June 13-17, 2014; San Francisco, CA Day #2 Highlights - Draft

Executive Highlights

Hello from San Francisco, where we’ve just wrapped up the second day of ADA 2014. Saturday featured loads of clinical data as well as the opening of the exhibit hall and poster hall. It was a big day for insulin – we got our first look at phase 3 data on Lilly/BI’s insulin glargine and Novo Nordisk’s ultra-rapid-acting FIAsp, and saw longer-term data on Novo Nordisk’s IDegLira, taking us back to the original DUAL I presentation last year. Over in the exhibit hall, we saw a great deal, including (though not right in the hall), a private demonstration of the astoundingly simple insertion procedure for Intarcia’s implantable exenatide mini-pump. Technology sessions covered a wide array of topics, including CGM, the artificial pancreas, glycemic variability, U500 insulin in pumps, and a new type 2 diabetes partnership between Medtronic and Sanofi (wow!). The day wrapped up with the conference networking reception, which (hopefully) won’t hurt the attendance for the conference 5K early tomorrow morning.

Sunday promises to be another packed day – for those who are lucky enough to be in attendance, check out our thorough ADA 2014 Preview for a rundown of the day’s most exciting sessions. Also, don’t forget to wear red to support the ADA’s movement to Stop Diabetes, and stop by our team’s poster (142-LB) on the costs of diabetes in the US as well as our sister company dQ&A’s (59-LB) poster on the implications of stigma in diabetes.

Below, we’ve listed our top ten drug highlights, our top five tech highlights, and a few other highlights and honorable mentions for good measure. At the end of our report, we include detailed reports on some of the day’s most important presentations.

Top 10 Drug Highlights

1. We had the privilege of attending a private demonstration with Intarcia on the training process for placement and removal of the ITCA 650 exenatide mini-pump. The company had a private training suite within the Exhibit Hall where their clinical nurse force were training investigators who are already participating in their global phase 3 program. The insertion and removal procedures were very simple, with the insertion taking a matter of minutes and removal a matter of seconds. The device is implanted through a tiny, 4 mm incision using a pretty fool-proof insertion device that we could see any kind of health care provider learning how to use. No sutures are even needed – the incision is essentially covered with a Band-Aid. See full details below within our exhibit hall report.

2. Dr. Tim Heise presented pretty compelling PK/PD data showing that Novo Nordisk’s faster-acting insulin aspart (FIAsp, aka NN1218) has a clinically significant faster onset of action than its predecessor, Novolog (insulin aspart). This early-stage study in people with type 1 diabetes (n=36) found that the time to first appearance for FIAsp after co-administration with a standardized meal was just 3.6 minutes compared to 9.8 minutes for insulin aspart (it is quite notable that the insulin was dosed at the same time as the meal, since this is likely when many patients actually take their prandial insulin, rather than the 15-30 minutes prior to eating that is optimal for current rapid-acting analogs). The time to 50% maximum concentration for FIAsp was 27.3 minutes compared to 34.5 minutes for insulin aspart. The earlier onset also translated into greater blood-glucose lowering in the first two hours after insulin administration and meal challenge. After one hour, the postprandial blood glucose excursion was, on average, 22 mg/dl lower on FIAsp than on insulin aspart, and after two hours, it was 26 mg/dl lower. Glucose area under the curve after two hours was 26% lower with FIAsp than with insulin aspart, and area under the curve after six hours was 33% lower. Notably, FIAsp achieved this earlier onset of action with no increase in the rate of hypoglycemia (or hyperglycemia) or any other safety or tolerability concerns.

3. For the first time, we saw phase 3 data for BI/Lilly’s investigational insulin glargine LY2963016 – it appears to act very similarly to Lantus. Drs. Thomas Blevins (Texas Diabetes & Endocrinology, Austin TX) and Dr. Julio Rosenstock (Dallas Diabetes & Endocrine Center, Dallas, TX) presented on LY2963016’s demonstrated non-inferiority to Sanofi’s Lantus in patients with type 1 and type 2 diabetes. Though the product is not being submitted as a biosimilar to the FDA, Dr. Rosenstock made clear that “scientifically, LY is a biosimilar.” In the ELEMENT 1 trial, patients with type 1 diabetes achieved an average A1c reduction of 0.4% after 24 weeks compared to a 0.5% reduction for patients receiving Lantus, and 35% of LY2963016 users reached the target A1c of 7% compared to 32% of Lantus users. In the ELEMENT 2 trial, patients with type 2 diabetes achieved identical A1c reductions of 1.3% from a baseline of 8.3% whether they were given the investigational glargine or Lantus, and 49% of patients treated with LY2963016 reached the target compared to 53% of patients treated with Lantus. In both trials, the incidence of adverse events, including hypoglycemia, was also similar between the groups, and the researchers concluded that there were no clinically significant differences between the two products.

4. Dr. Stephen Gough (University of Oxford, UK) presented one-year results of the original 26-week DUAL I trial on IDegLira, a combination of Novo Nordisk’s fixed-ratio combination of the ultra-long-acting basal insulin Tresiba (insulin degludec) and GLP-1 agonist Victoza (liraglutide). The 52-week results were remarkably consistent with the results of the original 26-week study, which were first presented at last year’s ADA (read our coverage). From a baseline of ~8.3%, patients in the IDegLira arm achieved a mean final A1c at 52 weeks of 6.4% (reduction of 1.8% from baseline), a statistically significant improvement over insulin degludec’s final A1c of 6.9% (reduction of 1.4%) and liraglutide’s 7.1% (-1.2%). The theme of conserved results also applied to fasting plasma glucose (IDegLira was significantly better than liraglutide but not insulin degludec), hypoglycemia (IDegLira was associated with 37% less confirmed hypoglycemia than insulin degludec monotherapy), and body weight (IDegLira was fairly weight neutral and fell squarely between the weight gain of insulin degludec and weight loss of liraglutide). The constancy of efficacy and safety results from the original 26-week results was reassuring for several reasons – it reduces the likelihood that the 26-week findings were due to chance, and also demonstrates that the combination product’s efficacy is not only strong, but also fairly durable (patients’ mean IDegLira dose was flat from week 26 to week 52).

5. Dr. Geremia Bolli (University of Perugia, Perugia, Italy) rounded out previously-released topline results from Sanofi’s EDITION III trial of U300 insulin glargine, which investigated the effects of the initiation of U300 versus standard insulin glargine in insulin-naïve type 2 diabetes patients on oral agents alone. Similar to trials EDITION I and EDITION II, results showed non-inferiority in A1c reduction; however, there was no significant reduction in the percentage of patients with ≥1 severe or confirmed nocturnal hypoglycemic events (≤70 mg/dl) from nine weeks to six months of treatment. In today’s full results, analysis was tweaked to include the full six-month study period, leading to slight significance in favor of U300 (HR 0.76; 95% CI 0.59-0.99). With the benefit in hypoglycemia weighted to the initial weeks of treatment, it remains unclear if this reflects a meaningful difference in the clinical setting – as patients in EDITION III had less severe diabetes compared to EDITION I and II patients, the hypoglycemia benefit of U300 may be limited to those already more prone to hypoglycemia. See below for more details.

6. In front of an overflowing audience, Dr. Jacqueline Koehler reviewed the current preclinical and clinical data surrounding the risk of incretins and pancreatitis/pancreatic cancer. Dr. Koehler synthesized the current state of affairs very cogently: much of the debate over incretins and pancreatic safety has been fueled by a few publications of preclinical and clinical data that have not been reproducible. The majority of the available clinical data has come from retrospective database and case-controlled observational studies, which are subject to numerous biases and limitations. In particular, she explored the possibility for over-diagnosis based on elevated pancreatic enzyme levels (a marker of pancreatitis that is not, in itself, sufficient for diagnosis). Dr. Koehler suggested that the highest quality clinical data on this issue will come from the large cardiovascular outcomes trials (CVOTs) ongoing for incretin-based therapies – she found the neutral pancreatic findings from SAVOR and EXAMINE “promising” and remarked that they demonstrated that if any risk exists, it is so low that it was not even detected with a 16,000+ person trial (SAVOR). She noted that we will have to wait for more data from the outcomes studies to draw better conclusions on the benefit/risk profiles for incretin-based drugs.

7. Dr. Melanie Davies (University of Leicester, United Kingdom) presented, for the first time, full details of the phase 3a SCALE Diabetes trial, which investigated the effectiveness of Novo Nordisk’s liraglutide 3 mg for obesity in people with type 2 diabetes. This is the first presentation of the full data of this phase 3 trial after topline results were announced all the way back in March 2013. Treatment with liraglutide 3.0 mg dose led significantly greater weight loss and reductions in A1c versus placebo (6% vs. 2%). See below for more details.

8. Dr. Carmen Valcarce presented the positive results of a phase 1b/2a study of TransTech’s liver-selective glucokinase activator (GKA) TTP399. The trial studied three doses of TTP399 in 120 type 2 diabetes patients on baseline metformin therapy for 42 days. In that time period, the highest dose (800 mg twice daily) led to an absolute A1c reduction of ~0.9% and a placebo-adjusted reduction of ~0.5% at the end of the study (mean baseline of ~8.1%), with action on both fasting and postprandial glucose (the postprandial effect appeared strongest). A highlight of the results was a sub-analysis showing that the drug’s efficacy was largely preserved in patients that were fairly well controlled at baseline (A1c < 7.5%) – while the placebo arm (n = 8) in this subgroup held steady at around 7.2% A1c, the high dose arm (n = 8) saw an A1c reduction to a mean of 6.4%, making for a greater placebo-adjusted difference (-0.8%) than was seen in the overall cohort. Dr. Valcarce fully acknowledged that the GKA class is burdened by previous failures, which were largely due to increases in lipids or liver enzymes as well as high rates of hypoglycemia; she highlighted that TTP399 was not associated with any increase in lipids, insulin secretion, or hypoglycemia. Those safety data, as well as the drug’s efficacy independent of baseline A1c, might indicate that this compound might be an especially effective tool for intensifying therapy in moderately well controlled type 2 diabetes patients.

9. Biodel’s Dr. Alan Krasner presented weaker than expected full results on the phase 2 study of the ultra-rapid-acting recombinant human insulin, BIOD-123 – topline data was shared in September 2013. Our takeaway after seeing these full results was that data interpretation is challenging for many reasons – there were large baseline group imbalances in gender, differences in basal insulin doses, and an open-label design that may have led to ascertainment bias. Overall, BIOD-123 was non-inferior to Humalog as measured by change in A1c – there was a non-significant 0.17% treatment difference in favor of Humalog (baseline A1c: 7.3%), and the 95% confidence interval [-0.01, 0.35] just barely met the non-inferiority margin of 0.4%. [Note: this was highly similar to what was observed in the phase 3 trial of MannKind’s Afrezza, which had a 0.19% treatment difference in favor of aspart and a [0.02, 0.36] confidence interval that also just barely met the non-inferiority endpoint.] Ten-point profiles and CGM did not demonstrate consistent postprandial glucose differences between BIOD-123 and Humalog, despite a clear postprandial benefit observed during a liquid meal challenge test (~15 mg/dl improvement with BIOD-123). There was higher injection site discomfort with BIOD-123, a problem that has plagued Biodel since Linjeta – however, these events disproportionately came from certain trial sites, suggesting the possibility of ascertainment bias (the trial was an open-label design). Less basal insulin was used in the BIOD-123 arm, and there was a non-significant trend towards higher overnight glucose levels with BIOD-123 – this could suggest basal insulin was sub-optimally titrated in the BIOD-123 arm. Overall, lots more questions than answers flowed out of this study.

10. The Poster Hall also opened today with several gems: (i) Lilly presented AWARD-4 results, the first phase 3 trial in which a GLP-1 agonist (dulaglutide) has been studied in conjunction with meal-time insulin and found the combination to be better than basal/bolus therapy; (ii) one poster explored the potential for flexible dosing with Sanofi’s U300 version of insulin glargine and found it to be comparable to fixed dosing; (iii) another outlined evidence for the preferential hepatic action of Lilly’s basal insulin peglispro; (iv) a poster delineated renal outcomes in SAVOR: Onglyza treatment improved urinary albumin creatinine ratio, but did not produce a difference in hard renal outcomes; (v) another poster on BI/Lilly’s SGLT-2 inhibitor found that empagliflozin reduced microalbuminuria; (vi) medication adherence rates to GSK’s once-weekly injectable GLP-1 agonist Tanzeum (albiglutide) were found to be better than that to once-daily oral comparators; and (vii) Sanofi’s Lyxumia (lixisenatide) established an advantage in postprandial glucose lowering compared to Novo Nordisk’s Victoza (liraglutide).

Top Five Technology Highlights

1. At a sold-out, standing room only dinnertime corporate symposium from Dexcom, Dr. Steven Russell (Massachusetts General Hospital, Boston, MA) updated the audience on his group’s development of a bionic pancreas that delivers both insulin and glucagon using input from the Dexcom Gen 4 CGM. Dr. Russell announced that they would begin a two-week home-use study of the system in just two days. Monitoring will be minimal, and freedom will be high: patients will even be allowed to drive while under closed-loop control! Dr. Russell is also conducting clinical PK/PD research on Xeris’ glucagon, which is liquid-stable for up to two years at room temperature. He hopes to use this stable glucagon in a pivotal trial (more than three months long!) in 2015, with FDA review “as early as 2016” and possible approval in 2017. Dr. Bruce Buckingham (Stanford University, Stanford, CA) then discussed the use of sensors in pediatric patients. He emphasized that BMI and age do not affect CGM accuracy, citing an unpublished sub-analysis from one of his group’s camp studies with Medtronic’s Enlite (Buckingham et al., Diabetes Care 2014). With regard to the Dexcom Share remote monitoring device, Dr. Buckingham lightheartedly commented that “FDA approval is pending…with a pregnant pause.” Also, Ms. Davida Kruger (Henry Ford Hospital, Grosse Point, MI) presented an overview of how professional CGM can help patients, especially those who learn to treat trends, as opposed to individual numbers, and who do not get caught up in the expectations and dreams of perfect glycemic control. Look out for more details in our ADA 2014 full report.

2. Dr. William Tamborlane (Yale University, New Haven, CT) provided a concise and organized overview of the past year in artificial pancreas research, focusing on the safety of low glucose/predictive suspend and overnight closed-loop. Regarding the latter, he noted that “the holy grail of unsupervised full closed-loop control may be just around the corner, given the results from Dr. Hovorka’s recent study. Dr. Tamborlane’s presentation covered four main studies: Beck et al., Diabetes Care 2014 and Sherr et al., Diabetes Care 2014 (both demonstrating the safety of low glucose/predictive suspend); Hovorka et al., Diabetes Care 2014 (demonstrating the safety of unsupervised overnight closed loop); and Buckingham et al., Diabetes Care 2013 (no impact of short-term hybrid closed loop immediately following diagnosis). Though closed-loop studies have demonstrated feasibility in the inpatient setting, Dr. Tamborlane explained that there are still some key obstacles to broad outpatient use: making the device user interfaces easy to use and establishing redundant safeguards to minimize the risk of excessive insulin administration.

3. Early in the afternoon, the highly regarded Drs. Irl Hirsch (University of Washington, Seattle, WA) and Richard Bergenstal (International Diabetes Center, Minneapolis, MN) discussed whether glycemic variability (GV) matters in the development of long-term complications. Although the talk was technically a debate, the speakers shared many views (“I am a supporter of the Irl Hirsch ‘Beyond A1c’ Movement,” disclosed Dr. Bergenstal). Both physicians think that hypoglycemia is extremely clinically important, both favor wider use of CGM, both would like to see outcomes-based research that can definitively assess the importance of glycemic variability, both think that coefficient of variability is probably the best metric for research on GV. (Dr. Hirsch made some references to a clinical trial on which he and Dr. Bergenstal are collaborating – we assume this is FLAT SUGAR – that will compare different metrics for GV to see which correlate best with inflammation and reactive oxygen species.) Still, there were some controversies. For example, noting that rates of complications have fallen in the US for the past 20 years, Dr. Bergenstal attributed the change to clinical focus on A1c in the wake of DCCT. Dr. Hirsch instead proposed that the game-changer was the development of Lantus (Sanofi’s insulin glargine), which led to wider use of basal-bolus insulin therapy. He said that before Lantus, many patients had tried to get by with one or two daily shots of NPH or lente insulin; Dr. Hirsch said that in this way, development of NPH and lente set the field back by 50 years.

4. Dr. Anand Velusamy (King's College Hospital NHS Foundation Trust, London, UK) presented very positive results from an uncontrolled study examining the impact of U500 insulin delivered via pump. The study included very poorly controlled (baseline A1c: 10.4%), highly insulin resistant patients (mean daily dose: 306 units) with type 1 (n=3) and type 2 diabetes (n=11). A1c declined by an impressive 1.9% at six months (n=14), 2.3% at 12 months (n=11), and was maintained out to 36 months (n=6). At the same time, total daily insulin requirements declined from 306 units at baseline to 244 units at 12 months and 250 units at three years. Weight did not change significantly, with patients gaining an average of 2 kg at 12 months and three years (baseline: 108 kg). Perhaps most notable were the cost implications – using U500 in the pump vs. U100 insulin was estimated to save ~2,200 British pounds per patient per year (~$4,000 USD). Though the study was uncontrolled and patients did receive nursing support, we thought these were very strong clinical results in a highly challenging population. Of course, this gels with efforts from companies like Insulet, Tandem, and Medtronic, who are all now actively pursuing type 2 focused products (Insulet’s U500 OmniPod with Lilly; Tandem’s 480-unit reservoir t:slim; Medtronic’s new type 2 business unit). The need is incredibly great in the severely insulin resistant population, and it’s great to see movement from industry that corresponds to the positive clinical data that continues to accrue on this front.

5. Today, Medtronic and Sanofi jointly announced a “strategic alliance” focused on improving the management of type 2 diabetes. This announcement was first alluded to in Medtronic’s Analyst Day ten days ago. The partnership will pair Sanofi's insulin portfolio and drug development expertise with Medtronic’s background in insulin pumps and CGM – a particular priority is new drug-device combinations, including new form factors that are affordable, convenient and easy to-use. We could imagine multiple products that could come out of the alliance, especially prefilled patch pen-like wearable devices (like Valeritas or CeQur) or simplified prefilled insulin pumps. Additionally, we wonder if a concentrated insulin partnership is in the works, similar to the approach and Insulet and Lilly are taking. The companies also plan to collaborate on “care management services” through a program designed to guide type 2s failing on orals onto insulin therapy. Implementation of the alliance is “subject to the negotiation and execution of a definitive agreement between the companies,” which makes it sound like there is much to be hammered out. As a reminder, Sanofi and Medtronic have an existing agreement in place serving specific type 1 patients in Europe with implantable pumps.

Also…

1. Dr. Francesca D’Addio (Harvard Medical School, Boston, MA; and San Raffaele Hospital, Milan, Italy) presented a series of studies conducted in Poland and China on the controversial potential of autologous hematopoietic stem cell transplantation (AHSCT) to cure newly-diagnosed type 1 diabetes patients. The tested question is a version of the Voltarelli Cocktail. The approach uses high doses of immunosuppressants (cyclophosphamide and antithymoctye globulin [ATG]) to largely wipe out the immune cells. Patients are then “rescued” with the AHSCT, and the hope is that the immune system will redevelop without islet autoimmunity. The therapy, which was tested in 65 patients in three sub-studies, yielded some fairly striking and, more importantly relatively long-lasting benefits (for context, past biological approaches to curing type 1 diabetes have only had a temporary affect, if any). Insulin independence was achieved in all patients at least once during the trial, and persisted for an average of 18 months. Over 32% of patients remained insulin independent until their last follow-up (not disclosed). This efficacy was backed up by significant decreases in insulin requirements, significant and sustained increases in C-peptide, and a massive sustained mean A1c reduction from 10.1% to 6.0%. Such benefit did not come without cost – the frequency of severe side effects was fairly high, and the list included neutropenic fever, alopecia, fever, and one death due to sepsis that may or may not have been related to the therapy, which is immunocompromising (34/65 patients experienced an adverse event).  

2. The grand ballroom was packed for this highly anticipated debate in which the legendary Dr. Jay Skyler (University of Miami, FL) argued a resounding “yes” for whether there is value in controlling A1c in reducing cardiovascular disease risk. In savvy debate strategy, Dr. Skyler cut straight to the rebuttal by addressing the infamous trilogy of studies – ACCORD, ADVANCE, and VADT – that failed in primary analysis to show statistically significant CVD risk reduction due to glycemic control. Yet Dr. Skyler argued that inadequate study length, competing medications like ACE inhibitors and statins, and prior history of CVD did not provide room to see benefits of glycemic control on CV risk reduction. Notably, subgroup analyses in each of these trials of patients without CV event history proved that earlier intensive treatment could in fact reduce CV risk. In support of his argument, Dr. Skyler also reviewed the STENO-2 study, EDIC/DCCT, and UKPDS, which all showed significant CV risk reduction only after long-term follow-up. Early intensive treatment provides long-term benefits, i.e. a “legacy effect,” and such follow-up evidence may shape future treatment guidelines, Dr. Skyler argued. Dr. Michael Farkouh (Mount Sinai Hospital Toronto, Ontario) acknowledged Dr. Skyler’s assertion that strict control of A1c values in people with diabetes can prevent damage to the microvasculature, and that “aggressive” treatment of type 1 diabetes in young individuals can result in fewer overall cardiovascular events in those individuals. However, he maintained that there is no solid evidence that tight control of A1c in type 2 diabetes reduces macrovascular complications. He suggested that some of the resources spent working to lower A1c levels in those with type 2 diabetes should be spent to work toward reducing LDL levels and providing statins to diabetes patients. Dr. Farkouh also raised some concerns regarding adverse macrovascular outcomes associated with intensive glycemic control and aggressive treatment of type 2 diabetes. See below for full details on their presentations, as well as the question and answer session.

3. Close Concerns own Kelly Close (San Francisco, CA) gave an impassioned talk on the patient’s perspective in drug and device development for pediatric diabetes, centering on three key questions: (i) “What are the hardest parts about managing pediatric diabetes?” (ii) “What are the biggest unmet needs in pediatric diabetes?” and (iii) “What would be a complete home run for young patients with diabetes?” Diabetes management for pediatric patients is rife with frustration – though the field is moving ahead on many fronts, there remains work to do, with continuing effort needed to keep the patient at the center of drug and device development. See below for more details on the session, which will be reporting on in detail.

4. Dr. John Kirwan (Cleveland Clinic, Cleveland, OH) presented a clever and elegant study suggesting that exclusion of the foregut in roux-en-y gastric bypass (RYGB) is key for the surgery’s glycemic effects. The Cleveland Clinic team, including famous bariatric surgeon Dr. Philip Schauer, placed G-tubes in the excluded stomach during 14 people with obesity and type 2 diabetes’ RYGB procedures (11 of the participants were female; they had an average BMI of 49.2 kg/m², diabetes duration of 7.7 years, and A1c of 7.5%). The G-tube enabled researchers to conduct mixed meal tolerance tests (MMTTs) as if the foregut had not been excluded during the procedure, since the mixture would pass through both the foregut and hindgut. Compared to a pre-operative oral MMTT, both post-operative MMTTs caused a greater level of insulin secretion, with the oral MMTT causing the greatest amount of secretion. Similarly, the post-operative oral MMTT identified the greatest levels of C-peptide secretion and beta cell function. In contrast, a similar degree of insulin resistance improvement from the pre-operative oral MMTT was seen for both the oral and the G-tube post-operative MMTTs. These results suggest that adaptations arising from the foregut exclusion might provide a key mechanism for understanding diabetes remission after RYGB. The idea that skipping the upper intestine may remit diabetes suggests that a bad actor in the upper intestine might be involved in the etiology of the disease. Such a factor may be considered an “anti-incretin” – i.e., an intestinal peptide that causes diabetes instead of improving it.

5. The exhibit hall opened today, which seemed to have less fanfare, attendance, and excitement than we’ve seen in the past. Our coverage today includes the following companies: AstraZeneca (new Bydureon pen still deemphasized), BD, BI/Lilly, Dexcom (G4 Platinum Professional vs. Medtronic iPro2), Eisai, Glooko (Bluetooth sync and Joslin HypoMap), GSK (new Tanzeum pen), Insulet, J&J Janssen, J&J LifeScan/Animas, Lilly, Medtronic (MiniMed Duo on display, next-gen pump platform displayed), Merck, Novo Nordisk (pre-launch of the FlexTouch pen), Sanofi, Takeda, Tandem, Type 1 Diabetes TrialNet, Valeritas, and Vivus.

Honorable Mentions

Dr. Roberto Calle (Pfizer, Groton, CT) shared the results of a double-blind four-week escalating dose study on the company’s phase 2 FGF21 analog PF-05231023. As of the company’s 1Q14 report, it appeared that the company dropped the candidate, but this has not been confirmed. The trial’s results were largely in line with the clinical data seen on Lilly’s discontinued FGF21 analog: there were robust improvements in lipids (50% reduction in triglycerides, 20% reduction in LDL-C, 25% increase in HDL-C), and a very rapid loss of body weight (5.5 kg or 12 lbs in just four weeks), but the trend towards reduction in glucose levels did not reach statistical significance. This led Dr. Calle to suggest that while the candidate shows promise for dyslipidemia and obesity, its potential for type 2 diabetes is lower, and would only come through weight effects. Excitement in FGF21 as a target for metabolic conditions including diabetes remains, but work is still being done to develop molecules with a better effect on glucose.

In reference to Lewis Carroll’s “Through the Looking Glass,” Dr. Katie Weinger (Joslin Diabetes Center, Boston, MA) acknowledged that patients with diabetes must not only believe but also accomplish the seemingly impossible with diabetes self-care. The challenges of living with diabetes abound – complicated treatment regimens, demanding lifestyle requirements, comorbidities, stress on family relationships, and competing priorities of daily life to name a few. It is these daily challenges that diabetes education can help with, but only if providers tailor education approaches to fit the individual patient. Dr. Weinger wisely acknowledged that the challenges and perceptions of diabetes vary with the patient’s type of diabetes, stage of disease, ability to organize and cope, health beliefs and lifestyle priorities, social and family support, involvement with health care team, and socioeconomic environment and thus educational approaches should vary accordingly. She also presented data from an NIH-funded study evaluating the efficacy of using cognitive behavioral strategies during an educator-led group education for diabetes patients with poor glycemic control. See below for more details.

During the ADA/JDRF Symposium, Dr. Anette-Gabriele Ziegler (Helmholtz Zentrum Munchen, Munich, Germany) proposed several different ways type 1 diabetes could be screened for in the broader population. Dr. Ziegler thinks the most cost-effective screen would be to test three-year-olds for multiple antibodies. Dr. Ziegler selected the age of three years, because in TEDDY and a study in Finland this age was associated with the highest incidence of islet autoantibodies. By Dr. Ziegler’s estimate, if one were to screen 200,000 three-year-olds, 500 would test positive, and 450 would develop type 1 diabetes before they were 20 years old. This screen would identify 45% of all cases of type 1 diabetes diagnosed before the age of 20 years. During a subsequent panel discussion, the concern Dr. Ziegler raised with this approach is that trends in type 1 immunotherapy research suggests it will be easier to prevent the onset of autoimmunity than to reverse established autoimmunity. Thus, Dr. Ziegler thinks it might be more necessary to screen newborns for genetic risk. Unfortunately, this would be substantially less cost effective: screening HLA risk at birth (as was done in TEDDY) means that 2,672 out of 200,000 screened newborns would test positive, and only 284 would develop type 1 diabetes by age 20 years – this would represent 28.4% of all future type 1 diabetes cases by age 20 years. Of course, at this point, an effective method for preventing type 1 diabetes autoimmunity has not been identified, so selecting a screening method is likely putting the cart before the horse.

In a President, Healthcare, and Education Address peppered with Bob Dylan song clips, Dr. Marjorie Cypress (ABQ Health Partners, Albuquerque, NM) spoke about the big problems in diabetes today: stigma, costs, healthcare delivery, healthcare literacy and numeracy, and social determinants of health. She noted remaining prejudices against diabetes amongst patients and providers, additionally highlighting the entrenched role social and economic factors play in propagating diabetes. She concluded her talk with a call to join ADA’s efforts in spreading awareness and taking action in the community, to a standing ovation. See below for more details.

 

Detailed Discussion and Commentary

Drugs

Oral Presentations: Prandial Insulin Therapy

Faster-Acting Insulin Aspart Improves Postprandial Glycemia vs. Insulin Aspart in Patients with Type 1 Diabetes Mellitus (T1DM) (129-OR)

Tim Heise, MD (Profil Institute for Clinical Research, Chula Vista, CA)

Dr. Tim Heise presented pretty compelling PK/PD data showing that Novo Nordisk’s faster-acting insulin aspart (FIAsp, aka NN1218) has a clinically significant faster onset of action than its predecessor, Novolog (insulin aspart). This early-stage study in people with type 1 diabetes (n=36) found that the time to first appearance for FIAsp after co-administration with a standardized meal was just 3.6 minutes compared to 9.8 minutes for insulin aspart (it is quite notable that the insulin was dosed at the same time as the meal, since this is likely when many patients actually take their prandial insulin, rather than the 15-30 minutes prior to eating that is optimal for current rapid-acting analogs). The time to 50% maximum concentration for FIAsp was 27.3 minutes compared to 34.5 minutes for insulin aspart. The earlier onset also translated into greater blood-glucose lowering in the first two hours after insulin administration and meal challenge. After one hour, the postprandial blood glucose excursion was, on average, 22 mg/dl lower on FIAsp than on insulin aspart, and after two hours, it was 26 mg/dl lower. Glucose area under the curve after two hours was 26% lower with FIAsp than with insulin aspart, and area under the curve after six hours was 33% lower. Notably, FIAsp achieved this earlier onset of action with no increase in the rate of hypoglycemia (or hyperglycemia) or any other safety or tolerability concerns.

• FIASp’s structure and formulation: FIAsp’s molecular structure is identical to the insulin analog aspart (Novo Nordisk’s Novolog), which means that the proline at position B28 in the native insulin peptide has been substituted with aspartic acid. Its excipient formulation is what makes it different from Novolog. FIAsp has two excipients: nicotinamide, a vitamin B3 that is an absorption modifier, and arginine, a naturally occurring amino acid that is a stability enhancer. Dr. Heise highlighted that both of the excipients are on the FDA ingredients list for approved drug products for injection. Thus, with the established safety profile of Novolog, FIAsp should have very few safety concerns.
• The study presented was a randomized, double-blind, cross-over, meal challenge study comparing the PK/PD of FIAsp with insulin aspart (n=36 people with type 1 diabetes). Patients received a single dose of FIAsp or insulin aspart (0.2 U/kg) together with a meal (600 kcal standardized liquid meal consisting of 67% carbohydrate, 17% protein, and 16% fat). Prior to dosing, blood glucose was normalized to 100 mg/dl using IV insulin infusion (stopped no later than five minutes before study drug dosing). After a 3-12 day washout period, patients received another meal test, this time with the opposite drug than they received at the first meal test.
• FIAsp had a faster onset of appearance and greater exposure during the first two hours after dosing. FIAsp’s mean onset of appearance was just 3.6 minutes after dosing compared to 9.8 minutes for insulin aspart (a highly statistically significant difference). The time to 50% maximum concentration for FIAsp was 27.3 minutes compared to 34.5 minutes for insulin aspart.
• Total drug exposure (area under the curve over 10 hours), maximum concentration, and time to maximal concentration were essentially equivalent between FIAsp and insulin aspart. This means that FIAsp’s PK curve was simply shifted to the left of insulin aspart. In other words, it has a faster onset but few other PK differences.
• The earlier onset of appearance translated into greater blood-glucose lowering in the first two hours after administration and meal challenge. After one hour, the postprandial blood glucose excursion was, on average, 22 mg/dl lower on FIAsp than on insulin aspart, and after two hours, it was 26 mg/dl lower (statistically significant). Glucose area under the curve after two hours was 26% lower with FIAsp than with insulin aspart (statistically significant).
  
  • Total glucose area under the curve over six hours was reduced by 33% with FIAsp compared to insulin aspart.
• The incidence of hypo- and hyperglycemia requiring intervention was similar between FIAsp and insulin aspart. Investigators intervened at 50 mg/dl and 306 mg/dl for hypo- and hyperglycemia, respectively. On FIAsp, 20% of patients required hypoglycemic intervention compared to 23% on insulin aspart. On FIAsp, there were zero interventions for hyperglycemia, and there was one for insulin aspart.

Questions and Answers

Q: What was the actual time between the injection and the beginning of the meal?

A: About one minute. Basically, they injected and started to eat.

Q: What are the requirements to get faster-acting aspart approved by FDA?

A: The regulatory requirement is similar to that of other drugs. Because the molecule is the same, there was no necessity for a phase 2 study. So basically after the phase 1 studies, the company directly moved directly into phase 3 and these trials are ongoing. It will be like any other drug.

Q: What is the objective of the phase 3 program?

A: First objective is obviously safety and efficacy under more real-world conditions. So the phase 3 studies will investigate safety data and will look into A1c, hypoglycemia, possibly also quality of life and other things.

Q: What was the time to maximum insulin concentration vs. aspart?

A: If I recall correctly it was about 1 hr for both – the time to maximum was not significantly different.

Safety and Efficacy of Ultra-Rapid-Acting Human Insulin Formulation BIOD-123 in Patients with Type 1 Diabetes

Alan Krasner, MD (Biodel, Danbury, CT)

Biodel’s Dr. Alan Krasner presented full results on the phase 2 study of its ultra-rapid-acting human insulin, BIOD-123 – topline data was shared in September 2013. Our takeaway after seeing these full results was that data interpretation is challenging for many reasons – there were large baseline group imbalances in gender, differences in basal insulin doses, and an open-label design. Overall, BIOD-123 was non-inferior to Humalog as measured by change in A1c. There was a 0.17% treatment difference in favor of Humalog (baseline A1c: 7.3%), though the 95% confidence interval [-0.01, 0.35] just barely met the non-inferiority margin of 0.4%. [Note: this was highly similar to what was observed in the phase 3 trial of MannKind’s Afrezza, which had a 0.19% treatment difference in favor of insulin aspart and a [0.02, 0.36] confidence interval that also just barely met the non-inferiority endpoint.] Ten-point profiles and CGM did not demonstrate consistent postprandial glucose differences between BIOD-123 and Humalog, despite a clear postprandial benefit observed during a liquid meal challenge test (~15 mg/dl improvement with BIOD-123). There was higher injection site discomfort with BIOD-123, a problem that has plagued Biodel since Linjeta – however, these events disproportionately came from certain trial sites, suggesting the possibility of ascertainment bias (the trial was an open-label design). Less basal insulin was used in the BIOD-123 arm, and there was a non-significant trend towards higher overnight glucose levels with BIOD-123 – this could suggest basal insulin was sub-optimally titrated in the BIOD-123 arm. Overall, lots more questions than answers flowed out of this study, and it is perhaps not a surprise that Biodel has not firmed up a partnership on this asset. 

Questions and Answers

Q: There were differences in meal tests in favor of Biodel. But there were no difference in real life. Was the timing of injection before the meal different?

A: They should have been the same. The instructions were to dose the prandial insulin immediately before the meal – in the liquid meal challenge and also at home. We do believe that is practically when most patients take prandial insulin – just before meals.

Q: Together with the previous speaker, ultra-rapid-acting insulins showed lower postprandial glucose excursions. In your study, there not a change in A1c. What level of postprandial reduction is needed to see change in A1c? Perhaps 10-15 mg/dl may not be enough to see a change in A1c. Second, I’m a clinician – how important is this in my clinical day-to-day management?

A: I don’t know the answer to your first question. I don’t know how much postprandial reduction you need for an A1c reduction. Our data is a little complex because of imbalances by chance in dosing. It’s hard to interpret the A1c data. The liquid meal challenge was more controlled circumstances. Glucose was measured by a lab analyzer. It’s possible that some of the home-based readings result from variability and noise in measurements. And differences in dosing that contributed as well.

I don’t know the answer to using it in clinical practice. I would guess these insulins would be used as rapid-acting analogs are used now. We often say take insulin right before meals. We know based on recently published data that may not be the optimal time to take lispro and aspart. Good ultra rapid-acting analogs may be ideal for taking just before meal.

Dr. Melanie Davies (University of Leicester, UK): Thank you very much. There is some promise here, but there is still some work to do.

Oral Presentations: Basal Insulin Therapy

Similar Efficacy and Safety with LY2963016 Insulin Glargine Compared with Lantus Insulin Glargine in Patients with T1DM: The ELEMENT 1 study (69-OR)

Thomas Blevins, MD (Texas Diabetes & Endocrinology, Austin, TX)

Dr. Thomas Blevins presented phase 3 data from the ELEMENT 1 study indicating that Lilly’s biosimilar LY2963016 insulin glargine had efficacy and safety profiles comparable to Lantus in patients with type 1 diabetes when combined with insulin lispro. In the study, LY2963016 insulin glargine demonstrated non-inferiority to Lantus in terms of A1c reduction; patients achieved A1c reductions of 0.4% with LY2963016 insulin glargine and 0.5% with Lantus at 24 weeks from a baseline of 7.8%, with 0.3% reduction for both treatments observed at 52 weeks. Thirty-five percent of LY2963016 insulin glargine users and 32% of Lantus users achieved A1c levels of 7.0% after 24 weeks; both user groups experienced a 62% incidence of adverse events at 52 weeks, and the total hypoglycemia rate stood at 77 events per patient per year with LY2963016 insulin glargine and 80 with Lantus. Dr. Blevins concluded that the two products in combination with lispro had similar efficacy and safety profiles with no clinically significant differences.  

• The ELEMENT 1 study was a phase 3, open-label clinical trial involving 535 patients with type 1 diabetes who were randomly assigned to receive basal-bolus therapy with either the investigational glargine (N = 268) or Lantus (N = 267) in addition to insulin lispro. The study lasted 24 weeks, with a follow-up through 52 weeks. The patients had an average BMI of 25 kg/m² and an average A1c of 7.8% at baseline, and all of them had been receiving treatment with insulin glargine, insulin detemir, or NPH prior to the study.
• The results of this study demonstrated that LY2963016 insulin glargine is non-inferior to Lantus in terms of the primary endpoint of A1c reduction. After 24 weeks, the group receiving the investigational glargine had achieved an A1c reduction of 0.35% compared to a 0.46% reduction for the group receiving Lantus. Additionally, 35% of the participants in the investigational glargine group had reached the target A1c of 7% compared to 32% of the Lantus group.
• The investigational glargine also demonstrated non-inferiority on a number of secondary endpoints related to safety and efficacy. There was no significant difference between the groups in fasting plasma glucose reduction, body weight change, or daily insulin dose. The frequency of adverse events was 62% in both groups after 52 weeks, and both groups had similar rates of hypoglycemia (77 events/patient/year with LY2963016 and 80 with Lantus after 24 weeks), allergic events (8% of people receiving LY2963016 and 4% of people receiving Lantus), and antibody responses (9% of the LY2963016 group and 6% of the Lantus group).

Questions and Answers

Q: When looking at safety data like insulin antibodies, I’m not interested in mean levels, I want to know if there are a few people who are severely affected. Your presentation addresses the wrong question. Are there 1-2% who have severe problems?

A: Let me defer to the next presentation where you’ll hear more about how antibody levels and response were measured.

Similar Efficacy and Safety with LY2963016 Insulin Glargine Compared with Lantus Insulin Glargine in Patients with T2DM: The ELEMENT 2 Study (64-OR)

Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)

Dr. Julio Rosenstock presented the phase 3 results of the ELEMENT 2 study, which compared the safety and efficacy profiles of Lilly’s investigational LY2963016 insulin glargine to the currently marketed Lantus insulin glargine. The study demonstrated non-inferiority of LY2963016 compared to Lantus in terms of A1c reduction; patients in the LY2963016 group (N = 376) achieved an average A1c reduction of 1.3% after 24 weeks compared to a 1.4% reduction for the Lantus group (N = 380) from a baseline of 8.3%. 49% of LY2963016 insulin glargine users reached the target A1c of 7%, compared to 53% of Lantus users. The frequency of adverse events was also similar – 52% for LY2963016 insulin glargine and 48% for Lantus – as was the number of hypoglycemic events, with 21 events per patient per year for LY2963016 insulin glargine and 22 for Lantus. Dr. Rosenstock concluded that the two insulin glargine formulations have equivalent efficacy and safety profiles and that there is no clinically significant difference between them.

• The ELEMENT 2 study was a phase 3, double-blind clinical trial involving 759 patients with type 2 diabetes who were randomly assigned to receive either the investigational glargine (N = 376) or Lantus (N = 380) for 24 weeks. The average age of the participants was 59, average weight was 90 kg, and baseline A1c was 8.3% for both groups. All patients had received treatment for diabetes for at least 2 years, 60% with insulin and 40% with oral medications.
• The results of this study demonstrated that LY2963016 insulin glargine is non-inferior to Lantus in terms of the primary endpoint of A1c reduction. Both groups had an average A1c of 8.3% at baseline; the average at the end of the study was 7.0% for the group receiving the investigational glargine compared to 6.9% for the Lantus group. Additionally, 49% of the participants in the investigational glargine group reached the target A1c of £ 7.0% compared to 53% in the Lantus group.
• The investigational glargine also demonstrated non-inferiority on a number of secondary endpoints related to safety and efficacy. There was no significant difference between the groups in fasting plasma glucose reduction, body weight change, or daily insulin dose. The frequency of adverse events was 52% with the investigational glargine compared to 48% with Lantus, and both groups had similar rates of hypoglycemia (21 events/patient/year with LY2963016 and 22 with Lantus) and allergic events (6% of people receiving LY2963016 and 7% of people receiving Lantus).
• Dr. Rosenstock was clear that he considers this product to be a biosimilar insulin glargine, despite the regulatory complexity surrounding this designation. He explained that although it will not be classified as a biosimilar by the FDA, it meets the scientific criteria of  (i) high similarity to the reference product; (ii) minor differences in clinically inactive components; and (iii) no clinically meaningful differences in terms of safety, purity, and potency.

Questions and Answers

Q: Very nice study. I have one question about antibody response: it’s hard to measure antibodies with a high degree of sensitivity, so can you tell us more about the assay you used?

A: I can’t give you specifics on that, but there will be a presentation later that I encourage you to attend.

Q: This was very nice, congratulations. I have one comment about your second slide where you referred to the regulatory designation in the US and “other geographies.” “Other geographies” includes many, many other countries with different rules!

A: Yes, so in my judgment, it is a biosimilar because it has all the specific criteria. I was speaking from a regulatory perspective; here it has to go through a different pathway, so it’s just regulatory terminology. In essence, scientifically, LY is a biosimilar.

Q: Biosimilar guidelines suggest looking for biosimilarity in the most sensitive population – in this case, patients with type 1 diabetes. In this study, you’ve selected the population that would be least likely to show differences, not people who’ve been using insulin for a long time.

A: We had people who’ve been using insulin for 10 years. 60% of participants were insulin naïve, 40% were previously on insulin – we took the whole type 2 spectrum. For a change, you’re wrong!

One-Year Efficacy and Safety of IDegLira in Patients with Type 2 Diabetes (65-OR)

Stephen Gough, MD (University of Oxford, Oxford, UK)

Dr. Stephen Gough presented findings from a 26-week extension of the original 26-week DUAL I trial on Novo Nordisk’s IDegLira, the fixed-ratio combination of Novo Nordisk’s ultra-long-acting basal insulin Tresiba (insulin degludec) and GLP-1 agonist Victoza (liraglutide).  The 52-week results were remarkably consistent with the results of the original 26-week study, which were first presented at last year’s ADA (read our coverage). From a baseline of ~8.3%, patients in the IDegLira arm achieved a mean final A1c at 52 weeks of 6.4% (reduction of 1.8% from baseline), a statistically significant improvement over insulin degludec’s final A1c of 6.9% (reduction of 1.4%) and liraglutide’s 7.1% (-1.2%). The theme of conserved results also applied to fasting plasma glucose (IDegLira was significantly better than liraglutide but not insulin degludec), hypoglycemia (IDegLira was associated with 37% less confirmed hypoglycemia than insulin degludec monotherapy), and body weight (IDegLira was fairly weight neutral and fell squarely between the weight gain of insulin degludec and weight loss of liraglutide). The constancy of efficacy and safety results from the original 26-week results was reassuring for a few reasons – it reduces the likelihood that the 26-week findings were due to chance, and also demonstrates that the combination product’s efficacy is not only strong, but also fairly durable (patients’ mean IDegLira dose was flat from week 26 to week 52).   

• Following the 26-week trial DUAL I study, the investigators began an additional 26-week long extension study. Attrition rates were approximately equal among the three arms. Out of the 1,442 patients that completed the 26-week DUAL I study, 84% completed the extension phase. Notably, the mean daily dose of IDegLira remained steady during the full 26-week follow-up, while the average dose in the insulin degludec group rose slightly.
• Results from the extension study showed that IDegLira’s A1c-lowering efficacy was stable through 52 weeks – overall many of the efficacy values were remarkably similar from the 26-week results. IDegLira yielded a final absolute A1c reduction of -1.8%, versus insulin degludec (-1.4%) and liraglutide (-1.2%) from an average baseline of 8.3% (p<0.0001 for both comparisons). Percentages of patients who met A1c targets also remained stable: IDegLira users continued to achieve A1c targets of 7% and 6.5% (78.2% and 66.9% of patients, respectively) significantly more than insulin degludec users (62.5% and 49.2%) and liraglutide users (56.5% and 38.2%).
• Compared to insulin degludec, IDegLira still yielded significantly fewer episodes of confirmed hypoglycemia, showed decreased glycemic variability, and resulted in no weight gain. At 52 weeks, IDegLira users experienced only 63% of the hypoglycemia rate of insulin degludec users, a significant difference (p<0.0001), although it was still much higher than the rate for liraglutide. Hypoglycemia rate ratios remained relatively stable from 26 weeks to 52 weeks. Post-prandial glucose excursions were significantly smaller for IDegLira users compared to insulin degludec users for every meal. IDegLira also resulted in slight weight loss (0.4 kg, ~1 lb), compared to insulin degludec’s 3 kg (~5 lb) weight gain and liraglutide’s 3 kg (~7 lb) weight loss, all of which were relatively stable after the first 26 weeks.
• Compared to liraglutide, IDegLira showed significantly greater reductions in fasting plasma glucose as well as fewer GI adverse events. After 52 weeks, fasting plasma glucose in the IDegLira arm (103 mg/dl) was comparable to that in the insulin degludec arm (108 mg/dl), but still significantly lower than that in liraglutide users (132 mg/dl) (p<0.0001 for the IDegLira – liraglutide difference). Percentage of subjects with nausea remained stable after the initial 26 weeks, with IDegLira users reporting more nausea than insulin degludec but less than liraglutide (overall incidence was very low compared to the first few weeks of the trial). Adverse GI events associated with liraglutide usage were also mitigated in IDegLira. Events included diarrhea (10.2% of IDegLira users, compared to 6.8% for insulin degludec users and 16.3% for liraglutide users), the common cold (13.9%, 12.6%, 13.3%), headache (12.8%, 10.9%, 14.6%), nausea (10.3%, 3.9%, 22.3%), increased lipase (5.8%, 4.4%, 8.5%), vomiting (5%, 2.4, 9.2%), and decreased appetite (2.7%, 0.5%, 7.3%).
  
  • In terms of serious adverse events, four major adverse cardiovascular events occurred in the IDegLira group, and one each occurred in the insulin degludec and liraglutide groups (note that the IDegLira arm was randomized 2:1:1). Total adverse events still did not differ significantly after 52 weeks: 71.2% IDegLira users experienced adverse events, compared to 70.6% insulin degludec users and 77.2% liraglutide users. Rates of serious adverse events remained low across the board. After 52 weeks, 4.6% IDegLira users, 5.3% insulin degludec, and 5.8% liraglutide users experienced serious adverse events.

Questions and Answers

Q: I wonder about the ratio between insulin and liraglutide. The average dose of liraglutide in IDegLira was 1.4 mg. What about patients who used 20 to 30 units of insulin in the combination product, because they would have received liraglutide less than 0.6 mg, and far less than 1.2 mg, the effective dose of liraglutide. Can you speak about the distribution of doses, and how subgroups compared with high doses versus low doses for each of the drugs?

A: This is a fixed ratio of degludec and liraglutide. The question is: what ratio should you have to suit the most people? We know that 40% of the patients did get the max dose and 70% achieved the target A1c. There are patients who could benefit from a little more insulin or a little more liraglutide, but on the whole a great portion of patients responded and a large portion reached the target of 7%. Obviously some may benefit from free mixing but this combination seemed to work pretty well.

Comment: I was wondering if patients using less than 30 units of insulin did better on the combination, or would there be no difference between IDegLira and degludec?

A: I don’t have those analyses with me.

Q: The hypoglycemia data is very encouraging, but I was wondering whether it was reduced calorie intake or decreased gastric emptying.

A: I’m not sure we know the exact answer to that, but we know that liraglutide has very little, if any, effect in terms of gastric emptying in the long term, at least relative to the shorter-acting GLP-1 receptor agonists.

New Insulin Glargine 300 U/ml: Glycemic Control and Hypoglycemia in Insulin Naïve People with T2DM (EDITION 3) (68-OR)

Geremia B. Bolli, MD (University of Perugia, Perugia, Italy)

Dr. Bolli provided the full results of Sanofi’s EDITION III trial of U300 insulin glargine, elaborating on topline results from late last year. As a reminder, EDITION III was a six-month, randomized, open-label trial investigating the effects of the initiation of U300 (n=435) versus standard insulin glargine (n=438) in insulin-naïve type 2 diabetes patients with inadequate control on oral agents alone. Similar to trials EDITION I and EDITION II, results indicated non-inferiority in A1c reduction, with declines of -1.42% with U300 (baseline A1c 8.5%) and -1.46% with standard insulin glargine (baseline A1c 8.6%; p=ns). As noted in topline results, compared to EDITION I and II there was no significant reduction in the percentage of patients with ≥1 severe or confirmed nocturnal hypoglycemic events (≤70 mg/dl) from nine weeks to six months of treatment, at 15.5% with U300 versus 17.4% with insulin glargine (HR 0.89; 95% CI 0.66-1.20). However, this difference became significant in full results when the analysis was extended to include the full six-month study period, with 17.9% of patients experiencing ≤1 event with U300 versus 23.5% with insulin glargine (HR 0.76; 95% CI 0.59-0.99). Though suggestive of benefit, with the improvement in nocturnal hypoglycemia weighted to the initial weeks of treatment, it remains unclear if this will translate to a meaningful difference in the clinical setting – as patients in EDITION III likely had less severe diabetes compared to EDITION I and II patients, the hypoglycemia benefit of U300 may be limited to patients already more prone to hypoglycemia.

• EDITION III aimed to investigate the efficacy and safety of the initiation of U300 versus standard insulin glargine in insulin-naïve type 2 diabetes with inadequate glycemic control on oral antidiabetic medications. Patients were randomized to initiation of U300 (n=435) or standard insulin glargine (n=438) with follow-up of six months. Baseline oral agents were continued with the exception of sulfonylureas due to the potential for confounding hypoglycemia. Patients in both groups demonstrated similar baseline age (58.2 with U300 vs. 57.2 years with standard insulin glargine), BMI (32.8 vs. 33.2 kg/m²), and diabetes duration (10.1 vs. 9.6 years). Use of oral agents was similar between both groups at baseline as well (90.6% vs. 92.0% on metformin, 59.1% vs. 58.6% on sulfonylureas, and 20.7 vs. 22.4% on DPP-4 inhibitors).
• Similar to EDITION I and II, results indicated non-inferiority in A1c reduction, with declines of -1.42% with U300 (baseline A1c 8.5%) and -1.46% with standard insulin glargine (baseline A1c 8.6%) after six months of treatment (p=ns). Likewise, there was no difference in percentage of patients at target A1c <7.0%, at 43% with U300 versus 42% with standard insulin glargine (p=ns). Mean fasting plasma glucose levels were non-significantly different in both groups as well, declining from roughly 180 mg/dl to 120 mg/dl.
• As noted in topline results, compared to EDITION I and II there was no significant reduction in the percentage of patients with ≥1 severe or confirmed nocturnal hypoglycemic events (≤70 mg/dl) from nine weeks to six months of treatment, at 15.5% with U300 versus 17.4% with insulin glargine (HR 0.89; 95% CI 0.66-1.20). However, this difference became significant when the analysis was extended to include the full six-month study period, with 17.9% of patients experiencing ≤1 event with U300 versus 23.5% with insulin glargine (HR 0.76; 95% CI 0.59-0.99). Percentage of patients with ≤1 severe or confirmed hypoglycemic events was additionally significant at any time of day for the full six-month study period  (46.2% vs. 52.5%; HR 0.75; 95% CI 0.57-0.99). By time of day, the difference in hypoglycemic events appeared most concentrated in the early morning with continuation to the early afternoon.
• Interestingly, there was a 17% increase in total insulin dose in patients treated with U300 versus standard insulin glargine at the end of the study, at 0.62 versus 0.52 units/kg/day – this has been consistent across the EDITION studies, though the clinical impact remains unclear. Change in body weight remained similar between both groups, at +0.4 kg (0.9 lbs) with U300 versus +0.7 kg (1.5 lbs) with insulin glargine (p=0.278).

Questions and Answers

Q: Can you clarify the time of day of dosing in both groups?

A: There was no question about the timing of dosing. Everyone in the program received basal insulin from anytime between dinnertime and bedtime – so only an evening injection.

Dr. John Buse (University of North Carolina, Durham, NC): At the end of the study, the A1c was identical but the dose with U300 insulin glargine was 17% higher. From your figure, it appeared most of that 17% was titrated after the eight-week mark. Thus, is it possible that the decline in fasting glucose was faster in the U300 arm?

A: A smart question from a smart man. We have data from self-monitoring of blood glucose that does not support your hypothesis, but it needs to be further analyzed.

Q: Why would the dose requirement be higher with U300?

A: The increased insulin requirement is consistent across studies – it was also shown in EDITION IV. The reason isn’t immediately clear. One hypothesis is that when you increase the concentration you slow down the absorption rate – this results in a more constant and pharmacokinetic release but with some loss of the initial effect. I think we need more studies to understand this effect.

Q: Would it be possible that U300 may be better called U250?

A: The official definition is that one unit of insulin is defined by the molecules of insulin in that volume. This is different than the clinical relevance of comparing units across therapies. So I don’t think it practically means anything to give 10% more or 10% less of insulin in units as long as the clinical outcomes are compared.

Oral Presentations: New Developments in Clinical Obesity

Liraglutide 3.0 mg for Weight Management in Obese/Overweight Adults with Type 2 Diabetes: Results from the SCALE™ Diabetes 56-Week Randomized, Double-Blind, Placebo-Controlled Trial (97-OR)

Melanie Davies, MD (University of Leicester, United Kingdom)

Building on topline results originally released in March 2013, Dr. Melanie Davies offered a comprehensive overview of the phase 3a results from the 56-week SCALE Diabetes trial, which assessed the efficacy of Novo Nordisk’s liraglutide 3.0 mg for weight management in 846 overweight or obese adults with type 2 diabetes. At baseline, study participants had an average weight of 105.9 kg (223 lbs.), BMI of 37 kg/m², and A1c of 8.0%. Treatment with liraglutide 3.0 mg led to significantly greater weight loss at 56 weeks compared to placebo. Specifically, participants in the liraglutide 3.0 mg arm achieved an average weight loss of 5.9% from baseline, compared to 4.6% with liraglutide 1.8 mg and 2.0% percent with placebo. Treatment with liraglutide 3.0 mg also resulted in clinically meaningful reductions in A1c level as well as in systolic blood pressure. The most common side effects were gastrointestinal issues like nausea and diarrhea. Liraglutide was generally well tolerated, with no new safety signals identified.

• Essentially half (49.9%) of the participants randomized to liraglutide 3.0 mg achieved at least 5% weight loss, compared to 35.0% with liraglutide 1.8 mg and 12.7% with placebo. In the liraglutide 3.0 mg arm, 22.1% achieved weight loss of at least 10%, compared to 13.3% of those given liraglutide 1.8 mg and 3.8% of those given placebo.
• Participants in the liraglutide 3.0 mg arm achieved an average reduction in A1c of 1.3%, compared to an average reduction of 0.4% in the placebo arm. At 56 weeks, 72.3% of participants in the liraglutide 3.0 mg arm and 22.9% of participants in the placebo arm achieved an A1c of 7% or lower. Participants in the liraglutide 1.8 mg arm experienced an average A1c reduction of 1.1%; 69.6% of participants in the liraglutide 1.8 mg arm achieved an A1c of 7.0% or lower.
• Participants in the liraglutide 3.0 mg and 1.8 mg arms experienced greater improvements in systolic blood pressure compared to participants on placebo, with a mean reduction of 3.5%. There were no differences in diastolic blood pressure between the liraglutide and placebo arms.
• Dr. Davies commented that there were no pancreatitis events observed during the trial. She stated that there was a mean increase of 10 units in lipase activity within the liraglutide arms.
• No fatal adverse events occurred, with the exception of one death that occurred after the study due to stroke. 92.9% of participants taking liraglutide 3.0 mg reported adverse events (8.8% serious, 12.3% severe, and 9.2% leading to withdrawal). Nausea, diarrhea, constipation, and vomiting were the most common adverse events. By 24 weeks, most all nausea events were resolved.
• Dr. Davies pointed out that participants on sulfonylurea background therapy had higher incidences of hypoglycemia. For participants on sulfonylurea background therapy, 43.6% in the liraglutide 3.0 mg arm experienced symptomatic hypoglycemic episodes, compared to 27.3% in the placebo arm. For participants not on background sulfonylurea therapy, 15.7% in the liraglutide 3.0 mg arm experienced symptomatic hypoglycemic episodes, compared to only 7.6% in the placebo arm. Less than 3% of participants on sulfonylurea background therapy and liraglutide 3.0 mg experienced a severe hypoglycemic episode.
• No differences in safety and tolerability were observed between liraglutide 3.0 mg and 1.8 mg, except for gastrointestinal adverse events. 65% of participants in the liraglutide 3.0 mg arm reported having gastrointestinal issues (e.g.,  nausea and diarrhea), whereas only 56% of participants in the liraglutide 1.8 mg arm and 39% in the placebo arm experienced GI adverse events.

Questions and Answers

Q: Can you tell us more about the participant who died?

A: This patient died after the 52 weeks of the study. The death was 44 days after the trial ended, so about six weeks later. It was a male in his fifties who had cardiovascular complications and he had a stroke. We don’t believe it had to do with the treatment.

Q: Have you thought about the weight loss being due to the sulfonylureas?

A: We haven’t compared that yet, but the majority of participants were not on sulfonylurea therapy.

Q: Can you comment on the side effects of nausea with regards to the weight loss seen early on?

A: The percentage of nausea seen was about 15%. There is some suggestion that nausea and GI side effects may correlate with weight loss, but we haven’t specifically looked at this in the study. Overall though, the rates of nausea are relatively low compared to other GLP-1 agonists.

Oral Presentations: Novel Therapeutic Agents

TTP399, a Liver-Selective Glucose Kinase Activator (GKA), Lowers Glucose and Does NOT Increase Lipids in Subjects with Type 2 Diabetes Mellitus (T2DM) (122-OR)

Carmen Valcarce, PhD (TransTech Pharma, High Point, NC)

Dr. Carmen Valcarce presented the positive results of a phase 1b/2a study of TransTech’s liver-selective glucokinase activator (GKA) TTP399. The trial studied three doses of TTP399 in 120 type 2 diabetes patients on baseline metformin therapy for 42 days. In that time period, the highest dose (800 mg twice daily) led to an absolute A1c reduction of ~0.9% and a placebo-adjusted reduction of ~0.5% at the end of the study (mean baseline of ~8.1%), with action on both fasting and postprandial glucose (the postprandial effect appeared strongest). A highlight of the results was a sub-analysis showing that the drug’s efficacy was largely preserved in patients that were fairly well controlled at baseline (A1c < 7.5%) – while the placebo arm (n = 8) in this subgroup held steady at around 7.2% A1c, the high dose arm (n = 8) saw an A1c reduction to a mean of 6.4%, making for a greater placebo-adjusted difference (-0.8%) than was seen in the overall cohort. Dr. Valcarce fully acknowledged that the GKA class is burdened by previous failures, which were largely due to increases in lipids or liver enzymes as well as high rates of hypoglycemia; she highlighted that TTP399 was not associated with any increase in lipids, insulin secretion, or hypoglycemia. Those safety data, as well as the drug’s efficacy independent of baseline A1c, might indicate that this compound might be an especially effective tool for intensifying therapy in moderately well controlled type 2 diabetes patients.   

• Before diving into the data, Dr. Valcarce acknowledged that the GKA class has largely fallen from favor in the diabetology community. Roche and Takeda were among the companies that discontinued GKA programs in the past few years, and data on earlier agents in the class showed adverse effects such as increased hypoglycemia, increases in lipids, and elevated liver enzymes. TransTech’s recipe for success is to ensure a high degree of liver selectivity, as action at the pancreas can lead to hypoglycemia through glucose-insensitive induction of insulin secretion. Additionally, TransTech believes that a successful GKA must not interfere with the endogenous glucokinase regulatory protein (GKRP) in order to avoid adverse events. TTP399 meets these two criteria, and Dr. Valcarce presented a summary table of preclinical and early clinical results showing that the compound appears to be succeeding where others failed. In testing so far, TTP399 has not demonstrated increases in hypoglycemia, lipids, or liver toxicity.
• The six-week multiple-dose phase 1b/2a study enrolled 120 type 2 diabetes patients on stable metformin therapy. Drug doses tested were 400 mg BID, 800 mg QD, and 800 mg BID, all versus placebo. Over the 42 days of the study, patients spent three one-week periods in the clinic to conduct meal challenge tests, monitor PK, and monitor blood glucose through three-day CGM periods. Patients had a mean baseline BMI of ~31 kg/m², a mean A1c of ~8.0% – 8.2%, and a mean diabetes duration of 8 - 11 years.
• TTP399 appeared to be safe at all doses, with no imbalances in symptomatic hypoglycemia or liver function tests. There was a slight imbalance in the number of patients with at least one treatment-emergent adverse events between the high dose group (19/30) and placebo (12/30), but this did not seem highly worrying due to the relatively small size of the trial.
• TTP399 800 mg twice daily (the highest dose) led to a placebo-adjusted A1c reduction of ~0.5% at day 42, with action postprandially and (to a lesser extent) on fasting plasma glucose. The A1c-lowering efficacy increased in a dose-dependent manner – the 800 mg once daily dose led to a ~0.4% placebo-adjusted A1c reduction. Factors that made the placebo-adjusted values appear modest include fairly robust placebo group performance (reduction of 0.4%) as well as the short duration of the trial.
• Notably, the A1c reductions seen with TTP399 did not seem to be highly correlated with baseline A1c. In fact, in a subgroup of patients with a baseline A1c at or below 7.5%, patients in the 800 mg twice daily group (n = 8) saw a ~0.8% placebo-adjusted reduction in A1c, and the vast majority achieved an A1c at or below 6.5%. Dr. Valcarce considered this baseline-A1c-independent efficacy one of the highlights of the trial results. 
• Dr. Valcarce ended by suggesting that TTP399’s efficacy profile could make it suitable for intensive glucose control. The company is poised to begin a six-month phase 2b study for TTP399.

Questions and Answers

Q: The numbers in this trial were pretty small, but it did seem like this compound had a good effect in patients that were well controlled.

A: yes, although at the higher end of the baseline A1c spectrum the A1c lowering was increased, there was still a robust effect at the lower end.

Q: This is interesting data, given what we know about this class. The liver has a high degree of autoregulation to keep glycogenolysis and gluconeogenesis constant. Do you plan to do experiments for a longer duration of six to 12 weeks, and perhaps measure hepatic glucose?

A: We’ve done that with animals, and we have not found any signs of tachyphylaxis. In the clinic, that is what we will test next. We will do a six-month phase 2b study.

Q: What is the outcome of the glucose that enters the liver?

A: The glucose is oxidized. It does make sense to know where the glucose that is being taken up by the liver due to TTP399 is going, but you could ask the same thing about metformin, or a DPP-4 inhibitor. But in this case, the literature suggests that it is oxidized.

Moderator comment: It is a little different though, right? Increasing glucose uptake is different than metformin, which reduces hepatic glucose production. You mentioned steatosis, which has been an effect of concern for this drug class. You did not test these patients in terms of liver fat or biopsies, but have you seen it in rodent models?

A: We have not. We did test in ob/ob mice with existing steatosis, and found that we actually improve hepatic steatosis. We also did tests in normal mice, and did not see any detrimental effects.

Symposium: Update on GLP-1 based Therapies – Effects on Exocrine and Endocrine Pancreas (Supported by an Unrestricted Educational Grant from Merck)

Inconvenient Truths – Clinical Data Informing the Safety of Incretin-Based Therapies

Jacqueline Koehler, PhD (Samuel Lunenfeld Research Institute, Toronto, Canada)

In front of an overflowing audience, Dr. Jacqueline Koehler reviewed the current preclinical and clinical data surrounding the risk of incretins and pancreatitis/pancreatic cancer. While there was no new data in the presentation, she synthesized the current state of affairs very cogently: much of the debate over incretins and pancreatic safety has been fueled by a few publications of preclinical and clinical data that have not been reproducible. The majority of the available clinical data has come from retrospective database and case-controlled observational studies, which are subject to numerous biases and limitations. In particular, she explored the possibility for over-diagnosis based on elevated pancreatic enzyme levels (a marker of pancreatitis that is not, in itself, sufficient for diagnosis). Dr. Koehler suggested that the highest quality clinical data on this issue will come from the large cardiovascular outcomes trials (CVOTs) ongoing for incretin-based therapies – she found the neutral pancreatic findings from SAVOR and EXAMINE “promising” and remarked that they demonstrated that if any risk exists, it is so low that it was not even detected with a 16,000+ person trial (SAVOR). She noted that we will have to wait for more data from the outcomes studies to draw better conclusions on the benefit/risk profiles for incretin-based drugs.

• Retrospective, observational studies are plagued by a number of limitations and biases, including the potential for over-diagnosis of pancreatitis based solely on elevated lipase levels. About 10-20% of people with type 2 diabetes exhibit elevated baseline lipase levels with no other symptoms for pancreatitis, independent of incretin treatment (Steinberg et al., Gastroenterology 2012). GLP-1 agonist treatment can increase median lipase activity ~5-10 U/L (remaining within the normal range, but persistent until treatment discontinuation), as shown in phase 3 trials of Novo Nordisk’s Victoza (liraglutide 1.8 mg), liraglutide 3 mg for obesity, and Lilly’s dulaglutide. The majority were unaccompanied by pancreatitis events, but the overall elevations of lipase levels in this population makes an accurate diagnosis of acute pancreatitis more challenging – clinicians who are not as thorough as to use imaging to confirm the diagnosis may over-diagnose based on lipase levels alone. Dr. Koehler, thus, emphasized the need for formalized procedures to assess these adverse events (e.g., in randomized-controlled studies).
• Dr. Koehler highlighted all of the CVOTs for incretin-based therapies that are ongoing, or recently completed, saying that the neutral pancreatitis findings in SAVOR and EXAMINE were “promising” and suggest that any risk of pancreatitis is very low (0.3-0.4% chance over median follow ups of 1.5-2 years in these two trials).
• Finally, Dr. Koehler reviewed the FDA and EMA’s independent assessment (published in NEJM February 2014 – see our report here). She characterized this undertaking as extremely thorough, noting that the agencies evaluated all preclinical and clinical data, including more than 250 toxicology studies in over 15,000 rodents and almost 2,500 non-rodents, 120 pancreatic histopathology slides, their own commissioned pancreatic toxicology studies with exenatide, all clinical safety databases to date including more than 200 trials, and results from the recent SAVOR and EXAMINE outcomes trials.

Posters

Better Glycemic Control and Less Weight Gain with Once-Weekly Dulaglutide vs. Once-Daily Insulin Glargine, Both Combined with Premeal Insulin Lispro, in Type 2 Diabetes Patients (AWARD-4) (962-P)

J Jendle, J Rosenstock, L Blonde, V Woo, J Gross, H Jiang, Z Milicevic

The poster for AWARD-4, which (as Lilly noted) is the first phase 3 study to evaluate a GLP-1 agonist in combination with mealtime insulin, demonstrated that dulaglutide used in addition to Lilly’s Humalog (insulin lispro) (dulaglutide/lispro) provided better blood sugar control through 52 weeks relative to basal/bolus therapy with Sanofi’s Lantus (insulin glargine) and insulin lispro (glargine/lispro). The dulaglutide/lispro arm (using the higher 1.5 mg dose of dulaglutide) achieved an absolute mean A1c reduction of 1.64%, while the glargine/lispro arm achieved a reduction of 1.41%, both from a baseline of 8.5%. The difference in the efficacy was statistically significant, and the reductions in both groups were relatively durable through week 52. Significantly more patients in the high-dose dulaglutide/lispro arm achieved an A1c goal of 7.0% or less at weeks 26 and 52, although the magnitude of the differences was not very large; significantly more patients in the high-dose dulaglutide/lispro arm achieved a goal of no more than 6.5% at 26 weeks, but the difference at 52 weeks was not statistically significant. The dulaglutide arm had a sizable 3.4 kg (~7.5 lb) weight advantage over the insulin lispro arm, and weight in that arm was fairly flat from baseline to week 52 (an initial slight decline followed by a very gradual regain). As might be expected, dulaglutide/lispro was associated with significantly less overall hypoglycemia and nocturnal hypoglycemia than glargine/lispro. GLP-1 agonists are generally noted for their postprandial glucose control, but the longer-acting agents have a more pronounced impact on fasting glucose. As a result, as these data show, combination of a once-weekly agent like dulaglutide with mealtime insulin is an option, although we still see GLP-1 agonist/basal insulin combinations as the combination class to watch out for.

New Insulin Glargine 300 U/mL: Efficacy and Safety of Adaptable vs. Fixed Dosing Intervals in People with T2DM (919-P)

Matthew C. Riddle, Geremia B. Bolli, Phillip D. Home, Richard Bergenstal, Monika Ziemen, Isabel Muehlen-Bartmer, Marek Wardecki, Laetitia Vinet, and Hannele Yki-Jarvinen.

Dr. Matthew Riddle and colleagues conducted two sub-studies of Sanofi’s insulin glargine (Lantus) 300 U/ml comparing the effects of fixed dosing (FD) vs. adaptable dosing (AD) in 198 type 2 patients. The sub-studies were part of two larger, six-month open label studies comparing glargine 300 U/ml to glargine 100 U/ml: EDITION 1 (basal insulin plus mealtime insulin; n=53 for FD and n=56 for AD) and EDITION 2 (basal insulin plus oral anti-diabetic medications; n=44 for FD and n=45 for AD). To generate the sub-studies, participants who completed the glargine 300 U/ml on-treatment during the main trials were re-randomized to either FD (injections at 24 hour intervals) or AD (injections at 24 ± 3 hr intervals; participants were asked to use an injection interval of exactly 21 hours or 27 hours at least twice a week).  Endpoint measurements were taken at month nine (three months after the re-randomization) and the intent-to-treat analysis included data from 194 patients. In both sub-studies, the primary endpoint – change in A1c – was comparable between the FD and AD groups. Similarly, the FD and AD groups had comparable rates of adverse events, overall hypoglycemia, and nocturnal hypoglycemia. Based on this data, the authors conclude that type 2 patients who occasionally adapted the timing of their glargine 300 U/ml injections did not compromise the safety or efficacy of the drug. 

• Baseline characteristics were comparable between the FD and AD groups within each sub-study, and between the two sub-studies: average age of 57-61 years, A1c of 7.2-7.5%, and percent male of 43-50%.
• Variability in the timing of injections between the FD and AD groups were measured by recording the time between two consecutive injections during the last seven days before the two endpoint assessments, which occurred one-and-a half and three months following the re-randomization. In the FD group, a low percentage of patients administered injections outside of a 24 ± 1 hr interval (13% for the EDITION 1 sub-study and 11% for the EDITION 2 sub-study). As would be expected, larger percentages were recorded for the AD group (37% and 48%, respectively). Notably, a fraction of patients in the AD group injected their insulin more than three hours above or below the standard 24-hour interval (14% for EDITION 1 and 19% for EDITION 2).
• In both sub-studies, the FD and AD groups experienced similar changes in A1c, fasting plasma glucose, and eight-point SMPG profiles after three months (see table below; note: A1c increased slightly in EDITION 1 sub-study). Furthermore, the participants made only small changes to their mean daily basal insulin dose, and these changes were similar across the FD and AD groups in both sub-studies.

	EDITION 1		EDITION 2
	FD	AD	FD	AD
Change in A1c
Baseline A1c	7.21%	7.17%	7.41%	7.47%
Change	0.21%	0.15%	-0.12%	-0.25%
Mean difference between groups	0.05%		0.13%
Change in Fasting Plasma Glucose
Baseline FPG	132 mg/dl	121 mg/dl	128 mg/dl	129 mg/dl
Change	26 mg/dl	21 mg/dl	-8 mg/dl	-5 mg/dl
Mean difference between groups	4.9 mg/dl		-3.8 mg/dl

• In both sub-studies, the FD and AD groups had similar rates of overall and nocturnal (midnight to 6 am) hypoglycemia (see table below). Only one event of severe hypoglycemia was reported in the sub-studies (in the FD group of Edition 1).

	EDITION 1		EDITION 2
	FD	AD	FD	AD
Percent experiencing any hypoglycemia*	65%	57%	42%	37%
Percent experiencing nocturnal hypoglycemia*	24%	25%	23%	17%

^* numbers estimated from graph

Basal Insulin Peglispro Demonstrates Preferential Hepatic vs. Peripheral Action Relative to Insulin Glargine in Healthy Subjects (886-P)

Robert R. Henry, Sunder Mudaliar, Siak Leng Choi, Theodore P. Ciaraldi, Debra A. Armstrong, Jeremy Pettus, Parag Garhyan, Mary P. Knadler, Scott J. Jacober, Eric Chen Quin Lam, Helle Linnebjerg, Niels Porksen, Melvin J. Prince, and Vikram P. Sinha

Dr. Robert Henry et al. conducted a single-center, randomized, open-label trial comparing the sites of action of Lilly’s basal insulin peglispro (referred to as LY2605541) vs. Sanofi’s insulin glargine (Lantus) in eight healthy male participants (mean baseline age of 26 years and BMI of 24 kg/m²; all had fasting plasma glucose <108 mg/dl ). The study measured the drugs’ abilities to suppress endogenous glucose production (EGP, which reflects their actions on the liver), as well as their abilities to stimulate the glucose disposal rate (GDR, which reflects their actions outside the liver – i.e., peripheral action). The participants underwent four eight-hour euglycemic clamp studies (maintained at 90 mg/dl): the first three with primed, continuous infusions of LY2605541 (five doses ranging from 5.1 to 74.1 mU/min), and the fourth with insulin glargine (either 20 or 30 mU/m²/min). The investigators used D-[3-³H]-glucose infusion to assess EGP and GDR. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. Notably, the LY2605541 dose needed for 100% EGP suppression had little effect on GDR. In contrast, the glargine dose required for a comparable suppression of EGP led to an increase in GDR. These results indicate that in healthy males, LY2605541 exhibits greater hepato-preferential action compared to insulin glargine.

Effect of Saxagliptin on Renal Outcomes (544-P)

O Mosenzon, D Bhatt, L Litwak, M Shestakova, G Liebowitz, B Hirshberg, A Parker, N Iqbal, B Scirica, R Ma, I Raz

This poster presented renal outcomes results from SAVOR-TIMI 53, the cardiovascular outcomes study for BMS/AZ’s saxagliptin (Onglyza). As a reminder, SAVOR randomized 16,452 patients with type 2 diabetes and established cardiovascular disease or multiple risk factors to saxagliptin or placebo for a median follow-up of 2.1 years (presented initially at ESC 2013; stratification of results by baseline renal function presented at ACC 2014). As noted in the primary analysis, patients treated with saxagliptin demonstrated more improvement in albumin to creatinine ratio (ACR; 11% vs. 9%; p<0.01) and less worsening in ACR (13% vs. 16%; p <0.01) versus placebo-treated patients, with greatest benefit observed in patients with known baseline microalbuminuria (31.3% returned to normal albuminuria vs. 25.7%; p<0.0001). Interestingly, this effect appeared independent of glucose control, with improvement in ACR similar in patients with A1c decline of >0.5% at one year versus those without. However, this benefit to ACR did not translate to significant differences in predetermined renal outcomes with saxagliptin, including doubling of serum creatinine (HR 1.04; 95% CI 0.83-1.30), initiation of chronic dialysis, renal transplant, or serum creatinine >6.0 mg/dl (HR 0.90; 95% DI 0.61-1.32), or composite end point of death and all of the above (HR 1.08; 95% CI 0.96-1.22).

Sodium Glucose Cotransporter 2 (SGLT2) Inhibition with Emplagliflozin Reduces Microalbuminuria in Patients with Type 2 Diabetes (1125-P)

David Cherney, Maximilian von Eynatten, Soeren Lund, Stefan Kaspers, Susanne Crowe, Hans Woerle, Thomas Hach

This study pooled data from four phase 3 randomized, controlled trials to examine the effect of empagliflozin on urine albumin to creatinine ratio (UACR) in type 2 diabetes patients with microalbuminuria. Of the 2,477 patients who were randomized to placebo or empagliflozin in the 24 week trials, 458 patients on placebo (n=157), empagliflozin 10 mg (n=146), and empagliflozin 25 mg (n=155) started with microalbuminuria (UACR 30-300 mg/g). At week 24, patients on empagliflozin had significantly lower UACR for both the 10 mg (30% reduction; p <0.001) and 25 mg (25% reduction; p=0.004) dose. Finally, the treatment group did not have more adverse events than the control. These findings suggest that SGLT-2 inhibitors like empagliflozin could be renal-protective. Only one SGLT-2 inhibitor is being studied in a renal outcomes trial, J&J’s Invokana in CREDENCE.

• The three groups of patients with microalbuminuria had similar baseline characteristics in terms of mean A1c, blood pressure, BMI, UACR, eGFR, age, and time since diagnosis of diabetes. Mean A1c levels for the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups were 8.13%, 8.26%, and 8.18%. Average blood pressure was 132.0, 132.8, and 133.6 mmHg, and average UACR was 61.9, 57.5, and 60.1 mg/g, respectively. Mean BMI was ~28-29 kg/m² and mean age was ~55-57 years.
• Patients with microalbuminuria treated with empagliflozin displayed a significant reduction in A1c and blood pressure. At week 24, patients on empagliflozin 10 mg and 25 mg showed significant placebo-adjusted reductions in A1c of 0.56% from a baseline of 8.26% (p <0.001) and 0.62% from a baseline of 8.18% (p <0.001). After accounting for placebo effects, blood pressure for these groups also decreased by 3.6 mmHg (p=0.011) and 3.5 mmHg (p=0.012), respectively.
• Of all the patients in the four clinical trials, patients with microalbuminuria experienced a greater relative reduction in UACR. For the overall pooled population (n=2349), the percentage decrease in geometric mean UACR at week 24 for the empagliflozin 10 mg and 25 mg groups were only 10%, compared to 30% and 25% for the patients with microalbuminuria.

Medication Compliance Rates of Weekly Albiglutide vs. Daily Oral Comparators in Phase III Trials (994-P)

LA Leiter, RA Scott, J Ye, MC Carr

This study compared the rates of compliance between GSK’s once-weekly GLP-1 agonist albiglutide (now Tanzeum following its recent US regulatory approval) and three once-daily oral comparators (glimepiride, pioglitazone, and sitagliptin) in HARMONY trials 3, 5, and 8. Overall compliance was consistently higher in both the albiglutide and albiglutide matching placebo groups than in any of the oral comparator groups. Low compliance was defined as ≤ 80% compliance – many providers would probably love to get long-term adherence of 80%. Low adherence was more frequent in the oral comparator groups (7.5% to 14.9%) than in the albiglutide groups (1.6% to 2.3%). Compliance was measured at each visit using pen and/or pill counts. While the results bode well for patient compliance on albiglutide, it will be important to conduct follow-up studies in real-world clinical settings. Device design has a major impact on adherence for GLP-1 agonists – see our GSK exhibit hall coverage (from today as well) for an overview of how the administration process works.

Effect of Lixisenatide vs. Liraglutide on Glycemic Control, Gastric Emptying, and Safety Parameters in Optimized Insulin Glargine T2DM ± Metformin (1017-P)

JJ Meier, J Rosenstock, A Hincelin-Mery, C Roy-Duval, A Delfolie, HV Coester, T Forst, C Kapitza

This study compared the effect of Sanofi’s Lyxumia (lixisenatide) and Novo Nordisk’s Victoza (liraglutide) on postprandial glucose in patients with type 2 diabetes ± metformin after optimal insulin glargine titration. In an 8-week, open-label trial, patients were randomized to three treatment arms: lixisenatide 20 µg (n=46), low-dose Victoza (liraglutide 1.2 mg; n=44), and high-dose Victoza (liraglutide 1.8 mg; n=46). Lixisenatide showed a benefit over both liraglutide doses in lowering postprandial glucose and delaying gastric emptying. All arms benefited from decreased A1c and body weight, with liraglutide 1.8 mg arm seeing the greatest decrease in body weight. Symptomatic hypoglycemia was slightly more frequent in the lixisenatide arm (14 events vs. 9 and 10 events in the liraglutide arms), whereas more GI side effects were noted in the liraglutide treatment arms (17 in lixisenatide vs. 21 and 22 events in the liraglutide arms). One case of severe symptomatic hypoglycemia was noted in the lixisenatide arm. Overall, both lixisenatide and liraglutide provided improved glycemic control, with lixisenatide offering a greater effect on postprandial glucose and gastric emptying and liraglutide providing a slightly better safety profile. This finding is not surprising given our understanding of short-acting

AUC PPG (h)(mg)/dl	lixisenatide 20µg	liraglutide 1.2 mg	liraglutide 1.8mg
Baseline mean ± SD	282.2 ± 120.9	280.1 ± 99.9	307.0 ± 103.2
Week 8 mean ± SD	63.6 ± 117.9	171.7 ± 95.2	156.7 ± 62.2
LS mean change from baseline ± SD	-240.2 ± 20.0	-131.8 ± 20.2	-157.1 ± 21.0

Technology

ADA Diabetes Care Symposium – New Drug Therapies, Innovative Management Strategies, and Novel Drug Targets

Best of Diabetes Care 2013-2014 – Artificial Pancreas Developments

William Tamborlane, MD (Yale University, New Haven, CT)

Dr. William Tamborlane provided a concise and organized overview of the past year in artificial pancreas research, focusing on the safety of low glucose/predictive suspend and overnight closed-loop. Regarding the latter, he noted that “the holy grail of unsupervised full closed-loop control may be just around the corner, given the results from Dr. Hovorka’s recent study. Dr. Tamborlane’s presentation covered four main studies: Beck et al., Diabetes Care 2014 and Sherr et al., Diabetes Care 2014 (both demonstrating the safety of low glucose/predictive suspend); Hovorka et al., Diabetes Care 2014 (demonstrating the safety of unsupervised overnight closed loop); and Buckingham et al., Diabetes Care 2013 (no impact of short-term hybrid closed loop immediately following diagnosis). Though closed-loop studies have demonstrated feasibility in the inpatient setting, Dr. Tamborlane explained that there are still some key obstacles to broad outpatient use: making the device user interfaces easy to use and establishing redundant safeguards to minimize the risk of excessive insulin administration.

• Why do we need an artificial pancreas? First, too many type 1 diabetes patients fail to achieve A1c goal – Dr. Tamborlane highlighted the latest data from T1D Exchange, which suggests that adolescents have an average A1c of 9.0%! Second, he noted that severe hypoglycemia remains an ever-present danger, and based on T1D Exchange data, patients with a high A1c are not at reduced risk. Third, the burden of care is “extremely high” and has increased with the translation of new diabetes technologies into clinical practice.
• Dr. Tamborlane described the iterative progression to an artificial pancreas, starting with low glucose suspend and predictive low glucose suspend, followed by nighttime closed-loop + daytime open-loop – the latter has emerged as a debate in the field, as some believe the regulatory path is easier for a 24-hour automated system (daytime treat-to-range + nighttime treat-to-target) vs. an overnight-only system. Said Dr. Tamborlane, “If you told a parent that their child could go to bed and reliably wake up at 120 mg/dl with no hypoglycemia, parents would take this is a moment.”
• Dr. Tamborlane covered two papers relating to the safety of low glucose/predictive low glucose suspend:
  
  • Beck et al., Diabetes Care 2014 – Frequency of Morning Ketosis After Overnight Insulin Suspension Using an Automated Nocturnal Predictive Low Glucose Suspend System.  The study concluded that two-hour pump suspends are safe and won’t result in DKA or excessively dangerous ketone levels.
  • Sherr et al., Diabetes Care 2014 – Safety of Nighttime 2-Hour Suspension of Basal Insulin in Pump-Treated Type 1 Diabetes Even in the Absence of Low Glucose. Dr. Tamborlane noted that one of the FDA’s main concerns with the Veo/MiniMed 530G was the safety of two-hour suspends when the CGM was reading inaccurately low. This clever study had patients program a two-hour zero basal rate on random nights, regardless of the current glucose level. The study concluded that systems that suspend basal insulin for two hours are safe and do not lead to clinically significant ketonemia even if the blood glucose level is elevated at the time of the suspension.
• Hovorka et al., Diabetes Care 2014 examined overnight closed-loop under free-living conditions in 16 young people with type 1 diabetes. Dr. Tamborlane highlighted that the study was done in the “real world” and demonstrated the efficacy and safety of nighttime closed loop + daytime open loop. Indeed, overnight closed loop increased time in zone by a median 15% and reduced mean overnight glucose by a mean of 14 mg/dl. Said Dr. Tamborlane, “The holy grail of unsupervised fully closed-loop control (i.e., overnight) may be just around the corner.”
• Buckingham et al., Diabetes Care 2013 – Effectiveness of early intensive therapy on beta-cell preservation in type 1 diabetes. This ambitious study examined whether three to five days of inpatient hybrid closed loop at the time of diagnosis could preserve C-peptide one year later. There was “absolutely no difference” in A1c, CGM, or the rate of C-peptide decline between the intervention and control groups. This was a major disappointment when these results were first shared, as many had high hopes for this study. Dr. Tamborlane commented that in new onset type 1 diabetes “it appears we’ve already achieved about as much as we can achieve in slowing the loss of residual beta cell function by maintaining strict glycemic control,” regardless of using closed loop or open loop.  

Professional Interest Group Discussion: Professional Interest Group Discussion on Complications

Glucose Variability (Dysglycemia) and Diabetes Complications – Does it Matter? (Con)

Richard Bergenstal, MD (International Diabetes Center, Minneapolis, MN)

Dr. Richard Bergenstal asserted that he is a “supporter of the Irl Hirsch ‘Beyond A1c’ Movement,” in the sense that beyond can mean “in addition to.” However, he argued that hypoglycemia is a more important focus for this “movement” than glycemic variability. Hypoglycemia has been shown to be associated with mortality, complications, emergency-department visits, hospital admissions, cost, and worse quality of life. Therefore Dr. Bergenstal believes that clinicians should start to supplement the A1c with standardized, CGM-based metrics of hypoglycemia developed by himself and his colleagues; he said that in the long term perhaps A1c could even be replaced by CGM-based time in range. As for glycemic variability, he said that it has been definitively linked only to reactive oxygen species and inflammation. In conclusion Dr. Bergenstal challenged Dr. Hirsch to conduct outcomes-based research on whether glycemic variability matters for complications. 

• Dr. Bergenstal acknowledged that A1c is not perfect, but he argued that is widely applicable and that its use has led to better health for people with diabetes. He noted that rates of microvascular and macrovascular complications in diabetes have fallen dramatically since the mid-1990s (Gregg et al., NEJM 2014) – a decline that he attributed in part to the focus on A1c control since DCCT and UKPDS. Dr. Bergenstal also referenced the theory that A1c is not an appropriate metric for African-Americans or Hispanics, due to biological differences in glycation. However, he dismissed this theory based on evidence presented on the prior day by Dr. Elizabeth Selvin.
• Dr. Bergenstal argued that clinicians should assess their patients by supplementing the A1c with CGM-based metrics of hypoglycemia. Specifically, he favors standardizing CGM data analysis using a format developed by himself and his colleagues – the Ambulatory Glucose Profile (AGP) (Bergenstal et al., J Diabetes Sci Technol 2013). The AGP includes the percentage of time spent below 70 mg/dl, 60 mg/dl, and 50 mg/dl, based on at least two weeks of CGM. He explained that these cutoffs correspond to counterregulation of low blood sugar, adrenergic symptoms, and neuroglycopenia, respectively.

Glucose Variability (Dysglycemia) and Diabetes Complications – Does It Matter? (Pro)

Irl B. Hirsch, MD (University of Washington, Seattle, WA)

The highly regarded Dr. Irl Hirsch provided a resolute, yet balanced, argument for glucose variability as a key factor in the development of diabetes complications. Dr. Hirsch noted that his interest in dysglycemia was originally piqued by the results of the DCCT study, which demonstrated that intensive treatment of type 1 diabetes reduced the risk of complications relative to conventional treatment. However, A1c levels seem to explain less than 6.6% of the variability in retinopathy risk (Lachin et al., Diabetes 2008). This point is subtle and sometimes ignored; indeed, Dr. Hirsch quipped that “the majority of researchers don’t understand the DCCT.”. Dr. Hirsch believes that glycemic variability is one of the factors that explains why people with the same A1c values have different complications risks. Even more controversially, Dr. Hirsch also suggested that the development of NPH and Lente insulins may have “set diabetes therapy back over 50 years,” because they led patients to use twice daily premixed insulin rather than basal-bolus therapy. In particular, Dr. Hirsch was referring to the fact that pre-mixed insulins do not provide the glycemic control that basal-bolus therapies with modern insulins now do; he cited data illustrating that the introduction of prandial insulins in the late 1990s, which reduced blood glucose spiking, have been associated with a reduced prevalence of diabetic retinopathy.

• As a reminder, the results of the DCCT trial indicated that intensive treatment of type 1 diabetes reduced the risk of sustained retinopathy relative to conventional treatment. The trial enrolled 1,441 type 1 diabetes patients, aged 13-39, for a mean of 6.5 years. Intensive treatment involved pump therapy or at minimum three insulin injections/day, while conventional therapy consisted of only one or two insulin injections/day. Based on these data, Dr. Hirsch argues that the blunting of postprandial spikes in the intensive treatment group may have been partially responsible for the reduced risk of microvascular complications.
• Dr. Hirsch proposed that the diabetes community has been fooled by the statistics surrounding the DCCT results, such that “the majority of researchers don’t understand the DCCT.” In particular, one conclusion drawn from the DCCT results was that “96% of the beneficial effect of intensive vs. conventional therapy on the progression of retinopathy is explained by the reduction in the mean A1c levels.” A1c levels do explain the majority of the difference between intensive and standard groups, but in fact the between-group difference explains only 6.6% of the overall variability in retinopathy risk (Lachin et al., Diabetes 2008). Thus the vast majority of complications risk is explained by other factors – perhaps including glucose variability. He encouraged the audience to be skeptical of oversimplified statistics, noting that “the average human has one breast and one testicle.”
• Dr. Hirsch proposed that “introduction of insulin glargine, NOT the DCCT, is the major event” that improved type 1 diabetes insulin therapy in the US in the mid-1990s. He believes that glargine was the reason so many more patients started using basal-bolus therapy, which he said provides superior postprandial control compared to premixed insulins using NPH or Lente insulin. Speaking through a character in his slideshow, Dr. Hirsch provocatively suggested that perhaps “the development of NPH and the Lente insulins … set diabetes therapy back over 50 years” because these drugs encouraged use of premixed formulations.
  
  • “This was my ‘Aha’ moment,” explained Dr. Hirsch, citing data from 1998-2003 that investigated the frequency of insulin injections per day and the prevalence of diabetic retinopathy, which demonstrated a negative correlation between these variables over this time period. Dr. Hirsch suggested that the increase in the frequency of insulin administration reflected greater glycemic control, which appeared to be correlated with fewer diabetes-related complications.
• Glycemic variability has been shown to result in significant alterations of normal homeostasis, such as increased oxidative stress and inflammation. However, Dr. Hirsch recognized that the mechanism by which glycemic variability might mediate diabetes complications remains unclear. He does believe that a randomized control trial would bear out his hypothesis that dysglycemia increases the risk of cardiovascular events – so do we!

Questions and Answers

Q: Variability in A1c over time has also been associated with complications. Could you discuss this?

Dr. Hirsch: In DCCT, variability in A1c has been associated with diffrences in retinopathy and nephropathy; this work was done by Dr. Kilpatrick with publicly available data. I’m curious what you think about that, Dr. Bergenstal.

Dr. Bergenstal: My point was that throwing out A1c doesn’t make sense. The relevance of A1c variability is all the more reason to measure A1c. To Dr. Hirsch’s point about Lantus being important, I think that if there wasn’t DCCT, there would be no Lantus or pre-meal bolusing. Why try to create better products to get A1c down if it didn’t make a difference? I’m not opposed to optimizing glycemic variability; we just need to do trials to show that it makes a difference in terms of complications.

Q: There is a lot of evidence that the postprandial state can be a toxic period of time. And when it’s more toxic, the higher glucose levels are. Oxidative stress and inflammation are increased in those who are hypoglycemic.  Could you comment on the basic studies showing these effects?

Dr. Bergenstal: We have a lot of data to say it seems like a bad thing. We don’t have data to say how, if we intervene to reduce it, that will improve outcomes. Sometimes we’re surprised with randomized control trials and what they end up showing. We end up agreeing. My point wasn’t that glycemic variability is a bad thing or doesn’t make sense. It just doesn’t make sense to call it a marker right now. Let’s do the trial and see what we get, then we’ll be able to add it.

Dr. Hirsch: I would be fine with glycemic variability incorporating hypoglycemia as one component of that.  We want to do everything possible to reduce hypoglycemia. No one would disagree with that. On that point alone, we would want to reduce glycemic variability to reduce hypoglycemia. That may be more true in the type 1 population. If you go and look at retinopathy, there was always more in type 1 than type 2. The reason is because we had much more variability and the retinopathy had an opportunity to express itself sooner. That’s always been something I’ve thought. No way to prove that. But we use that to make a hypothesis. In fact, Dr. Bergenstal is on a committee to study these issues, and hopefully we’ll have an opportunity to present and address these issues soon.

Q: This meeting throws some doubt on A1c as a predictor of complications, and on its use as a diagnostic marker.

Dr. Hirsch: A1c is the best biomarker we have that we know of. We will continue to use it, and we should. I’m not bashing what we’ve learned in DCCT, UKPDS, or ACCORD. My point is that I want to find a better gold standard, and I think it might be CGM.

Dr. Bergenstal: That I agree with completely.

Q: Will you please comment on the contribution of A1c, glycemic variability and hypoglycemia on microvascular complications between type 1 and type 2 patients and, in the type 2 group, between insulin users and non-users?

Dr. Hirsch: We might have to have another session to discuss that.

Dr. Bergenstal: That’s a rather large topic. The A1c seems to be important in both, and hypoglycemia is important in both, and glycemic variability has more room for improvement in type 1s. So wherever it turns out to fit, it will play a big role in type 1s.

Q: Both of you made a case for a better definition or biomarker of variability. Dr. Bergenstal, you specifically said not to use CONGA. Could you address what the problems are and suggest what might be feasible biomarkers?

Dr. Bergenstal: I was a little joking about CONGA. For glycemic variability to rise up to a translatable factor we can address, we have to standardize it. I don’t think we’re even there yet with hypoglycemia, so that was my first push. Please let’s know which interventions cause more hypoglycemia. SD is commonly used; coefficient of variation is probably better. Interquartile range is best for practice, I think, because you can visualize it, and patient can see it. I think that coefficient of variation and IQR are some of the markers I would push for.

Dr. Hirsch: CGM is available only to a small number of people on a regular basis. Even with fingersticks, I can’t get strips for patients not using insulin anyway. I think over time that things will transform by using CGM-based definitions. I am partial to coefficient of variation because it accounts for both mean and standard deviation. That said, I think it needs to be based on evidence more than what Rich and I think. In the study that he and I are conducting, we will be looking at patients using CGM and seeing which measures of glycemic variability correlate best with reactive oxygen species, inflammation, and hypoglycemia – symptomatic or not. We will be able to speak more scientifically than we can now. 

Q: Apart from the quantum availability, the rate availability seems to be important. Therefore, chunking the data in smaller quantums, like fructosamine, would be more useful than glucosamine, which chunks the data into bigger intervals. What do you think about that?

Dr. Hirsch: If we had a very reliable biomarker to use in addition to A1c, that would be good. For example, we don’t have good access to glycated albumin in the US, especially for patients with renal disease, which, to your point, that’s looking at a smaller time with respect of average glucose. We are going to develop better metrics for looking at this. None of this really matters unless we look at associations with complications and hard endpoints. Looking at cytokines in a test tube is not enough

Dr. Bergenstal: I agree. We’re all in agreement on this point. I’d rather have a short one [biomarker] and a long one – called glucose – than a bunch of middle ones.

Q: With today’s tools, we can mimic but we cannot match what the individual without diabetes has. Can you start showing what the young, non-diabetic shows when they are measured with CGM?

Dr. Bergenstal: Yes, I had a slide in my presentation, but I took it out. It’s amazing what those profiles look like.

Dr. Phillip Cryer: I would hope that pharma and that those in design of clinical trials would consider inclusion of rigorously measured CGM data – ongoing, throughout – for all clinical trials that involve drugs with potential to cause hypoglycemia – insulins, sulfonylureas, glinides. I appreciate the nice things both of you said about me. Our work started in the 1970s. It took off only with a collaboration with the master of human metabolic physiology and pathophysiology, who is here today: Jack Gerich.

Q: If you look at pediatric downloads, we see that blood glucose goes all over the place.  In fact, SD in these patients is nearly double what it is in adults. But studies have described that the years before puberty counts less than the years after puberty. I’m having trouble understanding. Could you help me solve this

Dr. Bergenstal: I don’t even understand my own kids, so I don’t know if I could help you.

Dr. Hirsch: When I read recent reviews on this, before/after puberty business, in my reading, I saw this as controversial. So this is good to know. I learned something. My guess is that the world of pediatrics is different from the world of adults. You don’t see retinopathy with children. It would be fascinating to put a CGM on a group of 8-year-olds and compare that to a group of 20-year-olds with the same amount of variability. Will you see the same amounts of oxidative stress? Right now, it’s all speculative. We need data. But that’s a study we could do.

Q: Which variability parameter should we use to measure glycemic variability?

Dr. Bergenstal: We discussed this briefly. For research purposes, coefficient of variation seems like a good one. But you also want to use this as a teaching point, so I recommend interquartile range. Those are the two I like.

Dr. Hirsch: For research, I also like coefficient of variation. In clinical practice, all the meter downloads give standard deviation (SD), whether you like it or not. I have learned to like it because I have learned how to use it. You can’t look at it by itself, because it depends on the mean. I like to see SD x 3 to be less than the mean. This is difficult to do. Failing that, I see whether SD x 2 is less than mean. But this works only if the mean between 120 mg/dl and 180 mg/dl. In the clinic when using SMBG – and that’s what we’re talking about now, because almost everyone has access to that – I like low blood glucose index (LBGI). I can explain Dr. Kovatchev’s formula to patients, and patients really understand it.

Q: Can you give some brief comments on determir vs. others insulins in glycemic variability?

Dr. Hirsch: It may be true that variability of different insulins do differ. If so, then you have to translate what that means for glucose. And if someone is on prandial insulin, that complicates things.

Dr. Bergenstal: We’re in an era now when we need CGM to compare one insulin to another. We need a proper protocol, looking at hypoglycemia, etc.

Also…

Oral Presentations: Novel Therapeutic Agents

The Worldwide Experience with Autologous Non-Myeloablative Hematopoietic Stem Cells Transplantation in New-Onset Type 1 Diabetes (124-OR)

Francesca D’Addio, MD, PhD (Harvard Medical School, Boston, MA; and San Raffaele Hospital, Milan, Italy)

Dr. Francesca D’Addio presented a series of studies conducted in Poland and China on the controversial potential of autologous hematopoietic stem cell transplantation (AHSCT) to cure newly-diagnosed type 1 diabetes patients. The tested question is a version of the Voltarelli Cocktail. The approach uses high doses of immunosuppressants (cyclophosphamide and antithymoctye globulin [ATG]) to largely wipe out the immune cells. Patients are then “rescued” with the AHSCT, and the hope is that the immune system will redevelop without islet autoimmunity. The therapy, which was tested in 65 patients in three sub-studies, yielded some fairly striking and, more importantly relatively long-lasting benefits (for context, past biological approaches to curing type 1 diabetes have only had a temporary affect, if any). Insulin independence was achieved in all patients at least once during the trial, and persisted for an average of 18 months. Over 32% of patients remained insulin independent until their last follow-up (not disclosed). This efficacy was backed up by significant decreases in insulin requirements, significant and sustained increases in C-peptide, and a massive sustained mean A1c reduction from 10.1% to 6.0%. Such benefit did not come without cost – the frequency of severe side effects was fairly high, and the list included neutropenic fever, alopecia, fever, and one death due to sepsis that may or may not have been related to the therapy, which is immunocompromising (34/65 patients experienced an adverse event).

• Patient enrollment:  This study enrolled patients at three centers in Poland and China. People had at least one autoantibody (most were GAD-positive), no complications, and age 12-35 (mean age of 20). At the Joslin Symposium, Dr. Jay Skyler (University of Miami, FL) critiqued prior trials of this approach, stating that participants in the trials were not well characterized leaving some doubt about their disease state. In line with this observation, yesterday’s oral included relatively little details on the patients’ baseline characteristics.

Age (years)	20.4 years
% Male	63%
BMI (kg/m2)	18.1
DKA or DK history
- No DKA (%)	43 (66%)
- DKA (%)	21 (32%)
- DK (%)	1 (1.5%)

• Treatment protocol: People were treated with a three-step AHSCT regimen. The first step, hematopoietic stem cell (HSC) mobilization, involved treatment with cyclophosphamide (an immunosuppressant) and granulocyte colony stimulating factor (GCSF, which stimulates cell growth, particularly of regulatory T cells). Cells were harvested and frozen. The next step was a preconditioning process with additional cyclophosphamide and rabbit antithymocyte globulin (ATG; an immunosuppressant). Finally, the CD34+ hematopoietic stem cells (which can become many different components of the blood, including immune cells) were infused into the patient.
• Following the therapy regimen (which includes large doses of immunosuppressants), patients’ immune systems largely recovered. Neutrophil levels stabilized following a spike, while white blood cell counts stabilized, albeit at what appeared to be a lower level than baseline.
• Insulin independence was achieved in the majority of patients at six months post-transplant. According to Dr. D’Addio, all patients achieved insulin independence at least once, ~60% were insulin-independent at six months post-transplant, and nearly 40% of patients remained insulin independent. A substantial A1c reduction accompanied this improvement – on average, patients went from a mean baseline of ~10% down to a mean of ~6.0% at 12 months, with only a slight rebound afterwards. C-peptide levels increased significantly and stayed elevated through 48 months (a positive sign given that many other biological approaches to type 1 diabetes have only shown a temporary effect, if any). Results are to be published in Diabetes shortly.
• The team represented by Dr. D’Addio’s categorized patients as responders or non-responders – as we understand it, responders were those who remained insulin independent at six months. Responders had a much more robust reduction in A1c (~8%) compared to non-responders (~4%). Responders also had more than double the average increase in C-peptide, and around a third the incidence of diabetic ketoacidosis. Predictors of being a responder included receiving a greater number of cells during infusion as well as a more recent diagnosis of type 1 diabetes (15 - 20 weeks between diagnosis and infusion was the average in the responder pool). Looking for a responder pool with AHSCT seems like it may be a wise idea, as the therapy involves a relatively high incidence of concerning side effects.
• Although the efficacy demonstrated by AHSCT in this trial was certainly striking, loss to follow-up could have introduced a bias. Dr. D’Addio presented a chart representing each of the 65 patients as a horizontal bar, showing the length of their study enrollment as well as their insulin dependence status. It appeared that a number of patients did not make it to 48 months, and if patients that saw poorer results were more likely to discontinue enrollment, it could have introduced a degree of bias. However, loss to follow up is factor in any clinical trial. 
• AHSCT was associated with a number of adverse effects, some serious. A full 34 of the 65 participants experienced at least one adverse event; in terms of serious events, the incidences of neutropenic fever, alopecia, gastric tract symptoms, and rashes were fairly high, although it was difficult to quantify the exact incidence of each from the table Dr. D’Addio presented. There was one death due to sepsis, which could be treatment related given the approach substantially weakens the immune system. During Q&A, Dr. D’Addio also acknowledged that cyclophosphamide has been linked with infertility, although this was not observed during the study. Dr. D’Addio acknowledged that the incidence of severe side effects would likely limit this therapy to selected individuals with type 1 diabetes, unless safer HSC-based options are developed. 
• The appropriateness of the Voltarelli cocktail has been hotly debated at past meetings on type 1 diabetes cure research. At the 2013 Rachmiel Levine Diabetes and Obesity Symposium, Dr. Richard Insel (JDRF, New York, NY) stated his belief that the original Voltarelli cocktail would not be safe enough for use in children and adults (he questioned whether attendees would be willing to put their own children through the treatment), and acceptable in the eyes of regulatory agencies. Instead, Dr. Insel encouraged researchers to take the principles from the Voltarelli cocktail and learn how to apply them safely. At the Joslin Symposium in 2013, Dr. Jay Skyler (University of Miami, FL) called the Voltarelli cocktail a “heroic” attempt to fight the disease given its relatively high mortality risk.
• As a result of this approach’s concerning safety signals, the risk/benefit assessment might limit it to very specific type 1 diabetes patients, at least until safer variations of the process are perfected. Several such approaches are already in development – for example, at 8 AM this morning, in W-2006, Dr. Michael Haller (University of Florida, Gainesville, FL) will present positive results for low-dose antithymocyte globulin (ATG) in combination with granulocyte colony stimulating factor (GCSF); an approach that has been dubbed “Brazil Lite” (in reference to it being a less intense version of the Voltarelli cocktail).

Questions and Answers:

Q: Can you tell me more about the transplant procedure?

A: Patients underwent the initial steps, and once cells reached certain numbers, cells were then collected and frozen. Patients underwent a conditioning regimen using cyclophosphamide and ATG, then the cells were thawed and infused into the patients. Patients were also treated with antibiotics, which is standard procedure for stem cell transplantation.

Q: Where do the cells go once they are infused?

A: We don’t know. We could not track the cells. We would like to know where they go – it would be interesting to check.

Q: Could you talk more about the side effects of the transplant procedure?

A: The adverse events that occurred mostly occurred in the first 12 months. The only thing I can say is that some of the compounds used in this procedure have some toxic qualities. Another trial published by a group in Brazil has showed that cyclophosphamide can induce infertility in the long term. We have not observed that so far.

Q: Did you check if antibody positivity determined who was a responder?

A: We did not check if there was a correlation, but that is a good suggestion.

Oral Sessions: New Developments in Clinical Obesity

Early Diabetes Remission After Gastric Bypass Surgery is Explained by Exclusion of the Foregut (101-OR)

John Kirwan, PhD (Cleveland Clinic, Cleveland, OH)

Dr. John Kirwan presented a clever and elegant study suggesting that exclusion of the foregut in roux-en-y gastric bypass (RYGB) is key to the surgery’s glycemic effects. The Cleveland Clinic team, including famous bariatric surgeon Dr. Philip Schauer, placed G-tubes in the excluded stomach during the RYGB procedures of 14 people with obesity and type 2 diabetes (average BMI of 49.2 kg/m², and A1c of 7.5%). The G-tube enabled researchers to conduct mixed meal tolerance tests (MMTTs) as if the foregut had not been excluded during the procedure. Compared to a pre-operative oral MMTT, both post-operative MMTTs caused a greater level of insulin secretion, with the oral MMTT causing the greatest amount of secretion. Similarly, the post-operative oral MMTT identified the greatest levels of C-peptide secretion and beta cell function. In contrast, a similar degree of improvement in insulin resistance was seen for both the oral and the G-tube post-operative MMTTs. These results suggest that adaptations arising from the foregut exclusion might provide a key mechanism for understanding diabetes remission after RYGB. The idea that skipping the upper intestine may remit diabetes suggests that a bad actor in the upper intestine might be involved in the etiology of the disease. Such a factor may be considered an “anti-incretin” – i.e., an intestinal peptide that causes diabetes instead of improving it.

• The trial enrolled 14 people with obesity and type 2 diabetes who were undergoing RYGB. The average A1c was 7.5%, and BMI was 49.2 kg/m². Eleven of the participants were women. Overall, participants had an average age of 46.5 years, and type 2 diabetes duration of 7.7 years.
• When people received an oral MMTT post-operation their insulin response area under the curve (AUC; ~7,000 uu/mlŸ*3hr) was significantly greater than either the G-tube MMTT (~4,000 uu/mlŸ3hr) or the pre-operation RYGB (~1,000 uu/mlŸ*3hr). Similarly, people’s C-peptide AUC was greater during the post-operation oral MMTT (~2,000 ng/LŸ*3hr), than either the post-operation G-tube MMTT or the pre-operation MMTT (both ~1,000 ng//L*3hr)Ÿ. In line with this, pancreatic beta cell function was found to be significantly better with the post-operation oral MMTT than for either the pre-operation MMTT or the post-operation G-tube MMTT (which had similar levels of function to one another).
• Participants’ fasting blood glucose levels, fasting plasma insulin, and insulin resistance levels were similar whether the MMTT was delivered either orally or via the G-tube.
• The idea that skipping the upper intestine may remit diabetes suggests that a bad actor in the upper intestine might be involved in the etiology of the disease. Such a factor may be considered an “anti-incretin” – i.e., an intestinal peptide that causes diabetes instead of improving it. In the past, we have heard that a potential anti-incretin has been identified: the NP266 peptide, which when virally overexpressed in mice increases fasting plasma glucose and deteriorates glucose tolerance. It is silenced in mice by duodenal jejunum bypass. It is elevated in the blood of obese humans and is reduced after RYGB. It is also overexpressed specifically in the intestines of animals with type 2 diabetes and is silenced by bypass.

Questions and Answers

Q: You mentioned the incretin effect – it has been proposed that could be glucagon or GIP. Did you look at those?

A: We do not have data on glucagon yet. We have debated whether we would go there. We are not sure how strong a role glucagon is playing. GIP and GLP-1 are obviously major candidates here. GLP-1 measurements show a pattern that is similar to insulin – an increase in GLP-1 with the oral administration, and regression with the G-tube. We have published some of these data where we see strong effects of GLP-1. In our animal studies there is some role that needs to be considered for the foregut. Particularly attractive I think is some kind of anti-incretin.

Q: Did you look at gastrin levels?

A: We have not measured gastrin in these patients. That could be a compensatory mechanism. It leaves a lot of work to be done.

Current Issues: Can Better Control of HbA1c Reduce Cardiovascular Risk?

Pro – There is Value in Controlling HbA1c

Jay Skyler, MD, MACP (University of Miami Miller School of Medicine, Miami, FL)

The grand Moscone North ballroom was packed for this highly anticipated debate in which the legendary Dr. Jay Skyler argued a resounding “yes” for whether there is value in controlling A1c in reducing cardiovascular disease risk. In savvy debate strategy, Dr. Skyler cut straight to the rebuttal by addressing the infamous trilogy of studies – ACCORD, ADVANCE, and VADT – that failed in primary analysis to show statistically significant CVD risk reduction due to glycemic control. Yet Dr. Skyler argued that inadequate study length, competing medications like ACE inhibitors and statins, and prior history of CVD did not provide room to see benefits of glycemic control on CV risk reduction. Notably, subgroup analyses in each of these trials of patients without CV event history proved that earlier intensive treatment could in fact reduce CV risk. In support of his argument, Dr. Skyler also reviewed the STENO-2 study, EDIC/DCCT, and UKPDS which all showed significant CV risk reduction only after long-term follow-up. Early intensive treatment provides long-term benefits, i.e. a “legacy effect,” and such follow-up evidence may shape future treatment guidelines. Dr. Skyler also cautioned that data on macrovascular effects of intensive treatment have been less conclusive in these studies and require further evaluation – a sticking point that his opponent in the debate Dr. Michael Farkouh (Mount Sinai Hospital Toronto, Ontario) later emphasized.

• Starting with ACCORD, Dr. Skyler argued that the early termination provided an inadequate amount of time (3.5 years) to show risk reduction in standard MACE (major adverse cardiovascular events – non-fatal MI, non-fatal stroke, and CVD death) with glycemic control. Importantly, when assessing the primary outcome by subgroup, two thirds of patients who had no history of CV disease showed statistically significant risk reduction in MACE.
  
  • Similarly, in ADVANCE, those patients with no history of macrovascular disease and microvascular disease showed 14% and 11% risk reduction in MACE, respectively. Additionally, concurrent medication of ACE inhibitors and statins may have masked the risk reduction benefit of glycemic control in ADVANCE.
  • VADT data showed similar results, where patients with baseline coronary artery calcium (CAC) scores of 0-10 showed benefit with intensive therapy. CAC scores infer the presence of coronary atherosclerosis by measuring the amount of calcium in the coronary arteries. Unsurprisingly, with larger baseline CAC scores (increasing up to 400), benefit of glycemic control decreased. Dr. Skyler emphasized, “If you start glycemic control early enough such that you don’t have background disease, you have much greater chance of success in reducing CV risk.”
• To further support his argument, Dr. Skyler reviewed the STENO-2 study, EDIC/DCCT, and UKPDS, which all showed significant risk reduction in composite CV score was only apparent after long-term follow-up. With a friendly shout out to Dr. Rury Holman (lead co-investigator of UKPDS) in the front row, Dr. Skyler highlighted that UKPDS’ “legacy effect” underscores this importance of long-term follow-up in showing statistically significant risk reduction.
• Regarding the 22% increased risk of all-cause mortality in ACCORD, which resulted in the trial being terminated early, Dr. Skyler clarified that the patients who died during the trial “were patients whose A1c did not go down even with intensive treatment.” The ACCORD trial design required that providers had to increase treatment even if A1c <6.0% if more than 50% of SMBG tests over four days were >100 mg/dl for fasting glucose or >140 mg/dl for two-hour post-prandial glucose. Treatment was lessened only in the presence of hypoglycemia. In an illuminating example, Dr. Skyler asked the audience if anyone would use this standard treatment with their patients. Not a single hand in the 400-person crowd raised their hand. He emphasized that such an extreme treatment strategy for glycemic control allows room for adverse events.

Con – There Is No Proven Value in Controlling HbA1c

Michael Farkouh, MD (University of Toronto, Toronto, Ontario)

Dr. Michael Farkouh acknowledged Dr. Skyler’s assertion that strict control of A1c values in people with diabetes can prevent damage to the microvasculature, and that “aggressive” treatment of type 1 diabetes in young individuals can result in fewer overall cardiovascular events in those individuals. However, he maintained that no solid evidence demonstrates that tight control of A1c can reduce macrovascular complications in type 2 diabetes. He suggested that a focus on glycemic control is not sufficient when considering people with type 2 diabetes, especially given the very real threat of serious macrovascular complications.  He suggested instead that some of the resources spent lowering A1c levels in type 2 diabetes should be spent reducing LDL levels and providing statins to more diabetes patients. Dr. Farkouh also raised some concerns that adverse macrovascular outcomes, including heart failure, might be associated with intensive glycemic control and aggressive treatment of type 2 diabetes. He concluded his presentation by calling on the audience to consider whether these safety concerns might make the risks associated with tight glycemic control too great for any potential benefit.

• Dr. Farkouh outlined some reservations regarding data on glycemic control presented in the ACCORD trial. He suggested that a more careful analysis of the cardiovascular death rate might be necessary, since much of the difference in mortality rate resulted from unexpected, sudden death. Given the sudden nature of much of the mortality in individuals with higher A1c levels, Dr. Farkouh noted that these deaths might reasonably be attributed to metabolic aberrations or neurologic influences on the heart, rather than the degree of glycemic control in affected individuals.
• Dr. Farkouh highlighted the dangers of focusing on tight glycemic control in type 2 diabetes while neglecting other measures of health. He described diabetes as a “cardiovascular disease with an endocrine basis,” and suggested that LDL levels and blood pressure might actually be more important measures of overall health in people with type 2 diabetes than are A1c levels. Dr. Farkouh noted that great improvements in the quality and length of life could be made by investing additional resources in reducing LDL levels and providing more type 2 diabetes patients with statins to help prevent adverse cardiovascular outcomes. He stated that an ideal LDL level to aim for might be as low as 40 mg/dl, or 1 mmol/l, and he implied that many people with type 2 diabetes are fairly far off this number due to a relative lack of focus on LDL control in diabetes therapy. Although Dr. Skyler said that a higher A1c level predicts higher cardiovascular risk in people with diabetes, Dr. Farkouh maintained that there is no hard evidence at this time to support any such trend – we assumed the long-term UKPDS data was one starting point. .

Questions and Answers

Q: If you are using SAVOR as a negative study, Dr. Farkouh, you’re tagging at the end of long studies for CV risk reduction. We would need a long-term study evaluating excellent control starting from the beginning of type 2 diabetes for a long period of time. In all these studies, combination with insulin and sulfonylureas all induced hypoglycemia. This is a challenge for all these studies

Dr. Michael Farkouh (Mount Sinai Hospital, Toronto, Ontario): I was pointing to SAVOR because we thought it would be our savior. In a meta-analysis, it showed 30-40% risk reduction. I only mentioned it because of side effects. I agree with you completely. We have a lot of hypotheses, and we have “fuel” to do another UKPDS-like trial. We have to start our therapies earlier and follow more mechanisms earlier. I don’t think we understand much yet on the CV side.

Dr. Jay Skyler (University of Miami Miller School of Medicine, Miami, FL): We need to appreciate that SAVOR is a two-year study. If you want to see differences in outcomes, you need to do the study for long enough. My bias is that SAVOR was designed to show no increased risk. That’s what FDA guidelines require. If you wanted to show benefit, you have to design a longer-term study to achieve beneficial effect with any intervention. I would want to look at people in the earlier course of the disease and follow them for a longer time. I think also that in long-term studies, we need better adherence, as Dr. Farkouh pointed out. We need to see that patients can get the benefit that we are trying to provide. In the real-world, non-adherence is even worse. There is a 22% chance that people starting on a statin will continue on that statin long-term. We need to pay more attention to getting patient adherence.

Dr. Bernie Zinman (Mount Sinai Hospital, Toronto, Ontario): Dr. Skyler, when you talked about VADT, you showed that attractive curve to suggest short duration and mentioned that you haven’t seen that published. Well that was probably because that analysis was flawed. In actuality, the analysis wasn’t done carefully.

Q: I have a question for Dr. Farkouh: You seemed to emphasize that it is important not to rely too much on subgroup analyses and extrapolation. If I recall, you suggested that we should try to lower LDL cholesterol to 40 mg/dl or 1 mmol, is that correct? Is that number an extrapolation, or is there any clinical evidence that 1 mmol might be a good target?

Dr. Farkouh: That was an opinion of my own, it was not evidence based. There is some evidence, since it has been suggested that human LDL levels were in that range when we were still hunter-gatherers. In the JUPITER trial, LDL cholesterol levels were brought down to about 50 mg/dl, but in most studies involving people with diabetes we are nowhere near achieving this goal. That may be due in part to some biological difference in those with diabetes versus those without. However, I believe that with some of the new drugs in development we can lower LDL levels to an acceptable range in people with diabetes, and that this should be something to look for.

Comment: I wanted to emphasize the importance of duration of studies and the consequence of that on effect of reduced glucose on CV outcomes. I would point to a longer-term follow up of VADT that could address that. We have a poster that shows the effects of 5-6 yrs of intensive control, showing CV outcomes were reduced at longer term follow up.

Q: What would you recommend in the case of a patient treated with insulin who has an A1c around 6% and who is otherwise doing well, but has a remote history of cardiovascular disease and is on a statin? Would you relax the therapy or keep it the same?

Dr. Skyler: I think that if there were instances of significant hypoglycemia I would relax the therapy, but if not and the patient is achieving a low A1c, I see no compelling reason to change the treatment.

Dr. Farkouh: I agree completely. I have a number of patients in that range and I don’t see any issue with that as long as they aren’t having any adverse effects as a result of the treatment.

Q: Dr. Farkouh, do you believe it’s feasible to do a mega trial showing that reduction in A1c is effective in reducing CV risk? If yes, what would be your idea for this kind of trial?

Dr. Farkouh: Yes, I do believe it’s possible. It comes down to newer agents, particularly with GLP-1 agonists and DPP-4 inhibitors. As you know, there are a number of ongoing studies that we need to report on, and we need to be measuring not just MI and stroke, but also heart failure. I don’t want to say we need new trials; there are some very exciting ongoing trials that could provide useful information and show CV benefit. Let’s see what happens here. The cardiovascular community is very excited about GLP-1 agonists.

Q: I think Dr. Farkouh made an excellent point in suggesting that there isn’t any great evidence for a reduction in macrovascular events associated with decreased A1c levels in people with type 2 diabetes. Is there any scientific evidence that demonstrates an improvement in cardiovascular outcomes associated with tighter glycemic control? I understand that the scientific evidence for this in people with type 1 diabetes is excellent. Also, Jay, how would you prioritize different interventions for type 2 diabetes, including glycemic control, lipid levels, and blood pressure interventions?

Dr. Skyler: I don’t think that any clear-cut evidence for a link between macrovascular outcomes and glycemic control exists at this point. Meta analyses suggest that tighter glycemic control may benefit some people with diabetes. In terms of decreasing the overall number of cardiovascular events, lowering blood pressure and lowering LDL levels are both more important than improving A1c levels. I believe I made that point during my presentation. We need to treat the whole patient, so it is important to address all of those parameters in some capacity. I still believe that it is worthwhile to try to improve glycemic control, whether or not there is any improvement in the number of macrovascular events, since tighter glycemic control is bound to benefit microvascular outcomes.

Comment: I agree, I am also not particularly anxious to have patients lower their A1c levels for the purpose of avoiding cardiovascular events, since I know they’re going to see a major microvascular benefit.

Comment: We are talking about glycemic control being equivalent to A1c control. But in my point of view, I’m looking at A1c in diabetes patients as a cardiologist might look at one node in an EKG. A1c doesn’t reflect the entire picture. Do you have any comments on this?

Moderator: Yes, A1c isn’t the best measure of CV risk, but it’s the best measure we have of glycemic control. In DCCT the difference between outcomes from conventional to intensive was almost entirely explained by A1c.

Q: I recently read a paper that I think is very important with respect to this debate, it was published by Hanson in Diabetologia 2013. The study looked at the causes of death in all people with diabetes in Denmark. In this study, there were 47 deaths observed to be caused by cardiovascular events in people with diabetes for every one death caused by a microvascular event. I don’t mean to undercut the importance of avoiding blindness, dialysis, amputation, and other consequences of microvascular problems, but I think we need to seriously consider prioritizing therapies that address macrovascular outcomes as well given these results.

Dr. Farkouh: I am familiar with that data and I think it’s compelling. I believe we are not treating patients effectively. It is important to consider that some people might benefit from improving their glycemic control, but I think we’re undertreating patients on other fronts as I pointed out earlier.

Dr. Skyler: Michael said it.

Comment: I presented one of my studies based on primary data from UKPDS here at ADA. I looked at the trajectory of A1c over two years and immediately before MACE measures. In these patients (n=20,000), when looking at A1c along with lipids, blood pressure, and BMI, patients who have A1c >7.5% for over 2 yrs, have an 8-25% increased risk of MACE. But at the individual level of A1c and effect on MACE there is no significant effect. When risk factors are looked at together – and my study was a seven-year follow up – A1c in conjunction with other risk factors showed a visible CV risk outcome.

Dr. Skyler: Yes, that’s interesting. There are a number of studies that do this in a multitude of ways.

Moderator: I’d add that your study doesn’t address the issue of intervention. If you intervene, what’s the outcome?

Q: I think it is interesting that we are forced to look at macrovascular outcomes, but that we consider microvascular disease. Our priorities might also be different if we were to look at microvascular outcomes like blindness, or renal failure, but to see death from renal failure we would have to be looking ten to twenty years out. I am intrigued by coronary scans, and other considerations of the course of macrovascular disease, besides the marker of death as an endpoint.

Dr. Skyler: Here, you seem to be touching on the biomarker enigma that exists in so many different places. It is not just limited to myocardial infarctions or cardiovascular deaths. It is very tough to validate biomarkers – the whole process is a fishing experiment to some extent. We need to do prospective studies with hard outcomes in order to validate, which becomes part of the dilemma, but it is certainly worth considering.

Q: Why is the timing so different for risk reduction for CVD, lipids, and BP lowering? We don’t have a very good understanding of biologic mechanisms. What is the mechanism for glycemic control?

Moderator: The underlying pathophysiology may be different, so you need to intervene with different agents at different times.

Dr. Farkouh: There is a constant risk over the course of a patient’s lifetime. When you get to the point of having diabetes, that’s where there may be a more important role. Once you have it, the slope of a curve isn’t that steep and takes time to make an outcome difference. Patients may be so far gone. All the data lends itself to intervening early and even before diabetes.

Q: Can you comment on the whether or not you think statins might be responsible for an increased risk of diabetes in some cases, and whether this should be a consideration before prescribing statins to those with prediabetes?

Dr. Farkouh: This data comes from JUPITER and other studies linking statin use with diabetes. When we have drilled down more extensively, we find that folks that develop diabetes are already on the road to diabetes, in that they typically have two or three risk factors. In JUPITER I believe the time differential in terms of developing diabetes was only 100 days between the two groups. I also just read something suggesting that many patients on statins do not exercise to the same degree as those not on statins, so that could be a contributing factor also. I don’t know exactly what prompts the correlation between statin use and the development of diabetes, but it does not seem to greatly accelerate the process anyway. 100 days is a very small time difference.

Q: If a patient had prediabetes would you put them on a statin?

Q: Wouldn’t you agree that the potential benefit of using the statin far outweighs the risk of developing diabetes?

Dr. Farkouh: I agree, I would place the patient on a statin if I thought it was necessary. I think the benefit is far greater than the risk.

Q: Rosiglitazone basically pushed the FDA to set guidelines for requirements for CV safety studies. However, now a second look at that data isn’t as convincing, yet the CV requirement still exists. The unintended consequence is that a lot of major diabetes companies are getting out of diabetes because of these CVOTs. Our company [Takeda Pharmaceuticals] is committed to diabetes, but our senior management now continuously asks, “Why are we still in diabetes?” Is there any move from diabetologists and cardiologists to get together and say, “Okay, it was the right precaution at that time, but looking back, we have other data. We should reassess whether this I necessary.” These requirements are pushing major pharma companies to focus a lot of R&D in other fields like oncology. Major pharma is on their way out, like Roche got out altogether.

Dr. Skyler: The need to demonstrate safety was precipitated by rosiglitazone and maybe that wasn’t the right case at the time, but I don’t think that matters anymore. CVD is a major consequence that causes death in diabetes. That being the case, we don’t want to give medications that might increase CVD risk. To demonstrate that there is no increased risk may be the right thing to do, even though the initial stimulus may not apply anymore. I think it is perfectly reasonable to ask for benefit. I wouldn’t back away from FDA’s stance.

Dr. Farkouh: I think one benefit of the guidance is that it got the cardiovascular community in the diabetes game, and we needed to be. Heart failure is really important and needs adjudication and regulation. The guidance may have been reactionary, but it was right.

Dr. Zinman: I think we’re far better off today with those studies to talk about safety early in the lifecycle of drug. This could be a long debate.

Comment: It raises a point that I fully agree with; long-term safety should be done. However the question is when should it be done, premarketing or around marketing?

Dr. Zinman: Studies are initiated after launch or at the same time. As you know, it’s not a requirement to be done before. It’s a big debate that could go on for hours, so we’re going to hold off on that.

Q: Dr. Farkouh, you mentioned diastolic heart failure. If I am not mistaken, women have a higher risk of diastolic heart failure, is this correct? Why is that? It seems like most cardiologists seem to pay more attention to systolic heart failure than diastolic heart failure, do you think this is an issue that needs to be addressed?

A: I think this a very important issue. Systolic heart failure used to be regarded as a more serious condition, but in fact both systolic and diastolic heart failure have equally poor outcomes. I am not aware of any difference between sexes in the relative rates of systolic or diastolic heart failure.

Q: When studying drugs for CV endpoints, a confounding issue is that the populations are usually people who have advanced disease stages in order reach a required event rate. I understand though that the studies could be even longer and more expensive if the population used people early in disease progression. Should we start earlier on?

Dr. Skyler: You raised the big dilemma. If you want to show the benefit Dr. Farkouh talked about, you should assess people early, but you’re right, those CVOTs would be very long and expensive. But these are measuring safety, so trials are looking at people who may have increased risk in order to meet that event endpoint. It’s a clear dilemma and there is no easy solution to doing a bigger study that is long enough with both categories.

Symposium: Strategies for a Pathway for Drugs and Devices for Pediatric Diabetes Care

The Patient Perspective

Kelly Close, MBA (Close Concerns, San Francisco, CA)

We will be sharing data from all the speakers in this session following ADA. In the meantime, Close Concerns’ own Kelly Close gave an impassioned talk on the patient’s perspective of drug and device development in pediatric diabetes, centering on three key questions: 1) “What are the hardest parts about managing pediatric diabetes?” 2) “What are the biggest unmet needs in pediatric diabetes?” and 3) “What would be a complete home run for young patients with diabetes?” She stressed that diabetes management can be extremely challenging, causing frustration for patients, families, and providers that turns into challenges relating to care that can ultimately affect ultimate outsides. While there remains work to do in improving therapeutics and training providers in psychosocial support techniques, the field is moving ahead on many fronts. Overall, continuing effort should be made to keep the patient at the center of drug and device development, particularly with respect to industry investment, the regulatory process, and access to care. Our full slides can be accessed here.

• “What are the hardest parts about managing pediatric diabetes?” For pediatric patients with diabetes, each day is a new rollercoaster. The unhealthy food environment, coupled with changes in exercise and patterns, makes insulin dosing and initiating new treatments taxing. Despite one’s best efforts, glucose levels can fall out of range, leading to feelings of frustration (with the associated carb-overcompensation or the familiar “rage bolus”) and aloneness. Parents face particularly stress, with children at earlier ages unable to care for themselves; with multiple needlesticks, diabetes care often involves having to frequently hurt your child as well. This can all be compounded by social stigma – DQ&A recently surveyed hundreds of patients in its diaTribe panel, with many patients and parents of patients noting feeling increased stigma around their or their loved one’s diabetes (results to be presented here at ADA 2014 in poster LB-59).
• “What are the biggest unmet needs in pediatric diabetes?” Data from the T1D Exchange indicates mean A1c levels out of goal across all age ranges, still with substantial rates of DKA and severe hypoglycemia. This may be partially due to difficulties with education and access to care: data suggests underuse of the best therapies available, with <10% of patients on CGM across all age ranges. In addition to improved therapies, with the psychological challenges associated with chronic disease, there needs to be improvement in the psychosocial support provided to patients as well – the current reimbursement system leaves little time for counseling in appointments, with minimal dedicated training for providers in offering emotional support.
•  “What would be complete home runs for young patients with diabetes?” With many still limited to NPH insulin, improved access to care with affordable co-pays would strongly benefit patients. Though children spend the majority of their time at school, school officials may not be trained in diabetes care, with concerns often surrounding liability issues as opposed to appropriate management. Lastly, patients would benefit from an even greater focus on patient-centered drug and device development, with emphasis on prioritizing peace of mind, reduced pain, and ease of use – we see Sanofi’s hiring of Dr. Anne Beal as “Chief Patient Officer” and FDA’s new “patient-focused drug development” (though diabetes is not on the planned list of disease areas) as strong steps in the right direction.

Exhibit Hall

AstraZeneca

AstraZeneca’s main booth was a towering, white and purple sleek booth in the center of the hall near the back wall. Featuring a double deck structure, big white banners along the top of the booth advertised the company’s diabetes and endocrine products (Bydureon, Byetta, Onglyza, Kombiglyze, SymlinPen, and the newly approved Myalept). The first floor was lined with wavy white leather couches, plush purple and gold carpeting, and had soft purple lighting - an aesthetic departure from the blue and white of old BMS/AZ joint alliance booths. A never-ending line of people queued up for coffee and tea at the booth's entrance.  Six-paneled flatscreens on the front and sides of central structure each advertised one of AZ's six main diabetes products. The main central structure was flanked by tall flat screen panels, each showing A1c, weight loss, and other clinical data for their products, with a focus on Byetta, Bydureon, and Farxiga. The panels extolled the extra-glycemic effects of each of these, including the weight loss and blood pressure benefits of these drugs. Unfortunately, as was the case at AACE, there was no mention of the new Bydureon dual-chambered pen in any of the booth's materials or anywhere on display. This is the new Bydureon device developed to eliminate the need for manual patient-end reconstitution of the powdered drug. The FDA approved it in March, and AZ has guided for a 2H14 launch. We had to ask a rep to walk us all the way around to the cave-like Medical Affairs nook hidden away in the back. There, a representative walked us through the steps to use the new pen. The pen is fairly large - we estimate that it was about 8-9 inches long fully extended with a circumference somewhat smaller than that of a US quarter. The needle was also relatively large, a 23-gauge needle, but is 1 mm shorter than the one in the current Bydureon system. We learned that the needle could not be any smaller due to the microsphere technology of the drug. For comparison, Lyxumia's pen in the EU can be used with 29- and 32-gauge needles. The current Bydureon system uses a 23-gauge needle as well, however, and we have not heard negativity around it (we've used it and it didn't hurt!). In general, we think the new pen will be a slight convenience upgrade over the old complex process. The representatives at the booth were not able to give us more specifics on when it might launch, although we did learn at AZ's exhibit hall booth at AACE that it would likely be priced similarly to the old Bydureon system. The instructions for use are as follows:

1) Take the pen out of the refrigerator and let it sit at room temperature for 15 minutes.

2) Inspect the powder and diluent through the chamber's viewing windows to ensure that they are not discolored.

3) Attach the needle to the pen.

4) Twist the knob at the bottom of the pen to combine the powder and solvent.

5) Shake until fully mixed. It is recommended to tap the pen against the palm about 80 times, rotating the pen 90 degrees ever 15-20 taps, to ensure proper mixing (the representative acknowledged that this sounded like a lot of shaking), but patients may also check halfway through to see if the powder has been fully mixed (there is an image in the user guide to help patients determine what the window should look like fully mixed). There was no actual powder or solvent in the demo pen, but there were images placed in the viewing window showing what the patient might see if it were fully mixed or not. The fully mixed suspension should be homogeneously white with no particles or clumps.

6) Twist the knob at the bottom of the pen again until you hear another click.

7) Remove the cover for the needle and swab the injection site.

8) Inject, pressing down and holding for 10 seconds.

BD

We quickly spotted BD’s booth from two prominent ceiling signs that read, “Helping all People Lead Healthier Lives.” The exhibit space included a three-foot wide panel at each corner, and a long wall across one of the shorter sides of the booth. The exhibit focused on “IT,” or injection technique, with the takeaway that BD’s shorter needles (Ultra-Fine 6 mm needle for syringes or the Ultra-Fine Nano 4 mm pen needle with EasyFlow technology) will improve technique (rotating injection sites and injecting the needle at the right angle, to name a few). Each panel included a short video demonstrating how better injection technique will reduce pain, decrease lipohypertrophy, and improve the consistency of insulin delivery. The video alternated between research results from BD’s own work and pictures of smiling patients with quotes such as, “Less Pain – IT matters” and “IT – consistent insulin delivery.” On the larger wall, there was a screen projecting an aerial view of the center table, where “Lipo Larry” was spread out on an examination table – this dummy invited attendees to feel the lipohypertrophy on Larry (surprisingly difficult!) – we found this didn’t draw as many attendees as the real patient at EASD; however, the hands on participation was nonetheless appreciated. Unsurprisingly, the representative we talked to could not provide any information on BD’s potential patch pump/pen or its CGM partnerships with JDRF (a standalone CGM as well as an insulin infusion set/CGM).

BI/Lilly

This booth was a bit toned down compared to last year, with a sleek white appearance instead of the signature exuberant purple. Large rectangular screens provided safety and efficacy data on Tradjenta and Jentadueto. There was little in the way of entertainment beyond the standard coffee and espresso stand. As the much more elaborate Lilly Diabetes booth also included information on Tradjenta and Jentadueto, there seemed to have been an effort to consolidate the two displays. A wall next to the medical information booth outlined the many new diabetes products in BI/Lilly’s pipeline (e.g., the SGLT-2 inhibitor empagliflozin and BI/Lilly’s new insulin glargine formulation), and it will be interesting to see whether this booth receives more attention in the future if those drugs are approved.

Dexcom

Dexcom had one of the largest booths we’ve ever seen it display, sporting yet another new clever marketing slogan: “Don’t just meter. Monitor.” We love that message for patients. The main news of the booth was Dexcom’s recently approved Professional version of the G4 Platinum (read our report) – bold signage offered providers that use the Medtronic iPro2 a free trade-in for the G4 Platinum Professional system (receiver + transmitter). To qualify, providers must purchase two boxes of G4 platinum sensors and send in their iPro2 system by September 30, 2014. A comparison table emphasized the advantages of the Professional G4 Platinum over the iPro2, including performance (real-time [Dexcom] vs. retrospective [iPro2]), flexibility (unblinded/blinded vs. blinded only), duration (seven days vs. three days), comfort (26 gauge vs. 23 gauge), and convenience (two calibrations/day at any time vs. four calibrations/day during stable glucose state). Meanwhile, providers currently using the professional edition of the Seven Plus will get a free upgrade to the G4 Platinum Professional system (provided they purchase two boxes of sensors). The remainder of Dexcom’s booth was dotted with marketing materials of all sorts, headlined by the first official brochure we’ve seen on Dexcom Share (in the final stages of FDA review, per Dexcom’s 1Q14 call). The flyer showed a mom hugging her son under a picture of the G4 Platinum receiver in the Share docking cradle – across the top was the phrase, “Remote viewing of glucose activity between your patients and their loved ones is now made possible through Dexcom Share.” Other signage and handouts marketed Dexcom’s two other recent developments – “many plans” now offer Dexcom CGM as a pharmacy benefit, “simplifying the process and making it more affordable than ever for patients” (a highlight of the AACE 2014 exhibit hall); and the FDA approval of a pediatric indication for the G4 Platinum.

Eisai

Eisai’s coral, navy blue, and white booth consisted of a number of interactive activities while highlighting Eisai/Arena’s anti-obesity medication, Belviq (lorcaserin). Similar to last year’s ADA, several flower arrangements were scattered around the booth, seemingly referencing to Belviq’s trial names: BLOOM, BLOOM-DM, and BLOSSOM. On the outside of the booth’s walls, screens lit up with animations of scales, sneakers, and stethoscopes, portraying Belviq as “proven weight loss with lasting impact.” In one corner – under a sign asking, “What are you made of?” – representatives conducted full body analysis on attendees, providing them with their BMI, percentage fat etc. The booth’s center wall declared “Pledge and Poll.” Here, attendees were asked questions about their experiences with obesity and to pledge to start conversations about weight with their patients. Another wall had illuminating screens of Belviq’s trial data. A representative offered to give us an overview of Belviq on an interactive screen, in which he showed us clinical data on its weight loss and glycemic levels, its safety profile, and Eisai’s free trial and savings programs. Upon asking how Belviq compared to Vivus’ Qsymia, the representative said that he was not going to “bad talk” Qsymia since he had heard positive reviews of that drug as well. We enjoyed the interactive and friendly atmosphere of Eisai’s booth.

Glooko

Glooko’s small booth in the back of the hall attracted a crowd interested in learning about the Joslin HypoMap, which we first reported on earlier this week. As a reminder, this contextual survey will sit within the Glooko app and help providers and patients identify and improve hypoglycemia unawareness. Our trip to the Glooko booth was headlined by a demo of the company’s Bluetooth adaptor, which is hopefully expected to launch this summer. This small plastic rectangular box (about 1.5 in x 0.5 in) will plug into the 27+ meters that Glooko supports and wirelessly send data to the Glooko app. It looked quite seamless to us, and as we understand it, the company is working on seamless background sync that would not require the app to be open.

GSK

GSK’s booth was located towards the back of the exhibit hall. It was large, and fairly sparse, though very welcome – the only drug-related content came in the form of four displays featuring the raw label for GSK’s approved but not-yet-launched once-weekly GLP-1 agonist Tanzeum (albiglutide; branded Eperzan in the EU, where it was also recently approved). Most of the booth was uncluttered, with plush purple-carpeted floors and a few chairs and couches where attendees could rest, recharge their electronic accouterments, and much on some very sweet granola. Attendees had to walk to a separate GSK medical booth to see a demo of the single-use pen and administration process for Tanzeum – the drug does require reconstitution, and as with the new (much bigger) Bydureon dual-chambered pen, the reconstitution process is contained within the pen and takes slightly upwards of 15 minutes. As opposed to the Bydureon pen, however, albiglutide does not need to be stored in the refrigerator if it is used within a few weeks after purchase. Patients will first twist the pen to the first stop, mixing the contents of the powder chamber and water chamber. Next, the patient will gently shake the pen five times, then place it upright in an empty cup for at least 15 minutes (thankfully for forgetful patients, the pen can rest at this stage for up to eight hours and still be usable). After the break, the patient once again shakes the pen gently five times, twists to the second stop, and then administers the drug. We imagine that GSK’s conference booths will get much more exciting following Tanzeum’s launch, which will likely occur in the third quarter.

Insulet

Insulet sported a smaller booth than we’ve seen in the past, though it was well located near the hall’s main entrance – location is everything! A large sign proclaimed the benefits of the second-gen OmniPod, “Easy to use, wearable, and waterproof.” Pictures of patients tended to display the OmniPod on the tricep, putting a clear emphasis on the product’s small size and wearability. Eager attendees could step up to one of three podiums and receive a demo of the OmniPod system. We did not notice any of the giveaways that Insulet has had in the past, which have included general posters on pump therapy, solid chocolate OmniPods, or demo pod kits (though perhaps these were just not noticeable when we walked by). There was no mention of yesterday’s announcement that the integration partnership with Dexcom is back on. 

Intarcia

Intarcia did not bring a formal booth to the exhibit hall, but instead had a private training suite where their clinical nurse force were training investigators who are already participating in their global phase 3 program.  The nurses and investigators were demonstrating the insertion and removal process for the ITCA 650 exenatide mini-pumps. The placement and removal procedures were astoundingly simple. The mini-pumps can be inserted into the patient’s abdomen, upper thigh, or back of the arm. Once the area is sanitized and a local anesthetic is applied (which means the patient is awake during the procedure), a tiny incision is made with the tip of a scalpel – it looked to be about only 4 mm wide. The match-stick sized ITCA 650 device is then loaded into a thin tube in the insertion device. The insertion device looks like, and is about the size of, a small water squirt gun with the thin tub attached to the “spout” of the gun. The tip of the beveled tube is inserted into the incision at about a 45-degree angle until it is just under the skin, at which point the tube is slid further into the incision, but parallel to the skin keeping it very close to the surface. The insertion device is then stabilized with the free hand, and a sliding trigger is engaged such that the tube releases hold of the ITCA 650 mini-pump, leaving it in the body while the tube retracts back into the device out of the skin. No sutures are needed – the incision is essentially covered with a band aid. If the device has been properly inserted very close to the skin’s surface, retrieval takes a matter of seconds. One of the ends of the ITCA 650 mini-pump is tented up against the surface of the skin, where another tiny 4mm incision is made on the tip where you intend to remove it, and it simply pops right out. Then the new ITCA 650 mini-pump is loaded in the same location in just a matter of a couple minutes.  For chronic therapy this would only be done once or twice a year.  If the device has been placed too deeply beneath the skin, then retrieval may be more difficult – the company learned this in phase 2, so all investigators in phase 3 have been trained and certified by a global nurse educator force to ensure that the device is inserted just beneath the skin. Management informed us that over 5,000 procedures have been performed in phase 3 at this point, representing over 2,800 patients enrolled, who receive an initial three-month titration implants (20 ug/day) followed by six-month full-dose implants (60 ug/day).

J&J LifeScan/Animas

LifeScan/Animas’ presence is shrinking in J&J Diabetes Care’s real-estate, from approximately two-thirds of the booth at the EASD exhibit hall to only about one-third of the booth here at ADA 2014. Clearly, the success of Invokana has shifted the company’s marketing priorities. Fortunately, one Animas representative assured us that J&J is here to stay in Diabetes Care, an emphasis during the recent Medical Devices Business Review Day. At the very front of J&J’s booth was an approximately six-foot tall, one-foot wide white board with sticky notes covering almost one-half of it; upon closer examination, we found that J&J representatives had posed the question, “How can we engage families of patients with diabetes to be positive agents of change?” HCPs were invited to write their response on a sticky note and put it on the white board – creating a very crowd-sourced mini market research project. Some of the more common responses were to increase community and family education to reduce stigma and spread the responsibility of care (our sister company dQ&A has an entire poster on diabetes stigma this year – see it tomorrow in abstract 59-LB). Turning to Animas, it was not a surprise that representatives declined to comment on the timeline of the Animas Vibe – as a reminder, the Medical Devices Business Review Day noted that the company had just responded to questions from the FDA (this has been under review for over one year). Similar to booths over the past few years, Animas OneTouch Ping pumps floated in water to show off the water resistance feature. LifeScan was relegated to one small, circular counter space that displayed the company’s meters, including the OneTouch VerioSync recently launched in the US in January. Representatives from Animas and LifeScan were unable to comment on either a launch date for the Finesse (at the MD&D day, the Finesse was expected to launch within 24 months) or launch metrics on the VerioSync in the US. For those attendees who were feeling peckish, the center of the booth featured iced tea, sesame sticks, goldfish, almonds, peanuts, craisins, and dark chocolate covered pretzels.

Janssen

Like last year, Janssen occupied about a third of the large, centrally located J&J exhibit. As a reminder, J&J's SGLT-2 inhibitor Invokana was approved by the EU in November last year and launched in the UK this February, and so it retained a prominent place in their exhibit. Several large interactive touchscreens surrounded a posh lounge area with white sofas where visitors could compare glucose reabsorption in healthy people and in people with diabetes as well as explore the mechanism for SGLT-2 action. The touchscreens also recounted the various benefits of Invokana, highlighting the reduced A1c, weight loss, and lowered blood pressure observed with the drug. The booth’s artistic theme from last year also made a reappearance, with several easels set up for painting tiles, to eventually compiled in a mosaic.

Lilly Diabetes

Walking into the exhibit hall, this booth was not hard to find thanks to the bright red circular display hanging from the ceiling. Just as at last year’s ADA, this exhibit was modeled after a home; visitors were greeted by a brick “fireplace” with a crackling onscreen fire and then proceed into a living room complete with a stand giving out delicious espresso and a huge flat-screen TV playing ESPN, along with photos of smiling patients and doctors on the walls and quotes about life with diabetes prominently displayed on screens. The other “rooms” of the house were more topical; one room featured Humulin U-500 and the chance to find out your “U-500 IQ,” and a window overlooking the “front porch” displayed the BI/Lilly products Tradjenta and Jentadueto along with several signs reminding providers to ask about new safety information, including a boxed warning about the risk of lactic acidosis with Jentadueto. The “kitchen” of the house was dedicated to Humalog, with Lilly’s various pen devices comprising the centerpiece of the table. Another creative “room” was modeled after an elementary school classroom complete with children’s desks and cubbies with lunchboxes, with an emergency glucagon rescue kit and reassuring messages for parents about hypoglycemia interspersed among these props. Several rows of iPads on one of the outer walls of the booth offered a trip through Lilly’s long research and development history, and a large screen was devoted to their novel basal insulin peglispro. Finally, Lilly continued to highlight its innovative partnership with Disney and its resources for children and teens.

Medtronic

Medtronic’s packed, expansive booth had a disproportionately large crowd gather in one area: the international section. On display was the company’s MiniMed Duo combination insulin infusion set/CGM sensor, which launched earlier this month (read our detailed report). Elsewhere in the booth, the emphasis was on the Veo with Enhanced Enlite (international section) and the MiniMed 530 with Enlite (US section). Notably, pictures on the wall showed the next-gen MiniMed 640G pump platform, which we cannot ever recall seeing displayed in a US exhibit hall. The new pump platform was flanked by a smartphone and tablet device running what looked like closed-loop control – this implied that a future Medtronic pump like the MiniMed 670G (which will offer hybrid closed loop, per the Analyst Day a couple weeks ago) will send data to smartphones and tablet devices. Dotted throughout the booth was a line of experimental Medtronic clothing, which had pump-sized pockets sewn directly into the shirt. Other pipeline items from the Analyst Day – the MiniMed Flex “hybrid pump,” the Enlite 3 sensor, and the type 2 business – were not mentioned in the booth.

Merck

Merck’s booth promoted the ability to use the Januvia franchise (Januvia, Janumet (combination sitagliptin and metformin HCl) throughout the natural history of type 2 diabetes. Large panels around the booth guided HCPs to “help patients on their journey.” For example, HCPs could visit different stations on this journey, including “newly diagnosed,” “earlier,” “later,” and “renal insufficiency.” The “newly diagnosed” area highlighted Janumet’s greater A1c improvement than metformin alone. Whereas, the “later” or “when insulin is added” section described how Janumet gets to the “root of the problem” by improving beta cell function, and has a “strong A1c lowering affect with insulin.” One corner (comprising a little over 25% of the booth’s footprint) was dedicated to Merck’s education program “Steps to Diabetes Goals” – a revamped version of its previous program “Steps to Balance.” “Steps to Diabetes Goals” features a more patient friendly website, where they can receive support and educational information on blood sugar, losing weight, being active, stressing less, eating smarter, and managing type 2 diabetes. Additionally, the website encourages patients to connect with their doctor, and provides tools to make appointments more effective (e.g., a discussion guide). Finally, this section enabled HCPs to experience one of the symptoms of hypoglycemia (blurred vision) with goggles that distorted one’s vision. The respectable aim of this activity was to help HCPs better empathize with their patients’ experiences – we have noticed an increasing trend at industry events and booths of having HCPs experience being a doctor (for example, at IDF 2013, Novo Nordisk had HCPs try taking a saline injection).

Novo Nordisk

Novo Nordisk’s central ADA booth once again received prime placement right at an entrance of the exhibit hall. As opposed to last year, this year’s booth lacked a second-story presence – that award went to AZ’s double-decker structure – but it compensated by having an expansive footprint. The design motif was once again a clean bright white, with hardwood floors and well-lit displays and screens for each of the major products on display. The continuous aerial banner that ran the circumference of the booth (which included video screens) highlighted two products: Novo Nordisk’s once-daily GLP-1 agonist Vicotza (liraglutide) and the brand-new FlexTouch pen for the basal insulin Levemir (insulin detemir). We learned from a sales representative that the Flex Touch will be shipped out to wholesalers in just a few days, and that ADA is the product’s debut party. The most visible one-third of the booth, the side fronting the entrance to the hall, was entirely dedicated to the FlexTouch. The new pen is currently the only pre-filled insulin pen with no push button extension, meaning that the button end of the pen does not telescope out when dialing up to a bigger dose and requires less thumb extension. We found the company’s main catchphrase, “Because we can’t redesign thumbs, we designed the FlexTouch,” quite clever, especially when emblazoned on the image of a thumb struggling to reach a hyper-extended button on a non-FlexTouch pen. The same displays advertised other benefits, including: (i) maximum dosing up to 80 units; (ii) an end-of-dose click to notify patients when the pen has finished administering the drug – we tried this out, and it was clear from the very pronounced final click that the injection was complete; and (iii) that the pen is available on more than 96% of managed care plans nationwide (comparisons included on the FlexTouch displays suggested that this figure beats out coverage for the flagship Lantus pen). During the year following the FDA Complete Response Letter for Tresiba (insulin degludec), Levemir has benefitted from the marketing investments that were made in preparation for Tresiba’s launch, and has been Novo Nordisk’s fastest-growing insulin as a function of % sales growth (see our Novo Nordisk 1Q14 Report for details). The marketing metaphor for Levemir (the drug product itself) was a Newton’s Cradle (the row of swinging metal balls on strings that is a corporate office mainstay), with the tagline “Initiate the momentum of control with Levemir” – each of the metal balls represented one of Levemir’s benefits, including “better weight loss than Lantus.” 

• Separated from the Levemir section by the A1c test desk, the central portion of the booth was largely given to the Victoza, and included displays noting that the product is the most-prescribed GLP-1 therapy worldwide and the number-one prescribed new-to-incretin brand among endocrinologists. The rearmost portion of the booth had a lot going on. One corner had a “live agenda theater” complete with stepped seating, featuring two rotating presentations, one on the FlexTouch, and another on the company’s “triple bottom line” approach to sustainability. Facing outwards onto the hall floor, a long line of people were signing up for Novo Nordisk’s signature 5K, while others were learning from a cluster of representatives talking about the Diabetes Attitudes Wishes and Needs 2 (DAWN2) study (tagline: “How can we change what we do not understand?”). A series of representatives and desks with pens were dedicated to the topic of Novo Nordisk devices (“imagined by patients, engineered by Novo Nordisk”).
• We were wondering what happened to the main NovoLog (insulin aspart) and Team Novo Nordisk exhibits, until we found them co-locating at their own separate (albeit much smaller) booth nearby. Multiple members of the team were present, and two displays and a small group of sales representatives discussed NovoLog and the new NovoPen Echo (a half-unit-adjustable pen targeted for children, with a memory function that was drawn interest even from adults – apparently samples are flying off the shelves). Novo Nordisk was the sponsor of a set of rest-and-recharge stations around the exhibit hall.

Sanofi

The massive spiral-shaped Sanofi booth of soft whites and deep blues has some familiar features: the massive line of people waiting for CDs containing all the ADA abstracts and posters (very useful for us as we finish our full report of the top posters and abstracts), and a five-foot tall Lantus Solo-Star pen that served as a major photo-op for exhibit hall attendees. In a time span of less than two minutes, we saw three different groups ask to have their picture taken with the pen, which – despite the ADA policy of no photography in the exhibit hall – didn't seem to bother the Sanofi representatives. We saw this popular structure last year in Chicago as well, and Sanofi keeps bringing it back, capitalizing on its unusual appeal. Also notable was Sanofi’s repeated emphasis on their Lantus mantra that was printed on nearly every wall of the exhibit: “The ONLY basal insulin with DATA that show proven sustained HbA1c control over 6 years, exclusive once-daily 24 hour coverage, and demonstrated long-term CV safety.” It appears that the message Sanofi wants to drive home is that Lantus is the most established and well-known basal insulin: the front of the booth, a ten-foot tall 3D message read out “Go with the one you know.” The booth largely stuck to that single product and message, as Lantus’ is Sanofi’s major product in the US (the GLP-1 agonist Lyxumia [lixisenatide] is currently only available in Europe).

Takeda

While many companies choose to display statistics and numbers to catch exhibit hall attendees’ eyes from afar, Takeda’s more intimate approach required attendees to walk up and interact with the handful of iPad-operated displays themselves. Takeda, who launched the DPP-4 inhibitor Nesina (alogliptin) about a year ago, is currently pushing Nesina as well as Kazano (alogliptin/metformin) and Oseni (alogliptin/pioglitazone). According to Takeda, although the ADA standards of care finds DPP-4 inhibitors to only offer modest A1c reductions in comparison to TZDs (thiazolidinedione), many providers and patient find similarly significant A1c reductions under both treatments. Further, they find that Oseni offers greater A1c reductions than either alogliptin or a TZD alone. The results of a Japanese head-to-head study (the COSVA trial) comparing Nesina to Merck’s Januvia (sitagliptin) and Novartis’ Galvus (vildagliptin) are being presented as a poster (1024-P).

Tandem

Tandem’s booth was smartly located near the product theater area of the Exhibit Hall, reprising the company’s modern, wood-floored, glassy look. The company did not have any new marketing or products to share information about – as a reminder, FDA submission of the G4 Platinum integrated t:slim is expected this month, while submission of the 480-unit t:slim is expected in mid-2014.

Type 1 Diabetes TrialNet

Type 1 Diabetes TrialNet had a table in the nonprofit wing of the exhibit hall. TrialNet representatives highlighted the group’s recently added ability to complete trial education and screening for its Pathway to Prevention study. The website www.pathway2prevention.org educates potential participants on the trial, and takes them through the screening and consent processes. People are then sent a testing kit, which they can take to any Quest Diagnostics site in the US to have blood drawn and kit completed. Approximately six weeks later people will either receive a letter stating that they do not have any autoantibodies, or a phone call explaining the autoantibodies they tested positively for and prevention trials they can participate in. TrialNet has enrolled over 300 people in this manner. TrialNet is currently enrolling patients in three prevention studies, depending on his/her risk level: (i) oral insulin prevention trial, for people with a low risk for type 1 diabetes, (ii) abatacept prevention trial, for people with a moderate risk, and (iii) a teplizumab prevention trial for people with a high risk (read Kelly’s open letter in diaTribe about the importance of people enrolling in this last trial here).

Valeritas

The company’s highly visible, elevated, green signage announced their presence near the rear of the exhibit hall. Advertising the V-Go, their simple, electronics-free insulin delivery device for type 2 diabetes, the booth featured numerous catchy slogans: “Disposable Delivery” and “Take the Next Step” were plastered on signage, while the pithier, “Freedom to Go,” subtly labeled the shirts of the booth marketers. The booth also featured persuasive educational materials delivered via iPads and interactive video presentations (lots of screens, to be sure!), comparing the hassle factor of traditional MDI to the ease of use of the wearable V-Go. The campaign also highlighted the tragic rates of non-adherence that lead to poor glucose control – the simplicity of discretely bolus dosing with the V-Go, especially through clothes, is certainly a key advantage of the product. Notably, the booth also featured a device demonstration, presented at the center of the display, which was a neat way to gain some insight into the actually use of the V-Go. As of Valeritas’ presentation at JPM 2014, the company had discussed potential to go public in 2H14 though we believe most who had considered this were likely not pursuing it given changes in the market even in this short period! Valeritas has a published-only abstract on the V-Go at ADA 2014 (2373-PO), with positive long-term follow-up data from the prospective, open-label, multicenter SIMPLE study – at nine months, the overall population of 149 patients had a 0.7% A1c decrease after switching to V-Go (Baseline: 8.7%), with the long-acting insulin cohort experiencing the greatest A1c benefit (-1.2%). We imagine “time in zone” changes were very positive though CGM wasn’t used.

Vivus

Vivus’ purple and white booth was positioned in the back right corner of the exhibit hall and stood tall with a projecting banner, advertising Qsymia (phentermine/topiramate ER) as providing “significant weight loss for 1 year in obese patients.” A larger-than-life-sized, semi-translucent-blue rendering of an obese individual on the front wall had a speech bubble exclaiming “significant weight loss that is clinically meaningful.” A representative gave us an overview of Qsymia on one of the several interactive touch screens, explaining how the drug was a combination of two drugs (phentermine and topiramate) and showing us graphs of its weight loss effects. On the safety and tolerability side, the representative commented that although the side effect dysguesia (altered taste) can be unpleasant, Qsymia’s distortions of the taste of carbonated beverages can actually help prevent patients from consuming excessive soda and other unhealthy drinks. Upon our asking how Qsymia related to Eisai/Arena’s Belviq, he responded that no head-to-head data is yet available, but that the drug works through a different pathway.

Honorable Mentions

Special Lectures and Addresses: President, Health Care & Education Address and Outstanding Educator in Diabetes Award Lecture

President, Health Care & Education Address – The Times They Are-a-Changin’

Marjorie Cypress, PhD (ABQ Health Partners, Albuquerque, NM)

In her President, Healthcare, and Education address, Dr. Marjorie Cypress discussed the evolving environment of diabetes care, with support from clips of Bob Dylan’s “The Times They Are A-Changin’.”  Dr. Cypress highlighted five specific problem areas for why diabetes prevalence continues to rise. First, she pointed out the continued stigma against diabetes, with peers, healthcare professionals, and even patients themselves often blaming the disease on personal failures rather than health and social factors. Second, costs associated with diabetes are astronomical, with one in five healthcare dollars spent on diabetes for a total $245 billion. Third, delivery of care is compromised due to a shortage of endocrinologists and other healthcare professionals. Fourth, healthcare literacy and numeracy are lacking, especially in those who were previously uninsured. Fifth, socio-ecological factors such as sedentary behaviors and an environment that facilitates unhealthy eating contributes to the rise in diabetes. Dr. Cypress ended her presentation with a review of ADA’s work and encouraged audience members to take action. “We cannot do this alone,” she said. “We need you.”

• Dr. Cypress began her presentation by telling us we are losing the war against diabetes and obesity. In a sobering chart, she showed how diagnosed diabetes prevalence rose from 4.8% in 1980’s to 6.4% in 1999-2004, and 8.3% in 2005-2010. Obesity rates paralleled diabetes, affecting 5.5% of the population in 1980’s to 7.7% in 1999-2004, and 9.3% in 2005-2010.
• Diabetes remains stigmatized, even today. Dr. Cypress gave examples of common statements about the disease, such as: “It’s their own fault,” “If they would just stop eating and exercise,” and “They’re just lazy.” Citing an example of a nurse who scoffed at “non-compliant” diabetes patients, Dr. Cypress said healthcare professionals are a huge part of the problem since many of them are blaming and shaming the patient. This is in addition to patients who self-impose unneeded restrictions, and schools, employers, and insurance companies that discriminate against diabetes patients. Dr. Cypress believed this stigma could be eradicated by education, saying that “I can’t help but think that lack of insurance reimbursement for diabetes self-management education… by certified diabetes educators is discrimination,” to which the audience erupted in applause.
• Diabetes costs continue to rise. Diagnosed diabetes costs the US $245 billion with roughly 70,000 deaths per year. Despite the prevalence of diabetes (29.1 million in the US), Dr. Cypress presented 2013 data from the NIH demonstrating that the field is vastly underfunded compared to cancer (prevalence of 12.5 million) and HIV/AIDS (prevalence of 1.2 million). The NIH funds $2,818 per HIV/AIDS patient, $441 per cancer patient, but only $47 per diabetes patient.
• Delivery of diabetes care remains limited by the shortage of endocrinologists and diabetes healthcare professionals. Audience members snapped their fingers in support for Dr. Cypress’ call to action to expand the scope of healthcare professionals in the field of diabetes to nurses, physician assistants, pharmacists, and behaviorists/psychologists. She suggested that medical school curricula change to focus on team care.
• Healthcare literacy and numeracy remain hugely problematic. Only 8.6% of uninsured adults have even basic level of healthcare numeracy knowledge. Furthermore, with the passage of the Affordable Care Act, more of these patients are coming into the healthcare system. Discouragingly, Dr. Cypress said 91% of previously uninsured diabetes patients cannot understand glucose meter readings, interpret “sliding scale” regiments, titrate oral medications or insulin, or adjust insulin for carbohydrate content, suggestive strong need for improvement in diabetes education.

Outstanding Educator in Diabetes Award Lecture: Six Impossible Things Before Breakfast – Examining Diabetes Self-Care

Katie Weinger, PhD, RN (Joslin Diabetes Center, Boston, MA)

Dr. Weinger argued that the White Queen in Lewis Carroll’s “Through the Looking Glass” knew something about diabetes when her highness told Alice, “When I was younger I always did it for half an hour per day. Why sometimes I’ve believed as many as six impossible things before breakfast.” In Dr. Weinger’s opinion, patients with diabetes must not only believe but also accomplish the seemingly impossible with diabetes self-care. The challenges of living with diabetes abound – complicated treatment regimens, demanding lifestyle requirements, comorbidities, stress on family relationships, and competing priorities of daily life to name a few. It is these daily challenges that diabetes education can help with, but only if providers tailor education approaches to fit the individual patient. Dr. Weinger concluded with data from an NIH-funded study evaluating the efficacy of using cognitive behavioral strategies during an educator-led group education for diabetes patients with poor glycemic control. 

• Dr. Weinger presented data from an NIH-funded study (n=222) evaluating the efficacy of using cognitive behavioral strategies during group education for patients with poor glycemic control. Patients were randomized to three different education groups: (1) structured behavioral group education (n=74) including cognitive restructuring strategies, (2) attention control education (n=74), or (3) individual control education (n=74). In the first two education arms, patients received two, five-hour education sessions per week while patients in the individual education arm could schedule as many individual appointments with his/her diabetes educator as desired.
• In an analyses of all patients by group after 12 months, the attention control group had the greatest reduction in A1c (~0.6%) overall (baseline 9.0% across all groups). However amongst the subgroup of patients with type 1 diabetes, the structured behavioral group had the greatest A1c reduction (~0.4%) while in patients with type 2 diabetes, the attention control group had the greatest A1c reduction (~1.0%). From this data, Dr. Weinger concluded educational approaches must be tailored depending on type of diabetes and cognitive behavioral strategies like cognitive restructuring may be most effective for patients with type 1 diabetes. Dr. Weinger added that this study received a second round of funding for a five-year follow-up study currently being conducted, with follow-up study indicating patients have maintained glycemic improvements though still not at A1c targets.  
• An often-overlooked categorization, the phase of diabetes progression – onset, health maintenance and prevention, early complications, or dominating complications – is important to the type of diabetes support and education necessary. Dr. Weinger noted that during diabetes onset, patients must often rapidly adapt to new, demanding self-care regimens and prescriptions, requiring rapid-learning skills and intensive education. The second phase of health maintenance and prevention is where most patients reside and the stage in which Dr. Weinger commented “we hope to keep them in as long as possible until someone finds a cure.” While this is the stage at which patients start consolidating their new lifestyle and healthcare habits, the competing demands of raising a family, transitioning into college, or a stressful job can often diminish the priority of self-care. Thus this phase is particularly important to target with support and continued education.
• When complications start to arise, Dr. Weinger noted that this stage is often when patients can have drastically different responses. For some patients, early complications can either serve as a wake-up call for improving self-care. Yet other patients respond to this stage with fatalism and become incapacitated believing they can no longer manage their diabetes. It is particularly crucial that providers learn to tailor support and education to maximize health and quality of life at this phase if not before, in order to prevent progression to dominating complications in which diabetes self-care is often left to the wayside as comorbidities that require more care or cause more pain are prioritized.

Joint ADA/JDRF Symposium: The Changing Presentation (or Face) of Type 1 Diabetes (Supported by a grant from The Leona M. and Harry B. Helmsley Charitable Trust)

Enhanced Prediction of Type 1 Diabetes Using Genes, Antibodies, and Metabolic Markers

Anette-Gabriele Ziegler (Helmholtz Zentrum Munchen, Munich, Germany)

Dr. Anette-Gabriele Ziegler (Helmholtz Zentrum Munchen, Munich, Germany) detailed our current understanding of the different “checkpoints” of type 1 diabetes development, and why people progress from one stage to the next. Looking to a future when either islet autoimmunity or symptomatic type 1 diabetes itself can be prevented, Dr. Ziegler proposed several different ways type 1 diabetes could be screened for in the broader population.

• Dr. Ziegler made the case that type 1 diabetes can be divided into six stages: (i) islet autoimmunity, (ii) dysglycemia, (iii) asymptomatic hyperglycemia, (iv) symptomatic hyperglycemia, (v) established type 1 diabetes, and (vi) established type 1 diabetes with associated complications).
• Dr. Ziegler explained that the rate of progression through the stages of type 1 diabetes development appears to be affected by a person’s age of seroconversion, gender, and non-HLA susceptibility genes. Dr. Ziegler noted that environmental exposures (e.g., being born via a C-section) may ‘pre-condition’ the rate of progression through these stages, even before seroconversion has occurred.
• Dr. Ziegler thinks the most cost-effective screen would be to test three-year-olds for multiple antibodies. Dr. Ziegler selected the age of three years, because in TEDDY and a study in Finland this age was associated with the highest incidence of islet autoantibodies. By Dr. Ziegler’s estimate, if one were to screen 200,000 three-year-olds, 500 would test positive, and 450 would develop type 1 diabetes before they were 20 years old. This screen would identify 45% of all cases of type 1 diabetes diagnosed before the age of 20 years. During a subsequent panel discussion, the concern Dr. Ziegler raised with this approach is that trends in type 1 immunotherapy research suggests it will be easier to prevent the onset of autoimmunity than to reverse established autoimmunity.
• One screening strategy that could be used to identify people at high-risk of developing islet autoimmunity is to screen newborns’ genetic risk. Screening HLA risk at birth (as was done in TEDDY) means that 2,672 out of 200,000 screened newborns would test positive, and only 284 would develop type 1 diabetes by age 20 years – this would represent 28.4% of all future type 1 diabetes cases by age 20 years. Alternatively, Dr. Ziegler has identified the ten alleles most predictive of developing type 1 diabetes (which are somewhat different than those conferring risk for islet autoimmunity). A newborn screen of these alleles would result in 1,236 positive identifications (out of 200,000 screenees), of which 241 would develop type 1 diabetes by the age of 20 years (representing 24.1% of type 1 diabetes cases).

 

-- by Melissa An, Adam Brown, Eric Chang, Hannah Deming, Jessica Dong, Andrew Foley, Hannah Martin, Nina Ran, Emily Regier, Katherine Sanders, Joseph Shivers, Jenny Tan, Manu Venkat, Alasdair Wilkins, Vincent Wu, Michelle Xie, Rebecca Xu, and Kelly Close