse events reported for insulin pumps between 2005 and 2009, the highest number on the slide for any medical device. Relatively speaking, the number of adverse events per insulin pump unit was 4.3, in the upper tier for devices (though not the highest). We weren’t exactly clear on what the denominator came from, as that would suggest just over 60,000 pump units, far too low to represent all pumps in the US. Dr. Sacks also pointed out that over 8,000 adverse events were reported for blood glucose meters between 2005 and 2009, though the large number of units available put the adverse event per unit statistic quite low.
Questions and Answers
Q: We did not have an opportunity to talk about closed-loop devices. I think it is very important to introduce regulations in advance of these products, so that we don’t have the same problems as with the open loop.
A: I think you make a very important point. The FDA tries not to proscribe to companies what to do. In the US, there is a very big ongoing debate about this. The FDA is involved, and they do listen to clinicians, they listen to patients, and they listen to manufacturers. Then, they set regulations. I do agree with you – looking at the potential problems before they occur is a very important way to prevent them. [Editor’s Note: We were surprised Dr. Sacks did not mention the final FDA Artificial Pancreas Draft Guidance, issued in November 2012 (see our report at http://close.cx/APGuidance)]
Q: I’m the President of the German trade association for in vitro diagnostics. We as industry are more than willing to have this discussion and have a higher level of quality. We are more than willing to meet all of you.
[Applause]
Q: In India, we use pumps, pens, and devices a lot. If a device like a pump or CGM is manufactured in the US, and a diabetologist is having a complaint, can they directly report it to the FDA from India?
A: That’s a good question. Anybody can access the FDA’s web database and can report a problem. The FDA would be more than happy to listen to complaints about devices, particularly if they are approved and used from another country. You might be the first person that picks up a problem.
Corporate Symposium: Ambulatory Glucose Profile (AGP) and New Sensor Technology – The Next Frontier in Diabetes Management (Sponsored by Abbott)
ADVANCES IN SENSOR TECHNOLOGY AND IMPLICATIONS FOR DIABETES MANAGEMENT: INTRODUCING FLASH GLUCOSE MONITORING
Jared Watkin (VP of Technical Operations, Abbott Diabetes Care, Alameda, CA)
In the most anticipated presentation of the symposium, the highly-regarded Abbott R&D expert Mr. Jared Watkin introduced a product in development in a new category: Flash Glucose Monitoring. This was quite bold of Abbott and very unexpected from our view – they are introducing a new category of diabetes technology to help meet the unmet needs of patients on BGM and CGM. This is intended to offer a “widely acceptable alternative” to traditional blood glucose monitoring, while at the same time collecting enough glucose data to allow generation of ambulatory glucose profile (AGP) reports. It is based on the core FreeStyle Navigator CGM technology (a wired enzyme), which will be worn on the body like a CGM, and have an accompanying receiver-like device (“the reader”). Notably, early product specs include that the product will be factory calibrated (!), (yes, that means it will require no fingerstick calibration) and be wearable for 14 days. Since it does not get continuous data, it will obviously not have CGM alarms – instead, to see the real-time glucose value, glucose trend arrow, and eight-hour trend graph, a reader is scanned over the sensor patch, which allows wireless collection (via RFID) and display of the glucose data on the color touchscreen reader device. While it could give “CGM-like” data if someone “scanned” the system over the sensor every five minutes, we believe this device is more likely to be used to get intermittent data quite easily – no fingerstick, no blood, and what sounds like little hassle. The data is transferred in a “flash,” hence the category name. In the first small clinical study in 12 patients with type 1 diabetes, the system (using prospective factory calibration) showed an overall MARD of 8.5% vs. YSI reference glucose and 93% of points in Zone A of the Parkes consensus error grid – very good early accuracy data, and Mr. Watkin assured the audience that larger trials will be coming. Pending a CE Mark, the product is expected to launch in 2H14 in Europe. We think the concept is quite novel and discuss more about its potential positioning and value below. Broadly speaking, Abbott’s investigational Flash Glucose Monitoring system is not intended to compete directly with traditional CGM – rather, it’s intended as a new category of glucose monitoring that has many of the options that those researchers pursuing non-invasive monitoring wanted years ago; note this is not non-invasive, exactly, but the notion of a “scan” makes it seem like it may as well be. As noted, we don’t expect to see many traditional CGM users switching to this new system, though we do think it will help expand the continuous glucose sensing market to BGM users who have perhaps resisted the technology due to cost or perceived hassle factor (fingerstick calibration, alarms, etc.). Key questions will relate to pricing of course; we believe the AGP software will make it easier for patients to better manage their diabetes than they have been able to with BGM to date; cost effectiveness studies could help ensure reasonable pricing, we hope, to make this even more attractive to payers. Payers should like the adherence implications, that is for sure. More thoughts below.
- Overall, this move is a very bold step by Abbott – and could ultimately be disruptive if all goes as planned – a lot of steps (reimbursement codes, payer discussions, . Ultimately, it’s an innovative product concept, that if it works as well as discussed, could help patients manage their diabetes better, could help HCPs assist patients more easily, and could help payers since patients should be able to manage their diabetes better, and more cheaply. The implications on the competitive front are larger for BGM than CGM in our view; the easier CGM is to use, and the more straightforward and less hassle the CGM becomes, the greater the use will be. BGM on the other hand has drastically reduced reimbursement; if the IP and reimbursement goes well with Abbott’s technology – both still uncertainties – then we could envision more patients overall looking to their glucose data. This would certainly expand the market, but BGM would be at risk for losing patients to the new technology – although with 5,000 new patients prime for glucose monitoring of some sort in the market each day in the US, we also think the market is ripe for growth – and potentially disruption. We discuss below the patient groups who might be most obvious choices for paying more and using a new technology like Abbott’s Flash Glucose Monitoring system.
- We think there’s an obvious plus here for Big Pharma, if this product could help patients titrate drugs better, figure out how drugs are working, figure out how to use insulin more effectively, etc.
- Speakers posited in this session that current methods for generating comprehensive glucose data – both CGM and BGM – “have significant issues.” While blood glucose meters are widely available, they bring with them several downsides, according to the presenters: pain, hassle, inconvenient fingersticks that limit data continuity, and the impracticality of overnight data. CGM addresses the data density issue, but it only has 3% penetration – according to Mr. Watkin, this stems from cost, lack of reimbursement, and data interpretation challenges.
- Mr. Watkin introduced the Flash Glucose Monitoring concept, which is intended to be an alternative to blood glucose meters, provide the advantages of continuous data for reporting (AGP), and help overcome the key issues with both technologies. Specifically, the product has been designed to better address unmet needs by eliminating the need for fingerstick calibration, increasing sensor wear time, and improving industrial design/ ergonomics.
- Flash Glucose Monitoring centers around a calibration-free, 14-day sensor and a wireless reader. The product reflects improvements based on the original FreeStyle Navigator wired enzyme technology. The sensor patch is worn for 14 days, factory calibrated, and requires no fingerstick calibration (not even at startup). We assume the absence of a radio (that CGM has) lowers the costs substantially.
- The system’s sensor patch continuously reads the glucose levels and stores them, but does not constantly send them to a receiver (i.e., collecting data and storing it on the transmitter for later download). However, a quick scan of the reader over the sensor patch collects and displays the real-time glucose number, trend arrow, and eight-hour glucose trend. In other words, continuous CGM data is available, but is not constantly pushed to the receiver – it requires a scan to gather it, which is then transferred in a “flash” to the reader. The data would be stored on the sensor patch and downloadable to an ambulatory glucose profile (AGP) report. The AGP report is an essential part of the product; the piece of this technology must, of course, be easy to download, etc. We loved the readouts, with the yellow, green, and red symbols – this is going to be extra easy to understand. It is planned to be usable on PCs and Macs and to be accessible via USB. Making sure patients understand how to read and use AGP would clearly be essential.
- Mr. Watkin provided a brief overview of the R&D work leading up to the system’s 14-day wear and factory calibration. The technology is based on the wired enzyme from Abbott’s FreeStyle Navigator. For this product, Abbott worked on significantly improving the stability of the sensor. In a publication from Hoss et al. (JDST 2013), data from 55 subjects showed that the sensor’s signal was stable over 14 days. Another paper from Hoss et al. (just accepted to JDST) evaluated use of four concurrent sensors in the same patient. Results showed minimal between- and within-subject variability from a single sensor lot, suggesting factory calibration is possible.
- Abbott fights the commercial losses prompted by competitive bidding here in the US. CMS’ price cuts have negatively affected the entire industry’s profitability, leaving significantly fewer funds overall for R&D and new product development, to say nothing of quality control and ongoing customer service.
- We believe the most likely candidates for this product are intensively managed patients and their HCPs that have not embraced CGM (for whatever reason – cost, the need for fingersticks, inaccuracy, perceived hassle factor regarding alarms, etc.), but would appreciate having more glucose data. In short, we think this new category has the potential to attract a range of patients– certainly, CGM has low enough penetration that there is plenty of room to grow it even if a number of people also turn to this new alternative. We also believe that those most drawn to this will be those that haven’t turned to CGM and aren’t really CGM candidates:
- People who can’t afford CGM
- Pregnant patients
- Elderly patients (while this is a challenging group, we can see this being especially appreciated by children of elderly patients “Mom! Can you scan your glucose for me!”)
- Type 2 patients who need to monitor diabetes closely when making therapeutic changes
- Inpatients
- People with pre-diabetes and at high risk of “converting” to type 2 diabetes (this is probably a group for which it will be challenging to gain reimbursement; on the other hand, if we want to work on prevention as a country – this should be an easy way for people with pre-diabetes to monitor process)
- People who are at high risk of type 1 diabetes but do not want to use traditional blood glucose monitoring
- More on the product front … the system uses standard NFC wireless protocols (RFID) – we assume this is cheaper than the current RF-based methods of CGM transmitter-receiver wireless communication. Certainly, it reduces the size of the on-body component relative to the FreeStyle Navigator substantially. We recall that as one of the big criticisms of the Navigator, especially in pediatrics.
- A picture of the investigational system showed a very low profile, round sensor patch and a color touchscreen reader similar in form factor to the FreeStyle InsuLinx. Abbott’s Flash Glucose Monitoring system is intended to have a “simple and low pain” sensor application. Certainly, the small low profile sensor patch made it appear like this is possible. We believe sensor insertion is an issue for many patients and a deterrent for starting CGM, so this would be warmly received. That said, comfort level is in the eye of the beholder, and this was quite challenging to assess.
- You can see a picture of the system on our @diaTribenews twitter feed at: https://twitter.com/diaTribeNews/status/382113806165352448/photo/1.
- Abbott’s current marketing tagline for the system is, “The revolution will be bloodless. A new era in glucose monitoring.” (Note this is not blood glucose monitoring.) To register for updates on Flash Glucose Monitoring, go to www.AbbottNextFrontier.com/register. The company describes it as “designed to offer a widely acceptable alternative to BGM testing while at the same time, offering the ability to conveniently collect sufficient data to allow the practical generation of AGP reports.”
- Mr. Watkin detailed the first feasibility study of Abbott’s Flash Glucose Monitoring system in 12 patients with type 1 diabetes. Sensors came from a single lot and were prospectively calibrated at the factory based on lot specific in-vitro data and a predetermined sensor calibration scheme. Patients wore the system for 14 days. Readings from the system were compared to FreeStyle Lite and venous YSI values taken during three eight-hour sessions (two replicates taken every 15 minutes).
- The investigational system demonstrated strong accuracy in this early study – MARD was 8.5% vs. YSI (n=1,582) and 9.6% vs. FreeStyle Lite fingersticks (n=882). A solid 91% of values (vs. YSI) and 93% of values (vs. FreeStyle Lite) fell in Zone A of the Parkes Consensus Error Grid.
- Mr. Watkin showed per subject MARDs – relative to YSI, all subjects experienced a MARD between 8% and 10% (i.e., a tight distribution with no outliers). The comparison was more variable vs. FreeStyle Lite – most patients were in the 8-10% MARD range, with one patient at a MARD of 6%, two at a MARD of 12%, and one at a MARD of 14%. Mr. Watkin said the company was “very encouraged” by these early results.
- Abbott’s intention is that this new system will have the same indication as FreeStyle Navigator in Europe – a claim to dose insulin off the readings, except in cases of hypoglycemia or when glucose is changing rapidly. If the system is truly intended to replace fingersticks – as Mr. Watkin emphasized – we think this is a critical claim to get - although virtually all SMBG meters are used to dose insulin, and none, as we understand it, has this on its label. The MARD certainly looks good enough to achieve such a claim, though that may have to be confirmed in a larger study. Certainly, factory calibration becomes more challenging when sensors are produced at a larger scale.
- There are various next generations following the first that Abbott could take this technology. For example, perhaps the next generation could scan the data with a smart phone and then use an app that can then transmit data to anyplace.
- Flash Glucose Monitoring would be a new category distinct from BGM or CGM – the main design goal of researchers is to overcome some of the limitations of each technology. Abbott said that historically speaking, the disadvantages of CGM have been cost, hassle factor, the need for fingersticks, inaccuracy (though much improved now), and alarm fatigue. All these fronts have improved and will continue to improve, of course – though only as fast as the regulatory landscape allows. For BGM, the disadvantages are gaps in data, hassle factor, and the pain of doing fingersticks. Abbott’s system appears to be designed to address most of these factors. The key question will be whether it can overcome the high cost of traditional CGM – and whether it can garner a code that pays well enough to be substantially above Medicare reimbursement for traditional BGM. We assume the 14-day wear and avoidance of constant receiver communication (i.e., smaller and less expensive disposable component?) will make it cheaper than current CGM. For this product to really expand the market and capture a wider base of patients, the cost factor will obviously be a critical component.
- We look forward to seeing future clinical studies of Abbott’s system, which will be critical to demonstrate cost-effectiveness and reimbursement. To date, payers in Europe have made access to CGM very challenging, which stems from the high current cost of CGM combined with only moderate clinical efficacy. Results show overall A1c reduction ~0.5% in many studies; this is incredibly frustrating of course, since CGM reduces hypoglycemia for most people, which of course narrows the A1c drop. FDA doesn’t yet embrace “time in zone” but we are hoping this will be added as another endpoint in time. We expect that if this investigational system could show stronger clinical efficacy – a result of higher wear time and perhaps reduced hassle factor for patients – reimbursement would be an easier battle. And, we are very optimistic that in fact the system will enable easier diabetes management – proving this would be a major win.
- The Flash Glucose Monitoring system is not intended to compete directly with traditional CGM– Mr. Watkin made it clear that the goal is to be an alternative to BGM, and to gather additional data to support robust glucose data analysis with AGP reports. Alarms are a feature that hardcore users of CGM relish, and the Flash Glucose Monitoring concept obviously, by design, doesn’t have this feature.
- We were disappointed, though not totally surprised, to hear nothing about a US timeline or regulatory strategy. We expect the biggest point of contention in the US would center on the indication to dose insulin off of the system’s readings. Broadly speaking, we wonder what level of CGM accuracy the FDA would require for a fingerstick replacement claim. We suspect a sub-10% MARD, which this system has, though it’s tough to say for certain. On the other hand – we don’t know that the system would really have to have this indication. Obviously traditional SMBG meters are used routinely for insulin dosing, but none have this indication on their labels.
- As for other blood glucose monitors, as noted, this could be a disruptive play if it works well and is reimbursed well – receives a good code, etc. Obviously, many things have to go right in order for that to happen, but we also think some smart cost-effectiveness studies using this technology could be put together. The road to getting new codes is not an easy one, not is building the argument for the need for a new technology, but a lot of thought has been put into this. It is early to call what the payer view would be, but right now, we do not think patients view their insulin delivery or other drug management particularly well – Close Concerns’ sister company dQ&A has data that is fairly depressing on how optimized patients and diabetes educators think insulin pump basal rates are, for example – contact richard.wood@dQ&A.com if you would like more information on this.
AGP THEORY AND METHODOLOGY
Roger Mazze, PhD (International Diabetes Center, Minneapolis, MN)
Dr. Roger Mazze, pioneer of the one-page ambulatory glucose profile (AGP) glucose data report, provided a historical overview of the standardized report’s development - the AGP glucose data report is clearly being highlighted as an essential part of the new system (see above). His talk was largely similar to that given at ATTD 2013. He highlighted some of the AGP’s underlying principles in one of our favorite quotes of the symposium: “No matter where we are, whether in China, the US, Spain, or Peru, we can all share the same information using the same language…We wanted to develop something that would compel us to act, rather than stand idly by. In medicine, patterns, rather than numbers, are often the basis of action.” Dr. Mazze walked attendees through some of the research behind the AGP, highlighting that 14 days is the optimal amount of CGM data to predict the next 30 days. For a highly detailed review of the ambulatory glucose profile and the joint March publication in DT&T and JDST, see our report at http://www.closeconcerns.com/knowledgebase/r/30df7b1d.
USING AGP IN CLINICAL PRACTICE — HOW, WHERE, WHEN
Richard Bergenstal, MD (International Diabetes Center, Minneapolis, MN)
Dr. Richard Bergenstal built on Dr. Mazze’s presentation by running attendees through the specific elements of the ambulatory glucose profile (AGP_ – as a reminder, it’s a one-page standardized CGM report containing a statistical summary of blood glucose data, a visual view (modal day report with indicator lines), and a daily thumbnail view. These were hammered out in an International Diabetes Center/Helmsley Charitable Trust expert panel and subsequently published in JDST and DT&T in March – see our comprehensive coverage at http://www.closeconcerns.com/knowledgebase/r/30df7b1d. The market is begging, in our view, for a way to standardize data, and Abbott is very smart to move toward this end. Dr. Bergenstal’s talk also highlighted the clear areas for opportunity in type 1 diabetes (improving A1c and hypoglycemia) using data from the T1D Exchange, the barriers to CGM use (cost is #1 in his view – we think it is also product improvements that have recently or will be soon addressed, like pain of sensor insertion, lack of good software, etc – all things that are also changing and improving in CGM), and why two weeks of CGM data is optimal. His talk fit quite nicely in with Dr. Mazze’s and continued building the symposium’s argument that AGP is a very useful and meaningful tool for patients and providers.
- Using data from the T1D Exchange, Dr. Bergenstal framed his presentation by discussing the clear areas of opportunity in type 1 diabetes: high A1c levels and high rates of severe hypoglycemia are too high. At the “excellent” 67 centers, A1c’s are “not where we want them to be” – an average of 8.3% in the youngest age groups and a high of 8.7% in adolescents. Combined with the “incredibly high” 7-19% annual rate of severe hypoglycemia (seizure or coma or use of glucagon) in the Exchange this makes glycemic improvement difficult - “We try hard to get the A1c better, but we bump up quickly against severe hypoglycemia.”
- While CGM can help with A1c and severe hypoglycemia, rates of use are far too low. Using previously presented data from the Exchange, Dr. Bergenstal highlighted that CGM users have lower A1c levels regardless of whether they use a pump or MDI. “This reinforces that this should be a technology we should be thinking about if we’re trying to get better on A1c.” But “sadly,” regular use of CGM ranges from just 2-5% of patients in the Exchange. “It’s not being used,” said Dr. Bergenstal.
- Dr. Bergenstal provided his view of the barriers to CGM use, starting with cost (“this has to come first, unfortunately”). He emphasized that cost comes in two forms: to the patient and to the healthcare team. Others barriers he highlighted included: accuracy and convenience (“they’re getting better, so we’re making progress, but there is always room for improvement”); incorporation into clinical practice (“a big area…the patient walks in and the data appears – that’s what we want”); improved outcomes using CGM (“we need more outcome trials”); and the challenges of incorporating CGM into clinical practice.
- Studies indicate that 12-15 days of CGM data “will reflect the next three months very well.” This is based on a paper from Xing et al., DT&T 2011.
DEMONSTRATING THE VALUE OF AGP
Howard Wolpert, MD (Joslin Diabetes Center, Boston, MA)
Dr. Howard Wolpert’s presentation on the value of AGP covered three main areas: 1) using CGM data in real-time diabetes decision making; 2) identifying hypoglycemia risk from glucose variability (a future direction in continuous glucose data analytics); and 3) using AGP to identify glycemic trouble spots. Area number two was most interesting – Dr. Wolpert has developed a traffic light system that estimates the likelihood of a hypoglycemia event (even in the absence of a low glucose reading). The goal is provide a visual metric that can help guide clinicians in identifying time periods of the day to minimize hypoglycemia risk. The lights are based on glycemic variability – a red light means there is a high risk of hypoglycemia, while a green light means there is a low risk of hypoglycemia (i.e., the clinician can feel comfortable increasing the insulin dose at that time of day. We loved the simple quick-take of this traffic light approach and feel that it’s a very useful addition to the AGP.
PANEL DISCUSSION
Richard Bergenstal, MD (International Diabetes Center, Minneapolis, MN); Roger Mazze, PhD (International Diabetes Center at Park Nicollet, Minneapolis, MN); Howard Wolpert, MD (Joslin Diabetes Center, Boston, MA); Helene Hanaire, MD (University of Toulouse, Toulouse, France); Jens Kroger, MD (Center of Diabetology Hamburg Bergedorf, Hamburg, Germany); Gerry Rayman, MD (Ipswich Hospital, NHS Trust, UK); Jared Watkin (VP Technical Operations, Abbott Diabetes Care, Alameda, CA)
Selected Questions and Answers
Q: When will Abbott’s Flash Glucose Monitoring technology be available in the market?
Mr. Watkin: The intention is that it will become available through the CE Mark process in the second half of 2014.
Q: Is Abbott’s system sufficiently reliable for bolus or hypoglycemia correction without fingerstick testing? Do you need a fingerstick for a clinical decision?
Mr. Watkin: For the current FreeStyle Navigator product in Europe, its indication for use claim is that you can take action based upon the result from the CGM under certain conditions. The recommendation to always confirm with a fingerstick applies to confirm hypoglycemia (or if you suspect it) and if the glucose is changing rapidly. We expect to have the same claim with the Flash Glucose Monitoring system. There have been a number of outcome studies with Navigator since the product launched. The product, when used in that manner, does result in improved outcomes.
Dr. Wolpert: One of the issues here is the increased signal stability with the wired enzyme. I think about data from Navigator use in the JDRF CGM trial. The patients using CGM were instructed to do adjunctive fingersticks. We determined after the trial that in 40% of Navigator users, they were not doing any fingersticks apart from calibration measurements – and we had 25 patients on Navigator for six to 12 months. All these individuals that weren’t doing adjunctive fingersticks had improved in glycemic endpoints – either in A1c or a reduction in hypoglycemia. There is a learning curve. Once patients got confident in the signal stability and accuracy of device, they stopped doing the fingersticks.
Dr. Bergenstal: We know patients tend to use the data sometimes as it is now, and all the recommendations are to recheck glucose. I like the concept of the arrow. If the arrow is going up and there is a rapid change, you might want to check. It seems in the other situations with a reliable sensor with those kinds of MARDs – and we need the trials done to verify this – it seems reasonable to use that data.
Q: In Sweden, all clinics working with diabetes are downloading blood glucose meter, CGM, and pumps to two separate software: Diasend or Medtronic’s CareLink. Is this going to be another system? Or will it use an open one that will download into Diasend? And since we use CGM in parallel to both MDI and pump treatment, we are used to using trend arrows, alarms for high and lows, and predictive alarms. Will this be usable in real time? Not only by the scan thing, but to have it on site all the time for the parents.
Dr. Mazze: In terms of devices from different manufacturers downloadable into the same system, all of our developmental work is towards that goal. We are working with some companies, not manufacturers of devices, to produce a means of grabbing glucose data from SMBG or CGM devices and then processing it in such a way that a single report can be made. We are doing studies to show how feasible that is in the flow of standard office practice. It appears to be that manufacturers, from their side, are willing to consider opening up their codes so that at least this could be done. The alternative is to ask each manufacturer to have a toggle option to display an AGP common report structure, which still allows them to produce proprietary reports as well.
Mr. Watkin: Abbott is developing this system as an alternative to the blood glucose meter. We are not trying to develop it as an alternative to CGM. We understand some patients would prefer alarms. We believe that penetration of CGM is low. We are trying to develop the Flash Glucose Monitoring system to be a solution to the problem for people who do blood glucose monitoring.
Q: On behalf of consumers, what is the likely access and cost of the system? CGM is not currently supported by governments in many countries. What is the likelihood of this new technology becoming more available? Or will it only available for those that can afford it?
Mr. Watkin: We clearly recognize access and reimbursement is an important issue. We are not able today to share price information. It’s too early. We are not going to launch the product until the second half of next year. We are committed to doing reimbursement studies. We know what that takes. We’re totally aware of those issues of access and reimbursement that have held back technologies.
Dr. Bergenstal: More people need access. We need broad access, and we need it at an affordable rate. Wouldn’t it be a dream if it could be available at a rate comparable to blood glucose meter? That’s the beauty of the Flash Glucose Monitoring concept – the potential that there could be more access to more glucose data. For those of us in this business for a long time, the patterns and trends from looking at this data are so critical. More people need that access. I certainly hope that this will be something available to the masses, not to the few.
Dr. Hanaire: You presented it as an alternative to blood glucose meters, not CGM. We all agree to the need for that.
Dr. Hank Veeze (Diabeter Clinics, Netherlands): What’s the minimum number of SMBGs to give a proper and validated result in AGP?
Dr. Mazze: Over the years, we have tested a variety of ways to test the minimum daytime values needed, given that patients cannot test frequently overnight. From all the studies, we would say four random tests each day for two weeks – and random is the key. It must be random. That will give us enough of a picture that comes close to the daytime CGM pattern. It won’t be anywhere near what CGM provides, but as a replacement or as a surrogate for equivalent CGM data. What we’re currently doing is one step further. Using CGM data to derive a pattern of testing that would provide even greater accuracy with SMBG data. We’re withdrawing CGM data points and asking, “What is the minimum number of points that give us within 10% the same quantitative values that you would get for CGM for the same period of time?”
Dr. Bergenstal: We agree that the data should be available and downloadable and storable. We are working with various manufacturers – Diasend, SweetSpot, and Glooko – to get the data into the EMR. As you download it, why not put it into the file? That is possible with EMR manufacturers, but it just takes some work. We’ve been able to do that with some of the largest ones in the US.
Dr. Veeze: If you have a local system, you can drive your own logistics and fill your dashboard. You can look at patients and know when to make phone calls, especially with children. It gives rise to priority lists.
Dr. Bergenstal: We agree completely. The future of collecting data is identifying patients and who you should intervene with. I agree that coming down the road, this data should be used with at-risk patients. Howard? If you had profiles on a 1,000 patients, what prompts you to say, “This is high risk.”
Dr. Wolpert: One obvious area is severe hypoglycemia. That’s illustrated by T1D Exchange data. Recent data suggests that $13 billion a year is spent from hospitalization related to severe hypoglycemia. From the standpoint of investment of time, the returns are more immediate. That’s an obvious area for focusing.
Dr. Bergenstal: You developed a stoplight system. Having that show up and say, “Let’s call these 22 patients.” You’re right on.
Q: To overcome the reimbursement issue, you must be creative to show payers and governments what we can do to save money. What are you doing on the front? Any plans to work with the Continua consortium of 200 companies? I think this is the way to go.
Mr. Watkin: We have no specific plans, but if anyone is interested in talking, we would.
Dr. Bergenstal: You’re doing in-house work, but can you reassure us that more studies are coming and we’ll look for more and more data?
Mr. Watkin: I’m not in a position to talk in detail today. In this particular health economic climate, we need those sorts of trials to deliver cost benefit.
Q: There is amazement that the sensor can really be stable over 14 days. You get the same MARD on day one as day 13 or 14? That’s impressive. Can you comment on that? Second, can you give a little more dialogue to us on how it can be calibrated in the factory? It’s such a new concept for us.
Mr. Watkin: The really true reason why fingerstick calibration is needed is to correct for sensor drift and loss of signal. There are various theories about biofouling. That’s not something we see. If you can get a stable sensor, there is no need to keep on resetting the calibration. The other piece is the variable of between patient and within patient variability. That subject within blood glucose meters has been addressed – for instance, accuracy and hematocrit. With our sensors, there is a limited difference between sensors from concurrent insertions. We’re glad people find it impressive. It didn’t happen overnight – there was work behind it. Getting those two things right is what allows it to be a 14-day sensor without fingerstick calibration. I’m not going to tell you how we did it! [Laughter]
Q: I’ve been living 63 years with diabetes, was the past president of IDF, and I’m happy with this development. I’m not cynical, but after a long period of time, this is just the next step. It’s just really a next step. What we are missing is you are talking about patients – where are two, four, six, seven patients? Where are the people living with diabetes? They must tell you about hypos. Sorry Abbott, but please, next time, have patients up there. And don’t say, “No that’s not possible because of a conflict of interest.”
Dr. Bergenstal: We appreciate your perspective. Thank you for your long journey in dealing with this and adding knowledge and perspective. We attempted to be patient centric. And we see that we have failed. We tried to show that interaction with the patient is enhanced with this tool. But your advice is good – let’s bring the patients in and have them tell us about it. Your advice is well taken.
Corporate Symposium: How New Technologies & Social Media Can Improve the Lives of People with Diabetes (Sponsored by IDF Europe)
PATIENT AND COMMUNITY ENGAGEMENT, OUTREACH PROGRAMS FOR MHEALTH AND EPATIENT
Paul Buchanan (CEO TeamBG, Great Britain, UK)
Mr. Paul Buchanan, founder of TeamBG (a diabetes and exercise non-profit) and Great Britain Diabetes Online Community (#gbdoc on twitter), relayed to the audience how a type 1 diabetes diagnosis at age 45 shaped the development of his twitter community and founding of TeamBG. Most notable was his discussion of the mHealth Grand Tour, a unique clinical study to examine the role of technology in diabetes management. Participants rode from Brussels to Barcelona from September 5 to September 18 wearing the Dexcom G5 CGM. Each rider had his or her glucose levels (as well as heart rate and bike computer statistics) transmitted wirelessly to smartphones – very cool! The data from the ride is currently being analyzed at the University of Newcastle (we can’t imagine the number of data points), and Mr. Buchanan remarked that he hoped the results would demonstrate a “clear need for technology in the management of chronic conditions.” It’s great to see such a cool use of the G5 out in the real world – as a reminder, Dexcom has said the Gen 5 CGM system (mobile platform, new transmitter, new algorithm, improved applicator), will be rolled out in several stages over the next two years.” We know many patients that are clamoring for a mobile CGM platform – what will be most interesting is to see how things go with the FDA. Certainly, Dexcom Share will be an early indicator, which was submitted to the FDA in July.
- Mr. Buchanan said that when he was diagnosed, there was no place for patients to ask questions that affected their daily life (e.g., What happens with my license? How will this affect my mortgage?) After participating in a US weekly twitter conversation (#DSMA), Mr. Buchanan decided to start his own for other patients with diabetes in Great Britain. The conversations have been a great success, with thousands of participants in 22 countries at the end of the first year. For more information, see #GBDOC’s impressive website at http://www.gbdoc.co.uk/gbdoc/About_gbdoc.html
- Mr. Buchanan called the inability for patients to send healthcare data from France to their HCP in the UK “madness,” and highlighted the need for regulators to examine what will keep patients the safest. For Mr. Buchanan, this means keeping the communication lines open between HCPs and patients. We certainly agree, though we think a key challenge is in presenting data in a way that providers can digest and in a reimbursement system where they can get paid.
- “Health is like religion…it has to be made personal to be sustainable.” Mr. Buchanan emphasized that patients have to want to incorporate tools into their life in order to be successful He questioned why we expect apps will be any different from past technologies (such as scales and mirrors) that have failed to change our behavior throughout the years. He noted that technologies have to be a tool to engage patients rather than a to be used as a regulatory stick. Mr. Buchanan also cautioned app developers to remember that patients are not the same as “normal consumers” and developers must consider what will engage patients the most.
- TeamBG encourages people with diabetes to achieve their exercise goals, and also educates people with diabetes about the benefits of sports and exercise. For more information, see TeamBG’s website at http://www.teambloodglucose.com/TeamBG/Mission.html
USE OF SOCIAL MEDIA & NEW TECHNOLOGIES FROM THE PERSPECTIVE OF PWD
Claire Pesterfield, RN (Cambridge University Hospitals NHS Trust, Cambridge, UK)
Ms. Claire Pesterfield, a self-described “diabetic diabetes nurse,” delivered a lively talk balanced by her ability to speak from the dual-perspective of a healthcare provider and a patient living with type 1 diabetes since the age of 13 years. Her well-structured presentation alternated between the HCP and patient voice, allowing her to highlight the disparities and alignments that exist between their respective desires. One of her biggest points was that people with diabetes lead multifarious lives with many more demands than just management of their chronic condition; however, the price for not letting diabetes-care be all-consuming is often felt in the clinic. Ms. Pesterfield then advocated on behalf of patient-centered goals that aim to achieve optimal control within acceptable limits. Currently, Ms. Pesterfield sees doctors’ focus as being purely on reaching rigid target A1c targets. Additionally, Ms. Pesterfield expressed the need for more technologies and strategies that are seamless, safe, and effective. Given the title of her talk, we were disappointed that Ms. Pesterfield did not capitalize on her unique position as a provider and a patient to discuss how both can leverage the diabetes online community. She briefly mentioned the ability of Facebook to dispel social isolation; however, she did not delve into the power of other online platforms to disseminate information and engage stakeholders.
HOW MOBILE SOLUTIONS CAN HELP PEOPLE WITH DIABETES
Benjamin Sarda (Orange Healthcare, France)
Mr. Benjamin Sarda explained that when he began his career, the main focus of his customers (typically government and pharmacies) was to reduce the cost of healthcare. This could be done in three ways: getting rid of hospital beds, getting rid of bad habits, and getting rid of emergency medical events. Mr. Sarda remarked (rather astutely, we thought) that efforts to eliminate one problem typically lead to another. Within the past five years, however, technology has provided some solutions to take on these three problems. He outlined several ways that innovations have helped decrease readmission rates and increase patient compliance in cases like sleep apnea and cardiac events. Mr. Sarda used the last part of his presentation to describe the mHealth Grand Tour (which we saw a brief video synopsis of!) – he hopes this study, which used the Dexcom Gen 5 CGM system, will provide data showing that technology is useful for better healthcare in patients with diabetes. We, too, are excited to hear the results of this trial since good technology can really make a profound difference in glycemic control (provided it is used in an optimal way). We wish Mr. Sarda had spent more time discussing diabetes-specific technology, though much of his presentation focused on other healthcare examples.
- CGM, heart rate, and bike data from the mHealth Grand Tour is currently being analyzed at the University of Newcastle. The information that will be analyzed includes how riding affects blood sugar levels during the day and night; how different athletes manage their diabetes (insulin and glucose); how high-performance athletes with type 1 diabetes manage their diabetes compared with non-competitive athletes with type 1 diabetes; and how people with diabetes can teach people without diabetes how to prevent low blood sugar levels during a ride.
Panel Discussion
Moderator: Sophie Peresson, MA (IDF Europe Regional Director, Brussels, Belgium)
Panelists: Paul Buchanan (Founder and CEO, TeamBG, Great Britain, UK); Claire Pesterfield, RN (Cambridge University Hospitals NHS Trust, Cambridge, UK); Benjamin Sarda (Head of Marketing, Orange Healthcare, France)
Q: I have a challenge for you two, Mr. Buchanan and Ms. Pesterfield. There is a huge problem of discrimination of people with diabetes. How can you protect personal data, for example when you are applying for a job? How do you make sure that your employer is not seeing that you have diabetes on social media outlets such as Facebook?
Mr. Buchanan: It is an interesting question. I suppose you have to get to a point of having interviewers asking interviewees to view their social media profiles. However, what interviewers are seeing on social media is not limited to chronic conditions. There are also people on social media who post themselves doing very stupid things. I think in order for social media outlets such as Facebook to be used more as a forum for chronic diseases, social media needs to become a more mature platform. From the perspective of protecting personal data, the easy answer is to look at current mobile technology and banking, which use encrypting. It is true that even these can be hacked – any data can. So, one reply is to regulate employment law and educate people on what is appropriate to put on social media; another reply is to look at social platforms that allow you to develop an avatar or a personality that you can use to be anonymous. There are few people in GBDOC [Great Britain Diabetes Online Community] that are personally identifiable, and those posts are rational and published responses. You need to remember that with any community you get extremes in ideas.
Mr. Sarda: If someone posts on the internet that he or she has type 1 diabetes, there is nothing you can do about it. Most countries have regulations on nonmedical data, and it is not legal to use the same data centers to host YouTube and personal medical data. Most players are asked to invest in dedicated data centers with high-level security centers for medical data. In Europe, the standards for health data are higher than the standards for protecting bank data. But if you put everything on Facebook… [shrug].
Q: I was interested in the CGM data and its transmission from country to country. I just assumed that if I had a mobile phone app, I could send data without being restricted by regulations. IDF and various member associations are very much involved in advocacy, and we have regular sessions in Parliament to discuss these big issues. What can these organizations do to help change regulations to make things easier?
Mr. Buchanan: I am happy to speak from a patient’s perspective. The reason for this challenge is that there is no harmonization across member states. There is no standardized language or protocol, and in some counties it is illegal to transmit patient information outside the boundaries of that particular country. For instance, there was one case in which CGM data had been moving across several countries. Data was being sent to smart phones, where patients weren’t allowed to see it because it was blinded, and then to a cloud based platform, where there had to be a delay of 30 minutes before the information was made visible to ensure that there was no chance of people making therapeutic decisions based off the data. Why does it take four to six years to bring a device to market? Because of the regulatory framework! By the time regulators make up their minds that something is safe, we have already moved on. There is a lack of innovation today not because of the costs of innovation itself, but the costs of the time scale to get the approvals. We still need regulatory approval, but it can be harmonized; the regulatory framework needs to move in time with technological solutions that currently exist as well as those developing for future use.
Mr. Sarda: Each and every country in Europe has their own regulation about medical data; is not the same from country to country. From an industry perspective, we need a common agreement. There is an international third party that is writing down guidelines for standardization; this will help make things cheaper and safer. As for the time issue, we need to be FDA cleared – we want to provide patients technologies and solutions that are strong and validated.
Comment: It seems to be that you have highlighted the extraordinary situation of being unable to transmit data across countries. This is a challenge for organizations such as IDF and other chronic disease associations – we need to show this to parliament and make them see the actual problems that you face.
Ms. Peresson: We know what the problems are from a diabetes perspective, and Benjamin brought in the other perspective. I think that starting to have this conversation with all stakeholders will speed up developments, but we are only beginning the discussion now. If you want to contact us, please do not hesitate. I will now ask the panelists if there is anything they would like to add to close the session.
Mr. Buchanan: I want to challenge the audience and EASD. I am going to read you some quick, terrifying statistics for those of you who are new to diabetes. There are thousands of children with diabetes in Great Britain. The median A1c is above 8% – this has not improved in a decade. In ten years, the world has revolutionized in terms of social media, the Internet, and global communication. Why is there such a disparity between this and diabetes? Diabetes has one of highest failure rates for chronic condition there is. Why is this? Out of every one million people with diabetes, 841,000 patients fail on all measures of success that the UK has decided upon. It cannot be that technology is what is stopping us from succeeding. This is your business and this is your industry. We need you to do this. Please be good at what you do.
Ms. Pesterfield: I’ve had diabetes for 20-odd years, and I’ve been a diabetes nurse for half of it. It’s frustrating because we’ve seen so many things come in, but we still have some of the same frustrations and regulations. I’m often caught on the fence between what I want as a patient and what I can offer as a healthcare professional. One problem is that people only look to the next year and next election to find things to fund, and we need to start looking 20-30 years ahead in order to make those funding decisions.
Corporate Symposium: Technology and Innovation in Type 1 and Type 2 Diabetes Care (Sponsored by Sanofi)
NEW INNOVATIONS IN TECHNOLOGY
Steve Edelman, MD (University of California, San Diego, CA)
Dr. Edelman gave a fast paced review of new innovations in technology, including insulin pumps (OmniPod, t:slim, V-Go), BGMs (iBGStar, MyStarExtra), CGM (focused on the Dexcom G4 Platinum), mobile health and remote monitoring (Medtronic mySentry, Dexcom Share and Gen 5), and the artificial/bionic pancreas (Dr. Ed Damiano/Steven Russell; “very, very impressive”). Most notable was his mention of Sanofi’s new MyStarExtra meter – it is the first meter to provide an estimated A1c value, a three-day fasting glucose average, and trend arrows for both statistics – we are big fans of these features, since they give more actionable data and motivation for patients to improve. The device apparently uses a “specific algorithm,” though we wonder if it relies on the ADA equation for the relationship between average glucose and A1c: 28.7 x A1C - 46.7 = estimated average glucose. Dr. Edelman spoke very positively about the new meter, noting, “I’m a big believer in point-of-care testing.” In particular, he believes the three-day average will be “tremendously helpful for type 2s titrating basal insulin.” We really hope to see the device in person in Sanofi’s exhibit hall booth. Dr. Edelman did not discuss launch timing or the product’s regulatory status.
- In insulin pumps, Dr. Edelman highlighted the second-gen Insulet OmniPod, Tandem’s t:slim, and Valeritas’ V-Go. He noted advantages of each device that make life easier and more convenient for people with diabetes: smaller size (Insulet OmniPod); high in human factors (Tandem t:slim; “you don’t have to read the instruction manual”); and very easy bolusing (Valeritas V-Go; “MDI patients use about 30% less insulin on the V-Go and control improves”).
- Dr. Edelman believes the future of glucose data will revolve around the smartphone and “contextual awareness.” In other words, utilization of the sensors commonly found in today’s smartphones to tie blood glucose to location (GPS), activity (accelerometer, gyroscope), and previous history. In his view, the unmet need is wireless sensor data aggregation with multivariate analytics. Dr. Edelman hopes to one day see an “automatic food recognition” app that could scan a plate and tell the user very accurately its carb, protein, and fat content – that would be something! The app could be informed by GPS data (e.g., driving up to McDonalds) and even give a suggested portion size and a prediction of postprandial blood glucose. We are drooling at the thought of it. . . Said Dr. Edelman, “Mobile health is going to be of tremendous help in taking some of the variables out of diabetes.”
- “CGM is the greatest advantage for people with type 1 diabetes since the discovery of insulin.” Dr. Edelman provided an enthusiastic and impassioned review of CGM, characterizing it as a technology that can “take some of the unpredictability out of diabetes.” Indeed, if he had to choose, he would pick a CGM over insulin pump therapy. He also believes that every type 1 is a good candidate for CGM. In the future, Dr. Edelman asserted that all insulin pumps “MUST” have a screen that shows the CGM value. He was clearly a huge fan of the Dexcom G4 Platinum and had several slide with pictures of the receiver and sensor.
- Dr. Edelman highlighted Drs. Ed Damiano and Steven Russell’s work on the bionic pancreas. He described Ms. Kelly Close’s experience in the trial: “She didn’t have to think about her diabetes. She could actually eat things she normally wouldn’t eat.” Dr. Edelman noted that the current iPhone-based research platform “doesn’t look that practical, but they are working towards a more wearable system.” For more on the bionic pancreas, see our coverage on the summer camp study at http://www.closeconcerns.com/knowledgebase/r/0b79c500.
- Dr. Edelman believes there are several challenges for the AP going forward: lag times; responding accurately to large meals/exercise; sensor accuracy; unpredictability of subcutaneous insulin; universal connectivity; and delivery of more than one beta cell hormone. We think progress is happening on all these fronts, except for the last one – it would be great to hear more about co-formulating insulin and amylin, since so many have talked about this potential combination.
Corporate Symposium: InsuPad – Improvement of Insulin Therapy – A New Option (Sponsored by InsuLine)
IMPACT OF INSUPAD ON GLYCEMIC CONTROL AND INSULIN REQUIREMENTS – RESULTS OF THE BARMER STUDY
Andreas Pfützner, MD, PhD (IKFE Institute for Clinical Research and Development, Mainz, Germany)
Dr. Andreas Pfützner presented results from a study done by InsuLine in conjunction with BARMER-Ersatzkasse (a large German payer). Over three months, MDI patients using the InsuPad site-warming device achieved similar glycemic control using 12% less total insulin and 28% less prandial short-acting insulin vs. the MDI control group. Out of the 135 patients who were included in analysis, the majority of study participants were obese, type 2 diabetes patients, although type 1 patients were included in the study. Dr. Pfützner emphasized that patients in both groups achieved a 0.5% drop in A1c levels after training (baseline: 7.2%), and this drop continued to 6.3% for both arms. Notably, although both groups experienced a reduction in A1c levels, patients in the InsuPad group experienced about half of the number of hypoglycemic events per person vs. the control group (p<0.05) – this has been a clear theme in recent ultra-fast insulin trials of MannKind’s Afrezza (type 1), Biodel’s BIOD-123, and Halozyme’s Hylenex preadministration. Dr. Pfützner enthusiastically shared with the audience that all patients who participated in the treatment group planned to continue using the InsuPad, and many patients in the control group have already expressed their desire to switch to InsuPad – a great indication of patient approval, we think!
- This study was an open-label, randomized, parallel design with 145 patients (mean A1c: 7.2% and mean weight: 235 lbs). There were 51 female and 94 male participants. The average age of patients was 62 years, and there were 13 patients with type 1 diabetes. All patients were using insulin analogs (Lantus plus a short-acting insulin) with a high total prandial dose (>60 units per day, in order to show a larger magnitude in change between groups). Patients were recruited from 13 German sites.
- Patients had an initial four-week run-in period in which their basal glucose was optimized to normal fasting levels, as used in the ORIGIN trial, and each patient received the same education on insulin treatment and lifestyle. Patients were then randomized to either the test group or the control group. Participants were required to check-in with their physicians only one more time at the end of the three months. While there was an optional bi-weekly phone check-in, the researchers really wanted to evaluate how the InsuPad worked in a non-clinical setting.
- Notably, patients in the InsuPad group experienced about half of the number of hypoglycemic events per person vs. the control group (p<0.05). This was following the glucose optimization period. Despite the improvement in hypoglycemia, bodyweight remained consistent for both groups.
- Overall, patients using the InsuPad used 12% less total insulin (p<0.001) and 28% less prandial insulin vs. the control group. There was no significant change in basal insulin use for either arm, nor was there a change in hyperglycemia (>250 mg/dl).
- The 13 type 1 patients who participated in the trial and used the InsuPad also experienced an overall 18% reduction in insulin dose (p<0.05) when analyzed separately from the rest of the group. There were two female and 11 male patients with type 1 diabetes, with a mean age of 50 years, a mean A1c of 7.2%, and a mean body weight of 203 lb. Patients using the InsuPad also experienced less frequency in hypoglycemic range vs. control (p<0.06 – although Dr. Pfützner remarked it would have been significant with one more participant).
- A subgroup undergoing a mealtime tolerance test (n=24) corroborated these real world results – patients on the InsuPad achieved similar glycemic control but with ~20% less insulin. Dr. Pfutzner pointed out that patients using InsuPad had an insulin onset about 30-minute earlier than the control. This test occurred twice during the study and was conducted to ensure biological correspondence to what the researchers were observing in their real-time patients. Eight patients were excluded due to very high basal insulin levels. The mealtime tolerance test was given to patients at physician visit two and three for participants.
- Safety data looked positive for the InsuPad – there were 13 serious adverse events (seven in the InsuPad group), and none were related to the device. There were a total of 500 adverse events in the study, with 200 in the InsuPad group. There was one case of “burning,” which turned out to be an allergy to the adhesive – this has now been changed. Dr. Pfützner joked that your “iPhone is more likely to overheat” than the InsuPad.
- As a reminder, InsuPad is a heated insulin delivery device for MDI users. The product is composed of a disposable pad for one-day use and reusable unit that contains the rechargeable battery and electronics. The product works as follows: 1) patient connects electronics to disposable pad and places the pad on the skin; 2) patient injects meal insulin through the opening in the pad; and 3) InsuPad is activated automatically with each injection to deliver heat and stop after few minutes; and 4) patient removes InsuPad from the skin after three to four injections, the electronics are removed from the disposable pad and recharged, and the disposable pad is disposed of normally. See a picture here: http://www.insuline-medical.com/products.
- Dr. Pfützner remarked that a lot of thought has gone into the device’s design: to ensure that patients changed their insulin pad everyday, the device has a plastic frame that opens and closes like a window (appropriately called a fenster, the German word for “window”). The moment the pad is taken out of the frame, the frame will break so the patient cannot use the device until the frame is replaced. Participants in the study were given two re-chargeable heating units so participants could they could charge each unit every other day.
- Dr. Pfützner noted that $3,200 per patient per year is lost to mild hypoglycemia in diabetes, according to a study done by Novo Nordisk with Tresiba (insulin degludec). There, Dr. Pfützner explained, the reduction in hypoglycemia demonstrated to insurance companies that it would actually save money in the long-term; InsuPad is already reimbursed by major funds in Germany, and InsuLine is waiting for total reimbursement, which they will hopefully get within the next month.
Questions and Answers
Q: First of all, congratulation on a well-conducted study. My one comment is that you did very well getting all your patients being compliant with education; you would not have gotten that in the US; they would not do that in the US. I was hoping you could explain your rationale behind excluding subjects with high basal levels in the mealtime tolerance test group?
A: First, let me address your comment. If a patient in Germany goes on insulin therapy, he or she is required to get structured training and attend a real class. This started about 15-20 years ago, and the pharmaceutical companies took it up. Regarding your question, the rationale in excluding high insulin resistant patients was to show a difference in how much insulin patients took; however, even those with high insulin resistance had the same impact on glycemia on the InsuPad. The results do not matter if you analyze 24 or 32 patients. However, there is a huge standard deviation because of the noise that the eight patients add since their baseline is so high. This patient population is not really the best one to demonstrate pharmacokinetics in. We are going to investigate this in next study in smaller, slimmer patients with type 1 diabetes.
Q: You noted that there was a difference in response to the InsuPad. It is interesting that we see that in the insulin reduction. Who were the patients who had a 50% or 40% reduction in insulin?
A: This goes back to what I was saying in response to the previous question. We could not have anticipated the seriously obese being of interest, but the seriously obese benefited the most from the savings in insulin.
Comment: I want to make a comment about a high-insulin dose. We did a study that looked at subjects who had a high insulin dose. We examined the effect of increasing the dose of insulin in a standardized setting, and we looked at pharmacokinetic profiles and the delay in absorption with an increasing dose of insulin. We believe with higher insulin users, there is a greater relative benefit of using ultra-fast insulin.
Q: Did all participants use the same needle length?
A: No. We recommended that they use 9 mm needles, but they used the same pens they had been using before. We cannot answer if there was a difference between needle lengths because we did not examine that in the study.
Corporate Symposium: Personalized Diabetes Management – The Journey to More Efficient and Effective Solutions (Sponsored by Roche)
USE THE DATA – REALITY, OPPORTUNITIES, AND FUTURE OPTIONS OF MOBILE HEALTH
Irl Hirsch, MD (University of Washington School of Medicine, Seattle, WA)
To begin, Dr. Irl Hirsch posed the challenging question, “Why is there so little enthusiasm for downloading data?” While the current method of downloading data is cumbersome, time-consuming, and frustrating, Dr. Hirsch remarked that a transition to the cloud (virtual data storage) could help standardize and ease the downloading process for patients and HCPs. Turning specifically to the frustrations HCPs face, Dr. Hirsch noted downloading data is time-intensive and awkward, with a different cable for every device. To emphasize this point, Dr. Hirsch showed a graph of the average length of download time, highlighting that some meters take as long as ten minutes (although he did remark that the new Dexcom CGM only takes 10 seconds to download). However, Dr. Hirsch believes that the poor use of technology is "about to change” due to cloud-based storage – patients will be able to sync glucose values immediately with their smartphone and send data to anyone. Dr. Hirsch also highlighted that in order for mHealth to succeed, there need to be clinical trials, clear regulatory pathways, and collaboration between government, payers, and industry sponsors. In conclusion, he acknowledged the utility of technology and urged HCPs in the audience to agree on a common goal in order for mHealth to decrease cost, improve outcomes, and save time.
- Several studies indicate that data downloading or computer self-management improve patient outcomes. Dr. Hirsch showed one study demonstrating that downloading data helps patients with type 2 diabetes (Frits et al., Diabetes Technology Therapeutics 2013) and another review that demonstrated that patients who used computer-based diabetes self-management showed a significant A1c reduction of 0.2% compared to controls (Pal et al., The Cochrane Library 2013).
- Smartphones may be one way to leverage mHealth. Dr. Hirsch noted the increase in penetration of smartphones (Spain led in 2012 with 63%!), and emphasized the many healthcare apps that are coming out.
- Data from the T1D exchange (n~26,000) indicate that 68% of patients never download their meters, and only 10% download once-monthly. Further, 22% download their CGM less than once a month. Dr. Hirsch remarked (and we agree!) that patients often face similar challenges as HCPs: consistently downloading data is time-consuming, it is difficult to know what to do with all the data, and, some patients lament, their physicians don’t ever look at the data.
- Since beginning to compete against him on a health app, one of Dr. Hirsch’s patients has experienced a 1% decline in A1c. This patient had previously never engaged in any activity, which all changed after buying a Fitbit and “friending” Dr. Hirsch. The patient is consistently out-walking Dr. Hirsch every week. We think this speaks to the potential for mHealth to make exercise and diabetes more social, more competitive, and more fun. We know lots of companies are working on this, and we hope to see much more coming out soon.
Questions and Answers
Dr. Hans DeVries (Academic Medical Center, Amsterdam, Netherlands): Would it be possible to convince industry to adopt one simple cable for all meters?
Dr. Irl Hirsch: Theoretically, it would be possible – especially if there was one cable for PC and one for Mac. We put the man on the moon in 1969, and we can’t get a cable everyone can use? If we can beam everything to cloud, the cable issue might not be as important. But I do share your frustration about the cables.
CONTINUOUS GLUCOSE MONITORING – CLINICAL APPLICATIONS FOR HIGH PERFORMANCE SENSORS
Hans DeVries, MD (Academic Medical Center, Amsterdam, The Netherlands)
In this presentation examining the history and future of continuous glucose monitoring (CGM), Dr. Hans DeVries concluded that the current CGM is good enough and getting better. Dr. DeVries reviewed data demonstrating that CGM can lower A1c levels in patients who wear the monitor consistently; however, he also drew attention to the fact that initially, CGM did not appear to change the rate of severe hypoglycemia – likely because, Dr. DeVries remarked, when patients are hypoglycemic it is often too late for them to respond to an alarm (an exception is Medtronic’s low glucose suspend). Dr. DeVries also commented on the accuracy of CGM, remarking that performance in hypoglycemia has not increased greatly in the past eight years. However, he is optimistic about the future of CGM – the Dexcom G4 Platinum has a much-improved MARD over the Dexcom STS (13% vs. 21%), and he called the prototype Roche sensor’s MARD of 9.2% a “magical thing,” as it breaks the double digit mark. We continue to look forward to more data on this in-development sensor. Dr. DeVries spoke positively regarding low glucose suspend (LGS), noting the ASPIRE in-home study’s finding that LGS can reduce minor hypoglycemia without increasing overall mean glucose levels. Posing the question of whether we need better CGM, Dr. DeVries remarked that it is a mixed bag: while patients experience A1c and hypoglycemia benefits with current CGM, they still find false alarms annoying and there is a high discontinuation rate among those who try CGM. Overall, he concluded that while CGMs are satisfactory now, they need to improve to see greater adoption.
- Dr. DeVries specifically highlighted Dr. Trang Ly’s ADA 2013 study, which found that use of the Medtronic Veo (Enlite CGM plus low glucose suspend) eliminated severe hypoglycemia in 46 patients with hypoglycemia unawareness. In the six months prior to baseline, the number of severe hypoglycemia events was comparable between the groups: six in the low glucose suspend group and five in the insulin pump-only group. Notably, after six months on low glucose suspend, the number of severe hypoglycemia events dropped from six to zero (!) in the low glucose suspend group, compared to an increase from five events to six events in the group on a pump only. When the talk was presented at ADA, Dr. DeVries called it “the most important study at this whole meeting.” For more details on this study, please see page 90 of our ADA 2013 full report at http://www.closeconcerns.com/knowledgebase/r/94f937d8 or the September 25, 2013 publication in JAMA (Trang Ly et al.).
- Current CGMs have MARD values around 16% in hypoglycemia, according to data from Luijf et al., Diabetes Technology & Therapeutics 2013. Dr. DeVries highlighted that these values are similar to those observed eight years ago in a study of a needle type sensor (CGMSgold) and microdialysis sensor (GlucoDay) (Wentholt et al., Diabetes Care 2005). We believe that on the whole, CGM accuracy in hypoglycemia has improved – especially with the Dexcom G4 Platinum – though there is certainly still room to improve.
- One study by JDRF put the price of CGM at $100,000 per quality-adjusted life year, although, Dr. DeVries highlighted, there is dearth of information on cost-effectiveness. We would emphasize that cost-effectiveness data is driven by clinical data from older trials of CGMs using earlier generation devices. We suspect clinical outcomes would be better in large-scale trials using more up-to-date systems – in turn, cost-effectiveness would look much better. Many experts have also criticized QALYs for providing only a very crude measure of a therapy’s value.
- Dr. DeVries noted that only seven countries (according to our count) have a structured method for patients to gain reimbursement for their CGM, and the cost must go through insurance on a case-by-case basis in other countries.
Questions and Answers
Q: I have a question about the psychosocial burden of diabetes. Diabetes and diabetes therapies create burdens for the patient. Many people don’t like CGMs, not just because they don’t want to be reminded of their diabetes, but because there are so many alarms associated with the CGM; it really makes their diabetes visible to them. Also, there are teachers who make kids turn off their alarms. In terms of reimbursement, what would you say to the clinician who asks who would benefit the most from a CGM?
A: I think you need to disentangle that a little bit. When you talk to reimbursement authorities, you enter a whole new playing field where there is separate terminology and everything comes down to mainly one thing: lowering A1c levels. You have done a good job if you explain why severe hypoglycemia is important and all of the things you have touched upon that are critical for daily life.
How can a clinician select a patient that will benefit? I tend to turn to trials and studies first. Physicians do a poor job if they predict who is going to benefit and who will not. You could argue that the best thing is to pre-negotiate with the patient and agree on a benefit that is measureable and the patient can realistically achieve. After six months of using CGM, you can ask the patient what he or she thinks of the device, and you can look at how the data says you should proceed. If you don’t have reimbursement, this tends to overtake the discussion. I have seen patients who had severe hypoglycemia unawareness, and they couldn’t get reimbursement unless their A1c levels were above 8.5%. Once their levels were high enough, then they could get CGM.
Q: There is early data from Dr. John Pickup that adherence is a predictor of success. What are the main effects determining adherence and how do we improve adherence?
A: If you ask a few people why they discontinued using CGM, they will likely tell you it was because of the false alarm rate. If patients are woken up two to three times a week because of an alarm, they typically don’t want to use the device. Others will be difficult to convince to use CGM if they don’t think they will benefit. Also, if patients have to calibrate twice a day and are consistently noticing large differences between their finger sticks and their device, then they will be less willing to trust the device. Accuracy and alarms are the main things we can focus on to improve adherence.
Q: In studies with lower A1c levels, are patients dosing insulin based on the CGM, or are they required to do fingersticks?
A: The patients are “required” to do fingersticks, but we all know they don’t all the time; patients use logical reasoning. If they have just eaten and their device shows a high blood glucose value, they are going to give themselves an insulin injection. If you’ve just played tennis and you tend to come out low, but your device says you’re high, you take a finger stick before dosing.
Media Symposium: Personalized Diabetes Management – The Optimal Solution for Enhanced Confidence, Efficiencies and Outcomes? (Sponsored by Roche Diabetes Care)
PERSONALIZED DIABETES MANAGEMENT - WHAT IS ROCHE DIABETES CARE'S TAKE ON IT?
Matthias Schweitzer, MD (Roche Diabetes Care, Mannhein, Germany)
Dr. Matthias Schweitzer opened this media symposium with an introduction to Roche’s commitment to personalized and integrated diabetes medicine. The talk was a basic primer of Roche’s model for personalized diabetes care, a feedback loop comprised of the following six-steps: 1) structured patient education, 2) structured testing of new devices and therapies, 3) structured documentation of outcomes, 4) structured analysis of outcomes, 5) personalized treatment based on the preceding analysis, and 6) treatment efficacy assessment in everyday life. In accordance with the 2012 ADA/EASD guidelines, Roche’s model avoids algorithmic A1c standards in favor of customized glycemic targets. Dr. Schweitzer positioned accurate blood glucose information as the essential prerequisite of the model. He expressed confidence in the reliability of Roche BGM technologies (particularly Accu-Check) and also underscored the value of CGM systems in contributing useful blood glucose data. According to Dr. Schweitzer, translating blood glucose readings into meaningful action for patients requires improved connectivity between BGM devices, mobile applications, and online platforms so that healthcare teams can provide individualized feedback based on real time input. His talk concluded with the notion that while the distinct components of Roche’s model have been clinically validated, the next milestone in realizing the value of personalized diabetes care is evidence from pilot studies that evaluate the efficacy of the system functioning as an integrated whole.
- According to Dr. Schweitzer, the shift towards personalized diabetes management emerged from various demands in the current system. Healthcare and economic pressures, as well as the rise of new technologies, acted as drivers of innovation. The most pressing impetus for personalized solutions, however, were data indicating that patients spend only four hours per year with their endocrinologist versus 8,756 hours self-managing their diabetes. Given this profound discrepancy, Dr. Schweitzer noted that patients need a system that keeps them educated and invested in their diabetes care on a daily basis, when they are largely making therapeutic decisions by themselves.
- Each component of their feedback-loop model for personalized diabetes care has been clinically evaluated in order to demonstrate medical value and efficacy. Because the six steps of Roche’s model (outlined above) have been individually validated, Dr. Schweitzer pressed that now is the time to implement the entire personalized diabetes management process with optimized blood glucose monitoring technologies.
- Dr. Schweitzer illuminated the multi-step process of evaluating system performance that allows Roche to “explain why Accu-Chek provides true and reliable data.” A traceability chain, intense quality control measures, patient support and education, and system safeguards are parts of Roche’s process to test its products and ensure they generate portfolios of accurate blood glucose data.
- Dr. Schweitzer thinks translating data into information useful for decision-making is the next step towards achieving personalized therapy. Dr. Schweitzer commented on Roche’s commitment to “structured testing” and “connectivity.” Both of these concepts entail developing systems that link BGMs to mobile devices and online platforms, where information can be downloaded, transmitted to, and interpreted by medical professionals in order to inform individualized therapy decisions. Because studies indicate that patients largely self-direct their diabetes care, Dr. Schweitzer also promoted the advancement of BGMs and associated mobile applications that provide medical functionality to patients on a daily basis outside of the clinic.
- Dr. Schweitzer believes that in order to achieve this model of personalized therapy, glucose information and resulting feedback will also be gathered from continuous glucose monitors (CGMs). However, he emphasized that CGMs will need to meet rigid standards of accuracy in order to prove credible to HCPs and patients. Dr. Schweitzer highlighted the precision of the CGM sensor Atos-P, which he believes meets two essential accuracy measures: 1) no deviation between CGM sensor and blood glucose readings, and 2) agreement between two CGM sensors acting in parallel (data points are superimposable).
WHICH FACTORS CAN SUPPORT IMPROVED ADHERENCE AND CONFIDENCE IN DIABETES MANAGEMENT? – A PSYCHOLOGIST’S PERSPECTIVE
Bernd Kulzer, PhD (Research Institute of the Diabetes Academy Mergentheim, Bad Mergentheim, Germany)
Dr. Bernd Kulzer, a diabetes psychotherapist, identified factors that improve patient adherence and medical outcomes in diabetes care. Drawing on the six-step cycle elucidated in Dr. Matthias Schweitzer’s (Roche Diabetes Care, Mannhein, Germany) preceding talk, Dr. Kulzer argued that personalized diabetes treatments tailored to a patient’s individual profile is the key to increasing medication adherence. In line with Dr. Schweitzer’s assertion that diabetes is largely self-managed, Dr. Kulzer stressed that the process of encouraging sustainable behavioral change begins with continuous education and ongoing support for patients and those at risk of developing diabetes. The major steps in achieving a personalized system are 1) evaluations of an individual’s ability to manage diabetes therapy, 2) feedback informed by structured blood glucose measurements, 3) treatment change based on individual characteristics and SMBG profiles, and 4) regular assessments of treatment efficacy before returning to step one. Dr. Kulzer believes that this cycle should perpetually revolve to maintain adherence, repeating at varying time intervals to ensure that treatment paradigms readily adapt to patients’ changing circumstances and behavioral patterns.
- Patients with low adherence have worse glycemic control, higher rates of hospitalization, and greater risks of mortality than those who regularly follow their treatment protocols. The need to improve adherence is clearly evidenced by striking statistics showing adherence rates to be 60-70% for oral medications, lower than 20% for behavioral targets, and approximately 80% for insulin dosages. Dr. Kulzer quoted a finding that $200 million US dollars would be saved if adherence improved to a rate >80%. That is an enormous economic payoff – and the adherence rate would not even be 100%!
- Dr. Kulzer made a point to differentiate “adherence” and “compliance;” the latter term he thinks is a dated and unfitting term. In Dr. Kuzler’s opinion, adherence is a complex process that is determined by many factors, of which the patient is just one player. In contrast, he argued that “compliance” depicts the patient as passive agents in their care. Dr. Kulzer strongly favors the term “adherence,” as it suggests that patients actively agree with their therapy recommendations and have developed healthy partnerships, premised on strong communication, with their HCPs.
PANEL DISCUSSION
Moderator: Ute Volkmann (Roche Diabetes Care, Mannheim, Germany)
Panelists: Jorge Garcia Alemán, MD (Hospital Quirón Málaga, Málaga, Spain); Paul Buchanan (CEO TeamBG, Great Britain, UK); Iain Cranston, MD (Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom); Bernd Kulzer, PhD (Research Institute of the Diabetes Academy Mergentheim, Bad Mergentheim, Germany); Matthias Axel Schweitzer, MD (Roche Diabetes Care, Mannhein, Germany)
Ms. Volkmann: You mentioned the topic of adherence and how it differs among different individuals. Can you give an example of this?
Dr. Kulzer: Different patient groups have different needs. Personalizing the therapy using evidence means that you can get an impression of each patient’s needs and goals.
Ms. Volkmann: Why do you think a bolus insulin advisor would be beneficial?
Dr. Schweitzer: Variability is reduced with bolus calculations – it is a classic biofeedback process. If you have data that allows you to be confident about your decisions, you get better about making decisions. As an example, if I estimate that a given meal is 80 grams, the next time I have that that same meal, I’ll remember that I estimated 80 grams but that my sugar was really high after. I need to be able to work out whether my estimation of 80 grams was wrong or if my insulin calculation was wrong. If you have confidence in your data, that eliminates one of these questions.
Comment: I understand that personalized diabetes management is key, but what does it change from a patient’s perspective?
Mr. Buchanan: Technology allows personal relationships to develop, and it also allows for context, meaning that as a patient, I’m no longer turning up once a year for a 15-minute consult about meaningless data, such as my A1c number. With technology, a doctor can provide a narrative context for that data. That difference will really shape the future of healthcare delivery.
Ms. Volkmann: Can you support that with experiences from your practice?
Dr. Alemán: The most important part is the fact that you can build a relationship with patients. Patients do say to us that they feel more confident.
Dr. Cranston: Data isn’t enough. What we need to make a change towards personalized medicine is information. Tools that help us change data into information are really key. What a particular test means at a particular time is what we need to know for patients.
Ms. Volkmann: If a patient sends in data and you review it and send back feedback, do you think you have closer patient/ doctor relationship?
Dr. Alemán: Yes, the relationship does improve because patients do more consultations with increasing frequency.
Mr. Buchanan: In this platform, one of well managed personal diabetes care, having somebody at the other end of the platform who can provide feedback is very important. There are always times when you are struggling with something, and you need an objective third party to point out even the obvious based on real live data instead of something that happened 3-6 months ago.
Dr. Cranston: We train people to interpret their own data, which can be incredibly difficult because it is really hard to be truly objective about your own data. That process of making data into information requires the role of an objective other.
Comment: How does this platform work on a day-to-day basis? How do you transfer information back to the patient? How do you follow-up on the information generated by this platform?
Dr. Alemán: I’m not sure if I properly understand your question, but we try to see the data and provide a response with recommendations on how to improve treatment in a maximum of three days. We also work to see our patients once a month. The new version of eConnecta was born because patients needed more real time responses, so we are exploring the possibility of real time monitors to send in information so that we can quickly detect and respond to problems.
Comment: How do you communicate this?
Dr. Alemán: Messages and sometimes the phone when we detect important problems.
Dr. Schweitzer: Developing a solution is important, and one solution is getting data from a BGM to a mobile phone. Having the data on a smart phone will open up opportunities of messaging, sharing, and data transfer — essentially, connectivity to all kinds of platforms. There are challenges, but we are sure we can overcome this. These platforms on smart phones will be the future. It is a robust opportunity to work with and exchange data.
Dr. Cranston: In terms of the quality of electronic communication, we see forms that are very effective and some that are very ineffective. Some of it can be automated, but it’s also a challenge because that back-and-forth dynamic you get when you’re communicating is hard to replicate in electronic communication and support.
Dr. Kulzer: You have to have communication that fits. Web consultations, Facebook, and Twitter work for some, but not others.
Dr. Schweitzer: One of the potential barriers to this development is the structures on which our health care systems run, which are slow to change.
Ms. Volkmann: How can Facebook and Twitter help increase motivation for people with diabetes? Do you think talking about their daily diabetes routines and experience sharing actually helps?
Mr. Buchanan: Certainly! Social media is imperative for global communication. It enables people to share their lived experiences and dispel their social isolation. The DOC [diabetes online community] is quite huge on Twitter. In fact, I founded the GBDOC, and at the end of our first year we had reached 26 million people in impressions in 22 countries, and even helped extend a similar platform to many other countries! Social media is a great place for healthcare and industry professionals to observe and listen to conversations – some of which they wont approve of – that take place in the patient community. That is where patients discuss their issues and proposed solutions, even if they’re not ones that we would prescribe. It’s incredibly powerful for the dissemination of new therapies, tools, and skills.
Ms. Volkmann: What about those who aren’t so tech-savvy?
Dr. Kulzer: Most people would like to have more feedback from their doctor. Right now, you have approximately four chances per year to get feedback, and it would be nice to have more. New technologies have a really good chance to provide a solution to this. It’s not that a person doesn't like smart phones, but that doctors haven’t had a chance to integrate such technology into clinical routine. This is the biggest barrier in our health care system.
Mr. Buchanan: There is a lot of bureaucratic resistance to social media and tech medicine based on the fear that healthcare provides will be overwhelmed by patients wanting to communicate every detail, every day. Yes, at certain times you will have groups who need intensive management, but you also have some who you don’t need to see for years, and some you need to see only four times a year. Better use of technology would allow healthcare providers to intervene with patients who really need it when they need it, but of course it's a step into the unknown.
Comment: In the end, it all comes down to the same thing: time – be it on the phone, on Twitter, or in person consultations. There is a lot of talk about systems, hardware, and software and developing these platforms, but we’re not considering that we’re paying for peoples’ time in developing this. It’s not worth it to me if it compromises my time with my doctor.
Dr. Cranston: The technology allows us to actually use time more efficiently. That is what tech is for, isn’t it?
Comment: What is the next business model that you mentioned in your talk?
Dr. Schweitzer: We would basically get paid to enable certain therapies’ success. For instance, if a drug promises a certain outcome, you only get reimbursed if it upholds that promise. It would be a robust improvement for diabetes management and people with diabetes. The ultimate goal is to enable therapy success, which then gets reimbursed.
Dr. Cranston: Healthcare business models are slowly changing from an activity-based model to an outcome-based model. It's a move in the right direction, but the challenge with chronic disease and outcome-based models is that we have to choose the right outcomes that are practical in time scales that are relevant. Outcome based models work well for simple pathologies or surgical procedures. Chronic disease modeling is much more difficult, and although it’s clear that we’re going in the direction of an outcome-based model, it’s going to be very slow change.
Comment: Can you say something about economic effects of this new business model?
Dr. Cranston: My short answer is that I can’t really. I’m not qualified. It would be more conversational remarks. Hospitals are brick and mortar investments in the healthcare process. Much of what happens in hospitals doesn’t need to happen there, though the conglomeration of expertise makes it cost efficient. If we move things out of the expensive hospital environment, this helps for short term, but for the long-term it makes little difference economically. Hospitals will remain a long-term part of our care; we just need to make them more efficient.
Dr. Kulzer: It wont cost you more for increased patient and doctor interaction, but you will have better outcomes, hopefully.
Ms. Volkmann: In order to succeed in personalized diabetes therapy, we need all parties to get involved. Healthcare providers, patients, and members of industry are needed to bring this to life and make it efficient for patients.
7. Obesity, Prediabetes, and Metabolic Surgery
Oral Presentation: Technologies to Transform Diabetes
INTERIM 12 MONTH RESULTS FROM A POST MARKET CLINICAL TRIAL OF DJBL TREATMENT OUTCOMES IN SUBJECTS WITH TYPE 2 DIABETES AND/OR OBESITY
Julian Teare, MD (Imperial College, London, UK)
Dr. Julian Teare enthusiastically shared results from a 12-month study of GI Dynamics’ EndoBarrier, calling the gastrointestinal liner, “a genius invention.” The study enrolled 45 participants with type 2 diabetes (mean age: 50 years; mean diabetes duration: 5 years; mean BMI: 40 kg/m2). After 12 months of wearing the EndoBarrier, A1c declined by 1% from a baseline of 8.5% - we note that nearly all of the decline came in the first three months, with no noticeable change in A1c over the next nine months. Mean total body weight loss was 10% (-26 lbs from a baseline of 245 lbs), representing a 4.4 kg/m2 drop in BMI. Questions and skepticism definitely arose on the safety side, as there were a total of 13 device removals, nearly one-third of all patients in the study. Only three were categorized as “device related” (melena, anchor movement, abdominal pain), another five were due to “patient preference” (e.g., discomfort; we thought this could have been considered “device related”), and the last five related to “bleeding risks” (i.e., other comorbidities or new medications). Dr. Teare countered in Q&A that the average duration of implant was 10.5 months, meaning most patients made it the whole year (we wish he had discussed median implant time as well). He also mentioned that the number of explants in this study was higher than in previous studies of EndoBarrier. We look forward to data from Dr. Teare’s upcoming 160-patient study start next year, which will compare EndoBarrier N=80) to standard medical therapy (n=80). Notably, it will also include two-year follow-up, so it will be possible to see what happens to glucose and weight post-explant – that was a key piece of missing data in this study. For more on the device, including the status of the US ENDO trial, see our report at http://www.closeconcerns.com/knowledgebase/r/74d4f90f.
- As expected with such weight loss, improvements were also seen in a number of other metabolic and cardiovascular safety parameters: fasting glucose (-27 mg/dl from a baseline of 167 mg/dl), systolic blood pressure (-8 mmHg from a baseline of 138 mmHg), diastolic blood pressure (-3 mmHg from a baseline of 77 mmHg), total cholesterol (-9 mg/dl from a baseline of 167 mg/dl), LDL cholesterol, and triglycerides all improved as well.
- There were a fairly high number of device removals in this study. Three removals were classified as “device related” – melena (day 33), anchor movement (day 148), abdominal pain (day 283). On the latter, the patient wanted to keep the device in, but reached a point where she couldn’t. There were 10 “non-device related removals” – five were classified as “patient preference” and five related to bleeding risks (TIA, DVT, atrial flutter, gout needing NSAIDS, and an MI with stent insertion).
Questions and Answers
Q: Beautiful data, congratulations. Do the patients have any special dietary restrictions?
A: At the beginning of the study, they are on a liquid diet. Gradually, solid food is introduced. The initial phase does lead to calorie restriction. As they use the device, they go to a relatively normal diet.
Q: Were there changes in the dietary preferences of patients?
A: We haven’t put this into this study. In the next study, we will look at specific food preferences. Anecdotally, we do see a change away from high calorie foods to more high protein foods. It’s the same thing as you would see in gastric bypass, but we will assess it more formally.
Q: Was there a change in gut flora during/after implantation?
A: We will be looking at the microbiome in this subsequent study. How does the gut flora affect diabetes and obesity? It’s a huge question to be answered. We hope get insights from use of this device?
Q: What’s the follow-up on some of these patients. What happens post-explant to control of diabetes and weight?
A: I don’t have much from this study. But I do have company data. There is a gradual re-accumulation of weight and a gradual rise in A1c. It’s not at the same rate as the weight has been lost. It takes a lot longer for the weight to return. In the subsequent study, we will have a two-year follow-up to determine how long and durable the effect of the device is.
Q: Could the device remain in longer? Can you say whether people had the device could have it reinserted at a subsequent time?
A: There are some concerns about leaving the device in for longer. Our understanding will evolve over time about the optimal duration of use. Lots of patients had it and didn’t want it removed. They said, “Why are you taking it out? Why not leave in for longer? Can you put it back in?” The answer seems to be yes.
Q: I wanted to talk about another study sponsored by diabetologists that is to the interest of everyone. We’re looking at liraglutide plus EndoBarrier. We’ll also see what happens in the year after taking it out. Those are the answers we should have.
A: You also need to mention the inclusion criteria – failure on liraglutide to go on EndoBarrier.
Q: That’s right. You’ve got nowhere to go at that point besides increasing insulin.
A: It’s a question about where the role of devices should fit. The 15-year UKPDS data showed that earlier use in the development of diabetes might be beneficial and translate to a lasting benefit later in life. It makes more sense to me. I’m not a diabetologist. I’ve come to this arena with a fresh mind.
Q: Do you have any patient reported outcomes on this treatment? And second, you had nearly one third of all patients that had the device removed. Can you comment?
A: I can comment. In Holland, there was a six-month study and there was one removal. We seem to have a higher proportion of removals with the longer duration of the study. These are things that happen to people with diabetes. The average duration of implant was 10.5 months. Most people got pretty close to one year overall. With any intervention, there are those for whom it doesn’t work. Five people got some discomfort or it wasn’t working for them. That was patient preference. Patient-based outcomes were not a formal part of this study, but it will be a formal part of the next study.
Oral Presentations: Beta Cell Function in Vivo
BETA CELL FUNCTION AND INSULIN SENSITIVITY AFTER ROUX-EN-Y GASTRIC BYPASS IN PATIENTS WITH TYPE 2 DIABETES AND NORMAL GLUCOSE TOLERANCE
Kristine Bojsen-Møller, Degree (University of Copenhagen, Copenhagen, Denmark)
Dr. Kristine Bojsen-Møller presented a one-year study (n=10 people with type 2 diabetes and 10 with NgT) of people who underwent roux-en Y gastric bypass (RYGB) to determine the surgery’s impact on type 2 diabetes pathophysiology. People’s pathophysiology was profiled (using OGTT, hyperinsulinemic clamp, iv glucagon test, and dexa) pre-operation, one week post-op, three months post-op, and one year post-op. She found that the improvements in glycemic control seen after gastric bypass can be explained by the rapid improvement in hepatic insulin sensitivity, improved peripheral insulin sensitivity, and better beta cell function recipients experience.
- RYGB was associated with a BMI reduction of 10 kg/m2 (from a baseline of 49 kg/m2) and, in people with type 2 diabetes, an A1c decline from 7.0% to 5.7%.
- Dr. Bojsen-Møller found that people’s hepatic insulin sensitivity (as measured by glucose production) was increased at one week and remained at the improved level through one year.
- Peripheral insulin sensitivity (as measured by glucose disposal) was unchanged at one week and was improved at three months and one year. At one year, the improvement in peripheral insulin sensitivity was correlated with a person’s weight loss.
- Turning to beta cell function, Dr. Bojsen-Møller found that insulin secretion following an iv glucagon challenge remains unchanged in people with type 2 diabetes following RYGB. In contrast, people with NGT’s insulin secretion decreased overtime following their RYGB. Additionally, while insulin secretion after an iv challenge adapt to improved sensitivity in people with NGT at baseline, it does not adapt in people with type 2 diabetes.
- In response to an OGTT, however, people with type 2 diabetes’ insulinogenic index significantly increased from baseline to month three. It remained significantly elevated at year one. Thus, people with type 2 diabetes experienced an increase in beta cell function as measured by an OGTT.
- Additionally people with type 2 diabetes experienced large increases in GLP-1 though not GIP.
Questions and Answers
Q: Do you speculate that RYGB increased the incretin effect?
A: I would suggest that.
Q: I do not understand why the liver sensitivity improves. What is responsible for that?
A: We do not believe that it is the incretins impacting the hepatic or peripheral tissues. I think that it is only the caloric restriction and subsequent weight loss. It is only the improvement in beta cell that is due to incretin effect.
Q: If you restricted patients food intake for one week, would you get a similar impact on hepatic sensitivity?
A: Yes. There are studies showing even larger improvements in insulin sensitivity with caloric restriction in people with type 2 diabetes. It would be beautiful to have a larger study of this topic.
Symposium: Bariatric Surgery in Type 2 Diabetes – An Update
METHODS AND RESULTS OF BARIATRIC SURGERY
Dimitri Pournaras, MD (Imperial College, London, United Kingdom)
In an opening to the symposium dedicated to bariatric surgery and diabetes management, Dr. Pournaras presented an overview of outcomes from surgical weight loss interventions in patients with diabetes and made several suggestions for future practice. Importantly, he noted that in 2009, diabetes remission was redefined as maintaining a normal A1c <6% and a fasting glucose level <100 mg/dl for at least one year following surgery. Given these modifications to the criteria, diabetes remission rates have significantly dropped from calculations based on previous standards (e.g., for gastric bypass, rates are now 40% vs. ~60% before). Interestingly, Dr. Pournaras interpreted these findings as positive, claiming they support his view that we should be shifting measures of success away from remission rates, which are antiquated, to glycemic control, which is used as a gauge in all other diabetes treatments. Regarding type 2 diabetes recurrence, Dr. Pournaras noted that short-term remission rates are 43%, while long-term are 24%. He argued that we should look to cancer’s combinatorial treatment approach to amend our approach to bariatric surgery and diabetes care – we certainly agree with him that combination therapy, especially early in the course of type 2 diabetes, will result in better outcomes. In Dr. Pournaras’ opinion, our standard evaluation should “not be best medical therapy vs. surgery, but best medical therapy vs. best medical therapy plus surgery.” One study that assessed intensive medical therapy alone vs. combined with surgery found that using both doubled the percentage by which A1c levels were lowered, from 1.5% to 3%. In addition, Dr. Pournaras advocated on behalf of redirecting end goals for surgery to be focused on the reduction of diabetes related co-morbidities and macrovascular complications, as is currently being done in the evaluation of new diabetes drugs. In general, we left with the impression that Dr. Pournaras believes strong efforts should be made to bridge the separation between bariatric surgery and diabetes treatments in the conventional paradigm in order to improve patient outcomes.
- The most common weight loss operations – adjustable gastric banding, roux en Y gastric bypass, and sleeve gastrectomy – have shown considerable success and safety, with very low in-hospital mortality rates (0.07% in 2013 as indicated by the NBSR) and significant improvements in A1c levels.
Questions and Answers
Q: On what basis do you decide what type of bariatric surgery a patient should receive?
A: If a patient doesn’t know the answer, we ask that they go back to a patient support group. These are the most educated patients you will ever meet. I listen to patients, they tell me the truth.
Q: Can you predict which patients will go into remission before doing the surgery?
A: I wish I could! Like I said, we need to know who benefits most. Having had diabetes for a long time and having been on insulin lowers your chance of remission, but that doesn't mean that those individuals should be denied surgery – in fact, they may be the ones who benefit the most. It is an area of ongoing study.
Q: Is bypass surgery better than sleeve gastrectomy? Also, with an EndoBarrier liner, how long do you keep it in?
A: The EndoBarrier liner is licensed for 12 months, but you can do repeated therapy. The picture of what happens after is less clear, some put the weight back on and some don’t. In response to your first question, there is no significant difference, though they do work in different ways. My feeling is that with bypass you get more weight loss, but we need more studies for long-term data on gastrectomy. It hasn't been around for very long so there are less data.
Q: Clearly a sleeve can be a different thing to a different surgeon.
A: The technique for sleeve gastrectomy is variable. We have to standardize what we do so that our data can be interpreted in a way that’s useful.
Q: You showed quite impressive data about clinical outcomes. Can you tell us about patient satisfaction and quality of life?
A: Quality of life data are out there. Every study I know shows very good improvements in quality of life. In our experience, these patients do very well. I’ve seen patients who have had pretty severe surgical complications and still do not regret having it. These are some of the most satisfied patients I have seen in surgical practice.
Q: What are advantages and disadvantages, both immediate and late, of bypass surgery and sleeve?
A: The biggest limitation is that there needs to be very close follow up.
Q: Have you explored the intragastric balloon as form of weight loss surgery?
A: We know that as soon as you remove the balloon you gain the weight back. It’s mainly a good option for patients who are too heavy for surgery or too high-risk to undergo another form for surgery.
Q: If you get second thoughts after the operation, is it possible to reverse it?
A: We tell patients that gastric bypass is irreversible, but technically you can reverse it. It is a very demanding and dangerous procedure, however. The sleeve is reversible but you gain the weight back straight away.
Q: Could you do an oral glucose tolerance test after bariatric surgery?
A: It’s safe and we have definitely done it, but we’ve moved away from this method and are using the new criteria for remission.
Q: You have not given any data on any long-term nutritional deficiencies.
A: Data are available. For both banding and gastric bypass, there aren’t any major concerns.
DIABETES PREVENTION AND REMISSION AFTER USUAL CARE AND BARIATRIC SURGERY
Lars Sjöström, MD, PhD (University of Gothenburg, Gothenburg, Sweden)
Dr. Lars Sjöström, former primary investigator of the Swedish Obesity Subjects (SOS) study, strongly critiqued the current BMI-based eligibility criteria for bariatric surgery. He argued that it is invalid to base the criteria around BMI since baseline BMI does not predict any treatment effects so far examined, including surgery’s impact on diabetes prevention or remission. Instead he believes that eligibility decisions should place more importance on metabolic variables. Indeed, he presented data suggesting that a person’s baseline insulin and glucose levels are better predictors of treatment effect than BMI. Reviewing the SOS’s results, Dr. Sjöström underscored that bariatric surgery is able to robustly prevent type 2 diabetes over the long-term in people who are prediabetic and nondiabetic obese. Additionally, in the short-term, bariatric surgery causes diabetes remission in the majority of people with type 2 diabetes undergoing the procedure. However, after 20 years, ~75% of initially remitted patients have relapsed. It is unclear though, if they remit to a less severe form of type 2 diabetes than they had pre-operation. What research does show, however, is that people are less likely to develop diabetes complications even if they do relapse. Notably, it appears that people who have had diabetes for shorter periods of time are more likely to experience remission. Thus, Dr. Sjöström called for people to treat deteriorating glucose metabolism early, and suggested that people with prediabetes should potentially be recommended for surgery.
Questions and Answers
Q: Thank you for sharing such an impressive result from this landmark study. Given your expertise, if you were to design your SOS today, which procedures would you recommend?
A: Weighing successful treatment and dangers, if I were to design the SOS today, I would randomize between usual care and intensive care and gastric bypass. Of course biliopancreatic diversion has more radical effects on the metabolism.
Q: What did you seen in NAFLD?
A: We have only liver enzymes, so nothing sophisticated there with which to look at the liver.
Q: Are there data in patients with BMI under 30 kg/m2? There are some ethnic groups who show substantial incidence of diabetes in the 25 kg/m2 range.
A: There are some published data between 27 kg/m2 and 35 kg/m2. There are several studies ongoing. I think the end result will show that gastric bypass will influence the diabetic state markedly.
Q: You showed us a quite high relapse rate in the entire operated group. Can you break this out by surgery?
A: We have data, but we had only on the order of 500 patients, so we are not powered to look at the results in the surgical subgroups – especially in gastric bypass, since that was not the main surgery performed. In our study, remission is not significantly different with bypass than the other surgeries, though this could be due to the powering.
Q: Do you think that even if remission is transient it is still having a long-term impact on complications? Or perhaps when you have the relapse the severity of the disease is reduced?
A: We must remember that our definition of diabetes is an arbitrary cutoff and does not describe the whole story. A lady in Madrid has a paper in press where she shows that even in patients who have relapsed after initial remission, other CV risk factors are still improved. So this might be the reason why we see an effect on diabetes complications despite the fact that patients relapsed into diabetes.
Q: Are there any guidelines available for the control of diabetes after bariatric surgery?
A: Most surgeons don't use any diabetes treatment at all during the first years after surgery unless they are part of a study. As diabetes relapses are seen after five to ten years, I think the clinical practice is to treat these patients. The first-line drug, as I understand it, is metformin. I don't think that there are generally accepted rules and there are no randomized studies proving how we should do this best. This certainly begs for more study.
Comment: If BMI is not an indication for the surgery and to operate on people with diabetes does not have very good results, then the main indication to operate is in people with impaired glucose tolerance.
A: I don't think that is the main conclusion. We have the best results in preventing diabetes in people with impaired glucose tolerance. I am not saying that we should not treat the diabetic patients. Even if they relapse it appears that they still avoid more diabetes complications. We have shown strong 20-year results on diabetes complications. I think we should operate on people with diabetes.
Q: You did not mention anything about safety concerns. Also can you comment on bariatric surgery’s cost-benefit?
A: We had five post-operative mortalities in the study. When we started in 1987 a lot of studies reported up to 5% post-operative mortality. We trained the surgeons heavily before they were allowed to recruit patients and that might be why we were able to keep the mortality low. On cost benefit analysis, we have some early analysis on our five — six year data. At that time, there was no cost benefit, but there was also no decreased benefit. If we repeated this study today I think we would have a cost benefit. We published a JAMA paper last year, showing that the use of medications was quite dramatically reduced as compared to the control group. More investigations must be done. It took us 13 years until we saw a significant effect on mortality so I think look at cost benefit at five, ten years is much too early.
PATHOPHSYIOLOGY OF BARIATRIC SURGERY
Ele Ferrannini, MD, PhD (University of Pisa, Pisa, Italy)
Dr. Ele Ferrannini described the pathophysiology of Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion (BPD). Detailing and comparing the two procedure’s effects, he demonstrated that BPD improves insulin resistance more so than RYGB. An ongoing trial suggests that the reason for this could be BPD’s stimulation of the secretion of bile acids. Thus, bile acids could be an interesting treatment option. Dr. Ferrannini also noted that current research suggests that the best way to determine if a person with diabetes will respond to bariatric surgery is their beta cell function – the better a person’s beta cell function the better the treatment’s effect. Dr. Ferrannini therefore echoed Dr. Lars Sjöström’s (University of Gothenburg, Gothenburg, Sweden) call for modifying the eligibility criteria to discount BMI and focus on metabolic parameters (in the case of Dr. Ferrannini specifically beta cell function).
Satellite Session: 6th CIBERDEM Annual Meeting
PREDAPS STUDY: DATA PRESENTATION
Francesc Xavier Cos, MD (Institut Catala de la Salut, Barcelona, Spain)
Dr. Francesc Xavier Cos presented baseline data from PREDAPS, a prospective, observational study being conducted of people with and without prediabetes in Spain (n=2,022). The aim of PREDAPS is to determine the risk of a person with prediabetes developing type 2 diabetes or vascular complications, and the risk factors associated with those progressions. Participants visited a participating primary care center and were between the ages of 29 and 75 years; people with and without prediabetes were enrolled (1:1). At baseline 21.5% of the 1,184 participants with prediabetes, 51.9% had prediabetes as defined by A1c and impaired fasting glucose, 26.7% only had prediabetes as defined by A1c, and 21.5% only had impaired fasting glucose. Risk factors positively associated with prediabetes included 1) age; 2) past family medical history of type 2 diabetes (particularly a maternal history); 3) past medical history of high blood pressure, dyslipidemia, or coronary heart disease; 4) gestational diabetes; 5) having offspring; 6) use of antihypertensive or lipid-lowering agents; 7) obesity; and 8) high triglycerides, fasting plasma glucose, or A1c. Risk factors negatively related with prediabetes included tobacco consumption and consumption of daily sweets. We wonder if the association of consuming sweets with not having prediabetes could be the result of people aware of their prediabetic status making lifestyle changes, including improving their diet. Unfortunately, Dr. Cos did not state what percentage of participants with prediabetes was aware of their disease status entering the trial. Dr. Cos is planning to follow the study population for ten years, though this is dependent on funding. We hope he is able to accomplish this as we think a fuller understanding of prediabetes’ pathology could help researchers develop agents to prevent the progression to type 2 diabetes. Additionally, it will be interesting to see how prevalent vascular complications are among people with prediabetes in this study.
Questions and Answers
Q: We are attending a lot of people of different ethnicities. How did you account for minority status?
A: We have not explored that yet. There is a very low rate of minorities across Spain. If we recruited minorities, we would likely find a disproportionate number of minorities in places like Barcelona. However, that would bias our overall recruiting.
Q: Don't you think that your cohort should start implementing the lifestyle protocol used in Look AHEAD?
A: Look AHEAD was also presented at ADA. To be honest, when we compare our data to other countries – it is clear that our standards are very high. Still, lifestyle is a challenge. We are also involved in the DE-PLAN project. The DE-PLAN project has obtained strong results in Catalonia. It took high-risk patients, was found to work and was cost efficient. So I think this is how we can implement lifestyle intervention in primary care. I think that doing four hours just one time and then providing reminders – like in the diabetes educator-PLAN- is reliable and doable. However, doing it with a coach is not affordable for any system.
8. Novel Therapies, Basic Science, and Additional Topics
Opening Ceremony: Presidential Address
WELCOME TO BARCELONA
Andrew Boulton, MD (President, European Association for the Study of Diabetes, Düsseldorf, Germany)
In a completely packed session (a projector was set up outside the auditorium!), the great Dr. Andrew Boulton gave his presidential address, focusing on the EASD’s role in research, education, and lobbying. Dr. Boulton noted the success of this year’s annual meeting, highlighting that there were 2,300 abstracts submitted this year, the second highest number ever received (fewer than 50% were accepted). Dr. Boulton also announced four new study groups within the EASD, including diabetes and cancer and non-alcoholic fatty liver disease. Turning to EASD’s mission, Dr. Bolton added the unofficial role of championing better research in Europe, specifically pointing to the controversies surrounding incretins and cancer – the former has certainly been one of the biggest topics in the drug world in the last few months. It was stirring to hear Dr. Boulton commend the ADA, EASD, and IDF’s quick response to the incretins and pancreatitis issue. He further cited the EMA CHMP’s conclusion and the results of the SAVOR and EXAMINE trials, which demonstrated little evidence for the link between incretins and pancreatic cancer (for more information, please see http://www.closeconcerns.com/knowledgebase/r/72400858 and http://closeconcerns.com/knowledgebase/r/549a0f4a). On a very exciting note, Dr. Boulton then highlighted the September Diabetes Technology Society’s (DTS) meeting on surveillance of blood glucose meters following FDA clearance that took place in Washington DC – he characterized it as another way that agencies such as the EASD should play a role. In line with his comments during the final panel, he also expressed support for a post-market surveillance program in Europe, too (for more detail see our report). Finally, programs such as the Alliance for Biomedical Research in Europe (BioMed Alliance) and the European Foundation for the Study of Diabetes (EFSD) allow EASD to support research through collaboration with other organizations and industries. He mentioned the one million euros for the new EFSD/Sanofi collaboration for clinical diabetes research, as well as the great success of researchers who have participated in a similar EFSD/Eli Lilly collaboration.
Award Lecture: 7th Albert Renold Lecture
THE PANCREATIC ISLET: MORE THAN THE SUM OF ITS PARTS?
Patrik Rorsman, MD, PhD (University of Oxford, Oxford, UK)
Dr. Patrick Rorsman delivered a thought provoking lecture on the pathophysiology of pancreatic beta, alpha, and delta cells in type 2 diabetes from the perspective of electrophysiology. His fast paced lecture had three main takeaway messages on islet cell biology: 1) rodent and human islets are not the same, 2) type 2 diabetes involves impaired beta cell function, not just mass, and 3) glucagon and somatostatin secretion are implicated in diabetes, in addition to insulin. We were particularly fascinated by Dr. Rorsman’s explanation for how molecular/cellular defects resulting in too much KATP channel activity in islet cells at high glucose levels (e.g., via reduced metabolism) can result in 1) impaired glucose-stimulated insulin secretion, 2) reduced glucagon secretion during hypoglycemia, and 3) paradoxical stimulation of glucagon during hyperglycemia. He noted that type 2 diabetes islets and fetal islets are similar in their electrophysiological response, suggesting that diabetic islets do not die as much as they revert to their fetal state. Dr. Rorsman also asserted that insulin secretion predominately inhibits glucagon secretion by stimulating the secretion of somatostatin. Thus, he proposed that somatostatin receptor antagonists could be an effective therapy for people with diabetes. Unfortunately, he sighed, “pharma has fallen out of love with somatostatin receptor antagonists.”
- Dr. Rorsman noted that one theory for why insulin secretion is biphasic is the presence of different insulin granule pools within beta cells: readily releasable granules on the cell’s edge and reserve granules found closer to the cell’s interior. The first phase of insulin secretion would result from the exocytosis of a pool of readily releasable granules and the second phase would result from the later exocytosis of reserve granules.
- Under this model, people with type 2 diabetes lack the first phase of insulin secretion and have a reduction in second phase insulin response due to their loss of beta cells and, therefore, insulin granules.
- Dr. Rorsman believes these functional pools exist, but that the model of beta cell loss does not explain the distortion of insulin secretion’s biphasic nature. His evidence is that sulfonylureas are able to restore the first phase of insulin secretion – a phenomena difficult to explain if the granule pools from which the insulin originates do not exist anymore after beta cells are lost. Additionally, he estimates that a person’s total daily requirement of insulin could be supplied by only 5% of beta cells’ granule content. Thus, he thinks it is unlikely that the 30-40% reduction in beta cell mass reported with type 2 diabetes is severe enough to cause a shortage of insulin granules.
- Instead, Dr. Rorsman thinks beta cells’ electrophysiology can explain biphasic insulin secretion. According to Dr. Rorsman, biphasic insulin secretion is due to differences in beta cells’ action potential upon detecting elevated glucose levels. At first the beta cell emits high amplitude action potentials. Action potential amplitude appears to be correlated with the extent of insulin secretion. Thus, these initial high amplitude action potentials drive the first phase of insulin secretion. After a short period of time, however, the beta cell begins firing action potentials with a lower amplitude, though it continues to do so for a longer period of time. This pattern of action potentials results in the second phase of insulin secretion.
- Additionally, his model explains type 2 diabetes’ loss of the first phase and impairment of the second phase of insulin secretion. Dr. Rorsman hypothesized that impaired glucose metabolism causes the beta cell’s potassium ion channels (ATP-sensitive potassium channel) to incompletely close. This causes the beta cells to be partially depolarized and less electrophysiologically responsive to glucose. Beta cells’ sluggish electrical response to rises in glucose would then cause the loss of the first phase of insulin secretion. Beta calls would also have a reduced rate of action potential firing, explaining the diminished second phase of secretion. Additionally, since the cells are partially depolarized, they would sometimes fire spontaneous action potentials at low glucose levels. This, Dr. Rorsman noted, might explain people with type 2 diabetes’ elevated basal insulin secretion.
- Dr. Rorsman voiced support for the use of glucose kinase activators. He explained that in one study (Doliba et al., Am J Physiol 2011) Roche’s piragliatin (now discontinued) a glucokinase insulin activator normalized insulin secretion by accelerating glucose metabolism.
- Dr. Rorsman hypothesized that glucose-induced inhibition of glucagon secretion is mediated by insulin but by somatostatin. For background, insulin secretion is known to stimulate the secretion of somatostatin and some people believe it drives the inhibition of glucagon secretion. Dr. Rorsman, however, presented data showing that if you inhibit the secretion of somatostatin, insulin’s impact on glucagon secretion is significantly reduced.
- Thus, Dr. Rorsman proposed that somatostatin receptor antagonists could be an effective therapy for people with type 2 diabetes. He noted that somatostatin receptor antagonists greatly improve diabetic rodents’ glucose counter-regulation. Unfortunately, he sighed, “Pharma has fallen out of love with somatostatin receptor antagonists.”
- According to Dr. Rorsman, alpha cells intrinsically regulate the secretion of glucagon at low glucose levels (which do not produce an insulin response) in an electrophysiological manner. In contrast to beta cells, normal alpha cells have large action potentials in the presence of low glucose levels, stimulating the secretion of glucagon. When glucose levels increase, the amplitude of the alpha cells’ action potentials declines, reducing the amount of glucagon secreted. Thus, normal alpha cells secrete some glucagon when glucose levels are low and top when glucose levels are high.
- In type 2 diabetes, however, alpha cells’ electrophysical regulation of glucagon secretion becomes impaired. Similar to beta cells in type 2 diabetes, alpha cells become less electrophysically active. The resultant infrequent action potentials coming from alpha cells results in reduced glucagon secretion in the presence of glucagon. When glucose levels rise, the type 2 diabetes alpha cell begins firing its low-amplitude action potentials at would a normal alpha cell. This means a person with type 2 diabetes paradoxically secretes more glucagon in these presence of hyperglycemia than hypoglycemia.
- Turning to the other pancreatic cells, Dr. Rorsman questioned if diabetologist’s focus on the beta cell over the alpha and delta cell is warranted. He explained that type 2 diabetes’ impact on glucagon and somatostatin secretion is actually more dramatic than its impact on insulin secretion.
- Dr. Rorsman catalogued the many differences between rodent and human islets. Given these differences, he questioned if the detailing of the rodent islet’s biology was a waste of time, since “rodent diabetes is not a major clinical problem.”
Award Lecture: 48th Minkowski Lecture
THE HEART OF THE MATTER: BETA CELLS IN DIABETES
Miriam Cnop, MD, PhD (Universite Libre de Bruxelles, Brussels, Belgium)
In front of a packed lecture hall and crowded overflow lobby (which was far larger than the typical overflow room), Dr. Miriam Cnop walked us through her and others’ research on the biology of beta cell dysfunction and death. Dr. Cnop framed the topic by noting that though the beta cell’s demise is central to the pathogenesis of type 2 diabetes, the underlying mechanisms of this phenomena is poorly understood. Dr. Cnop believes that a key regulator of this process is epigenetics. Since human beta cells have long lifespans (a person’s beta cell population is largely established by the time a person is 20 years), they are exposed to environmental stresses over a long period of time and can acquire epigenetic alterations. Indeed, islets from people with type 2 diabetes have been shown to have epigenetic dysregulation, as indicated by differential DNA methylation. Dr. Cnop identified endoplasmic reticulum (ER) stress as a key mechanism of palmitate-induced beta cell dysfunction (palmitate is a saturated fatty acid). Thus, she hypothesized that ER stress induced by saturated free fatty acids is a potential contributory mechanism for beta cell failure, as well as insulin resistance, in type 2 diabetes.
- Dr. Cnop’s first assertion was that beta cell dysfunction and apoptosis – not defective beta cell regeneration – are key components of type 2 diabetes. She pressed that little to no evidence exists for beta cell neogenesis or replication in adult obesity of type 2 diabetes. Instead, Dr. Cnop underscored that research exists suggesting that a person’s beta cell population is probably established by the time they are 20 years old.
- Due to a beta cell’s long existence, they have nearly a lifespan over which to acquire epigenetic alterations, according to Dr. Cnop. These epigenetic modifications can establish stable alterations in gene expression. Dr. Cnop explained that these modifications play a key role in beta cell biology and potentially in the pathogenesis of diabetes. Indeed, islets from people with type 2 diabetes have differential DNA methylation in more than 250 genes affecting beta cell function and survival, pointing to epigenetic dysregulation.
- Dr. Cnop hypothesized that ER stress might represent a common molecular mechanism for the development of insulin resistance and beta cell failure. Dr. Cnop identified ER stress as a key mechanism of palmitate-induce beta cell dysfunction. Additionally, ER stress is believed to be present in liver, fat, and muscle in obesity and diabetes, potentially resulting in insulin resistance. Dr. Cnop suggested that future research should determine if the ER stress response can be modulated to prevent or treat type 2 diabetes.
- Additionally, Dr. Cnop suggested that tRNA modifications could be a novel mechanism of beta cell failure. This hypothesis is grounded on the association between TRMT10A deficiency, a defective tRNA modification, and early onset diabetes (as well as microcephaly).
Ceremonial Lecture: 45th Claude Bernard Lecture
FROM ONE FAMILY TO 10,000 MEN: GENES MEET PHENOTYPES IN DIABETES
Markku Laakso, MD, PhD (University of Eastern Finland, Kuopio, Finland)
Dr. Markku Laakso, recipient of the 45th Claude Bernard award, began his presentation by quoting Claude Bernard: in the study of disease “the real and effective cause of a disease must be constant and determined…anything else would be a denial of science in medicine.” Dr. Laakso presented genetic examples that highlight the ability to use specific genetics and mutations to determine associations between genes and disease. These, Dr. Lasskso noted, provide the ability to move from phenotype-based genotyping to genotype-based characterization. Dr. Laakso also remarked that a benefit of using genetics is that as the specificity of phenotyping increases, the strength of the gene-disease association similarly increases (i.e., a mechanistic phenotype provides a greater association than that of a clinical phenotype). Similarly, he noted that rare alleles have a larger effect size than common alleles, since rare alleles are more easily linked to specific phenotypes. Dr. Laakso concluded by noting that although we have begun to explore causal genes, risk genes, and causal and risk genes together, we still have to explore deep phenotyping, gene and environment interaction, gene expression, epigenetics, and systems biology to identify the “type 2 diabetes missing heritability” (which Dr. Laakso says is around 90%). We appreciated Dr. Laakso’s examination of phenotypes and hope that such examinations will help us learn more about the genesis of diabetes and how to effectively treat the disease.
- To illustrate the benefits of using specific genotypes and phenotypes to learn about diabetes, Dr. Laakso presented many examples from past and present research. Some of these include E1506K mutations (which cause mutations in insulin secretion), mutations in the endoplasmic reticulum (that lead to impaired insulin secretion), and PPAR-γ mutations and polymorphisms (which have been shown to lower BMI and improve insulin sensitivity).
- Dr. Laakso illustrated many methods of analysis, such as proton nuclear magnetic resonance spectroscopy (proton NMR spectroscopy), linkage analysis, and whole genome sequencing. These methods can be used to find lipoprotein particles (proton NMR), genetic mode of inheritance (linkage analysis), and rare alleles (genomes sequencing).
Oral Presentations: Novel Therapeutic Agents and Insights
DISSOCIATION BETWEEN METFORMIN PLASMA EXPOSURE AND ITS GLUCOSE-LOWERING EFFECT: A NOVEL GUT-MEDIATED MECHANISM OF ACTION
John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)
After proposing how metformin’s therapeutic effects might be mediated primarily at the level of the gut, Dr. John Buse discussed findings of two clinical studies of a new formulation of metformin, metformin delayed release (Met DR; Elcelyx’s NewMet), that substantiate this hypothesis. In a single day dosing, four-way crossover trial in healthy subjects (n=20) comparing the pharmacokinetics of Met DR to other formulations, Met DR had significantly reduced bioavailability and lower plasma exposure compared to metformin IR and metformin XR. In a five-day, three-way crossover study comparing the effects of Met DR versus metformin IR in type 2 diabetes patients (n=24), metformin DR and metformin IR treatment led to similar and significant improvements in fasting plasma glucose, GLP-1, and PYY from baseline, with Met DR having markedly lower metformin exposure. Adverse events were fairly even across treatments, with the suggestion of improved GI tolerability with Met DR. Based on the findings from these two studies, Dr. Buse concluded that metformin’s glucose-lowering action depends on gut epithelial exposure, not on plasma exposure. Encouragingly, he stated that Met DR directed to the lower bowel may provide maximum efficacy with improved tolerability at lower doses (≤1,000 mg total daily dose), and that it could potentially be used in patients with moderate to severe renal impairment, as reduced plasma metformin exposure would be expected to reduce the risk of lactic acidosis.
- Dr. Buse cited evidence supporting the hypothesis that metformin’s mechanism of action is largely mediated at the level of the gut. Perhaps the strongest available evidence to date, metformin was shown to be acutely effective at lowering glucose when administered intraduodenally, but not when administered intravenously in STZ rats (Stepensky et al., Drug Metab Dispos 2002). In addition, Dr. Buse stated that in other studies, the level of metformin in blood had little relationship with its efficacy as a glucose-lowering agent. He also noted that metformin has been documented to increase secretion of GLP-1 and PYY (secreted by L-cells, which are predominantly found in the lower bowel), raising the possibility that plasma exposure may not be necessary for metformin’s therapeutic activity.
- Dr. Buse described metformin delayed release (Met DR), a new formulation of metformin that bypasses the upper bowel to deliver its full dose to the lower bowel, where absorption is poor. Thus, metformin DR plasma absorption is ≤25% in the lower bowel, and more of the delivered dose remains in the lower bowel (the site of action). Met DR also enables a maximally effective dose at lower total doses than current metformin formulations. This is expected to reduce the incidence of nausea (upper GI-tract related), and reduced plasma exposure may allow for use in patients with renal impairment.
- In a single day dosing, four-way crossover trial in healthy subjects (n=20) comparing the pharmacokinetics of metformin DR to other formulations, Met DR had significantly reduced bioavailability and lower exposure when compared to metformin IR and metformin XR. Participants in the trial received 24-hour dosing of 1,000 mg metformin IR BID, 1,000 Met DR BID, 500 mg Met DR BID, and 2,000 mg metformin XR QD in a randomized sequence, with a 3-7 day washout period between treatments. Compared to metformin IR and metformin XR, Met DR had lower peaks in plasma metformin concentration; overall, 1,000 mg Met DR BID and 500 mg Met DR BID resulted in 52% and 68% lower relative exposure, respectively, than 1,000 mg metformin IR BID (p<0.0001), and 48% and 65% lower relative exposure than 2,000 mg metformin XR QD (p<0.0001).
- In a five-day, three-way crossover study comparing the effects of Met DR versus metformin IR in type 2 diabetes patients (n=24), fasting plasma glucose was significantly and similarly reduced with metformin DR and metformin IR. In the study, participants received five days of 1,000 mg metformin IR BID, 1,000 mg Met DR BID, and 500 mg Met DR BID treatment in a randomized sequence, with seven-day washouts between treatments. Notably, Met DR BID decreased systemic exposure, with respective 45% and 57% decreases for 1,000 mg Met DR BID and 500 mg Met DR BID versus 1,000 mg metformin IR BID (n=19; p<0.0001). All three treatments led to significant improvements from baseline in fasting glucose, GLP-1, and PYY.
Questions and Answers
Q: Your conclusions were quite bold. How much of the changes in weight with metformin can be explained by changes in GLP-1 and PYY?
A: We certainly can’t see that from these studies. There are ongoing 12-week studies where the company has reported that the primary endpoint was met at four weeks, but there were really no details beyond hat provided. Weight loss with metformin is quite modest, and the mechanisms have not quite been worked out yet.
Q: What about the anti-proliferative and anti-mitogenic effects of metformin in this different formulation?
A: Here with this formulation, we are delivering metformin to the lower bowel. The lower bowel exposure is quite similar to the 2,000 mg dose of metformin, provided differently. Whether plasma exposure is required for some other action other than glucose lowering is unknown. Particularly with regards to anti-proliferative effects, I think those are somewhat under question, and how important they are clinically is unclear.
Q: Can you elaborate on why you see less diarrhea with this new formulation?
A: It would be speculation, but what I would suggest is that we don’t see more diarrhea than we see with previous formulations of metformin. In particular, when we use the 500 mg dose twice a day, the amount of metformin being delivered to the lower GI tract is on par with the current 2,000 mg dose of metformin. I do believe that there is a notion that metformin in the lower bowel may have some relationship to diarrhea as an adverse effect. We think the major difference will be less nausea, because of less delivery of metformin to the upper bowel. I think the pre-formed hypothesis is that rates of diarrhea would be similar, though it might be modestly less.
EFFECT OF A DUAL AGONIST OF GLUCAGON-LIKE PEPTIDE-1/GLUCOSE-DEPENDENT INSUINOTROPIC PEPTIDE (MAR701) ON INSULIN SECRETION RATE AND GASTRIC EMPTYING IN HEALTHY VOLUNTEERS
Marcus Hompesch, MD (Profil Institute for Clinical Research, Chula Vista, CA)
Dr. Marcus Hompesch presented the results of a phase 1 study investigating the effects of Roche’s GLP-1/GIP dual agonist candidate MAR701 on insulin secretion and gastric emptying in individuals without diabetes — this data was first presented as a poster at this year’s ADA. As background, Roche purchased Marcadia (the initial developer of MAR701) in 2010 for nearly $300 million, and MAR701 was a major part of the deal. In 3Q12, Roche dropped MAR701 from its pipeline after completing a phase 1 trial in 4Q11, and soon added a different GLP-1/GIP dual agonist (MAR709/RG7697) to its pipeline. The trial Dr. Homepsch presented enrolled 24 patients without diabetes (BMI between 20-30 kg/m2), and randomized them to either exenatide twice daily or MAR701 4, 8, or 16 mg before performing a graded glucose infusion test. People’s insulin secretion rate was significantly augmented for all doses of MAR701 compared to placebo; however, the magnitude of the increase with MAR701 was substantially less than that seen with exenatide twice daily. While exenatide significantly slowed gastric emptying, no dose of MAR701 demonstrated a significant impact on gastric emptying compared to placebo. The most common adverse effects seen with MAR701 were hypoglycemia (which generally occurred after the cessation of glucose infusion) and nausea (which was not dose dependent). Based on the overall adverse event profile seen in the trial, Dr. Homepsch characterized the drug as being safe and well tolerated. We were somewhat disappointed by the candidate’s weak effects compared to exenatide (addressed during Q&A), but on the bright side, the data indicate that Roche’s decision to cease development of MAR701 was probably not due to a worrying safety signal. We will be very interested to see if Roche’s GLP-1/GIP dual agonist MAR709 demonstrates more impressive results.
Questions and Answers
Q: I am interested in these dual agonists, but don’t they have to prove that they are better than GLP-1 agonists? This is something that this study doesn’t provide. In many situations the deceleration of gastric emptying contributes to the effectiveness of GLP-1 therapy.
A: I agree — we probably have to demonstrate superiority here. The data from this trial will help us come up with new hypotheses. It remains to be seen if these dual agonists will be more effective.
Q: Looking at your gastric emptying data, it looks like there is no GLP-1 action. How can you be sure that you are hitting both the GLP-1 and GIP receptors in vivo?
A: That is a good question. You are correct that we would have expected to see an impact on gastric emptying. There is no evidence that both receptors are being hit based on this study. That hypothesis is based on preclinical data.
Q: One advantage of GLP-1 agonists is the glucagon suppression. What’s going on with glucagon with MAR701?
A: That is an effect needs to be investigated.
Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
INADEQUATE PLASMA ADIPONECTIN RESPONSE CHARACTERISES NON-RESPONSIVENESS TO PIOGLITAZONE IN INDIVIDUALS WITH IMPAIRED GLUCOSE TOLERANCE: RESULTS FROM THE ACT NOW STUDY
Devjit Tripathy MD (University of Texas Health Science Center, San Antonio, TX)
It’s long been known that TZDs can prevent or delay the onset of type 2 diabetes. In the ACT NOW study (of people with impaired glucose tolerance (IGT)), the hazard ratio for pioglitazone (Actos, Takeda) compared to placebo was a stunning 0.28. However, some individuals don’t respond to TZDs. In this work, Dr. Tripathy showed that an increase in plasma concentration of adiponectin was a key marker of responders (i.e. people who regressed to normoglycemia) in the ACT NOW study. This rise also was associated with better glucose tolerance, insulin sensitivity and beta cell function. However, it’s important to note that the finding has nothing to do with baseline adiponectin – only the change after treatment starts. Nonetheless, this finding could be helpful in switching non-responders to alternative therapies. In this case, Dr. Tripathy suggested that GLP-1 agonists might be the next best choice for diabetes prevention therapy.
- TZDs have been shown to have a marked effect in preventing or delaying the onset of diabetes. But there are a significant number of individuals who don’t respond to TZDs. So the object of this work is to find a marker that would predict when TZDs are likely to work (or not). Note that the conversion rate from IGT to t2dm is in the range of 3-13% per year.
- Results from the ACT NOW study in over 600 patients with impaired glucose tolerance (IGT) were reported in 2011. Pioglitazone (Actos, Takeda) had an impressive hazard ratio of 0.28 to conversion to diabetes, compared to the placebo group after 2.4 years. In this trial ‘responders’ started with IGT and regressed to normal glucose tolerance (NGT). ‘Non-responders’ either maintained IGT or progressed to diabetes. There were no material differences in baseline age, BMI and insulin sensitivity between responders and non-responders.
- If we stratify increases in adiponectin over the trial into three groups, there was a clear relationship between the tertiles and progression to diabetes – the highest increases were least likely to get diabetes and most likely to regress to NGT. (The placebo group showed no change in adiponectin). Better glucose tolerance, better insulin sensitivity and better beta-cell function were also associated with responders and with higher plasma adiponectin. But it’s important to note that baseline adiponectin doesn’t predict the response to pioglitazone, it’s the change in plasma adiponectin after treatment that is the key marker.
Questions and Answers
Q: Is the change in adiponectin causal or just a marker?
A: We think it’s both a marker and a causative factor. There are no human trials, but animal models show that increasing adiponectin has direct insulin sensitizing effect.
Q: Is the effect sustained?
A: We followed up for 6 months, and the effect is sustained at least for that long.
Q: If a patient didn’t respond to pioglitazone, what other agents would you try?
A: I think that a GLP-1 agonist would be the next choice.
Oral Presentation: New Frontiers in Autoantibody Epidemiology
ENTEROVIRUS RNA IN LONGITUDINAL BLOOD SAMPLES FROM CHILDREN AT THE HIGHEST GENETIC RISK OF TYPE 1 DIABETES; AND THE DEVELOPMENT OF ISLET AUTOIMMUNITY: THE MIDIA STUDY
Ondrej Cinek, PhD (University Hospital Motol, Prague, The Czech Republic)
Dr. Ondrej Cinek presented research on whether or not a link exists between enterovirus infection and the development of type 1 diabetes. Dr. Cinek tested blood samples (taken at age three, six, nine, and 12 months, and then annually thereafter) from a sub-group (n=48 cases of autoimmunity and 98 matched controls) of the MIDIA cohort that had a single HLA-DQ-DR genotype, which confers the highest genetic risk for type 1 diabetes – thus, he limited the impact genetic heterogeneity in the study population could have on the results. Dr. Cinek found no overall association between the presence of enterovirus RNA in the blood (indicating an enterovirus infection) and the development of type 1 diabetes. The odds ratio (1.26, 95% CI: 0.72-2.18), however, trended in favor of a positive association existing. Additionally, Dr. Cinek found a significant association between enterovirus infection and development of type 1 diabetes at the time of seroconversion (OR=~10; studied antibodies were to insulin, GAD65, and IA-2). Dr. Cinek could not draw any conclusions with regards to causality due to neither event (i.e., infection or seroconversion) being detected first. Additionally, the study was limited by its use of wide time windows (12 months) between blood sampling after the first year of life (and the mean age of seroconversion was 4.3 years). Thus, it is possible (and we imagine likely) that one event preceded the other between samplings. We note that the TEDDY study found that, at least in children with rapid-onset type 1 diabetes, there was no significant association between type 1 diabetes and enterovirus infections (for more details on the TEDDY trial, please see our October 4, 2013 Closer Look at http://www.closeconcerns.com/knowledgebase/r/429fd994).
- For background, the MIDIA (Environmental Triggers of Type 1 Diabetes) study followed a Norwegian birth cohort to identify environmental predictors of type 1 diabetes.
Questions and Answers
Comment: Very nice work and great presentation. Your main finding suggests a signal at seroconversion. If I remember correctly, you tested at three, six, nine, and 12 months of age and then annually. You had pretty wide annual intervals after the first year, so there was a lot of data censoring. You cannot say that the signal was actually at seroconversion. It could have been at anytime leading to seroconversion.
A: The interval is wide. It is perhaps too wide and it was a compromise we made given the willingness of parents and limited resources. We think that using blood cells instead of plasma increases the window with which we can peak at the process. We believe we see low-grade positivity with this process.
Comment: I think your data is pretty consistent with what has been recently shown. We don't see an association between enteroviruses in the stool and the progression of diabetes. But we do see that association in serum. So I think it all fits.
A: I would not be so sure it fits with the stool sample. We still believe that it might be a different cousin to this testing strategy.
Q: Are there any differences between being positive for one antibody and for multiple antibodies?
A: I cant answer that now. We are looking into that.
Q: What was the mean age of seroconversion?
A: About 4.3 years.
Comment: That means that the seroconversion most often occurred dedicated during the annual windows, which, as you mentioned, was too long.
Q: Your conclusion is different than what I read in your abstract. Can you comment on that?
A: The original abstract was based on a first pass through the data. We later went through and used stricter rules on what to and not to include. We decided to be on the safer side.
Oral Presentation: FGF-21 Cures It All?
GLUCAGON LIKE PEPTIDE 1 (GLP-1) IN COMBINATION WITH FIBROBLAST GROWTH FACTOR 21 (FGF-21) ENHANCES BROWNING OF WHITE ADIPOSE TISSUE
Tamer Coskun, MD, PhD (Eli Lilly, Indianapolis, IN)
Dr. Tamer Coskun presented results from a study investigating the molecular mechanisms underlying previously reported findings of synergistic body weight loss with GLP-1/FGF-21 combination therapy in mice. We haven’t seen too much data on FGFs so we wanted to include this despite the basic science focus (which is usually not our area of focus). Whereas GLP-1 is thought to reduce body weight through promoting satiety and suppressing appetite, FGF-21 lowers weight via increasing energy expenditure. When co-administered, GLP-1 and FGF-21 caused significantly greater body weight reduction (27% decrease beyond control) in diet-induced obese mice compared to treatment with either GLP-1 or FGF-21 alone (7% and 12% loss beyond control, respectively). Interestingly, even though only GLP-1 is implicated in lowering energy intake, combination treatment resulted in a robustly greater response in food intake suppression than with GLP-1 alone. Similarly, the increased energy expenditure induced by FGF-21 was significantly augmented with GLP-1, particularly during the light photoperiod when mice were sleeping. Following the completion of the 14-day treatment, researchers found that combination treatment upregulated mRNA expression of UCP1 and PGC-1a in epididymal white adipose tissue, suggesting that a transformation of white adipose tissue to a brown adipose tissue state is responsible for the pronounced weight loss observed. Furthermore, leptin signaling and sensitivity may have been potentiated, as GLP-1 and FGF-21 combination treatment increased leptin receptor expression in metabolically active peripheral tissues. The “browning” of white adipose tissue and resulting profound decrease in body weight indicates that future obesity treatments should explore the possibility of targeting mechanisms involved in both energy intake and energy expenditure.
Questions and Answers
Q: Have you tried this in humans in some way?
A: This year in Keystone we disclosed some human data with FGF-21 treatment. In one month, we observed about a two-kilogram weight loss in the treatment group vs. placebo group. However, we did not investigate the mechanistic approach or make any energy expenditure measurements.
Q: Data have shown that FGF-21 levels are already elevated in a prediabetic state. What do you think about this?
A: Yes, FGF-21 in obese and any kind of diabetes state is higher than normal. However, with pharmacological treatment with FGF-21, you see a weight-lowering effect, even though those animals initially had higher FGF-21 levels.
Q: You showed an increase in UCP1. Can you comment on protein levels? What kind of white adipose tissue do you work on?
A: We work on epididymal white adipose tissue. Protein levels of UCP1 increased in the white adipose tissue, but we don’t have that data for liver, so I can’t speak to that.
Q: Did you look at effects on brown adipose tissue?
A: I haven’t shown that here, but we did look at it. In this study, there was a trend of increase in UCP1 levels in brown adipose tissue, but it wasn’t significant.
Q: What about the discrepancy you observed in light vs. dark phases? It seems to me that the synergistic effect was more pronounced in the light phase. Did you make anything of this?
A: Losing weight while sleeping – that’s an ideal condition (laughs). They were like the control group since they were sleeping and their activity level didn’t change, but they were burning more calories.
Q: Can you comment on the huge increase in leptin receptors you found? Did you check the signaling of leptin in cells?
A: One explanation is that an enormous weight loss in a short period of time might be the cause because normally, if you administer leptin, you don't see any effect. However, when mice lose weight, you can restore leptin sensitivity. We didn’t track this at different time points. We looked at the end of the experiment after 30% weight loss. At day 8, weight loss was about 15%, so a certain degree of weight loss might trigger leptin sensitivity, though we haven’t looked at it in much detail.
BROWN ADIPOSE TISSUE, A SINK OF GLUCOSE DISPOSAL? EFFECTS OF FGF-21 ON GLUCOSE METABOLISM IN BROWN ADIPOSE CELLS
Francesc Villarroya, PhD (University of Barcelona, Barcelona, Spain)
There is a growing body of evidence suggesting that brown adipose tissue (BAT) is a site of glucose uptake and utilization, and this study attempted to uncover the role of FGF-21 in inducing this activity. BAT has been shown to release FGF-21 following thermogenic activation (heat production), and thus cold-adapted rats had a markedly increased output of FGF-21. Assessment of the effect of FGF-21 expression in BAT (from mouse primary cultures) on markers of glucose metabolism found rapid induction of regulatory kinases such as ERK1/2 and p38, as well as machinery needed for glucose oxidation. Additionally, both in vivo and in vitro, FGF-21 was found to significantly induce expression of transcripts for genes associated with glucose uptake and oxidative/thermogenic activation. In parallel, exposure to FGF-21 in BAT resulted in a dose-dependent induction of glucose transporters, particularly GLUT4 and GLUT1. Dr. Villarroya postulated that FGF-21 operates through an autocrine signaling effect, whereby BAT is a sensitive target of the FGF-21 it produces, though other hypotheses exist. Researchers found these effects to be independent of the presence of insulin, making it an attractive strategy to heighten glucose disposal in patients with diabetes. Further research, however, is needed to evaluate the potential of BAT activation by FGF-21 to help prevent hyperglycemia. In our opinion, the most exciting part of the talk was the mention that results such as these support the emerging view that BAT may have endocrine properties and be a source of various hormones, FGF-21 only being one of many. Dr. Villarroya concluded by stating that the possibility is currently being investigated, and we will be sure to keep a watch out for any new developments on this front.
Questions and Answers
Q: What’s happening to fatty acid oxidation?
A: Fatty acid oxidation has some particular complexities because it is hard to mimic the uptake of triglycerides into BAT, which happens in vivo, when studying the system in vitro.
Q: Have you done any postprandial studies to look at FGF-21 expression in BAT?
A: We have not managed this yet.
FGF21 RESISTANCE RELEVANT TO INSULIN RESISTANCE IN SKELETAL MUSCLE OF PATIENTS WITH TYPE 2 DIABETES
Min Suk Lee, MD, PhD (Ajou University School of Medicine, Suwon, South Korea)
Dr. Min Suk Lee presented human data (n=12 people with NGT and 16 with type 2 diabetes), suggesting that people with type 2 diabetes have FGF21 resistance. In the study, people with type 2 diabetes had higher levels of FGF21 in skeletal muscles than their healthy counterparts. However, people with type 2 diabetes had lower levels of active FGF receptor, FRS2α (FGF receptor substrate 2α), and ERK 1/2 in skeletal muscles. Additionally, in vitro studies palmitate (a kind of free fatty acid) was found to significantly blunt the action of FGF21, suggesting that FGF21’s impact might be reduced in people with type 2 diabetes (who tend to have higher levels of palmitate). If Dr. Lee’s hypothesis that people with type 2 diabetes have FGF21 resistance is true, we wonder what impact this phenomena could have on the efficacy of agents looking to treat type 2 diabetes by increasing FGF21 levels. For example, BMS has a PEG-FGF21 listed in “early development” (post discovery through phase 2). At MDDD 2012, Dr. Guoqiang Jiang (Director of Knowledge Discovery, Worldwide Licensing, Merck, White House Station, NJ) stated that he believes that Amgen and Pfizer/CovX are also investigating FGF21 analogs (for more details on Dr. Jiang’s comments, see page 21 of our MDDD Full Report at http://www.closeconcerns.com/knowledgebase/r/208ea837).
Oral Presentation: Health Economic Aspects of Diabetes: Happy, Healthy and Prosperous
DIABETES CARE FROM THE PATIENT'S PERSPECTIVE: COMBINING RISK FACTORS WITH PATIENT REPORTED OUTCOMES MEASURES AND CAPABILITIES IN THE NATIONAL DIABETES REGISTRY IN SWEDEN
Sixten Borg, MSc (Copenhagen University Hospital, Slagelse, Denmark)
Mr. Sixten Borg began by explaining that both the healthcare provider and patient perspectives contribute to diabetes management and outcomes. Evaluations of diabetes care, however, often neglect the patient half, instead focusing entirely on traditional risk factor control (i.e., A1c, blood pressure, and cholesterol levels). The present study attempted to address this skew by developing a tool to measure the patient’s perspective. The tool is comprised of two dimensions: 1) PROMs (patient reported outcomes measures), or the self-management capabilities of the patient and 2) PREMs (patient reported experience measure), or patients’ judgments of their diabetes care. Item response theory (IRT) scales were designed and validated through an analysis of 1,124 type 1 diabetes patients and 1,792 type 2 diabetes patients. Increased A1c was associated with lower PROM and PREM scores, though this pattern was not observed when the data were stratified by blood pressure and LDL levels. Notably, the 10% of patients with the lowest PROM values did not differ from other patients with regards to their risk factor measures, whereas the 10% of patients at highest risk according to medical estimations did not differ from other patients with regards to their PROM values. Because these findings suggest that healthcare professional and patient evaluations of diabetes care diverge significantly, researchers concluded that the optimization of health-related quality of life scores is contingent on integrating both valuable perspectives.
- Evaluations of PROM took into consideration the patient’s self-management skills, emotional wellbeing, feelings of safety, and ability to perform social and work related activities.
- Evaluations of PREM were experience oriented, with a particular focus on the patient’s access to staff, services, and information, as well as their involvement in therapy decisions.
Questions and Answers
Q: For people with higher A1c levels in a good care environment like Sweden, where there are paradoxically higher rates of hypoglycemia, is it possible that your findings are reflecting associated co-morbidities rather than glucose control itself?
A: I should admit – I'm a statistician. I’m not completely at home with the diabetes-related terminology, but that sounds like it could be a possibility.
Symposium: Pathophysiological Phenotypes in Type 2 Diabetes
TREATMENT OF TYPE 2 DIABETES BASED ON PATHOPHYSIOLOGICAL KNOWLEDGE
Stefano Del Prato, MD (University of Pisa, Pisa, Italy)
Reflecting on treatment individualization with the ADA/EASD position statement, Dr. Stefano Del Prato questioned whether HCPs should individualize treatment for a person’s specific type 2 diabetes pathophysiology in addition to the factors explicitly mentioned in the document. He pressed that it is rational to want a pathophysiological treatment because it will treat a specific defect rather than merely compensating for it. Dr. Del Prato noted that the current arsenal of drugs might make it feasible to treat patients pathophysiologically, assigning at least one drug to each component of Dr. Ralph DeFronzo’s (University of Texas Health Science Center, San Antonio, TX) “Ominous Octet” of pathophysiological defects in type 2 diabetes. Dr. Del Prato then touched upon Dr. DeFronzo’s triple therapy (metformin plus pioglitazone plus exenatide twice daily), as it is based on pathophysiology. Dr. DeFronzo’s finding that initiation of triple therapy at diagnosis results in superior glycemic control compared to the conventional step-wise method previously endorsed by the ADA (metformin followed by subsequent addition of a sulfonylurea and then basal insulin) provides further evidence, in Dr. Del Prato’s mind, that type 2 diabetes can be treated pathophysiologically and that it can improve glycemic control compared to a more compensational approach (for more details on Dr. DeFronzo’s triple therapy results, please see page 8 of our ADA 2013 Report – Treatment Algorithms and Strategies at http://www.closeconcerns.com/knowledgebase/r/76f49d51). However, the triple therapy is tailored to the average pathophysiology of type 2 diabetes, not a person’s unique presentation. Dr. Del Prato lamented that our current understanding of type 2 diabetes biomarkers and genetics does not enable practitioners to fully individualize treatment based on a person’s specific pathophysiology.
- Dr. Del Prato made the case that it is logical to treat type 2 diabetes in a pathophysiological manner. Dr. Del Prato explained that a compensatory approach (e.g., sulfonylureas) might improve glycemic control in the short-term; however, it does not necessarily control the diseases’ underlying mechanisms. For example, he explained that sulfonylureas (SFUs), DPP-4 inhibitors, and GLP-1 agonists can be used to stimulate beta cell insulin secretion. However, while SFUs induce beta cell apoptosis in cultured humans islets (Maedler et al., J Clin Endocrinol Metab 2005), GLP-1 treated islet cells appear to be protected (Fanila et al., Endocrinology 2003). Given the importance of beta cell mass in type 2 diabetes, Dr. Del Prato suggested that incretin mimetics (unlike SFUs) might be able to modify the pathophysiology of type 2 diabetes.
- Dr. Del Prato, therefore, did not list SFUs as a pathophysiological treatment for impaired insulin secretion or any other component of the ominous octet. During Q&A he noted that SFUs would be a pathophysiological option for people with a defect in the beta cell’s potassium channel. Indeed, people with MODY due to certain mutations impacting this channel respond particularly well to SFUs.
- Dr. Del Prato showed that each component of the “Ominous Octet” of pathophysiological defects in type 2 diabetes can be addressed by a currently available agent and that more options are in development. Below are the agents he noted for each pathogenic characteristic of type 2 diabetes.
Table 1: Choices for Pathophysiological Treatment of Type 2 Diabetes
|
Defect |
Available Agents |
Agents in Development |
|
Impaired insulin secretion |
DPP-4 inhibitors and GLP-1 agonists |
Glucokinase activators, GPR agonists, and IL-receptor antagonists |
|
Decreased incretin effect |
DPP-4 inhibitors, GLP-1 agonists, and bile acid sequestrants. |
- |
|
Increased glucose reabsorption |
SGLT-2 inhibitors |
- |
|
Increased lipolysis |
Thiazolidinones (TZDs) |
Dual and pan PPARs activators, and 11HSD inhibitors |
|
Decreased glucose uptake |
Thiazolidinones (TZDs) |
Dual and pan PPARs |
|
Neurotransmitter dysfunction |
Bromocriptine (Santarus’ Cycloset) |
- |
|
Increased hepatic glucose production |
Metformin and TZDs |
Glucokinase activators and glucagon receptor antagonists |
|
Increased glucagon secretion |
DPP-4 inhibitors and GLP-1 agonists |
Glucagon receptor antagonists. |
- The pathophysiology of type 2 diabetes is believed to vary among patients. Dr. Del Prato supported this hypothesis, citing evidence that Arabic people have substantially lower insulin sensitivity while Japanese people have a higher insulinogenic index (Abdul-Ghani et al., Diab Metab Syndrome 2007).
- Thus, Dr. Del Prato would like for HCPs to be able to personalize their patients’ treatment according to their underlying pathophysiology. For example, he believes a person with more insulin resistance of peripheral tissues than at the hepatic level, might benefit more from a TZD than metformin, since TZDs have a greater impact on insulin-mediated glucose uptake.
- Unfortunately, such individualization is not currently possible due to the lack of validated biomarkers of the disease’s underlying pathophysiology or predictive alleles. α-hydroxyburate might be a biomarker of insulin resistance and the development of type 2 diabetes (Gall et al., PLoS ONE 2010; Ferrannini et al., Diabetes 2013); however, Dr. Del Prato thinks it needs further validation. Similarly a number of potential beta cell biomarkers exist (e.g., insulin, amylin, IA-2, etc.), yet they have also not been validated.
- Dr. Del Prato emphasized the importance of early intervention, citing ACCORD, ADVANCE, and VADT as evidence that late intervention cannot reverse CV damage, while citing UKPDS as demonstrating that early intervention has both positive microvascular and macrovascular effects.
- While discussing the impact metformin has on type 2 diabetes pathophysiology, Dr. Del Prato noted that metformin might act as a GLP-1 enhancer and sensitizer (Cho and Kieffer, Diabetologia 2011). He therefore hypothesized that combining metformin and incretin mimetics, could potentially be synergistic. Indeed, a two-year study of sitagliptin and metformin found that when the agents are taken as an initial combination therapy, patients achieve better glycemic control than with monotherapy with either agent (Williams-Herman et al., Diab Obese Metab 2010). However, it was not clear that the two drugs’ glycemic benefit was multiplicative rather than additive. Additionally, the glycemic control gradually degraded over the two years. Dr. Del Prato noted that some people think that combining exenatide and metformin could be more durable; however, he thinks longer studies with both DPP-4 inhibitors and GLP-1 receptor agonists are needed before any conclusions can be drawn.
- Dr. Del Prato also briefly explained that glucose appears to stimulate the release of GLP-1 from certain pancreatic alpha cells (alpha-TC1/6 cells). If this occurs within the body it would mean that GLP-1 is not solely a gut hormone secreted by the intestinal L cells. Dr. Del Prato’s group is presenting this research in a poster at EASD (#578).
Questions and Answers
Q: One thing you have not addressed is the possibility of looking at the response to treatment in patients and then making a decision on whether to continue drug use?
A: You are right, but I don't see that as being much different from what we are currently doing. I think that nowadays trial and error might be the only option we have, on top of phenotypic characterization. On the contrary I was elaborating on the possibility to individualize treatment since diagnosis on the basis of the main pathophysiologic mechanism(s).
Q: But Stefano don't you think that we forget to stop a drug the patient is not responding to?
A: Oh for sure, but I don't think that has anything to do with the pathophysiology, rather to our own clinical inertia.
Q: We do some personalize insulin, based on a person’s glucose profile. Do you think we can personalize orals around the glucose profile too?
A: Yes we can do that but that is not pathophysiologically driven, rather it is phenotype driven.
Q: Could C-peptide be of any use in determining type 2 diabetes pathophysiology?
A: C-peptide is a potential biomarker for beta cell function. However, I think that C-peptide is a tricky marker as it is still dependent on prevalent glucose levels. We need biomarkers that are totally independent of the environmental condition.
Q: Is there no place for SFUs?
A: I think that if you can identify a prevalent defect at the level, for instance, of the potassium channel as it occurs for some neonatal forms of diabetes SFU are treatment of choice. I understand that this is not a typical condition in type 2 diabetes, but it makes the point for a treatment based on pathophysiologic knowledge. And this was the issue I was trying to elaborate upon: whether or not it is possible to base treatment on the pathophysiology .
CAN GENOTYPING AID IN THE CHOICE OF ANTIDIABETIC THERAPY?
Leif Groop, MD, PhD (Lund University, Malmö, Sweden)
Dr. Leif Groop explained that although certain genetic variations do appear to impact a person’s response to a given anti-diabetic agent, the effect is too slight to justify genetic screening. Some evidence exists, according to Dr. Groop, that genetic variations have a small impact on the efficacy of sulfonylureas (TCF7L2), metformin (OCT1 and ATM), and DPP-4 inhibitors (CTR1). Instead of pharmacogenetics helping to identify who will respond to a given agent, Dr. Groop remarked during Q&A that it could be more effective at determining who will experience more severe side effects on a drug (at least based on medical experience with other diseases). For example, the odds ratio of developing statin-induced myopathy is 4.5 (95% CI, 4.7 to 61.1) if a person taking statins has a SCLO1B1 variant (SEARCH Collaborative Group, NEJM 2008). Dr. Groop noted that genetics could also help researchers identify new therapeutic approaches.
- Genetic studies discovered that people with certain melatonin (MTNR1B) alleles have an increased risk for developing type 2 diabetes (Lyssenko, Nat Genet 2008). Investigators subsequently learned that these risk alleles led to increased expression of melatonin, suggesting that melatonin impairs insulin secretion. Indeed, MTNR1B knockout mice have heightened insulin secretion. Risk genotype carriers of MTNR1B have increased expression of MTNR1B in human islets. Thus, Dr. Groop recommended further investigation into the role of melatonin in glucose homeostasis. Dr. Groop hypothesized that melatonin helps defend the body from nighttime hypoglycemia, since its levels are highest at night.
Questions and Answers
Q: Given the low risk associated with each allele, perhaps we are better off stratifying patients by biological pathways.
A: Absolutely, if you really did know those biological pathways. What I think we really need is better outcome data. When you treat people you just add on additional drugs so it is hard to dissect the effect of each drug. You are right though. Of course all pathways going into impaired insulin secretion could have an effect. I forgot to mention one recent study where they showed that a variant in the CTR1 gene actually predicted response to DPP-4 inhibitors, but again the effect size was modest.
Q: People these days seem to be more concerned about side effects than efficacy. What is the potential role of pharmacogenetics in identifying people with regards to side effect response?
A: I think the odds of that working are greater. My guess would be that pharmacogenetics could help us more in predicting side effects than in determining who will respond. In the cancer field they have very good data that if you have a variant in one of those genes that a drug will have really severe side effects.
Symposium: Psychosocial Issues in Diabetes
AN OVERVIEW OF THE DAWN2 STUDY
Mark Peyrot, PhD (Loyola University, Baltimore, MD)
As a prelude to the new data presented by Dr. Pouwer in the following talk, Dr. Peyrot provided a comprehensive overview of the rationale and intended aims of the DAWN2 Study. DAWN2 (Diabetes Attitudes Wishes & Needs), a “multinational, multidisciplinary, and multi-stakeholder survey study,” seeks to create a holistic and collaborative platform in which the three main stakeholders in diabetes management (patients, their families, and their healthcare providers) can engage in meaningful dialogue that ultimately improves the health outcomes and quality of life of patients. Similar to the original study completed in 2001, DAWN2 highly prioritized strengthening psychological and psychosocial support and treatments for people with diabetes. However, while the overarching mission of DAWN2 shares many similarities with its predecessor, Dr. Peyrot made special note of several advances in methodology adopted by the new study. One of the most notable changes is the shift from an information-gathering approach to a “person-centered chronic care” model that provides a basis for action and sustainable change. In line with this revamped mentality, DAWN2 is unique in that it includes family members of adults with diabetes, as well as the personal narratives of ALL 15,438 (!) global participants, making it the largest qualitative study of people with diabetes to date. We were quite impressed by the mindfulness that went into achieving comprehensive geographic coverage and far-reaching demographic representation; the 17 countries that participated in the study represent four continents, varying levels of economic development, and a diverse spread of ethnic groups. As Dr. Peyrot explained, the invaluable benefit of this all-inclusive sampling is the creation of a global community that countries can leverage for cross-national comparisons, inspiration, and partnerships. DAWN2 lays a strong foundation for benchmarking, an empirical standard for assessing quality of life that countries can use to establish a baseline and measure future progress. We are excited to track DAWN2 as its many promises unfold – continue reading below to learn more about the latest outcomes of this visionary attempt to change the landscape of diabetes care.
DAWN2: PSYCHOSOCIAL ADAPTATION AND QUALITY OF LIFE
Frans Pouwer, PhD (Tilburg University, Tilburg, The Netherlands)
Dr. Frans Pouwer presented results from the DAWN2 (2nd Diabetes Attitudes, Wishes, and Needs) study performed in 17 countries throughout North America, South America, Africa, Europe, and Asia. The study provides qualitative and quantitative data on the psychosocial burdens and benefits that diabetes places on patients, their families, and HCPs. Dr. Pouwer broke the presentation into five areas of research (see below), with a quotation from the qualitative data within each section. Additionally, some data were presented by country, so that people could compare their nation to the international average and note areas in which they could improve. Going forward, Dr. Pouwer remarked that in addition to the 5th International DAWN Summit to be held this April in The Netherlands, all 17 countries would be part of a multi-stakeholder collaboration to develop national action plans. At the end, Dr. Pouwer spotlighted the six DAWN2 posters at EASD this year (be sure to check them out!) as well as the DAWN2 booth in the exhibit hall (unsurprisingly sponsored by Novo Nordisk). Much of the data presented today were a review of what we learned at ADA this year; for additional statistics, please see page 327 of our report at http://www.closeconcerns.com/knowledgebase/r/94f937d8.
- Dr. Pouwer began by examining the impact of diabetes on quality of life (QOL). DAWN2 found that 14% of people with diabetes reported likely having depression, a percentage that he remarked was two-to-three times higher than in those without diabetes. Additionally, 46% of people with diabetes reported distress because of their condition (the rates were particularly high in southern and eastern Europe, Africa, and Asian countries); 39% of patients said that diabetes interfered with their daily life, and 56% reported that they were very concerned about the risk of hypoglycemia. Dr. Pouwer noted that while these statistics underscore the negative impacts of diabetes, positive impacts, such as bringing families closer together, exist as well.
- DAWN2 is unique in that it examined the family perspective of diabetes. The study revealed that of the total number of family numbers surveyed, 35% reported feeling a burden from caring for a relative with diabetes and 61% admitted being very worried about the risk of hypoglycemia for their family member. Additionally, 46% of family members would like to be more involved in helping their relatives with diabetes cope with their feelings (which is uplifting, since 72% of HCPs called family involvement “vital” for good diabetes care). In terms of personal health, Dr. Pouwer noted that 45% of family members responded that the incidence of diabetes in the family reduced their own physical health, and 35% felt that it adversely impacted their emotional well-being. Interestingly, these findings are similar to the values obtained when the same questions are posed to patients themselves.
- Dr. Pouwer discussed the importance of active involvement from people with diabetes, highlighting the need for improved self-management. Dr. Pouwer particularly called for greater exercise after noting that patients only exercise more than 30 minutes a day about four days a week. DAWN2 asked HCPs what they thought would be helpful for patients with diabetes to do, such as come to appointments with questions. Dr. Pouwer remarked that HCPs saw improved resources as the “cornerstone for good self-management” (about 60% of HCPs identified a need for improvement in this area and believed it would lessen the burden of diabetes).
- Patients need quality diabetes care that includes psychosocial support. Dr. Pouwer was “shocked” that almost 70% of individuals were not asked about their emotional well-being by their HCP. Interestingly, while 52% of HCPs believed they had asked their patients how diabetes affected their lives, only 24% of patients responded that their HCPs had done so. Looking for the silver lining, Dr. Pouwer’s remarked that at least this suggests HCPs are willing to ask these questions – they just need to take more time. Additionally, patient education is lacking; less than half of people with diabetes participated in any educational program. It appears that more education would be optimal, since 63% of HCPs desired more training. The majority of HCPs (59%) also wanted increased availability of psychological support, and 54% said they would like to better communication among the healthcare team.
- Finally, Dr. Pouwer discussed discrimination and societal stigma in diabetes management, noting that he thinks this is the first time this issue has been investigated in 17 different countries. Patients with diabetes, families of those with diabetes, and HCPs all believed that patients with diabetes experienced discrimination, intolerance, or lack of support from their community. If you are interested in learning more about this critical issue, Dr. Pouwer mentioned that one of the six DAWN2 posters at this year’s EASD examines how discrimination due to diabetes is associated with diabetes-related stress (PS 095; 1142).
PANEL DISCUSSION
Mark Peyrot, PhD (Loyola University, Baltimore, MD); Frans Pouwer, PhD (Tilburg University, Tilburg, The Netherlands)
Q: You clearly need to be congratulated on such an ambitious study. The results are very interesting. What are your plans in terms of analyzing the qualitative data? If I understand correctly, you have a large amount of qualitative data from 17 countries in almost 17 different languages. It is a great undertaking to analyze themes throughout this data. However, I think it is particularly important because you could be criticized for your representativeness; for example, you have a very small sample from China even though the population of Chinese with diabetes is quite large. With the qualitative data, you do not face that issue. What are your plans for the analysis?
Dr. Peyrot: Before I answer your question, let me respond to your point about the representative nature of the quantitative data. It is not based on proportion but on the number of people in the sample. Population size is irrelevant. In terms of the qualitative data, the first step was to translate everything into a standard language, English. All countries have their own qualitative data so they can do their own analysis, but we had our own team come up with a coding system for the major data set after translation. Our team came up with the codes and tested the inter-rater reliability and made sure that all the raters would produce the same ratings – we wanted to make sure everything was valid and accurate. After that, we coded our 15,000 responses. We have also looked at the listing of the various codes and have identified themes that we want to address. There is a paper in progress. Also, you can go to the presentation of our poster, “Qualitative insights into diabetes psychosocial needs and strategies from the perspective of healthcare professionals in DAWN2,” tomorrow; our qualitative leader will be there and you could discuss particulars there. If you want to see an example of the analysis we have done, that is a good place to start.
Q: Can you say a little more about family members? You say that they have to be involved in patient care, but what does that mean?
Dr. Peyrot: That is literally the question we asked of the people solicited for the study. We wanted to ask them questions about what they would do for their family members with diabetes, and we wanted to assess what having support and what not having support from family does to diabetes management.
Q: For the first time, you showed the standard set of measures that can be used, which I think is great. How do you think this same data can be used for other countries not involved in this study?
Dr. Pouwer: Researchers in other countries can initiate comparable studies to learn more about the specific situation in their countries. That is one initiative; I think that is a good first step.
Dr. Peyrot: One of our goals for this study was to validate what measures might be useful across countries. Some of the measures were completely standardized once they were used in hundreds of studies, but we developed new instruments and we validated cross-culturally to make sure they were useful everywhere. We wanted to make sure we had cross-cultural reliability everywhere. Additionally, a country could look at where they fall in the ranks of other countries; are we near the bottom or top? This is especially important for new instruments of measure, such as those for HCPs and family members of people with diabetes.
Q: Congratulations on your DAWN2 study. What kind of sub-analysis are you planning to do? Are you planning to show data comparing patients with type 1 diabetes vs. type 2 diabetes? For example, are you going to look at the psychological effects in patients with type 1 diabetes vs. type 2 diabetes? Also, you noted that patients with type 2 diabetes had been diagnosed for at least a year. How do you plan to examine the attitudes of patients with type 2 diabetes who have been diagnosed for less than a year?
Dr. Peyrot: It is difficult to do a country-by-country analysis for a scientific audience because the sample size is about 100 to 150; you do not have the same type of rigor as you do with larger sample sizes. For our scientific publications, we need to pool countries. Turning to type 1 diabetes vs. type 2 diabetes, one number that you could look at is hypoglycemia between the group groups. You could also look at the impact of patient centered care in type 1 diabetes and type 2 diabetes, or between genders. You asked a good question. I would say we have plans, but trying to describe them is beyond the scope of this session. We try to look at it from a multivariate risk point of view so that we don’t pull out one factor and determine a correlation that is actually confounded with other factors.
Q: This study is mainly looking at problems associated with diabetes. How could patients resolve these problems? Did you look at a period of resolution for the problems?
Dr. Pouwer: I have to respectively disagree. I think this is one of the few studies that looks at positive effects within patients and families. Many patients responded to our qualitative portion with “I live a healthier life,” or “I changed my eating habits,” or “I have more family cohesion.”
Dr. Peyrot: I think you raise an important question. The prior session was looking at risk factors. We are also looking at protective factors to ameliorate these negative effects. For example, patient centered care contributes to a sense of empowerment, which leads to being able to successfully manage disease. We are trying to identify challenges that patients face and how they can overcome them. We are trying to do this not only by looking at one person, but by looking at the family and supporters and healthcare team. We need to address exactly those things that you are talking about, and we need to come up with effective solutions that are shared by a variety of stakeholders.
Symposium: From Gene Loci to Function: What Have We Learnt?
FROM GENETICS TO MECHANISM-BASED INTERVENTION
John Todd, PhD (Cambridge Institute for Medical Research , Cambridge, UK)
Dr. John Todd highlighted the importance of understanding disease pathology in a talk that focused on the IL-2 pathway in type 1 diabetes. He outlined the IL-2 pathway and described a new study that attempts to treat type 1 diabetes using IL-2. To fully understand the pathology of type 1 diabetes, Dr. Todd explained, it is necessary to understand how genes and the environment interact; the first step in that process is determining the genes that are involved. Turning specifically to type 1 diabetes, Dr. Todd noted that ~0.1 IU/ml of IL-2 will increase the number of T-regulatory cells in fresh, whole blood, and if raising the levels of IL-2 in vivo also increase the level of T-regulatory cells, this could potentially protect against type 1 diabetes. While raising levels of IL-2 in vivo has not worked in past studies, Dr. Todd remarked that previous research might have used IL-2 levels that were too high (e.g., 4.5 x 106 IU subcutaneously three times a week for four weeks). Dr. Todd concluded by outlining his current study, the Adaptive Study of IL-2 dose on Regulatory T cells in Type 1 Diabetes (DILT1D), which examines the relationship between doses of IL-2 and T-regulatory cell activation and frequency. Although the study is still recruiting patients with type 1 diabetes (ClinicalTrials.gov Identifier: NCT01827735), Dr. Todd remarked that they have already “learned quite a lot.” We look forward to hearing results at a future meeting.
- Type 1 patients in Dr. Todd’s study will receive escalating levels of IL-2, with two participants per dose level. Patients will be studied at early activation (50 minutes and 24 hours post-dosing) as well as at extended time points. Currently, there have been 10 participants, with a goal of 40 by 2014.
- Participants could receive up to 1.5 x 106 IU/m2 of IL-2. Other doses include: 0.04 x 106 IU/m2, 0.15 x 106 IU/m2, 0.6 x 106 IU/m2, and 1.0 x 106 IU/m2.
- Previous studies have used what Dr. Todd called “too much” IL-2. Dr. Todd highlighted the IL-2 + rapamycin trial, remarking that at day 28 T-regulatory cells significantly increased in number but later declined. Additionally, the IL-2 also increased natural killer (NK) and T-efficiency cells.
- Dr. Todd reminded the audience that the FUT2 nonsecretor status links a susceptibility for type 1 diabetes with a resistance to infection, emphasizing the importance of the gene-environment interaction. He remarked that FUT2 is strongly associated with the composition of Bifidobacteria in the human intestine, which suggests that there might be a three-way interaction between genetics, infection, and the microbiome.
- There are many risk alleles that are common among inflammatory diseases; Dr. Todd particularly highlighted how closely Juvenile Idiopathic Arthritis (JIA) and diabetes resemble each other in their genetic architecture. Understanding genes and pathways that are protective against inflammatory diseases, such as the impairment of the IL-6 in JIA, may be helpful for developing new therapies.
- As a reminder, T-regulatory cells, which are mis-regulated in people with type 1 diabetes, are IL-2 dependent. T-regulatory cells are dependent on the transcription factor FOXP3, which in turn switches of the IL-2 gene. CD4 memory cells have IL-2 receptors and also produce IL-2; the production of IL-2 from CD4 cells down-regulate the amount of T-regulatory cells produced and decreases the amount of IL-2 produced. Additionally, T-regulatory cells have a suppressive effect on T-effector cells.
Questions and Answers
Q: I think that the genetic comparison between JIA and type 1 diabetes is intriguing. When you look at genes that are similar and different between the two disorders, are there any clues on which genes may indicate an autoimmune response against tissue?
A: There are genes that are shared between JIA and also type 1 diabetes, but there are also genes that differ – genes that are disease-specific or disease-unique. For example, consider the IL-2 pathway in diabetes. There is a set of shared genes that drive autoimmunity as well as genes that drive disease specificity.
Corporate Symposium: Innovative Comprehensive Approaches to Addressing Diabetes Challenges (Sponsored by Sanofi)
INNOVATIONS IN CLINICAL PRACTICE: ACHIEVING OPTIMAL DIABETES HEALTH MEASURES
Richard Bergenstal, MD (International Diabetes Center, Park Nicollet, Minneapolis, MN) and John Misa, MD (Park Nicollet, Minneapolis, MN)
International Diabetes Center Executive Director Dr. Richard Bergenstal and Park Nicollet Chief of Primary Care Dr. John Misa reflected on their experience during their institution’s transition from a fee-for-service-based institution to a pay-for-performance model under its current status as an Accountable Care Organization (ACO), describing how systems, targets, and algorithms in diabetes care are changing. During their presentation, they focused much of their discussion on Park Nicollet’s focus on achieving the “triple aim” (Berwick et al., Health Affairs 2008) – improving the patient experience, improving the quality of care, and reducing costs simultaneously. To achieve the triple aim, many changes have taken place, including changes in reimbursement structure (e.g., paying for quality instead of services provided, and participating in shared savings), the implementation of reporting recently developed robust quality measures, and ongoing enhancements of the patient experience. Based on the metrics it has tracked, Park Nicollet documented an increase in the quality of care, reduced costs, and a steady level of patient satisfaction with the overall care experience over the past few years. Putting it in more tangible terms, Drs. Bergenstal and Misa noted that when comparing the quality of care in 2012 to 2000, patients in the HealthPartners health plan (HealthPartners and Park Nicollet are now a combined entity) saved 417 hearts, 72 legs, and 745 pairs of eyes each year.
- Across the state of Minnesota, the D5 – an aggregate of five target goals for diabetes – is now used as a standardized quality measure for diabetes care. When the D5 was first measured, achieving the D5 consisted of: having blood pressure <130/80 mmHg, LDL <100 mg/dl, and A1c <7%; being tobacco free; and taking aspirin daily, if 40 years or older. Since then, some of the targets have been relaxed. Currently, achieving the D5 consists of: having blood pressure <140/90 mmHg, LDL <100 mg/dl, and A1c <8%; being tobacco free; and taking aspirin is there is a history of vascular disease. Notably, the D5 measures are now being used as the quality measures for diabetes care for Accountable Care Organizations across the nation. When D5 data first came out, Park Nicollet had about 7-8% of its diabetes patients achieving all five goals. In efforts to improve the percentage of patients achieving the D5, a number of measures were instituted at Park Nicollet (some of which are described in more detail below). Park Nicollet is at the top of the pack, with 51% of its diabetes patients achieving all five targets (for comparison, the state average is approximately 38%). To explain their relative success at Park Nicollet, Drs. Bergenstal and Misa noted that they don’t just aim for an A1c below 8% – they want some patients at 7% or lower. If they only aimed to get all patients below an A1c of 8%, about half would still end up above that target. Though Park Nicollet has hit a plateau at around 50%, Drs. Bergenstal and Misa believe that with more team and technology based care innovations they can eventually get around 70% of their patients to achieve the D5.
- Park Nicollet implemented a number of initiatives to improve the patient experience and the quality of care both between and during visits. To follow patients better, Park Nicollet created a comprehensive registry that enables healthcare professionals to see how their patients are doing throughout the year, and reach out as appropriate before they even schedule their visits. Now, between visits, Park Nicollet staff are beginning to monitor patients’ glucose data, and contact those who are out of range or who need help. At Park Nicollet, between-visit communications are an important way for healthcare professionals to maximize the value of the limited time they have during visits (by taking care of administrative and logistical details beforehand), and also to ensure ongoing care in between visits.
- About five years ago, Park Nicollet transitioned to the medical home. Drs. Bergenstal and Misa explained that this represented a paradigm shift at their institution toward team-based care, a model in which doctors, nurses, diabetes educators, and other healthcare professionals work together to look at all chronic conditions for a given patient. After Drs. Bergenstal and Misa referenced a position statement by the American College of Physicians (Doherty et al., Annals of Internal Medicine 2013) offering principles to support effective team-based patient care, they emphasized that the medical home is here to stay. Currently, Park Nicollet runs care conferences, bringing together larger healthcare teams (e.g., including pharmacists and case managers) to make sure they’re delivering all necessary parts of care for high-risk patients.
- In addition to quality measures, Park Nicollet is now tracking the costs of patient care. Using a system developed by HealthPartners, doctors at Park Nicollet now have the ability to see the total cost of care their patients incur. For example, for a patient who spends the winter in Arizona who ends up needing prescriptions and hospital visits while there would have his or her costs associated back to Park Nicollet. Dr. Bergenstal referenced a July 16, 2013 Wall Street Journal article titled “Mixed Results in Health Pilot Plan,” which noted that of 32 health systems in the Pioneer ACO program, all improved the quality of care, but only some were successful at reducing costs in tandem.
- Park Nicollet view patients and their family members as partners in ongoing efforts to improve care at both the institutional and individual level. Dr. Misa stated that they now start board meetings with patient stories, noting that their stories are much more impactful than what he himself can bring to the table as a healthcare manager. In addition, healthcare professionals at Park Nicollet engage in shared decision making with their patients, discussing factors such as weight, side effects, costs, risk of hypoglycemia, glucose-lowering ability, daily glucose-testing requirements, and daily routines when deciding on therapy choice.
Satellite Session: DIRECT – Personalized Medicines in Type 2 Diabetes
OBJECTIVES AND OPPORTUNITIES
Hartmut Rütten, MD, PhD (Sanofi, Frankfurt, Germany)
Dr. Hartmut Rütten outlined the objectives and opportunities of the DIRECT (Diabetes Research on Patient Stratification) consortium, which includes over 20 academic institutions and four pharmaceutical companies (Novo Nordisk, Sanofi, Eli Lilly, and Servier). Overall, the consortium aims to identify and validate biomarkers for glycemic deterioration and treatment response, in efforts to further individualize treatment for type 2 diabetes. As such, the DIRECT consortium intends to: 1) provide a high-quality European database that includes detailed phenotypic information; 2) provide a systems biology platform integrating clinical data, biological data, genomics, metabolomics, and other relevant data; 3) develop novel data mining tools and algorithms to generate stratification and response biomarker candidates; 4) develop industrialized biomarker assays; 5) validate biomarker candidates; and 6) assess response (or lack of response) to established therapies in well-defined subpopulations. In closing, Dr. Rütten highlighted a number of opportunities the DIRECT academic/industry consortium provides, including access to well-characterized cohorts, access to a broad range of technologies, and access to a large European database for systems biology. For more information on DIRECT, please visit: www.direct-diabetes.org.
WHAT ARE WE DOING, AND WHEN WILL WE DELIVER?
Ewan Pearson, PhD (University of Dundee, Dundee, United Kingdom)
Dr. Ewan Pearson discussed the DIRECT consortium’s progress to date, emphasizing its focus on developing biomarkers to predict glycemic deterioration (Work Package 2 [WP2]) and treatment response (WP3). To better phenotype glycemic deterioration (WP2), DIRECT consortium members are looking at a number of measures (e.g., MMT, MRI for liver and pancreatic fat, GWAS, targeted and non-targeted metabolomics, metagenomics, etc.) both for those with prediabetes (n=2,700) and those with recently diagnosed diabetes (n=1,000) over an 18-month follow-up period. In WP3, DIRECT consortium members aim to perform extensive phenotyping of extreme drug responders and non-responders to gain insight into potential biomarkers for treatment response. For example, DIRECT investigators intend to assess a wide array of measures for those treated with GLP-1 agonists, including (but not limited to): beta cell function at initiation, hyperglucagonemia at baseline (and suppression by drugs), GLP-1 secretion at baseline, beta cell GLP-1 sensitivity, the impacts of drugs on gastric emptying, targeted and non-targeted metabolomics, and genomics. In addition to GLP-1 agonists, the consortium will also be looking at metformin and sulfonylurea extreme responders and non-responders, and will be investigating predictors and mechanisms for diabetes remission following bariatric surgery.
Questions and Answers
Q: It’s great that you’re looking at the usual suspects – metformin and sulfonylureas. Is there any provision for any of the new promising pipeline drugs to plug into this model and predict their success in clinical trials?
A: Academic study sites are limited to dealing with available drugs. But, a number of these [new candidates] are being developed by [our] pharma partners. One would hope at the very least that signals we get might impact [how they look at] response to their drugs. What we would like to get is their data, and bring it into the database, but it may be a bit more of a challenge.
9. Exhibit Hall
- Alere: While the Alere booth was situated in a back aisle of the exhibit hall, the familiar purple-and-white logo rotating on the corner of the booth caught our eye. Upon entering, we were initially attracted to the large “X” made out of metal rods and containing nine numbered buttons – the game gave visitors 30 seconds to press as many buttons as they could in the order that they lit up (a harder challenge than expected!). Above the game was the phrase “co-ordination and reaction,” reflecting the company’s promise for “rapid results and improved outcomes”. While we can’t say that we were varsity players, the representatives still let us put our name on the leaderboard. Turning toward Alere’s products, the booth featured devices relevant to diabetes, including the Afinion Lipid Panel Test (an eight-minute point-of-care test to determine concentrations of total cholesterol, HDL, LDL, triglycerides, non-HDL, and Cholesterol/HDL ratio) and the Afinion A1c Test (a three-minute point-of-care A1c test, which representatives proudly noted was the fastest in the field). In the area where visitors were ushered for more information, Alere had a map denoting the more than 25 countries in which the company is based, a reminder of the global nature of the EASD meeting.
- Bayer: Bayer’s booth focused entirely on its alpha-glucosidase inhibitor Glucobay (acarbose), with no information on their blood glucose meters. Although we also saw a focus on Glucobay at last year’s EASD booth, it was notable not to see a single meter or mention of a meter in the booth. Bayer’s booth was positioned along an outside edge of the exhibition hall, directly in front of the Animas/LifeScan and to the left of BD’s booth. “Glucobay” was looped gently across the tops of most stations in mint green writing that complemented the similarly colored carpet. One Glucobay station sported the same game as last year, giving attendees 40 seconds to identify five differences between two pictures of a hamburger and french fries shaped like a tarantula; each missing item in the second picture represented something that would have raised a patient’s post-prandial glucose level (for example, one french fry was missing). We thought it was a clever way to incorporate learning into the booth. Additionally, each picture described benefits of taking Glucobay, including phrases we saw last year like: “Protect them from the danger of glucotoxicity.” Other phrases revolved around Glucobay’s ability to lower the risk of CV events. After participants successfully completed the game, they exchanged their win for a USB with publications on the efficacy of the drug. There were large monitors with the results of two trials, one indicating that acarbose is a better add-on to metformin than glibenclamide, and the second highlighting the success of acarbose as an add-on to DPP-4 inhibitors (it decreases levels of GIP and increases levels of GLP-1). Bayer also had an espresso station and sitting area to relax during a busy exhibit hall.
- BD: The BD booth resembled the focus of ADA and AADE and was divided into three sections: its 4 mm needle, lipohypertrophy, and needle safety. On the far side, there was a live demonstration of lipohypertrophy with a real diabetes patient. A representative from BD Medicine described the dangers of lipohypertrophy and how to avoid it, which included using a 4 mm needle. The rep explained that the needle is short enough to avoid reaching muscle and is also small enough to provide extra area for insulin infusion – both aspects decrease the risk of lipohypertrophy. At the end of his presentation, the representative even demonstrated how to detect lipohypertrophy on the patient; after the official presentation had ended, the patient even offered to have members of the audience try to find lipohypertrophy on his abdomen (we saw at least two people take advantage!). For those not yet ready to palpate in an Exhibit Hall, attendees could also enter a raffle to win a lipohypertrophy educational briefcase. Attendees seemed excited after the live presentation, and we expect that even more visitors will be drawn to the demonstration in the next few days – the screen with a countdown to the next demonstration was smart marketing! Also near this side of the booth was a mannequin with a rubber abdomen, which one representative used to demonstrate how easy it is to hit muscle when using a needle longer than 4 mm; the floor immediately turned red, indicating that the needle had gone through the “subcutaneous tissue” of the mannequin. We’ve got to hand it to BD – they are one of the best at interactive booth demos! The other end of the exhibit was dedicated to needle safety, with descriptions and demonstrations of the company’s dual protected needles. A rep noted that these are especially useful for patients with needle-phobia. In the middle of the booth, there was a large screen describing what BD does (since it is a US company), and also what they do and plan to do internationally. When we questioned reps on when there would be EasyFlow technology needle in Europe, they responded that they are “looking to keep moving forward” on that front.
- BMS/AZ – We were eager to see BMS/AZ’s booth to see how the EU launch of their SGLT-2 inhibitor Forxiga (dapagliflozin) is progressing. A giant representation of a sugar dispenser with a spigot first caught our attention as we approached the booth. We then noticed Forxiga’s logo (a picture of which can be seen at https://m1.behance.net/rendition/modules/77430853/disp/f1d4d899ba37bf5611b5dc6261f2ea94.png), which has a prominent downward arrow down the center, reflecting the agent’s mechanism of action. Three brightly colored squares surround the arrow, which meandering through the booth we learned reflect Forxiga’s lowering effect on A1c, weight, and blood pressure. Indeed, a survey of HCPs BMS/AZ were conducting on touch screens showed (at the time of our visit) that the two aspects HCPs who have tried Forxiga value most are 1) its delivery of effective A1c and 2) impact on weight loss and blood pressure. The other characteristics prescribers value (in order of decreasing ranks) are 3) its insulin independent mechanism, 4) that is it easy to understand and explain, and 5) its convenience for patients. We were slightly surprised that substantially fewer HCPs listed these latter two aspects as the item they value most when compared to the top three characteristics. HCPs who have not tried Forxiga yet indicated that they are also interested in the same characteristics of Forxiga, in approximately the same order. Overall, the booth was largely dedicated to Forxiga, however, BMS/AZ tied Forxiga into the rest of their portfolio (Bydureon, Byetta, Onglyza, and Kombiglyze) at screens throughout the booth, explaining to HCPs how they can individualize patient care using the Alliance’s agents. Additionally, HCPs could “connect, shake, and inject” Bydureon under the tutelage of a representative at a stand in one corner of the booth.
- Boehringer Ingelheim: BI’s booth was adjacent to the massive booth of its alliance partner Lilly. The space was brightly lit and was very open, giving it a cheery feel. The sound of chirping birds emanated from a Kinect motion-controlled video game, in which players flew around a simulated landscape as a bird (the mascot for BI/Lilly’s Tradjenta and Jentadueto). Next to the game was a life-sized artificial purple tree, with bright yellow plastic birds constructing their own nests. Two modestly-sized banners stated that Tradjenta (spelled Trajenta in Europe) demonstrated sustained A1c reductions over two years of clinical study, and that some patients experienced reductions of up to 1.2%. The other half of BI’s booth featured an educational campaign on SGLT-2 inhibitors, which did not mention any specific drug names (understandably so, as empagliflozin is still under regulatory review in the US and EU and thus cannot be marketed).
- Cellnovo: Cellnovo did not have a booth at EASD 2013, but met with us to provide an update on the progress of their insulin pump system. The company has been conducting patient studies in the UK, leading up to multi-center usability trials over the next few weeks. The company is still aiming for a UK commercial launch before the end of 2013, a roll out to other European countries following the UK launch, and a plan to file in the US in 2014. The company received a CE mark in Europe roughly a year ago. In recent weeks, the company has obtained third party data on pump accuracy and precision for basal and bolus delivery and for occlusion performance, and it compares well to other commercially available pumps. A strong differentiating feature of the system is remote monitoring and data management – it’s possible to see all historic data from the handset and pump via an online web portal in near real-time. The touchscreen handheld has a cellular data connection, and notably, the system can also trigger text message alerts. We were also interested to hear about a new ‘Before and After’ analysis for meals – this should really help patients and HCPs optimize meal-specific bolusing. As a reminder, the Cellnovo system consists of four components – a pump/rechargeable battery unit, a disposable insulin cartridge, a color touchscreen handset with an integrated meter, and a cloud-based data management system. Cellnovo’s system is more of a patch pump than a traditional pump, though it still requires a very short 0.4 inch (1 cm) infusion set.
- CeQur: Although CeQur was not present in the EASD Exhibit Hall, the company’s corporate symposium reminded us of the benefits of the PaQ insulin delivery device for patients with type 2 diabetes. It was once again valuable to see the data from a two-week feasibility trial of PaQ, results that we originally saw at ADA 2013 (see page 99 at http://www.closeconcerns.com/knowledgebase/r/94f937d8). On the usability side, none of the trial’s 18 participants had difficulty using PaQ, notable since there was only one hour of training – that simplicity is not to be underestimated in our view, particularly in the type 2 population. Participants listed “improved control” and “invisible to others” as some advantages of the product. CeQur also presented CGM data that demonstrated trends toward improved glucose control and less glycemic variability. As a reminder, CeQur recently closed a $27 million Series B round of financing, money that will be used to increase PaQ manufacturing as well as to fund activities related to US regulatory approval (presumably clinical trials, usability studies, user fees, etc.). PaQ received a CE Mark in November 2012 in Europe, and as we understand it, a focused EU launch is expected in late 2013 or 2014, with a broader launch in 2015. The device is three-day insulin patch pump with seven preset basal doses (16, 20, 24, 32, 40, 50, or 60 units per 24 hours) and two-unit on-device bolusing. We look forward to seeing this product launch in Europe and eventually the US, since simple and discreet insulin delivery is such an unmet market need in the type 2 diabetes arena and since the field needs new alternatives based on the high number of type 2 patients not at their glycemic targets (~45% in the US) and the significantly lower percentage not on insulin (under 30% on any insulin and even fewer on mealtime insulin).
- Dexcom: The Dexcom booth represented the company’s smallest of the major 2013 conferences, to be expected given the more challenging reimbursement environment for CGM in Europe – that said, the placement of the booth was terrific and traffic was quite good. The exhibit’s back wall reiterated the main news from Dexcom’s ATTD 2013 booth: a CE Mark for use of the G4 Platinum CGM in patients as young as two years old. Dexcom has now begun marketing in this population, something it had not yet started at ATTD in February. At the booth’s central table, attendees could talk to reps and see a demo of the G4 Platinum receiver. Along the left side, Dexcom’s Studio software and pattern recognition were available for demo. Unlike ADA and AADE, the Dexcom Share remote monitoring product was not on display. Those looking for brochures could peruse them in five different languages, reflecting just a smidgeon of the 22 countries where Dexcom CGM is now available. This was very impressive. We asked the rep specifically about China, as it has been mentioned in recent earnings calls. His comments confirmed the comments by Dexcom management in the 2Q13 call – the key is deciding what product to go to China with, since the regulatory review takes more than two years and first requires an FDA approval. In line with one of Dexcom’s marketing messages of the year, a sign declared, “CGM first – the first step for success.” That marketing really targets a more traditional belief (by some) that pumps should come before CGM, a more simplistic view. In our view, the decision to adopt a pump, a CGM, or perhaps both should be left up to sound clinical judgment and patient needs and preferences – reimbursement, of course, will always weigh in.
- Diasend: The online data management company’s booth had a clearly visible slogan as we entered: “Easy diabetes communication.” Indeed, Diasend is now compatible with an 70+ devices, including several new additions: Insulet’s second-generation OmniPod, Ypsomed’s myLife Unio BGM, Dexcom’s G4 Platinum, Bayer’s Contour Next, and even pendiq’s smart insulin pen. Diasend has also launched compatibility with mobile apps like Glooko and Sanofi’s iBGStar. In addition to new devices, the platform’s newest innovation allows users to compare pump setting changes over time. Looking to the future, Diasend hopes to include more pump features – one of the biggest pieces of user feedback has been a desire to see everything on one page. We asked about the standardized Ambulatory Glucose Profile report for CGM data (a major focus of Abbott’s symposium on Day #2), and the rep told us it’s “easy” to do on a technical front. The “hope” is to have this available on Diasend next year. Last, Diasend is deciding how to incorporate all the data from activity trackers – we think this would be a huge win for patients and providers, though the rep made it clear to us that the value of additional data must be balanced against information overload. As a result, Diasend is still brainstorming on how to best present this data. We’ll stay tuned!
- GI Dynamics: Located toward the center of the exhibit hall, GI Dynamics’ booth featured “EndoBarrier” in large letters on a central rectangular sign. Flanking both sides of the EndoBarrier sign were dual downward triangles – one orange and one purple – next to the words “weight loss” and “diabetes control.” GI Dynamics’ signage also had a faceless, computer-generated obese patient whose intestinal tract showed through a transparent body (a similar approach to that used by Vivus at recent US conferences). To educate attendees about the company’s gastrointestinal liner, representatives were standing by two tables to demonstrate the EndoBarrier insertion procedure on iPads. After we watched the informative video, we learned that in Germany, a national nutrition group is working to develop guidelines on what foods are well tolerated after EndoBarrier implantation. When we asked the representative what happens if the device does not settle correctly in its position just below the stomach, he responded that it is nearly impossible to misplace it due to the design of the released tubing. Outside of the exhibit hall, we also heard results from a 12-month study of the device in a technology-focused oral session. After 12 months of wearing the EndoBarrier (n=45), A1c declined by 1% (baseline: 8.5%) and mean total body weight loss was 10% (-26 lbs from a baseline of 245 lbs). Some questions and skepticism arose on the safety side, as there were a total of 13 device removals, nearly one-third of all patients in the study. Questions aside, we noted that the exhibit was swamped with curious visitors after the presentation, a reminder of the sincere interest in novel therapeutic approaches that improve diabetes control and weight.
- Insuline: Approaching Insuline’s booth, we were immediately drawn in to a marketing video promoting the InsuPad, the company’s wearable heated pad for MDI users. Clips featured HCPs and patients extolling the benefits of faster insulin absorption: 45% less hypoglycemia and 28% less prandial insulin (results from the just-reported 145-patient Barmer reimbursement study in Germany; see Dr. Andreas Pfützner’s presentation elsewhere in this report). As a reminder, the InsuPad includes a disposable adhesive pad (replaced every day) and a rechargeable heating unit. The whole on-body portion is quite slim and a bit smaller than the second-generation OmniPod. We appreciated a full demonstration of the device, which struck us as quite user friendly and unobtrusive. Patients apply the disposable pad once per day, which has a plastic hinged door that holds the heating unit. When it’s time to inject insulin, patients open the door and inject their insulin into exposed skin through an oval-shaped opening. Upon closing the door, the heating unit warms the area to 40 degrees Celsius (104 degrees Fahrenheit) for 50 minutes. Though the temperature sounded quite hot to us, the device only felt warm to the touch. The heating unit needs to be recharged every 24 hours (based on four injections per day). Notably, the InsuPad will be launching in October in Germany with full reimbursement (i.e., no out of pocket costs for patients). For other countries, Insuline will have an online store –starter kit will cost 98 euros and include two heating units and five disposable pads. A 30-day supply of disposable pads will cost 49 euros (a nice recurring revenue stream!). Patients will be able to buy the device online only after obtaining a prescription – according to the rep, this includes the US, though we were somewhat skeptical this will be possible. We look forward to hearing real-world experiences with the device, as the market need for faster-acting insulin is so great.
- Janssen’s booth occupied about one third of the overall J&J exhibit. Although the CHMP gave a recent positive opinion on J&J’s SGLT-2 inhibitor, Invokana, the company still does not have actual approval. Upon entering the booth, visitors were greeted with a cross section of the renal system that surrounded an introductory video to the role of the kidney in type 2 diabetes management. The exhibit was mostly “self-serve” with regards to information: visitors could stand at one of several computer stations to sign up to receive more information on Invokana online, or visitors could walk themselves through interactive touch-screens with a few slides on SGLT-2 inhibition and the benefits of reversing glucotoxicity. We imagine J&J is excited to be bringing a product like Invokana to market – in the EU, reimbursement is a giant and everpresent challenge but the potential to help patients easily is great, especially with a drug with a unique mechanism of action.
- J&J Animas: At the end of sprawling LifeScan booth, there was a large picture of the Animas Vibe that highlighted its bolus options, bolus calculator, shortcuts, fine-tuned control, high-contrast screen, uninterrupted insulin delivery, waterproof nature, and accurate carb counter. One counter highlighted the Animas Vibe purely as a pump, and a second showed the device used in conjunction with the Dexcom G4 Platinum CGM. As a reminder, this combination was just approved in Canada at the beginning of September. As of the last update in Dexcom 2Q13, Animas had just received a round of written questions from the FDA regarding approval of the pump. We have not heard of an updated timeline but are excited for prospects in the US – we imagine Animas is as well so it can get a pump with sensing on the market, particularly since it seems like integrated pump / CGM products will get the best reimbursement.
- J&J LifeScan: The J&J Animas/LifeScan booth had sleek white walls with dark blue accents, including lights radiating out from behind each display case. All of LifeScan’s OneTouch products were displayed alongside each other and the slogan, “A World Without Limits for People with Diabetes.” This has been in LifeScan’s marketing for years and is such a compelling message for patients. The products in the booth included the OneTouch Delica lancing device and several meters: OneTouch SelectSimple (a buttonless meter targeted towards emerging markets), OneTouch Verio Pro+ (a hospital meter), OneTouch Verio IQ (pattern recognition, and the new OneTouch Verio. Representatives were pleased to welcome back the Verio IQ after it was removed from the market earlier this spring (see our report at http://www.closeconcerns.com/knowledgebase/r/fe264e79). The new OneTouch Verio meter was a focus of the booth’s marketing – signage emphasized the meter’s large high-resolution color screen, which gives lots of information without needing push any buttons: 1) the blood glucose level in large font; 2) a color-coded indicator circle for low, in-range, and high blood glucose results; and 3) automatic messages (e.g., “Your average over the last 7 days is 6.2 mmol/l”). We are especially big fans of the color coded results – we think the subtle psychology and context that color gives the numbers could really help patients visualize results and remind them when it is appropriate to intervene. Certainly, patients on the Dexcom G4 Platinum CGM have widely cited the color receiver screen as a big benefit of the product (read our test drive at http://diatribe.org/issues/48/test-drive). We also like the messages feature, which LifeScan has dubbed “Progress Notes” – very motivational! There were no reps on hand when we walked through the booth, though the LifeScan UK website suggests in can only be pre-ordered right now.
- Lexicon exhibited for the first time at a major diabetes meeting, which we found very exciting. The booth was simple, with a backdrop of the company’s logo and slogan, “Discovering Breakthrough Treatments for Human Disease.” Lexicon had copies available of the three posters it is presenting at EASD – two of them concerning positive phase 2b results on blood pressure, body weight, or triglycerides findings from the phase 2b study of LX4211 (the company’s SGLT-1/SGLT-2 dual-inhibitor), and the third concerned preclinical data on the blood glucose-lowering effects of an SGLT-1 inhibitor (LX2761) in mice. Visitors could also take printouts with educational information on SGLT-1 and SGLT-2 inhibition as well as a list of the company’s peer-reviewed publications on LX4211.
- Lilly: Similar to previous conferences, Lilly’s exhibit was modeled after a home, with a different product or theme featured in each room of the house. Humalog was prominently featured in the “kitchen,” where Humalog pens were displayed under glass casing. The dining room contained examples of Lilly’s new Savvio Humalog pen, which is smaller than its predecessor (the Savvio is not yet available in the US). iPad displays in the “children’s playroom” featured Lilly’s innovative partnership with Disney to provide resources for children and teens with diabetes. The DPP-4 inhibitor Tradjenta (linagliptin) occupied a small corner of the booth, but when we asked about the drug, we were referred over to Boehringer Ingelheim’s nearby booth, which had more information on the drug. A separate room featured the Diabetes Conversations toolkit, which was sponsored by Lilly and developed by Healthy Interactions in collaboration with IDF. The booth displayed examples of diabetes “conversation maps” that providers could use with patients of all ages to facilitate productive discussions on diabetes management. The maps were quite bright and full of information — we were impressed and assume that while they may present somewhat of an information overload for some patients, for others who are more “information seekers”. On a positive note for attendees, Lilly also sponsored a fairly large internet terminal adjacent to its booth.
- Medtronic: Walking up to the Medtronic booth, it was impossible to miss the plasma screens and signage exclaiming, “Proven stellar results – only with the MiniMed Veo system.” Prominent statistics boldly summarized the results of the ASPIRE in-home study of the Veo published in NEJM at ADA 2013: 38% less hypoglycemia exposure, 30% fewer hypoglycemia events, 0 severe events. For complete coverage of this trial, see page 90 at http://www.closeconcerns.com/knowledgebase/r/94f937d8. Walking in to the booth, we were excited to see Medtronic’s newest remote monitoring product, Connected Care, on display. This portable, hockey-puck-sized hub has a cellular chip in it that sends pump and CGM data directly to CareLink and a mobile app. As we understand it, the portable device’s battery is rechargeable and the hub would not have to be plugged into a wall (i.e., it could be carried in a backpack and pump/CGM data would be wirelessly sent to CareLink). At ATTD 2013, it was only advertised on a video screen, so it was great to see it on the demonstration table for the first time. We arrived to the booth for the 10:30 am demo, but it was not working at the time. The rep told us there is no launch date as of yet, as the product is still in the prototype phase (the goal is to make it smaller). We think parents will love it. For some, it also may have an advantage over Dexcom Share, since Share will need to be plugged into the wall (though Dexcom’s Gen 5 will send data straight from the transmitter to the smartphone). The last major update in the Medtronic booth came on the Enhanced Enlite sensor (called “Enlite 2” on Medtronic’s F4Q13 earnings call) – the product received CE Mark within the last three weeks. It has two main innovations: an 80% reduction in implanted volume size over the Enlite and improved sensor-transmitter communication. The rep could not tell us if the size reduction translates into better accuracy, as that “has not been tested yet.” Similar to the Enlite, Enlite Enhanced will still be six-day wear. Attendees seeking some competition could answer multiple-choice questions about Medtronic products, diabetes, or general knowledge questions – these were pretty hard! Results were displayed prominently on a large electronic leaderboard next to the popular European coffee station.
- Mendor: The Mendor display case was set against a sleek, black wall with a can’t-miss TV screen – a video played a loop of a young adult using the all-in-one Mendor Discreet meter, which contains an integrated blood glucose meter, lancing device, and test strip cartridge (a bit like the Accu-Chek Mobile). The representative demonstrated how to use the device, which is approximately the size of an iPhone and as thick as a deck of cards. Between the sleek booth and the looping video, Mendor made a clear pitch for its target audience: young adults who desire a meter that is discreet to use. A representative also showed us Mendor’s cloud-based software, Balance, which is compatible with 21 meters. This is great to see, since all too often, meter software is brand-specific (though this is changing with systems like Glooko, Diasend, and hopefully Dexcom’s SweetSpot platform). Before we even had a chance to ask, the representative informed us that Mendor would not be filing with the FDA soon, primarily because of the long regulatory process. Exiting the booth, we also noticed that A. Menarini, Mendor’s new partner, had an enormous ping-pong-table-sized model of Discreet meter (marketed as GlucoMen READY). While there was not much other information besides a pamphlet, it was nice to see the collaboration.
- Merck Sharp & Dohme: Located toward the center of the exhibit hall, the MSD booth had a stronger emphasis on Januvia’s (sitagliptin) cardiovascular profile than the Merck booths at ADA and AADE, or the MSD booth at EASD 2012. Two of the most prominent displays detailed TECOS, Merck’s CVOT of sitagliptin and results from a pooled analysis showing that Januvia did not increase the incidence of major adverse cardiovascular events (MACE). When we asked a MSD representative about what MSD is concluding from SAVOR-TIMI 53, BMS/AZ’s CVOT for Onglyza (saxagliptin), he highlighted that the trial showed that saxagliptin has “no benefit; no risk. It is like taking a placebo – a lollypop.” In contrast, he noted, early findings with sitagliptin “suggest it might have a benefit” and MSD is looking forward to seeing TECOS’ results in 2014. In terms of glycemia, he remarked, MSD’s competitors have conducted head-to-head trials of their agents versus sitagliptin, and have opted not to publish the data, since it is not in their favor. We believe this increased focus on CV safety is in line with a broader trend at EASD 2013, where CVOTs and CV profiles are one of the hottest topics.
- Nipro Europe: Nipro Europe occupied a medium-sized booth where we were able to learn about the company’s meters, including two that are not available in the US. Nipro’s traditional, full-featured meter is its TRUEresult, which has seven, 14, and 30-day averaging capabilities as well as testing reminder capabilities. The TRUEresult mini, which is not available in the US, has many of the TRUEresult’s capabilities but at a much smaller size – it looks more like a snazzy USB drive than a blood glucose meter. The exhibit also featured the TRUEresult twist (known as the TRUE2go in the US), and the TRUEresult twist 2. These are tiny, pocket-sized meters, strip containers, and lancing devices all in one. They come in three colors and are most popular with children. The TRUEresult twist 2 is an upgraded version of the TRUEresult twist, and is not available in the US. The TRUEresult twist 2 has increased memory capacity as well as averaging capabilities.
- Novartis: The Novartis booth had a large, lit-up billboard that highlighted the theme of the booth: “Diabetes and Me.” Signs around the booth promoted the company’s DPP-4 inhibitor Galvus (vildagliptin) and fixed dose combination with metformin (e.g., “Powerful 1.1% reduction in A1c – efficacy you can see.” The focal point of the booth was an opportunity to meet “interactive patients” at several stands – these used a pair of headphones, an iPad, and a large screen with a virtual patient projected onto it. Booth-goers used the iPad to select different patients, ask them predefined questions, and hear their recorded answers. Patient 1 explained that even on metformin, her blood glucose levels remained uncontrolled. Patient 3, on the other hand, had impaired kidney function and fear of hypoglycemia. We thought it was a very cool way for attendees to interact with a broad spectrum of realistic patient case studies. The conversational experience was clearly targeted at HCPs, though we noticed that it did not overtly promote Novartis’ products. Our only criticism of the experience came after learning from a rep that the “interactive patients” were actually actors reading scripts. In the future, we hope to see companies increasingly use real patients with diabetes in their marketing – we think doing so is more persuasive, shows that a company is patient focused, and reflects authentic marketing. Upon exiting the booth, signs for Lucentis, Novartis’ diabetic macular edema drug, proclaimed, “See your success in the eyes of your patients."
- Novo Nordisk’s exhibit was devoted entirely to Tresiba (insulin degludec) today – we hear that the exhibit will rotate themes each day such that, for example, that on day #4 it will be dedicated to Victoza, etc. Uncharacteristically, the long, rectangular booth was tucked away towards the back of the hall, but we could spot the neon green shirts of the sales representatives from a mile away. Apparently others could too because the exhibit was swarming with people while we visited. The sleek green and white booth’s centerpiece was a giant, forest-green parachute anchored to heavy block letters reading “7.0%,” suggesting Tresiba provided a smooth ride down to goal. Visitors could either learn about Tresiba’s benefits at individual stations staffed with sales representatives and FlexTouch demo pens, or a 27-screen panel at the front of the booth. After filling out a worksheet asking questions such as “What are the three key benefits of Tresiba?” (correct answers: A1c reduction, reduction of nocturnal hypoglycemia, and flexible dosing), visitors earned a notebook to take home. A food station at the center served coffee and lunch wraps. Finally, at the back of the booth, visitors could meet members of Team Novo Nordisk, the cycling team made entirely of members with type 1 diabetes. Text on the exhibit walls politely reminded attendees in Spanish that Tresiba was not yet approved in Spain. Novo Nordisk had a second satellite booth devoted to the results of the DAWN2 study, which confirmed that physical, financial, and emotional burdens associated with diabetes are carried by patients’ entire families. We were glad to see so much focus on the behavioral elements of diabetes.
- Roche: The Roche booth, prominently located upon entering the hall from registration, had a square in the middle surrounded by three circular areas. Each circle represented a different aspect of care: therapy optimization, patient engagement, and efficiency. Within each were two computers with representatives standing nearby to demonstrate how various Roche meters fit under each category. Under the ‘therapy optimization’ heading, reps showed attendees how the Roche data downloading works. In the ‘patient engagement’ circle, we saw how easy the FastClix lancing device is to use. The rep demonstrated it along with the Accu-Chek Compact Plus, noting how the integrated system reduces the burden on the patient to carry separate supplies around. Turning toward the center of the booth, one side of the square had a television screen rotating between advertisements of meters and key meter features, such as a better bolus calculator. A second side of the square touted that all Roche meters meet the new ISO standards – and even stricter standards. Strategically, Roche prominently flashed this on the side of the booth facing the interior of the Exhibit Hall. With all of the discussion of BGM post-marketing surveillance and strip accuracy (in both the US and Europe), we think this was a smart move on Roche’s part. The third wall showed a flow circle of “personalized diabetes management,” moving from “structured education” to “treatment efficiency assessment” to “personalized treatment” to “analysis” to “data documentation and visualization” to “structured blood glucose monitoring” and back to the start. The last side of the wall housed one of the many coffee stands in the exhibit hall and a seating area, ready to give weary visitors a rest.
- Sanofi: The company’s large booth enjoyed front-and-center placement, adjacent to the entrance most attendees used to enter the exhibit hall, and was abuzz with activity. As opposed to Sanofi booths we have seen at recent US conferences, which have been more low-key, its EASD booth was packed with displays — a testament to the number of new products Sanofi was showcasing. The front half of the booth was dominated by exhibits for Lyxumia (lixisenatide), the company’s new once-daily GLP-1 agonist. Rather than standing alone, the Lyxumia portion of the booth was interspersed with information on Sanofi’s bestselling basal insulin Lantus (insulin glargine). A series of displays titled “A Positive Addition” noted that Lantus primarily affects fasting glucose, Lyxumia primarily effects postprandial glucose, and therefore the two used in tandem can provide an effective and comprehensive way to lower patients’ A1cs — this text was accompanied by an image of a Lantus pen and Lyxumia pen overlaid at right angles, forming a plus-sign. Perhaps because of the space required for the new Lyxumia display, Sanofi’s rapid-acting insulin analog Apidra barely had any presence in the booth — after some searching, we managed to find one single display for the insulin off to one side. A great deal of space was dedicated to the company’s new JuniorStar insulin pen, designed for younger diabetes patients (the JuniorStar is currently not available in the US). A series of large displays highlighted the device’s design features, including the fact that it is lightweight yet robust, can administer half units of insulin, is easy to read, requires less pressure for injection, and can easily be dialed down. The pen was part of a featured campaign to “Lighten Lives” of type 1 diabetes patients. The MyStarExtra meter (made by AgaMatrix) was on display for the first time this year — the meter provides patients with a three-day fasting glucose average, a trend arrow, and even an A1c estimate! Sales representatives noted that the product is launching in Spain and Italy this year, with more countries to follow in 2014. This was one of the new products we were most excited to see. There will also be updates of meters coming for the newest iPhones, as we understand it, and there will be an Android system as well.
- Takeda: Takeda’s booth focused on its trifecta of DPP-4 inhibitor-based therapies: Vipidia (alogliptin), Vipdomet (alogliptin/metformin), and Incresync (alogliptin/pioglitazone). The booth carried a bike theme throughout, with ample pictures of bicycle parts and themed slogans (e.g., “In type 2 diabetes every component matters”). The booth’s central counter featured a coffee bar and iPads with a presentation on alogliptin. A sign on the side of booth proudly proclaimed the recently published alogliptin CVOT results (EXAMINE): “Vipidia is the first and only DPP-4 inhibitor to demonstrate proven CV safety in type 2 patients with recent acute coronary syndrome in a clinical trial” (White et al., NEJM 2013; see our complete coverage of EXAMINE at http://www.closeconcerns.com/knowledgebase/r/2a8925c5). A different side of the exhibit contained handouts on studies of pioglitazone: a meta-analysis to assess cardiovascular risk (Lincoff et al., JAMA 2007) and secondary prevention of macrovascular events (PROactive; Dormandy et al., Lancet 2005).
- VPD: As we passed by this small booth, we couldn’t help but notice the glossy posters advertising the 2in1 Smart BGM that plugs into the headphone jack of an Apple iPhone/iPad/iPod and Samsung Galaxy SIII. Unlike Sanofi’s iBGStar meter, the 2-in-1 meter does not function as a standalone device – to test blood glucose, it must be plugged into the headphone jack with the app open. The product has a CE Mark and is currently available in 12 countries in Europe (the rep specifically mentioned Norway, Sweden, Denmark, Slovenia, Slovakia, and Austria). Distribution varies in each country, and the rep assured us that the device has reimbursement. A sign advertised the “special exhibition price” of 45 euros for the small thumbnail-sized meter and 100 test strips. In the US, the meter will be marketed under the brand “Gmate Smart.” We asked the rep about FDA approval, and he told us that it was submitted to the agency, though “lots of questions” came back (we presume because it doesn’t function as a standalone meter like the iBGStar). The rep lamented that very innovative products are challenging, as they fall outside the rules (“It’s like Steve Jobs,” he said). We previously wrote about this product in Closer Look on August 20, 2012. At the time, the South Korea-based company, Philosys, expected FDA approval of the Gmate Smart in 3Q12. Obviously, that has not panned out. We will certainly look for any news on the device, though are not optimistic approval is coming anytime soon. Still, we think the product is an encouraging and valuable idea – the meter is very tiny, the data upload is very easy, and patients nearly always carry their smartphones with them.
- YOFiMeter: Tucked in a small booth in the middle of the exhibit hall the YOFiMeter booth drew us in with the tagline, “First cellular all-in-one BGM” next to a Qualcomm partnership logo. In short, this seems to be the ultimate all-in-one meter – a single handheld contains a 20-strip cassette (Infopia strips), a lancing cassette, a color touchscreen, a cellular chip that automatically sends data to the cloud, and a built-in pedometer. All the rep would tell us was that it would be on the market “next September.” It was unclear if this was EU, US, or both, though we’d assume EU to start. After watching a short video of various patients using the device (e.g., an elderly person, a teen skateboarding), we got a demo of the meter. It works as follows: 1) slide a plastic bar forward on the side of the meter to expose a test strip; 2) press finger against lancing port hole on the side of the device; 3) press lit up button to lance finger; 4) apply blood to strip; and 5) get result (it took about seven seconds by our count). The meter prominently displayed the result on the color touchscreen, offered extensive tagging capabilities (exercise, carbs, insulin, other medications, even leaving a voice note!), and automatically sent the blood glucose result to the cloud (we didn’t see any demonstration of the system’s backend or a web portal). Similar to Telcare’s meter, a test is followed by a feedback message (we got a green thumbs up) and a time in range chart. All of it seems customizable as well (e.g., you can choose the picture that is displayed after a test). We found the system quite easy to use, especially the highly responsive touchscreen. We look forward to learning much more about the device, especially where and when it will launch. Intuity has been developing the all-in-one POGO device for quite a while (without the cellular chip or color touchscreen), though we understand it’s been difficult to get through the FDA. YOFi’s website (http://www.yofimeter.com) is just a single page right now with a company logo, two slogans (“Diabetic living made easier” and “Dawn of a new era in BGM technology”), and a contact email address: info@Yofimeter.com.
- Ypsomed: The sprawling bright green Ypsomed booth had a corner devoted to each of the company’s areas of focus: ClickFine pen needles (new 4 mm x 32 gauge), the Insulet OmniPod, infusion sets, and the Unio blood glucose meter. We immediately talked to a rep about the new second-gen OmniPod, a major focus of the booth’s marketing. Notably, we learned that ~10,000 patients in Europe are on the OmniPod (as of Insulet’s 4Q12 call in February, the company had 45,000 patients on the OmniPod, up 50% from 30,000 at the end of 2012). We asked the rep where the OmniPod is not currently available in Europe – it sounds like France, Italy, and Spain though we are working to verify this. The rep emphasized that France is particularly challenging on the reimbursement front. We appreciated another demo of the Unio blood glucose meter system, which has a compactly designed, integrated case that conveniently positions the meter, strips, and lancet device for fast testing. Attendees looking for freebies could take their turn at a Play+Win slot machine-type game, while hungry booth-goers could grab green apples, chocolates, and pretzels.
-- by Adam Brown, Poonam Daryani, Hannah Deming, Jessica Dong, Hannah Martin, Manu Venkat, Vincent Wu, and Kelly Close