September 15-19, 2014; Vienna, Austria; Day #1; Highlights – Draft

Executive Highlights

Greetings from the first official day of EASD 2014, which was jam P-A-C-K-E-D with 17 corporate-sponsored symposia. Today’s drug symposia had a major emphasis on GLP-1 agonists, with a smattering of talks on SGLT-2 inhibitors and insulin and diabetes technology. The big highlight on the technology side was the debut of Abbott’s FreeStyle Libre. Below, we enclose our top 10 highlights and honorable mentions, followed by detailed discussion and commentary from select talks and sessions.

1. The highly anticipated Abbott symposium debuted the FreeStyle Libre Flash Glucose Monitoring system, including pricing (59.90 euros for the touchscreen reader and 59.90 euros for each 14-day sensor) and accuracy details (MARD: 11.4%).
2. We covered four (!) full presentations dedicated to cardiovascular outcomes trials for diabetes drugs that covered a range of perspectives, including what to expect from future CVOTs and a hypothesis on the heart failure signal seen with AZ’s Onglyza (saxagliptin) in SAVOR. Lots here – thank you, Dr. Gough.
3. Dr. Bruce Buckingham (Stanford University, Stanford, CA) shared the first-ever data we’ve seen (unpublished) on Medtronic’s Enlite 3 sensor; overall MARD vs. YSI was an impressive 10.8% in a small eight-patient study.
4. Dr. Lutz Heinemann (Science & Co., Düsseldorf, Germany) addressed the need for smart diabetes management solutions that will lessen our medical burden at reduced costs.
5. Lilly’s symposium on GLP-1 agonist therapy opened with a very positive overview of the class and specifically of Lilly’s Trulicity (dulaglutide; currently under review) due to the agent’s uniqueness as a ready-to-use once-weekly formulation. We’re more optimistic about dulaglutide than we’ve ever been before and see growth for once weekly from more than Lilly.
6. We heard a number of talks focusing on the merits of GLP-1 agonists vs. basal insulin, a relatively new comparison to discuss, given that GLP-1 agonists have generally been known for their effects on postprandial glucose (especially AZ’s Byetta and Bydureon).
7. Dr. Melanie Davies (University of Leicester, Leicester, United Kingdom) presented at a dedicated Lilly/BI mini-session on the hot topic of biosimilar insulins, concluding that despite several obstacles, biosimilars will ultimately be very beneficial for patients. The world’s regulatory agencies have certainly spoken …
8. Later in GSK’s symposium, the highly regarded Professor Philip Home (Newcastle University, Newcastle Upon Tyne, United Kingdom) and the panel provided rapid-fire perspectives on the potential connection between GLP-1 agonists and pancreatitis/pancreatic cancer.
9. Recent Banting Award winner the great Dr. Daniel Drucker (Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada) addressed the contribution of glucagon to the pathophysiology of type 2 diabetes.
10. Dr. Bernard Zinman (Mount Sinai Hospital, Toronto, Ontario, Canada) called for a new paradigm for the treatment of type 2 diabetes involving aggressive combination therapy used early in disease progression. We were thrilled to hear this ~

Top 10 Highlights

1. The highly anticipated Abbott symposium on the FreeStyle Libre Flash Glucose Monitoring system did not disappoint a standing-room-only audience. Mr. Jared Watkin debuted the system (see pictures here), which received a CE Mark on September 3. We learned brand new details on the system’s accuracy from the CE Mark pivotal study, as well as pricing. Most notably, FreeStyle Libre will be priced reasonably, at just 59.90 euros for the touchscreen reader and 59.90 euros for each 14-day sensor. Payment will be out-of-pocket to start, though Abbott is currently recruiting for two six-month long reimbursement studies n=200+) to support European reimbursement (REPLACE in type 2, IMPACT in type 1). Notably, patients will NOT need a prescription to purchase the device at online web shops in Europe, which are expected to open over the next 30 days in France, Germany, Italy, the Netherlands, Spain, Sweden and the UK. The US pivotal trial will begin by the end of 2014. On the accuracy front, brand new data was shared from the 75-patient, 14-day pivotal CE Mark trial, where the factory calibrated FreeStyle Libre system demonstrated an impressive overall MARD of 11.4% vs. FreeStyle Precision BGM (consistent with previous feasibility studies). A quick-as-lightning on-stage demo of FreeStyle Libre wowed the audience with its simplicity and form factor (whoever planned the demo was brilliant – it took about five seconds, which itself was a major part of the brilliance), and we share much more below after an up-close look at the device and a stimulating concluding panel discussion. This symposium included a particularly valuable talk from Dr. Irl Hirsch, who shared optimism regarding the product’s potential in type 2 diabetes.

2. We covered four (!) full presentations dedicated to cardiovascular outcomes trials for diabetes drugs that covered a range of perspectives, including what to expect from future CVOTs and a hypothesis on the heart failure signal seen with AZ’s Onglyza (saxagliptin) in SAVOR. The highlight, in our view, was the call from Dr. Stephen Gough (University of Oxford, Oxford, UK) during AstraZeneca’s morning symposium for more realistic expectations for CVOT results, taking into account that the trials have been designed to prove safety rather than test for cardioprotection. He put forth the analogy that the “window” for cardioprotection closes with longer diabetes duration, and that the most effective way to intervene (and to test for cardioprotection) is soon after diagnosis, in patients with minimal established cardiovascular disease. Other highlights from presentations on CVOTs include:

• Dr. Hertzel Gerstein (McMaster University, Hamilton, Ontario, Canada) stated during Sanofi’s morning symposium that we are “blessed” to have over 130,000 patients enrolled in outcomes trials for diabetes drugs. He warned against being “seduced” by big data, arguing that some safety signals can only be uncovered through randomized control trials. We agree with this although we believe some trials should continue longer than others.
• Local Dr. Alexandra Kautzky-Willer (Medical University of Vienna, Vienna, Austria) provided a matter-of-fact overview of ongoing diabetes drug CVOTs during Lilly/BI’s afternoon session. She focused on the unique elements of EMPA-REG OUTCOME for Jardiance (empagliflozin), which is expected to be the first SGLT-2 CVOT to report and has “the potential to show cardioprotection,” as well as CAROLINA (which has an active comparator, glimepiride) for Tradjenta (linagliptin).
• Heart failure expert Dr. Robert Gilbert (University of Toronto, Ontario, Canada) provided a hypothesis on the heart failure signal seen in SAVOR during a Merck-sponsored symposium. He theorized that glucose lowering may have strained the heart’s energy supply – we felt that the modest difference in A1c (0.3%) between groups in the trial may undermine that argument slightly, but would hope to see the possibility investigated given the lack of plausible explanations for the signal up until now.

3. Dr. Bruce Buckingham (Stanford University, Stanford, CA) unexpectedly shared the first-ever data we’ve seen (unpublished) on Medtronic’s Enlite 3 sensor (part of camp studies with the MiniMed 670G hybrid closed-loop system). Overall MARD vs. YSI was an impressive 10.8% in a small eight-patient study (n=383 paired CGM-YSI points). In the more challenging camp setting, Enlite 3 still demonstrated a very solid MARD of 12.5% vs. Contour Next fingersticks (seven patients, n=529 paired points). This represents a marked improvement over the original Medtronic Enlite, which demonstrated an MARD of 14.1% in the clinic and 19% in camp studies (according to Dr. Buckingham’s slides). For context, he noted that the MARD of the Dexcom G4 Platinum was 10.4% in inpatient studies and 16.7% in the Bionic Pancreas camp study, putting Enlite 3 on more comparable footing (of course, these were not head-to-head studies, so it’s hard to say definitively how they compare). Dr. Buckingham underscored two points in this section of his broader presentation on technology: (i) dirty hands in the camp setting have a significant impact on CGM accuracy; and (ii) the Enlite 3 as part of the MiniMed 670G appears to be “significantly better” than its predecessor. As a reminder, Medtronic’s 2014 Analyst Day highlighted that the Enlite 3 CGM will have “intelligent diagnostics” and “improved accuracy & comfort” – the former could be responsible for the strong accuracy in the camp setting, where inaccurate calibrations are more common. In the past, Medtronic’s public presentations on CGM innovations have emphasized the potential for future systems to have smart algorithms that reject inaccurate fingerstick calibrations. Medtronic’s Enlite 3 sensor is part of a US study of the MiniMed 640G, which is expected to start this month.

4. Dr. Lutz Heinemann (Science & Co., Düsseldorf, Germany) addressed the need for smart diabetes management solutions that will lessen our medical burden at reduced costs. Noting that patients are not interested in data – “they want to forget about diabetes and live a normal life” – he noted that advances in telemedicine, mobile apps, and data management platforms can provide interim solutions that provide good glycemic control at affordable costs until more durable solutions are available (“artificial pancreas systems are close to a reality”). In fact, an informal poll of the audience (~300 attendees) revealed that ~99% carried a smartphone – this penetration was not particularly surprising in itself, though as Dr. Heinemann emphasized, the numbers belie the potential of the platform. He noted that the regulation of the app market has the potential to turn this low-cost tool into an effective data management solution. Dr. Heinemann cited cost-savings as the major driver of telemedicine as well, though the discussion of the technology brought up as many questions as solutions: How safe is the platform? How reliable is the advice provided? How will patient-physician interactions change? Ultimately, Dr. Heinemann called for more evidence, namely randomized control trials of long duration and large sample size, that will convince payers of the clear-cut benefit of telemedicine solutions; Dr. Heinemann noted that Roche has two such multicenter studies ongoing that are evaluating the company’s integrated Personalized Diabetes Management software among type 2 patients requiring insulin (A1c > 7,5%) in diabetes specialist (n=540) and general practice (n=474) clinics in Germany.

5. Lilly’s corporate symposium opened with a thorough overview of the GLP-1 agonist class and especially Lilly’s Trulicity (dulaglutide; currently under review) by Professor Anthony Barnett (Heart of England NHS Foundation Trust and University of Birmingham, Birmingham, United Kingdom). Professor Barnett urged providers to “think about the value of the drug, not just the cost of the drug” when making prescribing decisions. He also expressed excitement about the idea of GLP-1 agonist/SGLT-2 inhibitor combinations as a potential future therapy – we have heard this combination discussed more and more at recent meetings, given that GLP-1 agonists can blunt the counterregulatory glucagon response seen with SGLT-2 inhibitors. To close out the symposium, Dr. Juris Meier (St. Josef Hospital, Bochum, Germany) provided an optimistic perspective on the GLP-1 agonist class’ future potential, highlighting type 1 diabetes and obesity as near-term goals and suggesting that neuroprotection could be a longer-term scientific frontier. As we understand it, Lilly should be unveiling the unique “single-use pen” auto-injector imminently – the device looks to be remarkably patient-friendly, and potentially stands to give Trulicity a leg up in the important primary care market – it has jumped eons from the first version of Bydureon, in our view, and we think the composite will help the class to grow further. Lilly believes that Trulicity can really change the conversation, so to speak, when providers and patients have to begin injectable therapy and we agree – at minimum, HCPs will have a much shorter time in training patients.

6. We heard a number of talks focusing on the merits of GLP-1 agonists vs. basal insulin – To date, this is not a comparison we are used to hearing much about, given that GLP-1 agonists have generally been known for their effects on postprandial glucose although there certainly is more and more discussion about what is a substitute and what is a complement. To date, it seems accepted that longer-acting agents such as AZ’s Bydureon (exenatide), GSK’s Tanzeum/Eperzan (albiglutide), and Lilly’s Trulicity (dulaglutide) have more balanced effects on fasting and postprandial glucose, meaning that they can be seen as a viable alternative to basal insulin. In a GLP-1 agonist vs. basal insulin debate at GSK’s symposium, Dr. Philip Home (Newcastle University, Newcastle Upon Tyne, UK) took the side of GLP-1 agonists against Dr. Hans Devries (University of Amsterdam, Amsterdam, the Netherlands), highlighting the fact that GLP-1 agonists offer strong efficacy with a better weight and hypoglycemia profile. During a mini-debate on using GLP-1 agonists as an alternative or add-on to insulin during Lilly’s morning symposium, Dr. Francesco Giorgino (University of Bari Aldo Moro, Bari, Italy) cited data he presented at ADA from AWARD-2 to make a similar point. The versatility of the GLP-1 agonist class is nearly unmatched among diabetes drug classes (insulin comes to mind), and even given the slight stumble in sales growth we saw for the class in 2Q14, we believe that GLP-1 agonists are very underutilized relative to their potential. In their “next-gen” and combination forms, we expect revenues to be significantly higher for the class.

7. Dr. Melanie Davies (University of Leicester, Leicester, United Kingdom) spoke on the hot topic of biosimilar insulins at a Lilly/BI-sponsored session – the two companies’ insulin glargine formulation very recently became the first biosimilar insulin approved in Europe (read our report). Dr. Davies acknowledged that biosimilar insulin is a new and potentially very daunting topic for clinicians. She reviewed the obstacles posed by the complex manufacturing process and uncertain regulatory requirements for biosimilars, using Lilly/BI’s data package for its biosimilar insulin glargine as a case study to demonstrate the level of evidence required to assure regulatory authorities that a biosimilar insulin is clinically similar to the reference product. Dr. Davies also cautioned that although the introduction of biosimilars should lead to some cost reductions, the savings will likely be lower than anticipated and certainly not as dramatic as the discounts seen with generic small molecule drugs. Despite these challenges, Dr. Davies believes that biosimilar insulins will ultimately be very beneficial for patients, as they will help address the “genuine need” to increase access to a wider range of treatment options.

• Later in the day, at a Sanofi event, Dr. Thomas Danne (Diabetes Center for Children and Adolescents, Hannover, Germany) echoed many of Dr. Davies’ remarks. He noted that a wave of biosimilar insulins is imminent and stressed the need for adequate evaluation of the compounds’ safety due to the complexity of the manufacturing process.

8. Later in GSK’s symposium, Professor Philip Home (Newcastle University, Newcastle Upon Tyne, United Kingdom) and the panel provided rapid-fire perspectives on the potential connection between GLP-1 agonists and pancreatitis/pancreatic cancer – the general agreement was that a link to pancreatic cancer is unlikely, but that a slight increase in pancreatitis is possible and plausible, though it should not dissuade providers from continuing to use the class. Dr. Clifford Bailey (Aston University, Birmingham, UK) pointed to evidence from the Dr. Dan Drucker’s (Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada) group that GLP-1 is not expressed on exocrine ductal cells, suggesting that there should not be a direct effect. However, incretin expert Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany) shared that he and Dr. Juris Meier (from his study group) recently analyzed phase 3 data on GLP-1 agonists and saw a pattern that suggested the possibility of a slight increase, though not the tenfold elevation that some have suggested. Dr. Jane Reusch (University of Colorado, Denver, CO) eloquently stated that the pancreatitis risk cannot be dismissed, but can be managed through vigilance on the part of patients and providers.

9. Dr. Daniel Drucker (Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada) addressed the somewhat overlooked contribution of glucagon to the pathophysiology of type 2 diabetes to date. He explained that despite the availability of drug classes like GLP-1 agonists and DPP-4 inhibitors that suppress elevated glucagon levels in type 2 diabetes, the field still lacks a comprehensive understanding of the mechanisms underlying glucagon dysregulation. Although it is possible to produce impressive A1c reductions even when glucagon production actually increases, as is the case following bariatric surgery or treatment with SGLT-2 inhibitors, Dr. Drucker emphasized that clinicians should give preference to agents that counteract the abnormally high glucagon levels in type 2 diabetes. Dr. Drucker’s immense and broad expertise on the pathophysiology of type 2 diabetes made him a highlight of AstraZeneca’s morning symposium – read our coverage of Dr. Drucker’s Banting Award acceptance speech at last year’s ADA.

10. Dr. Bernard Zinman (Mount Sinai Hospital, Toronto, Canada) called for greater use of early aggressive combination therapy for type 2 diabetes to replace the current ineffective “treat to failure” approach. He highlighted that fixed dose combinations (FDCs) of metformin and newer drug classes are particularly attractive options that can improve adherence with minimal risk of weight gain and hypoglycemia. The packed audience appeared very receptive to Dr. Zinman’s message: 83% reported that they had already prescribed FDCs to their type 2 diabetes patients. When asked to predict which type 2 diabetes drug combination would be most commonly prescribed ten years from now, 84% selected either a combination of metformin, an SGLT-2 inhibitor, and a DPP-4 inhibitor or of metformin, and SGLT-2 inhibitor, and a GLP-1 agonist.

Honorable Mentions

• Dr. Arya Sharma (University of Alberta, Edmonton, Canada) opened Novo Nordisk’s morning symposium by encouraging his audience to “frame obesity in the context of the global diabetes epidemic,” an interesting twist in the more conventional argument that diabetes is a complication of obesity.
• In AstraZeneca’s well-attended (and slickly produced) morning symposium, an audience poll provided some insight on providers’ most important factors to consider when prescribing a DPP-4 inhibitor vs. another drug class. “Low risk of hypoglycemia” came in first with 39% of the vote, followed by “ease of use” (20%), “efficacy” (12%), and “established side-effect profile” (12%), attesting to how primary-care-friendly the class is. We were surprised that we did not hear weight neutrality – though we believe that for many is reflected in “established side-effect profile”. 
• Dr. Ele Ferrannini (University of Pisa School of Medicine, Pisa, Italy) called for a renewed push to pursue more aggressive glycemic targets, at least for portions of the population.
• On Sunday, Dr. Silvana Romio (Erasmus University Medical Center, Rotterdam, the Netherlands) presented preliminary incomplete results from the SAFEGUARD consortium’s ongoing epidemiological study, suggesting a possible increase in acute pancreatitis on the order of ~150%. The results from the full nine-database pool should be available by next year’s EASD; these results were based on only two of the databases. SAFEGUARD’s final findings on pancreatitis stand to impact the EMA’s overall assessment of the safety of incretin therapies, and so we will be watching closely for those results.

Detailed Discussion and Commentary

Corporate Symposium: Next Frontier in Diabetes Management – Will Flash Glucose Monitoring Deliver Improved Outcomes? (Sponsored by Abbott)

An Introduction to Flash Glucose Monitoring

Jared Watkin (VP, Technical Operations, Abbott Diabetes Care, Alameda, CA)

To a standing-room-only audience, Mr. Jared Watkin debuted Abbott’s FreeStyle Libre system (see pictures here), including never-before-shared details on the system’s accuracy and pricing. On the latter, FreeStyle Libre will be priced reasonably (some would say modestly!), paving the way for uptake in Europe as patients pay out-of-pocket at launch: 59.90 euros for the touchscreen reader and 59.90 euros for each 14-day sensor. We can’t imagine that many would buy them out of pocket over a long period; Abbott is currently recruiting for two six-month long studies to support reimbursement (REPLACE in type 2, IMPACT in type 1). Notably, patients will NOT need a prescription to purchase the device at online web shops in Europe, which are expected to open over the next 30 days in European launch countries. The US pivotal trial will begin by the end of the year. On the accuracy front, brand new data was shared from the 75-patient, 14-day pivotal CE Mark trial, where the factory calibrated FreeStyle Libre system demonstrated an impressive overall MARD of 11.4% vs. FreeStyle Precision BGM – consistent with previous data. An on-stage demo of FreeStyle Libre wowed the audience with its simplicity and form factor, and we share more below after an up-close look at the device and a stimulating concluding panel discussion. Though our expectations were very high coming into this talk, we were sufficiently impressed to see how Abbott is launching this novel glucose monitoring technology – the creation of a new category is unquestionably bold, though also a smart idea given the fraction of patients at goal, the low rates of CGM usage worldwide, and an increasingly constrained reimbursement environment. As a reminder, FreeStyle Libre received a CE Mark two weeks ago on September 3.

• In the 75-patient, 14-day pivotal CE Mark trial, Abbott’s factory calibrated FreeStyle Libre system demonstrated an overall MARD of 11.4% vs. FreeStyle Precision capillary fingersticks (87% of points were in Zone A of the Consensus Error Grid, 13% in Zone B). MARD was lowest on day one (15.7%), improved to 11.9% on day two, and hovered between 10.3% and 11.8% on days 3-14 – this was very impressive sensor stability given the one-hour warm-up, two-week wear, and factory calibration – presumably for a short trial, there likely was not too much hypoglycemia (we estimate it below). The study had 13,195 paired FreeStyle Libre-BGM data points (range: 23-498 mg/dl), though the specific fraction of points in different glucose bins was not provided on the slide; by our estimate, about 3% of values were <70 mg/dl. The MARD was not broken down by glucose range, so accuracy in hypoglycemia is an unanswered question at this stage (and indeed, the product label recommends a confirmatory fingerstick when hypoglycemic). Each patient wore two systems and the study took place at multiple US centers.
  
  • This overall accuracy was highly encouraging, especially for a 14-day factory calibrated sensor. It was also largely in line with data collected from Abbott’s pilot studies of the device, as well as the FreeStyle Navigator’s label. A potential criticism was the use of BGM as the reference device, as most CGM studies have some in-clinic days with YSI. However, this 14-day study was very real world and characterized the device’s accuracy as patients would experience it (i.e., relative to fingersticks).
  • Mr. Watkin compared the FreeStyle Libre’s accuracy to other CGM devices’ labels, noting that Abbott’s new product has “leading edge performance compared to other sensors in the field.” His slide was intended to make two clear points: (i) FreeStyle Libre has demonstrated better accuracy than other CGMs; and (ii) FreeStyle Libre requires dramatically fewer fingerstick calibrations.

*BG reference not available; **Data collected with a minimum of four calibrations per day, although product requires at least two calibrations per day.

• FreeStyle Libre will be priced very favorably at launch – 59.90 euros for the reader and 59.90 euros for each 14-day sensor. This equates to a modest 120 euros per month out-of-pocket, much cheaper than current CGM (e.g., per Dexcom 2Q14, average selling prices were ~$885 for the starter kit and ~$72 per sensor, or $288 per month – though in the EU, we are sure they are lower). The favorable pricing should put the novel technology within reach for some European patients at launch, given that reimbursement may not come for some time (see study information below). We commend Abbott for pricing FreeStyle Libre so favorably – this product has been years in the making, and the company easily could have priced it much higher to reap better margins and recoup R&D investment. The accessible price should help expand the glucose monitoring market, offering more patients and providers access to 24-hour glucose data and real-time trend information. We wonder what each reader and sensor cost to make.
  
  • All EU launch markets will have online web shops open over the next 30 days; notably, to our surprise, FreeStyle Libre will not need a prescription in Europe. Combined with the relatively modest pricing, the approach strikes us as more of a consumer product launch than a medical device – this of course jives with the overall uptake of digital health devices and sensors in general. The ability to order online, along with no need to see an HCP, should facilitate pull demand from patients, rather than pushing demand through the traditional medical device avenues (e.g., detailing to physicians, who recommend then product to patients).
  • There is still no formal US timeline, though it was encouraging to hear that a pivotal study will start before the end of 2014. We imagine the biggest gating factor will be the regulatory path to obtaining a replacement claim to dose insulin. Per Dexcom’s 2Q14 call, dialogue was ongoing with the FDA on that front. We salute companies for going through the red tape on this labeling point, and would point out that patients are already routinely dosing insulin off their CGMs in the real-world. Many investigators have said an MARD ~10% is accurate enough for dosing insulin, which would put FreeStyle Libre (MARD: 11.4%) and Dexcom’s G4AP algorithm (MARD: 9.0%) right in the ballpark.
• Abbott is in the process of conducting two six-month outcomes studies to support reimbursement – REPLACE (n=210 type 2s on MDI, A1c>7.5%) and IMPACT (n=225 type 1s on MDI or pumps, A1c <7.5%). Both studies are currently posted on ClinicalTrials.gov and are recruiting participants. The goal of the type 2 study is to show a change in A1c at six months, while the type 1 study seeks to improve time spent in hypoglycemia at six months. Both trials will compare FreeStyle Libre to standard SMBG. The A1c inclusion criterion is very smart in our view, and it’s good to see that both studies are quite large, especially for a CGM trial.
  
  • REPLACE (n=210 type 2s on MDI). This study will take place at 26 sites across Germany France, and the UK. The primary endpoint is change in A1c at six months vs. a control group plus using standard SMBG. The study will include a six-month extension for the device intervention group. Abbott is currently recruiting more than 210 patients with type 2 diabetes on MDI (A1c >7.5%). The study has a primary completion date in November 2014. Clinical trials.gov Identifier: NCT02082184.
  • IMPACT (n=225 type 1s on MDI or pumps). This six-month study will take place at 26 sites across the Netherlands, Germany, Spain, Austria, and Sweden. The primary objective at six months is to compare the impact on time in hypoglycemia (number of hours per day of hypoglycemia excursions <70 mg/dl) using FreeStyle Libre vs. standard SMBG. Abbott is currently recruiting more than 225 patients with type 1 diabetes on MDI or a pump (A1c <7.5%). The study has a primary completion date in May 2015. ClinicalTrials.gov Identifier: NCT02232698.
• An Abbott representative wearing the FreeStyle Libre sensor on her arm demonstrated the system on-stage. The room seemed to gasp as she pressed a single button to turn the touchscreen reader on, held the reader over the sensor, and obtained a glucose result/real-time trend arrow/eight-hour history on the device’s screen. The scan and data transfer took less than one second (accompanied by an audible beep), and the entire demo took less than five seconds. The demo illustrated a few important points worth underscoring: (i) small form factor of the sensor patch, which is the size of a two Euro coin in circumference and about two Euro coins in thickness off the body; (ii) the overall simplicity of the system; and (iii) the speed of data transfer from the sensor to the reader.
  
  • The FreeStyle Libre’s circular sensor patch is worn on the back of the arm and measures 35 mm wide (about the size of a two-Euro coin). The subcutaneous sensor itself is just 5 mm deep x ½ mm wide, very small indeed (Medtronic Enlite is 9 mm in length; Dexcom’s G4 Platinum sensor is longer, though the exact dimensions are not listed in the user guide). The FreeStyle Libre sensor is fully disposable and contains no reusable parts; a small battery sits in the sensor patch to power the sensor’s near-field communication to the reader device (Medtronic and Dexcom employ reusable transmitter). Notably, it is a big advantage that FreeStyle Libre does not have interference with acetaminophen, though it is contraindicated for use with high doses of aspirin. The sensor patch can transmit data to the reader through clothing, though they must be within 1-4 cm [0.5-1.6 inches] of each other.
    • The sensor patch is worn for up to 14 days, is water resistant, and requires no fingerstick calibration. The sensor automatically measures, captures and stores readings day and night. After insertion, the sensor requires a very short one-hour warm-up, better than both Medtronic and Dexcom. Overall, the on-body form factor is a vast improvement over the first-generation FreeStyle Navigator, which was criticized for a bulkier on-body component relative to Medtronic and Dexcom’s offerings.
  • The touchscreen reader has a color screen and a built-in FreeStyle BGM. The product is identical in look and feel to the FreeStyle InsuLinx meter, with the exception of the color screen. It is made entirely of plastic on the outside and weighs next to nothing. Aside from a single button to turn the device on and return to the home screen, the reader is navigated via an icon-driven menu on the touchscreen. We found it highly intuitive to navigate through, though would note the touchscreen is not quite as responsive as a modern smartphone (it requires a harder press, generally speaking). The tradeoff is worth it for the lower price and Abbott’s goal of getting this technology to as many patients as possible (though we could imagine future-generation versions could have a nicer screen).
    • The reader menu has just three icons: check glucose, view history, and settings – all were self-explanatory, and the view history had a nice slew of on-device reports (time in target, a mini ambulatory glucose profile plot, and a chart showing the number of hypoglycemia episodes by time of day).
    • The reader has a micro-USB port to recharge the reader and connect to a Mac or PC for download. A three-hour charge lasts one week, assuming ten scans per day. The test strip port uses Freestyle Precision test strips, which offer both blood glucose and ketone testing.
  • FreeStyle Libre has a major focus on software, both on the device and in the download reports. Reports on the touchscreen reader can provide some high-level and useful analysis for a quick glance at glucose trends over time. The download software reports (Mac and PC) are intended to “show the complete glycemic picture” through the ambulatory glucose profile modal day plot (developed at IDC), as well as a very helpful traffic light system (red, yellow, green). The latter made data interpretation and problem diagnosis very easy, and we salute Abbott for working with Joslin’s Dr. Howard Wolpert on this front.
• Abbott’s initial focus with FreeStyle Libre is on type 1 and type 2 patients on MDI or pumps, though panelists had ranging views on the product’s target population. Dr. Irl Hirsch was most adamant on its potential use in type 2s on MDI, while other panelists mentioned “everybody,” “all patients on MDI,” hypoglycemia-prone patients, patients with out of control A1c’s, pregnant patients, inpatients, visually impaired patients, and pediatric patients. Abbott has certainly designed the system to appeal to a broad swath of patients, and we look forward to seeing what populations resonate most with the technology, especially if Abbott secures reimbursement.
• Mr. Watkin shared positive data from user experience studies of FreeStyle Libre. No study sizes were provided and there was no background on how these questions were asked. Still, the data pointed to encouraging potential for strong patient uptake, especially in those that have avoided current CGM due to comfort/wearability:
  
  • 93% agreed that FreeStyle Libre is comfortable to wear.
  • 83% agreed that it was painless to apply the sensor; 100% agreed that it was painless/almost painless to apply the sensor. Mr. Watkin emphasized this particular finding, as discomfort has historically been a barrier to CGM use.  
  • 96% agreed that using FreeStyle Libre is an easy and discreet way to check glucose.
• Mr. Watkin provided background on how Abbott has solved a big R&D challenge in CGM: factory calibration. First, he underscored how Abbott’s wired-enzyme technology enables stable sensor performance over 14 days. It is not dependent on oxygen to provide glucose readings, and the sensor operates at a very low electrical potential. Abbott’s chemistry uses an osmium mediator bound to glucose oxidase via a polymer network (the presentation included a nice animation on this). In addition, Abbott uses special equipment to manufacture FreeStyle Libre with minimal sensor-to-sensor variation. A lot-specific calibration factor is applied, which provides signal stability over 14 days (Hoss et al., JDST 2013).
  
  • Factory calibration at this level of accuracy is a major R&D achievement that overcomes an important limitation of current CGM. In addition, it shifts the cost-effectiveness balance in favor of FreeStyle Libre, as virtually zero strips are required (Abbott recommends a confirmatory fingerstick in hypoglycemia or during times of rapid change).

Clinical Value of Sensor-Based Glucose Monitoring

Irl Hirsch, MD (University of Washington School of Medicine, Seattle, WA)

Dr. Irl Hirsch provided a historical perspective on glucose monitoring, starting with urine testing in the 1920s-1960s, progressing to blood glucose testing as early as 1964, and evolving to CGM in 1999. He emphasized that SMBG was what enabled the DCCT to happen, but “more than any single technology,” “the limitations” and “patient frustrations” with SMBG need to be appreciated. Dr. Hirsch then covered the history of CGM, including evidence that it can reduce moderate hypoglycemia. Turning to the “most important slide” of his presentation, he shared alarming data from the T1D Exchange (Weinstock et al., JCEM 2013) that severe hypoglycemia remains far too common, especially in those with a duration of diabetes >40 years (20% experienced one episode per year!). Though CGM use is growing, he highlighted low penetration in the T1D Exchange (9% of patients overall and 20% in patients >26 years) and frustrations with the technology. Looking to the future, Dr. Hirsch predicted two paths that glucose monitoring will follow: (i) greater penetration of traditional CGM in type 1 patients around the world, including better integration with pumps and progression to automated insulin delivery; and (ii) “a longer-wear factory calibrated system that allows more patients access to ISF [interstitial fluid] glucose readings, trending, and potentially improved A1c levels and less hypoglycemia for insulin-requiring patients with diabetes” (i.e., Abbott’s FreeStyle Libre, though he did not mention it by name). The positivity on FreeStyle Libre was notable to see from Dr. Hirsch, who has expressed some sincere pessimism (justified) in recent talks due to the challenging reimbursement environment in Washington State.   

• “Modern day diabetes treatment and the ability to prove metabolic control matters in the DCCT would not have been possible without SMBG. I think we forget about this.” However, “More than any single technology,” Dr. Hirsch said, “the limitations of SMBG need to be appreciated.” He added, “More than any single technology, SMBG frustrates patients!”
• “The enemy in these patients is not A1c. The enemy remains hypoglycemia.”  Dr. Hirsch shared recent data from the T1D Exchange on the frequency of severe hypoglycemia related to type 1 diabetes duration (Weinstock et al., JCEM 2013), characterizing it as “The most important slide in my presentation.” Patients >31 years old with a diabetes duration of <20 years reported severe hypoglycemia episodes (tightly defined as seizure or coma) at a frequency of ~7-8% per year, while those with a duration of diabetes 20-40 years reported episodes at a frequency of 12-16% per year. Strikingly, patients >31 years old with a diabetes duration >40 years reported severe hypoglycemia episodes at a frequency of 17-22% per year. To make matters worse, Dr. Hirsch emphasized that this population is “exploding” in the US.
• “Why is CGM stopped?” – Dr. Hirsch cited a July 2014 Diabetes Care paper that examined CGM use in the T1D Exchange, including why patients quit CGM. Importantly, the study examined older-generation Dexcom and Medtronic sensors, and the reasons cited below (especially pain) have improved with the newer G4 Platinum and Enlite sensors.

*Dexcom Seven Plus, Medtronic

• Dr. Hirsch shared CGM penetration and A1c data from the T1D Exchange – he noted, “CGM has become much more popular” since the Exchange enrolled patients three years ago. Dr. Hirsch emphasized that the CGM data is just an association, though the data is interesting nonetheless.

CGM Use by Age in the T1D Exchange

Mean A1c – CGM Users vs. Non-CGM Users in the T1D Exchange

Clinical Case Studies of Type 1 and Type 2 Diabetes from the SIGN Study

Ramzi Ajjan, MD (Leeds University, UK)

Dr. Ramzi Ajjan presented findings from the SIGN Study in type 1 and type 2 patients on multiple daily injections (MDI). The 100-day, multicenter study randomized patients to therapy with the FreeStyle Navigator CGM (alarms disabled, a sort of way to mimic the FreeStyle Libre) and SMBG (control). Patients reviewed their ambulatory glucose profile (AGP) with a clinician. Notably, type 1 and type 2 patients responded quite differently to the intervention – type 1 patients experienced no significant change in time in range (70-180 mg/dl; quite surprising), a trend toward a reduction in A1c (-0.4%; p=0.069), and a significant drop in time spent in hypoglycemia (-0.5 hrs/day; p=0.047); by contrast, in type 2 patients, time in range improved significantly (+1.4 hours/day; p=0.042) and A1c dropped significantly (-0.8%; p=0.0002), while time in hypoglycemia was unaffected (-0.1 hours/day; p=0.30). Dr. Ajjan called both findings a success – the mitigation of hypoglycemia in type 1s was a very positive sign (“hypoglycemia is the enemy”), while the significant improvements in overall glycemic control in type 2 patients were clinically meaningful. This study informed the design and inclusion criteria of the now-recruiting reimbursement studies – see Mr. Watkin’s talk for more details. In closing, Dr. Ajjan switched tracks to highlight clinical cases of patients in the SIGN study and, notably, previewed Abbott’s recently updated AGP software; this single standardized CGM download report now features a traffic light-esque modal plot that simplifies data into a neat red-yellow-green color graphic (see pictures here).

• The multicenter SIGN study featured nine UK sites and included patients with type 1 (n=42) and type 2 (n=45) diabetes who had been on MDI for >6 months prior to enrollment (baseline A1c: 7.5-12.0%). Patients underwent a 15-day baseline period with masked CGM prior to randomization into the SMBG (type 1: n=13; type 2: n=15) or FreeStyle Navigator intervention (type 1: n=29; type 2: n=30) for ~85 days; patients in the control had masked CGM for the final 15 days of the study. We note that the study’s final analysis (time in range, time in hypoglycemia, etc. – see below) compared control vs. intervention cohort performance over these 15 days.
• The primary endpoint of SIGN was time in range (70-180 mg/dl) as opposed to A1c; Dr. Ajjan made sure to highlight this point. In his view, the notion of lowering A1c as the “best” (and only) approach to improving clinical outcomes is outdated; instead, he suggested that mitigation of hypoglycemia and glucose variability are equally important contributors to patient outcomes – in his view, time in range accomplishes this goal more effectively than A1c.
• Findings from SIGN suggested that the use of CGM without alarms, combined with AGP reports, benefitted both type 1s and type 2s. The most notable results are summarized below:
  
  • Type 1: The intervention did not significantly change time in range, which was a surprise (-0.4 hrs/day; baseline: 11.3 hours/day; p=0.49), However, it did reduce time in hypoglycemia (-0.5 hrs/day; baseline: 1.3 hrs/day; p=0.047) and trended towards a significant improvement in A1c (-0.4%; Baseline: 9.0%; p=0.069).
  • Type 2: The intervention significantly increased time in range (+1.4 hrs/day; baseline: 13.3 hrs/day; final: p=0.042) and was associated with a significant reduction in A1c (-0.8%; baseline: 9.0%; p=0.0002). Notably, this tighter control came without significantly affecting time in hypoglycemia (-0.1 hrs/day; baseline: 0.6 hrs/day; p=0.30). Given that few studies have assessed CGM in type 2 diabetes patients, we appreciate Abbott’s effort to explore efficacy in this population. Though Dr. Ajjan did not reference the FreeStyle Libre, we think this observed efficacy in the population speaks to the potential of FreeStyle Libre to meaningfully improves clinical outcomes in insulin-requiring type 2 patients.
  • The frequency of blood glucose tests per day declined significantly for both type 1 (-2.4 tests/day; baseline: 4.6 tests/day; p<0.0001) and type 2 patients (-1.9 tests/day; baseline: 4.0 tests/day; p<0.0001) following the intervention. Dr. Ajjan noted that this reduction stemmed from patients’ confidence in their diabetes management due to use of the Navigator. No device related adverse events were reported other than “expected insertion site symptoms.”
• In a review of clinical case studies, Dr. Ajjan called attention to the clinical value of the Ambulatory Glucose Profile (AGP); this simple one-page graphic consolidates CGM data (see example here from Mr. Watkin’s talk) and summarizes glucose data with time-in-range statistics and a shaded modal day plot (median, interquartile range, and 10/90% bounds). Dr. Ajjan presented AGP as a solution to the complexity of typical CGM outputs; we heard multiple comments during Q&A echoing this sentiment and noting the cost-effectiveness of the platform -- “the limited time that you have [with patients] is used much more effectively.”
  
  • The on-screen dashboard is the newest feature of the software (see picture here). The graphic consists of a simple 3 × 5 modal day plot that summarizes a patient’s CGM data over the course of the day. Rather than representing this information with numbers, a series of algorithms simplifies the data into a red-yellow-green color scheme. For example, if a patient was consistently experiencing lows in the morning, the corresponding spot in the matrix would be marked red; that same spot could also be marked yellow (mediocre control) or green (great control), allowing providers to efficiently and easily identify trouble spots and patterns. Notably, we heard positive reviews of the software from diabetes educators at AADE 2014. We are particular fans of the traffic-light approach, which makes interpretation of expansive CGM data much easier.

Panel Discussion

Q: Can you please clarify, how soon after placing the sensor on a patient you give them the reader? Does the doctor have the reader at first? Also, how long does it take the sensor to warm up? How can glucose be monitored during this time?

Mr. Jared Watkin (VP of Technical Operations, Abbott Diabetes Care, Alameda, CA): The product is designed for use by patients, not by doctors. Patients will have their own reader. The sensor starts giving readings after a 60 minute warm-up period. During that one hour, patients can utilize a built-in blood glucose meter.

Q: So if something happens in that hour, you can monitor with a blood glucose meter?

Mr. Watkin: Yes.

Q: The relationship between glucose variability and long-term complications is not clear. What about in type 1 diabetes – how important is glucose variability to cardiovascular outcomes?

Dr. Irl Hirsch: The real answer is we don’t know yet. All I can say is, I hope we find out soon. We are just finishing our large feasibility study called FLAT SUGAR. Hopefully, results will be announced and published, and we can go on to a more definitive study. It’s something we discuss and debate, and something we don’t have a definitive answer to yet. I think we would all agree – A1c by itself is incomplete. If we just take A1c by itself, as a way to look at diabetes, I think we’re missing an important message.

Dr. Hans DeVries (Academic Medical Center, Amsterdam, Netherlands): A rep actually offered the device to me, and I used it – even though I don’t have diabetes. I must agree that my first impression was very positive. Initially, will it be bought out of pocket? Can you also talk about pricing?

Mr. Watkin: There will be some variation in price in countries depending on local taxes, etc. However, the reader kit will be priced at 59.90 euros; each 14-day sensor itself will be 59.90 euros. It’s also going to price slightly differently in different countries when you consider private reimbursement, etc. But that is going to be the cost of the device prior to reimbursement.

[Comment]: The Netherlands will be the first country in which the device is launched on September 22.

Dr. Barry Ginsberg (Diabetes Technology Consultants, Wyckoff, NJ); If you factor out the inaccuracy of BGM at 6%, the accuracy of the sensor is 9%. My question is about AGP, which is a very nice professional device as far as I can tell. But aside from a few of my engineer patients, I cannot imagine using that report as way to evaluate glucose. The problem then, is we only make changes every three months, which is too rare. Any comments?

Dr. Ramzi Ajjan (Leeds University, UK): You raise a good point. One of the problems is that we don’t spend enough time with patients to explain what we’re doing. It is a danger – we use the device, make a change, and then wait three to four months to make another change. We’re trying to change that practice with this device. We’re trying to teach patients. They like to know what’s going on. Consultation should take a little bit longer and is something we’ll need to see with this new device. This is a new era of glucose management.

Dr. Ginsberg: My time with patients is actually not limited – we were a leading center in the DCCT. But I cannot imagine teaching this to my wife...

Dr. Ajjan: With some patients, everything is difficult. With other patients, they will benefit. And we’ve seen that already.

Dr. Hirsch: What we will typically do is talk to educators, pharmacists, and nurses when starting a new device. We will be sure to do the same with this device. As far as the AGP is concerned, patients can look at that and make conclusions; they can also use Abbott’s website. There are a lot of instructions.

Mr. Watkin: We did a lot of work with AGPs, which Stefano showed. We generated data off Navigator; we have an AGP working group; we got feedback on AGP from both healthcare providers (HCP) and patients. HCPs find it extremely useful and insightful. Patients themselves very quickly achieved an understanding of the software. The profile showed an improvement in overall control. There is always a danger with complex reports when you try to simplify them. AGP does help HCPs and patients understand CGM data.

Dr. Ajjan: I would like to answer with another question. How can we explain variability to patients when it requires mathematical formulas? The advantage of this approach is that you have a teacher – a visual teacher. You can easily explain: this is the median; this is the variability. It is more difficult to explain something with numbers as opposed to pictures.

Comment: To respond to Dr. Ginsburg, we’ve studied this in 300-400 patients, and I’ve been overwhelmingly impressed by ability of patients to understand the picture. In particular, if you look at an AGP output of someone with diabetes vs. someone without, you can easily point out what is good and what is not. The other way to look at it is to simply say that you want lines to be flat – narrow in range without lows. Those four dimensions of profiles can quickly tell patients how they are doing at every time of the day. Patients can see how they’re doing, especially overnight and after meals. When working with patients, you typically have to ask 20-30 questions to figure out what’s happening, and you don’t know if the answer matches with what’s happening in practice. With AGP, you can lay it out more clearly and identify, this is what happens when you wake up, etc. Patients think you’re so smart. You can illuminate this whole conversation, such that the limited time you have with patients is used much more effectively.” That whole piece of what’s normal and what’s not. This software can help to get that message across. People can pick it up very fast. That’s my feedback from my experience.

Dr. Ellie Strock (International Diabetes Center, Minneapolis, MN): A question about interference. This is based on Navigator technology. One of the challenges, particularly in some of the CGM devices out there, is interference with things like acetaminophen. Does FreeStyle Libre have a problem with that?

Mr. Watkin: No, we don’t have acetaminophen interference. In labeling, there are some precautions, such as aspirin (salicylate) at high levels.

Q: I conduct research on the self-management needs of people with visual impairment. SMBG is a really significant difficulty for many people with visual impairment. There are talking meters available, but in the US, they are all offshore meters that have questionable accuracy. Many of the barriers to glucose monitoring are eliminated with this device for visual impairment, except that the display is very visual. Have you considered adding an audio function? And the numbers are not insignificant. Nearly 20% of people with diabetes have significant visual impairment in the US, according to the CDC. It’s quite a significant group. The numbers are comparable in many other countries.

Mr. Watkin: This version of the product does not have audible alerts. The system is much easier to test with than other devices; anyone can do it, even with people with visual impairment. However, we understand the need for audible reports.

Comment: Adding audio is not a difficult thing; I do work at a university, and I’d be happy to speak with you after this session.

Comment: I have a question about the accuracy issue. The ISO standard, as well as most of the details of the data referring to the device itself, is only a very partial picture. You don’t see the impact of the user (e.g., not washing hands) that reduces accuracy drastically. For some reason, this fact is ignored. I think it’s a very important issue to address. When looking at accuracy, you should look at real-world accuracy. This is one area of immediate impact for non-invasive glucose monitors; when people are typically looking at accuracy levels, they’re looking at theoretical values, so you should really look at the real and practical accuracy.

Dr. Hirsch: You are absolutely correct. You will be seeing a study published online very soon that I was involved in that looks at the accuracy of two CGMs, and the MARDs are not quite what you would expect for those reasons. In real life, things are not as good as in ideal circumstances. You will see that study within the next week or two.

Q: We have some online questions. What are the plans to make this available for pediatric use?

Mr. Watkin: Obtaining a pediatric claim is a priority for us. The rules say that the first thing you have to do is get approval in adults. We certainly recognize the potential in the pediatric population. It’s a priority for us to execute that work and get that out.

Q: Who would be an ideal candidate for using this device?

Dr. Hirsch: Right now, 20% of adults are using CGM, and that number is rising quickly. At the same time, you’re seeing asymptomatic hypoglycemia. We have a majority of patients who don’t use CGM and don’t do glucose testing. In my practice, it’s the type 2s on MDI that really add to our challenge. Medicare will only allow for three strips per day, and if a patient is using MDI, I want a minimum for four tests/day, if not more. In the T1D Exchange, the average is 5-7 tests/day depending on age. Given that majority of patients are on MDI and not on CGM, I can’t think of any reasons not to be on this technology. If you think about cost, you can do the equivalent of 7-8 tests/day and the cost is the same regardless of how many times you swipe. It’s hard to think of a patient who wouldn’t benefit. I’m jealous you got it before us in the US.

Dr. Ajjan: The short answer: Everybody. But that’s not going to happen. The long answer is: groups at risk of hypoglycemia, groups that can’t control glucose with current testing; groups who need to test a lot; inpatients, since hypoglycemia is common in hospital; patients who are post-myocardial infarction. It’s endless in terms of what category of patients can use it.

Dr. Stefano Genovese (IRCCS MultiMedica, Sesto San Giovanni, Italy): All MDI patients can use the device, especially type 2 patients with high postprandial hyperglycemia. The device can also be used to determine whether a particularly therapy is effective; there is a wide range of patients who could benefit.

Ms. Watkin: We’ve designed the device, so that a wide population can use it. The target we talked about was MDI patients. But we’ll take feedback and see what we can do.

Q: You can use the system in two ways. Prospectively, you can take a blood glucose reading anytime you want. You can also use the device retrospectively, since you’ve built a nice analysis system. But it seems that the FreeStyle Libre value does not input into the bolus calculator?

Mr. Watkin: This has the bolus calculator feature of InsuLinx, meaning you can use the bolus calculator when you do a fingerstick test. But for bolus calculators based on ISF readings, there is no accepted protocol...

Q: So it’s a regulatory problem?

Mr. Watkin: It’s a clinical data problem. And then we would need regulatory approval.

Comment: So you cannot use the swipe reading in the bolus calculator?

Mr. Watkin: Bolus calculators are based on blood glucose readings. There is no published data out there for bolus calculators based on ISF readings.

Comment: This product also has applications in determining treatments that would be efficacious. Algorithms right now are looking at individualizing treatments to patients. With this device, you can look at first- or second-line treatment to assess patterns within patients and figure out how to target therapies. We don’t have technology to do that right now. It would really help our decision-making to have that information, so that we can look at what’s actually happening and determine whether a therapy is working or not. Long term, it’s going to be much better at improving out efficacy.

Q: Can we use other sites for the sensor? Can we use the device in pregnant women?

Mr. Watkin: The device is currently only approved for use on the back of the arm. We are exploring other sites. It was not labeled for use in pregnancy, but it was not contraindicated either. It’s going to be up to the judgment of physicians. We have not done studies in pregnant women.

Q: Do you have any experience evaluating performance during MRIs or other scans?

Mr. Watkin: You do have to be very careful with MRIs. Regarding other scans, we haven’t done evaluations yet.

Q: When will this be available in different countries? I have heard September 22 in Sweden and the Netherlands, and then more countries in the beginning of October. What about the US?

Mr. Watkin: We intend to be a global product. The US is a very important market. We’re not going to make predictions. We are initiating pivotal trials for the US before the end of the year.

Q: Has any thought been put into changing the software of the meter so that it can be used with different consecutive patients? I ask because this is attractive for hospital use.

Mr. Watkin: At the moment, the focus is on personal use. With any new technology, we’re looking to see where it can be applied, including hospitals. And we understand that other versions will be attractive in other markets and scenarios.

Q: Where do you get this new system?

Mr. Watkin: There will be web shops coming live in the next 30 days across the launch countries. It’s just a website, similar to Amazon. You go in, sign up, register, and get product delivered to you directly via mail. There is online help for utilization of the product. It will be out in the next 30 days in launch countries.

Q: Are there any price reduction plans for those who agree to use it for one year?

Mr. Watkin: Anyone interested in that can talk to my commercial colleagues here. There will be starter kits where the price is improved and with subscriptions. I’m the wrong person to talk about that.

Q: What has to be done before rollout to patients?

Mr. Watkin: As I said, there’s going to be a lot of online distribution. We have spent time with endocrinologists and diabetologists and nurse educators to get them familiar with the product before making it available to patients.

Q: In the year 2019, what might be the role of this technology in patients?

Mr. Watkin: The product is in widespread acceptance, and we bring comprehensive glucose control to all. If we do that, we will be well satisfied.

Dr. Genovese: It’s a real novelty device. Together with the patch clamp, this is the real future of type 1 management.

Dr. Ajjan: If you think about poor control on MDI, one is not testing or doesn’t know what to do. Devices like this will help both groups. This has potential to take over both groups; I would like to see this.

Dr. Hirsch: The world of SMBG and CGM has been focused on type 1. I see this as potential giant introduction into an exciting new technology in type 2 diabetes. Especially patients on insulin and MDI. The excitement is about what could potentially happen to control that population.

Corporate Symposium: Modern Type 2 Diabetes Management – The Experts’ Guide to the Universe of Choices (Sponsored by AstraZeneca)

Preventing Cardiovascular Complications in Type 2 Diabetes: Disappointment or Opportunity?

Steven Gough, MD, PhD (University of Oxford, Oxford, UK)

Dr. Steven Gough’s presentation very eloquently framed many of the issues that have impacted the interpretation of cardiovascular outcomes trials. His central metaphor was that of a closing window: the room for glucose lowering to improve long-term cardiovascular outcomes is likely highest early in the course of the disease, before the burden of calcified atherosclerosis, hypertension, and other risk factors worsen. He encouraged the audience to set realistic expectations regarding ongoing cardiovascular outcomes trials (CVOTs) because they were designed to examine safety and have enrolled patients with higher CV risk and longstanding diabetes, for whom the window for cardioprotection is nearly closed. He specifically noted that expectations were probably too high for SAVOR and EXAMINE given how short they were. Reading between the lines, it appeared that Dr. Gough was readying the audience for what will likely be a series of neutral results from ongoing CVOTs, encouraging them to not give up hope of real cardioprotection even if the data do not demonstrate a protective effect.

1.Dr. Gough outlined a “wish list” for future CVOTs:

1. They will recruit patients soon after diagnosis;
2. They will recruit patients with minimal established cardiovascular risk, at least compared to current CVOT populations;
3. They will last for longer than five years;
4. They will enroll a large study population.

1. Following Dr. Gough’s presentation, the audience responded to a poll on which glucose-lowering drug class has the highest potential to show a beneficial effect on CV outcomes – GLP-1 agonists came first with 39% of the vote (see below), although Dr. Gough countered that the design of the outcomes study is as important as the specific class being studied. The full voting results were as follows:

a.Question: “In your opinion, which of these glucose-lowering agents/classes has the highest potential to show a beneficial effect on CV outcomes?”

i.GLP-1 receptor agonists: 39%

ii.Metformin: 21%

iii.SGLT-2 inhibitors: 20%

iv.DPP-4 inhibitors: 13%

v.Insulin: 4%

vi.TZDs: 3%

vii.SFUs: 0%

Panel Discussion

Q: What do you think of the results of our poll?

Dr. Stephen Gough (University of Oxford, Oxford, UK): The most important thing is not the drug class, but the study design. If we want to see a benefit, we will need to use the right study designs. None of these outcomes studies are doing head-to-head comparisons. There are benefits to using glucose-lowering therapy; the most important thing is to use the right drug, at the right time, for the right patient.

Q: You mentioned that glucose lowering may not have much of an impact on cardiovascular outcomes late in the course of type 2 diabetes, but the recent ACCORD results seem to show that intensive control can still improve outcomes.

Dr. Gough: In my slide with the window shutting, I don’t think the window ever completely closed. There is always room for improvements, but the agents we’re talking about can’t do anything about calcified atherosclerosis. An intervention may work in advanced-stage patients, but that is not the ideal population.

Q: Can GLP-1 agonists be cardioprotective?

Dr. Tina Vilsbøll (Gentofte Hospital, Hellerup, Denmark): Overall, what we know today is that there are many pieces of the puzzle that go in the right direction, including lipids, blood pressure, and glucose levels. The one thing drawing in the other direction is the increase in pulse. We will not have the final answer to this until we see the results from the cardiovascular outcomes trials, but from what we have so far, the class at least appears safe.

Dr. Dan Drucker (Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada): One problem for all of us is that the patients in cardiovascular outcomes trials are not very similar to the patients we generally see in our practice. Even when we have all the results from the outcomes trials, we will still be looking at people in our clinic who don’t look like the people enrolled in those studies, and so those answers will not be definitive.

Glucagon Suppression in Type 2 Diabetes: Is It Important?

Daniel Drucker, MD (Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada)

Diabetologist extraordinaire Dr. Daniel Drucker discussed the somewhat overlooked contribution of glucagon to the pathophysiology of type 2 diabetes, explaining that despite the availability of drug classes like GLP-1 agonists and DPP-4 inhibitors that suppress elevated glucagon production, the field still lacks a comprehensive understanding of the mechanisms underlying glucagon dysregulation. He pointed out that there are significant differences in pancreatic islet physiology between species, limiting the applicability of findings from animal studies to clinical practice. He also presented data demonstrating that abnormal glucagon production is seen very early in the progression of type 2 diabetes – even patients with mildly impaired glucose tolerance have noticeable defects in both insulin and glucagon secretion. Dr. Drucker encouraged the use of diabetes drug classes that suppress glucagon secretion and consequently reduce hepatic glucose production, and he characterized glucagon receptor antagonists as an “extremely attractive new approach” to type 2 diabetes pharmacotherapy. However, he also acknowledged that impressive A1c reductions are possible even with an increase in glucagon and endogenous glucose production, as is evident in patients treated with SGLT-2 inhibitors or who have undergone bariatric surgery. He ultimately concluded that suppressing elevated glucagon production is one attractive option for addressing hyperglycemia in type 2 diabetes, but that far more research is needed to fully understand glucagon’s role in the pathophysiology of the disease.

Questions and Answers

Q: Do we know anything about the relationship between sulfonylureas and glucagon?

A: There’s not much data in that area. We tend to think that agents that target the beta cell should indirectly suppress glucagon, but the data showing potent suppression is more limited than we would like.

Q: Does glucagon have any effect on renal glucose production?

A: In animals, you can show under some circumstances that intestinal and renal glucose production rise in response to glucagon. In animal models of bariatric surgery, in preclinical studies, there’s a hint that it is regulated by glucagon. It’s very difficult in humans to show that renal glucose production is regulated by glucagon or that it contributes significantly to glycemia.

Q: Based on the bariatric surgery data, should I treat my bariatric surgery patients with a DPP-4 inhibitor?

A: There are several studies looking at that. It makes sense that since GLP-1 and GIP are elevated after bariatric surgery, so we might get a disproportionately wonderful benefit. We don’t have rigorous randomized controlled trials yet; it’s a great idea but we need evidence.

Is There a Role for Early Combination Therapy in the Management of Patients with Type 2 Diabetes?

Bernard Zinman, MD (Mount Sinai Hospital, Toronto, Canada)

Dr. Bernard Zinman called on providers to develop a new paradigm for the treatment of type 2 diabetes, explaining that an aggressive approach involving early initiation of combination therapy (already the dominant paradigm for the treatment of other diseases like HIV/AIDS) is likely to be far more effective than the current “treat to failure model” in addressing such a complex, progressive disease. He cited clinical inertia as a major obstacle to more effective therapy for type 2 diabetes and urged the audience to accept the reality that the vast majority of patients will not achieve long-term success with metformin alone. Dr. Zinman reviewed the pros and cons of several options for combination therapy, suggesting that fixed dose combinations of metformin and newer drug classes (namely GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors) hold great promise due to their robust A1c-lowering efficacy, low risk of hypoglycemia and weight gain, and fairly reasonable cost. He strongly criticized the risk-benefit profile of sulfonylureas, saying that “they have three advantages: they’re cheap, they’re cheap, and they’re cheap,” and that it is no longer necessary to accept weight gain and hypoglycemia as inevitable consequences of aggressively treating type 2 diabetes.

• Several polls suggested that the packed audience was very receptive to Dr. Zinman’s message: 83% of the packed audience said that they already used fixed dose combinations to treat patients with type 2 diabetes, and 84% selected either metformin + SGLT-2 inhibitor + DPP-4 inhibitor combinations or metformin + SGLT-2 inhibitor + GLP-1 agonist combinations when asked to predict which type 2 diabetes drug combinations would be most commonly prescribed ten years from now.

Questions and Answers

Dr. Chantal Mathieu (University of Leuven, Leuven, Belgium): Let’s be honest, the more pills we make patients take, the more strain we put on them. Is there an effect on adherence with FDCs?

Dr. Bernard Zinman (Mount Sinai Hospital, Toronto, Canada): It’s been clearly demonstrated in the context of therapeutics that pills taken once a day have much better adherence. That’s the advantage of FDCs; patients don’t care how many chemicals are in the pill, they just want to take one pill. If I prescribe multiple pills, it means there’s a problem, and that it’s serious. Cost is also a factor, and often the metformin component is free.

Dr. Mathieu: How does SGLT-2 inhibitor and incretin therapy impact glucagon?

Dr. Zinman: As Dr. Drucker discussed earlier, glucagon biology is abnormal starting early in type 2 diabetes, so anything we can do to decrease it is helpful. Dapagliflozin/metformin combinations led to an increase in glucagon, likely a compensatory response to prevent hypoglycemia. But when you add saxagliptin to dapagliflozin, you get a nice complementary mechanism where saxagliptin suppresses the increased glucagon, and that translates into better glycemic reduction.

Dr. Mathieu: Why do you think FDCs are valuable?

Dr. Zinman: They improve adherence, they tend to be cheaper, there are fewer side effects with lower doses. There’s a real barrier among diabetologists, who are very much fixated on the step-wise intensification approach.

Dr. Mathieu: What do the data say about combinations with insulin and novel therapies?

Dr. Zinman: That’s another area that’s exciting because of robust responses. With SGLT-2 inhibitors and insulin, you see dramatic changes in three areas: A1c, insulin dose, and weight loss. SGLT-2 inhibitors and insulin in type 1 patients has been studied; it’s not on-label right now, but there’s tremendous interest in pursuing it.

Dr. Jiten Vora (University of Liverpool, Liverpool, United Kingdom): [Directed at the audience] Why do you use FDCs?

Audience member: We use them because of better adherence, better glycemic control, and because they target different mechanisms.

Dr. Vora: When do you start?

Audience member: Early in the disease.

Audience member: We use DPP-4 inhibitor/metformin combinations because that’s what we have in Portugal. When we use them depends on patient. With some patients who have a high A1c or fasting glucose, we use them with very good results. Sometimes we use them early; it depends on patient.

Dr. Zinman: It’s obvious when someone presents with an A1c of 10% that you feel compelled to use combinations. I’m taking it one step further, saying it doesn’t matter what the A1c is; if you have type 2 diabetes, the beta cells will fail and it will progress.

Corporate Symposium: Perspectives on GLP-1RA Therapy – Advancements in T2DM (Sponsored by Lilly)

A Review of the GLP-1RA Therapy Landscape

Anthony Barnett, MD (Heart of England NHS Foundation Trust and University of Birmingham, Birmingham, United Kingdom)

Professor Anthony Barnett characterized the GLP-1 agonist class as an appealing therapeutic option for type 2 diabetes and highlighted Lilly’s once-weekly Trulicity (dulaglutide) as an “important addition to the armamentarium” of treatment options. In particular, he stressed that Trulicity would be the first once weekly GLP-1 agonist on the market that does not require reconstitution and the only one that has demonstrated equal A1c-lowering efficacy to Novo Nordisk’s Victoza (once daily liraglutide). He urged providers to “think about the value of the drug, not just the cost of the drug” when making prescribing decisions, as he believes benefits like weight loss and a reduced risk of hypoglycemia are crucial for patients but often not taken seriously enough by the medical community – certainly, hypoglycemia prevention has value as hypoglycemia is very costly. During Q&A, Professor Barnett described the limitations that high costs have placed on GLP-1 agonists’ uptake, particularly in the UK, where providers are encouraged to use the class only as a third line therapy or in combination with insulin. He also acknowledged the significant benefits of SGLT-2 inhibitors and expressed interest in the future potential of SGLT-2 inhibitor/GLP-1 agonist combination therapies, though he stressed that for many patients, GLP-1 agonists alone can be a very appropriate second-line treatment option.

• As a reminder, Trulicity is currently under regulatory review in both the US and the EU, with a final decision expected in late 2014. See our coverage of Lilly’s 2Q14 update for our most recent update on the candidate.

Questions and Answers

Q: What are the benefits of SGLT-2 inhibitors vs. GLP-1 agonists?

A: SGLT-2 inhibitors are a bit cheaper in Europe, so the thought is, “Why give a more expensive injectable rather than a cheaper oral medication?” There’s a significant place for SGLT-2 inhibitors. If you want to avoid injections and lose weight, then they’re a great choice. They’re not as efficacious generally, and there are issues with genital infections, use in elderly patients, and other safety concerns. There’s room for both classes; they’re not going to displace GLP-1 agonists.

Q: If dulaglutide comes to the market, will there be restrictions for renal impairment?

A: I don’t know. Regulatory agencies tend to be cautious at the beginning, so there may be restrictions. Over the long term, it looks safe for patients with renal impairment.

Q: What are your thoughts on the difference in weight loss between liraglutide and dulaglutide?

A: It is probably due to differences in the duration of action, or PK/PD differences, but we don’t have a good explanation. It’s a very small difference; it’s statistically significant but clinically very small.

Q: Which GLP-1 agonist is best for elderly patients?

A: That’s a difficult question. It depends on the license. Many elderly patients have renal impairment and in this respect the licenses for the GLP-1 agonists differ in how they may be used. A very important advantage of the class for the elderly is the low hypoglycemia risk. The elderly are the most adversely affected by hypoglycemia; that group is where most of the deaths and hospitalizations occur, especially in type 2 diabetes. You have to look at the labeling. There’s no particular reason that this class shouldn’t be useful for elderly patients.

Q: You mentioned many differences between different GLP-1 agonists, but what is the most important difference?

A: There are a lot of differences. Once weekly dosing vs. once or twice daily is a big differentiator. Reconstitution is a big problem, but we’re going to see this issue overcome with products like dulaglutide. It won’t be the only one; we will see other products that don't need reconstitution on the market in the future, but people may have difficulties using the two agents on the market now because of this issue.

Q: Could GLP-1 agonists be useful for the treatment of prediabetes?

A: Possibly. We would need to see data.

Q: Where do you position GLP-1 agonists in the treatment algorithm?

A: Because of absolute costs, in the UK we’re discouraged from using them as a second-line treatment. They’re usually used as an alternative to insulin or with insulin. For some patients, it would be entirely appropriate to use them second line. If a patient is failing on metformin, is overweight, and has a comorbidity from obesity like sleep apnea, I think a GLP-1 agonist is the treatment of choice because you will get the benefits of weight loss and glycemic control. The key is individualization. In our clinic, we certainly use GLP-1 agonists as a second-line treatment, as a third-line treatment, and with insulin.

Q: Does dulaglutide have as much of an effect on postprandial glucose as daily exenatide?

A: The effect is the same.

Q: Is there any potential for a GLP-1 agonist/SGLT-2 inhibitor combination therapy?

A: I’m not aware of any in development, but those would be very sensible studies.

Comment: An article was recently published that showed an increase in glucagon and hepatic glucose production with SGLT-2 inhibitors, so that combination might be better compared to a combination with DPP-4 inhibitors.

A: The big question is whether the weight loss would be additive or even synergistic with the different mechanisms.

Q: Will using a GLP-1 agonist delay insulin initiation?

A: It may; we’ve seen GLP-1 agonists used as an alternative to basal insulin. You can see the advantages if you look at the package of efficacy: not just A1c but weight loss and hypoglycemia. We’re using GLP-1 agonists before insulin, then we bring in insulin later if needed. I don’t think it’ll be the demise of insulin.

Q: In some countries, GLP-1 agonists are not as widely used because they’re not reimbursed for all patients. What’s the situation in the UK?

A: It’s mostly used as part of triple therapy and with insulin. One third of the use is with insulin.

Q: You mentioned that weight loss can be so different among patients taking GLP-1 agonists, with some people losing enormous amounts and others not at all. Are there any predictors of who will do well?

A: I don’t think there are any good predictors in an individual patient. At the population level, there have been studies, but with an individual patient it’s very hard to predict. People with a higher BMI tend to lose more weight, but I can’t say in an individual case who will lose more. In a clinical situation, I have patients who have lost 20-30 kg; one guy looks no different – he’s so overweight that a 20 kg weight loss isn’t noticeable – but he has lost that much weight. It’s difficult to say in an individual case who will lose the most. There are some practical issues in the UK because the NICE guidelines say that patients need to have an A1c reduction of 1% and lose 3% of their body weight for a GLP-1 agonist to be considered effective. That’s an issue because some people lose massive amounts of weight and don’t see a sufficient A1c drop, while others have an A1c drop of say 1.5% and don’t lose weight. Theoretically in either of those cases, you should stop the drug, but that would be ridiculous. The guidelines do say that individualization is paramount and that the "buck stops" with the clinician to do what is best for his/her patient.

Q: Are GLP-1 agonists as effective in non-obese patients?

A: The weight loss is not as great – people won’t waste away to nothing by taking a GLP-1 agonist. The percentage weight loss is essentially the same, but numerically more obese people lose more weight.

Future Perspectives for GLP-1 Receptor Agonists

Juris Meier, MD (St. Josef Hospital, Bochum, Germany)

Dr. Juris Meier ended the Lilly GLP-1 agonist symposium with an optimistic presentation on the class’ future potential, although he also mentioned some more practical recommendations for the present such as scenarios for using short acting vs. long acting GLP-1 agonists (see the table below). Dr. Meier began with Intarcia’s matchstick-sized implantable osmotic mini-pump ITCA-650, characterizing its efficacy as comparable with other long-acting GLP-1 agonists and highlighting the unique lack of injections. He displayed data on the strong efficacy seen with fixed-ratio GLP-1 agonist/basal insulin combinations (namely Novo Nordisk’s Xultophy [liraglutide/insulin degludec] and Sanofi’s LixiLan [lixisenatide/insulin glargine]), and also noted that the slow up-titration protocol with these combinations appears to attenuate the nausea experienced by patients on GLP-1 agonist monotherapy. He spoke quite positively on the use of GLP-1 agonists in type 1 diabetes, citing the improvements in weight, daily insulin dose, postprandial glucose, and insulin sensitivity seen in early studies (Sarkar et al., Diabetes Care 2014). He also mentioned GLP-1 agonists’ use for obesity, posting data on Novo Nordisk’s liraglutide 3.0 mg for obesity (which recently received a positive FDA AdComm vote), although he did not discuss this application in great detail.

• Dr. Meier characterized neuroprotection as an exciting new frontier for the GLP-1 agonist class. This suggestion is supported by a modest body of preclinical work (McClean et al., J Neurosci 2011) as well as very early clinical studies (Aviles-Olmos et al., JCI 2013). Neurodegenerative diseases such as Alzheimer’s have been theorized to have mechanistic connections with insulin resistance, although the body of knowledge in this area is quite limited.
• Intravenous GLP-1 agonist administration appears to preserve the class’ dose-responsive efficacy while largely abolishing nausea and vomiting seen with subcutaneous administration. Dr. Meier noted that intravenous administration could allow the class to achieve its full potential, although with current technology there is not a very patient-friendly way to achieve chronic IV drug administration.

Table: Recommended GLP-1 agonist subtype for different therapeutic applications

Symposium: Contemporary T2DM Management – Focus on Safety and Efficacy (Supported by the Metabolic Endocrine Education Foundation)

The Role of GLP-1 Analogs, DPP-4 Inhibitors, and TZDs in the Management of T2DM

Ralph DeFronzo, MD (University of Texas Health Science Center, San Antonio, TX)

Out of the three drug classes that Dr. Ralph DeFronzo was tasked with discussing, he had some clear favorites. He firmly stated that GLP-1 agonists and TZDs (in addition to SGLT-2 inhibitors) are the best agents we have for type 2 diabetes, while he downplayed DPP-4 inhibitors’ efficacy as weak. He spent a great deal of time highlighting early evidence on GLP-1 agonists’ positive effect on beta cell function, remarking that no other drug class has a similar effect. In the latter half of his talk, he highlighted the TZD class’ very durable efficacy. Citing the results from the full PROactive trial as well as an eight-year Kaiser Permanente database study, Dr. DeFronzo categorically stated that Takeda’s Actos (pioglitazone) does not cause bladder cancer.

• The points Dr. DeFronzo made in this presentation are in line with those we have heard at other meetings over the previous year – see our coverage of three of Dr. DeFronzo’s talks at CODHy Latin America earlier this year.

Corporate Symposium: Building a Brighter Future – Addressing Challenges in Patient Care (Sponsored by Novo Nordisk)

The Impact of Weight on Metabolic Health: Building and Advancing Current Knowledge

Arya Sharma, MD, PhD (University of Alberta, Edmonton, Canada)

Dr. Arya Sharma opened Novo Nordisk’s morning symposium with a strong emphasis that obesity is a key driver of the global diabetes epidemic. In explaining this, he presented the skyrocketing rates of obesity throughout the world and how BMI correlates positively with insulin resistance. Not only did he focus on diabetes, but Dr. Sharma also highlighted obesity’s association with many other conditions like cardiovascular disease – for example, the prevalence of hypertension increases with increasing BMI. He continued by acknowledging that obesity also brings about higher rates of obstructive sleep apnea (which he pointed out contributes to cardiovascular risk as well) and various types of cancer. To conclude, Dr. Sharma emphasized that “it is important to frame obesity in the context of the global diabetes epidemic,” as a treatment for obesity can help treat all of these other conditions.

-- by Melissa An, Adam Brown, Varun Iyengar, Emily Regier, Manu Venkat, and Kelly Close