June 5-9, 2015; Boston, MA; Full Report – Draft

Executive Highlights

In this final report, we provide our full coverage of the 75th Scientific Sessions of the American Diabetes Association (ADA), held at Boston Convention and Exhibition Center from June 5-9. In a year lacking any major news announcements  (like ORIGIN in 2012 or DCCT/EDIC CVD data in 2005), we still learned plenty – things that were surprising, daunting, and reassuring. Surprising, that more and more is happening and yet the mass media is nowhere. Daunting, in that the stuff we should be worried about (access to tools, access to care, stigma in every corner, massive R&D costs, the sheer scope of the problem) seems, following Boston, bigger and more difficult than we ever imagined. And reassuring, in that there’s more happening below the radar (and, in some ways, above) than we had realized. As a side note, we’re now as worried about HCPs as we are about patients – they aren’t advocating for themselves nearly as much as we would like to see (they are probably too busy taking care of patients), and the field must turn this around (working together, not in so many silos) so that the right people are being drawn into the field – and more of them. What should change? Better and easier and less time-consuming tools, heaps more non-doctors to help them, and better pay in places that need it, for their time and expertise (they are way too modest to ask in many places like the US – the discrepancy is everywhere, globally, but it’s too many places). Let’s also thank them more.

Indeed, in our increasingly complex field where there’s more happening than meets the eye – the number of “chapters” in our ADA report continues to expand and we continue our work in this report on giving you the “Twitter” view, if that’s what you want, the “paragraph” view (see our themes), and the detailed versions, to boot.

Some facts. This very successfully organized ADA gathering drew over 18,000 attendees, handily surpassing last year in San Francisco and the year before in Chicago.  ADA 2015 included over 15,000 clinicians, a 4% increase from ~14,400 last year, and an important record as it shows clinicians focus on learning, even amidst multiple constraints (the ADA is doing an admirable job with the younger generation of endocrinology fellows that does exist – we’re just concerned there aren’t enough of them and not enough motivation for the best and brightest into diabetes themselves or to help them – it’s absolutely a research concern as well).

The number of countries represented at ADA this year increased by nearly 10 percent to 130, compared to last year. International attendees represented an estimated 50% of all attendees, actually down from 60% last year. The countries with the largest contingents were Denmark, Japan, China, Canada, and Germany – the leading country last year, India, did not make the top five.

And we worked harder than ever for you this year with our alumni team (which thankfully grows each year – incredible to see these emerging doctors!) and amazing associates. They covered the most compelling of the record 800+ expert speakers at the five-day Scientific Sessions, which included 91 symposia sessions, 385 oral presentations, and 1,988 poster presentations. ADA received 3,698 abstracts this year, a 4% increase from 2014 – there is certainly no shortage of research, though the number of standout posters overall has gone down, according to many of the thought leaders.

Want to start with the big pic? We’ve sort through so many learnings, and in this final report, we include 39 themes and detailed commentary from 244 talks and discussions (oral presentations, symposia, lectures, panel discussions, meet-the-expert sessions, corporate symposia, and press conferences), along with coverage of 25 posters and 26 exhibits. We’ve narrowed the scope of some of our coverage – if you think we missed a major session of note, please be in touch.

Below, we have organized our writing into 16 specialized reports: (1) Big picture conference themes; (2) Insulin Therapy; (3) SGLT-2 Inhibitors; (4) GLP-1 Agonists; (5) DPP-4 Inhibitors; (6) Novel Therapies; (7) Type 1 Diabetes Cure Therapies and Pathophysiology; (8) Closing the Loop and Insulin Delivery; (9) Glucose Monitoring; (10) Digital Health; (11) Obesity and Prediabetes Care; (12) Diabetes Complications; (13)  Treatment Algorithms and Strategies; (14) Policy and Education; (15) Generic Drugs; and (16) Exhibit Hall and Investor Updates.

We’ve highlighted in yellow any presentations and commentary that we found particularly notable. Our full report includes over 200 talks that were either not published in our daily highlights reports or have been significantly expanded in the past two weeks – these titles are highlighted in blue (unless that talk was a notable yellow highlight).  

Our thanks to all our Closer Look subscribers for their support, which is so meaningful and broad in so many ways. Onward!

Themes

Diabetes Technology

Closing the Loop

• More than ever, ADA made it abundantly clear – closing the loop is now inevitable! And, it’s a question of “WHEN” and “HOW,” not “IF.” With Medtronic beginning its pivotal study of the 670G, other groups moving ahead or exploring their options (e.g., Animas, Bigfoot, Bionic Pancreas, Insulet, Tandem, Type Zero), academic investigators gearing up for very large scale efficacy trials, and a clear regulatory path, there seems to be less doubt that hybrid closed loop is coming near-term (Dr. Aaron Kowalski cited a ~2017-2018 timeframe). Indeed, UVA’s insightful and super-smart Dr. Stacey Anderson summed up the main session of artificial pancreas oral presentations with a succinct characterization of the status of systems: “SAFE during the day. HIGHLY EFFECTIVE overnight.” Dr. Kowalski also emphasized the field’s progress, noting that technical feasibility is now proven in all six stages of the original JDRF roadmap – it’s now time for commercial development and regulatory studies to support approval. Moving forward, Dr. Kowalski’s revised AP roadmap (Diabetes Care 2015) has just three steps: (i) low glucose suspend; (ii) predictive low glucose suspend; and (iiia) insulin-only closed loop or (iiib) multi-hormone closed-loop. The real challenges ahead are adoption and reimbursement – or as Dr. Kowalski suggested, appealing to people with diabetes (& loved ones), clinicians, and payers via three key metrics: glycemic control, “burden”, and value.
  
  • Competition is pushing the thinking and dialogue forward aggressively, and we can hardly wait for the host of longer-term, real-world data coming in the next one to two years. Rapid-fire presentations from Drs. Moshe Phillip (DREAM), Steven Russell (MGH), Roman Hovorka (Cambridge), and Boris Kovatchev (UVA) showed each group’s future planned large-scale efficacy studies, which may heavily depend on the NIH’s $20 million initiative, “Advanced Clinical Trials to Test Artificial Pancreas Device Systems in Type 1 Diabetes” – as we understand it, the one to three award recipients are expected to be notified quite soon. We were impressed to see how actively and ambitiously the academic groups are thinking about these bigger trials – an equally big set of questions surrounds how manufacturing and commercial devices will work (see below).
• The most illuminating artificial pancreas discussion centered on practical and hard-hitting questions: (i) What’s the appropriate control group in a pivotal study? (ii) Insulin-only vs. multi-hormone?; (iii) What’s the right device form factor and burden vs. risk tradeoff? (iv) Will organizations have manufacturing in place to submit a PMA application? (v) What’s the right business model? (vi) What do payers think? There is still a major difference of opinions on the right control group (MDI vs. SAP) and remaining uncertainty regarding device form factor, manufacturing, business models, and payers. The insulin-only vs. bi-hormonal debate is in the stay-tuned phase right now, as more comparative data is coming. That said, we would certainly like patients to have access to both – we don’t think one closed loop product will be right for every patient that could benefit from one.
  
  • A key point of debate emerged during the main closed-loop oral presentations session: “What is the appropriate comparator group in a pivotal closed-loop study?” Cambridge’s Dr. Roman Hovorka asserted that the appropriate comparator is sensor-augmented pump (SAP) therapy – closed loop should have to prove itself against the best therapy we have now. Conversely, MGH’s Dr. Steven Russell felt strongly that closed-loop studies should compare to individuals’ therapy at baseline, whether that’s MDI/SMBG, MDI+CGM, pump only, or pump+CGM. We think they are both right, and the much harder question is choosing which is more important to focus on initially. Close Concerns’ Adam Brown raised this question again at the invite-only JDRF/NIH Closed-Loop Consortium Meeting (contact here to get on next year’s list), and it sparked an even heartier debate and clear camps on both sides of the issue. DREAM’s Dr. Moshe Philip answered from an academic perspective, suggesting that SAP as the control group makes the most sense, since the studies are scientifically testing whether the addition of a closed-loop algorithm to SAP makes a difference. Dr. Russell again heartily disagreed, advocating for studies that are real-world enough to test effectiveness in a broad population of type 1s (especially the majority of type 1s that are on MDI) –  “This is not an academic exercise, he said, “We give people systems to improve their diabetes control. We don’t want to limit ourselves to the people using pumps.” Dr. Aaron Kowalski pointed out that the question has very important academic implications, since journal reviewers will criticize the choice of control group (probably no matter what). Others emphasized that the payer implications could be significant, since reimbursement and coverage will depend on the pivotal study design and included populations. Jaeb’s Dr. Roy Beck eventually stood up and admitted that both sides have a valid case (“I could easily write a point/counterpoint”), but he leaned towards Dr. Russell’s view – the current reality is that only ~15% of people in the T1D Exchange (at most) use sensor-augmented pumps. To get the penetration everyone is hoping for, AP studies need to expand beyond sensor-augmented pump users alone. We agree – pivotal trials should ideally enroll a broad spectrum of type 1s, including those on MDI/SMBG, pumpers, and those on SAP.
    • Medtronic’s MiniMed 670G pivotal study is a single-arm trial, yet another potential answer to this question! Medtronic is clearly trying to get something to market fast, rather than proving how much better it is vs. a comparator in a randomized study. This is smart from a timing perspective (first to market), though presumably means reimbursement at the same rate as the MiniMed 530G. That the FDA is allowing a single-arm study to serve as the pivotal trial also reflects how far the regulatory environment has come.  
  • ADA continued the fascinating insulin-only vs. bi-hormonal debate. We’ve certainly heard a range of opinions in recent months (e.g., Keystone 2014, DTM 2014, ATTD 2015, ENDO 2015), though true head-to-head data is really needed to show what incremental value glucagon adds to the equation. ADA was notable in that regard, providing fresh perspective from the newer-to-the-field McGill University team. In pooled results from two small randomized, crossover, overnight trials comparing insulin+glucagon to insulin-only closed-loop, the addition of glucagon reduced time spent in hypoglycemia by two-thirds (from 3% to 1% - a low base, but many patients would call that meaningful, and real-world rates of hypoglycemia are probably higher). Meanwhile, Drs. Ed Damiano and Steve Russell mentioned their own plans to do an exciting Bionic Pancreas glycemic set point study comparing an insulin-only configuration to an insulin+glucagon configuration head-to-head – we first heard this at GTC Bio in April, though we’ve since learned these will be quite robust studies, testing a variety of glycemic targets (100, 115, 130, 145 mg/dl are being considered) and offering some exciting comparative data. A separate Stanford set-point study will test an insulin-only version of the Bionic Pancreas at several algorithm set points, and will do so over a longer period of time. We think this data is critical to meaningfully advance the conversation on this topic. Perhaps our favorite commentary on this debate came from Yale’s Dr. Stuart Weinzimer in the Closed-Loop in Youth Symposium’s Q&A: “I think it’s a false argument to compare one against the other. What I would like to see are options for patients with diabetes and clinicians. I want to see an insulin-only system and a bihormonal system on the market. Then clinicians can choose and help patients choose what is best for them. So let the market decide.” Hear, hear!
  • What is the ideal form factor? Should a closed-loop algorithm reside on a smartphone? At the Psychosocial AP Workshop, the FDA’s Dr. Stayce Beck said that the Agency is “open to the idea of” an AP algorithm residing on a smartphone, but “there are lots of challenges” to hammer out – the risk mitigation sounds quite challenging, and it might even require working with phone companies to ensure that the algorithm takes precedence over other smartphone functions (that sounds like a nightmare). We’re not sure how open Apple and Samsung and LG and other device makers would be to that. BU’s Dr. Firas El-Khatib further pointed out that phones are very fluid – an algorithm might get approved with mitigated risk, but the phone will change if it is a personal device (e.g., downloading apps and new updates). Alternatively, AP developers could lock the smartphone and strip out all its functionality, but then the integration is arguably not as useful – patients will have to carry another phone. Of course, some may prefer the user interface on a stripped-down phone to a pump, so there are multiple solutions here. We do think the ideal convenience solution – a personal phone running an artificial pancreas algorithm – is possible to create and something that we expect to see happen down the road. Certainly, Dexcom has moved ahead with its Gen 5 CGM system – five years ago, no one would have thought a smartphone could function as the primary display device for CGM, but if all goes as the company expects, that could be on the market by the end of the year. From a product perspective UVA (Type Zero) and Bigfoot have alluded to AP systems potentially driven by smartphone algorithms; we assume Animas, Insulet, and Tandem are thinking more about algorithms embedded into their pumps.
    • The question of form factor could have critical implications for product development and market uptake of AP systems. As Dr. Aaron Kowalski noted in Q&A, “We’re going to butt up [i.e., max out] on the ability to improve glycemic control with artificial pancreas systems. The driver will be form factor and minimizing the burden of wear. The phone is an obvious component ... Where will people with diabetes be willing to take the risk for the benefit of a reduction in burden? ... How much do people with diabetes want it? What are the mitigations you can build in? The person with diabetes should have some voice in there.”
  • The field seems quite comfortable with (and even excited about!) the regulatory path for artificial pancreas systems. Equally important is the accompanying review of manufacturing and quality systems. FDA’s Dr. Stayce Beck pointed out that PMA submissions can’t just bring pivotal trial data – sponsors must have manufacturing capabilities in place. Notably, the FDA is working with JDRF on different manufacturing models (and presumably regulatory review) to enable “component artificial pancreas systems” – Dr. Beck said this is “not a small part” of the process, but it is also “not nearly as exciting” as the science. However, she urged the community to start shifting the conversation, since so many things go into an FDA review besides a positive pivotal study. The JDRF/NIH Closed-Loop Consortium Meeting left it a little unclear how (and if) academic groups will go from large-scale studies to regulatory PMA submissions. This is a big question for many groups – some, like the Bionic Pancreas team at MGH/BU have been less clear about who will manufacture the dual-chamber prototype pump they have been building (Tandem has de-prioritized this project, per its 1Q15 call), while others are more clear (Medtronic clearly has this question answered, along with customer service and infrastructure). It’s also a bit unclear if some of the upcoming large-scale trials will actually serve as true “pivotal” studies, since regulatory submission requires a final commercial-ready device. This is certainly the intent of the Medtronic/DREAM, Bionic Pancreas, and UVA (Type Zero) teams; we’re not sure about Cambridge. We agree with Dr. Beck that manufacturing is not a small issue, nor is the ability to go to market and offer customer support for a class III medical device – previous PMA and commercialization experience obvious helps. UVA has established a company, Type Zero, to do this, but the aforementioned steps are a tall order for any company, let alone a startup.
  • Medtronic has moved ahead of the competition and initiated a pivotal study of the MiniMed 670G, with other companies following along. Still, there are some tough business questions to answer. At the Psychosocial AP Workshop, type 1 advocate and industry consultant Ms. Marie Schiller said that closed-loop systems will “probably not” command a premium – “You either have to be at par or charge less.” This will presumably depend on the pivotal data that is generated, but it’s certainly a tall order for smaller pump companies to live up to: the R&D investment for an artificial pancreas system is significant, and pricing at parity may be tough economically speaking. In one sense, Ms. Schiller’s comment is not a surprising sentiment, considering payer frustration over diabetes (see payer expert Mr. Aaron’s David’s talk below) and increasingly constrained healthcare dollars; still, artificial pancreas systems have great potential to simultaneously improve A1c and significantly drive down or completely avoid severe and costly short-term events. That has never been seen before in type 1, and consequently, we assume some data might eventually support a premium. Would payers pay more for a system that results in a significantly better A1c AND a far lower rate of severe hypoglycemia? Presumably yes, but that will likely need to be shown over time in longer-term studies, since such events are unlikely to arise with enough regularity in a pivotal trial. Ms. Schiller further suggested that building a revenue model is something industry “is struggling” with. For standalone pump companies (i.e., not Medtronic), she called the necessary collaborative effort “one of the biggest hurdles,” since none have an in-house CGM. These are tough questions to address, and have probably contributed to why companies like Animas, Insulet, Roche, and Tandem have not moved faster on the closed-loop front.
  • ADA 2015 brought a mix payer views on the artificial pancreas, ultimately suggesting more education and engagement is needed. Most encouraging was highly regarded endocrinologist Dr. Kenneth Snow of Aetna (formerly of the Joslin), who had crystal clear advice for the entire room at the JDRF/NIH Closed-Loop Consortium Meeting: artificial pancreas systems may show benefits on A1c, hypoglycemia, and burden, and the data must clearly show that. This seemed pretty reasonable to us. Dr. Snow used the helpful analogy of buying a mouse trap – there are $3, $5, and $30 mouse traps, but when you go to buy a mousetrap at the store, there is no data to point out which is better. In that case, the consumer probably just buys the cheapest one. The same is true with the artificial pancreas: Aetna will pay for the “better mouse trap” if there are data to clearly suggest that. On the other hand was payer expert Mr. Aaron Davis, who highlighted near-non-existent payer understanding of severe hypoglycemia (mostly anecdotes, since there is no real data); major lack of consensus on unmet needs in type 1 diabetes; and low payer understanding of the different insulin pumps. Perhaps most surprising were some of the direct payer quotes from primary payer research:
    • “Plans may underestimate hypoglycemia. I led a team looking at the issue a few years ago. We were asking what hypoglycemia events cost, and we really don’t know.”
    • “There is more hypoglycemia risk in type 1, but I don’t have any data for type 1s. I appreciate that it can be disastrous, but I don’t know what we can do about it.”
    • “We recently did a survey of our insulin pump patients. 50% didn’t understand key pump features. We want to know more about what is going on with this technology.”
• Payers are clearly most concerned about cost-saving devices, not simply products that reduce mild/moderate hypoglycemia. The challenge for manufacturers is that proving reductions in severe hypoglycemia causing hospitalizations is a very long trial indeed. We hope these trials are eventually undertaken, though it’s hard to imagine a pivotal study could bring such data, unless trials are enriched with those at high risk of severe hypoglycemia. We also believe measures of hypoglycemia need to be more specific and standardized in artificial pancreas trials (i.e., severe hypoglycemia needing assistance, moderate hypoglycemia, etc.) – this could go a long way towards giving payers much better information.

Glucose Monitoring

• Drs. Irl Hirsch and Jeffrey Probstfield presented the long-awaited results of the FLAT-SUGAR pilot study – the 26-week, 102-patient feasibility trial met its primary endpoint, showing it is possible to randomize ACCORD-like patients to two groups (exenatide+glargine+metformin vs. rapid-acting insulin+glargine+metformin) and achieve significantly different glycemic variability (coefficient of variation) with a similar A1c (7.1% vs. 7.2% in this case). Dr. Hirsch believes it paves the way for a larger, longer outcomes study testing whether glycemic variability (GV) matters for long-term outcomes. What is somewhat unclear from the results is whether the magnitude of glycemic variability reductions are large enough to show long term differences in future outcomes – these patients did not seem to have as much hypoglycemia or variability as we would have expected, which makes us wonder about study effect. It would also be interesting to see this study in type 1 diabetes or using different therapies (e.g., SGLT-2s) to help demonstrate much larger variability differences. There is still plenty of analysis to do on this data, and it’s entirely possible different perspectives on variability will emerge over time. This was also an extremely challenging study to conduct, given the need to keep A1c’s the same, and we salute Dr. Hirsch for moving the needle significantly on the field’s understanding of glycemia – we believe a study linking variability and time in range to long-term outcomes may be essential for proving the value of multiple next-gen therapies/technologies.
• Consistent with ADA 2014, this was a lighter meeting for new CGM sensors, perhaps a testament to more focus on connectivity and significantly improved CGM accuracy/reliability. Indeed, the biggest highlights in glucose monitoring were arguably in the exhibit hall, where Medtronic showed off the upcoming MiniMed Connect device (remote monitoring of pump/CGM data), and Dexcom highlighted the new Share Receiver and accompanying iPhone/Apple Watch/Android Follow apps. These are very meaningful form factor improvements for patients and harried caregivers (who in our view never receive enough acknowledgement). We expect to continue to see progression on this front with Dexcom’s Gen 5 (FDA approval and launch by end of 2015) and Medtronic’s Guardian Mobile is in an ongoing pivotal study (n=100), with expected completion in July 2015. Looking back at ADA 2014, there was no filing or launch timeline for Dexcom’s Gen 5, and Medtronic’s Guardian Mobile had not been publicly announced – things are certainly moving much faster on the digital and connectivity sides.
  
  • An intriguing Dexcom abstract (5-LB) highlighted the power of cloud-based CGM data to illuminate the real-world patient experience. The retrospective study analyzed 50,000 hypoglycemic events in 1,177 Dexcom Share users, suggesting an event rate of 0.96/day/patient. Notably (though unsurprising to us as patients) the proportion of hypoglycemic events followed by rebound hyperglycemia was 18% within 60 minutes and 26% within 90 minutes. Even more interesting would be to know what rebound rebound hypoglycemia looked like (i.e., overtreating a rebound hyperglycemic episode, resulting in a subsequent second low). We also wonder what time-in-tight-target range (70-140 mg/dl) looked liked immediately following hypoglycemia and the 24-hour period following hypoglycemia. Those sub-analyses aside, this poster was a great reminder of the illuminating data cloud-based glucose monitoring can bring. Though RCTs have tremendous value in driving scientific discussion, they often fall short of offering real-world insight on the day-to-day rollercoaster of living with diabetes.
• In terms of next-gen CGM sensors, two posters caught our eye:
  
  • A Dexcom poster (955-P) provided a first look at human durability data from the company’s in-development Gen 6 sensor, suggesting that extended wear is indeed feasible over 10 days. The early findings were positive – 94% of sensors lasted to 10 days, though when Dexcom included all sensors in the analysis (i.e., including non-sensor-related CGM system failures), 79% lasted for the full period. The latter was lower than we would have expected based on our experience wearing the G4 Platinum. We continue to wonder if Dexcom will go for a 10-day wear indication for the Gen 6 sensor – management most recently indicated in April that it will move into a pre-pivotal trial this summer, with plans for a 1H17 commercial launch.
  • The latest human data from Medtronic’s orthogonally redundant CGM (combining an electrochemical + optical sensor) demonstrated very little marginal benefit relative to electrochemical alone - for the full seven-day period, accuracy improved very slightly with the redundant sensor (from 11.6% to 10.3%). The biggest advantage of redundancy came in the first 48 hours after insertion – MARD fell from 16.8% with the single electrochemical sensor to 10.8% with the orthogonally redundant sensor configuration on Day 1, and from 13.7% to 10.2% on Day 2.
• After lots of excitement at ATTD 2015 in Paris, Abbott’s FreeStyle Libre was unsurprisingly (given that it is not yet FDA approved) absent at ADA … though it still seemed to be on the minds of some international (and US) attendees. On the conference floor and in hallway conversations, we heard enthusiasm for the product’s potential, which has been on the European market for nine months now. Indeed, it was notable to see the extent to which attendees (from KOLs to clinicians to educators) were familiar with the device. The “No fingersticks” message continues to inspire awe, particularly in terms of how much insight it can bring type 2 patients who aren’t in good control, and type 1 patients not on CGM because of a real or perceived hassle factor. Adding to the “Libre Fever” (our wording), Dr. Steve Russell (MGH, Boston, MA) announced that the Bionic Pancreas team hopes to use the blinded version (Libre Pro – available in India now) in its pivotal Bionic Pancreas study. FreeStyle Libre has completed its pivotal study in the US, and we assume a regulatory submission is in the works or has possibly already happened – a big question is whether Abbott will obtain an insulin-dosing claim in the US. Of course, it may be moot, since patients will dose insulin off it anyways in the real world, assuming it is still factory calibrated.
• We were encouraged to see two notable abstracts relating glucose monitoring to healthcare costs and longer-term complications:
  
  • A retrospective database analysis compared CGM users to non-users, suggesting greater improvements in A1c (0.5%), an impressive 42% reduction in inpatient hospital admissions (all-cause), and a 17% reduction in emergency room visits. Dexcom’s Dr. Claudia Graham presented the results, which were gleaned from 14 million enrollees in Optum’s national US database. Though selection bias is certainly possible in this type of study, the data are encouraging and lend some credibility to the technology’s cost-saving potential. We continue to look forward to results from Dexcom’s DiaMond study, which should offer more scientifically robust data on the value of CGM. The 338-patient, 20-center study aims to understand CGM outcomes (including healthcare costs) in MDI users. The estimated study completion date is March 2016.
  • A late-breaking poster suggested an increased risk of mortality due to CMS’ competitive bidding program. Findings demonstrated that patients in competitive bidding test sites had more than twice as many inpatient admissions (982 admissions vs. 460) and more than double the associated costs ($10.7 million vs. $4.7 million) compared to a non-test site population, which translated into almost twice as many deaths (102 deaths vs. 60). Of course, the study does not imply causation, though the results are directionally interesting and potentially alarming. As a reminder, these data differ greatly from CMS’ April 2012 report on adverse outcomes associated with competitive bidding, which suggested that there was no disruption of access to supplies and no negative healthcare consequences associated with the program. Ultimately, the results raise red flags for what is already a heavily scrutinized program. Carryover from competitive bidding (which began in July 2013) continues to exert significant pressure on the market, which was nowhere more evident than in the exhibit hall: J&J was the only member of the Big Four BGM companies present (similar to last year, but very different from years past).
• ADA was an important meeting for diabetes data, headlined by Glooko’s partnerships with Medtronic, Dexcom, and Insulet. Tidepool was also present in the exhibit hall for the first time, demo-ing its upcoming blip software in Insulet’s booth. Meanwhile, data veteran Diasend updated attendees in its own dedicated booth, highlighting compatibility with 120 devices. The proprietary data siloes seem to be increasingly opening up, though there are plenty of remaining questions: What aggregation software will patients and providers prefer (i.e., Diasend, Glooko, Tidepool)? Will glucose monitoring reports be widely standardized to an output like AGP? What will it take to bring meaningful clinical decision support/analytics to patients and providers? Who will apply for the Helmsley Charitable Trust’s Diabetes Data Innovation Initiative? Will industry adopt the interoperability standards spearheaded by Dr. Joe Cafazzo, JDRF, and HCT? Will patients be able to easily port their data from one software platform to another?

Digital Health

• We did not see any truly notable data on mobile care delivery or telemedicine. We believe such digital health solutions can play a role in improved, more cost-effective diabetes care delivery in the coming years, though it’s still likely early days at this point (particularly in diabetes). This takeaway largely echoed what we learned at CES 2015 (January) and SXSW 2015 (March) – digital health has lots of potential, but the groundwork is probably just getting laid.
  
  • That said, the financial markets are showing tremendous recent optimism for digital health. Doctor On Demand just raised $50 million, Teladoc filed for a $100 million IPO a few weeks ago, Walgreens announced it is bringing MDLIVE to 25 states by December, and Fitbit raised an astonishing $732 million in its June 18 IPO (the market cap is now over $7 billion!). We believe these approaches are welcome, since there is so much room to improve care delivery on the provider side and engagement on the patient side. Those who are able to answer the biggest questions – provider adoption, patient adoption, scalable business models, reimbursement – have the biggest potential in our view. For now, the field is moving fast, but from a small base. . . time will tell what this means for diabetes care delivery and management. We are cautiously optimistic, though it may be some time before the consumer digital health trends meaningfully affect diabetes. 
• At DiabetesMine’s D-Data Exchange, AgaMatrix founder Sonny Vu’s keynote was a standout. He discussed the current 1.0 nature of wearables and where digital needs to go: passive data acquisition; insights and timely feedback; clinical effectiveness; and reimbursement. Of these challenges, Mr. Vu called feedback the hardest, but also the area with the most potential for behavior change. He astutely noted that most wearable devices fall short of passing the “turnaround test”: is something so useful and compelling that you would run home to get it if you forgot it? We love this as a lofty goal for diabetes device design; it’s a tall order, though we’re encouraged to see glucose monitoring increasingly moving in this direction, particularly with remote monitoring (for parents/caregivers), much greater accuracy (Dexcom’s G4AP algorithm), and factory calibration (Abbott’s FreeStyle Libre). Mr. Vu also sounded optimistic that the coming Gen 2.0 of wearables could help make wearables more compelling – devices will have better materials (metal, leather, ceramic), require less/no charging, enable wear for months, and better integrate into daily life. Mr. Vu called the ideal product design a combination of Harvard Medical School and Playskool: clinically effective and an amazing, delightful user interface.
• It was terrific to see two podium presentations on social media in the ADA main schedule. Social media guru and activist extraordinaire Dr. Joyce Lee (University of Michigan, Ann Arbor, MI) gave an outstanding presentation on the value of the diabetes online community, emphasizing the opportunities for patients and providers to learn from each other, to advocate for better policy, and to harness creativity and hacking abilities (e.g., Nightscout). DiabetesMine’s Ms. Amy Tenderich echoed these sentiments, stressing that social media can help patients share the burden of the disease and provide an avenue for discussing topics that are uncomfortable with providers. We see these presentations as a positive sign that social media is becoming more important in the eyes of the meeting’s organizers – and by association, we hope it’s becoming more validated for attendees too. The jury may still be out on the clinical value of social media, but in some sense it doesn’t matter – social media is free for patients, always on, and offers significant support where the healthcare system falls short. More important questions concern how nervous social media makes providers; how likely patients are to find misinformation online and act on it; and whether the very best online resources are getting into the hands of those who most need them.

Diabetes Drugs

Cardiovascular Outcomes Trials

• The long-awaited results from the TECOS and ELIXA CVOTs (for Merck’s Januvia [sitagliptin] and Sanofi’s Lyxumia [lixisenatide], respectively) were resoundingly neutral. While both trials had already reported topline neutral results, we were watching closely during the full results presentations for any hint of a divergence between groups or any notable imbalances in any secondary endpoints. We saw that the Kaplan-Meier curves for the primary cardiovascular composite endpoint were essentially superimposable in both trials, and there were no significant differences in any secondary cardiovascular outcomes. It was particularly reassuring to see the impressively neutral results (hazard ratio of 1.00) for heart failure in TECOS given prior concerns of a class effect on heart failure. As study investigator and renowned researcher Dr. Rury Holman (University of Oxford, UK) noted, the upper bound of the 95% confidence interval (1.20) was below the hazard ratio point estimate of 1.27 for heart failure hospitalization in the SAVOR trial. Interpretation of a slight imbalance in acute pancreatitis was mixed, but if a real effect exists, the consensus was that it is acceptably modest.
  
  • While reassuring in terms of safety, the continued flow of neutral results from CVOTs prompts broader questions about the value of these trials as they are currently designed. Both TECOS and ELIXA were powered to detect some level of cardiovascular superiority, but several speakers noted that their relatively short duration and “glycemic equipoise” design (aiming for minimal A1c differences between groups) would have made a superiority finding quite surprising. Presumably we are watching the field learn – this probably wasn’t obvious when the trials were being designed. The trial discussants, who are both renowned and highly respected researchers – Dr. Silvio Inzucchi (Yale University, New Haven, CT) for ELIXA and Dr. Allison Goldfine (Joslin Diabetes Center, Boston, MA) for TECOS – both raised larger questions about whether these studies are enrolling the right patients, running for long enough, and asking and answering the most relevant clinical questions. After seven years, four neutral trials, and hundreds of millions of dollars spent, we hope the FDA will feel compelled to consider these questions and bring together cardiology and diabetes researchers and other experts to assess where  the current paradigm stands for evaluating the safety of diabetes drugs represents the most effective use of limited healthcare resources. While escalating drug costs have received great attention of late, the complaints about high prices are virtually never in the context of higher costs of drug development or the lower number of years that drugs are available at non-generic prices. As we understand it, one recent drug that has come to market has cost in the multiple billions ($2-$3 billion) rather than the standard $1 billion typically mentioned. Part of this increased cost is due to cardiovascular outcomes trials. While the safety information is highly valuable and we would always want to make sure that safety has been established, it may be helpful at this stage to examine the 2008 guidance to better understand the value coming from multiple similar outcomes trials that are not designed to offer information on potential long-term benefits. There were multiple smart people in the field at both meetings FDA gathered to discuss elements of CVOTs – confidentiality of interim data and SAVOR and EXAMINE results. We think a similar gathering looking at a broader set of questions about the 2008 guidance would be helpful when thinking about implications for public health stemming from the guidance – particularly given Dr. John’s Jenkins commentary at the FDA Public Hearing on the Confidentiality of Interim Results in Cardiovascular Outcome Safety Trials last August, where Dr. Jenkins said that “it may be time to revisit the basis of cardiovascular studies for diabetes drugs” (see link for more context)
  • With regard to the DPP-4 inhibitor/heart failure controversy, we expect that the TECOS results will be positive for the class as a whole and particularly positive for Merck’s Januvia franchise. We imagine that the reassuring results from such a large, well-powered trial should largely rule out the hypothesis of a DPP-4 inhibitor class effect on heart failure. Since there is still no clear explanation for the divergent results in the three DPP-4 inhibitor trials, we expect that the FDA will likely assess each drug separately when evaluating potential label changes, which could potentially help bolster Januvia’s perception among providers – TECOS investigator Dr. Rury Holman (University of Oxford, UK) suggested that it is impossible to know exactly what was going on in SAVOR and EXAMINE but that risk-averse clinicians may “vote with their feet.” We do still think that the finding in SAVOR was more likely due to chance than a distinct drug-specific effects on heart failure, though we did hear slightly differing opinions on this question during the TECOS results presentation.
  • We are curious how researchers’ assessments of how to show superiority for newer classes have changed. This did not receive attention at the ADA and we hope that the field learns from the findings of these first few trials.

Basal Insulin

• Now introducing: the next wave of basal insulins. The basal insulin discussion at the past two years’ ADAs have focused on products like Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (insulin glargine U300) that appear to offer meaningful but not necessarily game changing advantages as monotherapy over existing options in terms of hypoglycemia and extended PK/PD. We do believe that now that Toujeo has been launched, the approach to teaching about the insulin to patients (using COACH) actually is fairly innovative – the “real world” experiences also appear to be positive, though it’s early and we’ll look forward to dQ&A satisfaction data on this front (for more information, contact dQ&A CEO Richard Wood at richard.wood@d-qa.com). We would also note that access help to patients on Toujeo seems to be been more extensive than we have seen previously – we’ll look forward to watching how this plays out. As we have said in previous years, we look forward to seeing combinations using GLP-1 and basal insulin – Sanofi will be using Lantus in combination with its GLP-1 lixisenatide and Novo Nordisk will be using Tresiba, once it is approved – that should likely give Novo Nordisk the edge on the basal insulin/GLP-1 combos and we’ll be interested to see how these are priced and where they land in the patient line up. This year at ADA, there was not as much on Tresiba and Toujeo and there was more on the next (potential) big things in basal insulin: the more physiologically compelling (though high-risk/high-reward) liver-selective peglispro (BIL) from Lilly and new once-weekly basal insulins.
  
  • The phase 3 data on peglispro was some of the most eagerly awaited data at ADA, and those watching were eager to hear both about safety issues that we knew would be discussed alongside the benefits. On the plus side, peglispro is the first basal insulin to demonstrate superior A1c reductions vs. existing long-acting insulin analogs across a phase 3 program – it also managed to do this with significantly less nocturnal hypoglycemia than Lantus (insulin glargine). Physiologically, liver-selective insulin more closely mimics endogenous insulin action and also has better weight effects vs. non-liver-selective insulin. However, peglispro also caused aberrations in liver fat, liver enzymes, lipids, injection site reactions, and (in some trials) increases in daytime hypoglycemia. While some researchers said none of these effects individually appeared to be an absolute dealbreaker (though the increased hypoglycemia in particular may be worrisome to patients in particular), taken as a whole (in the context of a conservative FDA) they pose a real threat to the drug’s hopes of approval following further study over the coming years. At this point most researchers appear willing to wait for the results of further study on the candidate, though the providers who believe that current insulin options are adequate will probably never be sold on peglispro. Even if peglispro itself does not make it to approval, however, it proves the benefits of liver selective insulin and could lay the groundwork for future candidates that achieve comparable efficacy and non-glycemic benefits with fewer side effects.
  • A different set of basal insulins is pushing the envelope into once-weekly dosing. The pioneers – still at a fairly early stage – include PhaseBio’s PE0139 (phase 1), Hanmi’s Hm12470 (phase 1), and AntriaBio’s AB101 (soon to begin clinical testing). Notably, PhaseBio is already examining a combination of PE0139 with its once-weekly GLP-1 agonist PB1023; that candidate was halted as a monotherapy after failing to achieve non-inferiority vs. Victoza in phase 2b, but a once-weekly GLP-1 agonist/basal insulin combination could well be a very appealing option for many patients. The key question for these agents is the degree of appeal of once-weekly insulins vs. once-daily options. In a presentation on that very topic, Dr. Ian Blumer (University off Toronto, Canada) suggested that the connection between insulin injection frequency and adherence exists but may not be as clear-cut as one would assume. He encouraged providers to consider other factors like injection discomfort that may drive lesser adherence – we repeatedly hear that pens and needles are becoming more patient friendly and less of a perceived barrier. Though we do think the convenience advantage would be meaningful for a once weekly insulin, to make it past regulators and payers these new agents will still need to match once-daily insulins on efficacy and safety – we would hope it is “real world” efficacy that the comparison is made.  

The Cost of Drugs

• The climbing cost of insulin and other drugs was a major topic of discussion this year. Dr. Irl Hirsch (University of Washington, Seattle, WA) led off with a dedicated presentation on day #1 critiquing the sharp rise in insulin prices over the past decade. He considers it unethical and unacceptable for cost to be a barrier for access to a lifesaving drug, and he certainly had a chorus of support among the audience. On the other hand, some (including Dr. Hirsch) point out that the drug is life-saving and that it isn’t surprising that the drugs are expensive. One audience member even invoked the Declaration of Independence in arguing that affordable insulin should be a right rather than a privilege. This issue is far from black-and-white: Lilly Diabetes President Mr. Enrique Conterno noted during the company’s Diabetes Business Update that net Humalog prices have been stable over the past several years, with rising list prices and simultaneously rising rebates to PBMs. It appears to be cash-paying patients who lose out, and we hope to see providers, patients, advocacy groups, foundations, professional associations like the ADA, and industry collaboratively work toward a more clear-cut approach that makes pricing and profitability less of a black box.

GLP-1 Agonists

• The future for GLP-1 agonists looks bright, especially considering the potential for combination with basal insulin along with innovative new delivery devices. The GLP-1 agonist class appears to be rebounding following a sluggish past two years, driven by new once-weekly options like Lilly’s Trulicity, GSK’s Tanzeum, and AZ’s Bydureon Pen. Looking ahead, we can see the class’ future bifurcating between two paths: (i) improved non-injectable delivery devices, and (ii) combination with basal insulin. We are excited to see how products like Intarcia’s implantable exenatide mini-pump ITCA-650 fare vs. Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s LixiLan (insulin glargine/lixisenatide) – we believe we’ll continue to see meaningful growth in this market. The 2015 GLP-1 market totaled a bit over $3 billion in 2014, and we expect that to grow at a faster rate from a higher base in 2015.
  
  • We were very impressed with the results from the DUAL V study, which compared Novo Nordisk’s Xultophy and Sanofi’s Lantus. The results after 26 weeks showed a mean A1c reduction of 1.8% from a baseline of 8.4% with Xultophy vs. a reduction of 1.1% from a baseline of 8.2% with continued Lantus therapy in type 2 diabetes patients also on metformin. But wait – there’s more! Xultophy boasted a more than 3 kg (~7 lb) weight benefit vs. Lantus (-1.5 kg [~3 lb] weight loss from baseline). Xultophy caused 57% fewer episodes of confirmed hypoglycemia (p<0.001) from around 5 episodes/subject/year to around 2 episodes/subject/year and an 83% reduction in nocturnal hypoglycemia (p<0.001) from roughly 1.2 episodes/subject/year to around 0.2 episodes/subject/year. We’re also looking forward to seeing topline phase 3 data for Sanofi’s LixiLan, expected in 3Q15. In terms of strong efficacy and well balanced side effects, the results from GLP-1 agonist/basal insulin combinations have been perhaps the best out there – though we will have to see the data, our sense is that patients may be able to start early on this therapy and stay on it longer than other alternatives.
  • We finally got to see the pivotal phase 3 data on ITCA-650. Mean A1c reductions were around 1.4% for the whole group from baseline, with placebo-adjusted efficacy that looked to be around 1.1%. This is roughly in line with what we’ve seen from other GLP-1 agonists, though efficacy was found to be even better in patients not taking a sulfonylurea (SFUs brought down the average since SFUs usually bring down A1c quite a lot at the start but the efficacy doesn’t last). In line with expectations for a GLP-1 agonist, ITCA-650 led to weight loss and nausea around the time of dose escalation. We thought the results were quite solid, though the company will have to work to manage expectations after an explosively positive past year in the news cycle that has built up a fair amount of hype. That said, the “forced adherence” of the compound is certainly attractive from an HCP perspective; as well if the coverage holds for the current insertion/removal codes, this therapy will bring welcome reimbursement for a PCP or endo office.
  • We do not expect either ITCA-650 or basal insulin combinations to completely win over the GLP-1 agonist market. Rather, we expect a fragmentation of the market as patients and providers individualize therapy based on the unique strengths and drawbacks of each option. Intarcia’s mini-pump should work particularly well for patients who face challenges with maintaining adherence or who are averse to regular injections. It has already demonstrated exceptional efficacy for patients starting with very high (>10%) baseline A1cs. The basal insulin/GLP-1 agonist combinations have the appeal of titratability, less nausea, and no need for an implantation procedure (that could be a positive or negative depending on reimbursement, time required, hassle factor, etc.). We also note that more conventional once-weekly GLP-1 agonists stand to be quite popular, especially when available in easy-to-use auto-injectors like Lilly’s Trulicity.

SGLT-2 Inhibitors

• A number of speakers framed euglycemic DKA as more of a manageable risk than a deal-breaker for the SGLT-2 inhibitor class – this has come up primarily related to type 1 patients. Dr. Julio Rosenstock (University of Texas Southwestern Medical Center, Dallas, TX), Dr. John Buse (University of North Carolina, Durham, NC), and Dr. Anne Peters (USC, Los Angeles, CA) all emphasized the importance of continuing to increase awareness of the risk, which was largely unknown until Dr. Peters first began drawing attention to it toward the beginning of this year. As noted, much of the concern at this point is focused on off-label use of SGLT-2 inhibitors in type 1 diabetes, as the risk/benefit profile is not as clear in that population as in type 2 diabetes (where the phenomenon appears to be more rare and influenced by clearer risk factors like surgery or insulin deficiency). Dr. Rosenstock predicted that the ongoing trials of SGLT-2 inhibitors in type 1 diabetes will likely conclude that the benefits (insulin-independent efficacy, reduced glucose variability and insulin doses, and improvements in weight and blood pressure) outweigh the risks for most patients. Dr. Buse similarly suggested that the phenomenon is unlikely to be a “showstopper” for SGLT-2 inhibitors as long as people are aware of it and know how to treat it. Dr. Peters took a somewhat more cautious tone, but she suggested that the class can still be used safely in some cases as long as appropriate precautions (i.e. low doses, frequent ketone monitoring, and good patient-provider communication) are taken; Dr. James Gavin send more should be known and urged the field to take a close look at what is happening, especially on the type 1 front.
  
  • While the mechanism of euglycemic DKA is not fully understood, the combination of reduced insulin doses and increased urinary glucose excretion appears to be what pushes patients over the edge in many cases. Dr. Rosenstock, Dr. Clifford Bailey (Aston University, Birmingham, UK), and Dr. Zachary Bloomgarden (Mount Sinai Hospital, New York, NY) all noted that insulin deficiency likely contributes to excess ketone production by pushing the body further into the fasting-like state originally induced by increased glucose excretion. While the potential for insulin dose reduction has been cited in the past as one of the main selling points for SGLT-2 inhibitors in type 1 diabetes (and for some patients with type 2 diabetes), this recent experience suggests that much more caution is warranted – for type 1 patients in particular, who are all taking the drug off label. We would note that not all of the reported cases have been linked to a reduction in insulin dose, suggesting that there are likely other risk factors at play.
  • The discussion of euglycemic DKA has continued to evolve since ADA. Dr. Peters, Dr. Buse, and Dr. Irl Hirsch (University of Washington, Seattle, WA) are co-authors on a case series that was recently published in Diabetes Care, marking the first major publication we’ve seen on the issue. It should certainly continue to increase awareness in the medical community and we applaud the trio for staying on top of the developing issue. The FDA and EMA are both currently investigating the phenomenon, and we imagine that some sort of label addition is likely in the future. The impact on the class’ prospects in type 1 diabetes will depend on the results from ongoing trials, which should provide much more clarity on the broader risk/benefit profile.

Novel Drugs

• Noticeably absent once again was the clear “next big thing” in terms of new drug classes for type 2 diabetes; the focus continues to shift towards making better use of existing drugs. Over the past two years, two of the potential frontrunners – GPR40 agonists and FGF21 analogs – took a step backwards with the discontinuation of Takeda’s phase 3 TAK875 (fasiglifam) and poor results on Pfizer and Lilly’s FGF21 analogs. The lack of major new drug classes is almost certainly due in part to the rising regulatory and reimbursement pressures in diabetes. The bar for new therapies is definitely much higher than it was even a few years ago. The true costs of the 2008 CV Guidance (namely the tens or hundreds of millions of dollars needed for outcomes trials) are now better understood by manufacturers, who are responding by slowing the flow of new therapies through phase 3 (as with Takeda’s once-weekly DPP-4 inhibitor) or even leaving diabetes, as BMS and Genentech both did and as Novartis is effectively doing but not putting any further focus on research efforts in type 2 diabetes.
  
  • Efforts to make better use of existing drugs have yielded some compelling products. Among new combination products, we continue to consider GLP-1 agonist/basal insulin combinations like Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s LixiLan (insulin glargine/lixisenatide) as well as SGLT-2/DPP-4 inhibitor fixed-dose combinations like Lilly/BI’s newly launched Glyxambi (empagliflozin/linagliptin) very impressive in terms of both efficacy, convenience, and tolerability. Intarcia’s ITCA-650 represents an innovative new application of a drug molecule (exenatide) that has been available in other forms for years (AZ’s Byetta). With the room for incremental improvement growing smaller, we expect to see more differentiation via patient support initiatives like Sanofi’s COACH programs for Toujeo and Afrezza. It is clearly true that patients can benefit from adherence programs as well as patient access programs. While oral formulations of existing injectable drugs continue to be seen as one of many holy grails for diabetes therapy, we didn’t see a lot of new data on this front at this ADA. Finally, we’ve noticed some intriguing but less conventional approaches, such as NuSirt’s combination of diabetes drugs with the amino acid leucine to boost effectiveness - this one sounds very exciting. We did not receive updates on the small number of new drugs like Elcelyx’s NewMet that garnered extensive attention in the future – we’re not sure what the case is for this particular drug but will work to get an update.
  • Despite the lower number of new drug classes moving through clinical testing, we’re excited by the groundswell of interest in the gut microbiome and brown fat. There was quite a lot of science on the scientific agenda on both topics. Both of these emerging areas of science hold potential far beyond type 2 diabetes: the microbiome is theorized to play a role in type 1 diabetes, as well, while brown fat could have broad therapeutic applications for metabolic diseases more broadly.
  • This year’s Banting Lecture – delivered by Dr. Philipp Scherer (UT Southwestern, Dallas, TX) – was dedicated to adipose tissue as a drug target for diabetes and other metabolic disease. Synthesizing years of rodent data, Dr. Scherer detailed the role of adipocytes in (i) the release of protein factors that impact systemic metabolism, with special emphasis on adiponectin (a protein that plays a key role in both glucose and lipid regulation); (ii) the buffering of critical lipid mediators; and (iii) the release of metabolites that impact one’s basal metabolic rate. Connecting these topics to drug development, he expressed confidence that adiponectin-receptor agonists can be a clinically useful new drug class.

Type 2 Diabetes Drugs for Type 1 Diabetes

• The use of type 2 diabetes drug classes in type 1 diabetes remains an area of great interest, though a bit more nuance has emerged in terms of the potential benefits. The most positive results on this front were the full phase 2 results for Lexicon’s SGLT-1/SGLT-2 inhibitor sotagliflozin (LX4211) in type 1 diabetes, which delivered (i) a roughly 0.5% placebo-adjusted reduction in A1c from a baseline of around 8% and reductions in postprandial glucose; (ii) a 32% decrease in bolus insulin dose (6% reduction with placebo) in the context of better glycemic control; (iii) a significant improvement in time-in-range and multiple metrics of glycemic variability, including a 68% time in zone with LX4211 compared to a 54% time in zone for placebo; and (iv) a relative weight benefit of slightly over 2 kg (~4 lbs) in a short time period. Of course, the euglycemic ketoacidosis issue will be key to address with SGLT inhibitors in type 1, although we’ve heard it suggested that SGLT-1/2 inhibitors should have less of a DKA risk than selective SGLT-2 inhibitors due to their stimulation of GLP-1 secretion, which should boost insulin secretion. This has not been tested and we will await news on this front, though it may need to be a bigger number of patients tested over a longer period of time to get a meaningful result. 
  
  • We saw results from two randomized controlled trials investigating Novo Nordisk’s Victoza (liraglutide) as an adjunct to insulin in poorly controlled type 1 diabetes; both showed substantial improvements in body weight and less need for additional insulin, but no significant added benefit on A1c or time in range. We would not rule out the potential for a greater benefit in the real world, as these two clinical studies were fairly small and the insulin-only control group performed unusually well, which is rarely the case in the “real world.” We are very eager to see results from two phase 3 Novo Nordisk-sponsored trials (ADJUNCT ONE and ADJUNCT TWO) investigating Victoza in type 1 diabetes within the next few months; this should hopefully provide a additional data points on the level of benefit patients can expect.
  • A T1D Exchange clinical trial on metformin in overweight/obese adolescent type 1 diabetes patients found improvements in certain cardiovascular risk factors, though the effects were modest. A bit surprisingly, there was no statistically significant improvement in A1c at the end of the trial, although metformin did slightly reduce patients’ daily insulin dose. While metformin is said to have potential to be anti-cancer, this is hard to test except in a very large and very long outcomes trial.

Additional Topics

Obesity Drugs

• We saw very little on obesity this year, both in terms of new science and commercial presence. On the scientific program, while GLP-1 agonists garnered some attention within obesity, other presentations on weight management had lower attendance; there was even a session that (in name, at least) debated the necessity of weight loss in diabetes  (“Weight Loss for Type 2 Diabetes – Nice, But Necessary?”). Obesity drugs had less presence within the exhibit hall, with Novo Nordisk’s relatively small booth on Saxenda (liraglutide 3.0 mg) having the largest footprint. The only other obesity company on the floor was Eisai, which had an modest pop up booth featuring Belviq (lorcaserin) near the back of the exhibit hall; neither Vivus with its Qsymia (phentermine/topiramate) or Orexigen/Takeda with Contrave (naltrexone/bupropion) were present. This level of engagement from the obesity drug companies stands in stark contrast to last year’s ADA where Belviq and Qsymia both had large, bustling booths (Saxenda and Contrave were not yet on the market then). The sharp drop-off in marketing from the obesity companies does not bode well, though we imagine the companies are saving their resources for meetings like Obesity Week. We do remain optimistic that Novo Nordisk’s expertise and resources within the immense diabetes market should help build a stronger bridge from diabetes care to obesity though since Saxenda is priced at such a high level, we do not think a major market will develop.

Prediabetes

• We were glad to see some big names focus on the need for greater access to treatment options for people with prediabetes. Most notably, during a symposium on the National Diabetes Education Program (NDEP), Dr. Ann Albright (CDC, Atlanta, GA) and the renowned  Dr. Judith Fradkin (NIH/NIDDK, Bethesda, MD) passionately pushed for the importance of managing prediabetes. Dr. Albright enthusiastically invited attendees to partner with the National Diabetes Prevention Program (NDPP), as she stressed the value of ensuring efficiency, availability, and distribution in diabetes care. During Q&A, attendees expressed frustration with the lack of metformin use in prediabetes, to which Dr. Fradkin discussed the challenges and opportunities involved in moving forward on a prediabetes indication for the drug. Several oral presentations looked at various interventions targeting people with prediabetes, evaluating how to most cost-effectively scale such efforts – we see digital health intersecting with this area in a big way in the future and would note that there was enough on digital health this year at ADA to merit its own report in our coverage.

PCSK9 Inhibitors

• Companies behind the exciting new PCSK9 inhibitors for LDL lowering were eager to spread the word about the new class. This could be seen in the exhibit hall as both Amgen and Sanofi/Regeneron made appearances with decently sized booths devoted to Repatha (evolocumab) and Praulent (alirocumab), respectively. In addition, Amgen hosted a breakfast corporate symposium on managing elevated LDL-C levels as well as a product theater that discussed the genetic models of PCSK9. Even Lilly, who currently has a PCSK9 inhibitor candidate in phase 2, provided an educational grant for a separate breakfast corporate symposium focused on “shifting the cholesterol conversation beyond statin therapy.” However overall, the attendance and enthusiasm from these events’ attendees may not have matched up to the companies’ ambitious efforts, as attendance at the dedicated PCSK9 sessions was on the low side. We don’t think that most doctors anticipate having access to this class for some years, which would have affected the participation. But as we recently learned from the recent EMDAC meetings on Repatha and Praulent, the drugs may have to wait a few more years prior to being indicated for the larger populations including those with high cholesterol like many people with diabetes, as many panelists strongly felt that a broader indication should not be approved until results from the drugs’ respective cardiovascular outcomes trials are released. Saving the drug for those who need it most until the outcomes trials are complete appears to be the wise choice, though a difficult one to make. Even so, the companies’ excitement for the drug class clearly shone through and marks industry’s – and our own – confidence in PCSK9 inhibitors’ eventual applicability in diabetes. Trying to demonstrate cardioprotection with glucose lowering drugs has proven to be a challenging task, but doing so should be easier with this new class of drugs that has demonstrated striking (50% or greater) reductions in LDL from baseline in a wide variety of patient populations. We’re cautiously optimistic about the results from the outcomes trials, expected in 2017/2018 though even with this class, we wonder if the trials are going to be long enough.

Programs to Support Young Scientists and Clinicians

• This year’s conference showcased several impressive efforts by the ADA to support young diabetologists. As ADA President of Medicine & Science Dr. Samuel Dagogo-Jack (University of Tennessee Health Science Center, Memphis, TN) noted in his opening address, a central problem in diabetes research is that major traditional sources of research support are in decline, leaving researchers competing for an ever-shrinking funding pie. This is an incredibly challenging climate for young researchers to enter, and those who do enter it may be more inclined to play it safe rather than pursue “high-risk/high-reward” projects with a greater chance of producing a breakthrough. Particularly given this context, we were very excited to hear the six brilliant recipients of the ADA’s Pathway to Stop Diabetes grants discuss their innovative projects during a closed session on the first day of the conference. The Pathway program aims to empower young researchers or those new to the field to tackle such potentially transformative projects, and we were struck by the energy in the room as the high-powered audience discussed the presentations and the larger questions facing diabetes research. We hope this is an open program next year. We were similarly inspired by the Focus on Fellows program, which aims to provide ambitious, talented fellows with valuable mentorship and research opportunities as well as much-deserved recognition of their decision to pursue endocrinology. This session was particularly valuable and XYZ all participated, on an impressive note. Such programs will be incredibly important to encourage young professionals to enter such a challenging field, and we applaud the ADA for making these efforts a priority for those looking to go into research – we hope that similar efforts are made for those looking to treat patients.

Insulin Therapy

Oral Presentations: Basal Insulin Analogs — New Evidence

Basal Insulin Peglispro (BIL) Is Superior to Insulin Glargine (GL) in Reducing HbA1c at 52 Wks in Insulin-Naïve T2D Patients (Pts) Treated with Oral Antihyperglycemic Medications (OAMs): IMAGINE 2 (93-OR)

Melanie Davies, MD (University of Leicester, Leicester, UK)

Dr. Melanie Davies presented full results of the IMAGINE 2 trial, a phase 3 randomized controlled trial comparing Lilly’s basal insulin peglispro (BIL) to Sanofi’s Lantus (insulin glargine) in insulin-naïve people with type 2 diabetes. The topline results of this trial had been announced all the way back in May 2014. Impressively, BIL actually demonstrated statistical superiority in A1c reduction (by 0.3% after 52 weeks) over market-leading glargine. Consistent with BIL’s liver-selective effects (and, thus, reduced peripheral effects), BIL treatment resulted in less nocturnal hypoglycemia, less weight gain, but higher serum triglyceride levels (11 mg/dl difference) and higher liver ALT levels (6 IU/L difference), which are a marker for potential liver damage. As a reminder, Lilly announced earlier this year that it plans to delay BIL submission for at least two years – presumably because of these consistent liver safety signals.

• IMAGINE 2 was a phase 3 trial comparing Lilly’s basal insulin peglispro (BIL) to Sanofi’s Lantus (insulin glargine) in people with type 2 diabetes who had never previously been treated with insulin. The primary endpoint of the trial was non-inferiority for A1c change after 52 weeks, and some key secondary endpoints were statistical superiority in A1c change after 52 weeks (if non-inferiority was met), total hypoglycemia, nocturnal hypoglycemia, patients achieving A1c <7%, and patients achieving A1c <7% without nocturnal hypoglycemia.
• IMAGINE 2 was a double-blind study (neither the patients nor physicians knew which drug the patient was taking), which is a challenging feat to pull off in the world of insulin trials. It was a treat-to-target study with 1,538 patients randomized 2:1 to BIL or glargine for 52 weeks. A prespecified cohort of 920 of the original 1,538 patients were also followed out to 78 weeks (keeping the same 2:1 randomization). In addition, liver fat content was examined via MRI in a small subgroup of 168 patients.
• At baseline, patients had an A1c of 8.5% and BMI of 32 kg/m². Over 96% were on background metformin therapy, 83% on background sulfonylurea therapy, and just over 20% were on three oral antidiabetic agents.
• BIL achieved a statistically superior A1c reduction compared to insulin glargine. After 52 weeks, BIL reduced mean A1c from 8.5% to 6.9% (for a mean reduction of 1.6%) compared to a reduction from 8.5% to 7.2% with glargine (mean reduction of 1.3%) (difference of 0.3% between BIL and glargine; p<0.001). This difference was still statistically significantly different at 78 weeks, although the sample size was substantially smaller (920 vs. 1,538 patients). Significantly more patients on BIL achieved an A1c <7%, and significantly more patients on BIL did so without nocturnal hypoglycemia. This relationship held true at 26, 52, and 78 weeks. After 52 weeks of treatment, 58% of BIL patients had achieved A1c <7% compared to 43% of glargine patients. Twenty six percent of BIL patients achieved A1c <7% without nocturnal hypoglycemia compared to 15% of glargine patients after 52 weeks.
• BIL resulted in less nocturnal hypoglycemia compared to glargine; meanwhile, total and severe hypoglycemia were similar between the two insulins. Specifically, the RR for cumulative nocturnal hypoglycemia was 0.73 (95% CI: 0.59, 0.91) for BIL compared to glargine.
• BIL also demonstrated a weight benefit compared to glargine. While patients on glargine gained 2.6 kg (5.7 lb) over 52 weeks, patients on BIL gained 2.1 kg (4.6 lb), representing a 0.5 kg (1.1 lb) weight benefit for BIL – we don’t see this as a meaningful advantage, but it is going the right way.
• However, BIL had unfavorable effects on liver enzyme levels and patients’ lipid profile. After 52 weeks, patients on BIL had a statistically significant 11 mg/dl triglyceride elevation compared to patients on glargine. This effect persisted to 78 weeks when the difference grew to an 18 mg/dl difference. LDL and HDL cholesterol remained unchanged. After 52 weeks, ALT levels, a marker of liver damage, rose from a baseline of ~29 IU/L to 34 IU/L in patients on BIL compared to a reduction from ~28 IU/L to 27 IU/L in patients on glargine (p<0.001). Significantly more patients in the BIL arm experienced ALT levels three times the upper limit of normal (3X ULN): 2.3% of BIL patients compared to 0.6% of glargine patients (p<0.05). No patient met the criteria for Hy’s Law, which is the set of criteria used to suggest that a drug has a high risk of causing liver injury.
• A subset of patients (n=168) had their liver fat content analyzed by MRI, showing that patients on BIL had more fat in their livers than patients on glargine (this is consistent with BIL’s liver-targeted actions) than patients. At 52 weeks, BIL patients had 12.6% liver fat compared to 10% in glargine patients (p<0.01). Dr. Davies noted that the liver fat discrepancy resulted from a decrease in baseline in the glargine group with no change from baseline in the BIL group.

Questions and Answers

Q:  What treat-to-target algorithm was used?

A: We used a fairly conventional algorithm. The target was an A1c <7% and fasting glucose of 3.9-7.2 mmol/L [70-130 mg/dl]. We used the 2-4-6-8 approach to increasing glargine and BIL, which was consistent with the Riddle algorithm that has been previously published.

Q: What is a possible explanation for the impact on weight?

A: With previous insulins we had hoped that reducing nocturnal hypoglycemia may have an impact on weight, but that hasn’t always been case. Here we know BIL does have a reduced effect on the periphery and that may result in increased lipolysis and reduced fat storage. So that may be well part of the difference we see in weight.

Q: Congratulations for proving it is possible to do a double-blind insulin study, which no one does anymore. Do you think, with the liver issues, there is just a slight increase of transaminases or do we have a real problem?

A: That’s a good question. We did look at liver fats in this study, and we didn’t see an increase in liver fats in the BIL arm, but a reduction with glargine. This effect has been seen in glargine trials before and to the same extent that we see here. There is a poster that extensively talks about the ALT and liver changes across the IMAGINE program that you can refer to. This may well be a result of hepatic adaptation. That might be one of the explanations. But obviously we should continue to look at longer-term follow up data.

Greater HBA1c Reduction with Basal Insulin Peglispro (BIL) vs. Insulin Glargine (GL) in an Open-Label, Randomized Study in T1D Patients (pts): IMAGINE 1 (95-OR)

Satish Garg, MD (University of Colorado, Aurora, CO)

Dr. Satish Garg presented the IMAGINE 1 study in type 1 diabetes patients. The results show plenty of upside but also a sizable list of the safety signals that were seen elsewhere in the IMAGINE phase 3 program. We walked away from this talk slightly less than positive, not because any of the individual potential red flags are insurmountable, but because there are fairly many of them for a phase 3 candidate that we believe will dampen overall enthusiasm. However the positives – a significant 0.37% A1c benefit, a 2 kg (~4lb) weight benefit, and 36% nocturnal hypoglycemia reduction – still make this a unique and compelling candidate. Lilly has delayed peglispro’s timeline to better understand changes in liver fat, and at this point it is far from certain that peglispro will reach the market, although we believe Lilly and the peglispro investigators have made a compelling case in favor of liver-selective insulin.

• Following a two-week lead in, patients were randomized to peglispro or insulin glargine for a 26-week primary endpoint analysis followed by a final treatment endpoint at 78 weeks. Patients had an average age of 39 years, average BMI of 25 kg/m², average A1c of 7.9%, and average diabetes duration of 15-18 years. The majority were on insulin glargine at baseline (~70%).
• Efficacy: Peglispro led to a 0.69% A1c reduction from baseline after 26 weeks compared to -0.33% with insulin glargine, for a statistically significant difference of 0.37%. The difference was largely preserved out to 78 weeks, with glycemic control deteriorating slightly in both groups between weeks 26 and 78. There was a significant 22 mg/dl difference in fasting glucose at week 26, and a significant (p=0.019) though not enormous reduction in between-day FPG variability.
• Hypoglycemia: At 26 weeks, there was a significant 36% reduction in nocturnal hypoglycemia. However, there was a 29% significant increase in total hypoglycemia and a significant imbalance in severe hypoglycemia (15% vs. 8% out to 78 weeks). This drew some worry during Q&A, and it is hard to believe as strongly in the efficacy benefit with increases in both total and severe hypoglycemia – we think this would be considered a major negative since there are other alternatives that do not increase severe hypoglycemia.
• Safety: There were definite increases in triglycerides (~20 mg/dl), liver enzymes (around six times more cases of ALT rising to more than three times the normal upper limit), and liver fat, though Dr. Garg provided some cautious reassurance that the differences are not highly dangerous at the magnitudes seen. Importantly, there were no cases of Hy’s Law. There were no changes in HDL or LDL cholesterol. There was an imbalance in injection site reactions not favoring peglispro.

Questions and Answers:

Q: It looks like the increase in daytime hypoglycemia may have been due to more aggressive increases in BIL than glargine, as there were differences in glucose and A1c?

A: Yes this was an open label study, but IMAGINE 3 was a double blind randomized trial and the data there is nearly identical. The A1c lowering in that trial was in fact a shade better. By the way, during the day when we saw more hypoglycemia, it was not related to the basal insulin – it was related to the prandial insulin. Most hypoglycemia episodes occurred within three or four hours of taking prandial insulin.

Q [Dr. Stephanie Amiel (King’s College London, London, UK)]: We’ve all been waiting for hepato-selective insulin, but these results were a bit disappointing. You can’t describe it as better glucose control if there is an increase in control with increased severe hypoglycemia. To have “better control” you need to improve both. I also take issue with the idea that the difference in daytime hypoglycemia was only due to bolus insulin, because the only difference in the regimen was the basal insulin. The previous speaker [Dr. Tim Heise] showed that insulin glargine doesn’t provide 24-hour coverage. With very long acting insulin, patients can’t be flexible with dosing around changes in their activity. I’m wondering if you could compare against Levemir twice daily, which has full 24-hour coverage.

A: Those are good points, and I wish we could have used twice-daily glargine in our protocol. You are right that there was an increase in severe hypoglycemia if you look at 78 weeks. It’s a marginal increase, and if you combine the results from IMAGINE 3 and IMAGINE 1 there was no increase in severe hypoglycemia. If you hypothesis is correct that the increase was related to basal insulin, we would have seen no difference, or an increase, in nocturnal hypoglycemia.

Dr. Amiel: It depends on when the patients were taking their once daily glargine. If you take it at night, you obviously get higher action at night than you do later in the day. I’m commenting on increased severe hypoglycemia during the day, which I think is a worry for our patients.

A: I think some of this can also be answered by another poster where we gave insulin flexibly, from a range between eight and 48 hours.

Q: Given the increase in liver fat, might there be an increased long-term risk of steatosis?

A: Clearly there was an increase in liver fat. I would remind you that this insulin is more specifically targeted to the liver. Up to 78 weeks, you see that liver fat barely goes above the normal range, which is 5.5, and at most here we went up to 5.8 or 6. Liver fat that causes hepatic steatosis or insulin resistance is in the hundreds or thousands. My wife is a radiologist and has done lots of work in this area. I am not highly concerned about the liver fat changes with this insulin.

Q: Did you look at patient satisfaction?

A: I don’t know how many patients fill in those questionnaires. No, this was not part of this study.

Q: The company has delayed the submission of this insulin by two years, according to a press release. What will the company do during that time?

A: I do not work for the company, as you know. I work for the University of Colorado. I’m sorry but I don’t think I’d be able to answer that exactly. All I know is that they’re looking into future studies to explain whether the changes in liver fat will have any significance down the road. 

Reduced Intra-Subject Variability of Basal Insulin Peglispro (BIL) Compared with Insulin Glargine (GL) in Patients with Type 1 Diabetes Mellitus (T1DM) (94-OR)

Tim Heise, MD (Profil, Neuss, Germany)

Dr. Tim Heise presented the results of a randomized, open-label study comparing the variability of the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of Lilly’s basal insulin peglispro (BIL) and Sanofi’s Lantus (insulin glargine). 75 patients with type 1 diabetes were randomized to receive a daily 0.5 U/kg dose of either peglispro or Lantus; blood samples were collected on days 8, 11, and 14 to assess the PK profiles of the two insulins, while 24-hour automated euglycemic clamps were performed to assess the PD profiles. Overall, the results suggested that peglispro had a flatter time-action profile than Lantus with a more even distribution of the glucose-lowering effect; the daily variability of both PK and PD profiles was statistically significantly lower for peglispro than for glargine. Dr. Heise concluded that this may have contributed to the superior A1c-lowering efficacy and reduced nocturnal hypoglycemia seen with peglispro vs. Lantus in other studies. These findings are potentially notable, as we see “time in zone” (and particularly avoiding severe hypoglycemia) as an important issue for patients that is too often overlooked by the medical and regulatory communities (to some extent this is understandable since less variability hasn’t been linked definitively with fewer complications). However, several attendees expressed skepticism about the results during Q&A due to limitations in the study design, and it remains to be seen to what extent they will be clinically meaningful.

Questions and Answers

Dr. Geremia Bolli (University of Perugia, Perugia, Italy): I want to point out some limitations of your investigation. You’re talking about PK, but you can’t really measure PK because the concentration of BIL that you report is not the free, biologically active insulin, but the total insulin, i.e. lispro bound to PEG which is not active. The total BIL insulin cannot be interpreted as “plasma insulin concentration” the way we traditionally use this parameter for example after NPH or glargine injection. So, your PK analysis for BIL is not valid, it is however for glargine. You also gave an unusually high dose of basal insulin, 0.5 U/kg for more than 1 weeks and this excess of basal insulin I am sure had to be compensated by reduction of prandial insulin dose and frequent snacking to prevent hypoglycemia. So, subjects were studied in metabolic conditions far from real life. Last, the total glucose infused over 24 h in response to same dose of insulin was much less with BIL as compared to glargine as to suggest that 1 unit of BIL is much less active than 1 unit of glargine, despite 1 unit of BIL contains 9 mmol of insulin which 50% more as compared to the 6 mmol in 1 unit of insulin glargine. Thus, the present formulation of BIL is not bioequivalent to glargine.

A: Your talk was nearly longer than mine! PK is not completely meaningful, but the comparison in variability may be meaningful even though the absolute levels are different. I agree that PD is more important, and PD was very much in line with PK. The 0.5 U/kg dose was higher than the dose patients used, which was around 0.3-0.4 U/kg because you need a higher dose to get a glucose infusion rate during the clamp, but we didn’t have lots of hypoglycemia.

Dr. Bolli: Thanks for agreeing that we can forget about the variability in PK, which wasn’t meaningful. You gave 0.5 U/kg of glargine, which resulted in high glucose utilization, higher than what people in real life need to regulate glucose metabolism in a post-absorptive state. My real point is that what you showed here is the difference in variability or potency of one unit of glargine vs. one unit of BIL. BIL is concentrated to 9 nM/ml and glargine is 6 nM/ml. Yet one unit of BIL was less effective than one unit of glargine.

A: I disagree. This is what patients will experience using equal units. It’s a fair comparison. This is the variability they will experience. There are limitations in all studies, but there’s not doubt that glargine’s variability is substantially higher with regard to both PK and PD. I think it’s very meaningful.

Q: Do you think we should use insulin glargine twice daily rather than once?

A: That’s a good point. Many type 1 diabetes patients do. It’s a very sensible thing to do, it’s just against the label.

Q: If I used BIL every other day, the variability would probably exceed the variability of glargine. It’s the ratio of frequency and half-life that matters. Was this study necessary, because it should be obvious? With a three-day half life, this should be expected. If it’s used less frequently, variability would go up.

A: I agree that the longer half-life should have advantages in variability. Glargine has a good time-action profile, but there are issues because it precipitates whereas others stay in solution.

New Insulin Glargine 300 U/mL Provides Sustained Glycemic Control and Reduced Hypoglycemia over 12 Months Compared with Glargine 100 U/mL in Japanese (98-OR)

Yasuo Terauchi, MD, PhD (Yokohama City University, Yokohama, Japan)

Dr. Yasuo Terauchi presented full-year results from the EDITION JP 2 study, which randomized 241 type 2 diabetes patients on basal insulin plus oral drugs to either Toujeo (insulin glargine U300) or Lantus (insulin glargine U100). At one year, both groups experienced comparable A1c reductions from baseline of around 0.3% from a baseline of 8%. The average daily dose of Toujeo was around 20% higher (0.36 U/kg/day vs. 0.30 U/kg/day), and the annualized rate of confirmed or severe hypoglycemia was significantly lower with Toujeo: 36% less (95% CI: 6%-56% less) at any time of the day, and 59% less (95% CI: 8%-82% less) nocturnally. Though the confidence intervals were wide, from the Kaplan-Meier curves there definitely did seem to be a benefit, particularly at night. Toujeo performed particularly well in this population from a body weight perspective, with 0.7 kg (~1.5 lbs) mean weight loss vs. 0.5 kg (~1 lb) weight gain with Lantus – seeing weight loss (as opposed to less weight gain) is unusual for a clinical trial with insulin, and the weight loss occurred regardless of whether patients were on a sulfonylurea at baseline, suggesting that reduction in sulfonylurea dose was not the culprit. All in all, we see EDITION JP 2 as contributing to the real differentiation for Toujeo vs. Lantus, although it is hard to get a great handle on the true degree of the hypoglycemia benefit due to the post-hoc slicing and dicing of those data. We see different factors resulting in success commercially for Toujeo including an intensive focus on access by Sanofi, increased attention on increasing adherence through COACH, and an easier-to-use pen (partly stemming from lower injection volume per unit). 

Safety and Efficacy of Insulin Glargine 300 U/ml (Gla-300) Compared with Other Basal Insulin Therapies in Patients with Type 2 Diabetes Mellitus (T2DM)—A Network Meta-analysis (NMA) (99-OR)

Hongwei Wang, PhD (Sanofi, Bridgewater, NJ)

Dr. Hongwei Wang presented a network meta-analysis of trials to indirectly compare Sanofi’s Toujeo (U-300 glargine formulation) with other basal insulins. Currently there are no head-to-head comparisons for U-300 against NPH, Tresiba, Levemir, or pre-mixed insulins. The network meta-analysis is a statistical tool used to integrate both direct and indirect evidence to make comparisons of U-300 glargine to these other insulins. We’ve seen more network meta-analyses at meetings as of late; for example, Lilly’s presented a network meta-analysis for Trulicity (dulaglutide) at EASD last year. The Toujeo analysis showed no difference in A1c change from baseline with U-300 glargine vs. comparators. However, rates of nocturnal hypoglycemia were significantly lower compared to U-100 glargine (Lantus), NPH, and pre-mixed insulin, as expected. Documented symptomatic hypoglycemia was also numerically lower on Toujeo compared to other insulins. Limitations of the study include that it utilized only study-level results, and the study populations and design characteristics might not be accounted for in the analyses. We do not believe these data add much new to the understanding of the safety and efficacy of Toujeo, but we imagine that Sanofi is interested in bolstering claims for Toujeo’s nocturnal hypoglycemia benefit since it was not able to include this claim in the label.

Improved Glucose Control Without Increased Hypoglycemia Risk at Any Level of HbA1c Reduction with Insulin Glargine/Lixisenatide Fixed-Ratio Combination (LixiLan) vs. Insulin Glargine Alone (169-OR)

Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Julio Rosenstock presented a post-hoc phase 2 analysis on Sanofi’s LixiLan (lixisenatide/insulin glargine) that found no correlation between A1c levels achieved with LixiLan and hypoglycemia risk. The 24-week study (n=323), presented at last year’s ADA, demonstrated striking A1c reductions in both the LixiLan and Lantus (insulin glargine) groups, with a slight but statistically significant advantage (1.8% vs. 1.6%) for LixiLan. While there was no difference between the groups in incidence of documented symptomatic hypoglycemia (≤70 mg/dl), the primary results did not indicate whether participants who achieved tighter control or larger A1c reductions were at increased risk of hypoglycemia. This analysis divided patients into subgroups based on their A1c at the end of the study (<6%, 6-6.5%, 6.5-7%, or >7%) and magnitude of A1c reduction from baseline (<1%, 1-1.5%, 1.5-2%, or >2%). Results showed no significant relationship between these parameters and rates of documented symptomatic hypoglycemia, challenging the traditional conventional wisdom that tighter control raises the risk of hypoglycemia – this of course has been seen in older outcomes trials like DCCT and UKPDS when far less stable insulins were used. The finding is not as surprising for LixiLan, as GLP-1 agonist/basal insulin combinations appear to come with a relatively low risk of hypoglycemia compared with insulin alone. It is definitely more surprising for the Lantus comparator arm, as more intensive control with insulin usually does mean more hypoglycemia. The lack of an increase in hypoglycemia with larger A1c reductions may speak to the skill of the study investigators – for now we would not necessarily assume that these findings are generalizable to less optimal settings although we do think that a more stable product like LixiLan would be associated with less hypoglcyemia.

Questions and Answers

Q: A number of observational studies have shown no association with hypoglycemia and baseline A1c, and large studies have been done recently. We think the lower we go, the more hypoglycemia we get. Why are we at that stage now?

A: I don’t know. We showed the same thing in ORIGIN. Regardless of baseline A1c, even if it’s 7.5% or 7%, that doesn’t mean people will have more hypoglycemia. If you drop 2%, it doesn’t mean you get more hypoglycemia. It’s very interesting. It may be a marker of other things.

Q: Were both groups pretty similar?

A: These are small numbers; when you split into so many groups you have 25-30 people per group, but that’s why they did all these trend analyses. They were very specific. Baseline A1c was a good predictor of subsequent A1c. You always say if you start at a higher A1c you get a bigger drop. Regardless of the drop, you eventually have a delta of 0.317.

Q: Are you sure the PK profiles of both are preserved or does glargine precipitate?

A: We have the PK/PD data and it’s pretty consistent. The formulation doesn’t affect PK.

Q: It looked like the insulin dose was the same. You didn’t save any insulin?

A: There was a little less insulin with LixiLan but not much. This was a very specific homogeneous population with early type 2 diabetes, which is why you saw that kind of response. We have other studies where we’ll see whether the difference is greater.

Unique Profile of the Weekly Insulin HM12470: Very Slow Onset of Action, Rapid Off-Rate Similar to Insulin, and Absence of Insulin Receptor Downregulation (96-OR)

Nina Wronkowitz (German Diabetes Center, Düsseldorf, Germany)

Dr. Nina Wronkowitz presented on the mechanistic profile of Hanmi’s novel basal insulin analog, HM12470, which has potential for once-weekly dosing given its long half-life (expected to be 132 hrs in humans). The candidate was recently advanced into phase 1 under the new name LAPSInsulin-115. Investigators in this study sought to characterize HM12470’s action at the insulin receptor, especially to allay any fears of mitogenic (cancer-inducing) activity due to HM12740’s very long half-life and the insulin receptor’s dual role in stimulating glucose uptake and in cellular proliferation. HM12470 showed a similar receptor dissociation rate compared to regular human insulin in a rat cardiomyoctye (heart cell) line overexpressing the human insulin receptor. HM12470 also had similar mitogenic activity and metabolic activity compared to human insulin. Uniquely, Dr. Wronkowitz reported that while regular insulin is known to cause downregulation of the insulin receptor in the chronic setting (>24 hrs), HM12470 does not induce insulin receptor downregulation, which suggests that each unit of HM12470 may have a more prolonged effect than each unit of regular insulin.

Questions and Answers

Q: What could be a possible mechanism for the lack of downregulation of the insulin receptor after exposure to this agent?

A: We have preliminary data showing that HM12470 is not internalized together with the insulin receptor after binding, so that’s the reason why the insulin receptor stays at the membrane and is not internalized and degraded. This could also be a reason for the very long half-life of HM12470.

PE0139, the First Recombinant Fully Human Monomeric Super-Long-Acting Basal Insulin to Display a Sustained Nearly Peakless Insulin Profile Following a Single Subcutaneous Dose in Subjects with T2DM Supporting Weekly Dosing (100-OR)

Poul Strange, MD, PhD (PhaseBio Pharmaceuticals, Malvern, PA)

Dr. Poul Strange outlined the results of a phase 1 single ascending dose trial (n=37; ClinicalTrials.gov Identifier: NCT01835730) of PhaseBio’s ultra-long-acting basal insulin PE0139 in patients with type 2 diabetes. PE1039 consists of native human insulin fused at the DNA level to an elastin-like peptide (ELP) polymer that allows for more gradual release and a longer duration of action. Participants were randomized to receive a single subcutaneous injection of either placebo or one of four doses (0.05-1.35 mg/kg) of PE0139 and were followed for 28 days to evaluate safety and tolerability. The trial also included secondary endpoints related to pharmacokinetics (PK) and glycemic control. Results showed that PE0139 was well tolerated at the doses tested, with mild injection site reactions the only notable adverse event identified. There were no concerning signals related to cardiovascular safety (such as increases in heart rate or blood pressure) and no indication of changes in liver enzymes. PK results showed that PE0139 was released at a relatively constant rate over the course of a week and produced significant reductions in fatty acids and fasting glucose. While Dr. Strange acknowledged that the study was too small to identify a clear dose-response curve, he stated that there were “real differences” between treatment groups and that the investigators were optimistic for future trials.

• PhaseBio plans to initiate a multiple-dose study of PE1039 in 3Q15 and is conducting preclinical experiments of the compound in combination with a once weekly GLP-1 agonist. The company announced in March that it had raised $40 million in Series C financing, which is expected to cover costs until the end of 2016. We assume that the potential GLP-1 agonist combination would involve PhaseBio’s once-weekly candidate PB1023, which was placed on hold as a monotherapy after failing to achieve non-inferiority vs. Novo Nordisk’s Victoza (liraglutide) in a phase 2b trial – we imagine that such a once-weekly GLP-1 agonist/basal insulin combination would be a very appealing option for many patients.

Questions and Answers

Q: How do you metabolize and excrete the biopolymer formulation of the microspheres? Do they break down subcutaneously or are they absorbed in the circulation?

A: They are self-aggregates that are slowly released but intact and then broken down. It might be a substrate for elastase. We haven’t done careful studies yet.

Q: Are they broken down in the circulation?

A: There or in the tissues. It stays around everywhere and gets excreted by the kidneys.

The In Vitro and In Vivo Pharmacology of AB101, A Potential Once-Weekly Basal Subcutaneous Insulin (97-OR)

Brian Roberts, MD (Mills-Peninsula Health Services, Emeryville, CA)

Dr. Brian Roberts presented preclinical results for AntriaBio’s once-weekly insulin AB101, a microsphere formulation of PEGylated human recombinant insulin. The formulation does not involve any modifications to the native human insulin structure, which Dr. Roberts highlighted as a potential safety advantage. In vitro studies of AB101 confirmed the expected binding kinetics at the insulin and IGF-1 receptors and demonstrated a pharmacokinetic (PK) and pharmacodynamic (PD) profile comparable to that of native human insulin. Dr. Roberts presented the results of a 14-day trial in rats (n=6 per group; 37.5 mg/kg AB101 or vehicle control) and dogs (n=3 per group; 10 mg/kg or 37.5 mg/kg of AB101) evaluating the effects of a single subcutaneous dose on insulin and glucose levels. Results showed a very flat effect on insulin and glucose levels over the first 24 hours after administration (the typical duration of action for current basal insulins) and then a gradual, sustained increase in insulin levels over approximately one week associated with a reduction in glucose; hypoglycemia was only present at the highest dose level for dogs. Dr. Roberts concluded that this data supports once-weekly administration of AB101 in humans at clinically relevant doses and that the slow onset should lead to improved insulin and glucose levels without the risk of hypoglycemia associated with an acute release of insulin. AntriaBio believes the smaller size of the AB101 PEG group should help AB101 avoid the degree of liver effects seen with Lilly’s peglispro (phase 3 data presented in this same session) – still, we imagine the company will be looking at liver safety and lipids very closely in clinical development given that it has created meaningful issues for Lilly.

• AntriaBio is currently conducting IND-enabling studies for AB101 and plans to submit an IND application in the near future. The company announced in January that it had raised $7 million in a private placement transaction that would enable initiation of a phase 1 trial in type 1 diabetes in 2H15, assuming the IND filing is successful. If all goes well, the company anticipates an approval by 2022.

Questions and Answers

Q: What are the key differences between AB101 and other approved basal insulins?

A: The key point is that AB101 is a formulated product and the extended duration is achieved through slow release. The PEGylation group is small, about 5 kD, and it has increased solubility in the polymer, allowing it to be injected and slowly released. It’s an elegant formulation that doesn’t require modification to the native hormone.

Q: In the non-diabetic animals, did you measure insulin levels at baseline?

A: The baseline was shown. The scale on the x-axis was hard to see, but the baseline levels were measured and were on the figures.

Oral Presentations: Assessing and Improving Adherence to Insulin Therapy

Does Insulin Adherence Decline With More Injections?

Ian Blumer, MD, (University of Toronto, Ajax, Ontario)

A provocative presentation from the charismatic Dr. Ian Blumer sought to demystify a thought-provoking question: Does insulin adherence decline with more frequent injections? Turning to geography for a lighthearted analogy, he suggested that the question may not be as straightforward as it appears, just as Mount Everest is not the world’s tallest mountain (that would be Mauna Kea in Hawaii, as Mount Everest is the world’s “highest” mountain). Similarly, Dr. Blumer suggested that there is more nuance to this debate than a yes or no answer. Taking on a behavioral view, Dr. Blumer suggested that there are other salient factors beyond injection frequency – such as patient-level motivation – that are at play when looking at adherence rates with injections. Indeed, in his view, it has not been definitely established that insulin adherence declines with more frequent injections (“though it probably does”). As a result, he advocated for providers to keep an open mind in thinking about the lurking variables (e.g., discomfort, inconvenience) that may drive lesser adherence. Ultimately, we appreciated this patient-oriented spirit from Dr. Blumer and applaud his effort to generate greater conversation about the psychosocial aspects of diabetes management. We are interested in HCP feedback to other questions about pens, like, if a pen is easier to use (less force), does his make a meaningful impact for patients? This seems to be the case for Toujeo and we’d love to understand any commercial benefit. We’d also love to better understand the degree to which oral drugs are delaying MDI – we certainly think they are but it’s hard to accurately forecast the degree to which this is happening.

Questions and Answers

Q: Does this question even make sense to begin with?

A: I think it does. I believe that we, as diabetes health care providers, often take it as a given that more frequent insulin injections in and of themselves increase the likelihood of missed doses without us first doing our due diligence and looking for –and addressing – other, modifiable factors that might be leading to missed doses; factors such as inconvenience or embarrassment giving insulin at work or school, injection discomfort, fear of hypoglycemia, and so on.

Q: Multiple injections are often synonymous with better control. However, can you argue that maybe MDI is not the best regimen?

A: I think that for our patients with type 1 diabetes, CSII or multiple daily insulin injections (MDI) are indeed far more likely to achieve better – and safer – control than using split-dose, mixed insulin therapy. For our patients with type 2 diabetes who require more than one insulin injection per day, MDI is also typically preferred over split-dose, mixed insulin. There is, however, a large subset of patients with type 2 diabetes who are on huge doses of insulin because of extreme insulin resistance – taking hundreds of units of insulin per day. For these patients I think it is far less important to tease out and fine tune the theoretical, minute benefits of one insulin regimen versus another and far more important to make sure the patients are getting enough insulin, however it is given. As I jokingly say, just pull up the dump truck and pour in the insulin!

Q: I do think that perhaps the number of injections is trumped by convenience and flexibility? Do you think we’re doing enough to help patients with diabetes?

A: Absolutely yes; many patients on MDI find it onerous to take the number of injections we ask them to and that they, ideally, ought to. I think that there are many patients on MDI who would be far better served by CSII and, in particular, would find it much more convenient to give boluses – including correction boluses – if they were on a pump. And even at that, using a pump is very labor-intensive and demands a great degree of hands-on patient effort in order to maximally benefit from it. As health care providers we ask so very much of our patients living with diabetes – all our patients with diabetes - and I think we have to be more sensitive to the demands we place on our patients and, moreover, we need to be more aware of the incredible work involved by the very fact of living with diabetes. So many patients are referred to me and within minutes of walking into the office for the first time they are in tears because they feel so incredibly burdened by an unremitting and pervasive feeling that their entire life revolves around their diabetes and its management. I can see the cloud lift as I tell them “we are going to change all that” and that “we will manage their diabetes around their life, not their life around their diabetes.” Better – and more convenient – therapies will go a long way to help us do this. I can’t wait for the artificial (bionic) pancreas to become routinely available. I believe this will be the single most life-changing and life-enhancing therapy for our type 1 patients (and many insulin-treated type 2 patients eventually) since the discovery of insulin.

Oral Presentations: Combining Basal Insulin and GLP-1 Agonists

Insulin Degludec/Liraglutide (IDegLira) is Superior to Insulin Glargine (IG) in A1c Reduction, Risk of Hypoglycemia, and Weight Change: DUAL V Study (166-OR)

John Buse, MD, PhD (UNC, Chapel Hill, NC)

Two years after taking the podium at ADA to present the strong results from the DUAL I study on Novo Nordisk’s GLP-1 agonist/basal insulin combination Xultophy (IDegLira; insulin degludec/liraglutide), Dr. John Buse returned to the podium to present the first phase 3 trial comparing Xultophy and class-leading basal insulin Lantus (insulin glargine). The study randomized 557 patients with type 2 diabetes already on Lantus + metformin to either intensify their Lantus therapy or switch to Xultophy. The results this time around were just as impressive as for DUAL I: after 26 weeks, Xultophy led to a 1.8% A1c decrease from a baseline of 8.4% to a striking final A1c of 6.6%; Lantus intensification led to a 1.1% reduction in A1c from 8.2% to 7.1%; the treatment difference was 0.6% and was statistically significant (p<0.001). Those who know the DUAL I data will know that the benefits do not stop there. Xultophy boasted a more than 3kg (~7lb) weight benefit vs. Lantus (-1.5kg [~3lb] absolute weight loss from baseline). Xultophy caused 57% fewer episodes of confirmed hypoglycemia (p<0.001) and a stunning 83% reduction in nocturnal hypoglycemia (p<0.001). There were also increases in certain quality of life metrics and 5.5 times more patients with Xultophy who achieved an A1c below 7% without hypoglycemia and weight gain. Incidence of nausea was below 4% throughout the trial; there were more subjects (58% vs. 51%) with adverse events but fewer severe adverse events with Xultophy. When compared beside new basal insulins that are struggling to show benefits vs. Lantus, these and other DUAL program results look quite compelling. We learned during Novo Nordisk’s analyst event at ADA (see our ADA Exhibit Hall & Corporate Updates Report) that the company will hold off on submitting Xultophy in the US until later this year, even though it has already resubmitted Tresiba (insulin degludec). This means that Xultophy is unlikely to become available in the US until late 2016 at the earliest.

• Q&A Highlights: Dr. Philip Home (University of Newcastle, Newcastle Upon Tyne, UK) and Dr. Naveed Sattar (University of Glasgow, Glasgow, UK) questioned whether DUAL V tested a fair comparison. Dr. Sattar noted that it was essentially a test of two drugs vs. one, although Dr. Buse made the good counterargument that it was a test of one injection vs. one injection. Dr. Home pointed out the potential for biased responses because DUAL V was open label – Dr. Buse pointed to DUAL II, a blinded trial in which Xultophy had similar efficacy. In response to a question of what to do in the sizable percent of patients that reached the maximum Xultophy dose, Dr. Buse speculated (after multiple disclaimers that what he was about to say involved very off-label use) that “creative” clinicians might double-dip from the same pen to achieve a higher maximum dose, especially because a >1.8 mg dose of liraglutide (Saxenda) has been approved.
• Study Design: DUAL V was an open label, randomized, phase 2b trial enrolling 557 type 2 diabetes patients for 26 weeks of treatment. Previous trials like DUAL I and DUAL II have compared Xultophy against one or both of its component drugs, whereas this trial was intended to shape clinical decision-making for providers of the many patients on Lantus that need improved glycemic control. Patients were randomized to either stay on Lantus, intensifying treatment as per a treat-to-target titration protocol, or to switch to Xultophy. The starting dose of Xultophy was pre-specified at 16 dose steps (16 U insulin degludec, 0.6 mg liraglutide) – as a result, a secondary goal of the trial was to confirm that switching patients from Lantus to Xultophy could occur smoothly and without greatly diminished glycemic control.
• Baseline Characteristics: Average age was around 60 years, average BMI was 32 kg/m², mean diabetes duration of 11-12 years, and mean A1c of 8.3%. All patients were on insulin glargine + metformin at baseline, with a mean pre-trial insulin dose of 31-32 U. 
• Efficacy Results:
  
  • A1c: From a baseline of 8.4%, the Xultophy group experienced a mean A1c reduction of 1.8%, reaching a strikingly low mean final A1c of 6.6%. By comparison, the group continuing and intensifying their Lantus therapy saw a change of -1.1% from a baseline of 8.2% to a final A1c of 7.1%. The difference in the A1c reduction was 0.6% in favor of Xultophy.
  • Fasting Glucose: There were no significant differences in fasting glucose over the course of the trial. If anything, at early points it seemed that the Xultophy group had a slightly lower mean FPG. The significance here is that patients were able to maintain glycemic control even when switching over to a 16 unit dose of Xultophy from their previous Lantus dose.
• Body Weight: Not only did Xultophy hold a 3 kg (~7 lb) weight advantage in terms of weight gain reduction over Lantus, patients on Xultophy actually lost weight (-1.4 kg [~3 lbs]) from baseline.
• Hypoglycemia: Patients on Xultophy had a statistically significant 57% lower risk of confirmed hypoglycemia than patients on Lantus (p<0.001). Even more positively for Xultophy, the combination led to a massive 83% reduction in nocturnal confirmed hypoglycemia (p<0.001) based on a smaller but still considerable number of events (195).
• Composite endpoints: In presentations of DUAL data, investigators have done a good job of showcasing Xultophy’s comprehensive benefits by presenting comparisons of the percentage of patients who achieve target A1c without hypoglycemia or weight gain. In this trial, 39% of patients achieved A1c targets with Xultophy vs. 12% with Lantus (p<0.001), for an odds ratio of 5.5.  
• Insulin dose: Patients in the Xultophy group leveled off at a mean dose of 41 dose units, whereas patients in the Lantus group experienced a continued climb, ending at 66 units at the end of the trial.
• Quality of life: Across the board in an SF-36 health-related quality of life questionnaire taken at the end of the study, Xultophy scored higher (or at least trended higher) than Lantus. The summary of physical quality of life showed a statistically significant difference in Xultophy’s favor, while the mental quality of life composite was a non-significant trend in Xultophy’s favor. More detailed quality of life data from DUAL V was published independently as a publish-only abstract (2550-PO).
• Adverse events: The rate of patients experiencing adverse events over the trial was higher with Xultophy than with Lantus (58% vs. 51%). Beyond noting that nausea was higher in the Xultophy group (though notably always below 4% - quite good given the GLP-1 agonist component), we did not get to see what else contributed to the imbalance. In contrast, the imbalance in serious adverse events tipped in Xultophy’s favor (3.9 vs. 6.7 SAEs per 100 patient-years).
  
  • In a qualitative description of adverse events, we learned that: (i) CV events were balanced between groups, with one stroke with IDegLira and one CV death with Lantus; (ii) There were no confirmed events of acute pancreatitis; (iii) There were two confirmed malignant neoplasm events with Xultophy and one treatment emergent confirmed event of metastatic pancreatic carcinoma in a subject previously treated with Xultophy; and (iv) there were no confirmed medullary thyroid carcinoma cases.

Questions and Answers:

Q: This seems to be a comparison of two drugs vs. one. Wouldn’t it be fairer to study IDegLira vs. insulin glargine plus liraglutide given separately, the way you have to give them currently?

A: There are other studies that have compared basal insulin + GLP-1 vs. basal plus bolus insulin. The difference in A1c in those trials was less, but the relative benefit for hypoglycemia was greater. I think this is a fair fight because we’re comparing one injection vs. one injection. The commonly used approach for type 2 diabetes is to just keep pushing the one injection. But yes, there is lots of room for many more studies.

Comment (Dr. Philip Home [University of Newcastle, Newcastle Upon Tyne, UK]): Few of us would treat patients failing glargine alone with glargine alone. It seems to be an irrelevant comparator. Isn’t there also a scientific problem with an open label study where you take some people on insulin glargine and move them to a new therapy? This could have impacted hypoglycemia and especially the quality of life questionnaire results.

A: There is a blinded study, DUAL II, where the insulin dose was capped and the primary goal was to examine the contribution of liraglutide. The results were similar in some ways, giving us reassurance that there can be meaningful results even in blinded situations. Secondly, the titration was conducted with equipoise and at the end of the trials the fasting glucose levels were essentially identical. Finally, in endocrine practices in the US and around the world, for patients with A1cs around the mid 8% range, the standard practice is to continue titrating insulin. I think this is a relevant comparison. That said, there is definitely room for further studies to examine other relative effects. Comparative effectiveness is going to be an important area for many years to come.

Q: In terms of patients at the maximum dose reached in treat-to-target, what options are there to keep pushing further with IDegLira?

A: The on-label use in this product, which is available in Europe, is that you would need to add something else. That could be an oral agent, but we don’t have many studies with SGLT-2 inhibitors combined with GLP-1 agonists, and certainly no studies of GLP-1 agonists, SGLT-2 inhibitors, and insulin combined on background metformin. Another possibility would be to add bolus insulin or more basal insulin. That decision would be based on patient characteristics. The off-label thing that one could … hallucinate, since GLP-1 doses higher than 1.8 mg are approved for obesity … one could have a very high-order hallucination about taking another dip on the same pen, continuing to increase the dose of the GLP-1 analog and basal insulin. But we have zero evidence on that. I know creative clinicians will find all kinds of things to do when a product is available.

Assessment of Glycemic Control by CGM in Patients with T2D Treated with IDegLira (170-OR)

Allen King, MD (Diabetes Care Center, Salinas, CA)

Dr. King presented the results of a post-hoc analysis of a DUAL I extension substudy examining changes in glycemic fluctuations over 52 weeks in insulin-naïve patients with type 2 diabetes treated with Xultophy (IDegLira; insulin degludec/liraglutide) (n=131) versus insulin degludec (n=64) or liraglutide (n=65) alone. 72-hour continuous glucose monitoring was performed at baseline and at 52 weeks, which showed that IDegLira treatment was associated with a greater reduction in mean interstitial glucose (IG) than liraglutide (p<0.0001), a greater reduction in postprandial IG versus insulin degludec (p=0.0288), and a greater reduction in time out of range versus liraglutide (p=0.0072). Dr. King commented that these observations may have contributed to the greater A1c reductions seen with IDegLira than with either component medication in the DUAL I study. For detailed information about DUAL I baseline characteristics and methodology, please see our coverage of the initial 26-week results presented at ADA 2013.

• IDegLira treatment was associated with a greater reduction in mean interstitial glucose (IG) than liraglutide (p<0.0001), a greater reduction in postprandial IG versus insulin degludec (p=0.0288), and a greater reduction in time out of range versus liraglutide (p=0.0072). Mean IG decreased 63.1 mg/dl, 64.9 mg/dl, and 45.0 mg/dl from baselines of 180-184 mg/dl with IDegLira, insulin degludec, and liraglutide treatment, respectively. Postprandial IG changed an average of -9.0 mg/dl, 3.6 mg/dl, and -3.6 mg/dl from baselines of 25-27 mg/dl with IDegLira, insulin degludec, and liraglutide treatment, respectively. Time outside of the IG target range (70-162 mg/dl) at the end of the study were 3.2 hours, 3.8 hours, and 5.6 hours from a baseline of 14-15 hours with IDegLira, insulin degludec, and liraglutide treatment, respectively.

Questions and Answers:

Dr. Philip Home (Newcastle University, Newcastle, United Kingdom): Nice study, and nice data. I just want to make a plea. These are supposed to be scientific sessions. There are things called standard deviations, confidence intervals, [etc.,] that would allow me to understand your data. Can we ask that that these have conventional measures of dispersion to go with the mean?

A: Some of the data was statistically analyzed, but the duration of the talk did not allow me to discuss them.

Superior Effects with Combination of Insulin Degludec (IDeg) and Liraglutide (Lira) (IDeg+Lira) Compared with Basal-Bolus Insulin Therapy (BB) in Hemodialysis (HD) Patients with Poorly Controlled Type 2 Diabetes (T2D): An Assessment by Continuous Glucose (171-OR)

Satoshi Funakoshi, MD, PhD (Jikei University, Tokyo, Japan)

Dr. Satoshi Funakoshi presented a unique study investigating the effects of GLP-1/basal insulin combination therapy on glycemic variability and control in 12 dialysis patients. For background, dialysis presents a challenge for glucose management because it can cause hypoglycemia. A potential mechanism to explain this effect is that glucose is cleared more quickly through the hemodialysis membrane than is insulin, so patients undergoing dialysis experience a temporary hyperinsulinemic state. Dr. Funakoshi’s study sought to compare the efficacy of basal insulin + GLP-1 agonist therapy (Tresiba + Victoza) compared to basal-bolus insulin therapy (Tresiba + Humalog) for controlling fasting plasma glucose and glucose variability in type 2 diabetes patients on dialysis. In this study, patients started on basal-bolus therapy and then transitioned to GLP-1/basal therapy. Glycemic variability was measured by CGM. As shown in the table below, during the basal-bolus portion of the study, patients experienced worse glycemic variability on days where they got dialysis (p<0.05 for mean amplitude of glucose excursions [MAGE] off vs. on). However, transitioning to GLP-1/basal therapy cut MAGE in half for both on and off dialysis days (p<0.05 for basal-bolus compared to GLP-1/basal), and the difference between on and off dialysis days was no longer significant. The GLP-1/basal combination also improved FPG. In conclusion, this small study suggests that the combination of insulin degludec and liraglutide can both improve glycemic control and glycemic variability in dialysis patients. This further bolsters GLP-1 agonists’ utility in patients with renal impairment, who may not be able to use therapies like SGLT-2 inhibitors or even metformin.

Table: Glucose variability (MAGE) and fasting plasma glucose (FPG)

	Off-dialysis days	On-dialysis days
Basal-bolus	MAGE = 108 mg/dL FPG = 166 mg/dL	MAGE = 133 mg/dL FPG = 145 mg/dL
GLP-1/basal	MAGE = 55 mg/dL FPG = 131 mg/dL	MAGE = 75 mg/dL FPG = 118 mg/dL

Questions and Answers

Q: The GLP-1 agonist label says not to use these drugs in people with renal failure. What is the PK of liraglutide in people on dialysis?

A: Insulin degludec and liraglutide are not removed by dialysis, and that is the point. The PK profile is not affected, as published last year.

Q: Did you look at the proportion of patients experiencing hypoglycemia both on and off dialysis?

A: We did not see any symptomatic hypoglycemia. During hemodialysis, the glucose drops not only because of the insulin issue, but also removing toxins improves insulin resistance peripherally. Removal of fluid improves over-hydration, which improves insulin resistance. pH goes up, which encourages glucose to go into cells. So all the factors push down glucose at the end of hemodialysis, but for some reason we did not experience symptomatic hypo.

Least Glucose Variability and Hypoglycemia Is Observed with the Combination of a GLP-1 Receptor Agonist and Basal Insulin (VARIATION Study) (167-OR)

Harpreet Bajaj, MD, MPH (LMC Diabetes and Endocrinology, Toronto, Canada)

Dr. Harpreet Bajaj provided interest-piquing if not completely surprising evidence that the combination of a basal insulin and a GLP-1 receptor agonist (RA) provides the least glycemic variability among several commonly used insulin regimens. The study enrolled 150 subjects (ages 18-80) with A1cs ≤7.5% who were on one of four stable diabetes regimens containing insulin for six months prior to the study (basal insulin + oral agent, basal insulin + GLP-1 RA, premixed insulin, MDI basal bolus regimen). In the six-day protocol, subjects continued their existing lifestyle and treatment regimens and were monitored with masked CGM as well as SMBG (≥4 times daily). A combination of a basal insulin + a GLP-1 RA resulted in significantly lower daily standard deviation of glucose than alternate regimens (SD = ~31 mg/dl vs. ~34 mg/dl with basal + oral agent, ~36 mg/dl with premixed, and ~38 mg/dl with basal-bolus MDI). Both the basal insulin + oral agent and basal insulin + GLP-1 RA regimens resulted in significantly lower self-reported hypoglycemia than the premixed or MDI regimens (basal + oral agent = 20% hypo rate, basal + GLP-1Ra = 17%, premixed = 35%, basal-bolus = 57%). Overall, the authors concluded that a combination of basal insulin + GLP-1 RA provides the least variability versus three commonly prescribed insulin regimens. While the difference in standard deviation was perhaps slightly more modest than we might have expected vs. MDI, but a ~20% improvement is still highly meaningful and could mean substantially less time at extreme ranges.

Synergistic Action of PE0139, a Super-Long-Acting Basal Insulin, and PB1023 a Weekly GLP-1 Receptor Agonist (168-OR)

Jim Ballance, PhD (PhaseBio Pharmaceuticals, Malvern, PA)

Dr. Jim Ballance presented pre-clinical data suggesting that PhaseBio’s long-acting basal insulin, PE0139, and weekly GLP-1 agonist, PB1023, could have synergistic effects when combined. For background, both agents use PhaseBio’s ELP biopolymer technology to prolong half-life. The GLP-1 agonist (PB) is in phase 2 and the insulin (PE) in phase 1. This db/db mouse study identified low doses at which PE and PB were inadequate as monotherapy for bringing glucose levels within control in response to an intraperitoneal glucose tolerance test. However, the combination of the two products normalized glucose control in a greater-than-additive fashion, even when using the same low doses of each individual component that were ineffective in the monotherapy arms. Synergistic (more than additive) efficacy has not been seen in the largest clinical trials of GLP-1 agonist/basal insulin combinations, although it is far from certain whether these preclinical results can be duplicated in humans. Dr. Ballance remarked that PhaseBio plans to commence a six-week phase 2 multiple ascending dose study with basal insulin PE in 2H15 with a PE/PB combination study to follow.

• For background, PE0139 and PB1023 use PhaseBio’s elastin-like polypeptide technology (ELP) to extend half-life. The ELP is a set of repeating five amino acid sequences (VPGXG where X is any amino acid except proline). The ELP polymer, when fused to a peptide of interest, confers a longer half-life to the peptide of interest by allowing the fusion product to undergo the process of “coacervation” under specific temperature and solvent conditions. Coacervation is a liquid-liquid phase separation, rendering the drug either available or not available to be absorbed. By varying the number of repeats in the ELP, the concentration of the protein, the concentration of salts in the solvent, and the hydrophilicity of the protein, one can control at what temperature the phase separation occurs and, thus, control the temperature at which the drug essentially becomes available to be absorbed. Thus, one mechanism by which ELP prolongs a drug’s half-life is via this slow, controlled release. The other mechanism is that ELP prolongs the protein’s circulatory half-life by reducing clearance from circulation.

Questions and Answers:

Q: Yesterday we learned [with Lilly’s basal insulin peglispro] that if you have a large hydrodynamic range, you get liver specificity with unwanted side effects. Did you test any of that with these insulins?

A: We haven’t studied it or seen anything yet but it’s something we will look out for.

Q: What happens to absorption if body temperature goes up or down [given that the effect of ELP is dependent on temperature]?

A: From a safety perspective, if the patient has an elevated temperature what will happen is the depot will be more stable. If you have someone plunging into an ice bath then that’s something one would have to look at. What we have studied so far is a prelude to longer study – we looked at what would happen if someone took the product directly from the fridge and injected it. There was no difference in PK there. It doesn’t matter if it’s cold when you inject it as long as it gets to the right temperature in your body.

Q: In the phase 2 study of your GLP-1 agonist, what did you see in terms of weight loss? I ask because the proportion of active moiety seems pretty small.

A: We didn’t see a big change in weight, but we also had liraglutide as a control arm, and we didn’t see weight loss in that group either. In any case, based on the protein’s structure, one would expect similar weight effects as dulaglutide or albiglutide.

Q: Have you looked into temperature variability systematically?

A: We have done one single ascending dose study so far. In the presentation yesterday, the error bars were very small so at least in that small group, it didn’t seem to be very variable, but we’ll obviously have to look at that going forward. The multiple ascending dose study is our next study.

Once-Weekly Combination of GLP-1R Agonist and Insulin (HM14220) Offers Improved Glycemic Control and Reduced Weight Gain Risk (172-OR)

Michael Trautmann, MD (Profil Institute for Clinical Research, San Diego, CA)

Dr. Michael Trautmann presented promising results from a series of early explorations of a novel once-weekly GLP-1/insulin combination from Hanmi Pharmaceuticals. Developed via the LAPSCOVERY platform, the compound is a combination of ^LAPS insulin 115 (phase 1 in the US), and efpeglenitide (HM11260C; an exendin-4 analog, phase 2b), which both have ultra long acting profiles suitable for weekly dosing. A combination of these compounds has shown similar PK/PD profiles to those of each product alone. When administered as a co-formulated once weekly product to diabetic rodents, the combination of ^LAPS insulin 115 resulted in greater A1c reductions than either product alone. Additionally, in a mild type 2 diabetes animal model, the weight gain seen with ^LAPS insulin 115 was neutralized by the combination product. Notably, in switching studies, switching diabetic mice to treatment with the ^LAPS combo after an initial 14 days of treatment with glargine resulted in significantly greater A1c decreases at six weeks versus either staying on glargine or switching to ^LAPS insulin 115. Similar results were seen in studies where mice were initially treated with liraglutide rather than glargine. These initial results are promising, as we feel a once weekly combination product could indeed improve adherence. We look forward to data from human studies on the topic, particularly to better understand how a once weekly product fares in face of every day glucose variations.

Posters

Liver Enzyme Results from 7 Basal Insulin Peglispro (BIL) Clinical Trials in Type 1 Diabetes and Type 2 Diabetes (989-P)

ML Hartman, S Zhang, E Bastyr III, AM Chang, SJ Jacober, and MJ Prince

This poster integrated liver enzyme data from phase 2 and 3 trials of Lilly’s basal insulin peglispro (BIL) where glargine was used as a comparator. As a reminder, liver enzyme elevation had been observed in BIL’s phase 2 program and was a cause for concern given the drug’s relative hepato-selectivity compared to other insulins. This study found consistent elevation of the enzyme ALT in both people with type 1 and type 2 diabetes at 26, 52, and 78 weeks. For background, ALT is a marker of liver inflammation and damage; it is a normal liver enzyme that can leak into the blood when liver cells are damaged. ALT elevation was evident within the first few weeks of treatment and persisted stably for the duration of treatment; it then trended back towards baseline after treatment discontinuation. In the type 1 diabetes trials, ALT hovered around 23 IU/L in the glargine arm compared to ~30 IU/L in the BIL arm. In the type 2 diabetes trials, ALT ranged from ~25-27 IU/L in the glargine arm compared to ~33-34 IU/L in the BIL arm. The investigators concluded that the ALT reversion towards baseline and the lack of cases of Hy’s Law (a criterion for more severe liver injury) suggests that there was no acute drug-induced liver injury. Generally the magnitude of ALT elevation was not egregiously large in the grand scheme of things. However we can see why investigators wanted to look into this further, as drug-induced liver injury is a serious and potentially fatal adverse drug effect and it isn’t clear the benefit is worth the uncertainty on a slew of questions. As such, we can understand why Lilly decided to further study peglispro’s liver effects and delay submission until at least 2017.

• For background, Lilly’s peglispro (BIL) is a basal insulin analog with relatively greater liver-selectivity than other insulins (which have relatively greater peripheral action), a flatter PK/PD, and a prolonged half-life (2-3 days). In phase 3 trials also presented in full at ADA, it showed superior A1c reductions compared to insulin glargine along with less weight gain. However, in both phase 2 and 3 trials, mean elevations in liver enzymes ALT and AST were also observed, suggesting the drug could be adversely affecting the liver.
• The analysis presented in this poster pools together liver enzyme data from seven trials of BIL vs. glargine. Three of the trials were conducted in patients with type 1 diabetes (one phase 2 and two phase 3 trials; n=1028 BIL and n=678 glargine) and four trials in patients with type 2 diabetes (one phase 2 and three phase 3 trials; n=2194 BIL and n=1464 glargine). Patients’ ALT, AST, alkaline phosphatase, and total bilirubin were measured at weeks 0, 4, 8, 12, 16, 26, 52, 65, and 78 as well as 4 weeks after drug discontinuation. Liver fat content was also measured by MRI in a subset of patients at weeks 0, 26, and 52.
  
  • For background on what each of these markers means: ALT and AST are normal liver enzymes that can leak into the blood stream when liver cells are damaged. Alkaline phosphatase is an enzyme normally found in bile canaliculi between liver cells that can back up into the blood stream if something is impeding bile flow from liver cells or out of the bile duct. Bilirubin is a normal byproduct of red blood cell turnover; it can back up if the liver is damaged and cause jaundice. Liver fat content is another marker for liver damage – when liver cells are damaged and lose the ability to oxidize fat for energy, fat can build up in liver cells.
• In patients with type 2 diabetes, BIL caused a slight increase in both ALT and AST. Mean baseline ALT was 28 IU/L and mean baseline AST was 24 IU/L. By week 78 on drug, ALT had risen to 34 IU/L in the BIL group compared to essentially no change in the glargine group (p<0.001), and AST had risen to 28 IU/L in the BIL group compared to no change in the glargine group (p<0.001). These elevations began soon after patients started taking the drug and persisted throughout treatment. The poster shows only ALT data for four weeks post-drug discontinuation, where mean ALT had come down to 30 IU/L.
• In patients with type 1 diabetes, BIL increased ALT but not AST. From a baseline ALT of 22 IU/L, patients on BIL rose to 29 IU/L after 78 weeks, whereas there was no change for patients on glargine (p<0.001). Again, the rise occurred soon after starting the drug and persisted throughout treatment. Four weeks after BIL discontinuation, ALT returned to ~24 IU/L.
• The authors suggest that the ALT reversion towards baseline suggests that the drug did not cause acute liver injury. Indeed, 100% of BIL-treated type 1 diabetes patients who experienced an ALT ≥ 3X the upper limit of normal (ULN) either returned to baseline or had a ≥20% decrease in ALT after discontinuing the drug. The corresponding figure for the type 2 diabetes population was 91%.
• The subset of patients who had liver fat content analyzed by MRI showed a roughly 1.5-2 fold increase of liver fat content between glargine and BIL (3% vs. 6% in type 1 diabetes, ~9% vs. 12% in insulin-naïve type 2 diabetes, and ~9% vs. 15% in type 2 diabetes patients previously treated with insulin).
• No patients met the criteria for Hy’s Law (ALT ≥3X the upper limit of normal plus total bilirubin ≥2X the upper limit of normal). Hy’s Law is a rule of thumb that predicts that a drug is at high risk of causing fatal drug-induced liver injury.

Lipid Changes During 26-Wk Treatment with the Novel Basal Insulin Peglispro (BIL) vs. Insulin glargine (GL) or Insulin NPH in 6 IMAGINE Trials (990-P)

H Ginsberg, B Cariou, T Orchard, L Chen, J Luo, E Bastyr III, J Bue-Valleskey, A Change, T Ivanyi, S Jacober, J Jacobson, B Hoogwerf

This analysis pooled data from 5,583 patients in six of the phase 3 IMAGINE trials (four in type 2 diabetes and two in type 1 diabetes) to examine the effect of Lilly’s basal insulin peglispro compared to insulin glargine (Sanofi’s Lantus) and NPH on lipid profiles. Individual phase 2/3 trials of peglispro have found potentially worrisome elevations in triglycerides (in addition to potential liver safety signals), prompting this analysis to more fully characterize patients’ lipid profiles. The authors compared the changes in apolipoprotein A-I, apolipoprotein B, free fatty acids, HDL and LDL cholesterol, and triglycerides after 26 weeks of treatment with the three types of insulin.  They found significantly elevated triglyceride levels with peglispro compared to insulin glargine and NPH, which varied depending on whether patients were insulin-naïve or not. In insulin-naïve type 2 diabetes patients (n=2,179), triglyceride levels decreased with insulin glargine and NPH but did not change with peglispro. In type 1 and type 2 diabetes patients (n=3,404) previously exposed to insulin, triglyceride levels were unchanged with glargine but increased 15-25% with peglispro. There were no significant differences in other lipid parameters examined (HDL and LDL cholesterol, apolipoproteins A-I and B). The results were not surprising, as elevated triglycerides have emerged as one of several potential safety concerns with peglispro as the IMAGINE trials have reported results. We see this as just one aspect of peglispro’s overall high-risk/high-reward profile and wonder whether the additional safety studies Lilly plans to conduct in lieu of a submission this year will investigate this signal  in addition to the concerns about liver toxicity. 

• The authors propose that the differences in lipid profiles could be tied to peglispro’s hepato-preferential properties. The authors suggest that the release of free fatty acids from adipose tissue, decreased lipoprotein lipase activity in adipose tissue, or increased hepatic de novo lipogenesis could contribute (separately or jointly) to the differences in triglyceride levels.

Efficacy and Safety of Technosphere Inhaled Insulin: Systematic Review and Meta-Analysis (96-LB)

G Westcott, E Balk, A Pittas

This systematic review and meta-analysis analyzed the efficacy, safety, and patient acceptability of Sanofi/MannKind’s recently launched inhaled insulin Afrezza. The analysis included 12 randomized controlled trials that met eligibility criteria (n=5,273). However, many trials were designed to demonstrate non-inferiority, which could lead to bias, and most were 24 weeks or less in duration, limiting the ability to draw conclusions about long-term effects. In adult patients with type 1 diabetes or insulin-requiring type 2 diabetes, the analysis found that Afrezza was slightly less effective than subcutaneous insulin at improving glycemia (net difference 0.16%; 95% CI 0.06-0.25%). However, Afrezza was associated with less weight gain (net difference 1.6 kg; 95% CI 2.1-1.6 kg) and severe hypoglycemia (odds ratio 0.61; 95% CI 0.35-0.92) compared to subcutaneous insulin. In patients treated with Afrezza, there was an increased risk of a mild, transient, dry cough (odds ratio 7.82; 95% CI 6.14-10.15) and a greater decline in FEV1 (a measure of lung function) (net difference 0.038 liters; 95% CI 0.049-0.026). Finally, those treated with Afrezza were more likely to discontinue participation than those treated with an active comparator. The study authors concluded that long-term safety data is needed and that subcutaneous insulin continues to be a better option for patients who can tolerate needles. While long-term data is clearly important, we do feel that the clinical appeal of Afrezza’s faster action profile, hypoglycemia and weight advantages, and ease of administration should not be underestimated. As of MannKind’s 1Q15 update in May, sales of Afrezza had gotten off to a relatively slow start, which the company attributed mainly to administrative issues like doctor appointment lags, spirometry scheduling, and prior authorizations. The product has generally had a very positive reception on social media since its launch, and we continue to believe it holds significant potential for a wide range of patients.

Improved Postprandial Glycemic Control with Faster-Acting Insulin Aspart in Subjects with Type 1 Diabetes Using CSII (994-P)

B Bode, L Hyveled, SC Tamer, P Ybanez, M Demissie

Dr. Bruce Bode et al. conducted a randomized controlled trial that evaluated the effects of Novo Nordisk’s faster-acting insulin aspart and standard NovoLog (insulin aspart) delivered via continuous subcutaneous insulin infusion (CSII). Over 14 days, this study measured two-hour postprandial glucose responses in 43 adult patients with type 1 diabetes. Following two hours, the Faster Aspart group had a significantly greater reduction in plasma glucose levels than the insulin aspart group in a direct comparison (a mean of -18 mg/dl, n=43, p<0.05). There was a trend towards a benefit in one hour post-administration as well (roughly -9 mg/dl), though it was not statistically significant. The preliminary indications of superiority in plasma glucose reduction and hypoglycemic duration complement positive data we’ve seen already and have led to phase 3 trials that are currently underway for evaluations of efficacy and safety in a larger sample population.

• The phase 1, double-blind randomized controlled trial compared changes in 2-hour postprandial glucose response in the faster aspart (n=43) and insulin aspart (n=42) groups via CSII. Their secondary objective evaluated the two formulations of aspart with regard to efficacy, safety, and pump-related endpoints after the 14-day trial period. The test study group had baseline and demographic characteristics with a mean age of 48, BMI of 27.0 kg/m², a 24-year duration of type 1 diabetes, and a starting A1c of 7.5%. Both groups were given a standardized meal and their mean plasma glucose levels were assessed continuously from 60 minutes prior to the meal to 240 minutes after the meal.
• The faster aspart group had a significantly greater glucose lowering effect than insulin aspart two hours after the standardized meal in a direct comparison (roughly -18 mg/dl, p<0.05). The secondary endpoint supported this finding at the 1-hour interval although this difference was not statistically significant (-9 mg/dl, p>0.05). Regarding safety profiles, the duration in hours of hypoglycemia was slightly greater in the insulin aspart group, although the difference was not significant at the <3.0 mmol/L level. In addition, no new safety issues occurred in both treatment groups.

Current Issues: Are They Really Worth It? Debating the Value of New Insulins in the Management of Type 2 Diabetes

New Insulins are Worth It

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

Dr. Richard Bergenstal argued in favor of the value of new insulins. After showing data indicating that on a national level patients on insulin are not achieving desired glycemic goals he argued that we can’t keep using the same insulins in the same ways if we want better glycemic outcomes. Following this, he provided an overview of some novel basal insulins (Novo Nordisk’s Tresiba [insulin degludec], Sanofi’s Toujeo [insulin glargine U300], and Lilly’s peglispro [BIL]) and bolus insulins (Sanofi’s Afrezza, Novo Nordisk’s Faster-acting Aspart) and what potential they have shown in PK/PD and phase 3 studies. Specifically, he highlighted how Tresiba and Toujeo provide similar A1c reductions vs. insulin glargine but have benefits in terms of hypoglycemia and flexible dosing. As noted multiple times in this report, we also believe there are additional benefits to Toujeo like better focus on access, the COACH behavioral program, and an easier-to-use pen, and we expect to see greater other benefits with Tresiba. Peglispro is associated with superior A1c reductions compared to Lantus, as well as less nocturnal hypoglycemia (see above for data we learned today on peglispro). Dr. Bergenstal ultimately argued that novel insulins should meet a triple aim of quality (based on A1c without hypoglycemia), patient experience, and cost. Dr. Bergenstal highlighted that CGM data may help us judge quality (via identifying lows, time in range, etc.) and also noted that we will need to make efforts to curtail the costs of insulin (via guidelines for selective prescribing, biosimilars, etc.) if current efforts don’t make needed insulins available.

• Dr. Bergenstal argued that we can’t keep doing the same thing with insulins if we want better results. Based on NHANES data, the percent of people with A1cs <7% hasn’t markedly improved over the last one to two decades among those with insulin. We thus need better insulin management – but questions remain about when to start, and how to adjust it, and deliver it.
• New basal and bolus insulins have potential for clinical value based on PK/PD profiles and phase 3 data, although ultimately they will need to be proven in the real world. For example, Tresiba has a long half-life, a flat profile, and four fold less variability than glargine.  Notably, although A1cs are similar with Lantus vs. Tresiba, the latter is associated with less nocturnal hypoglycemia and is compatible with flexible dosing. Toujeo is more concentrated than Lantus and has a significantly flatter profile. Like Tresiba, it causes similar A1c reductions vs. Lantus, but is associated with both less nocturnal and overall hypoglycemia. Peglispro is long acting with a flat profile, is associated with superior A1c reductions compared to glargine, and results in less nocturnal hypoglycemia (although total hypoglycemia was not reduced). Meanwhile, Afrezza and Faster Aspart have shown promise in PK/PD studies for their fast onset of action.
• Dr. Bergenstal suggested that new insulins (and in fact all novel drugs) fit a triple aim for healthcare delivery. This triple aim consists of: (i) Quality (based on A1c without hypoglycemia), (ii) patient experience (including safety, minimal side effects, and flexibility with regards to daily life activities), and (iii) acceptable costs. He noted that while we wait for more precise markers to guide diabetes therapy, CGM can help judge a patient’s response to a particular drug (i.e. how much time a patient is low each day, what percent of values is in range). The FDA should not shy away from CGM – it should in fact insist on it. In terms of cost, he noted that if new insulins cost more, they may end up being limited to high risk hypoglycemia. Other efforts to moderate the costs of insulins  (i.e. guidelines for selective prescribing, expansion of biosimilars, healthcare reform to improve coverage) may be needed if current efforts don’t make insulins available.

New Insulins are Not Worth It

David Nathan, MD (Massachusetts General Hospital, Boston, Massachusetts)

Dr. Nathan argued that the current enthusiasm for new(er) insulin analogs for use in type 2 diabetes represents a triumph of advertising over substance, as the promise of effective and safer insulins for type 2 diabetes has not been demonstrated and costs continue to escalate with no end in sight. This is not the first time we’ve heard Dr. Nathan voice a conservative opinion on the value of today’s new drug options, making him a great fit to take on this side of the debate. Though Dr. Nathan recognized that insulin analogs have PK profiles that more closely mimic human physiology than older insulins, he emphasized that the clinical evidence of the benefits of insulin analogs for type 2 diabetes has been limited. In various meta-analyses, insulin analogs have not shown a glucose-lowering benefit or reduced risk of severe hypoglycemia versus regular or NPH insulin according to Dr. Nathan – we do not believe that most trials resemble “real life” exactly and certainly believe there is a benefit away from NPH for certain subgroups in particular. Dr. Nathan commented that the main benefit of newer basal insulin analogs appears to be a reduction in nocturnal or nonsevere hypoglycemia; as such, he questioned the appropriateness of their use for broad swaths of the type 2 diabetes population, given the high costs of such analogs – Dr. Irl Hirsch (University of Washington, Seattle, WA) had a lot to say about the high costs of insulins on the first day of the meeting. We certainly do not believe that “one size fits all” and that less expensive insulins may well be adequate for some patients though some will not be able to deal with the relative lack of stability.

• Dr. Nathan posited that though the PK profiles of rapid-acting and long-acting insulin analogs mimic physiology more closely, they have not demonstrated significant clinical benefits in efficacy or reductions in hypoglycemia beyond older insulins in patients with type 2 diabetes. In a meta-analysis of 13 randomized controlled trials, rapid-acting insulin analogs only had an average A1c reduction of 0.09% beyond regular human insulin; severe hypoglycemia was rare and the difference in incidence was not statistically significant between the two insulin types (Monami et al., Diabetes Obesity Metabolism 2009). In a meta-analysis of 12 randomized controlled trials, there was no significant difference in A1c lowering or severe hypoglycemia between NPH insulin and long-acting insulin analogs (Monami et al., Diab Res Clin Pract 2008). Another meta-analysis found no clinically relevant differences between long-acting insulin analogs and NPH insulin (Horvath et al., Cochrane 2007). Dr. Nathan pointed out that there is no difference in overall hypoglycemia or severe hypoglycemia between insulin degludec and insulin glargine (Diabetes Care 2012). However in both meta-analyses of long-acting insulin analogs versus NPH insulins, long-acting insulin analogs were associated with a lower risk of nocturnal hypoglycemia – we see this as a benefit that is highly meaningful to patients.
• Though Dr. Nathan acknowledged that Sanofi’s inhaled insulin Afrezza has a better PK profile than insulin lispro, he concluded that it does not confer any significant clinical benefits beyond injected rapid-acting insulin analogs. Dr. Nathan highlighted that in clinical trials for Afrezza, the inhaled insulin was at best non-inferior to injected rapid-acting insulin, and it only managed to bring a small minority of study participants to goal (an A1c of ≤7%). He mentioned that analysts are skeptical that Sanofi can turn around the Afrezza launch – arguably it’s too early to assess the success of Afrezza’s launch – but noted there may still be a chance yet as direct-to-consumer advertisements are coming. From our view, the ability to get more patients and more HCPs to try more insulin is a positive.
• Dr. Nathan emphasized that the introduction of new insulin analogs has not driven costs down; on the contrary, insulin analogs experienced some of the biggest prices hikes of any drugs in recent history. This was the second major presentation we covered at ADA to address explicitly with the high cost of insulin – the first was Dr. Irl Hirsch’s presentation on the topic on Day #1. According to a FiercePharma analysis, the price of Lantus and the price of Levemir each increased 29.9% in 2015. Over the past five years, Levemir increased 169% in price, and Lantus increased 168%. A now well-known and much-cited Bloomberg piece noted that these price increases were in all-but-identical increments – when the price of Lantus went up, the price of Levemir followed shortly thereafter. Unfortunately, Dr. Nathan’s talk did not address the changes made in rebates by companies to pharmacy benefit organizations. As such, Dr. Nathan asserted that the idea that competition is going to lower prices does not seem to be working – we had heard that idea related to biosimilars, and we think it’s early to know – presumably insulin prices will certainly be reduced by it’s hard to know by how much. Dr. Nathan commented that pharmaceutical companies do not appear to be struggling financially – their profit margins are comparable to those of banks (~20%), which is more than the profit margins of carmakers, oil/gas companies, and companies in media. There is no question from our view that there is great variability across the board in this measure.  

Rebuttal

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

Dr. Richard Bergenstal said that both he and Dr. Nathan are in agreement about the need for good glucose control and affordability. He said that the field has made good advances in bringing down hypoglycemia considerably. However, it needs to take a broader patient centered view to help patients live the way they want. The field also needs to do better in terms of costs. He argued that companies could afford to keep innovating if they had a higher cost at the beginning that later comes down.

Panel Discussion

Q: If cost were not an issue, would there be a role for analogs in type 2 diabetes?

Dr. Nathan: It would be much easier to swallow; I’m offended by the price that goes along with them. I do want more tools to manage patients with diabetes, and there may be specific patients with schedules and lifestyles that require different insulin. I use and appreciate the variety, but it’s just that the hard data doesn’t support the costs. If they were to cost the same, I would be much happier.

Dr. Bergenstal: At the moment, they are looking at the right patients but there do seem to be benefits. If costs were equal, their market share would go up.

Q: It seems like with the human insulins, at least in DCCT and UKPDS, the patients treated more intensively had cardiovascular benefits. Do you know whether trials with analog insulins have shown cardiovascular benefits on scale with older insulins? Do you think analog insulins can be trusted for safety?

Dr. Nathan: Glycemia is very important, but glycemia achieved by drug X will have the same results as drug Y. The studies you mentioned were done with non-analog insulins. You would probably get the same results with analog insulins, but in terms of direct data, those were with older insulins.

Q: Have they been tested adequately for safety? We saw the first Lantus cancer issue many years ago. I think that testing of insulins has been adequate.

Dr. Bergenstal: Lantus had a large trial with ORIGIN. Degludec is in midst of large CV trial.

Q: I’m a nurse practitioner in a hospital setting and I’ve recognized that prices of insulin go up every year. I do have contracts with certain companies for both basal and prandial. In last couple of years, I’ve recognized the increased cost in insulin, and this year I got tired of it, and pushed hard, such that if I didn’t get pricing wanted, I would switch to a different company. What are we doing as a larger healthcare community in US to get prices down? Some patients to pay $500 per vial of glargine, some pay $300 per vial.

Dr. Bergenstal: I don’t think we’re speaking as one voice yet as a community. David mentioned the cancer community. There was a Sloan-Kettering group of oncologists saying that they were not paying for more expensive oncology drug, and the price was reduced. I think speaking as one voice, requesting insulins be provided at an affordable cost or copay so those who can benefit have adequate access to these important medications, will make a difference.

Dr. Nathan: Bill Harman is better suited to answer question than we are. The argument is that patients are insulated from the real price of the drug. Someone is paying for this stuff; with all deference for international visitors, the US pays for it because EMA and Canada negotiate. We have been very ineffective in pushing this agenda, and I think do need to be more effective.

Q: The reason why drug companies charge is because they can. There is absence of a regulatory environment that prevents them from doing so. Why hasn’t ADA as an organization pushed harder? What can the organization do? It isn’t doing much because there is a lot of drug company money that supports this meeting, but it seems like it should take a stand as an organization.

Dr. Nathan: Right on target. That’s why we’re not on leadership currently.

Dr. Bergenstal: The ADA, while not specifically advocating for lower drug costs,  has been pushing very hard for healthcare reform policies that are a great benefit to people with diabetes and in many case provide access to decent insurance coverage.

Q: I am a visitor from Saudi Arabia. Are there differences between traditional insulin and newer insulins in terms of effects other than hypoglycemia?

Dr. Nathan: There is a weight difference. When these results were first reported, detemir was shown to have less weight gain pretty consistently. In terms of site injection reactions, more concentrated insulins give more local site inflammation. I’m not aware of major other differences other than that.

Dr. Bergenstal: There are a few differences in the weight moderation, hypoglycemia, and schedule and life flexibility.

Q: Branded human NPH insulins have increased in price. Excluding Wal-Mart’s ReliOn, did the slide looking at price increases include NPH?

Dr. Bergenstal: Yes, human insulins have gone up as well.

Q: Have pharmaceutical companies provided reason as to why human insulin is more expensive?

Dr. Nathan: It’s the same human NPH insulin – manufacturing hasn’t changed one iota. In terms of rationale, I don’t remember children asking for rationale when asking for more money.

Dr. Bergenstal:  There is no generic or biosimilar. There was a period of time when you got into development, just like metformin, which was expensive in its day but not for long.

Q: I have a hypothesis for the reason that pricing is out of control: there are enough patients to go around for everybody. It’s a plot of net profit growing vs. people.

Moderator: He doesn’t have an answer.

Q: This is a comment for Dr. Bergenstal. Despite the anecdotal nature of some of the posters, if you go look at some of the posters addressing prediction of hypoglycemia, some of those directly address issues raised by Dr. Bergenstal. One issue is regarding new basal insulin, which is the only reason why there was a small but significant difference in nocturnal glucose. This has been published and advertised by companies. Fasting glucose is designated to be < 100 mg/dl in studies. Many patients who have insulin don’t need fasting insulin < 100 most patients see in clinic don’t need glucose of 90 fasting. By doing that in the studies you put the patients deliberately at risk to have hypoglycemia that they would not have otherwise. This is the question of how studies are designed.

Dr. Nathan: I agree; if it were designed to lower fasting glucose, we would be pushing harder on NPH night before. You’re going to either achieve that goal or you won’t and it raises the issue of whether you’re going to have more hypo overnight.

Dr. Bergenstal: Some of the recent targets in some of the Type 2 studies have been more 80-130 versus 90, which we have a hard time achieving in anyone.

Q: We’re lucky to have human insulin since the new analogs more expensive. Still today in type 2 diabetes, I think SMBG is the most important. In Germany it’s not so expensive; every German has to be insured. If you make less than 5000 euros per month, you have to have social public assistance. In Germany, the manufacturer has to pay back to social insurance so that new insulin is not more expensive than human insulin (aside from Tresiba). That is a strong position for the patients.

Dr. Nathan: We both agree that cost control is critical.

Q: Dr. Bergenstal has said that one of the ways to moderate costs is to have guidelines that would restrict it from patients where it is likely to be a cost deficit. Dr. Nathan’s talk suggested those types of guidelines are not going to be effective. Instead of not listing the drug, maybe professionals should restrict its use to a smaller group of patients, the same as the choosing wisely movement.

Dr. Bergenstal: I wouldn’t say the guidelines aren’t effective. They haven’t been written. Who are the high-risk patients and who is identifying them? It is incumbent upon them to identify who are good candidates.

Q: Is there a consumer demand for insulins? What has been the role for direct consumer marketing?

Dr. Nathan: Without disempowering the consumer from choosing medications that he or she may benefit by, one has to wonder whether TV advertisements or printed advertisements are the way to do that. You should discuss pluses and minuses with a healthcare provider, come to a solution, one that both patient and physician can live with in terms of their choice. The TV advertisements tend to be problematic.

Dr. Bergenstal: We need informed discussions with good material and shared decision-making. Let’s sit down with pros and cons.

Q: I’m from India. I think we have been extremely unfair to insulin-making companies in the world. When we go back to any scientific lectures, hypoglycemia is the biggest limiting factor in starting insulin. We are painting 76% reductions in nocturnal as completely irrelevant to this debate. We are painting the pharmaceutical industry as a villain. They cannot increase the price. If you took a bottle of milk so many years ago, it was a few cents, and now it’s a few dollars. They can increase the price. Every other industry can increase cost, but somehow we don’t take the cost of production into consideration when we say should insulin should cost less for poor people. We are criticizing insulin manufacturers as if they are the villain, even though they’re bringing new products which make life better. I think it’s a very unfair criticism of industry. Scientific issues we discuss like reduction in hypoglycemia, flexible administration, and good quality of life are important, so if the price comes at a premium, we have to accept it. We ask pharmaceutical companies to donate to conferences and research. Where will the money come from?

Dr. Nathan: I don’t work for pharma. I’m a physician and a researcher, and my goal is to provide the best possible care to my patients. Both of us agree it has to be accessible and affordable. My job is not to argue for the profit-making pharma industry. I don’t accept honoraria, and want to be able to speak unfettered for patients. Uncontrolled insulin pricing is unacceptable, and someone needs to speak out against it. I count many people who work in or with pharma as my friends, but I cannot abide by their pricing. Some people who need insulin to survive may not afford it.

Dr. Bergenstal: I hope you heard me emphasize three-fourths of my presentation on the benefits of newer agents in hypoglycemia risk and quality of life. But they have to be accessible. It can be done at a cost that’s reasonable.

Q: I work at the FDA and want to understand more what you mean by the phrase “added benefit.” For new insulins, what added benefits do you anticipate?

Dr. Bergenstal: I think less hypoglycemia is probably the biggest benefit. You want A1c to come down – it’s a tried a true marker, even though it’s derided now. You want good A1c lowering with less hypoglycemia. Can these new analogs provide those, and improve quality of life? The FDA could evaluate this more precisely by doing some continuous glucose monitoring in these studies, and sort out the amount of hypoglycemia that is severe or moderate. The problem with these trials is that the people who need these therapies the most aren’t in the initial trials. People at high risk often haven’t made it into the trial, and only get access later after drugs are approved.

Symposium: Costs of Medications for Diabetes

Changing Costs of Insulin Therapy in the US

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

Dr. Irl Hirsch took the stage to tackle the tough but very timely topic of the increase in insulin prices over the past decade. We heard him speak passionately on this subject at Keystone last year. He views the current scenario of skyrocketing copays or completely unaffordable out-of-pocket costs for insulin as unacceptable, especially given that prices have risen so sharply in the past decade and that three of the six drugs that have had the sharpest price increases in the past five years are insulins. Patient-level solutions include Walmart and Costco insulin for those paying cash and manufacturers’ support programs; he mentioned but did not endorse online international pharmacies. As bigger-picture solutions, he listed: (i) clinical guidelines that incorporate cost-benefit analyses, (ii) value-based pricing based on panel decisions (though he wouldn’t want providers who work with insulin companies to be excluded), (iii) allowing importation (which he recognized as unrealistic, and probably not in patients’ best interest anyways), (iv) educating more providers about human insulin, and (v) advocacy. On the latter point, he characterized the ADA and JDRF for arguably not doing enough direct advocacy work on insulin prices and access – former ADA President Dr. Mayer Davidson noted during Q&A that he tried to get the ADA to take on the issue 15 years ago but was turned down. Continuing to speak frankly, he shared results of an Access to Medicine ranking of the companies that best provide drugs to developing countries, noting that Novo Nordisk is high (#2) on the list, with Sanofi at #8 and Lilly near the bottom at #17. We applaud Dr. Hirsch for repeatedly taking on a topic that is so controversial and tricky to discuss comprehensively. We were not surprised that he received a few rounds of applause during his talk and Q&A. 

• During Q&A, Dr. Hirsch expressed a sense of disillusionment with coupon programs for new drugs. He noted that these programs help drugs “infiltrate” the market and lead to pent up demand for products that may or may not have the best clinical benefit, to the point that payers have a hard time saying no to price increases. He characterized it as a strategy that he refuses to buy into anymore. Also during Q&A, the conversation took on a more philosophical tone when an audience member quoted the Declaration of Independence that every American deserves life (in addition to liberty and the pursuit of happiness). He suggested that unbearably high insulin costs are potentially unconstitutional, in addition to being immoral.
• Dr. Hirsch began with an overview of the history of insulin pricing. Setting the stage with Drs. Banting and Best’s altruistic sale of their insulin patent for $1, he noted how insulin prices stayed fairly low for decades before starting to climb in the 1990s and early 2000s. In his view, however, nobody could have predicted the tremendous rise in insulin prices that followed from 2005 to the present.
• In an attempt to better understand the cost trends over the past decade, Dr. Hirsch drew a distinction between the different metrics for insulin pricing. He downplayed the significance of AWP list prices (the “ain’t what’s paid” price) due to its vulnerability to “fraudulent” manipulation. Even wholesaler prices have increased far more rapidly than the medical consumer price index. The “usual and customary” price paid at the consumer level is often unreasonable and may be rising even faster than list prices, with a disproportionate impact on uninsured patients who pay out of pocket.
• Digging deeper into the theme of insulin sticker shock, Dr. Hirsch noted that out of the 30 name brand drugs that have doubled in price over the past five years, three of the top six were insulins. Humulin U500 – which Dr. Hirsch has selected as a target before – was second on the list. Novo Nordisk’s Levemir (insulin detemir) and Sanofi’s Lantus (insulin glargine) were #5 and #6 on the list, respectively. Using goodrx.com price data, he cited a 508% increase in Humulin U500 between 2005 and 2015, along with sizable price increases in the same time period for Lilly’s Humalog (insulin lispro), NovoLog (insulin aspart), Lantus, and Levemir).
  
  • Just as worrying as the increase in price, in Dr. Hirsch’s view, is the way those increases have happened. He cited a Bloomberg article from earlier this year that received a great deal of attention on the parallel identical increases in price for Lantus and Levemir. He noted that these parallel increases occurred 13 times. However, when asked during Q&A whether this pattern should trigger anti-trust litigation, he did not comment one way or another. 
• Dr. Hirsch noted that insulin prices vary greatly across different geographies. He characterized this as a problem not just for the US, but also for manufacturers in terms of their reliance on one market for a large share of income.
• As an imperfect but necessary solution, Dr. Hirsch argued in favor of better training for new physicians on human insulin for type 2 diabetes – he did, however, stand more strongly by analog insulin for type 1. From his observations, many young residents have no experience with NPH or regular human insulin for type 2 diabetes. However, Dr. Hirsch suggested that for many type 2 diabetes patients, regular human insulin works just as well.   
• Dr. Hirsch did not voice confidence that the introduction of biosimilar insulins will be a true game changer for insulin prices. Although he acknowledged that they will attenuate some of the growth in prices, he noted that discounts vs. existing options are not expected to be very significant and that Sanofi and Lilly will both be entering the biosimilar field to recapture some of the share they might lose to the biosimilars.
• In addition to prices, Dr. Hirsch called out some of the more ridiculous practices he has seen from insurers regarding insulin. These include Medicaid’s resistance to paying for an insulin pen (vs. vial and syringe) for a patient who lost an arm to a sarcoma as well as strictly monitored one-at-a-time insulin vial dispensation, even if a patient is traveling. These practices, as well as skyrocketing out of pocket costs, are forcing patients to use regular human insulin in pumps and in some cases are even causing patients to ration their carbohydrate intake.

Questions and Answers (Expanded):

Dr. Mayer Davidson (UCLA, Los Angeles, CA): About fifteen years ago, a bunch of us became concerned about insulin costs. We approached the ADA to put that on their agenda – to go to congress on this. They turned me down and said that they had more important issues to deal with. As one potential source of optimism, in Germany insulin glargine is not so expensive because the government simply refused to pay. Now there are some pharmacies like Express Scripts that are negotiating and not paying what’s demanded, which may cause a small improvement.

A: The reason why Kaiser and Group Health have been so successful is by just saying no. For the most part we haven’t said no to the manufacturers. With coupon programs, new drugs infiltrate the patient population, leading to pent up demand that makes it harder for the payers to say no. It’s not a strategy I’m going to buy into anymore.

Q: We have a tremendous number of people on Medicare that we are taking back to NPH. We also recommend the Walmart ReliOn insulin. Most of our Medicare patients don’t realize that when they’re in the donut hole, they can fill out the low income subsidy form and, if they qualify, they can get scripts for $3 to $6. If they don’t qualify, they can get the letter of denial and apply for pharma assistance. But they have to fill out the form. Especially with U500, what is going on is absolutely shameful.

A: You’re absolutely right about the Walmart ReliOn insulin.

Q: When we worked together on the first articles we wrote in Clinical Diabetes, we predicted that new analog insulin would vastly increase the cost of insulin. The situation is getting much worse. In Georgia, we were telling patients to go to Walgreens and through the buyer’s club they could get regular human insulin cheaper than at Walmart. The Feds discovered it and then said that Medicare patients can’t use the out-of-pocket service. Now they have to put their purchases through Medicare Part D. The problem is that with high deductible insurances, this is going to become more widespread. Do you think that the rise of PBMs such as Express Scripts may buffer that?

A: I don’t really have any direct contact with Express Scripts or any of the PBMs, so I can’t even speculate about that.

Q: Do pharma companies lose money when they market and sell to countries in the EU where they sell at lower prices? You showed the graph with the price increases – it looks suspiciously like price fixing. Do you have any idea if there is potential for antitrust legislation kicking in?

A: I never wanted to be a lawyer or work with one, so I can’t comment on the second question. It will be interesting to see how prices change when biosimilars come to bear. We also don’t have patients screaming about the costs of strips like they were five years ago. When the government got involved, everyone started generally paying less for strips. Something like that may happen here. And I’m not sure if insulin companies make money when they charge less. There is no transparency there. [Editor’s note – we would like to better understand rebates in this argument.]

Q: We are all responsible for the lives of the patients we see. In the 18^th Century when our country was coming together, the Declaration of Independence called for life, liberty, and the pursuit of happiness. The lives of Americans, and people around the world, are now dependent on money for a product they need to save their lives. This is immoral, illegal, and should never be practiced. [applause]

A: Thank you for your comments.

Biosimilar Insulins – How Will They Be Regulated and Marketed?

Lutz Heinemann, PhD (Science & Co., Düsseldorf, Germany)

Dr. Lutz Heinemann spoke comprehensively about biosimilar insulins, which stand to shake things up following years of a stable insulin market. Starting with regulatory topics, he argued in favor of harmonizing biosimilar regulations around the world, as currently there is a great deal of variation (including many countries with no laws on the books about biosimilars). He cited his group’s recent article surveying the biosimilar regulatory landscape. On the key issue of how biosimilars will be priced, he collected and averaged different forecasts for biosimilar insulin price reductions, coming up with ~35%. However, 35% off the estimated $32 billion insulin market in 2019 would be $11 billion, and Dr. Heinemann expressed uncertainty whether manufacturers would tolerate such a step down in revenue. From our view, presumably next-gen insulins and basal insulin/GLP-1 combinations would not go down in price. In a review of different stakeholders’ views on biosimilar insulins, he cited a common lack of comprehensive understanding on the part of patients and prescribers. Both groups may feel hesitant to embrace switches to biosimilars without being at least consulted because the move would be for cost savings rather than clinical benefit. New pens or dosing practices with biosimilars may lead to confusion, and if patients have a bad experience with a biosimilar it may undermine their trust in both biosimilars in general and in their caregivers. Clearly, a high-stakes game!

• One of the most illuminating portions of the presentation, in our view, was a review of perspectives on biosimilar insulins across a range of stakeholders:

Patients	Love-hate relationship with “their” insulins Limited understanding of the topic – why switch? Wary of moves to save money that don’t involve them or at least consult them Risk of confusion: new product names, new pens (dosing errors) Bad experience could mean lost trust in physician and/or healthcare system
Physicians	Limited understanding of the topic – why switch? Longstanding cooperation with insulin manufacturers – most have had good experiences Wary of moves to save money without involving them Risk of confusion with new names and pens Potential safety concerns?
Insurers	With recent increase in costs, even small reductions in price could mean large savings They have experience with saving money on strips, so why not insulin? Could this lead to a race to the bottom? Will they force switches? Low prices may look attractive at first glance, but how will manufacturers invest in new research?
Manufacturers	Not willing to reduce biosimilar price much due to high investments in regulatory approval, more costly manufacturing process vs. generics Established manufacturers will reduce prices to maintain share If the decreases in prices are too great, some manufacturers may withdraw Will the increase in the global market counterbalance the price reduction?

• Cost savings from the price of biosimilar insulins may be counterbalanced by other factors. Dr. Heinemann noted that biosimilars my drive greater usage of pens for insulin administration, which are likely to be more costly per unit than vial and syringe insulin. Efforts to educate patients and physicians about biosimilar insulins and potentially new pens/devices will come at some cost. Patient confusion (potentially leading to inaccurate dosing) has its own cost. If biosimilars are not properly quality checked, decline in metabolic control or side effects from subpar products would further chip away at costs savings.
• In line with Dr. Irl Hirsch, who spoke before him, Dr. Heinemann does not believe that biosimilars will overtake the market, at least not unless governments take big steps to help them. He wondered aloud whether insulins could be subjected to a bidding process like CMS competitive bidding for test strips – he did not come out strongly one way or another, but noted to “be careful what you wish for.”
• Dr. Heinemann issued a call for action regarding the regulatory approach for biosimilar insulins. Currently, different regulatory approaches mean different levels of safety between countries. He thinks harmonization is needed to ensure that people across geographies have access to safe insulins. Furthermore, he is not sure that today’s guidelines for biosimilars answer the full range of clinically relevant topics – he would advocate for clinical trials with head-to-head comparisons. Finally, Dr. Heinemann would like to see registries to help evaluate biosimilar insulins once they are on the market.
• Dr. Heinemann discussed the status of biosimilar insulins in a few geographies where they are more available:
  
  • India: Insulin copies have been on the market for years from a number of companies, though there have been scandals due to bad quality products. Because of these scandals, patients have relatively little trust in manufacturers and insulin copies have been slow to enter the market. Price differences between branded and copied insulins are minimal due to low pressure from payers, although the baseline for branded insulin prices is lower in India.
  • Latin America: Here, governments buy insulin in tenders, meaning that insulin access changes every few months. In Mexico, an insulin glargine copy marketed by Gan Lee is available.

Global Pattern of Cost of Branded and Generic Drugs

Richard Pratley, MD (Florida Hospital – Sanford-Burnham Translational Research Institute, Orlando, FL)

During his presentation, Dr. Pratley compared the costs of branded and generic diabetes medications across countries and examined how local regulations can impact drug pricing. He explained that European countries are more able than the United States to control drug pricing, because they have centralized regulatory authorities in place to tend to this matter. As a result, diabetes medication costs only accounted for 5.4% of direct medical expenditures related to diabetes in the United Kingdom, whereas they accounted for 12.9% of direct medical expenditures related to diabetes in the United States (The Economist 2007). In closing, Dr. Pratley stated that pharmaceutical pricing is highly complex, with many key stakeholders and little transparency; as such, prices are lower where there is clear regulatory oversight.

• Dr. Pratley explained that the average wholesale price (AWP) can be thought of as a list price or sticker price that can be used as a starting point for bargaining. A benchmark that has been used for more than 40 years, the AWP is a price set by the manufacturer in collaboration with publishers. It is not defined by the government, and does not include discounts or rebates, which can reduce the price significantly.

Questions and Answers

Q: What’s the answer to this problem? Is it generic formularies? Is it better negotiations with pharma?

A: It’s pretty clear a market-based approach like we follow in the US is not the optimal approach to deliver high quality medications to our patients. We pay more money for our medications than any other country in the world, perhaps unfairly. Increasingly there are going to be pricing pressures coming through different channels, including employers. They’re going to demand generic medications, step care as they already do, and an explanation of the value of more costly and brand medications – what the value proposition is for a drug that costs 10 times that of a generic.

Regulation and the Economics of Drug Development

Joseph DiMasi, PhD (Tufts University, Boston, MA)

During his presentation, Dr. Joseph DiMasi discussed drug development and regulatory approval time trends, FDA review division productivity, and biopharmaceutical R&D costs. He noted that diabetes compounds approved from 2000 to 2014 got to market quicker, on average, than new drugs in general, but that the development times and number of subjects in clinical trials for diabetes medications has been increasing (largely due to the 2008 cardiovascular risk guidance, though he did not stress this point too heavily). In his analysis of FDA review division productivity, Dr. DiMasi found that productivity was only slightly below average for the metabolism and endocrinology division. Dr. DiMasi presented data showing that R&D costs have increased each decade since the 1970s, which he found to be due largely to increased clinical development costs, and to a lesser extent, due to a recent drop in the success rate of drug development (from 1995 to 2007, only ~12% of drugs that entered clinical development gained FDA approval).

• The average time required for clinical development of diabetes medications increased 1.6 years following the 2008 cardiovascular risk guidance. For the eight diabetes medications approved by the FDA from 2000 to 2008, clinical development took an average of 4.7 years, whereas for the nine diabetes medications approved from 2009 to 2014, clinical development took an average of 6.3 years. Dr. DiMasi noted that for drugs approved between 2000 and 2014, clinical development of diabetes medications took less time on average than drugs for other therapeutic areas – 5.7 years versus 6.8 years overall.
• For FDA drug approvals between 2000 and 2014, regulatory review took slightly longer for diabetes medications than for other therapeutics (16.9 months versus 15.2 months overall). Notably, he highlighted that none of the 17 diabetes medications approved between 2000 and 2014 received FDA priority review status, whereas more than half of all antineoplastic, AIDS, endocrine (excluding diabetes), and anti-infective therapies received priority review during this time period.  

Questions and Answers

Q: I have a question about the clinical development costs. It seems like that’s the major contributor to increased cost of drug development. It seems to be driven by the number of subjects primarily. Is that related to the new regulation for cardiovascular outcomes assessment, or what seems to be driving that?

A: In part. The results of other data you can look at show that clinical trial complexity has increased over this period of time, more is being done, more procedures in particular, and more protocol amendments. Another major driver of increase in cost actually is the high failure rates for drugs entering the clinical pipeline. You now have more failures per approval.

Q: If I asked you to look in your crystal ball, what do you see in the future? Are there any trends developing that may bend some of these cost curves?

A: I think in the short term costs will probably increase. There is potential for significant change in the future called personalized medicine, which may play a bigger role in drug development where science reaches the point that we can have good predictors of who will respond. If you’re able to get a good idea of who is going to respond on a per compound basis, it can certainly reduce the cost.

Comment: I was astonished by the lack of priority reviews for type 2 diabetes therapeutics. I think people need to understand diabetes kills people. The number of years lost in total for diabetes is pretty similar or even higher than years lost for cancer. That should be mentioned to people to understand that issue.

A: I absolutely agree that the burden of disease is quite high.

Q: When you look at the growth of cost in R&D in the pharma industry, have you compared it to R&D costs in other industries? What’s unique about the pharma industry?

A: What is maybe unique is that it is the most heavily regulated industry. I’m not saying it shouldn’t be, but that’s just the fact of life. There are enormous health and safety regulations, as well as economic regulation (mostly abroad). Also, it’s just a very, very long and risky process. I’m not sure there is any other industry with all those elements together.

Symposium: Effect of Intensive Insulin Therapy on Patients with Newly Diagnosed Type 2 Diabetes

Effect of Intensive Insulin Therapy on Patients with Newly Diagnosed Type 2 Diabetes

Longyi Zeng, MD, PhD (Sun Yat-Sen University, Guangzhou, China)

This presentation reviewed several studies demonstrating the beneficial effects of short-term intensive insulin (STII) therapy on patients with newly diagnosed type 2 diabetes. Previous studies led by investigators in China and elsewhere in East Asia have shown that, when implemented early in the course of type 2 diabetes mellitus, treatment with intensive insulin therapy for two to three weeks can induce a glycemic remission, wherein patients are able to maintain normoglycemia without any anti-diabetic medication. In a 2014 meta-analysis published by the journal Lancet, the proportion of participants in drug-free remission was about 66% after 3 months of follow-up, about 59% after 6 months, about 46% after 12 months, and about 42% after 24 months.

• China Expert Consensus STII Therapy Guidelines recommend that newly diagnosed patients with type 2 diabetes, who have an A1c of >9% or a FPG>11.1 mmol/L participate in short term insulin therapy. STII therapy could take the form of basal plus prandial insulin, continuous subcutaneous insulin infusion (CSII), or premixed insulin taken two or three times a day. There is still no clear consensus about the most appropriate endpoints for initiating treatment and how long to maintain STII therapy after normalization of glycemia.
• There are still several unanswered questions and challenges: Notably, there are barriers to implementing this program to primary care settings. Although endocrinologists are often the most comfortable initiating STII treatment, they are not likely to make the initial type 2 diabetes diagnosis. As a result, systems need to be put into place training primary care physicians and key support staff to initiate this treatment. Additionally, it will be exciting to see whether STII will reduce overall health cost by improving long-term glycemic control and thereby reduce the overall microvascular complications.
• Since STII is a relatively new option for patients with type 2 diabetes, more efforts are needed to educate practitioners and patients about the potential risks and benefits of the treatment.

Questions and Answers

Q: The shortage of diabetes educators limits the universality of this program in China. Would it be the nurses or doctors who implement this program?

A: I think that diabetes education is not only the responsibility of doctors or nurses. We have to share the responsibility of diabetes education. The other thing is that it is very busy in the offices of doctors and nurses, so we have to use some newer technologies such as web apps.

Q: How early should you start STII?

A: Open to investigation.

Symposium: The Impacts of Hypoglycemia in Diabetes

Common Mistakes in Using Insulin: Hypoglycemia Risk and A1c

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

Dr. Geremia Bolli began his lecture by discussing the challenges of insulin therapy, which he believes is “more of an art than a science.” He reviewed several current limitations, including the narrow time window in which insulin should be delivered and the non-physiologic nature of subcutaneous delivery. Dr. Bolli highlighted the relationship between A1c, severe hypoglycemia and complications seen in the DCCT, arguing that sometimes providers might need to set a more ambitious A1c goal to prevent complications but other times they may need to allow a higher A1c value in order to prevent hypoglycemia. He focused the remainder of his talk on insulin mistakes, referencing research that attributes 9.2 percent of emergency department visits to insulin-related hypoglycemia and errors (Geller et al., JAMA Intern Med, 2014).  Dr. Bolli listed clinician errors, self-administration errors (including injection in lipo-hypertrophic areas), using the wrong insulin, self-monitoring errors, and miscalculations as just a few of many errors with life-threatening consequences. Dr. Bolli concluded with strong recommendations to reconcile the current limitations of insulin therapy with A1c goals while preventing mistakes. He urged providers to individualize glycemic targets and argued that we should devote more resources to education than to new technologies and insulin preparations; he believes education and time spent with patients are among the most important factors in remedying this problem.

Corporate Symposium: Addressing Postprandial Glucose Excursions in T2DM with Inhaled Insulin (Supported by Sanofi)

Current Thinking: Glucose Control and Postprandial Hyperglycemia

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

Dr. Irl Hirsch discussed the important contributions of postprandial hyperglycemia to diabetes pathology, which he argued are somewhat overlooked in current guidelines. He explained that it would theoretically make sense to target postprandial glucose earlier in the type 2 diabetes treatment algorithm given the strong association with cardiovascular morbidity and mortality in past studies. Additionally, there are already significant postprandial excursions that occur by the time fasting glucose is elevated. However, he then reviewed the evidence that led to the establishment of basal-only regimens as the standard way to initiate insulin therapy in type 2 diabetes – namely, the significant hypoglycemia that occurs with current rapid-acting insulins. He also referred to results from the HEART 2D study that challenged the connection between postprandial hyperglycemia and adverse outcomes by showing no difference in CV risk with prandial vs. basal insulin, though he noted that the difference in postprandial control between the two groups was quite small. Based on this somewhat conflicting evidence, Dr. Hirsch suggested that the field can either abandon the theory that addressing postprandial hyperglycemia improves outcomes or find better tools that do not cause hypoglycemia – not surprisingly, he would prefer the latter approach. Dr. Hirsch has taken a leading role in collecting better data on the independent effects of glycemic variability in diabetes, including the FLAT-SUGAR trial presented at this very meeting.

• During his talk, Dr. Hirsch also highlighted an unpublished ACCORD analysis of mortality risk with various medications. The analysis was originally performed in response to the rosiglitazone (GSK’s Avandia) scare, and it did not find any association between either rosiglitazone or pioglitazone (Takeda’s Actos) and increased mortality. However, it did find a significant ~25% increase in mortality with prandial and premixed insulin, supporting Dr. Hirsch’s hypothesis that the excess hypoglycemia produced by existing rapid-acting insulins may lead to negative long-term outcomes. On a more positive note, the analysis also found a significant reduction in mortality risk with exenatide – an intriguing signal that begs further investigation in a long-term prospective trial (as we understand it, most ongoing CVOTs of GLP-1 agonists are likely not powered to detect such a benefit). Of course, a major caveat is that these results came from a post-hoc analysis that (according to Dr. Hirsch) the investigators concluded was not robust enough to publish. Patients treated with insulin, for example, are likely to have been at poorer control or have more longstanding diabetes, on average, which could explain the increase in mortality seen. However, analyses like these do raise some important questions about the potential impact of various type 2 diabetes drug classes on long-term outcomes.

Management of Postprandial Hyperglycemia with Insulin

Bruce Bode, MD (Atlanta Diabetes Associates, Atlanta, GA)

Dr. Bruce Bode discussed the potential of Sanofi/MannKind’s inhaled insulin Afrezza to address the need for more therapies to treat postprandial hyperglycemia. Echoing the sentiments from Dr. Irl Hirsch’s talk in the same symposium, Dr. Bode explained that the risks of hypoglycemia and weight gain, the inconvenience of multiple daily injections, and the stigma associated with insulin are all major challenges with current rapid-acting insulins, and there is a clear need for more effective options. He downplayed the past concerns about Pfizer’s less-than-successful previous inhaled insulin Exubera to some extent, suggesting that the primary issue was flawed marketing. Dr. Bode then reviewed clinical trial data showing a fast-on, fast-off profile, strong glucose-lowering efficacy, and improvements in weight and hypoglycemia with Afrezza. He characterized the product as safe and well tolerated, suggesting that the transient cough at the beginning of treatment is the main issue for patients and stressing that pulmonologists are “not concerned” about any effects on pulmonary function. Overall, Dr. Bode believes Afrezza should hold great appeal for many patients, particularly those who dread insulin injections. He also suggested that Afrezza could be particularly appealing in combination with an ultra-long-acting basal insulin like Sanofi’s Toujeo (insulin glargine U300) or Novo Nordisk’s Tresiba (insulin degludec). Uptake of Afrezza has been modest since its launch in February, and this appears to be largely due to administrative and logistical issues like spirometry scheduling and prior authorizations, and we believe the future potential is still quite high.

Panel Discussion

Richard Pratley, MD (Sanford-Burnham Translational Research Institute, Orlando, FL), Irl Hirsch, MD (University of Washington, Seattle, WA), and Bruce Bode, MD (Atlanta Diabetes Associates, Atlanta, GA)

Q: I have a patient who is 77 years old who was diagnosed at the age of 60. His C-peptide is undetectable, and he has a BMI of 23 kg/m². So he’s non-obese and has beta cell dysfunction. He was using an insulin pump, but he needed to switch since he has severe dementia. There is a clear pattern – his sugar goes up to almost 300 mg/dl 2-2.5 hours after a meal, then goes really low before the next meal, despite dropping the Levemir down to 2 and 6 units. I’m suspicious there may be an issue with gastric emptying – he has rapid gastric emptying. I’m labeling him as having type 1 diabetes, and treating as if he has type 1 diabetes. What do I do? Do I add GLP-1? Acarbose? Inhaled insulin?

Dr. Hirsch: First of all, you have to be very careful about gastric emptying studies. The nature of the study is that it has to do with glucose levels at the time. It can be extremely misleading. The other thing is that your patient most likely has type 1 diabetes. JDRF now estimates that half of people with type 1 diabetes are diagnosed as adults. If you wait too long, you’re not going to find antibodies. You can have type 1 diabetes for decades and still have a bit of C-peptide. It’s not as discriminatory as you think in terms of sensitivity or specificity. The real challenge is with timing of the prandial insulin. If there were no cognition issues, I would get the patient on the sensor and tighten his control. The reason it is so tough is that the dose of insulin is important, but the timing of prandial insulin is as important if not more important. That’s really the issue.

Dr. Bode: The benefit of inhaled insulin is that it doesn’t cause that much hypoglycemia – it’s fast in and fast out. Could this person do this? You’d have to try it and see what happens. If it works in your clinic, he can go home and try it. Right now, he’s going low and high and he’s a mess. You’re looking at assisted living for him. This guy has type 1 diabetes. Acarbose or GLP-1 would certainly suppress glucagon, but for someone like that, you still have to take rapid-acting insulin.

Q: If you were in my shoes, would you try giving him a GLP-1?

Dr. Bode: Because his BMI is 23 kg/m², no. If he had a BMI of 35 kg/m², I’d try it.

Q: If a patient inhaled insulin and then coughed, within how many seconds can you see that the dose is OK and does not need to be repeated?

Dr. Bode: With inhaled insulin, once it’s inhaled it goes into the deep tissue in two to four minutes. You might cough some out, but typically it’s an irritation you feel and later dry cough. It’s not persistent. There’s irritation of some particles in the back. Most people tolerate it and get over it in three to five days. It does cause people, especially those with type 1 diabetes who have been injecting all the time, to not want to do this any more after trying it. 

Q: Because the inhaled insulin has a quick out, what have you seen in postprandial glucose with a fatty meal?

Dr. Bode: In general in our type 1 trial, we saw a 35 mg/dl difference in plasma glucose, favoring inhaled insulin. However, when we looked at glucose during the day, the next pre-meal was higher, and the post-meal didn’t change. Our problem was that we didn’t have good enough basal during the day, because a fatty meal is going to absorb in three to four hours. This insulin is gone in 2.5 to three hours. You might have to inhale 90 minutes after you’re high. You can read blogs like afrezzauser.com and they’ll tell you how to do it. For example, it might be something like, “For cereal, inhale once. For pizza, take two fours and one four afterwards.”

Q: Does it stack?

Dr. Bode: It doesn’t stack because it is so quick.

Q: Do you use it as a correction insulin?

Dr. Bode: I was with Anne Peters today. She was telling me that for some people with type 1 diabetes, inhaled insulin is the best correction dose she has ever seen. It quickly gets it down, with no hypoglycemia. The reason why patients like it is because they can take it without getting hypoglycemia. In trials, we told people to take a correction dose after 90 minutes if they were above 180 mg/dl. Only 20% ever did. One of my patients, who always participates in my trials, usually comes in with an A1c of 9-10% and usually gets down to about 8.1-8.4%. With Afrezza, he exited the trial at 6.4%. I asked him what the heck he was doing. He said, “You don’t get it doc. I can take it and get my glucose down without crashing.” 

Q: Is there any effect on taste?

Dr. Bode: It’s mixed. Some say it has a little metallic taste. One said it tasted like lemon drops. People have different perceptions. In general, most people didn’t comment.

Dr. Pratley: All this inhaling doesn’t give you the munchies?

Dr. Bode: It’s fast in fast out, with a reduction in weight relative to traditional prandial insulins.

Dr. Pratley: Here’s a question I think it’s worth talking about. What can you say about Afrezza and lung cancer?

Dr. Bode: In their’s [MannKind’s], Pfizer’s, Lilly’s, and Novo’s [inhaled insulin] programs, there was no signal of increased lung cancer risk. However, there were some that got lung cancer. There were four lung cancers in the MannKind development program. Some occurred very early. How do you get lung cancer in 70 days? Others occurred 380 days post being on it. Two were smokers and two were non-smokers. Lung experts/oncologists think that this is pretty normal for the population, but the FDA mandated a long-term five-year 8,000 patient trial, including those at high risk (e.g., smokers, older people) to see what happens.

Corporate Symposium: Insulin-Based Options – Current Treatment Strategies and the Potential Impact of Emerging Options on Patient Outcomes (Supported by Novo Nordisk)

Where Are We Going from Here? Advances in Insulin-Based Treatment

Chantal Mathieu, MD, PhD (KU Leuven, Leuven, Belgium)

After explaining the need for new basal insulins, Dr. Mathieu provided an overview of Novo Nordisk’s Tresiba (insulin degludec), Sanofi’s Toujeo (U-300 insulin glargine), and Lilly’s peglispro. Throughout her presentation, she emphasized longer duration of action (>24-hour half-life) and reduced risk of nocturnal hypoglycemia as the main advantages of these new basal insulins. For insulin degludec specifically, she highlighted flexible dosing as another advantage.  

• Dr. Mathieu explained the need for new basal insulins. She commented that current basal insulins (by which she meant Lantus [insulin glargine U100] and Levemir [insulin detemir]) have still too much variability in their glucose-lowering effect, must be administered the same time every day, do not always last 24 hours, and cannot be mixed with other products.
• Subsequently, she provided an overview of Tresiba, Toujeo, and peglispro:
  
  • Tresiba: Dr. Mathieu emphasized that Tresiba reduces nocturnal hypoglycemia for both patients with type 1 diabetes and patients with type 2 diabetes. She mentioned that there is flexibility in time of dosing with insulin degludec – the medication does not lose its efficacy or safety when dosed flexibly (8-40 hours between doses) instead of at a fixed time each day (Meneghini et al., Diabetes Care 2013, Mathieu et al., JCEM 2013). In addition, Dr. Mathieu explained that Tresiba and insulin aspart (Ryzodeg) can be successfully co-formulated while retaining their individual action profiles.
  • Peglispro: After highlighting insulin peglispro’s liver-selective activity, Dr. Mathieu she discussed some of the medication’s benefits and risks. In clinical trials, insulin peglispro has been shown to reduce nocturnal hypoglycemia risk, and cause less weight gain than other insulins (though the mechanism remains unknown). However, increases in triglycerides, AST, and ALT were observed in clinical trials for insulin peglispro; as a result, Eli Lilly delayed its regulatory submission.
  • Toujeo: Dr. Mathieu stated that though Toujeo is associated with less nocturnal hypoglycemia than Lantus, higher doses of insulin are required to achieve the same glucose-lowering efficacy. In addition, Dr. Mathieu mentioned that in trials, Toujeo caused less weight gain than Lantus; however, there are no explanations for this observation at this moment in time.
• Dr. Mathieu discussed the synergies achieved by combining insulin and GLP-1 therapies, focusing her discussion on Novo Nordisk’s Xultophy (IDegLira; insulin degludec/liraglutide). In DUAL I, Xultophy treatment led to substantially better A1c control than either component treatment alone, caused less hypoglycemia and less weight gain than insulin degludec alone, and caused less nausea than liraglutide alone.

Insulin as a First-Line Therapy

Richard Pratley, MD (Florida Hospital Diabetes Institute, Orlando, Florida)

Dr. Richard Pratley addressed a less-than-filled ballroom in this corporate symposium to discuss the advantages of insulin as a first-line therapy for patients with type 2 diabetes. He first explained the rationale behind initializing insulin therapy, then discussed the process of starting and intensifying the therapy, and concluded with a review on the barriers to insulin therapy. His presentation challenged the existing paradigm of waiting until the rest of the type 2 diabetes therapeutic toolbox has been exhausted before moving to insulin. In his view, first-line insulin therapy could be a useful option in the context of individualized therapy.

• Dr. Pratley rationalized the introduction of initial insulin therapy by citing data from the UKPDS study. This study indicated that despite the common conception that metformin alone should be the primary line of treatment, the addition of insulin may provide relatively higher levels of glycemic control. At six years after initial diagnosis, more than 50% of patients needed insulin to reach their fasting glucose targets.  These results then translated to a consideration of insulin as a primary line of treatment for severe hyperglycemia.
• Dr. Pratley reviewed the various types of insulin and their activity profiles, then discussed the benefits and downsides of the progression from basal insulin, to basal plus prandial insulin, to premixed insulin. The most important takeaway in terms of benefits was that the emergence of analogs has provided marked increases in glycemic control as well as reduction in hypoglycemic events. He noted that MDI more closely mimics the physiological mechanism of action for insulin. Despite the benefits of progressive insulin therapy, more intensive therapy increases the risk of hypoglycemic events, which themselves have their own set of complications. We see the theoretical value of this argument though believe that PCPs do not like to prescribe mealtime insulin, broadly speaker.
• For each barrier to insulin therapy, Dr. Pratley recommended strategies to address their concerns. On the patient side, there may be frustration due to how long therapy takes as well as the fear of injections. However, he highlighted that the underlying concern comes from the fear of failing to meet the goals and endpoints towards managing glycemic levels. This fear has a prohibitive effect that delays the initiation of insulin therapy. Despite these barriers, Dr. Pratley asserted that insulin works and provides the most individualizable approach of all the existing therapies – we agree with this but think the barriers are many, particularly now that there are much easier to use and easier to prescribe orals. We do still think insulin will be very relevant however as type 2 patients are living longer and the need to individualize medicine for them is eventually very important.

Product Theaters

Afrezza – An Alternate Insulin Delivery (Sponsored by Sanofi)

Timothy Gilbert, MD (Imperial Health, Lake, Charles, LA)

We got to attend one of the first product theaters for Sanofi’s Afrezza. It didn’t include all the benefits we hear from patients, though it of course was boxed in by whatever was (and wasn’t) included by the FDA in the product’s prescribing information – the “wasn’t” includes hypoglycemia, ultra-rapid-acting, and weight benefits. Fortunately, the Q&A did answer some of the more critical questions on pulmonary function testing hassles and patient experiences. As for the presentation, ideally we would have loved a more targeted review at those (i) who don’t know the drug at all; and (ii) who are skeptical that the benefits are worth it vs. current insulins. The presentation started broadly with a discussion of the fraction of patients not at target, but did not discuss barriers to injection therapy (e.g., fear of needles) or postprandial hypoglycemia. Speaker Dr. Tim Gilbert focused on use of Afrezza in type 2 diabetes (type 1 was first mentioned 36 minutes in), though he did acknowledge in Q&A that most of his 12 Afrezza patient starts have been type 1s (this is also where the drug has seen a lot of early adopters to date). The two case studies provided a valuable window into how Sanofi is positioning the drug: (i) a type 2 not at goal maxed out on metformin and a DPP-4 (i.e., failing orals); and (ii) a type 2 not at goal on basal insulin. Indeed, Afrezza was positioned as a valuable tool for doctors to help basal insulin users with high A1cs but in-target fasting glucose levels (i.e., for whom increasing the basal insulin dose won’t correct the underlying problem). Overall, we do believe that Afrezza is a meaningful advance, though uptake will take some time to accelerate due to restrictions (lung function testing) and CME.

Toujeo — A Long Action Insulin Option (Sponsored by Sanofi)

John Anderson, MD (The First Clinic, Nashville, TN)

Dr. John Anderson took to the product theatre to explain why clinicians should prescribe Toujeo (U300 insulin glargine) to some of their patients instead of Lantus (U100 insulin glargine). Due to the FDA’s decision to exclude Toujeo’s nocturnal hypoglycemia data from the agent’s label, Dr. Anderson was restricted to describing the drug’s non-inferior efficacy (though at a higher dosage) as compared to Lantus, and not its improvement in nocturnal hypoglycemia. Fortunately, during Q&A an attendee specifically asked for a comparison of the two drugs’ hypoglycemia rates, enabling Dr. Anderson to highlight – with an emphasized and repeated acknowledgement that this data is off label – that in type 2 diabetes Toujeo demonstrated a statistically significant reduction in nocturnal hypoglycemia, and that in type 1 diabetes Toujeo had a statistically significant advantage in nocturnal hypoglycemia during the titration period (though not during the full trial). Though we had heard some early skepticism about the degree of Toujeo’s hypoglycemia benefit, more recent data (including the EDITION JP 2 study presented at this meeting) does seem to back it up and we think Sanofi’s ambitious set of upcoming real-world studies could make an even more convincing case. Dr. Anderson was then asked why he would prescribe Toujeo instead of Lantus; he highlighted that Toujeo is cheaper than Lantus thanks to Sanofi’s copay card for the agent and its lower nocturnal hypoglycemia rate, though he noted he will be able to provide a more nuanced answer after using it with his patients for a year. We have heard other doctors say that the pen is easier to use and we believe the COACH program is also quite valuable as it gives patients another connection point.

Questions and Answers

Q: Can you compare the hypoglycemia rate of Lantus vs. Toujeo?

A: First, the FDA considers it off-label to discuss the hypoglycemia data even though it was a secondary endpoint.  That said, in type 2 diabetes nocturnal hypoglycemia rate was significantly lower with Toujeo than with Lantus. In type 1 diabetes, it was not significantly different overall, though it was improved during the titration phase.

Q: What has your clinical experience with the drug been?

A: I am using it a lot more now. My patients are not coming back with hypoglycemia, in general. It is an easy pen to use. I haven’t gotten much three month or six month data with it since it is still new. I can’t say if I am seeing a difference between Lantus and other insulins.

Q: Why prescribe Toujeo over Lantus?

A: First, there is the lower rate of nocturnal hypoglycemia. Additionally, for many of my patients insulin has become very expensive. The copay card for Toujeo helps. I can’t fault anyone for considering staying with the same therapy. When we have new products on the market we have to get familiar with. I will be able to answer this question better in a year.

Q: Why do people need higher doses of Toujeo?

A: The most popular theory is that because Toujeo’s micro-precipitate is in the subcutaneous space for a long time you get more degradation as it sits there so you probably need a little more of it. To put this higher dose perspective, you have a patient on 35 U with Lantus they are looking at being on 38 or 39 U. So it’s not a big difference.

Q: Is Toujeo’s metabolite the same as Lantus?

A: It is. Its degradation is the same. However, it has a different PK/PD profile due to its concentration and how it acts in the subcutaneous space.

SGLT-2 Inhibitors

Oral Presentations: Experience with SGLT2 Inhibitors

A Randomized, Double-Blind, Phase 3 Trial of Dapagliflozin Add-On to Saxagliptin + Metformin in Type 2 Diabetes (105-OR)

Chantal Mathieu, PhD (University Hospital of Leuven, Leuven, Belgium)

Dr. Chantal Mathieu reported on results from a trial (n=320; ClinicalTrials.gov Identifier: NCT01646320) comparing the safety and efficacy of dapagliflozin (AZ’s Farxiga) vs. placebo as an add-on to saxagliptin (AZ’s Onglyza) and metformin in patients with type 2 diabetes. Participants received open-label saxagliptin plus metformin for a period of either eight or 16 weeks, depending on trial stratum. Those who had inadequate glycemic control (A1c of 7%-10.5%) after this open-label period were then randomized to placebo or dapagliflozin plus open-label saxagliptin and metformin. The primary endpoint was change from baseline A1c at week 24, with secondary endpoints including fasting plasma glucose, 2-hour postprandial glucose, body weight, and proportion of participants achieving A1c <7%. Overall, the combination of dapagliflozin, saxagliptin, and metformin led to greater A1c reductions (-0.82% vs. -0.10%), greater improvements in the secondary endpoints, and more participants achieving an A1c <7% than saxagliptin and metformin with placebo. Adverse effects were generally similar in the two groups with a low overall risk of hypoglycemia, though more participants developed genital infections in the dapagliflozin group compared to placebo (5% vs. 0.6%). Dr. Mathieu concluded that the addition of dapagliflozin to saxagliptin and metformin improved glycemic control and was well tolerated in patients with type 2 diabetes inadequately controlled on saxagliptin and metformin.

• AZ highlighted this trial during an Investor Day last November as part of an overall push toward early, aggressive combination therapy for type 2 diabetes. Management suggested during that presentation that results from this trial and another evaluating saxagliptin vs. placebo as an add-on to dapagliflozin and metformin could potentially support a triple fixed-dose combination, though such a product would not be submitted until 2017 at the earliest.

Questions and Answers

Q: Regarding data on adverse events, what about heart failure? The dapagliflozin arm has two heart failure events. What do you read from that?

A: We looked carefully at these patients. The first patient had heart failure very early on and had many other problems in addition to that. I don’t really remember more details about the other one. But if you’re asking if dapagliflozin can protect against heart failure, the numbers are too small to say anything.

Q: Should we be thinking about the sequence of medications?

A: I don’t know. But I think studies like this one can approach that question. It’s interesting to see what would happen if we switched the order in the same study. We’ll try to compare but there are different populations so that always makes it more difficult.

Q: Did you analyze the two strata differently? Were there any outcomes that were different?

A: They were not different.

Effect of Longer-Term Canagliflozin Treatment on eGFR in Patients with Type 2 Diabetes Mellitus and Various Degrees of Baseline Renal Function (107-OR)

Matthew Weir, MD (University of Maryland Medical Center, Baltimore, MD)

Dr. Matthew Weir presented results of three interrelated, long-term studies examining the effect of canagliflozin alone or compared with glimepiride and placebo on estimated glomerular filtration rate (eGFR) in people with type 2 diabetes. In the first two-year study, patients between 18 and 80 years old with a mean eGFR of 90 ml/min/1.73 m² received canagliflozin at 100 mg or 300 mg, or glimepiride. The second two-year study studied patients aged 55 to 80 years old with mean eGFR of 77.5 ml/min/1.73 m² who received canagliflozin at 100 mg or 300 mg, or placebo. The third study was one year in duration and featured patients older than 25 with stage 3 chronic kidney disease (eGFR of 39 ml/min/1.73 m²), who received canagliflozin at 100 mg or 300 mg, or placebo. Findings showed that participants’ eGFR initially decreased with canagliflozin but then stabilized or moved back toward the baseline within the first three to six weeks, remaining more or less unchanged over the next two years. eGFR progressively declined with glimepiride and did not change at all with placebo. Thus, participants on canagliflozin saw transient eGFR changes that attenuated over time and all study groups saw relatively consistent absolute effects, regardless of baseline renal function. The urine albumin to creatinine ratio (UACR) decreased with both the 100 mg and 300 mg canagliflozin doses, but it increased with glimepiride and placebo. Therefore, Dr. Weir concluded that eGFR changes with canagliflozin were overall not permanent and generally fairly weak. Of course, the most definitive answers regarding the effect of canagliflozin on renal function will come from the ongoing CREDENCE renal protection study, scheduled to complete in 2020.

Questions and Answers

Q: We sometimes see patients initiated on SGLT-2 inhibitors and then we see a drop in eGFR. Is there anything we should do?

A: I would do the same thing as I do with an ACE inhibitor or ARB. Check that the patient isn’t taking other anti-inflammatory or diuretic drugs.

Q: Did you have uric acid levels measured in your study?

A: We don’t have that. We know there aren’t significant changes.

Q: Are there any concerns with these drugs being used in patients on diuretics?

A: No, a lot of our patients were on diuretics.

Q: Thoughts on DKA?

A: The majority of reports of DKA occurred in type 1 diabetes. Very few are reported in people with type 2 diabetes. We don’t have any data to indicate the cause of ketoacidosis.

Oral Presentations: New Insights Into the Effects of Oral Agents

No Increased Risk of Cardiovascular Events with Dapagliflozin in Elderly Patients With Type 2 Diabetes Mellitus, Cardiovascular Disease, and Hypertension (15-OR)

Ingrid Gause-Nilsson, MD, PhD (AstraZeneca, Mölndal, Sweden)

AstraZeneca scientist Dr. Ingrid Gause-Nilsson presented the results of a post-hoc analysis of cardiovascular events in 1,263 elderly, high-cardiovascular-risk patients enrolled in 19 phase 2b/3 clinical trials (duration up to four years) for AZ’s Farxiga (dapagliflozin). This was a follow-up analysis to one presented at AHA last year (abstract 16682) for the full trial population, not just elderly high-CV-risk patients – that analysis found a hazard ratio of 0.79 (95% CI: 0.58-1.07) for MACE + unstable angina with dapagliflozin. The analysis presented at ADA was of interest because the elderly high-CV-risk subpopulation is arguably closer to the population that would be enrolled in a CV outcomes trial. Fortunately, there was no cause for worry in this analysis: the hazard ratio for MACE was 0.92 (95% CI: 0.51-1.64) for MACE and 0.82 (95% CI: 0.50-1.37) for MACE + unstable angina, with no imbalance in CV death, MI, or stroke. Analyses like these are somewhat reassuring from a safety standpoint but are nothing compared to the outcomes data we will have from the DECLARE-TIMI outcomes trial, though that is only expected to end in 2019.

• Dr. Gause-Nilsson cited a very slight imbalance in renal impairment/failure (13.7% with dapagliflozin vs. 11.3% with comparator therapy), although eGFRs appeared fairly stable – we didn’t see this as very worrying given that most diagnoses were based on laboratory values. There was a 5.8% incidence of genital infections with dapagliflozin vs. 0.8% with comparator therapy, as well as a very modest imbalance in urinary tract infections that emerged in longer studies. It was hard to interpret the glucose lowering efficacy results (mean difference of 0.4%) because some studies had active comparators.

Questions and Answers

Q: From the data here, I’m not surprised that there was no increase in cardiovascular risk. I’m surprised that this drug does not decrease cardiovascular events due to the effects on blood pressure, weight, and A1c. Is it just a matter of power?

A: The possible positive effects of these risk factors may need a longer follow up beyond four years.

Q: Were all of these events adjudicated?

A: The cardiovascular endpoints were adjudicated, but adverse events of special interest were not.

Posters

Glycemic Effects of SGLT2 Inhibitor Canagliflozin in Type 1 Diabetes Using Dexcom G4 Platinum CGM (932-P)

N Argeno and K Nakamura

Results of a retrospective review of 27 patients with longstanding type 1 diabetes using Dexcom’s G4 Platinum CGM (PCGM) showed that addition of J&J’s Invokana (canagliflozin) 100 mg to insulin provided statistically significant glycemic benefits. The study examined patient records, including 30-day CGM downloads, at baseline and after at least one month on canagliflozin (mean exposure of 3.7 months). 27 patients with similar baseline characteristics who did not undergo any change in therapy other than insulin adjustment served as a control group. Results showed that the addition of canagliflozin reduced mean CGM glucose, reduced blood glucose variability, improved time spent in target blood glucose range, and reduced A1c, systolic blood pressure, weight, and total insulin dose from baseline, with no significant change in renal function (serum creatinine or eGFR). The control group did not experience significant changes in any parameters from baseline. Canagliflozin therapy was generally well tolerated; there were three episodes of DKA in the canagliflozin group, two of which were attributed to pump site failure and one to a patient running out of basal insulin. These encouraging results illustrate the many potential benefits of SGLT-2 inhibitors in type 1 diabetes, though it remains to be seen what effect the concerns about euglycemic DKA will have on the class’ overall risk/benefit profile for type 1 – ongoing randomized controlled trials will hopefully offer more clarity.

• Baseline demographics for the canagliflozin vs. control group were well matched. The canagliflozin group (n=27) had a mean age of 52 years, duration of type 1 diabetes of at least 10 years (mean 34 years), and duration of CGM use >1 year (mean 4.8 years). The control group consisted of 27 patients (mean age 51) with “similar indications” who were judged to be eligible for canagliflozin therapy and did not undergo any treatment changes other than insulin adjustment.
• The study compared two sets of patient records, including 30-day CGM downloads, for each group. In the canagliflozin group, investigators examined records at baseline and after at least one month on canagliflozin (mean exposure of 3.7 months). For the control group, investigators examined the earliest most complete sequential pair of downloads between May 2013 and January 2015.
• Addition of canagliflozin led to significant improvements from baseline in a number of glycemic and non-glycemic parameters. Patients in the canagliflozin group experienced significant improvements in mean glucose (168 mg/dl to 147 mg/dl; p<0.0001), glucose variability (measured by standard deviation of CGM glucose; 68 mg/dl to 56 mg/dl; p<0.0001) and percentage of time in range (70-180 mg/dl) (57% to 70%; p<0.0001) from baseline. Canagliflozin also led to significant reductions in A1c (7.6% to 7.2%; p<0.0001), systolic blood pressure (122 mmHg to 114 mmHg; p=0.0089), total daily insulin dose (51 units to 45 units; p=0.0002), and body weight (89 kg to 87 kg; p=0.0007) from baseline. The poster did not directly compare final results in the canagliflozin vs. control groups, but the two groups were well matched at baseline and the control group did not experience significant changes in any parameters.
• Canagliflozin appeared to be well tolerated, with no significant changes in renal function and no cases of DKA attributed to the drug. Serum creatinine and eGFR were comparable at baseline and after canagliflozin treatment. Three cases of DKA occurred in the canagliflozin group: one at baseline attributed to pump site failure and two mild episodes in the follow-up period, one attributed to pump site failure and one to the patient running out of basal insulin and attempting to treat with rapid-acting insulin alone. There were no episodes of DKA in the control group.

Empagliflozin (EMPA) Decreases Glucose Exposure and Variability in Patients with Type 1 Diabetes (T1DM): Continuous Glucose Monitoring (CGM) Data (EASE-1) (1241-P)

S Famulla, T Pieber, J Eilbracht, D Neubacher, N Soleymanlou, H Woerle, U Broedl, and S Kaspers

This randomized, double-blind, placebo-controlled phase 2 trial examined the effect of Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), as an adjunct to insulin on glucose exposure (measured by area under the median glucose curve), interquartile range of glucose (IQR), and mean amplitude of glucose excursions (MAGE) in type 1 diabetes patients. For four weeks, 75 patients were randomized to placebo or one of three doses of empagliflozin (2.5 mg, 10 mg, or 25 mg), in addition to insulin (stable insulin dose during the first week and freely adjustable dose thereafter). There were significant improvements in glucose exposure and variability with all doses of empagliflozin vs. placebo following the one-week stable insulin period (p<0.05). However, all improvements were diminished at four weeks; significance was retained for glucose variability at all doses (p<0.001) and for glucose exposure only at the highest dose (p<0.05). Based on these results, it is somewhat challenging to tease apart the effect of the empagliflozin on glucose exposure and variability from the effect of stable insulin dosing in the first week of the trial. Time in range (>70 mg/dl to ≤180 mg/dl) was significantly improved with all doses of empagliflozin vs. placebo after one week (p<0.05) but only with the highest dose after four weeks (p<0.001).

• All groups had similar baseline characteristics. Average age was ~39-42 years and all patients were white. Mean A1c was ~8.2%-8.3%, average body weight was ~75-87 kg (165-192 lbs), and average systolic blood pressure was ~122-124 mm Hg in all groups. 7-day ambulatory glucose profiles (AGP) were generated based on CGM data collected over 24-hour periods.
• Glucose exposure and time in range (>70 mg/dl to ≤180 mg/dl) improved significantly from baseline with all doses of empagliflozin vs. placebo after one week, but the improvements remained significant (albeit diminished) after four weeks only at the highest (25 mg) dose. At one week, area under the median glucose curve decreased by 12.2, 30.2, and 32.9 mg/dl*hr more than the reduction observed in the placebo group (-0.9 mg/dl*hr) for the 2.5, 10, and 25 mg doses (p=0.04, p<0.001, p<0.001), respectively. However, at four weeks, a significant placebo-adjusted reduction was observed only with the 25 mg dose (-15.9 mg/dl*hr, p=0.03). Similarly, at one week, time in range increased by 2.6, 3.7, and 4.3 more hours per day with the 2.5, 10 and 25 mg doses of empagliflozin, respectively, vs. placebo (p<0.01, p<0.001, p<0.001), but the only significant result observed at four weeks was with the 25 mg dose (2.7 more hours per day than placebo, p<0.001).
• Glucose variability (IQR and MAGE) decreased significantly with all doses of empagliflozin compared to placebo at weeks one and four, though the reduction from baseline was less dramatic at four weeks. After one week of stable insulin dosing, the IQR for the placebo group decreased from baseline by a staggering 21.6 mg/dl. The 2.5, 10, and 25 mg doses of empagliflozin produced additional reductions of 14.0, 20.0, and 21.1 mg/dl, respectively (p<0.001 for all). After four weeks, placebo IQR had increased from baseline by 6.5 mg/dl. For the 2.5, 10, and 25 mg empagliflozin groups, IQR decreased from baseline by 15.4, 15.0, and 20.7 mg/dl, respectively (p<0.001 vs. placebo for all groups). Because placebo IQR increased from baseline at four weeks, the placebo-adjusted reductions with empagliflozin were larger than at one week, but the absolute differences from baseline were smaller.

The Combination of Insulin, Liraglutide, and Dapagliflozin as Triple Therapy for Type 1 Diabetes (130-LB)

N Kuhadiya, A Mehta, H Ghanim, J Hejna, A Makdissi, A Chaudhuri, M Batra, and P Dandona

Continuing their group’s pioneering work on liraglutide in type 1 diabetes, Dr. Kuhadiya and colleagues conducted a small (n=10), 12-week retrospective study of dapagliflozin in people with type 1 diabetes who had already been using liraglutide in addition to insulin for a mean of 11 months. At baseline, study participants had mean A1c 8.01%, mean glucose 172 mg/dl, age 56 years, age at diabetes diagnosis 29 years, BMI 29 kg/m², body weight 86 kg (189 lbs), daily carbohydrate intake 196 g, and blood pressure 125/75 mm Hg. Patients began dapagliflozin at 5 mg daily and, after 7±1 days, increased the dose to 10 mg daily. After 12±1 weeks of dapagliflozin therapy, patients had mean A1c reduction of 0.66%, body weight reduction of roughly 1.5 kg (3 lbs), mean glucose reduction of 28 mg/dl as monitored by continuous glucose monitoring, and daily carbohydrate increase 0f 30 g while insulin dose stayed constant (on average) at 0.7 U/kg. No additional hypoglycemia was observed, but one patient underwent diabetic ketoacidosis (DKA) despite normal glucose levels, within two days after up titrating their dapagliflozin to 10 mg daily. This patient had notably decreased their total daily dose of insulin from 32.9 to 28.5 U (0.45 to 0.39 U/kg) while also increasing their daily carbohydrate intake from 50 to 95 g. We look forward with great interest to randomized controlled trials of SGLT-2 inhibitors plus GLP-1 agonists in type 1 diabetes. As to the documented instances of euglycemic DKA associated with SGLT-2 inhibitors in type 1 diabetes, we hope that the risk can be minimized with education of patients and clinicians and with selective prescribing patterns – see our coverage of a recent Diabetes Care case series for more.

• This was a 12-week, n=10 retrospective study of dapagliflozin added to baseline therapy of liraglutide and insulin in type 1 diabetes.
• The study concluded that addition of dapagliflozin to insulin and liraglutide in patients with type 1 diabetes significantly improved glycemia. After 12 weeks of treatment, mean A1c fell by 0.66% (p=0.0004) and mean glucose decreased from 172 mg/dl to 144 mg/dl  (p=0.016), though  total insulin dose (0.7 u/kg) did not change. Time in range (70-160 mg/dl) increased from 45% to 56% (p<0.05) and time with glucose >160 mg/dl decreased from 48% to 37% (p<0.05). Daily carbohydrate intake increased from 166 g before the addition of dapagliflozin to 196 g after (p=0.04). Both body weight and BMI fell after dapagliflozin was added, from 87 kg to 85 kg (p=0.02) and 29 kg/m² to 28 kg/m², respectively.

	Baseline	12 wks
A1c (%)	8.0	7.4*
Mean glucose (mg/dl)	172	144*
Body weight (kg)	86	85*
Body weight (lbs)	190	187*
Body mass index (kg/m2)	29	28*
Daily carbohydrate intake (g)	166	196*
Daily insulin dose (U/kg)	0.7	0.7

                           * p<0.05

• Dr. Kuhadiya and his team advised caution when reducing insulin doses to avoid euglycemic DKA. One patient in the retrospective analysis developed DKA despite normal blood glucose concentrations within 48 hours of increasing the dapagliflozin dose to 10 mg/day. This patient’s dose of insulin had declined from 0.45 to 0.39 u/kg and carbohydrate intake had increased from 50 to 95g/day. With regard to other adverse events, one female patient developed a vaginal yeast infection that was successfully treated.

Symposium: Non-Insulin Adjunct Therapies in Type 1 Diabetes

The Potential Use of SGLT-2 Inhibitors in Type 1 Diabetes

Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Julio Rosenstock provided a nuanced but generally positive perspective on the potential of SGLT-2 inhibitors in type 1 diabetes. The key benefits include insulin-independent efficacy, reduced glucose variability and insulin doses, and improvements in weight and blood pressure. He strongly encouraged the audience to attend the presentation of full results from a four-week study of Lexicon’s SGLT-1/SGLT-2 dual inhibitor sotagliflozin in type 1 diabetes – the results were promising across the board, showing reductions in A1c (0.5% placebo-adjusted), postprandial glucose, and bolus insulin doses, improvements in glycemic variability, and a ~2 kg weight benefit. With regard to the recent concerns about euglycemic DKA, Dr. Rosenstock suggested that it is important for patients and physicians to be aware of the phenomenon but he framed it more as a risk to be managed rather than a deal-breaker. He also noted that a substantial portion of the reported cases occurred after reductions in insulin doses, which can contribute to the vicious cycle initiated when the body switches to a fasting mode (increased glucagon production, lipid oxidation, etc.) in response to increased glucose excretion; other speakers throughout the meeting expressed similar sentiments regarding the role of low insulin levels. We heard a great deal of commentary on euglycemic DKA at AACE last month as well, most of it similarly balanced. On the whole, we agree with Dr. Rosenstock’s belief that the ongoing trials of SGLT-2 inhibitors in type 1 diabetes will likely conclude that the benefits outweigh the risks for most patients, though it will be very important for patients to have a ketone meter and know when to use it.

Symposium: SGLT2 Blockers in 2015 (Supported by BI/Lilly)

Similarities and Differences Between SGLT2 Blockers

Robert Henry, MD (University of California, San Diego, CA)

Dr. Robert Henry reviewed the mechanism of action and clinical effects of SGLT-2 inhibitors, though he refrained from making claims about the relative benefits of specific agents given the lack of comparative data. He did discuss the potential added benefits of SGLT-1/SGLT-2 dual inhibitors like Lexicon’s sotagliflozin over pure SGLT-2 selective inhibitors due to increases in gut hormones like GLP-1 and PYY – he suggested that this may account for a small portion of the efficacy of J&J’s Invokana (canagliflozin), which has some slight SGLT-1 activity. He presented data demonstrating that all three currently approved SGLT-2 inhibitors offer A1c reductions of approximately 0.5%-1%, durable ~3% weight loss, blood pressure reductions, and positive changes in HDL cholesterol and triglycerides. On the negative side, Dr. Henry also discussed the increases in LDL cholesterol and hepatic glucose production seen with the class and the initial drop in estimated glomerular filtration rate (eGFR) that has prompted “lots of speculation” about harmful renal consequences, but he stressed that any impairment in kidney function appears to be transient. He briefly acknowledged the concerns about euglycemic DKA but did not offer further commentary – we were somewhat surprised that this did not come up during Q&A, as it has appeared to be top of mind for many providers at recent conferences. Dr. Henry closed with a discussion of SGLT-2 inhibitors’ broad potential in combination with other agents, particularly incretins, and of the need for long-term studies to elucidate their effects on bone health and renal and cardiovascular outcomes.

Questions and Answers

Q: With the rise in glucagon, we know after one month in the Ferrannini study that it was no longer significant. In your month-long study, were fasting glucagon levels increased?

A: Yes, they were. We did another study with dapagliflozin that also saw an increase in glucagon.

Q: The compensatory hepatic glucose production is found continuously after two to four weeks but A1c stays down. Do you really feel it attenuates the effect?

A: A1c comes down and stabilizes. In all preclinical studies, endogenous glucose production decreases, and in clamps the ability of insulin to suppress glucose production is improved, probably due to a reduction in glucotoxicity.

Q: You were clever not to conclude anything about whether one is superior to another. Looking into the trials with canagliflozin 300 mg, would you propose that this higher dose of canagliflozin is marginally superior to the others?

A: It is superior to the 100 mg dose, probably due to greater effects on glucosuria. What you’re probably asking is whether there is a significant effect of SGLT-1 inhibition that translates in people with type 2 diabetes. We haven’t done the studies completely, not with tracer uptake. My personal view is that it would be a small effect. I doubt we would be able to detect it as clinically significant. If it does, it would be in the postprandial period.

Q: What is your hypothesis for the elevation in LDL?

A: It wasn’t even noted initially in the individual studies. It wasn’t until all the data was together from all the phase 3 trials that people started to look more carefully. The bottom line is there are lots of postulates, and it appears from observation that glucose ingestion goes up with SGLT-2 inhibitors, so it makes it hard to explain. It remains unknown. It definitely is a phenomenon. At least the three approved agents all show it. Whether it’s different among the three, only head to head studies can answer.

Q: Do you think we have to worry about it?

A: I think the increase in LDL is small enough, zero to 8-9%, that it generally can be handled with statins and diet, and it probably won’t have an effect, though we have to wait for the cardiovascular outcomes trial.

Effects on Sodium Balance and Hypertension

George Bakris, MD (University of Chicago, Chicago, IL)

Dr. George Bakris focused on the modest blood pressure reductions observed with the SGLT-2 inhibitor class, questioning the underlying physiology. Clinical trials with the class have demonstrated a roughly 4-mmHg decline in systolic blood pressure. As most patients included in the trials were not hypertensive or were in good control, Dr. Bakris suggested that studies indicate this decline could be as high as 11 mmHg in hypertensive patients (he noted that based on FDA guidelines the drugs could technically qualify as antihypertensives). In a review of animal studies with the class, he confirmed that the drugs produce an acute natriuresis (urinary sodium excretion), though this effect becomes minimal with chronic use – suggesting it would not account for the entirety of the blood pressure reductions. Likewise, given that blood pressure reductions are the same in patients with advanced kidney disease in whom the osmotic diuresis induced by the class is reduced, he indicated this effect would also be insufficient to explain the blood pressure results. This is complicated as well by the rise in glucagon and increased sympathetic tone caused by SGLT-2 inhibitors, which should theoretically increase blood pressure. In the end, Dr. Bakris was unable to provide an answer for how the drugs produce blood pressure reductions – during Q&A, he hazarded a guess that another gut hormone may be involved, though this would require further study.

Questions and Answers

Q: I understand when these agents have been studied in those with reduced renal function they still see a very good decrease in blood pressure. How can you explain that?

A: I honestly don’t know; that’s the big question in my mind. The natriuresis and osmotic diuresis are proportional to kidney function, so it’s unclear to me what is going on. We have these countervailing mechanisms of sympathetic tone going against you. It’s pure speculation, but is it possible there is another gut hormone involved that is vasodilatory, through SGLT1 or leptin or some other mechanism? This would require further study.

Q: Is there reduced bicarbonate reabsorption with the class?

A: I’ve heard this. I will say in the studies we’ve done I have not seen a change in bicarbonate at all. Nor have I seen a change in potassium. It may be interesting but not clinically relevant.

Comment: In my practice I see greater declines in blood pressure than mentioned.

A: One of the things I do routinely is I stop the diuretic when I start an SGLT2. That’s exactly what you’ll find – these studies usually people are on one antihypertensive and it’s not a diuretic.

Which Patients Might Benefit the Most?

Vincent Woo, MD (University of Manitoba, Winnipeg, Manitoba, Canada)

After briefly mentioning the SGLT-2 inhibitors currently on the market or in development and discussing where SGLT-2 inhibitors are currently positioned in diabetes guidelines, Dr. Vincent Woo provided his opinions on which individuals with type 2 diabetes may benefit most from SGLT-2 inhibitor therapy. He believes that SGLT-2 inhibitors would be particularly fitting for those who are trying to achieve early intensive glucose lowering, those with a high baseline A1c who need combination therapy, and insulin users. Dr. Woo noted that the best predictors of response to SGLT-2 inhibitor therapy are high baseline A1c and high eGFR; meanwhile, baseline BMI has no predictive value for A1c or weight. In closing, Dr. Woo mentioned several other potential areas of application for SGLT-2 inhibitors in the future: prediabetes, type 1 diabetes, obesity (in combination with other agents), and diabetic nephropathy.

Questions and Answers

Q: Which patients are most likely not to benefit from the class and have the most side effects?

A: Obviously, we have a number of patients who have incredibly poor adherence. If you don’t take the drug, you won’t benefit. People who might have side effects to the medication, as has been alluded to earlier, are those who experience reductions in blood pressure and do not monitor it correctly. They can get hypotension and dizziness. I have heard that those on low-carb diets may potentially not do as well either. I haven’t seen data on this, but it makes sense. Obviously, renal function is key, and as A1c is lower, A1c lowering with SGLT-2 inhibitors is lower too. 

Q: Some of my colleagues mentioned anecdotally that balanitis is more common in uncircumcised males.

A: The clinical trials support that those who are circumcised experienced less balanitis.

Nonglycemic Effects of SGLT-2 Inhibition: Long-Term Risks vs. Potential Benefits

Richard Gilbert, MD, PhD (University of Toronto, Toronto, Ontario, Canada)

Dr. Richard Gilbert provided a great overview of a complex area of diabetes science: why SGLT-2 inhibitors might (or might not) have renal protective effects. The theory caught our attention in a big way when we learned about J&J’s CREDENCE outcomes trial for Invokana (canagliflozin); before then, the prevailing opinion was that – if anything – SGLT-2 inhibitors may have slight renal safety risk due to a slight reduction in eGFR in patients initiating therapy. However, that decrease may not be what it initially appears: Dr. Gilbert drew strong parallels to ACE inhibitors, which are renoprotective but show an initial drop in eGFR. Dr. Gilbert proposed a few potential mechanisms that could underlie a benefit. Increased sodium excretion causes a group of cells within the kidney called the macula densa to constrict afferent arterioles, reducing eGFR – this is the body’s mechanism to prevent sodium loss, but in this case it could help by reducing pressure in the glomerulus, where blood is filtered. SGLT-2 inhibitors may also increase uric acid excretion, and effect which is being examined more broadly as a way to improve chronic kidney disease (allopurinol is an example). Dr. Gilbert did note with caution that SGLT-2 inhibitors do not have as wide a range of beneficial effects in the kidneys as ACE inhibitors, meaning that a benefit is far from certain. For now, he is eagerly awaiting results from the CREDENCE outcomes study, which are expected in 2019.

Symposium: ADA Diabetes Care Symposium — Novel Clinical Interventions in Therapy That Impact the Management of Diabetes

Sotagliflozin, A Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes

John Buse, MD, PhD (UNC, Chapel Hill, NC)

Phase 2 data on Lexicon’s SGLT-1/SGLT-2 dual inhibitor sotagliflozin (LX4211), presented by investigator Dr. John Buse, snagged a spot at the massively well-attended Diabetes Care symposium. Although topline data was released over a year ago, making it into this session was a big deal – this was a standing-room-only event in the largest presentation hall of the conference and the abstract was concomitantly published online in Diabetes Care. The phase 2 study (n=33) ran for 30 days, finding improvements across the board, including: (i) a roughly 0.5% placebo-adjusted reduction in A1c from a baseline of around 8% and reductions in postprandial glucose; (ii) a significant improvement in time-in-range and multiple metrics of glycemic variability; (iii) a 32% decrease in bolus insulin dose (6% reduction with placebo) in the context of better glycemic control; and (iv) a relative weight benefit of slightly over 2 kg (~4 lbs) in a short time period. (We wouldn’t leave out the convenience of a pill for type 1 diabetes.) Improvements in GLP-1, PYY, and urinary glucose excretion suggest that both the SGLT-1 inhibition in the gut and SGLT-2 inhibition in the kidney contributed to efficacy. The presentation likely stokes interest in sotagliflozin for type 1 diabetes, which excitingly has moved into phase 3.

• We were glad to see CGM used for the duration of the 30-day study and applaud the way Lexicon has focused on “time in zone” to support sotagliflozin’s value in type 1 diabetes. With the room for A1c improvements narrowing with each new class of drugs, we see non-A1c parameters such as glycemic variability as increasingly important for novel products to prove their value for patients (and potentially also to payers if there are parallel improvements in insulin dose and hypoglycemia).
• The most commonly reported adverse effect with sotagliflozin was nausea, consistent with an increase in GLP-1. Around 25% of patients on sotagliflozin experienced nausea vs. 6% on placebo. However, Dr. Buse noted that nausea was generally of mild intensity, within five days of onset of treatment, and of short duration (1-2 days).
• Of interest given the euglycemic ketoacidosis issue with SGLT-2 inhibitors, Dr. Buse disclosed that there were two cases of DKA with sotagliflozin. However, he noted that both cases were assessed as pump related and explicitly stated that neither was “euglycemic DKA.” We have heard theories that SGLT-1/2 dual inhibitors may have a lower risk of euglycemic DKA, as they cause less volume depletion and also increase GLP-1 levels, both of which should help reduce the risk of excess ketones. With outcomes data soon to arrive (at least one) for SGLT-2 selective inhibitors, we wonder if Lexicon may look into ways to more conclusively back up their argument on SGLT dual inhibitors and DKA.
• In addition to the recently initiated phase 3 program in type 1 diabetes, Lexicon is also conducting a second phase 2 study (with JDRF support) studying sotagliflozin in younger, more poorly controlled type 1 diabetes patients.

Questions and Answers

Q: What is the impact of SGLT-1 inhibition on fasting vs. postprandial glucose?

A: I think that’s a little hard to estimate. I think the relative effect of the SGLT-2 transporter is about 20-fold greater than the SGLT-1 transporter using classic kinetics. What the relative contribution on the overall glucose profile is would be harder to estimate, but we believe the SGLT-1 contribution is real and perhaps as much as 50% of the effect.

Q: You said that the reason for the nausea in the study was the increase in GLP-1, but GLP-1 didn’t look like it was increased all that much in the study.

A: It is speculation, but as there was an increase in the two enteroendocrine hormones we looked at, it’s likely that there were increases in others. I’ll admit that that is speculation. More importantly, as opposed to previous hypotheses that SGLT-1 inhibition would be associated with intolerable GI events, the GI adverse event profile was really very mild.

Q: Why would sotagliflozin cause nausea when endogenous GLP-1 does not cause nausea?

A: I really can’t speculate further on that.

Q: Can you comment on the mechanism of the increase in GLP-1?

A: The notion is that by inhibiting proximal glucose absorption and shifting glucose further down the intestinal tract, it changes fatty acid metabolism by bacteria. Exactly the contribution of each of the changes in the enteroendocrine hormone changes is unknown.

Q: Could there be a long-term problem with the change in PYY acting as a vasoconstrictor?

A: That would be speculation. My personal belief is that it’s unlikely to be an issue, but there will be a full development program for the compound in type 1 diabetes, and we’ll be careful to examine cardiovascular endpoints. There is a modest decrease in blood pressure associated with sotagliflozin.

Q: With Ramadan coming up, how safe is it to continue SGLT-2 inhibitors during the fasting month?

A: I saw a paper or abstract that addresses that directly, and my recollection was that things looked pretty good. I had the same thought that a period of prolonged fasting, including no water, could limit the efficacy of these agents due to a loss of urine. But there is something published on that.

Best of Diabetes Care 2014: Diabetic Nephropathy – Biomarkers, Progression, and SGLT2 Inhibitors

George Bakris, MD (University of Chicago, Chicago, IL)

Dr. George Bakris selected three standout papers published in Diabetes Care in 2014 related to diabetes and kidney disease. Notably, Dr. Bakris praised the investigators of BI/Lilly’s SGLT-2 inhibitor Jardiance (empagliflozin) for running the only “proper” study of the effects of SGLT-2 inhibitors on blood pressure (according to Dr. Bakris, EMPA-REG BP was the only SGLT-2 trial that measured 24-hour ambulatory blood pressure rather than simply office blood pressure). Impressively, despite participants’ relatively normal baseline 24-hour ambulatory systolic blood pressure (SBP; ~131 mm Hg), empagliflozin treatment provided a placebo-adjusted reduction of ~3 mm Hg (10 mg dose) or ~4 mm Hg (25 mg dose) (Tikkanen et al., Diabetes Care 2014). For context, the FDA requires only a 5 mm Hg SBP reduction to approve an agent for anti-hypertensive indications, and patients enrolled in trials for anti-hypertensive agents would have much higher SBP at baseline. Therefore, this trial demonstrated that diabetes patients who also have hypertension control can expect significant blood pressure benefits from SGLT-2 inhibitors. The other two papers that Dr. Bakris selected identified promising biomarkers for monitoring diabetic nephropathy. First, urinary adiponectin (uADP) was found to be better than albuminuria, and equally as good as eGFR, in predicting progression from kidney damage to end-stage renal disease in type 1 diabetes (Panduru et al., Diabetes Care 2014). Second, serum TNFR1 concentration was identified as a strong predictor of all-cause mortality in patients with type 2 diabetes and chronic kidney disease (Saulnier et al., Diabetes Care 2014).

Corporate Symposium: Comprehensive Management of DM – Focus on SGLT-2 Inhibitors and Combination Therapy – Emerging Concepts of Renal Effects (Supported by AstraZeneca)

Contribution of the Kidney to Whole Body Glucose Homeostasis: A Critical Re-Evaluation

Zachary Bloomgarden, MD (Mount Sinai Hospital, New York, NY)

Dr. Zachary Bloomgarden provided a mechanistic overview of the kidney’s contributions to glucose homeostasis in people with and without diabetes, a topic that had been somewhat overlooked by the medical community prior to the arrival of SGLT-2 inhibitors. He explained that the kidneys play an important role in gluconeogenesis and appear to account for approximately half of the increase in glucose production seen in diabetes. He also presented evidence showing that the kidneys respond potently to insulin and catecholamines and potentially to glucagon, which likely contributes to much of the altered physiology in diabetes as well. Setting the stage for the subsequent presentations on SGLT-2 inhibitors, Dr. Bloomgarden closed with a review of the data showing a paradoxical increase in renal glucose reabsorption in people with diabetes and a direct relationship between hyperglycemia and the threshold for urinary glucose excretion.

SGLT-2 Inhibitors and the Kidney: Mechanisms and Clinical Efficacy

Lawrence Leiter, MD (University of Toronto, Toronto, Ontario, Canada)

Dr. Lawrence Leiter discussed the mechanism of action of SGLT-2 inhibitors in people with diabetes with both normal and impaired renal function. He began by highlighting the recently updated ADA/ EASD guidelines for type 2 diabetes treatment that include a key role for SGLT-2 inhibitors. He then walked attendees through the intestinal and renal roles of SGLT-1 and SGLT-2 in glucose absorption and discussed the rationale for development of SGLT-1 and/or SGLT-2 inhibitors. He commented that these classes might be able to be used in type 1 diabetes as well as type 2, focusing on the clinical data for Lexicon’s sotagliflozin (LX4211); he did not comment on the recent concerns about euglycemic DKA in this population. Dr. Leiter also emphasized that SGLT-2 inhibitors can still be efficacious in patients with impaired renal function, showing data demonstrating that canagliflozin and empagliflozin still have beneficial effects on A1c, body weight, and blood pressure in that setting. He acknowledged that there is a small risk of volume-related adverse events in certain patients but cautioned against writing off these drugs entirely in patients without normal renal function, even suggesting that the class may prove to be reno-protective.

SGLT-2 Inhibitors and the Kidney: Potential for Renoprotection

Matthew Weir, MD (University of Maryland, Baltimore, MD)

Dr. Matthew Weir provided a nephrologist’s perspective on the factors that contribute to diabetic kidney disease and the potential for SGLT-2 inhibitors to improve renal outcomes. He cautioned that there have not been prospective randomized controlled trials with RAAS blockers examining the effect of reductions in blood pressure or proteinuria on renal outcomes, though many secondary analyses have shown a benefit. There is strong evidence to support the use of renin-angiotensin system (RAAS) blockers like ACE inhibitors and ARBs, but Dr. Weir noted that they only lead to a ~20% reduction in adverse renal outcomes – “a nice start, but nothing to cheer about.” Turning to SGLT-2 inhibitors, he explained that at least in animal models, the drugs appear to reverse the impairment in tubular glomerular feedback (a mechanism by which the kidney corrects hyperfiltration) seen in early stages of diabetic kidney disease. Other effects of SGLT-2 inhibitors, particularly blood pressure reduction, could also potentially have a positive impact on kidney function. Dr. Weir also argued that the initial drop in estimated glomerular filtration rate (eGFR) seen with SGLT-2 inhibitors may actually be a positive sign, as a greater initial drop in eGFR was associated with better long-term outcomes in clinical trials of losartan. As Dr. Weir noted, the CREDENCE renal outcomes trial of J&J’s Invokana (canagliflozin), expected to complete in 2020, should provide much more insight in this area – this is one of the most exciting ongoing studies in diabetes in our view, and a positive outcome would be an enormous win for patients.

Exploring Mono- and Dual Therapy: Implications for Kidney Function

Stefano Del Prato, MD (University of Pisa, Pisa, Italy)

Dr. Stefano Del Prato discussed the safety of DPP-4 inhibitors in type 2 diabetes patients with renal impairment and emphasized the utility of combination therapies. He reviewed data showing that the efficacy of DPP-4 inhibitors in type 2 diabetes patients with moderate to severe renal impairment is the same as in those with normal renal function. In fact, DPP-4 inhibitors in type 2 diabetes have been associated with reductions in hsCRP (a marker of CV risk), albuminuria, and microalbuminuria, perhaps suggesting some nephron-protective effects. Dr. Del Prato continued by stressing that early achievement and durable maintenance of good glycemic control remains the most effective approach to reduce the risk of microvascular complications, suggesting that combination therapy that can simultaneously correct different pathogenic mechanisms is optimal. He emphatically stated that the lesson from UKPDS was that “monotherapy is going to fail no matter what treatment you’re going to use” and that “you will ultimately require a second intervention.” Dr. Del Prato thus pushed for starting with combinations as soon as possible, pointing to DPP-4 inhibitor/metformin and SGLT-2 inhibitor/DPP-4 inhibitor combinations as examples. However, he ended by noting that more studies are needed to provide greater clarity on which combinations to use and whether or not the effects are cumulative.

Panel Discussion

Q: What is the mechanism of the up-regulation of SGLT-2 in diabetes? Is it reversible in any other interventions?

Dr. Lawrence Leiter (University of Toronto, Toronto, Canada):  We talked about upregulation of SGLT-2 for those who are hyperglycemic and why it occurs. How? We don’t know. It’s an adaptive change so that you don’t pee out all your glucose and can preserve energy; at the same time, it may be maladaptive as well as it will preserve hyperglycemia. Will anything reduce the up-regulation? I am not aware of any studies on that. I would assume with chronic euglycemia, the up-regulation should come down to normal. The original data was based on only five patients.

Dr. Stefano Del Prato (University of Pisa, Pisa, Italy): We have experimental data showing that hyperglycemia associated with a lack of regulation of SGLT-2 was normalization of expression. It’s a secondary phenomenon. One hypothesis is that hyperglycemia is the inability to use glucose.

Dr. Yehuda Handelsman (Metabolic Institute of America, Tarzana, CA): Why do we have fat on us even though there’s so much food available? The body doesn’t know; it knows it should keep fat as energy for long-term need when there might be famine. I’m more simplistic. I think SGLT-2 is there to make sure it brings every glucose molecule it sees back to the system, and it tries to do so until it cannot. It looks simple: you bring down glucose and it stops doing it because it’s not exposed to as much glucose. That’s a simplistic view. The question is can we prove it.

Dr. Zachary Bloomgarden (Mount Sinai Hospital, New York, NY): It’s fascinating to realize there’s no physiologic way we can imagine the situation of diabetes having evolutionary pressure to cause increased expression of SGLT-2. It’s probably a more epi-phenomenon of something that evolved in response to dietary sodium and secondarily to glucose loads, but it’s a detriment.

Dr. Handelsman: It points out the fact that what we think is simple never is. Some of us were involved when we used to think the effects of bariatric surgery were mechanical, but it’s actually a very complex biological phenomenon involved with gut action. When SGLT-2 inhibitors came out, we looked at them as putting a block on a gate, when in reality it’s a quite complex metabolic phenomenon. We’re changing how SGLT-2 works. Is maladaptation going on? I asked Dr. Weir before whether glucagon works in the kidney? He’s been doing this forever, but no one’s studied this. How many of you remembered that the kidney does gluconeogenesis? I bet the majority of you forgot until five years ago. The body does have energy management that’s involved in insulin resistance. It’s a protective mechanism, though that’s a different story. The body tries to protect itself.

Q: Could you please comment on the side effects of hypokalemia and the warning risk of bladder cancer in SGLT-2 inhibitors? How clinically relevant are these?

Dr. Weir: On potassium, the potassium signal is miniscule at best especially if you compare it to clinical practice and put the patient on anti-inflammatory drugs or ARBs. The latter two tend to boost potassium. If you see any change, you might see 0.1 or 0.2 with SGLT-2 and that’s under conditions that are pretty unusual. I’ve looked at databases and written papers. This signal is minimal compared to other commonly used drugs. In any other patients with diabetes, monitor potassium as you feel comfortable. If they’re taking other herbal supplements, just pay attention to it. But I don’t think twice about it.

Dr. Leiter: With regard to bladder cancer, in the dapagliflozin clinical trials, there was an imbalance in the number of bladder cancers in those subjects on dapagliflozin, although the numbers were small. There is no plausible mechanism for it. The vast majority of these subjects had hematuria at baseline or shortly thereafter so it was likely just pre-existing bladder cancer that was unmasked during the clinical trial. Furthermore, there are no SGLT-2 receptors found in the bladder and no animal models have shown increased risk for it or any other cancer. The large, ongoing trial with dapagliflozin is the DECLARE study which is designed to look not only at cardiovascular safety but also to have a sufficient number of bladder cancers to assess risk; there are over 17,000 patients in the study. Importantly, this is monitored by a DSMB and no concerns have been expressed to date about the risk of bladder cancer.

Dr. Handelsman: AACE put together a panel looking at diabetes and cancer and medications and how they may affect it, and we did use a basic scientist to look at the time to effect. In none of the drugs, including dapagliflozin, did we find anything relevant. It’s possible that the numbers will change but right now it’s good news. Has anyone felt that potassium elevation is an issue managing patients on SGLT-2 inhibitors? When you give a diuretic, sometimes you think there will be less potassium, not more. There’s some data in some patients, specifically those with renal impairment, to be careful.

Q: Is volume status related to the mechanism of weight loss?

Dr. Del Prato: It’s most likely the diuretic effect that’s responsible for the very early reduction, but maintenance over four years is unlikely due to the diuretic effect. If you calculate it, the amount of sugar you lose through the urine accounts for a good deal of the reduction in body weight. There have also been investigations looking at body composition showing a reduction in all components of adipose tissue, both visceral and subcutaneous. There’s a real reduction in adipose tissue, which accounts for the 3-4 kg body weight reduction. The diuretic effect is early, the same as you see with a diet. On a diet, the initial drop is liquid loss and then it’s fat mass.

Dr. Handelsman: Any study with any drug compared to sulfonylureas showed similar results. It’s pretty much line in with everything.

Q: What are the effects on heart failure?

Dr. Leiter: In the five ongoing cardiovascular outcomes studies with SGLT-2 inhibitors, heart failure will be assessed and adjudicated as one of the clinical endpoints. To my knowledge, no study has been initiated specifically in patients with heart failure.

Dr. Handelsman: It’ll be interesting to see what the long-term effect will be. There’s a very small reduction in blood pressure. I don’t think it’s direct one to one but it’s possible.

Q: Initially based on its mechanism, we expected that SGLT-2 inhibitors should be more capable at lowering postprandial glucose. The recently announced guideline didn’t endorse them as a good choice for reducing postprandial glucose. In general, the overall data showed they were more reliable in reducing fasting glucose. What explains the lack of a postprandial effect?

Dr. Del Prato: I think the system works as a function, which has been explained: the more glucose the tubule sees, the more is lost through the urine. If you consider that the postprandial period is limited in duration compared to the non-postprandial period, the cumulative effect may be greater on fasting glucose, but the effect on postprandial glucose is there as well. I’m not sure I understand what you mean by a lack of effect.

Q: I mean it’s supposed to be more reliably dose-dependent on lowering postprandial glucose, but the published trials suggest that’s not the case.

Dr. Del Prato: Dr. Leiter alluded to that. We think that may be a compensatory mechanism from SGLT-1. Any time you increase the tubular load, more glucose is not reabsorbed by SGLT-2 but is available for SGLT-1. It accounts for more than 10% of the reabsorption, and now with a larger volume, it may reduce the effect.

Dr. Handelsman: The system works the moment it gets glucose. It’s the fastest thing it’ll respond to. I caution you not to rely primarily on phase 3 studies to assess postprandial effects. That’s true for all drugs. The FDA designed trials not to capture prandial glucose. That’s why in publications, you see differently. The clinical effects are quite impressive on both fasting and prandial. DPP-4 inhibitors have more effects on prandial than on fasting. GLP-1 works on the whole story. SGLT-2s also see prandial over fasting.

Q: Do we currently know how this drug’s mechanism increases LDL-cholesterol? Any mechanism?

Dr. Leiter: We don’t have a good explanation. These drugs do tend to raise LDL by a small amount of about 2%-3%. The higher dose of canagliflozin may raise it a little more by about 4%-5%. We don’t know why. Other diuretics also lead to a small increase in LDL. Another hypothesis is that we know there is compensatory overeating in patients on SGLT-2 inhibitors that limit the extent of weight loss; perhaps there is also a change in macronutrient consumption. But that’s totally speculative. There are no studies on food selection.

Dr. Handelsman: HDL also goes up. LDL barely changes. Clinically, hopefully long-term studies will show relative efficacy. ADA wants everyone on statins.

Q: Is there any relevant information about reduction in uric acid for renal protection and as a cardiovascular risk protector?

Dr. Weir: I’m not aware of consistent effects of SGLT-2 inhibitors on uric acid. If there are, they’re modest at best. I’m not aware of data tying uric acid to cardiovascular events. There is a directionality in the relationship to kidney function, but we don’t know which association drives what. That area needs to be explored. There may be interest in hypouricemic therapies, but they’re not prime time.

Satellite Corporate Event

Lexicon Pharmaceuticals Meet the Expert Session

John Buse, MD, PhD (UNC, Chapel Hill, NC), Paul Strumph, MD (Lexicon, The Woodlands, TX), David Powell, MD (Lexicon, The Woodlands, TX)

Lexicon hosted an evening meet-the-experts session following the presentation of positive phase 2 data on its SGLT-1/SGLT-2 dual inhibitor sotagliflozin earlier in the day. The panel discussion at the evening event touched upon the recent concerns about euglycemic ketoacidosis with selective SGLT-2 inhibitors, partly in response to questions about the two cases of DKA observed in the sotagliflozin trial. Dr. John Buse noted that both cases were assessed as pump related and were “clearly” not euglycemic. More broadly, in remarks reminiscent of his presentation on this subject at AACE, Dr. Buse suggested that the phenomenon is unlikely to be a “showstopper” for SGLT-2 inhibitors as long as people are aware of it and know how to treat it. Dr. Paul Strumph expressed hope that future trials will demonstrate a lower risk of DKA with SGLT-1/SGLT-2 dual inhibitors than selective SGLT-2 inhibitors, as the dual inhibitors cause less volume depletion and increase GLP-1 levels, both of which should help reduce the risk of excess ketones. With outcomes data soon to arrive for SGLT-2 selective inhibitors, we wonder if Lexicon may look into ways to more conclusively prove this suspected advantage. See below for a full transcription of the panel discussion, which also addressed topics including sotagliflozin’s effects on blood pressure, LDL cholesterol, and the GI tract as well as Lexicon’s development plans – Dr. Strumph confirmed that phase 3 is ongoing but declined to speculate on a launch timeline.

Panel Discussion

Q: Do you think DKA will be a showstopper in type 1 diabetes?

Dr. Strumph: I assume you mean with compounds in the SGLT-2 inhibitor class. It will be a risk-benefit decision. We now know that DKA with SGLT-2 selective inhibitors can be masked or present differently than practitioners are used to. It’s a burden on everyone in the field. We are a dual inhibitor, but we still have a burden to generate data to indicate that with appropriate protocols. We’re informing investigators and patients that DKA may be present and we will come to the regulatory authorities with a complete dataset showing risk and benefit. We believe the risk of DKA is still to be determined but with appropriate protocols, data will be available and it’s worth moving forward. So far, DKA is treatable if recognized early. DKA occurs in type 1 diabetes. It occurs in 5% of people every year on average. If the A1c is above 10%, it’s 20% per year. We’ve trained people to check ketones if they feel sick and their sugar is above a certain level. Now we have to train them to just check ketones if they feel sick. If it’s positive, implement “sick day rules” for treatment of ketones, which include frequent injections of short-acting insulin, and contact your doctor for further instructions. Ketosis can be treated and is usually reversible.

Dr. Buse: I’m pretty certain that in the Wild Wild West of people taking SGLT-2 inhibitors off label, for those therapeutic zealots, the rate of DKA is probably 10%. It’s maybe twice what you’d expect. The problem is only the euglycemic part. If we had a way of figuring that out, there would be no major issue. And we do, we tell people to check ketones if they don’t feel well, period. I suspect it will work out well. I’ve counseled patients not to take SGLT-2 inhibitors if they’ve had DKA, but if they want to, lower doses are less likely to be associated with DKA than the full dose that many take for weight loss. I don’t think it’s a showstopper or deal-breaker.

Q: What are the odds of the drug not getting to market?

Dr. Strumph: We’re coming to the market.

Q: Has the safety committee reviewed the decision that the DKA cases were due to the pump rather than the drug in view of recent reports?

Dr. Buse: The short answer is no because there was no DSMB. The longer answer is that it’s arguable who started the hoopla about this, but I think it was me, and the first case of DKA I saw was in this trial. One of the two cases was in our site and was clearly a pump issue. There was other stuff going on. There was nothing euglycemic about this. The person’s sugar was like 560 mg/dl. It was regular old DKA. I’m confident about that case. I’ve seen the details of the other and it also seems like a pump malfunction and was not euglycemic. It’s not like the cases that have been reported.

Q: The euglycemic cases might stand out because they’re unusual but if it’s happening to others, people might just be shrugging their shoulders.

Dr. Buse: We’ve done a database search. The index case for me was a person who, having seen the results in this trial, decided to do it on her own with canagliflozin and her personal physician and she got DKA. I would say there are a number of things SGLT-2 inhibitors do that might tip the balance. Less insulin exposure, more glucagon, volume constriction – a number of things make it easier. Some are less likely with an SGLT-1/SGLT-2 dual inhibitor. I’ve done a database search of 1,560 patients prescribed an SGLT-2 inhibitor and ten cases seem to be ketoacidosis in the setting of SGLT-2 inhibitor therapy. Nine out of ten have a glucose under 300 mg/dl. It’s mostly euglycemic. There are other cases of real DKA as well.

Dr. Strumph: It may be different with a dual inhibitor and I would like to provide data that it is different. First, I believe we will at least meet what’s out there on the market in terms of efficacy and based on lower urinary glucose excretion. With less glucuresis, you have less likelihood of volume depletion. If that’s true, and we will have to demonstrate it, but that would be less of a known risk factor for ketoacidosis. Additionally, we’ve seen a published preclinical study and since then some clinical studies showing that GLP-1 agonism decreases ketosis and decreases glucagon. We have provided data in this study, in type 2 diabetes, in healthy volunteers, and preclinically that GLP-1 increases with our drug and not with the selective SGLT-2 inhibitors. So two risk factors for ketosis may be less with our drug. Again, that’s forward-looking and we need data, but I look forward to being in the race.

Q: When are you planning to launch in the EU and the US?

Dr. Strumph: We’re in phase 3 and the completion date is public. I wouldn’t have a job if I talked about the launch date.

Q: What was the 24-hour increase in urinary glucose excretion?

Dr. Paul Strumph (Lexicon, The Woodlands, TX): We don’t have the 24-hour urinary glucose excretion data in type 1 diabetes, but we have data indicating a three-fold increase over three hours vs. placebo. We need to provide that data at a later time. In our type 2 diabetes dose-ranging study, the 24-hour range was between 50 and 60 mg with sotagliflozin vs. 15-20 g with placebo. Urinary excretion plateaued at 200 mg/day and didn’t increase with the maximum dose of 400 mg/day yet glycemic efficacy was better, consistent with the difference being the local effect on the GI tract of SGLT-1.

Q: How much ingested carbohydrate was not absorbed with sotagliflozin vs. control?

Dr. Strumph: We don’t have data in humans.

Q: Is GLP-1 increased?

Dr. Strumph: It is increased. In the type 1 diabetes study we only measured it at the mixed meal at breakfast, so we don’t have full data in type 1 diabetes.

Dr. David Powell (Lexicon, The Woodlands, TX): When we treated diabetic mice with sotagliflozin, we saw a marked increase in glucose in the small intestine and colon along with a decrease in the pH of colon contents, which we assume is due to fermentation of glucose to short-chain fatty acids in the colon. This dramatically increased circulating GLP-1 and PYY levels. The delayed glucose absorption, accompanied by blunted blood glucose excursions and increased GLP-1 levels, are all due to SGLT-1 inhibition and contribute to the improved glycemic control. We did not perform a study in these mice that quantitated the extent of glucose absorption.

Dr. John Buse (UNC, Chapel Hill, NC): I bet you won’t find much glucose in the stool. Malabsorption doesn’t really happen.

Dr. Powell: I agree, what we see is delayed glucose absorption. Some of the glucose is ultimately absorbed as short-chain fatty acids. This is an advantage because short-chain fatty acids are potent inducers of GLP-1 and PYY release by the colon.

Q: Should I be concerned about GI side effects?

Dr. Buse: It seems simple. The answer is yes, you should be concerned given the discussion about SGLT-1 inhibitors, but now you should be relieved because we did the experiment and there were no GI adverse events. There was mild nausea in three patients for one day early in therapy. It’s not an unreasonable concern, but it’s largely been mitigated.

Dr. Powell: If you look at humans treated with SGLT-1 inhibitors or people who lack SGLT-1 and eat a diet that contains some glucose, they may not have diarrhea from the dietary glucose but they may have abdominal pain and nausea. The mechanism depends on delayed glucose absorption in the small intestine. If enough glucose is eaten, they have symptoms. Humans lacking SGLT-1 tolerate glucose-containing diets over time. Mice fed a glucose-containing diet have diarrhea after receiving a high enough dose of a selective SGLT-1 inhibitor, but they adapt quickly. After a few days the diarrhea often completely resolves on the same diet and same dose of the inhibitor.

Dr. Buse: If you swallow the tablet, SGLT-1 is on the luminal side, and you have liquid sotagliflozin flowing past SGLT-1 and inhibiting those. Then the liquid keeps heading south and some is absorbed. How much of the SGLT-1 inhibition is first-pass on the luminal side and how much is in a steady state between the plasma and free exchange?

Dr. Powell: I don’t know if there’s much SGLT-1 inhibition from the systemic side. The SGLT-1 inhibition appears to occur on the luminal side. In the laboratory, we incubated sotagliflozin with cells expressing SGLT-1 and then tried to wash the sotagliflozin off. We found that the cells were unable to transport glucose for many hours after washing. Either sotagliflozin has a slow off-rate from SGLT-1 or it gets into the cells, can’t be washed off, and somehow inhibits SGLT-1 this way. I don’t totally understand the mechanism, but this inhibition may be more prolonged for sotagliflozin than for most SGLT-1 inhibitors that have been studied.

Dr. Buse: You have numerical insulin dose reductions that are similar across all meals and statistically positive for breakfast. How much of that is the tablet tumbling in front of the meal?

Dr. Powell: I was surprised how long glucose transport mediated by SGLT-1 was inhibited in cultured cells after sotagliflozin was washed off. I believe this effect explains why sotagliflozin has a prolonged ability to inhibit intestinal SGLT-1 in individuals with diabetes.

Q: What happens to LDL?

Dr. Strumph: There’s a small increase of 2-3 mg/dl, similar to SGLT-2 inhibitors. We don’t have much data in type 1 diabetes, but in type 2 diabetes it’s consistent with the SGLT-2 selective inhibitors.

Q: What has given you the confidence to run phase 3 trials in parallel?

Dr. Strumph: It’s the same confidence that has allowed all of the type 1 and 2 diabetes programs I’m aware of to not do trials serially by the time you get to phase 3. I can’t speak to what other SGLT-2 inhibitor companies are doing in type 1 diabetes, but it’s fairly common in diabetes, in type 1 diabetes insulin studies and type 2 diabetes insulin and molecule studies to do phase 3 in parallel. It’s too prolonged a process with a limited patent life to do long studies in series.

Q: What are the effects, if any, of sotagliflozin on blood pressure?

Dr. Strumph: It has been published in Diabetes Care that sotagliflozin demonstrated a reduction in blood pressure in type 2 diabetes. It was a dose-ranging study with 60 patients per arm, and with systolic blood pressure greater than 130 mm Hg, there was a reduction of 14 mm Hg. For normotensive people, a reduction was not seen. That’s very encouraging. The SGLT class tends to lower blood pressure, and we may be able to define better utility in type 1 diabetes lowering blood pressure. In the current study, placebo lowered blood pressure 3.9 mm Hg and sotagliflozin lowered it 4.9 mm Hg, so there was no difference.Q: What would happen if you added an alpha-glucosidase inhibitor?

Dr. Powell: Alpha-glucosidase inhibitors block absorption of glucose that is present in complex sugars. Unlike sotagliflozin, they do not inhibit the absorption of simple glucose molecules. The effect of both together would be additive at best in terms of efficacy.

Product Theater

Invokana: An Individualized Approach to the Treatment of Adults with Type 2 Diabetes (Sponsored by Janssen)

Serge Jabbour, MD (Jefferson University, Philadelphia, PA)

In this packed product theater, Dr. Serge Jabbour discussed J&J’s Invokana’s (canagliflozin) mechanism of action, its utility across a broad range of adult patients with type 2 diabetes, its dosing and administration, and its use in those with moderate renal impairment. He noted that in clinical trials, Invokana was effective and well tolerated across various circumstances – as monotherapy, in dual therapy, in triple therapy, in older patients, and with insulin. In particular, Dr. Jabbour highlighted that Invokana produced greater A1c reductions, less hypoglycemia, and more weight loss compared to glimepiride. He pointed out that in clinical trials, the top four most common adverse events were female genital mycotic infections (10-11%), urinary tract infections (4.3-5.9%), increased urination (4-5%), and male mycotic infections (~4%). He commented that if his patients experienced mycotic infections as a result of Invokana treatment, he would not discontinue Invokana, but rather, treat the infection. In closing, Dr. Jabbour mentioned that Invokana has been prescribed over 3 million times since launch, and has 75% preferred commercial and Medicare access – in a product theater at AACE, Dr. James Gavin (Emory University, Atlanta, GA) noted that these statistics are already out of date, as Invokana has now reached over 4 million prescriptions and achieved 80% coverage. During the subsequent panel discussion, Dr. Carol Wysham (Rockwood Clinic, Spokane, WA) and Dr. Jabbour both commented that ketoacidosis has been a rare occurrence among individuals taking SGLT-2 inhibitors; though this may be the case, Dr. Wysham intimated that these agents should be used with caution for patients with type 1 diabetes. 

Panel Discussion

Serge Jabbour, MD (Jefferson University, Philadelphia, PA), Carol Wysham, MD (Rockwood Clinic, Spokane, WA), and Greg Mitchell, MD (Anne Arundel Medical Center, Annapolis, MD)

Q: Can you discuss the potential risk of ketoacidosis with Invokana?

Dr. Wysham: There were 20 reports of ketoacidosis [captured by the FDA adverse event reporting system] among those who had been started on SGLT-2 inhibitor therapy. There is very little description of the cases themselves. Some were individuals with type 1 diabetes. Some had a precipitating cause – surgery, trauma, infection, dehydration. It appears to be a rare complication – over 400,000 patients or so received treatment in the reporting timeframe. It does appear that things that affect dehydration/food intake may be the precipitating cause. The problem is that we don’t understand the patient characteristics in detail. We suspect a significant proportion of them were on insulin, and that their doses were reduced upon starting the medication. Furthermore, when they get normal glucose values, they feel like they don’t need to take (as much) insulin, so I suspect some patients made additional adjustments.

Dr. Jabbour: Janssen looked at 17,000 patients – 10,000 in their phase 3 trials, and 7,000 in other trials. The incidence of ketoacidosis was less than 0.1%. It was very rare. There were only a small number of patients who experienced ketoacidosis. I wouldn’t change the way I practice on a daily basis because of this risk.

Dr. Wysham: We have patients with longstanding diabetes on MDI, and some are on insulin pumps. For those individuals, I would contemplate measuring C-peptide before they use an SGLT-2 inhibitor, just to make sure we are not dealing with someone who is so insulin deficient that they are at risk of ketoacidosis. 

Q: Is there any difference between the three SGLT-2 inhibitors?

Dr. Wysham: We don’t have any head-to-head studies so it’s really difficult to project any differences. There was a small study that looked specifically at the differences in urinary glucose excretion with dapagliflozin and canagliflozin. There was more urinary glucose excretion with canagliflozin. That’s the only head-to-head study I’m aware of, and it was in individuals without diabetes.

Dr. Mitchell: Canagliflozin is indicated for GFRs as low as 45, whereas dapagliflozin is only indicated for use in patients with eGFRs of 60 or above. In comparing selectivity, dapagliflozin may be a bit more selective. Canagliflozin has a bit of SGLT-1 inhibition, which may be the mechanism by which the 300 mg dose reduces postprandial glucose absorption.

Q: Is there a benefit of SGLT-2 inhibitors versus GLP-1 agonists?

Dr. Wysham: There are no head-to-head studies comparing the agents in terms of A1c. Both are effective, and both are associated with reductions in weight. Often times patients prefer orals over injectables.

Q: Are there any studies in type 1 diabetes?

Dr. Wysham: Phase 2 studies are in progress, but in light of the new reports of ketoacidosis, we should tread very lightly on that therapy [for use in type 1 diabetes].

Product Theater

SGLT-2 and DPP-4 Inhibition: Multiple Options for Improved Glycemic Control in Adults with Type 2 Diabetes (Sponsored by Lilly/BI)

James Gavin, MD, PhD (Emory University, Atlanta, GA)

Dr. James Gavin provided an overview of clinical considerations for prescribing BI/Lilly’s SGLT-2 inhibitor Jardiance (empagliflozin) and SGLT-2/DPP-4 dual inhibitor Glyxambi (empagliflozin/linagliptin). He placed a strong emphasis on the need for early combination therapy and extra-glycemic effects. At one point in his remarks he made an implicit contrast to J&J’s Invokana, stating that with Jardiance and Glyxambi, there is no need to adjust dosing based on GFR, just a hard cutoff of 45 ml/min/1.73 m² below which the drug is contraindicated. Conspicuously missing from the presentation was discussion of the cases of SGLT-2 inhibitor-associated ketoacidosis recently addressed by FDA. This was by far the audience’s most significant concern during Q&A. Dr. Gavin framed the unexpected ketoacidosis as a problem seen more in people already under some other sort of physiological stress, people using the drug off label (e.g., people with type 1 diabetes), and as an issue that providers can teach patients to monitor and avoid.

Questions and Answers

Q: I see that the risk of ketoacidosis is on many people’s minds.

A: The FDA announced a case series of some 20 cases or so. It is important to contextualize this. I don’t want to trivialize the fact that this was an important clinical observation in patients treated with SGLT-2 inhibitors. These patients were mostly type 1 patients, so they were using the drug off label. There were a few type 2 patients as well. In most instances, again to contextualize this, these are patients who were already under some form of stress. For example, surgical patients, hospitalized patients, patients who had reasons to be less hydrated than they should have been, and patients who were probably under-insulinized in the face of high glucagon levels, which would set up them up for increased ketone formation. Historically, the way we have taught patients is to use their blood glucose as a signal for being aware of ketone levels. If the blood glucose was high and they felt sick, that’s when we’ve told them to check ketones. We know now with these SGLT-2 inhibitors, we’ve removed the hyperglycemic signal as an alert for checking ketones. So we have to revise our old advice. Now we have to tell patients that if they are unable to remain hydrated or if they feel sick they may need to start checking ketones independently of what their glucose level is. That’s the only way we’ll know.

Q: Was there any evidence of synergism in therapeutic efficacy for Glyxambi?

A: One thing we’ve been puzzled about is the absence of a dose response relationship as we go from a certain dose to double or triple that dose. And then when we add different agents, if one agent has a 0.7% lowering of A1c and the other has a 0.8% ability, we don’t predictably always see 1.5% (additive) reductions or greater. That is simply not the physiology of these agents. And this is not new. We see this over and over. The only explanation I can offer is the closer you get to normal, the more difficult it is to see huge leaps beyond that. Which is why I’m encouraged by what I see with this fixed dose combination in the form of empagliflozin/linagliptin. We’re seeing people actually get to goal. This is 6.7-6.9% A1c. We see a level of efficacy that is still highly impressive even if not synergistic. One other principle – we’ve talked about this for years. There is much more benefit of submaximal doses of different agents working in concert than maximizing the dose of a single agent. We’re also seeing this come to light here.

Q: Has there been any trial of these drugs in teenagers?

A: I don’t think there’s a trial underway. There are some pediatric trials under way with some therapies including a DPP-4 inhibitor. I am not aware of any SGLT-2 inhibitors and certainly nothing with a combination product.

GLP-1 Agonists

Oral Presentations: The Evaluation of Lixisenatide in Acute Coronary Syndrome – The Results of ELIXA

Introduction

Rafael Diaz, MD (Estudios Cardiológicos Latinoamérica, Rosario, Argentina)

Dr. Rafael Diaz provided some context for the ELIXA results by discussing the enormous burden of diabetes and the associated excess risk of cardiovascular disease and mortality. He emphasized the complexity of the factors that contribute to CV risk and the need for a treatment approach that addresses multiple risk factors, including blood glucose. Notably, he focused specifically on the potential for cardioprotection with GLP-1 agonists, saying that ELIXA was designed to assess the potential beneficial effects of lixisenatide as well as its safety profile. This is somewhat surprising to us, as we might have expected speakers to emphasize the study’s primary objective of non-inferiority in order to discourage an overly negative interpretation of the results.

ELIXA Design and Baseline

Eldrin Lewis, MD (Brigham and Women’s Hospital, Boston, MA)

This double blind study randomized 6,068 patients with type 2 diabetes 1:1 to the short-acting prandial GLP-1 agonist Lyxumia (lixisenatide) or matching placebo. Patients were started on an initial dose of 10 ug/day lixisenatide that was down- or up-titrated to a maximum of 20 ug/day during a seven-day run-in period. All patients were within 180 days of an acute coronary syndrome event. The study’s primary composite endpoints were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina. Secondary endpoints included all-cause death, the percent change in urinary albumin/creatinine ratio from baseline to 108 weeks, the incidence of a primary endpoint + hospitalization for heart failure, and the incidence of a primary endpoints + hospitalization for heart failure + coronary revascularization. In terms of baseline characteristics, there were no significant differences between the groups’ lipid profiles, other cardiovascular risk factors, or baseline medications. For perspective, the international trial included 49 countries and 782 sites: 32% of patients were enrolled in Lain America, 26% in Central and Eastern Europe, 12-13% in North America, Northern and Southern Europe, and Asia Pacific, and 5% in Asia and Africa.

Results

Matthew Riddle, MD (OHSU, Portland, OR) and Marc Pfeffer, MD, PhD (Brigham and Women’s Hospital, Boston, MA)

Results from the ELIXA CVOT for Sanofi’s Lyxumia (lixisenatide) were resoundingly neutral. The hazard ratio for MACE was 1.02 (95% CI: 0.89-1.17), and the hazard ratios were also neutral for the expanded composite (MACE + unstable angina; HR 1.02 [0.89-1.17]), heart failure hospitalization (HR: 0.96 [0.75-1.23]), and all-cause death (HR: 0.94 [0.78-1.13]). No cardiovascular subgroup analyses deviated from neutrality and the Kaplan-Meier curves were fairly superimposable. Unfortunately, there was not even a hint of cardioprotection emerging towards the end of the trial. There were very modest average reductions in weight (0.7 kg [~2 lbs]) and systolic blood pressure (0.8 mmHg) with Lyxumia, with no effect on heart rate for most of the trial following a transitory 1 BPM increase over the first few weeks. Interestingly there was a slight attenuation in the usual rise in albuminuria over time (24% increase over two years with lixisenatide vs 34% with placebo; p<0.01), although it was far from a conclusive signal and there was no significant change in eGFR. Nausea and vomiting were increased roughly 3x but comparable with other lixisenatide trials, with discontinuation in just under 5% of lixisenatide patients due to GI side effects – this drove a very modest imbalance in overall adverse events (odds ratio: 1.3; 95% CI [1.1-1.5]), though severe adverse events were balanced (odds ratio: 0.9; 95% CI [0.8-1.0]). We were glad to see that there was no increase in pancreatitis or pancreatic cancer (neoplasms were actually imbalanced in lixisenatide’s favor). 

• Primary outcome: There was no significant difference in the primary endpoints of MACE + unstable angina: 13.4% (lixisenatide) vs. 13.2% (control). The hazard ratio was 1.02 (95% CI: 0.89-1.17; p<0.001). No subgroup analyses showed significant differences either: (i) cardiovascular morality was 5.2% (lixisenatide) vs. 5.1% (control); (ii) fatal/non-fatal myocardial infarction was 8.6% (lixisenatide) vs. 8.9% (control); (iii) fatal/non-fatal stroke was 2.0% (lixisenatide) vs. 2.2% (control), and unstable angina was 0.3%  (lixisenatide) vs. 0.4% (control). Hazard ratios were 0.98 (95% CI: 0.78-1.22) for cardiovascular morality, 1.03 (087-1.22) for fatal/non-fatal myocardial infarction, 1.12 (0.79-1.58) for fatal/non-fatal stroke, and 1.11 (0.47-2.62) for unstable angina. No subgroup analyses (gender, race, racial category, or region) caused any heterogeneity for the primary MACE+ outcome.
• Secondary outcomes: Hazard ratios were also neutral for the expanded composite: MACE + unstable angina + heart failure hospitalization (HR 0.97 [0.85-1.10]); MACE + unstable angina + heart failure hospitalization + coronary revascularization (HR 1.00 [0.90-1.11]); heart failure hospitalization (HR: 0.96 [0.75-1.23]), cardiovascular mortality + heart failure hospitalization (HR: 0.97: 0.82-1.16) and all-cause death (HR: 0.94 [0.78-1.13]).
• Other outcomes: Stratification by history of heart failure did not deviate from neutrality either. For heart failure hospitalization, hazard ratios were 0.93 (0.66-1.30) for patients with a history of heart failure and 0.97 (0.67-1.40) for patients without a history of heart failure – heart failure received slightly more attention due to recent theories of effects on heart failure with DPP-4 inhibitors, the other major type of incretin-based drug. For cardiovascular mortality + heart failure + hospitalization, hazard ratios were 0.97 (0.75-1.24) for patients with a history of heart failure and 0.96 (0.75-1.23) for patients without a history of heart failure.
• Glycemic control: There was a marginal improvement in A1c of 0.3% with Lyxumia that followed a “Nike swoosh” pattern, falling immediately after treatment initiation but then rising with time. The same relationship over time was seen with fasting plasma glucose, which dropped an average of ~5 mg/dl. Despite these improvements, the rate of hypoglycemia (28 per 100 patient-years) and severe hypoglycemia (0.3 per 100 patient-years) in lixisenatide patients was not elevated relative to placebo (26 per 100 patient-years and 0.6 per 100 patient-years, respectively).
• Cardiovascular risk factors: There were marginal improvements in weight (0.7 kg [~2 lbs]) and systolic blood pressure (0.8 mmHg), with no effect on heart rate (+0.4 beats/minute). There was a slight attenuation in the rise in albuminuria over time (24% increase over two years with lixisenatide vs. 34% with placebo; p<0.01) highlighted in the presentation – there is no clear cause and this could be a chance finding, but we hope it spurs at least some degree of further study.
• Non-cardiovascular side effects: Rates of diarrhea did not differ between the two arms though nausea and vomiting were increased roughly 3x (odds ratio: 8.4; 95% CI [4.8-15.9]) – this increase is comparable with other lixisenatide trials. There was a slight increase in the number of events leading to discontinuation of treatment (odds ratio: 1.7; 95% CI [1.4-2.9]) driven largely by GI side effects on lixisenatide patients (odds ratio: 4.2; 95% CI [2.9-6.2]). We were glad to see that there was no concern of systemic allergies associated with lixisenatide (5 events in each arm). Overall on-study malignancy showed no concerning signals as well with 89 diagnoses in lixisenatide patients vs. 78 in placebo. Sub-group analysis suggested no specific cancer rates were elevated either.
  
  • Notably, there was also no significant increase in pancreatitis (8 events vs. 5 events), although the number of events was small. We hear it increasingly acknowledged that acute pancreatitis may be a real side effect with incretin-based therapies, although if it is the risk appears to be acceptably small.   
• Changes in medications: There was an increase in the use of insulin, metformin, and SFUs in patients on placebo and a slight decrease in patients on Lyxumia.

ELIXA in Perspective

Hertzel Gerstein, MD (McMaster University, Hamilton, Ontario, Canada)

Though not particularly adventurous in terms of speculation or hypothesizing, we thought Dr. Hertzel Gerstein’s presentation did a very valuable job contextualizing the results from ELIXA. At multiple points, he put a positive spin on findings that could otherwise be perceived as neutral. For example, although the primary finding of cardiovascular neutrality perhaps fell short of the most optimistic expectations, Dr. Gerstein reminded the audience that glucose lowering is a proven and important goal in and of itself due to the impact on microvascular complications. He also characterized the modest 0.3% A1c difference between groups as a positive for lixisenatide; after all, investigators were using other agents in the placebo group to try and achieve the same targets and lixisenatide still came out ahead in terms of A1c. Dr. Gerstein noted that the unique study population (very high risk post-ACS patients) impacts how the findings can be generalized – other GLP-1 agonist CVOTs, he noted, do not enroll patients at the same level of risk.

Discussant

Silvio Inzucchi, MD (Yale School of Medicine, New Haven, Connecticut)

Dr. Silvio Inzucchi offered a very astute take on the implications of the ELIXA results for the broader questions surrounding type 2 diabetes drugs and cardiovascular disease. He began with a strong endorsement of the trial’s rigor and assured clinicians that it had convincingly answered the important question of whether lixisenatide is associated with excess cardiovascular risk. He then reviewed the existing data on the relationship between glycemic control and cardiovascular disease, concluding that sustained glucose reduction appears to provide a benefit but that it accrues over a very long time period (certainly longer than the duration of ELIXA and other CVOTs) and is likely attenuated in patients with existing cardiovascular disease. With regard to the effects of specific drugs, Dr. Inzucchi discussed the limited data available and emphasized the challenges of distinguishing the effects of specific agents from the impact of glucose-lowering itself. Overall, he predicted that ongoing CVOTs for diabetes drugs are unlikely to demonstrate cardioprotection unless a drug has dramatic off-target cardiovascular effect, which is unlikely. He raised several important broad questions about whether these trials are being designed in the best way possible and whether they are worth the enormous cost. However, he ended on a tantalizing note with a picture of a theoretical future ADA/EASD treatment algorithm in which the long current list of second-line therapies was simply replaced with a “drug X” that had achieved the “holy grail” of demonstrating CV benefit.

Panel Discussion

Q: This was a very well done study telling us a lot of important messages. However, as a clinical endocrinologist looking into aspects of hypoglycemia, it might be of interest to see what the change in insulin dose was. We’ve been told that the same number of people were on insulin in both groups, and the same with sulfonylureas, yet the protocol asked for a reduction.

Dr. Pfeffer: This was the first presentation and the data just went to the academic group for analysis. I can tell you the numbers but I don’t have granularity at this point.

Dr. Riddle: It’s a good question. We have access to the data but it hasn’t been analyzed, which we hope to get to soon enough. It will be interesting to know exactly how the doctors at the sites did manipulate the dose and what relationship the changes had to any outcomes.

Q: I noticed that there were regional differences in different parts of the world. What was the result in the Asian subgroup? Was it better than in the rest of world?

A: At this moment, I can’t tell you about the subgroups. We’re working on that analysis. Quite naturally, some groups are going to be on one side or the other. No group was out far enough that it caught our eye. Notably, North America was in the right direction. We still have to figure out the numbers.

Press Conference: ELIXA

ELIXA Press Conference – Selected Q&A

Matthew Riddle, MD (OHSU, Portland, OR) & Dr. Marc Pfeffer, MD, PhD (Brigham and Women’s Hospital, Boston, MA)

Q: If there is no benefit, why take this drug and subject patients to adverse events?

Dr. Riddle: This was not a glucose control comparison trial. This was a trial designed to see if there was any risk with this drug compared to other forms of treatment used. There was the possibility that the drug itself, independent of glucose control, could have favorable or unfavorable effects. In clinical practice, all diabetes drugs are used sequentially and in combination, with the goal of attaining the best possible glucose control without undue side effects, namely hypoglycemia. In another setting than this trial design, it seems rather likely that GLP-1 agonists could be used to improve glucose control, thereby reducing microvascular complications. Long term data from trials like DCCT/EDIC and UGDP show that glucose control can protect against cardiovascular disease. There is no reason from these results not to use GLP-1 agonists as another tool in the toolbox to maintain good glucose control.

Q: When GLP-1 agonists were first introduced, there was a hope that they would improve cardiovascular disease. Now these studies are coming out neutral. Are we content with these safety trials?

Dr. Pfeffer: It depends what you mean by working. They work by lowering A1c, and that can be proven with 200 patients. This safety issue is another elusive story, and we’re giving you the first installment. It’s my understanding that there are four other trials with different designs looking at cardiovascular end points. None will have 15-year follow up, so we’re all looking for short-term benefit, which in our case was not there, nor was there any short-term harm.

Q: Are your results transposable to other GLP-1 agonists, especially the longer-acting ones?

Dr. Riddle: The results are probably generalizable to broad populations since we had such a diverse collection of patients enrolled, but the generalizability of these findings for an individual GLP-1 agonists to the entire class is less certain. Especially vs. the longer-acting agents, the effective duration of action is very different. Whether this has an effect on cardiovascular risk or not is completely unknown. We know it has an effect on the best concurrent therapies. We advised investigators on the use of insulin and sulfonylureas during the daytime to protect against daytime hypoglycemia. Fortunately, as you know, there are other long-term safety trials being done with other long-acting GLP-1 agonists.

Q: You mentioned side effects like nausea. If the hope of benefit is only after 20 years of treatment, does this mean that we should not use this drug for patients over age 60 who may not reach another 20 years?

Dr. Pfeffer: From a cardiovascular point of view, we’ve always felt that concentrating on known conventional risk factors like lipids and blood pressure is what we should really be doing. But there is a focus on A1c not just for cardiovascular reasons. To treat the whole patient, we can’t ignore the other effects of glycemia. Nausea and vomiting are true side effects, but when you look at severe adverse events there was no difference vs. placebo. If a patient has trouble tolerating the agent, they of course should not be taking it, but most patients did not have serious trouble. Then it’s a question of how you can best control a person’s glucose over their lifetime.

Dr. Riddle: A sixty-year-old patients who is reasonably healthy at that age has upwards of twenty years life expectancy, which is plenty of time to accrue microvascular complications like retinopathy and neuropathy, which affect quality of life. There is some reason to predict that intervention at that age will make a difference for some patients, even if there is no effect on cardiovascular disease. Another point is that other agents we might use to treat glucose have other significant side effects. Insulin has hypoglycemia risk. This class has nausea in the range of 3-5% of patients who find it unacceptable. The proportion is about the same for metformin. Everyone is apparently enthusiastic about metformin, but about 5% of people can’t tolerate it.

Q: When you and your team designed ELIXA, was it clear from the beginning that this would only be a trial to rule out excess risk, or did you think it had the potential to show superiority?

A: In the design phase of this trial, the executive committee wanted the resources to do a superiority trial, which we did. We had enough events to be able to say that in this patient population, we did not see a benefit. We could have simply met the FDA guidance with a simpler and smaller study. We met the FDA guidance, we are safe by that rule, and we are comfortable telling you that we could not find a cardiovascular benefit.

Q: Is there any plan for a passive follow-up of this cohort to see if a benefit could emerge later on?

A: That is not happening, but what we will be able to do is further probe this data with biomarkers, dissecting out the population for risk based on novel biomarkers and conventional biomarkers.

Q: In terms of the amount of information that clinicians are getting out of these cardiovascular safety trials, is it panning out to be worthwhile, or could these resources be better used to do outcomes studies that would compare different regimens in a way that might show a benefit of one regimen over another?

Dr. Pfeffer: This question has nothing to do with our trial but with the climate in general. In 2008 when the question was raised whether these drugs were helping or hurting patients, the response was what you’re seeing. There are 140,000 human beings randomized into trials like others. This is the issue we have when an approval process is based on a surrogate, be it blood pressure, LDL, or hemoglobin A1c. You can get approved by doing something nice to the surrogate, but always in the back of your mind you’ll have that question. So, where should resources be spent? I feel very comfortable providing reassurance in this high-risk patient population, but in the absence of that we were dealing with a vacuum.

Oral Presentations: Combining Basal Insulin and GLP-1 Agonists

Insulin Degludec/Liraglutide (IDegLira) is Superior to Insulin Glargine (IG) in A1c Reduction, Risk of Hypoglycemia, and Weight Change: DUAL V Study (166-OR)

John Buse, MD, PhD (UNC, Chapel Hill, NC)

Two years after taking the podium at ADA to present the strong results from the DUAL I study on Novo Nordisk’s GLP-1 agonist/basal insulin combination Xultophy (IDegLira; insulin degludec/liraglutide), Dr. John Buse returned to the podium to present the first phase 3 trial comparing Xultophy and class-leading basal insulin Lantus (insulin glargine). The study randomized 557 patients with type 2 diabetes already on Lantus + metformin to either intensify their Lantus therapy or switch to Xultophy. The results this time around were just as impressive as for DUAL I: after 26 weeks, Xultophy led to a 1.8% A1c decrease from a baseline of 8.4% to a striking final A1c of 6.6%; Lantus intensification led to a 1.1% reduction in A1c from 8.2% to 7.1%; the treatment difference was 0.6% and was statistically significant (p<0.001). Those who know the DUAL I data will know that the benefits do not stop there. Xultophy boasted a more than 3kg (~7lb) weight benefit vs. Lantus (-1.5kg [~3lb] absolute weight loss from baseline). Xultophy caused 57% fewer episodes of confirmed hypoglycemia (p<0.001) and a stunning 83% reduction in nocturnal hypoglycemia (p<0.001). There were also increases in certain quality of life metrics and 5.5 times more patients with Xultophy who achieved an A1c below 7% without hypoglycemia and weight gain. Incidence of nausea was below 4% throughout the trial; there were more subjects (58% vs. 51%) with adverse events but fewer severe adverse events with Xultophy. When compared beside new basal insulins that are struggling to show benefits vs. Lantus, these and other DUAL program results look quite compelling. We learned during Novo Nordisk’s analyst event at ADA (see our ADA Exhibit Hall and Corporate Updates Report) that the company will hold off on submitting Xultophy in the US until later this year, even though it has already resubmitted Tresiba (insulin degludec). This means that Xultophy is unlikely to become available in the US until late 2016 at the earliest.

• Q&A Highlights: Dr. Philip Home (University of Newcastle, Newcastle Upon Tyne, UK) and Dr. Naveed Sattar (University of Glasgow, Glasgow, UK) questioned whether DUAL V tested a fair comparison. Dr. Sattar noted that it was essentially a test of two drugs vs. one, although Dr. Buse made the good counterargument that it was a test of one injection vs. one injection. Dr. Home pointed out the potential for biased responses because DUAL V was open label – Dr. Buse pointed to DUAL II, a blinded trial in which Xultophy had similar efficacy. In response to a question of what to do in the sizable percent of patients that reached the maximum Xultophy dose, Dr. Buse speculated (after multiple disclaimers that what he was about to say involved very off-label use) that “creative” clinicians might double-dip from the same pen to achieve a higher maximum dose, especially because a >1.8 mg dose of liraglutide (Saxenda) has been approved.
• Study Design: DUAL V was an open label, randomized, phase 2b trial enrolling 557 type 2 diabetes patients for 26 weeks of treatment. Previous trials like DUAL I and DUAL II have compared Xultophy against one or both of its component drugs, whereas this trial was intended to shape clinical decision-making for providers of the many patients on Lantus that need improved glycemic control. Patients were randomized to either stay on Lantus, intensifying treatment as per a treat-to-target titration protocol, or to switch to Xultophy. The starting dose of Xultophy was pre-specified at 16 dose steps (16 U insulin degludec, 0.6 mg liraglutide) – as a result, a secondary goal of the trial was to confirm that switching patients from Lantus to Xultophy could occur smoothly and without greatly diminished glycemic control.
• Baseline Characteristics: Average age was around 60 years, average BMI was 32 kg/m², mean diabetes duration of 11-12 years, and mean A1c of 8.3%. All patients were on insulin glargine + metformin at baseline, with a mean pre-trial insulin dose of 31-32 U. 
• Efficacy Results:
  
  • A1c: From a baseline of 8.4%, the Xultophy group experienced a mean A1c reduction of 1.8%, reaching a strikingly low mean final A1c of 6.6%. By comparison, the group continuing and intensifying their Lantus therapy saw a change of -1.1% from a baseline of 8.2% to a final A1c of 7.1%. The difference in the A1c reduction was 0.6% in favor of Xultophy.
  • Fasting Glucose: There were no significant differences in fasting glucose over the course of the trial. If anything, at early points it seemed that the Xultophy group had a slightly lower mean FPG. The significance here is that patients were able to maintain glycemic control even when switching over to a 16 unit dose of Xultophy from their previous Lantus dose.
• Body Weight: Not only did Xultophy hold a 3 kg (~7 lb) weight advantage in terms of weight gain reduction over Lantus, patients on Xultophy actually lost weight (-1.4 kg [~3 lbs]) from baseline.
• Hypoglycemia: Patients on Xultophy had a statistically significant 57% lower risk of confirmed hypoglycemia than patients on Lantus (p<0.001). Even more positively for Xultophy, the combination led to a massive 83% reduction in nocturnal confirmed hypoglycemia (p<0.001) based on a smaller but still considerable number of events (195).
• Composite endpoints: In presentations of DUAL data, investigators have done a good job of showcasing Xultophy’s comprehensive benefits by presenting comparisons of the percentage of patients who achieve target A1c without hypoglycemia or weight gain. In this trial, 39% of patients achieved A1c targets with Xultophy vs. 12% with Lantus (p<0.001), for an odds ratio of 5.5.  
• Insulin dose: Patients in the Xultophy group leveled off at a mean dose of 41 dose units, whereas patients in the Lantus group experienced a continued climb, ending at 66 units at the end of the trial.
• Quality of life: Across the board in an SF-36 health-related quality of life questionnaire taken at the end of the study, Xultophy scored higher (or at least trended higher) than Lantus. The summary of physical quality of life showed a statistically significant difference in Xultophy’s favor, while the mental quality of life composite was a non-significant trend in Xultophy’s favor. More detailed quality of life data from DUAL V was published independently as a publish-only abstract (2550-PO).
• Adverse events: The rate of patients experiencing adverse events over the trial was higher with Xultophy than with Lantus (58% vs. 51%). Beyond noting that nausea was higher in the Xultophy group (though notably always below 4% - quite good given the GLP-1 agonist component), we did not get to see what else contributed to the imbalance. In contrast, the imbalance in serious adverse events tipped in Xultophy’s favor (3.9 vs. 6.7 SAEs per 100 patient-years).
  
  • In a qualitative description of adverse events, we learned that: (i) CV events were balanced between groups, with one stroke with IDegLira and one CV death with Lantus; (ii) There were no confirmed events of acute pancreatitis; (iii) There were two confirmed malignant neoplasm events with Xultophy and one treatment emergent confirmed event of metastatic pancreatic carcinoma in a subject previously treated with Xultophy; and (iv) there were no confirmed medullary thyroid carcinoma cases.

Questions and Answers:

Q: This seems to be a comparison of two drugs vs. one. Wouldn’t it be fairer to study IDegLira vs. insulin glargine plus liraglutide given separately, the way you have to give them currently?

A: There are other studies that have compared basal insulin + GLP-1 vs. basal plus bolus insulin. The difference in A1c in those trials was less, but the relative benefit for hypoglycemia was greater. I think this is a fair fight because we’re comparing one injection vs. one injection. The commonly used approach for type 2 diabetes is to just keep pushing the one injection. But yes, there is lots of room for many more studies.

Comment (Dr. Philip Home [University of Newcastle, Newcastle Upon Tyne, UK]): Few of us would treat patients failing glargine alone with glargine alone. It seems to be an irrelevant comparator. Isn’t there also a scientific problem with an open label study where you take some people on insulin glargine and move them to a new therapy? This could have impacted hypoglycemia and especially the quality of life questionnaire results.

A: There is a blinded study, DUAL II, where the insulin dose was capped and the primary goal was to examine the contribution of liraglutide. The results were similar in some ways, giving us reassurance that there can be meaningful results even in blinded situations. Secondly, the titration was conducted with equipoise and at the end of the trials the fasting glucose levels were essentially identical. Finally, in endocrine practices in the US and around the world, for patients with A1cs around the mid 8% range, the standard practice is to continue titrating insulin. I think this is a relevant comparison. That said, there is definitely room for further studies to examine other relative effects. Comparative effectiveness is going to be an important area for many years to come.

Q: In terms of patients at the maximum dose reached in treat-to-target, what options are there to keep pushing further with IDegLira?

A: The on-label use in this product, which is available in Europe, is that you would need to add something else. That could be an oral agent, but we don’t have many studies with SGLT-2 inhibitors combined with GLP-1 agonists, and certainly no studies of GLP-1 agonists, SGLT-2 inhibitors, and insulin combined on background metformin. Another possibility would be to add bolus insulin or more basal insulin. That decision would be based on patient characteristics. The off-label thing that one could … hallucinate, since GLP-1 doses higher than 1.8 mg are approved for obesity … one could have a very high-order hallucination about taking another dip on the same pen, continuing to increase the dose of the GLP-1 analog and basal insulin. But we have zero evidence on that. I know creative clinicians will find all kinds of things to do when a product is available.

Assessment of Glycemic Control by CGM in Patients with T2D Treated with IDegLira (170-OR)

Allen King, MD (Diabetes Care Center, Salinas, CA)

Dr. King presented the results of a post-hoc analysis of a DUAL I extension substudy examining changes in glycemic fluctuations over 52 weeks in insulin-naïve patients with type 2 diabetes treated with Xultophy (IDegLira; insulin degludec/liraglutide) (n=131) versus insulin degludec (n=64) or liraglutide (n=65) alone. 72-hour continuous glucose monitoring was performed at baseline and at 52 weeks, which showed that IDegLira treatment was associated with a greater reduction in mean interstitial glucose (IG) than liraglutide (p<0.0001), a greater reduction in postprandial IG versus insulin degludec (p=0.0288), and a greater reduction in time out of range versus liraglutide (p=0.0072). Dr. King commented that these observations may have contributed to the greater A1c reductions seen with IDegLira than with either component medication in the DUAL I study. For detailed information about DUAL I baseline characteristics and methodology, please see our coverage of the initial 26-week results presented at ADA 2013.

• IDegLira treatment was associated with a greater reduction in mean interstitial glucose (IG) than liraglutide (p<0.0001), a greater reduction in postprandial IG versus insulin degludec (p=0.0288), and a greater reduction in time out of range versus liraglutide (p=0.0072). Mean IG decreased 63.1 mg/dl, 64.9 mg/dl, and 45.0 mg/dl from baselines of 180-184 mg/dl with IDegLira, insulin degludec, and liraglutide treatment, respectively. Postprandial IG changed an average of -9.0 mg/dl, 3.6 mg/dl, and -3.6 mg/dl from baselines of 25-27 mg/dl with IDegLira, insulin degludec, and liraglutide treatment, respectively. Time outside of the IG target range (70-162 mg/dl) at the end of the study were 3.2 hours, 3.8 hours, and 5.6 hours from a baseline of 14-15 hours with IDegLira, insulin degludec, and liraglutide treatment, respectively.

Questions and Answers:

Dr. Philip Home (Newcastle University, Newcastle, United Kingdom): Nice study, and nice data. I just want to make a plea. These are supposed to be scientific sessions. There are things called standard deviations, confidence intervals, [etc.,] that would allow me to understand your data. Can we ask that that these have conventional measures of dispersion to go with the mean?

A: Some of the data was statistically analyzed, but the duration of the talk did not allow me to discuss them.

Superior Effects with Combination of Insulin Degludec (IDeg) and Liraglutide (Lira) (IDeg+Lira) Compared with Basal-Bolus Insulin Therapy (BB) in Hemodialysis (HD) Patients with Poorly Controlled Type 2 Diabetes (T2D): An Assessment by Continuous Glucose (171-OR)

Satoshi Funakoshi, MD, PhD (Jikei University, Tokyo, Japan)

Dr. Satoshi Funakoshi presented a unique study investigating the effects of GLP-1/basal insulin combination therapy on glycemic variability and control in 12 dialysis patients. For background, dialysis presents a challenge for glucose management because it can cause hypoglycemia. A potential mechanism to explain this effect is that glucose is cleared more quickly through the hemodialysis membrane than is insulin, so patients undergoing dialysis experience a temporary hyperinsulinemic state. Dr. Funakoshi’s study sought to compare the efficacy of basal insulin + GLP-1 agonist therapy (Tresiba + Victoza) compared to basal-bolus insulin therapy (Tresiba + Humalog) for controlling fasting plasma glucose and glucose variability in type 2 diabetes patients on dialysis. In this study, patients started on basal-bolus therapy and then transitioned to GLP-1/basal therapy. Glycemic variability was measured by CGM. As shown in the table below, during the basal-bolus portion of the study, patients experienced worse glycemic variability on days where they got dialysis (p<0.05 for mean amplitude of glucose excursions [MAGE] off vs. on). However, transitioning to GLP-1/basal therapy cut MAGE in half for both on and off dialysis days (p<0.05 for basal-bolus compared to GLP-1/basal), and the difference between on and off dialysis days was no longer significant. The GLP-1/basal combination also improved FPG. In conclusion, this small study suggests that the combination of insulin degludec and liraglutide can both improve glycemic control and glycemic variability in dialysis patients. This further bolsters GLP-1 agonists’ utility in patients with renal impairment, who may not be able to use therapies like SGLT-2 inhibitors or even metformin.

Table: Glucose variability (MAGE) and fasting plasma glucose (FPG)

	Off-dialysis days	On-dialysis days
Basal-bolus	MAGE = 108 mg/dL FPG = 166 mg/dL	MAGE = 133 mg/dL FPG = 145 mg/dL
GLP-1/basal	MAGE = 55 mg/dL FPG = 131 mg/dL	MAGE = 75 mg/dL FPG = 118 mg/dL

Questions and Answers

Q: The GLP-1 agonist label says not to use these drugs in people with renal failure. What is the PK of liraglutide in people on dialysis?

A: Insulin degludec and liraglutide are not removed by dialysis, and that is the point. The PK profile is not affected, as published last year.

Q: Did you look at the proportion of patients experiencing hypoglycemia both on and off dialysis?

A: We did not see any symptomatic hypoglycemia. During hemodialysis, the glucose drops not only because of the insulin issue, but also removing toxins improves insulin resistance peripherally. Removal of fluid improves over-hydration, which improves insulin resistance. pH goes up, which encourages glucose to go into cells. So all the factors push down glucose at the end of hemodialysis, but for some reason we did not experience symptomatic hypo.

Least Glucose Variability and Hypoglycemia Is Observed with the Combination of a GLP-1 Receptor Agonist and Basal Insulin (VARIATION Study) (167-OR)

Harpreet Bajaj, MD, MPH (LMC Diabetes and Endocrinology, Toronto, Canada)

Dr. Harpreet Bajaj provided interest-piquing if not completely surprising evidence that the combination of a basal insulin and a GLP-1 receptor agonist (RA) provides the least glycemic variability among several commonly used insulin regimens. The study enrolled 150 subjects (ages 18-80) with A1cs ≤7.5% who were on one of four stable diabetes regimens containing insulin for six months prior to the study (basal insulin + oral agent, basal insulin + GLP-1 RA, premixed insulin, MDI basal bolus regimen). In the six-day protocol, subjects continued their existing lifestyle and treatment regimens and were monitored with masked CGM as well as SMBG (≥4 times daily). A combination of a basal insulin + a GLP-1 RA resulted in significantly lower daily standard deviation of glucose than alternate regimens (SD = ~31 mg/dl vs. ~34 mg/dl with basal + oral agent, ~36 mg/dl with premixed, and ~38 mg/dl with basal-bolus MDI). Both the basal insulin + oral agent and basal insulin + GLP-1 RA regimens resulted in significantly lower self-reported hypoglycemia than the premixed or MDI regimens (basal + oral agent = 20% hypo rate, basal + GLP-1Ra = 17%, premixed = 35%, basal-bolus = 57%). Overall, the authors concluded that a combination of basal insulin + GLP-1 RA provides the least variability versus three commonly prescribed insulin regimens. While the difference in standard deviation was perhaps slightly more modest than we might have expected vs. MDI, but a ~20% improvement is still highly meaningful and could mean substantially less time at extreme ranges.

Synergistic Action of PE0139, a Super-Long-Acting Basal Insulin, and PB1023 a Weekly GLP-1 Receptor Agonist (168-OR)

Jim Ballance, PhD (PhaseBio Pharmaceuticals, Malvern, PA)

Dr. Jim Ballance presented pre-clinical data suggesting that PhaseBio’s long-acting basal insulin, PE0139, and weekly GLP-1 agonist, PB1023, could have synergistic effects when combined. For background, both agents use PhaseBio’s ELP biopolymer technology to prolong half-life. The GLP-1 agonist (PB) is in phase 2 and the insulin (PE) in phase 1. This db/db mouse study found that both PE and PB were inadequate as monotherapy for bringing glucose levels within control in response to an intraperitoneal glucose tolerance test. However, the combination of the two products normalized glucose control in a greater-than-additive fashion, even when lower doses of each individual component were used compared to the doses used in the monotherapy arms. Synergistic (more than additive) efficacy has not been seen in the largest clinical trials of GLP-1 agonist/basal insulin combinations, although it is far from certain whether these preclinical results can be duplicated in humans. Dr. Ballance remarked that PhaseBio plans to commence a six-week phase 2 multiple ascending dose study with basal insulin PE in 2H15 with a PE/PB combination study to follow.

• For background, PE0139 and PB1023 use PhaseBio’s elastin-like polypeptide technology (ELP) to extend half-life. The ELP is a set of repeating five amino acid sequences (VPGXG where X is any amino acid except proline). The ELP polymer, when fused to a peptide of interest, confers a longer half-life to the peptide of interest by allowing the fusion product to undergo the process of “coacervation” under specific temperature and solvent conditions. Coacervation is a liquid-liquid phase separation, rendering the drug either available or not available to be absorbed. By varying the number of repeats in the ELP, the concentration of the protein, the concentration of salts in the solvent, and the hydrophilicity of the protein, one can control at what temperature the phase separation occurs and, thus, control the temperature at which the drug essentially becomes available to be absorbed. Thus, one mechanism by which ELP prolongs a drug’s half-life is via this slow, controlled release. The other mechanism is that ELP prolongs the protein’s circulatory half-life by reducing clearance from circulation.

Questions and Answers:

Q: Yesterday we learned [with Lilly’s basal insulin peglispro] that if you have a large hydrodynamic range, you get liver specificity with unwanted side effects. Did you test any of that with these insulins?

A: We haven’t studied it or seen anything yet but it’s something we will look out for.

Q: What happens to absorption if body temperature goes up or down [given that the effect of ELP is dependent on temperature]?

A: From a safety perspective, if the patient has an elevated temperature what will happen is the depot will be more stable. If you have someone plunging into an ice bath then that’s something one would have to look at. What we have studied so far is a prelude to longer study – we looked at what would happen if someone took the product directly from the fridge and injected it. There was no difference in PK there. It doesn’t matter if it’s cold when you inject it as long as it gets to the right temperature in your body.

Q: In the phase 2 study of your GLP-1 agonist, what did you see in terms of weight loss? I ask because the proportion of active moiety seems pretty small.

A: We didn’t see a big change in weight, but we also had liraglutide as a control arm, and we didn’t see weight loss in that group either. In any case, based on the protein’s structure, one would expect similar weight effects as dulaglutide or albiglutide.

Q: Have you looked into temperature variability systematically?

A: We have done one single ascending dose study so far. In the presentation yesterday, the error bars were very small so at least in that small group, it didn’t seem to be very variable, but we’ll obviously have to look at that going forward. The multiple ascending dose study is our next study.

Once-Weekly Combination of GLP-1R Agonist and Insulin (HM14220) Offers Improved Glycemic Control and Reduced Weight Gain Risk (172-OR)

Michael Trautmann, MD (Profil Institute for Clinical Research, San Diego, CA)

Dr. Michael Trautmann presented promising results from a series of early explorations of a novel once-weekly GLP-1/insulin combination from Hanmi Pharmaceuticals. Developed via the LAPSCOVERY platform, the compound is a combination of ^LAPS insulin 115 (phase 1 in the US), and efpeglenitide (HM11260C; an exendin-4 analog, phase 2b), which both have ultra long acting profiles suitable for weekly dosing. A combination of these compounds has shown similar PK/PD profiles to those of each product alone. When administered as a co-formulated once weekly product to diabetic rodents, the combination of ^LAPS insulin 115 resulted in greater A1c reductions than either product alone. Additionally, in a mild type 2 diabetes animal model, the weight gain seen with ^LAPS insulin 115 was neutralized by the combination product. Notably, in switching studies, switching diabetic mice to treatment with the ^LAPS combo after an initial 14 days of treatment with glargine resulted in significantly greater A1c decreases at six weeks versus either staying on glargine or switching to ^LAPS insulin 115. Similar results were seen in studies where mice were initially treated with liraglutide rather than glargine. These initial results are promising, as we feel a once weekly combination product could indeed improve adherence. We look forward to data from human studies on the topic, particularly to better understand how a once weekly product fares in face of every day glucose variations.

Oral Presentations: Update on GLP-1 Receptor Agonists

Clinical Impact of ITCA 650 in Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, 39-Week Trial (276-OR)

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

Results from Intarcia’s pivotal phase 3 FREEDOM-1 trial for the implantable exenatide mini-pump ITCA-650 were fairly strong, and even better in a pre-specified subgroup analysis. In FREEDOM-1 (n=460), the mean A1c reduction for the overall ITCA-650 group was 1.4% at the end of the trial (mITT analysis), and from the graph we would expect the placebo-adjusted efficacy to be around 1.1%. Notably, a pre-specified secondary analysis of efficacy by concomitant therapy found that patients not on a sulfonylurea did far better in terms of A1c reduction from baseline to week 39 (1.7% from baseline; we estimate ~1.4% placebo-adjusted) than those on a sulfonylurea (1.2% from baseline; we estimate ~0.9% placebo-adjusted). It looked to us like the SFU group was beginning to see the deterioration of glycemic control that is characteristic of the drug class, with an upswing in A1c towards the end of the trial. Especially because it was prespecified, we see these stronger results in non-SFU-taking patients (likely to be earlier-stage diabetes patients on average) as pretty persuasive. In terms of efficacy, the higher 60 mcg/day dose appeared to barely beat out the 40 mcg/day dose without much of a safety/tolerability sacrifice. ITCA-650 drove 2% placebo-adjusted weight loss from baseline at the higher dose, and from the abstract it looks like weight was still decreasing at the end of the trial. Composite outcome analyses showed that ITCA-650 helped more patients achieve a 1% or greater A1c reduction plus a >5% decrease in weight (21% and 17% with the two ITCA-650 doses vs. 6% with placebo).

• We were surprised that there was absolutely no hypoglycemia data presented – we hope to see those results soon, and would expect to see the results here to be worse in SFU users as well.
• ITCA-650 was associated with GI tolerability issues for some patients, although most of the risk was right around initiation and dose increases. Around 30% of patients on ITCA-650 40 mcg/day and 31% of patients on the 60 mcg/day dose experienced nausea vs. 10% on placebo; 19%-24% of ITCA-650 patients experienced vomiting vs. 2% on placebo. These issues were the primary drivers behind an imbalance in adverse events leading to discontinuation between the ITCA-650 group (9%-12%) vs. placebo (4%) – keep in mind that “discontinuation” means device removal in this case, not just the cessation of taking a pill or injection. Providing some reassurance, presenter Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas TX) did display data indicating that the vast majority of nausea cases occurred during initiation or dose escalation, returning to much lower background levels (<5%) afterwards. This fact should make the issue manageable, though we wish there was some way to more gradually step up the dose as can be done with some injectable GLP-1 agonists.
• Importantly for the patient experience, administration site events (bruising, irritation) were generally mild and transient. Intarcia has gone to great lengths to focus on the patient experience, including totally reworking the insertion procedure to make it much quicker and easier, a push that appears to have paid off.

Efficacy and Safety of Liraglutide Added to Insulin in Type 1 Diabetes: The LIRA-1 Trial (277-OR)

Thomas Dejgaard, MD (Steno Diabetes Center, Gentofte, Denmark)

This study, out of the prestigious Steno Diabetes Center, randomized poorly controlled, overweight type 1s to liraglutide 1.8 mg + insulin (n=50) vs. insulin alone (n=50). At 12 weeks, A1c declined 0.6% in the insulin+liraglutide group and 0.2% in the insulin-only group (p=0.001; baseline: 8.8%), but the placebo group had caught up by 26 weeks (-0.6% vs. -0.4%; p=0.15). [This was consistent with some anecdotal reports that the effect of liraglutide may “wear off” in some type 1s over time, perhaps necessitating cycling on and off it – we look forward to seeing Novo Nordisk’s longer-term type 1 data to address questions like this.] Liraglutide did cause very significant reductions in body weight at 26 weeks (-6 kg vs. +0.23 kg; p=0.015), much less need for additional insulin (+4 units vs. +14 units; p=0.02), and a non-significant trend towards less hypoglycemia. It was surprising to see that more insulin was needed in the liraglutide arm, but that probably speaks to the poorly controlled population and how aggressively the trial titrated patients’ insulin - certainly, an additional 4 vs. 14 units is 70% less additional insulin, which is what we would expect with liraglutide in type 1. The protocol of this trial is published in BMJ Open.

• This study was notable for a few reasons: (i) a randomized trial of liraglutide in type 1 (these have been single arm to date); (ii) studied in poorly controlled patients, a challenging and very important population to study; and (iii) included CGM (Medtronic iPro 2 with Enlite sensors).
• Two phase 3 trials investigating Victoza as an adjunct to insulin in type 1 diabetes (ADJUNCT ONE and ADJUNCT TWO) are scheduled to report within the next two to five months, per Novo Nordisk’s call in April.

Twelve Weeks Treatment with Liraglutide as Add-on to Insulin in Normal-Weight Poorly Controlled Patients with Type 1 Diabetes (279-OR)

Christian Frandsen, MD (Hvidovre Hospital, Hvidovre, Denmark)

In tandem with 277-OR (see above), the 40 patients in this second trial (still poorly controlled with a baseline A1c of 8.9%, but normal weight) had consistent results directionally on A1c (-0.5% with liraglutide vs. -0.6% with insulin alone; p=0.78), weight (-3 kg vs. +1 kg; p<0.01), and bolus insulin dose (-4 units vs. +0; p=0.02). There was no significant difference in time-in-range, hypoglycemia, or variability. Again, the results were a bit less positive than we would have expected, though it’s very difficult to draw broader conclusions about liraglutide in type 1 due to these studies’ small size and very strong results in the treat-to-target insulin-only group – we’re not sure either study had very real-world control groups.

Dose-Response Improvements in Glycemic Control and Body Weight Reductions With Hm11260c, A Once-Weekly GLP-1 Receptor Agonist with Liraglutide as Reference, in Type 2 Diabetes (T2DM) (278-OR)

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

Dr. Julio Rosenstock presented promising phase 2 data on Hanmi Pharmaceutical’s novel ultra-long-acting GLP-1 agonist candidate efpeglenatide (HM11260C), developed using Hanmi’s Long Acting Peptide/Protein DISCOVERY Technology (LAPSCOVERY). The 12-week long study randomized 254 adults with type 2 diabetes to HM11260C doses between 0.3 mg to 4 mg, placebo, or liraglutide 1.8 mg (although Dr. Rosenstock emphasized that this arm was used only for reference and not for statistical comparison). The findings showed that at week 13, HM11260C produced a dose-dependent reduction in A1c, fasting plasma glucose (FPG), and 7-point daily glucose. Specifically, from a baseline A1c of ~8%, the 3 mg and 4 mg doses saw fairly impressive mean A1c reductions of 1.4% and 1.6% respectively; the placebo and liraglutide arms respectively achieved A1c reductions of 0.4% and 1.4%. The proportion of participants reaching the A1c target of <7% was 86% (4 mg), 83% (3 mg), 23% (placebo), and 57% (liraglutide). On the weight loss front, reductions for the 3 mg and 4 mg doses of HM11260C were 3.0 kg vs. 0.2 kg with placebo and 2.6 kg with liraglutide. Regarding safety and tolerability, the profile of HM11260C was similar to that of liraglutide, with the most frequent adverse events being GI side effects. The heart rate increases also seemed to be less than those of liraglutide (though we wouldn’t read too far into this with a study of this size) and no neutralizing antibodies were found with HM11260C. Overall, Dr. Rosenstock noted that the 3 mg dose of HM11260C is fairly similar to liraglutide, with the 4 mg dose being slightly better than liraglutide. In conclusion, he highlighted that this data supports further investigation and clinical development of HM11260C alone as well as in combination with a weekly insulin.

Questions and Answers:

Q: I noticed that the lower doses had minimal nausea and vomiting. Would you recommend starting at the lower dose and titrating up?

A: Yes, the 3 mg to 4 mg doses had more nausea and vomiting. But they showed very robust reductions in A1c and weight. Whenever phase 3 comes, my own recommendation would be to do some gradual escalation.

Q: Looking at A1c, the two higher doses did not yet reach a plateau so they may have further reductions. I would recommend that if the study design were to be repeated, the primary endpoint should go on until there is a plateau, because it’s possible that the lower dose may catch up to the higher dose.

A: That point is well taken. This is just phase 2 to determine an idea of the doses. I’m personally skeptical that a 1 mg to 2 mg dose would make it, but it’s an interesting point.

Q: Is the PK/PD profile affected by renal function?

A: These are very large molecules so they don’t get absorbed in the kidney.

Efficacy and Safety of Once-Weekly Dulaglutide vs. Insulin Glargine in Combination with Metformin and/or a Sulfonylurea in Predominantly Asian Patients with Type 2 Diabetes (280-OR)

Jun Yang, MD (Lilly Suzhou Pharmaceuticals Co. Ltd, Shanghai, China)

Dr. Jun Yang presented a study showing superiority of Lilly’s once-weekly Trulicity (dulaglutide) over Lantus (insulin glargine) in type 2 diabetes patients predominantly in Asia. In a 26-week study of predominantly Asian participants with type 2 diabetes (n=165), participants were randomized to either Trulicity or Lantus in combination with metformin and/or a sulfonylurea. The findings showed that Trulicity led to greater reductions in A1c with weight loss and less hypoglycemia. Specifically, A1c reductions from a baseline A1c of 8.4% were 1.7% for the 1.5 mg dose of Trulicity, 1.3% for the 0.75 mg dose of Trulicity, and 1.2% for Lantus. The proportion of patients who reached target A1c levels (<7%) were 65%, 54%, and 41% for Trulicity 1.5 mg, Trulicity 0.75 mg, and Lantus, respectively. In addition, Trulicity was associated with greater weight loss from a mean baseline of 78 kg, with the 1.5 mg and 0.75 mg doses losing a mean of 1.5 kg (~3 lbs) and 0.9 kg (~2 lbs), respectively; the Lantus group, on the other hand, gained 1.0 kg (~2 lbs). On the safety front, Trulicity appeared to have a lower hypoglycemia risk, with the proportion of patients with hypoglycemia being 18% for the Trulicity doses vs. 29% for Lantus (this would have been even lower without the SFU usage). Trulicity was relatively well tolerated, with the exception of having more GI side effects compared to Lantus – 9% of Trulicity 1.5 mg and 5% of Trulicity 0.75 mg experienced nausea compared to 1% of Lantus. Lilly has worked hard to compare Trulicity to Lantus in a variety of applications (see AWARD-2 and AWARD-4), and the benefits definitely appear to be there for A1c, hypoglycemia, and weight.

Questions and Answers:

Q: So this was a predominantly Asian study. So the BMI was lower at 27 or 28. Did you look at the correlation of baseline BMI and A1c reduction? Did you check drug exposure in smaller patients?

A: We thought about GLP-1 exposure and BMI, which is why we conducted in lower-BMI patients. Before we decided this dosage, we did a simulation of this exposure in lower BMIs. There was about a 20%-30% increase of exposure due to dulaglutide in these kinds of BMI patients. We also have other PK trials in these same patients.

Mechanisms of Action of the Glucose-Lowering Effect of Lixisenatide in Combination with Insulin Glargine (281-OR)

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

Dr. Juris Meier presented results from a study evaluating the mechanistic differences between the short- and long-term effects of Sanofi’s Lyxumia (lixisenatide). The open-label study randomized 28 patients with type 2 diabetes treated with metformin to receive once-daily doses of either lixisenatide or insulin glargine (Sanofi’s Lantus) for four weeks, followed by combined treatment with both products for four weeks. At baseline, week 4, and week 8, participants underwent an intravenous glucose tolerance test and two mixed meal tolerance tests, one after breakfast (immediately after drug administration) and one after a late lunch (eight hours after breakfast). Results showed that lixisenatide increased first- and second-phase insulin secretion to a greater extent than insulin glargine and that the combination of the two had the greatest effect. Lixisenatide reduced postprandial glucose excursions after both meals but only delayed gastric emptying after breakfast; it also led to reduced insulin secretion after breakfast. Dr. Meier concluded that delayed gastric emptying is the main driver of lixisenatide’s immediate effects on postprandial glucose, and that this may induce an “insulin-sparing” effect that allows beta cells to “recharge” and secrete more insulin after a later meal, thereby reducing postprandial glucose even though very little lixisenatide remains in the system. Of course, as one attendee noted during Q&A, most people do not space their meals eight hours apart, so patients are likely still experiencing some direct effects of lixisenatide even at the second meal after dosing.

Questions and Answers:

Q: Why did you do a late lunch after eight hours instead of a more normal time frame like four or five hours?

A: We wanted to make sure people had achieved complete gastric emptying after the first meal.

Comment: I understand the scientific rationale, but clinically people eat breakfast at 7 or 8 AM and lunch at 12 or 1 PM, so they may still have some tail and see gastric emptying.

Q: You didn’t see an effect on gastric emptying at the late lunch. Was the explanation a different time-action profile regarding insulin secretion and gastric emptying or what?

A: We believe that eight hours after injection, there is probably no lixisenatide in the circulation, which is why there was no effect at all. All you see is probably secondary to what you induced after breakfast. I doubt after eight hours that there would be a direct effect. What you see later is probably indirect and mediated by the earlier insulin sparing.

The Influence of GLP-1 Receptor Agonists on the Heart Rate Using Holter Electrocardiography and Power Spectrum Analysis of Heart Rate Variability (282-OR)

Atsuhiko Kawabe, MD (Dokkyo Medical University School of Medicine, Tochigi, Japan)

Dr. Atsuhiko Kawabe presented data on a study that performed Holter-electrocardiography (ECG) and power spectrum analysis of heart rate variability before and after treatment of long-acting GLP-1 agonist liraglutide (titrated up to 0.9 mg) and short-acting GLP-1 agonist lixisenatide (up to 20 micrograms). The study randomized 40 people with type 2 diabetes to either the liraglutide or lixisenatide arm, observing and comparing the changes in the heart rate and frequency powers every hour in a 24-hour period. The findings showed that those in the liraglutide group experienced significantly greater increases in heart rate compared to those in the lixisenatide group. Specifically, the liraglutide group had a heart rate increase from 96,321 bpm to 117,376 bpm with significant increases observed every hour while the lixisenatide group experienced an increase from 99,618 bpm to 104,426 bpm with a significant increase at only three time-points throughout the 24 hours. From these results, Dr. Kawabe discussed that the drugs’ heart rate increases likely reflect the enhancement of sympathetic nerve activity, with each GLP-1 agonist’s enhancement of activity matching its half-life, ultimately suggesting that the half-life influences sympathetic nerve activity. In conclusion, Dr. Kawabe highlighted the Framingham study’s finding that heart rate elevation can increase both ischemic heart disease incidence and mortality, stressing the need for further investigation of GLP-1 agonists’ exocrine pancreatic action and these effects’ implications.

Oral Presentations: ADA Presidents Oral Session

Brain Reward-System Activation in Response to Anticipation and Consumption of Palatable Food is Altered by GLP-1 Receptor Activation in Humans (384-OR)

Liselotte van Bloemendaal, MD (VU University Medical Center, Amsterdam, Netherlands)

Dr. Liselotte van Bloemendaal presented data on GLP-1 agonists’ effects on brain reward-system activation, demonstrating that GLP-1 receptor activation may have important central mechanisms of action in reducing food cravings and preventing overeating. The randomized, placebo-controlled, crossover study (n=48) had healthy lean individuals, obese normoglycemic individuals, and obese individuals with type 2 diabetes undergo three fMRI sessions with the receipt of chocolate milk or a tasteless solution. For each fMRI session, the participants received either exenatide, exenatide with exendin 9-39 (a GLP-1 receptor blocker), or placebo. They found that BMI was negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of the receipt of chocolate milk in brain areas regulating reward, appetite, and motivation. Notably, exenatide vs. placebo increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk, which was paralleled by reductions in food intake (-23% in the lean arm; -24% in the obese arm; and -14% in the type 2 diabetes arm). On the other hand, the GLP-1 antagonist, exendin 9-39, largely blunted the effects on brain responses to chocolate milk and on food intake. Thus, Dr. van Bloemendaal concluded that GLP-1 receptor activation can decrease anticipatory food reward which may reduce food cravings, as well as increase consummatory food reward, which may prevent overeating. This  strengthens evidence for the drug class’ effect on the central regulation of feeding. At times like this we can’t help but wonder: is there anything GLP-1 agonists can’t do?

Questions and Answers

Q: Did you also measure subjective feelings of satiety and appetite?

A: We also asked subjects to rate their feelings of hunger, satiety and prospective food consumption. But we found no significant differences between the different test days in these ratings

Q: Have you statistically looked at the correlation of CNS response and subsequent food intake?

A: We didn’t look at that yet. In our previous study, in which we determined the effects of exenatide on brain responses to watching food pictures, we found that the exenatide-induced reductions in CNS responses correlated with exenatide-induced reductions in food intake.

Posters

IDegLira in Insulin-Naïve Patients with Type 2 Diabetes (T2D) Inadequately Controlled on Sulfonylureas (SU) Alone or in Combination with Metformin: The DUAL IV Study (1003-P)

HW Rodbard, BW Bode, SB Harris, L Rose, L Lehmann, H Jarlov, J Thurman

The DUAL IV trial randomized 435 people with type 2 diabetes to Novo Nordisk’s Xultophy (insulin degludec/liraglutide) or placebo. Topline results were first released in January 2014. After 26 weeks from a baseline A1c of 7.9%, the Xultophy arm achieved a mean 1.5% A1c reduction to 6.4% compared to a 0.5% reduction on placebo – this represents a substantial decrease from a somewhat low base. Nearly 80% of people on Xultophy achieved an A1c of <7% (the ADA goal) compared to only 30% of those on placebo. The Xultophy arm experienced statistically significantly higher rates of hypoglycemia (42% of Xultophy patients vs. 17% placebo), and the Xultophy arm also gained 1.0 kg (2.2 lbs) compared to a weight loss of 0.5 kg (1.1 lb) on placebo. The unfavorable weight result runs contrary to DUAL I and II results where Xultophy was associated with weight loss (0.5 kg in DUAL I for patients on 1-2 OADs, and 2.5 kg in DUAL II for patients previously on basal insulin). The higher rate of hypoglycemia is not unexpected with the addition of a GLP-1 agonist/basal insulin to SFU (in DUAL I and II, hypoglycemia rates on Xultophy were better compared to Tresiba [insulin degludec] or Victoza [liraglutide], and there was no placebo comparator). At the end of the trial the average dose of Xultophy was 28 dose steps (28 units insulin degludec/1.0 mg liraglutide) – this information had not been reported previously and demonstrates the power of relatively low doses. With regards to safety, the Xultophy arm seemed to experience a higher rate of elevated lipase (a potential marker of pancreatic damage; 9.7% of patients in the Xultophy were investigated for elevated lipase vs. 4.1% in the placebo arm, but statistical significance was not reported), which is consistent with the known effects of GLP-1. No other concerning safety issues were reported.

Efficacy and Safety of Liraglutide vs. Sulfonylurea Both in Combination with Metformin during Ramadan in Subjects with Type 2 Diabetes (LIRA-Ramadan): A Randomized Trial (1121-P)

S Azar, A Echtay, WMW Bebakar, S Al Araj, A Berrah, M Omar, A Mutha, K Tornoe, M Kaltoft, N Shehadeh

Fasting during Ramadan in patients with type 2 diabetes is associated with increased risk of severe hyper- and hypoglycemia. In this 33-week open-label trial, patients with type 2 diabetes on stable baseline sulfonylurea and metformin were randomized to switch to once daily liraglutide 1.8 mg and background metformin (n=172) or continue pretrial sulfonylurea and metformin (n=171). In this study, from a baseline A1c of 8.3%, liraglutide led to a mean A1c reduction of 1.2% vs. a -0.7% change with SFUs, for a statistically significant treatment difference of 0.6% in favor of liraglutide. A similar decline in fructosamine from start to end was seen in both the liraglutide- and sulfonylurea-treated groups, despite patients treated with liraglutide having lower fructosamine and A1c levels (baseline 8.3% to 7.2% at start in the liraglutide group vs. 8.2% to 7.8% in the sulfonylurea group) at the beginning of Ramadan. There were also fewer confirmed hypoglycemic episodes in the liraglutide-treated group (8.6% vs. 17.8%) – not particularly surprising given the agents being compared. Overall, this study indicates an improved safety profile with liraglutide versus sulfonylurea during Ramadan as well as improved glycemic control. We applaud Novo Nordisk for considering the unique needs of the Ramadan-observant patient population enough to support a full-scale clinical trial. These results are also important in the context of exploding diabetes prevalence in the Middle East.

• This was a 33-week open-label trial that compared a switch to liraglutide versus continuing pretrial sulfonylurea in patients with type 2 diabetes who fasted for Ramadan. In the study, patients with type 2 diabetes on stable baseline sulfonylurea and metformin were randomized to switch to once daily liraglutide 1.8 mg and background metformin (n=172) or continue pretrial sulfonylurea and metformin (n=171). Patients underwent a three-week dose escalation period followed by a six to 19-week maintenance period prior to four-week fast for Ramadan. Duration of diabetes was similar in both groups (8.0 years in the liraglutide group vs. 7.2 in the sulfonylurea group).
• During Ramadan, a similar decline in fructosamine (a measure that reflects recent blood glucose changes over a one to two week period) from start to end was seen in both the liraglutide (mean 291.8 to 279.0 μmol/L; baseline 320.3 μmol/L) and sulfonylurea-treated (mean 301.6 to 285.2 μmol/L; baseline 316.0 μmol/L) groups (p=0.43). This was despite patients treated with liraglutide having lower fructosamine and A1c levels (baseline 8.3% to 7.2% at start in the liraglutide group vs. 8.2% to 7.8% in the sulfonylurea group) at the beginning of Ramadan.

Insulin Degludec/Liraglutide (IDegLira) Improves Patient-Reported Impacts in Subjects with Type 2 Diabetes (T2D) Inadequately Controlled on Insulin Glargine (IG) plus Metformin (Met): Dual V Study (2550-PO)

M Brod, FC Perez Manghi, PA Garcia-Hernandez, P Norwood, H Jarlov, JH Kongso, I Lingvay

In an publish only sub-analysis from the DUAL V study, the full results of which were presented as an oral, researchers demonstrate that Novo Nordisk’s Xultophy (insulin degludec / liraglutide) improved patient-reported outcomes in type 2 diabetes patients inadequately controlled on insulin glargine plus metformin. Patient-reported impact of treatment on functioning and well being was assessed by Treatment Related Impact Measure for Diabetes (TRIM-D) and Short-Form 36 Health Survey (SF-36 v2). TRIM-D scores were summed from five subdomains – treatment burden, daily life, diabetes management, compliance, and psychological health-- and weighed together to give a total score. Change from baseline was higher with Xultophy verses insulin glargine for total score (p=0.003), treatment burden (p=0.017) and diabetes management (p<0.001) subdomains. The SF-36 validated multi-purpose questionnaire was grouped into eight domains that were further divided into a physical component summary (PCS) score and a mental component summary score (MCS). The improvements in PCS (p<0.001) and three of the physical domain scores – physical functioning (p=.045), bodily pain (p=.012), and general health (p=.008) -- were significantly greater with Xultophy compared to insulin glargine. The mental component summary (MCS) score and the mental domain scores, however, were similar for both arms.

• DUAL V was a 26-week, open-label trial compared the efficacy and safety of Xultophy versus insulin glargine in subjects with uncontrolled type 2 diabetes on 20-50U of insulin glargine and metformin. See above for the full coverage of the primary DUAL V results.

Efficacy and Tolerability of 39 Weeks of ITCA 650 (Continuous Subcutaneous Exenatide) in Poorly Controlled T2DM with High Baseline A1c (>10%) (1107-P)

Robert Henry, MD (VA San Diego Healthcare System, San Diego, California)

This poster presented the full results from the FREEDOM-1 HBL open-label study investigating Intarcia’s implantable exenatide mini-pump ITCA 650 in patients who fell above the baseline A1c cut point (10%) for the pivotal FREEDOM 1 study. Topline results from this trial were the first glimpse at phase 3 results we received from Intarcia, and even in the context of patients with high baseline A1c they were quite impressive. FREEDOM-1 HBL found a mean A1c reduction of 3.4% from a mean baseline of 10.8% after 48 weeks, with no comparator group in this open-label study. The ITCA 650 pump also sustained up to 3.0-4.0 kg (~7-9 lbs) greater weight loss, had satisfactory tolerability, and had low discontinuation rates at the target dose. While the pivotal FREEDOM-1 trial had results that were a bit more applicable for most patients, it is positive to see just how powerful ITCA 650 was in patients with the poorest control at baseline.

Symposium: New Developments with GLP-1 Receptor Agonists

Differentiating Current and Emerging GLP-1 RAs

Kathleen Dungan, MD (Ohio State University, Columbus, OH)

Dr. Kathleen Dungan reviewed the advantages (substantial A1c reductions, weight loss, low risk of hypoglycemia) and disadvantages (GI side effects, cost) of GLP-1 agonists and summarized the results of head-to-head studies of the various options. Her main big-picture conclusion was that longer-acting agents (like AZ’s Bydureon [exenatide once weekly], Novo Nordisk’s Victoza [liraglutide], Lilly’s Trulicity [dulaglutide], and GSK’s Tanzeum [albiglutide]) generally produce greater A1c reductions due to a greater effect on fasting glucose, while shorter-acting agents like AZ’s Byetta (exenatide twice daily) and Sanofi’s Lyxumia (lixisenatide) hold the advantage for immediate postprandial glucose reductions due to a greater effect on gastric emptying. Dr. Dungan otherwise declined to suggest advantages of specific agents over others, stating that clinicians have to evaluate the various criteria and make case-by-case decisions for individual patients. She did note that reconstitution and ease of administration could definitely be key differentiating factors for many patients – this would give the edge to ready-to-use products like Trulicity, Victoza, and Lyxumia. However, she also acknowledged that cost and insurance coverage often prove to be the deciding factors in practice – “it’s not really our choice or our patient’s choice.”

GLP-1 Receptor Agonists in Combination with Basal Insulin

John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)

Dr. John Buse, a leader on this frontier for several years, reviewed the bounty of evidence supporting the combination of GLP-1 agonists and basal insulin. He reviewed data for AZ’s Byetta (twice daily exenatide) added onto Sanofi’s Lantus (insulin glargine), Novo Nordisk’s Xultophy (insulin degludec/liraglutide), Sanofi’s LixiLan (lixisenatide/insulin glargine), and GSK’s Tanzeum (albiglutide) added onto insulin glargine. In all, when GLP-1 agonist/basal insulin combination therapy is compared to its component parts, it provides greater A1c-lowering efficacy, far less weight gain than basal insulin, minimal nausea, and no increased risk of hypoglycemia. Most GLP-1/basal combinations confer pretty stunning ~1-1.5% A1c reductions (often nearly normalizing glucose levels) with remarkably low rates of hypoglycemia. Furthermore, a recent meta-analysis demonstrated that GLP-1/basal therapy even outperforms basal-bolus therapy with regard to A1c lowering efficacy and reduced weight gain and hypoglycemia. Dr. Buse also discussed some unresolved issues under investigation – first, does adding insulin to GLP-1 agonist therapy work just as well as adding a GLP-1 agonist to basal insulin? The evidence supporting this comes from a study demonstrating that the addition of Novo Nordisk’s Levemir (insulin detemir) in patients with inadequate control on Victoza conferred an additional 0.5% A1c reduction (DeVries et al, Diabetes Care 2012). Secondly, could one use a long-acting “basal” GLP-1 therapy with prandial insulin? The AWARD-4 trial found that the combination of Lilly’s Trulicity (dulaglutide) and Humalog (insulin lispro) appeared to work just as well as Humalog and Lantus, and also conferred less weight gain and hypoglycemia.

• As a reminder, the rationale for combining these drug classes comes from their complementary efficacy and side effect profiles – basal insulin provides fasting glucose coverage, and GLP-1 agonists provide postprandial coverage. In addition, combining the two allows for uses of submaximal doses of each individual agent, thus minimizing dose-related side effects: nausea in GLP-1 agonists and weight gain and hypoglycemia in basal insulin.

GLP-1: To Use or Not to Use? Safety is the Question

Jane Reusch, MD (University of Colorado, Denver, CO)

Dr. Jane Reusch reviewed the current status of safety concerns associated with incretin-based therapies. She opened by acknowledging the very high potential for this class to be the game-changer that everyone hopes it will be. However, she remarked that due to the extremely high prevalence of diabetes, even rare side effects will ultimately affect large numbers of people, so it is important to tease out even uncommon safety issues. At the same time, she strongly cautioned against being too risk averse because the risks of any treatment must also be weighed against the very real risk of poor glycemic control (“diabetes is common and deadly”). We appreciated her very firm grounding in reality on this front. Dr. Reusch focused on the issues of cardiovascular outcomes and pancreatitis. In short, she stated that the data to date supports a neutral cardiovascular risk profile with reason to “keep our eyes open” for patients who might be predisposed to developing heart failure on DPP-4 inhibitors, and she believes future studies still have the potential to show some CV benefit of GLP-1 agonists (she named Novo Nordisk’s LIVE study of liraglutide in heart failure patients as an example). With regards to pancreatitis, she believes that there appears to be a real, but exceedingly small, signal in clinical trials. She opted not to comment on pancreatic or thyroid cancer due to the lack of rigorous data on these fronts. Ultimately, she reminded the audience that these small risks must be weighed against the benefits of improved glycemic control, weight loss, decreased hypoglycemia, and patients’ perception of self-efficacy with a treatment that works.

• With regard to cardiovascular outcomes, Dr. Reusch reported that the data so far support a neutral CV profile, though more data will become available over the next four years. She noted that the ELIXA CVOT for Sanofi’s Lyxumia (lixisenatide) would be presented the following day and will show neutrality – however, she reminded the audience that FDA-commissioned CVOTs are designed to rule out CV risk rather than demonstrate CV benefit. She also mentioned the now well-known findings from DPP-4 inhibitor CVOTs that showed overall neutral CV safety, but a slight signal for congestive heart failure (CHF). She stated that at this point there is no reason to be concerned about increased CV risk on incretin therapies, but that “we should keep our eyes open” for potential patients who might suffer from heart failure.
  
  • Notably, Novo Nordisk is evaluating a potential protective effect of its GLP-1 agonist Victoza (liraglutide) on cardiac function in patients with heart failure (protocol described in Jorsal et al., BMJ 2014; ClinicalTrials.gov identifier NCT01472640). During a March investor update, Novo Nordisk management also offered optimistic commentary on the potential for the LEADER trial (Victoza’s CVOT) to demonstrate cardioprotection, as there is greater exposure with a long-acting GLP-1 agonist like Victoza compared to a shorter-acting agent like Lyxumia or a DPP-4 inhibitor. 
• With regard to pancreatitis, Dr. Reusch believes there is probably a real, but exceedingly small, clinical signal. The FDA and EMA’s independent evaluations of postmarketing reports and clinical study databases found no reason for concern based on clinical data (Egan et al., NEJM 2014). However, while toxicology studies revealed no toxic pancreatic effects of high doses of incretins in healthy rodent models, there was an exacerbation of background pancreatic injury in diabetic mouse models (Egan et al., NEJM 2014). In addition, a recent publication examining pooled results from Victoza’s clinical trial program hinted at an increased pancreatitis risk (1.6 cases/1,000 patient-years of exposure on liraglutide vs. 0.7 cases/1,000 patient-years of exposure on active comparators) (Jensen, Diabetes Care 2015). However, another recent publication of a nation-wide case-control Danish database study suggested no increased odds ratio of incretin-use in patients with pancreatitis. Given all of this, Dr. Reusch concluded that the signal is probably there, but exceptionally small.

GLP-1 Receptor Agonists as Adjunctive Treatment in Type 1 Diabetes

Paresh Dandona, MD, PhD (University at Buffalo, Buffalo, NY)

Dr. Paresh Dandona discussed the many benefits of GLP-1 agonists in type 1 diabetes (sizable A1c reductions, more time in range, lower insulin doses, weight loss, lower carbohydrate intake) demonstrated in a study presented last year at AACE. Toward the end of the talk, he turned to his group’s intriguing retrospective analysis (130-LB) investigating triple therapy with insulin, Novo Nordisk’s Victoza (liraglutide), and AZ’s Farxiga (dapagliflozin) in type 1 diabetes, ambitiously speculating that such a combination could eventually allow at least 50% of patients with type 1 diabetes to achieve an A1c <6% (whoa). Results demonstrated significant reductions in A1c (0.7% from a baseline of 8%), mean plasma glucose (28 mg/dl), body weight (2 kg) and an 11% increase in time in range (70-160 mg/dl) with the addition of dapagliflozin to the other components. Notably, when either the GLP-1 agonist or the SGLT-2 inhibitor was stopped, “chaos reemerged” in terms of glycemic variability. Dr. Dandona also noted that one case of euglycemic DKA occurred during the study, which he attributed to an excessive reduction in the insulin dose – this is one of the first cases of euglycemic ketoacidosis we have heard reported from a clinical trial. We would love to see future prospective trials of this combination in type 1 diabetes and are curious how often it is currently used off-label in clinical practice – possibly very effective, but not cheap!

• There is always reason to be excited about drug combinations in diabetes, but a healthy dose of caution and patience are important in this case. Given the safety questions that are emerging with type 2 diabetes drugs used in type 1 (like euglycemic ketoacidosis), we imagine that triple combinations are still a ways down the road in terms of reaching the broader market. Additionally, results we saw elsewhere in the meeting on GLP-1 agonists in type 1, such as the LIRA-1 trial. did not come out glowingly positive. Still, there is plenty of reason to keep moving forward given that the unmet need for non-insulin therapies for type 1 diabetes to reduce glycemic variability is huge.

GLP-1 Receptor Agonists for the Treatment of Obesity

Sun Kim, MD (Stanford University, Stanford, CA)

Dr. Sun Kim reviewed the role of GLP-1 agonists in weight management as well as the drug class’ weight-dependent and weight-independent effects. She began by illustrating the weight loss effects of GLP-1 agonists in people both with and without type 2 diabetes, highlighting that added lifestyle intervention leads to greater weight loss and that people with diabetes experience less weight loss compared to individuals without diabetes. Dr. Kim explained that while the mechanisms of GLP-1 agonists are not completely known, the class is hypothesized to lead to greater weight loss due to mechanisms that act both centrally and peripherally – specifically by suppressing appetite (see our coverage of an oral on GLP-1 agonists’ central action in this report [384-OR]). Dr. Kim cited data from her lab’s study, which randomized people with prediabetes to either Novo Nordisk’s Victoza (liraglutide 1.8 mg) or placebo for fourteen weeks. The results showed that those on Victoza lost twice as much weight compared to placebo (-8% vs. -4% from baseline BMI of 32 kg/m²). The Victoza arm also experienced improvements in insulin resistance, with higher insulin concentrations and lower rises in glucose concentrations. When looking at the association between weight loss and these changes, Dr. Kim noted that degree of weight loss did not have any bearing on effect on certain endpoints, including heart rate and insulin concentration. From these findings, Dr. Kim highlighted the importance of understanding what effects of weight loss drugs are associated with weight loss and which ones are direct effects of the drug, especially in people without diabetes. For more on these separate effects of liraglutide, please see our coverage of new SCALE data on Saxenda’s (liraglutide 3.0 mg) non-weight-dependent impacts.

Panel Discussion

Q: We know from our clinical experience and seeing patients on these drugs that not everybody is a good responder. Some patients are poor responders to one drug. My question is if you change to a different GLP-1 receptor agonist, will that patient who is a poor responder to one then respond to a second?

Dr. John Buse (University of North Carolina, Chapel Hill, NC): The only study I know that answered this affirmatively was a comparison of exenatide BID to liraglutide. The point we were able to work out was that among the patients with high titer antibodies to exenatide, there was a subset that did not have particularly good responses to exenatide. When switched to liraglutide, they did have good responses. There may be a small subset (a few percent of patients) that don’t respond very well to exenatide due to antibodies, but will respond to liraglutide when the antibodies don’t cross react. That’s the only situation I’m aware of where you can switch from one to the other and change effectiveness.

Q: We have lots of diabetic patients using high doses of insulin, and when you combine it with a GLP-1 agonist, the dose of insulin decreases profoundly, and they lose weight. But after eight months or a year or so, you see patients start to need more insulin, as if there’s a sort of drug failure or no efficacy from the GLP-1 agonist. If we’re using the maximum dose, should we keep increasing the dose or say no and go back to insulin? These studies were for four months or six months in studies, so what happens long term?

Dr. Buse: We do have some studies out to a year. I don’t know of a specific analysis to tease out a subset that loses control later, but the eyeball view doesn’t suggest a particular loss of control. The only thing I can think of in your case is if patients were on a really high dose of insulin and added a GLP-1 agonist and had lots of weight loss related to calorie restriction, maybe when people stop losing weight, they start to require more insulin. That’s the only thing I can think of. I haven’t seen it in clinical practice or clinical trials.

Q: Would you increase the dose of the GLP-1 agonist to more than 1.8 mg?

Dr. Buse: We always used the maximum dose in the studies. In the prefixed combination, you titrate up as needed, which has its rationale as well. It depends on the exact formulation.

Dr. Matthew Riddle: What does the clinical experience from trials say about secondary failure?

Dr. Kathleen Dungan (Ohio State University, Columbus, OH): In general, for all these therapies, the durability of the agents is a very important outcome. This is the kind of data we need. And this is already underway with the GRADE trial. Probably, all agents have some failure rates over time. The best way to figure this out is to actually compare head-to-head in the long term to see when failure occurs.

Q: I have two questions. First, do you recommend the use of off label medications in the general clinical setting? And if it is to be used for individual patients do you recommend IRB approval for each patient? Secondly, do you consider hypoglycemia unawareness as an absolute contraindication for GLP-1 analogs?

Dr. Paresh Dandona (University of Buffalo, Buffalo, NY): As far as off label use is concerned, in general, there seems to be a consensus that once a drug is licensed, it is the prerogative of the physician to make the decision clinically as to how and when to use it. The other issue related to hypoglycemia is that certainly if you substitute GLP-1 RAs, any of them, in place of insulin, you will diminish incidence of hypoglycemia, and that might be justification of use for this class of drug with maximal oral therapy when you start injectable therapy. So clearly there is an advantage there. I teach my fellows that the beta cell is much more clever than all of us put together. The beta cell generates the right amount of insulin at the right time. That’s what the GLP-1 RA is doing for you.

Dr. Buse: Just to add that if you are doing off label things, particularly things that are way off label, like something that the package insert says not to do, it would be a good idea to have a conversation with the patient and document it clearly in the medical record that you did so. If you’re doing one patient at a time, there is no reason to go to the IRB, but if you’re doing it with the intent of collecting data and presenting it then you should definitely go to the IRB. On the second issue I agree with Dr. Dandona that in patients having issues with hypoglycemia, some of these off label uses of type 2 diabetes drugs suggests less hypoglycemia, but I think it can be a bit scary as you transition patients. So caution during the transition period would be wise.

Q: Does adding a GLP-1 agonist have an effect for highly insulin resistant patients?

Dr. Sun Kim (Stanford University, Stanford, CA): A majority of the prediabetes patients we studied had high insulin resistance and they had a benefit in terms of weight loss. So there’s a benefit there because when you lose weight you improve insulin resistance. Your question is two-fold: in non-diabetic people we’re enhancing insulin secretion, and it levels out after weight loss. In the type 2 diabetes population, weight loss and decrease in appetite will help towards becoming insulin sensitive, so it’s worthwhile to try.

Q: Is there evidence for adding it to MDI?

Dr. Buse: There is a paper I’m aware of by Dr. Lane from Asheville with people on very high doses of insulin who added a GLP-1 agonist. As I remember, it wasn’t very well controlled but there was a suggestion of benefit. There’s not a lot of data in that population. There is on TZDs, but there’s a real risk around fluid retention and weight gain. Very recently Raskin published a paper using bromocriptine QR on high dose insulin. It wasn’t controlled but there was a dramatic response.

Dr. Dandona: Unfortunately some patients don’t absorb all of the insulin. There were some studies published in 2004 led by CDEs where people were put on pumps and with a continuous infusion reduced their insulin dosages by 50-70% while improving A1c. It’s not an issue of tissue level resistance but bioavailability. Along the same lines, the beta cell is clever and delivers insulin at the right time to the right place. When you’re using a GLP-1 agonist it increases endogenous insulin, and that small amount makes more of a difference than hundreds of units.

Dr. Riddle: In the case of varying insulin resistance in a person using a lot of insulin, one question that comes up is adherence to injections and high doses, as that can contribute to difficulties in control. And there’s this general problem of behavioral aspect for any drug class. Dr. Reusch, can you comment on how we should be thinking about counseling of patients and how to optimize weight control and minimize hypoglycemia?

Dr. Jane Reusch (University of Colorado, Denver, CO): Related to high doses of insulin, I would concur with Dr. Riddle that you need to make sure that the patient is taking all of his or her insulin before making any adjustments. We also need to explain to patients requiring greater than 200 or 400 units of insulin that there might be other options in terms of injectability. They might be able to take U300 or U500, which may or may not improve absorption. You should never forget that they also need to eat less and move more. What I do is that I take a specific diet history to understand when they are eating and to try to find low-hanging fruit to use to get rid of specific carbohydrate calories. And when do they move? Can I increase that? Especially around mealtime, there is some new data from a Japanese poster here showing that if you hop up a couple flights of stairs with each meal, you can get a lower A1c.

Dr. Buse: Someone just texted me about late breaking poster #8: high dose insulin patients adding liraglutide vs. placebo in a blinded fashion ended up with a 1.1% A1c difference after 6 months. [Audience laughter].

Q: I was very impressed by the combination of GLP-1 receptor agonists and basal insulin and struck, particularly, by the lack of increase in hypoglycemia despite the incredibly aggressive achieved A1c goals. We’re all aware that GLP-1 receptor agonists have a glucose-dependent mechanism of action. But is that sufficient to explain why we have such a low risk of hypoglycemia?

Dr. Buse: I think everybody was surprised. We thought there would not be any more hypoglycemia with the combination, but that there was actually less hypoglycemia with a lower A1c is stunning. We think it might be a beneficial effect of GLP-1 on alpha cell function in addition to the presumed benefit on beta cell function. I think it remains unexplained. The observation has been seen over and over and over again.

Dr. Dandona: There is a beautiful study published about four years ago that looked at liraglutide in type 1 diabetes. In that study, following a meal, they put patients on a bicycle and gave them exercise. So they deliberately lowered blood sugar. What they discovered was that in spite of glucagon suppression at basal levels, once exercise and hypo came along, [patients on liraglutide] had a surge of glucagon. So there is evidence that there is conservation of glucagon that is released at the appropriate time.

Q: When you’re dealing with doses of 200-400 units and high resistance, you can’t forget that if they’re more diligent with eating and activity it makes a big difference. Are researchers looking at what type of weight is lost with these medications, like lean tissue vs. non-lean?

Dr. Kim: Some studies have said there’s more fat loss in particular. It’s not the preferentially lean tissue loss that you’re worried about. There’s nothing particular about weight loss with drugs vs. other means in terms of the degree of fat vs. lean tissue.

Q: It would be interesting to know down the road what percentage was lean vs. non-lean tissue. Maybe there could be a study looking at medication in combination with exercise, which might magnify the benefit.

Dr. Kim: I tried to make point in my presentation that with any weight loss drugs, if you don’t combine them with lifestyle interventions, the benefit is much less.

Dr. Reusch: In preclinical studies in rodents, we were able to demonstrate that the combined effects of exercise and a DPP-4 inhibitor or GLP-1 agonist have an additive effect on improvements in exercise function, but not as consistent of an effect on glucose.

Q: You shared information about SGLT-2 inhibitors in type 1 diabetes. As I was listening carefully, you talked about gentle adjustments of insulin. Can you expand on that please?

Dr. Dandona: If you get a great insulin deficit, relatively speaking, you could move into a situation of ketoacidosis, which has been talked about a lot. We’ve seen that in our patients. There’s a critical level that we’ve determined from our experience – this is the start of the story – you should not get to an insulin dose of less than half a unit per kilogram of body weight. As part of this initial enthusiasm, it’s important to settle to safe ways of doing things.

Corporate Symposium: Complementary Treatments to Enhance Insulin Efficacy: Theory and Strategies (Supported by Joslin and Sanofi)

Basal Insulin and Complementary Treatments: Summary of Pathophysiology and Pharmacology

Anne Peters, MD (University of Southern California, Los Angeles, CA)

The brilliant Dr. Anne Peters provided an overview of clinical considerations for initiating basal insulin therapy and selecting an add-on once basal insulin alone is inadequate. Dr. Peters set up the framework for the rest of the symposium with the following points: (i) in UKPDS, half of recently diagnosed people with type 2 diabetes required insulin after 6 years; (ii) hypoglycemia is the limiting factor for optimizing basal insulin therapy; and (iii) in the real world, people do not tend to get to treatment targets on basal insulin alone, likely because PCPs are hesitant to up-titrate insulin dose. Dr. Peters then reviewed the guidance on intensifying basal insulin therapy in the newly updated 2015 ADA/EASD position statement, which very much favors the combination of basal insulin and GLP-1 agonists.

Basal Insulin and Complementary Treatments: Basal Insulin Plus GLP-1 Agonists

John Buse, MD, PhD (UNC, Chapel Hill, NC)

The super-hero smart and highly renowned Dr. Buse reviewed the data in support of combining GLP-1 agonists with basal insulin therapy. He opened with a review of the rationale behind GLP-1/basal insulin combination therapy, noting strong glycemic control with additional benefits to hypoglycemia and weight loss observed in trials as compared to either of the components alone. Moving to the newer combinations, Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s LixiLan (insulin glargine/lixisenatide), he was encouraged by the convenience offered by combined single-injection devices. Despite strong evidence for the combinations, he noted it is still unclear where they should fit in the treatment toolbox – he hoped for future trials investigating this moving forward. He concluded with praise for the class: “I do believe this combination is here to stay and that they are also in need in the marketplace.”

• Dr. Buse opened with a review of the rationale behind GLP-1/basal insulin combination therapy. He noted the complementary glycemic effects, with increased portal insulin delivery (via GLP-1 agonism) and decreased glucagon secretion for postprandial control via GLP-1 and efficacy in reducing fasting plasma glucose via basal insulin. Looking to the GWCO study that combined insulin glargine and exenatide BID versus glargine and placebo, he highlighted the stronger decline in A1c with the combination (8.3% to 6.6% vs. 8.5% to 7.5%) with weight loss of 1.8 kg (4.0 lbs) versus weight gain of 1.0 kg (2.2 lbs). He noted additionally no increase in hypoglycemia (25% vs. 29%) though with increased nausea, diarrhea, vomiting, headache, and constipation.
• Dr. Buse moved to discuss the newer combinations of GLP-1/basal insulin, Xultophy and LixiLan. On Xultophy, he reviewed the DUAL trials (Dr. Buse himself presented the stellar DUAL I results at ADA 2013). He highlighted the stronger A1c declines and improved side effect profile of Xultophy versus either component alone. Looking to DUAL II, in particular, he stressed that in a blinded study, patients experienced similar rates of nausea, suggesting rates may similar when patients are unaware if the medication administered is nausea-provoking or not. Similarly, with LixiLan, he highlighted the improved A1c declines and weight loss seen with the combination versus insulin glargine alone. Finally, noting that comparisons of GLP-1/basal insulin may more appropriately be compared to a basal bolus regimen, he highlighted the results of a larger meta-analysis of three trials comparing the combination to basal bolus therapy that indicated an overall 0.1% greater decline in A1c as well as benefit to weight loss and hypoglycemia rates.
• Dr. Buse concluded by addressing some remaining unresolved issues in the use of GLP-1/basal insulin combinations. While the combination provides improved efficacy versus either of its component parts, he notes it is still unclear where it fits in the treatment algorithm as an enhanced insulin or enhanced GLP-1. It also remains unclear whether the combination should be used early or reserved for those failing either therapy. He hopes for trials looking at both approaches moving forward. In response to an audience question, he suggested that using GLP-1 agonist/basal insulin combination in type 1 diabetes is currently a “remarkably bad idea” given the need to get basal insulin titration exactly right, the lack of data on GLP-1 agonists’ efficacy in type 1 diabetes, and the cost.  

Joslin Needs Assessment Data: Exploring Some “Disconnects”

Richard Beaser, MD (Joslin Diabetes Center, Boston, MA)

Dr. Richard Beaser presented some insights on discrepancies between patients’, PCPs’, and specialists’ perspectives on GLP-1 agonist treatment. One big disconnect was that more than 70% of PCPs surveyed believed patients would be deterred by the painfulness of injections, whereas fewer than 15% of patients expressed the same concern – we do continue to hear that better devices and smaller needles are making injections less and less of an obstacle to overcome. PCPs identified A1c reduction and cost of treatment as the two primary considerations when deciding whether to prescribe GLP-1 agonists, whereas patients were most interested in the composite profile of glucose control with weight loss and reduced hypoglycemia risk. We found it surprising that cost seemed to show up more on PCPs’ radars. In contrast to PCPs, specialists were more likely to weigh patients’ other comorbid conditions and age. In focus groups, PCPs identified the need for better methods of learning about new medications – PCPs are currently inundated with new information every day and struggling with how to validate various sources and synthesize all of that new information into courses of action. With more manufacturers entering the GLP-1 agonist market and looking to help that market grow, we expect to see an increase in CME and other educational events on GLP-1 agonists directed at primary care.

Basal Insulin and Complementary Treatments: Overcoming Barriers and Developing Patient-Centric Treatments

Mark Peyrot, MD (Loyola University, Baltimore, MD)

Dr. Peyrot provided practical recommendations for providers for overcoming barriers to care in the treatment visit. In the treatment visit, he notes, patients and providers often have different perspectives – patients hope for immediate efficacy with limited side effects and a “less is more approach” to care, while specialists may instead look for convenience in prescription and more aggressive regimens. Overall, his recommendations focused on an “Ask, Don’t Tell” approach to joint decision-making, in which the provider works with the patient to assess barriers to care, review treatment options and alternatives, and support treatment decisions. He suggested that paying attention to patient perceptions and beliefs, rather than taking a didactic approach, could smooth the prescription process and produce better outcomes.

Selected Q&A/Panel Discussion

The panel began with a case discussion about a 50-year old man with type 2 diabetes referred by his PCP for inadequate glycemic control on metformin and pioglitazone. The patient has a fear of needles but is also fearful of the severe diabetes complications he witnessed in his family. As was the case during the presentations this session, there was an emphasis on how to engage PCPs. Selected Q&A are included here.

Q: What would you recommend and why?

Dr. John Buse (University of North Carolina, Chapel Hill, NC): I agree with a GLP-1 RA as the drug of choice in this case […]. My approach is to offer therapies I think are reasonably likely to get them to target. Then I will write the options down on a piece of paper for the patient and a couple of phrases of what I see as the advantages and disadvantages and ask them to reflect on what I just reviewed […]. I think in the long haul it improves adherence, and they understand why the other options weren’t chosen, compared to saying, “I think this is the best thing for you.” Some patients ultimately do want you to say that, and of course you can tell them what you think.

Dr. Anne Peters (University of Southern California, Los Angeles, CA): When we’re talking about an injectable, I show them an injectable because the needle is so tiny and so much easier than they think it will be. In the office, the physics of taking off the cap, makes them feel like it is an option. Theoretically they may get scared but when they see it, it becomes more of a real option. I suspect with enough time the patient should get the signal.

Dr. Richard Beaser (Joslin Diabetes Center, Boston, MA): One tactic I use if the patient favors an approach that isn’t my first choice, I might let them do it for a while as long as it is not harmful. This proves to them that it is not as effective a treatment as the one I preferred, so then I can move them onto the treatment I prefer subsequently. 

Q: Which GLP-1 would you choose? What properties are you looking for?

Dr. Buse: Right now we don’t have great data on the head-to-head comparison of the exenatide BID basal insulin combination versus long acting GLP-1. There’s certainly a lot more convenience today to the long acting GLP-1. The exenatide approach has benefits to postprandial glucoses so that could be good for a person who eats larger meals. Until I see more data, I’d focus on convenience though data coming with more variations of combinations.

Q: How do you address the PCP that has a lot of concerns as well?

Dr. Buse: I usually don’t call PCPs because they’re busy enough but I would just write in the note the titration scheme. For either a GLP-1 agonist or combination products likely to be available in the future should be very simple. These are very easy drugs to use compared to insulin.

Dr. Beaser: I would also encourage the PCP to look at postprandial glucose levels when a patient is on a GLP-1 agonist. If the patient is only measuring pre-meal values, then he may not see the effect of the GLP-1 and become discouraged.

Dr. Peters: In my neck of the woods, we email a lot. I have the patient summarize, in an email, what they think are the conclusions of what we discussed. And they email me and their PCP, and they have the three of us have a brief dialogue. I like that both because the patient is the one writing it, and we all can answer each others’ questions. PCPs don’t want to feel like you know everything and they know nothing. So there are ways to engage PCPs in doing this. Additionally, when I put a CGM on these patients and show the difference before and after, it’s amazing to see such an improvement in control. So use whatever tools you can use to engage your team.

Q: I’m wondering about the potential of IDegLira in type 1?

Dr. Buse: I think it’s a remarkably bad idea. Basal insulin is something you want to get right in type 1 diabetes, and GLP-1s are completely unproven in type 1 and extremely expensive. They’re not FDA approved. I certainly wouldn’t use the combination. If I were going to use a GLP-1, I would free style it. I’m not a huge fan of the approach.

Q: Can you comment on the combination of GLP-1 agonists and SGLT-2 inhibitors?

Dr. Peters: From my own clinical use I’ve used them in combination, and I think they work well. In some of my patients I’ve been able to get them off basal insulin on that combination with metformin. You could use a once-weekly GLP-1 RA and then that’s just two pills per day. However, it’s incredibly expensive, and we don’t have data supporting using it. On the other hand it does work. It’s a nice combination in terms of simplicity and effectiveness.

Q: If you have diabetes for 20 years can you still use GLP-1?

Dr. Buse: Even if you have a longer duration of disease you still respond very well. There is a loss of beta cell function in type 2 diabetes, and one of the major functions here is to restore beta cell function.

Corporate Symposium: Clinical Issues in Type 2 Diabetes: Discussions and Debates Around GLP-1 Receptor Agonists (Supported by AZ)

Lawrence Blonde, MD (Ochsner Medical Center, New Orleans, LA), Daniel Einhorn, MD (Scripps Health, La Jolla, CA), and Jaime Davidson, MD (University of Texas Southwestern Medical Center, Dallas, TX)

This AZ-sponsored breakfast symposium featured wide-ranging commentary on the advantages of GLP-1 agonists. The symposium was organized by topic area, with several short presentations and discussion on each topic rather than a series of longer individual talks, and our coverage is divided accordingly.

Potential as First Injectable Therapy

Speakers offered a very positive take on the use of GLP-1 agonists as the first injectable therapy for type 2 diabetes. Dr. Daniel Einhorn described the class as an underutilized option that is much more attractive than insulin as an initial injectable therapy, particularly given the recent advances in delivery devices and the availability of once-weekly products. He did not comment on the relative advantages of specific agents within the class, but from our perspective, Lilly’s Trulicity (dulaglutide) is the GLP-1 agonist that most fully embodies these selling points. In Lilly’s 1Q15 update, management shared that early uptake of Trulicity has been very strong, and we agree with the company’s prediction that the product will likely serve as a catalyst for growth of the GLP-1 agonist class as a whole. Improvements in other once weekly agents (i.e. AZ’s new Bydureon pen) should help as well. With regard to side effects, Dr. Jaime Davidson suggested that the amount of nausea and vomiting produced by GLP-1 agonists is often overstated and that much of the nausea patients experience is actually a feeling of satiety that they are unused to.

• Dr. Davidson also discussed other potential risks associated with GLP-1 agonists, including acute pancreatitis, thyroid cancer, and renal impairment. He reported that post-marketing surveillance of GLP-1 agonists has not revealed an increase in acute pancreatitis risk but suggested proceeding with caution nevertheless. He suggested that clinicians consider other treatment options if patients have a history of pancreatitis and educate patients about the signs of acute pancreatitis so the therapy can be discontinued if an issue arises. Dr. Davidson does not recommend GLP-1 agonists for patients with a history of thyroid cancers based on the increased risk of medullary thyroid carcinoma seen in rodents. He also does not recommend GLP-1 agonists for patients with renal impairment.

Combination Therapy

Speakers also expressed great enthusiasm regarding the use of GLP-1 agonists in combination with other agents. Dr. Davidson reviewed clinical data on GLP-1 agonist/basal insulin combinations, which we continue to see as one of the most exciting new type 2 diabetes drug classes on the horizon. During Q&A, speakers debated the most appropriate role for such combinations compared to GLP-1 agonists alone. Dr. Davidson suggested that GLP-1 agonist monotherapy would be most appropriate for patients with a lower baseline A1c, while Dr. Einhorn argued that a combination approach is preferable at any stage of the disease, all other factors (such as price) being equal. Dr. Einhorn also spoke more broadly about the benefits of combination therapy during his prepared remarks. He strongly advocated for initial triple therapy with metformin, a GLP-1 agonist, and pioglitazone, which has shown better results in terms of time to treatment failure and glucose variability than adding the therapies sequentially. Dr. Einhorn also pointed to GLP-1 agonists and SGLT-2 inhibitors as a logical combination with greater than additive weight loss effects in clinical trials. We expect to hear much more about this approach in the coming years: trials of exenatide/dapagliflozin and liraglutide/canagliflozin combination therapy are ongoing and expected to complete within the next two years. 

Obesity

Dr. Einhorn and Dr. Davidson discussed motivational interviewing and bariatric surgery as best practices in treating overweight and obese individuals with type 2 diabetes. Dr. Einhorn underscored the importance of motivational interviewing when discussing lifestyle changes to promote weight loss with patients in order to establish a trusting relationship with them. He emphasized that patients do not have to reach a perfect target to get a better outcome – we have heard many times that the disconnect between patients’ and providers’ weight loss expectations can be one of the most challenging aspects of treating obesity for clinicians. At the other end of the spectrum for obesity therapies, Dr. Davidson reviewed results from the STAMPEDE study showing significantly greater A1c reductions with bariatric surgery added to intensive medical therapy vs. intensive medical therapy alone. The type of bariatric surgery – gastric bypass or sleeve gastrectomy – did not have an effect on the A1c results, though gastric bypass had a slight edge in terms of the percentage of patients achieving diabetes remission. It is not entirely clear whether it was some factor unique to bariatric surgery or simply the magnitude of weight loss that was responsible for these results; we agree with Dr. Timothy Garvey’s (University of Alabama, Birmingham, AL) suggestion at Obesity Week last year that a trial evaluating the effects of surgery vs. equal weight loss achieved with obesity medications would be very intriguing.

Expanded Indications

The symposium concluded with intriguing presentations by Dr. Einhorn and Dr. Davidson on the many potential expanded indications for GLP-1 agonists, including NAFLD/NASH, neurodegenerative diseases, polycystic ovary syndrome, and type 1 diabetes. Novo Nordisk’s Victoza (liraglutide) is already being investigated in several of these indications: two phase 3 trials (ADJUNCT ONE and ADJUNCT TWO) in type 1 diabetes are scheduled to report within the next few months, although data from the LIRA-1 trial presented on ADA Day #5, while demonstrating some benefit, were not as positive as we had been hoping. We also heard about intriguing academic studies in NASH and Alzheimer’s disease have been completed or are underway. According to Dr. Davidson, off-label use of GLP-1 agonists in type 1 diabetes is already fairly common, and he said he personally has been very satisfied with the results. In our view, this is part of a larger trend away from the view of type 1 and type 2 diabetes as entirely distinct diseases, and we expect the use of type 2 diabetes drugs (particularly GLP-1 agonists and SGLT-2 inhibitors) in type 1 diabetes to become increasingly common in the coming years.

Panel Discussion

Q: Is there any data regarding initial combination therapy with a non-insulin agent vs. initial combination therapy with insulin?

Dr. Daniel Einhorn (Scripps Health, La Jolla, CA): In the triple therapy study, one group had insulin and the other did not.

Dr. Lawrence Blonde (Ochsner Medical Center, New Orleans, LA): It was an option to add insulin but did everyone get it?

Dr. Einhorn: Insulin, sulfonylurea, and metformin were the options. It would be interesting to find what percentage ended up on insulin and how early they got it. Another question is whether the injectable part is such an issue. We all feel much less of that now.

Q: Do you agree that GLP-1 agonists are more effective early in the course of diabetes while insulin is effective in the entire natural history of diabetes?

Dr. Jaime Davidson (University of Texas Southwestern Medical Center, Dallas, TX): There is plenty of data showing that GLP-1 agonists are effective no matter when we use them. I prefer early because they provide better weight loss and better control over everything, not just glucose. That’s the advantage of GLP-1 agonists.

Dr. Blonde: There was a study that showed that A1c reduction was a little bit greater in people earlier in the course of diabetes. But even in that trial people who had diabetes for 10 years or longer showed reductions.

Dr. Einhorn: Earlier is better for everyone.

Q: Is there any human data suggesting that GLP-1 agonists improve beta cell function or mass?

Dr. Einhorn: There is clinical data suggesting that beta cells behave better. Whether they’re bigger or there are more of them, they seem to behave better longer.

Dr. Davidson: If they actually improved islet function in humans, then we wouldn’t see the slow rise in A1c. It’s the best drug on durability but there’s still that slow rebound. And when you stop the drug, you saw what happened. If you discontinue, in four weeks you see an increase in glucose. This is treatment, not prevention.

Q: Does the significant weight loss depend on a high nausea rate? People have thought that people lose weight because they get nauseated.

Dr. Blonde: Even in patients without nausea or vomiting, there is still a significant difference in weight loss. Nausea and vomiting is not the primary driver of weight loss. GI side effects are not the primary reason for the weight loss.

Q: Do you have any data or recommendations on the relationship between timing of meals and time of dosing?

Dr. Einhorn: Exenatide twice daily should be taken within an hour of the two main meals of the day so that’s six hours apart. Once you do it once a week, the nice thing is if they forget to take it in the morning, they can take it in the afternoon and maintain the good control. If you can do it anytime or once a week, that’s a completely different life. If you miss a day, you can take it the next day.

Dr. Blonde: If you’re starting a patient on a medication that has to be taken the next day that’s injectable, they have to give it to themselves the next day. With a once-weekly agent, you can explain how it works and the clinician can say I’ll give it today, you go watch the videos and read about how to use it, and come back in a week for a short visit and see if you can do it then. It makes the intensity of training at the first visit much less if people don’t have diabetes educators who can do it. They don’t even half to come back one week to the day. There’s some flexibility that can make it easier to start.

Q: Is it more effective to add a prandial GLP-1 agonist or a once weekly GLP-1 agonist to basal insulin?

Dr. Einhorn: There haven’t been any head to head studies. The advantage of the once-weekly agent is it’s more likely to be taken consistently, and I’m guessing in real life the impact of missed doses might exceed the relative impact on prandial glucose. I believe very strongly that making it easy should be the guiding principle, because easy means it will be adhered to. People are living with this for many years, and once a week vs. twice a day can make a difference.

Dr. Davidson: Some people do need to use a prandial agent. If they can’t get adequate postprandial control, that’s another option that’s been effective.

Dr. Blonde: Soon we will have fixed-ratio combinations of GLP-1 agonists and basal insulin. Where would you put them in the sequence and treatment algorithm?

Dr. Davidson: We will see posters here of that combination. It’s very effective. To me it depends on where A1c is at the beginning. When AACE gets new data, we will fit them in the algorithm somewhere between 8% and greater, but never below. Most clinical trials with basal insulin have people with an A1c above 8%. The people who designed them are very intelligent. If you start with an A1c of 7.5%, you will increase the risk of hypoglycemia significantly.

Dr. Blonde: The studies did show that though there was less hypoglycemia than with insulin, there was more than with a GLP-1 agonist alone.

Dr. Einhorn: In general, I would consider lower doses of the combination early on. There’s an advantage to harnessing different targets from the very beginning. I share your caution about hypoglycemia, but for me it’s a matter of dose. All things equal, if I can get two peptides I will get two. If it were more expensive, that would sway the decision.

Dr. Blonde: Is there some benefit to early insulin that would be a reason to accept some hypoglycemia and weight effects? If not, maybe we should reserve it for later. Those studies will be coming. We don’t have the answer right now.

Product Theaters

Non-Adherence and Glycemic Control – A Real-World Look at the Issues and Challenges We Face (Sponsored By Intarcia)

Steven Edelman, MD (TCOYD, Del Mar, CA) & Troy Ross (Mid-America Coalition on Health Care, Overland Park, KS)

This was the first Intarcia-supported product theater we’ve seen out on the conference circuit so far, though as with Sanofi’s first product theater for the new inhaled insulin Afrezza there was no specific mention of Intarcia’s product. Instead, co-hosts Dr. Steven Edelman and Mr. Troy Ross made some general points about adherence, namely focusing on therapies that promote weight loss, reduce hypoglycemia, and have other benefits that are highly meaningful for patients. Though the content was valuable from a provider perspective and well delivered, we are more eager to see product-specific messaging once ITCA-650 draws closer to market.

A Case Study in Treating Adult Patients with Type 2 Diabetes (Sponsored by Lilly)

Stanley Schwartz, MD (University of Pennsylvania, Philadelphia, PA)

Dr. Schwartz led the product theater on Lilly’s once weekly GLP-1 agonist Trulicity (dulaglutide). Following an opening review of ADA treatment guidelines, he introduced Trulicity, emphasizing the once weekly dosing and noting that no reconstitution or shaking was necessary for administration. Moving to efficacy results, Dr. Schwartz underlined the strong glycemic control observed in the AWARD trials, suggesting Trulicity could be a good option before starting insulin due to the low incidence of hypoglycemia without weight gain. He concluded with practical tips from his clinical practice for educating patients in order to reduce nausea and vomiting rates.

• Following an opening review of ADA treatment guidelines, Dr. Schwartz introduced Trulicity, emphasizing ease of use with the auto-injector pen – the easiest-to-use device for any currently available GLP-1 agonist. With the pen, administration requires no reconstitution or shaking and the injection is delivered through a 29-gauge needle that patients never have to see. He felt that in his practice demonstrating this in office often helped patients get over preconceptions over pain and difficulty with injectables. He also promoted a sample pack offered by Lilly, which includes educational information and a savings card for patients to reduce costs.
• Moving to efficacy results, Dr. Schwartz underlined the strong glycemic control observed in the AWARD trials. Looking to AWARD-5, he noted 0.9-1.1% declines with Trulicity (baseline 8.1-8.2%) versus 0.4% with sitagliptin (baseline 8.0%). He also highlighted similar efficacy to liraglutide in AWARD-6 and insulin glargine in AWARD-2, suggesting Trulicity could be a good option before starting insulin due to the low incidence of hypoglycemia without weight gain.
• With regard to nausea and vomiting, Dr. Schwartz emphasized that in his practice he felt proper education could reduce event rates. He said it was important to teach patients that they will lose their appetite and not to eat in between meals out of habit. When eating, he instructs patients to stop eating at the first sign of fullness – continuing to eat when full, he suggested, prompts nausea. Anecdotally he felt these recommendations brought rates of nausea far below what was seen in trials.

The Effect of a Once-Weekly Therapy on A1C and Weight Over 3 Years (Sponsored by AstraZeneca)

Steven Edelman, MD (University of California San Diego, La Jolla, CA) & Kirsten Ward, CDE (Health Coach Boston, Boston, MA)

The renowned Dr. Edelman and fantastic Ms. Ward led a product theater on AZ’s GLP-1 agonist Bydureon (exenatide once weekly), highlighting the efficacy and safety profile of the drug. Following a review of the mechanism of action of GLP-1 class, Dr. Edelman moved on to highlight takeaways from the DURATION phase 3 trials, particularly emphasizing the strong A1c declines and maintained weight loss. He also noted the reduced nausea and increased potency as compared with Byetta, underlining the differences between the drugs. Ms. Ward concluded the session with a demonstration of the Bydureon pen, placing heavy focus on the SteadyStart post-prescription support system as a way to ease the patient’s transition to the drug – we see patient support program models like this as becoming increasingly important differentiators for new and existing drugs. Overall, it seemed the presentation aimed to reinforce the simplicity of prescription and administration – there was little mention of the single-use tray, which now accounts for only half of all monthly prescriptions.

• Following a review of the mechanism of action of the GLP-1 class, Dr. Edelman moved on to highlight takeaways from the DURATION phase 3 trials with Bydureon. In addition to strong A1c declines, he emphasized the weight loss observed in the trials, particularly noting the 5.5 lbs weight loss seen in DURATION-3 that was maintained until the end of the trial. Compared with Byetta, he reinforced the increased potency of Bydureon as well as reduced incidence of nausea.
• Looking to six-year safety data, Dr. Edelman underlined the lack of major hypoglycemia cases as well as the decreasing nausea with time. In the DURATION-1 extended trial, he noted that nausea declined from the initial controlled 30-week period at 0.85 events/year to 0.08 events/year by the end of six-year follow-up. Nevertheless, he cautioned that GI side effects serve as the primary adverse events directly related to GLP-1 administration. He also noted increased injection site reactions versus Byetta and insulin glargine given the components of the long-acting suspension.
• Ms. Ward went on to demonstrate the use of the Bydureon pen, promoting the SteadyStart program as a way to offer clinical educator support directly to patients. As described at last year’s product theater, the program includes full-time and on-demand educators and specialists to help educate patients on proper administration of Bydureon. The program includes a series of follow-up calls at 7, 30, 60, and 90 days post-prescription to ensure smooth transition to the pen. Patients have the option of enrolling in non-branded education sessions on healthy lifestyle change as well as opting in for dosing reminder emails. The concluding patient video included a series of testimonials in praise of the program and ease of use with the pen.

DPP-4 Inhibitors

Oral Presentations: Results from the Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS)

Study Rationale, Design, and Study Conduct

Jennifer Green, MD (Duke University, Durham, NC)

Dr. Jennifer Green opened the session with an overview of the aims, design, and execution of TECOS. She noted repeatedly that the goal was to determine the non-glycemic effects of sitagliptin on cardiovascular outcomes and that the investigators therefore aimed to minimize the difference in A1c between the groups. All aspects of disease management other than adjustment of the study drug were managed by patients’ own healthcare providers, and patients were allowed to use any diabetes drugs other than incretin-based therapies (though use of rosiglitazone was discouraged). The primary outcome of the study was time to first occurrence of CV death, non-fatal MI, non-fatal stroke, or hospitalization for unstable angina. Secondary outcomes included a secondary composite endpoint (the primary composite with hospitalization for angina excluded), individual components of the primary endpoint, all-cause mortality, hospitalization for heart failure, and a composite endpoint of hospitalization for heart failure or CV death. Differences in A1c, renal function, time to insulin initiation or addition of another oral medication, and medical resource utilization were also evaluated. All deaths, events in the primary composite, heart failure hospitalizations, cases of acute pancreatitis, and malignancies were independently adjudicated. Dr. Green shared that the trial had 90% power to exclude a hazard ratio of 1.3 (as required by the FDA) and 81% power to detect a 15% reduction in CV risk. She emphasized the fact that TECOS was a safety study designed to demonstrate non-inferiority rather than superiority.

TECOS Results

Rury Holman, FMedSci (Oxford Center for Diabetes, Endocrinology, and Metabolism, Oxford, United Kingdom)

Dr. Rury Holman presented the primary results from TECOS, which featured no major surprises. The hazard ratio for the primary composite cardiovascular endpoint (MACE + hospitalization for unstable angina) was 0.98 (95% CI = 0.89-1.08). The secondary  cardiovascular composite (MACE only) was also neutral (HR = 0.99; 95% CI = 0.89-1.10). Results for all individual components of the primary composite, and for all-cause mortality, were also neutral. Of course, all eyes were on the heart failure results to provide more clarity on the question of a DPP-4 inhibitor class effect. The answer was fully reassuring, with an almost impressively neutral hazard ratio of 1.00 – notably the upper bound of the 95% confidence interval was 1.20, which Dr. Holman noted was below the point estimate of 1.27 for hospitalization for heart failure in the SAVOR trial. There were non-significant numerical imbalances in pancreatic adverse events that went both ways. Based on a small number of patients with events, there were more cases of acute pancreatitis with sitagliptin. However, based on an even smaller number of patients with events, there was an imbalance in pancreatic cancer in sitagliptin’s favor. Dr. Holman did not appear to be unduly concerned about these imbalances, and we believe most major figures in the field feel inclined to agree with him.

• Of the 24 prespecified primary composite cardiovascular endpoint subgroup analyses, the only one to produce a non-neutral result was BMI, which demonstrated a modest but significant (p=0.03) interaction in favor of sitagliptin in obese patients. However, Dr. Holman cautioned against over-interpreting that result given the number of sub-analyses. Other factors, including age, sex, race, geographic region, history of heart failure, blood pressure, smoking, medications, baseline A1c, and diabetes duration, had no significant impact on the results. We agree it isn’t necessarily something to write home about though patients do care about this and it may be a driver of adherence.

• Dr. Holman stressed that the resoundingly neutral results “does not mean this drug is not working,” as the goal was to investigate any effects on CV outcomes unrelated to glucose lowering. We imagine that there is somewhat less potential for public disappointment with TECOS compared to ELIXA as there was less hope that DPP-4 inhibitors would be able to demonstrate cardioprotection. However, we cannot help but wonder whether a GRADE-like trial evaluating the effect of glucose-lowering achieved with sitagliptin compared to other diabetes drugs could have provided more clinically valuable results.
• The fact that Januvia emerged from TECOS unblemished should help the product retain its leadership in the DPP-4 inhibitor class, with AZ’s Onglyza (saxagliptin) and – to a lesser extent – Takeda’s Nesina (alogliptin) blemished by the heart failure question – fairly or not. In general, we see the neutral TECOS heart failure results as good for the class as a whole, and it increasingly looks like the signal in SAVOR was a matter of chance. In the context of a fairly homogeneous class of drugs, however, prescribers may choose to play it safe and go with Januvia.

TECOS From a Cardiologist’s Perspective

Eric Peterson, MD (Duke University School of Medicine, Durham, NC)

Dr. Eric Peterson discussed the broader implications of the TECOS results for patients with diabetes, framing them as a reassuring addition to the body of evidence in favor of DPP-4 inhibitors. He stated that diabetes is “remarkably important” from a cardiologist’s perspective and argued that the main goal of treatment, based on current evidence, is to reduce microvascular complications in a safe fashion. He presented an analysis showing no significant heterogeneity between SAVOR, EXAMINE, and TECOS with regard to the primary outcome and argued that the combined results support a strong safety profile for DPP-4 inhibitors in high-risk patients. Like other speakers in the session, Dr. Peterson suggested that the lack of a superiority finding could have been due to the relatively short duration of the trial (for us, that seems almost certainly true) or the fact that it was only designed to evaluate sitagliptin’s non-glycemic effects. With regard to heart failure, Dr. Peterson suggested that combining the results of the three trials may not be as reliable, though he also noted that the population characteristics and the definition and adjudication of heart failure were relatively similar in all of the studies. He acknowledged that the divergent results could have been due to intrinsic differences between individual agents but said that conclusion should be accepted only after excluding all other possibilities, including chance.

Discussant

Allison Goldfine, MD (Joslin Diabetes Center, Boston, MA)

The renowned Dr. Allison Goldfine reached similar conclusions as Dr. Peterson about the implications of the TECOS results and also raised important points about the need for a broader discussion regarding the current CVOT paradigm. She emphasized the goal of maintaining glycemic equipoise between the two groups during the trial and stressed that the results should thus be interpreted as demonstrating non-inferiority between sitagliptin and “placebo plus.” With regard to heart failure, she feels that the verdict is still out: she cautioned against lumping the results from the three DPP-4 inhibitor trials together or automatically ruling out a class effect based on the TECOS results. She believes there are a number of possible explanations for the divergent results in the three trials, including differences in trial design and execution, potential drug-specific effects on heart failure, or chance findings in some studies. In terms of the broader context of the 2008 CV Guidance, Dr. Goldfine encouraged greater engagement and discussion among the medical community on topics such as whether the trials are enrolling the right patients and asking and answering the most important clinical questions. We hope that the FDA will feel compelled to address some of these broader questions that Dr. Goldfine and others have put forward in the coming year, particularly if more and more trials continue to report neutral cardiovascular results given the number of studies, patients, and costs of these trials diverting resources from other potentially important scientific needs.

TECOS From an Endocrine Perspective

John Buse, MD, PhD (UNC, Chapel Hill, NC)

We thought Dr. John Buse’s interpretation of the TECOS results was one of the best presentations of the two CVOT sessions, and, indeed, of ADA. He spoke positively about TECOS, sitagliptin, and DPP-4 inhibitors as a whole when deserved, characterizing DPP-4 inhibitors as arguably the best-tolerated class of diabetes drugs. With regard to potential safety concerns he was not afraid to call it as he saw it, pointing to a pattern of more acute pancreatitis with DPP-4 inhibitors in CVOTs (though still based on fairly few events). Even with pancreatitis, though, he did not appear too worried, suggesting that the worst case is that acute pancreatitis is a real but still exceedingly rare complication of DPP-4 inhibitor therapy. He ended by noting that CVOTs as they are currently designed are important for ascertaining intermediate safety but are not helpful when trying to assess lifetime risk and the potential of long-term benefit. Our response to that last, from an advocacy perspective, is that that is really too bad.

• Dr. Buse began with background on the state of type 2 diabetes drugs today. He highlighted the explosion of new drug classes, many with interesting properties beyond glucose lowering. However, a lack of rigorously conducted outcomes trials has kept worries about safety lurking in the background.
• He next narrowed his focus to DPP-4 inhibitors, which guidelines currently place squarely as a second-line therapy after metformin. He characterized DPP-4 inhibitors as having excellent efficacy in their optimal setting of use, which is earlier in the disease course and in combination with metformin. He noted that DPP-4 inhibitors have the longstanding reputation as arguably the best-tolerated class of type 2 diabetes drugs. However, he noted that concerns about pancreatic safety remain.
• With the caveat that comparing between trials has many limitations, Dr. Buse noted a consistent imbalance in acute pancreatitis in DPP-4 inhibitor CVOTs. In SAVOR, the imbalance was 22 vs. 16 cases (p=0.42) not in favor of saxagliptin. In EXAMINE, the imbalance was 12 vs. 8 cases (p=0.5) not in favor of alogliptin. In TECOS, the imbalance was 23 vs. 12 cases (p=0.065) not in favor of sitagliptin. When placed together in comparison on a single slide, the data seemed more persuasive (though not yet definitive) in favor of a class effect on acute pancreatitis. Dr. Buse did not comment directly on the likelihood that the signal is real, but rather suggested that if a signal is real it is extremely rare and acceptable in the context of an otherwise safe and effective drug class.
  
  • It is interesting that the imbalances in pancreatic cancer have gone in DPP-4 inhibitors’ favor: 5 vs. 12 cases in SAVOR (p=0.095) and 9 vs. 14 cases in TECOS (p=0.032). As with the acute pancreatitis numbers, however, the imbalances are possibly due to chance, and if not the effect is still too modest to make too much of.
• In another across-trial comparison, Dr. Buse noted that severe hypoglycemia was very slightly more frequent in the treatment group vs. placebo for the three DPP-4 inhibitor CVOTs. However, he suggested that the marginal differences in A1c between groups could account for the difference.
• Dr. Buse noted that TECOS does not answer all of the remaining questions about DPP-4 inhibitors. He suggested that better long-term data on comparative effectiveness would be very valuable to have (NIH’s GRADE study should help somewhat though we see the absence of SGLT-2s as a major negative), as would longer-term safety exposure data and studies in lower-CV-risk patients to examine potential CV benefits.

Question and Answer Session

Q: Regarding the recently published AACE guidelines, they mention hospitalization for heart failure as a risk with DPP-4 inhibitors. What’s your comment?

Dr. Holman: The recent FDA Advisory Committee also covered that topic in light of the SAVOR-TIMI 53 and EXAMINE heart failure data and advised a label change warning people of a potential harm. When you see something of concern in a trial you should inform people, but the signal was not definitive and it will be interesting to see whether the new TECOS data will lead to a change.

Press Conference – TECOS

TECOS Press Conference – Selected Q&A

Rury Holman, FMedSci (University of Oxford, UK) & Eric Peterson, MD, MPH (Duke Clinical Research Institute, Durham, NC)

Q: Was there any planned passive follow-up of this cohort?

Dr. Holman: There was no passive follow up planned, as much as I’d like to do it. We did not receive the funding, and patients were not consented for it. [Editor’s note – this seems highly disappointing. We can’t imagine that it would cost very much.]

Q: Was this study a non-inferiority or superiority trial?

Dr. Holman: The study was designed as a non-inferiority analysis, but it was powered and we had enough patients for a superiority analysis. The reason was that at the time the study was designed, there was the belief that there may have been cardiovascular advantages for this class, though that has not been borne out. [We wonder, this has not been borne out in this time period? Or at all?]

Dr. Peterson: The study was not designed to look at the long-term effect of glucose lowering. That would have taken a much larger and longer study.

Q: Does one drug in this class offer advantages over the others? There was a signal with the others but absolutely nothing here. How do clinicians put that into practice?

Dr. Holman: That’s an impossible question. The first study out was SAVOR, with a statistically significant signal for a harm that was unexpected. The second one showed just a numerical imbalance. It could have been no signal, or not enough power to achieve statistical significance for the signal. The hazard ratios were 1.27, 1.19, and 1.00 for the three trials. If you are looking at the information and are very risk averse, you’ll vote with your feet. I don’t think we know whether the data from TECOS applies to the whole class. In the UK, DPP-4 inhibitors are third-line drugs mainly because of cost. At present, heart failure concerns have not changed the guidance. The drug we’re talking about in TECOS is the most popular, having been there the longest. Sitagliptin happens to be on my formulary, and I don’t feel the need to change my practice.

Q: Some had mentioned that the data does not show evidence of a benefit. Would you necessarily rule out benefit given that some of the landmark trials for glucose lowering – which is another issue – took years or decades to show a benefit [on the complications front]?

Dr. Holman: That’s a question that is true to my heart. Studies should be longer. People have type 2 diabetes for a lifetime, and studies that report in just one or two years are hard to interpret. Here, we have people going out to five years. If we were able to continue this longer, it is possible that you would have seen a benefit, or possibly even risk. The glucose issue is not the point. We designed out the glucose difference. All we can say is that this is the largest, longest study so far, and we see no harm or benefit.

Q: Given that these three outcomes trials haven’t show a benefit or a risk, and that they are large trials, in hindsight do you think the benefits we’ve gained have been worth the opportunity cost?

Dr. Holman: Hindsight is a wonderful thing. Regulators set up this requirement in the face of a number of adverse events that had been recognized for other drugs, and you know the first rule is to do no harm. I think it was appropriate to set those safeguards. Now that we know there is no difference, it’s easy to say that we could have done something else. My view is that if we spend money on trials like this, they should be longer and involve more agents so that we can get comparative results. That is a wish, but this is what we have today, and I’m delighted with the results.

Oral Presentations: New Insights Into the Effects of Oral Agents

Adding a DPP-4 Inhibitor to Ongoing Therapy with a GLP-1 Receptor Agonist and Metformin Increases Intact GLP-1, But Does Not Change Insulin or Glucagon Secretion nor Plasma Glucose Excursions Following a Mixed Test Meal in Patients with Type 2 Diabetes (10-OR)

Michael Nauck, MD, PhD (Diabetes Centre, Bad Lauterberg, Harz, Germany)

During his timely talk, the highly regarded Dr. Michael Nauck presented the results of his study examining the effect of adding DPP-4 inhibitor sitagliptin to ongoing therapy with GLP-1 agonist liraglutide and metformin for people with type 2 diabetes. The study enrolled 16 people with diabetes (mean age of 55 years; mean disease duration of 9.4 years; mean A1c of 7.5%), who were treated with metformin (2044 ± 266 mg/day) and liraglutide (1.2 mg/day for more than two weeks) prior to the study. Participants were then randomized to receive either one 100 mg PO dose of sitagliptin or placebo and were studied after an overnight fast with the drug administered 60 minutes before a standard mixed meal was eaten. The results found that those treated with sitagliptin had meal-induced responses of intact GLP-1 and GIP that were augmented by 78% and 90% (p<0.0001) respectively, while their total GLP-1 and GIP responses were reduced by 37%and 18%, respectively. On the other hand, their levels of insulin, C-peptide, glucagon, and glucose concentrations were not affected significantly (p=0.60-1.00). The influence of sitagliptin treatment on incretin plasma concentrations was similar to previous results in people with type 2 diabetes on metformin treatment alone, with concentrations increasing after a standard mixed meal. According to Dr. Nauck, these findings are most likely explained by the fact that GLP-1 receptors are maximally stimulated by liraglutide alone; he thus concluded that combination treatment with GLP-1 agonists and DPP-4 inhibitors is not recommended.

Questions and Answers

Q: How general will these results be for short acting GLP-1 agonists like exenatide?

A: My interpretation is that if you take a long acting GLP-1 agonist that exposes GLP-1 receptors to stimulation all day, then there is no ability for a DPP-4 inhibitor on top of that to further stimulate GLP-1 receptors. Also we could speculate with our results that there is no other mediator because otherwise there would be some additive effect. With exenatide’s published results, we interpret them exactly the same way. You only have two periods during the day where you are exposed to exenatide with perhaps 12 hours of a 24-hour period where there is no exposure to the drug and that gives the DPP-4 inhibitor the chance to kick in and do something.

Q: The benefit which was observed when sitagliptin was combined with exenatide twice daily as you suggested was due to the shorter half life of exenatide. It could be beneficial. In the case of liraglutide, if you are looking at the metabolism of liraglutide, we have seen some papers published with experimental work which suggests that although liraglutide is a DPP-4 resistant GLP-1 agonist, 5%-10% of liraglutide is broken down by DPP-4, so there is a theoretical possibility that if you add a DPP-4- inhibitor, the 5%-10% of the liraglutide that would normally be metabolized by DPP-4 would no longer be metabolized and therefore would have a beneficial effect. Could it be happening because of the single dose of sitagliptin? If you were using sitagliptin for a week, would you have a different result?

A: I think what you assume may be correct. At least liraglutide can be partially degraded by a DPP-4, so if you give a DPP-4 inhibitor, it’s preserved 100% or close to 100%. We will have a chance to look at liraglutide levels during our experiments, and I am looking forward to potentially seeing any differences induced by sitagliptin. Perhaps the changes in gastric emptying rates that we observed might be somewhat related to this phenomenon.

Major Cardiovascular Outcomes in the EXAMINE Trial According to ACE Inhibitor Use (12-OR)

William White, MD (University of Connecticut, Farmington, CT)

To a full room, Dr. William White presented results from the EXAMINE trial (the CVOT for Takeda’s Nesina [alogliptin]) with patients stratified by ACE inhibitor use at baseline. As a reminder, the primary results from EXAMINE presented at ESC in 2013 demonstrated cardiovascular non-inferiority with alogliptin compared to placebo. This analysis was conducted in response to concerns about the potential harmful effects of sympathetic nervous system activation caused by combined therapy with DPP-4 inhibitors and high dose ACE inhibitors. Results from this analysis were consistent with the overall findings and revealed that cardiovascular outcomes were not affected by ACE inhibitor use or the dose of the ACE inhibitor. This should provide some reassurance about potential interactions between alogliptin and ACE inhibitors in high-risk patients with type 2 diabetes, though additional studies would be required to draw broader conclusions about the DPP-4 inhibitor class.

• As previously reported, alogliptin was non-inferior to placebo with regard to the primary MACE composite endpoint (CV death, nonfatal myocardial infarction, nonfatal stroke). The event rates were 11.3% and 11.8% for the aloglitpin and placebo groups, respectively (hazard ratio=0.96; upper bound of one-sided repeated CI = 1.16).
• As expected, patients with no history of heart failure had much lower rates of MACE events than those with a history of heart failure, and there were no significant differences with alogliptin vs. placebo. The event rates for a composite of hospitalization for heart failure and CV death in patients with no history of heart failure were 4.9% and 4.2% for alogliptin and placebo, respectively (HR=1.14; 95% CI 0.05-1.54) and 13.9% and 15.7%, respectively, for patients with a history of heart failure (HR=0.90; 95% CI 0.70-1.17).
• As there is an activation of the sympathetic nervous system when DPP-4 inhibitors are used in combination with high dose ACE inhibitors, concerns have been raised regarding combined use of these two drug classes. To evaluate this risk, the EXAMINE trial investigators evaluated vital signs and CV outcomes in patients based on their ACE inhibitor use.
• When stratifying patients by their baseline ACE inhibitor use or dose, rates of cardiovascular outcomes were similar between patients receiving alogliptin and placebo. There were no significant differences in the MACE composite endpoint between the alogliptin and placebo groups in patients on ACE inhibitors (HR=0.97; 95% CI: 0.79-1.19; p=0.76) and those not on ACE inhibitors at baseline (HR =0.94; 95% CI: 0.73-1.21; p=0.62). Similar results were seen for the composite endpoint of CV death and hospitalization for heart failure (HR=0.93; 95% CI: 0.72-1.2 for those on ACE inhibitors and HR=1.09; 95% CI: 0.81-1.48; for those not on ACE inhibitors ). Furthermore, ACE inhibitor dose did not have any effect on CV outcomes. There were also no significant differences in systolic blood pressure, diastolic blood pressure, heart rate, or body weight based on ACE inhibitor use or dose. These data suggest that there is no interaction between ACE inhibitors and alogliptin when used in high-risk patients with type 2 diabetes, though additional studies would be required to draw broader conclusions about the DPP-4 inhibitor class.

Questions and Answers

Q: Are there any concern between interaction between ARBs and ACE inhibitors?

A: Not to my knowledge. In the EXAMINE trial approximately two-thirds of the  patients were on an ACE inhibitor. Hence, a much smaller percentage were taking other RAS agents.

Q. You concluded that there were no specific interactions between ACE inhibitors and alogliptin. When we look at past data, there are interactions between ACE inhibitors and other DPP-4 inhibitors. Is there something to do with alogliptin that is preventing angioedema?

A. We have thoroughly examined angioedema and other hypersensitivity syndromes and have not seen increased rates on alogliptin versus placebo regardless of ACE inhibitor use.

Cardiac Ischemic Outcomes and Hospitalizations in Patients with Type 2 Diabetes and Recent Acute Coronary Syndrome Treated with Alogliptin or Placebo: New Insights from the EXAMINE Trial (13-OR)

Yuichi Shimada, MD, MPH (Brigham and Women's Hospital and Harvard Clinical Research Institute, Boston, MA)

Dr. Yuichi Shimada shared results on cardiac ischemic events and cardiovascular hospitalizations in EXAMINE, the cardiovascular outcomes trial for Takeda’s DPP-4 inhibitor Nesina (alogliptin). As a reminder, topline results from EXAMINE were released at ESC 2013 and demonstrated cardiovascular non-inferiority between alogliptin and placebo. In this analysis, no significant differences were found between the alogliptin- and placebo-treated groups for any of the cardiac ischemic endpoints, with HR for myocardial infarction 1.07 (95% CI 0.87-1.31, p=0.53), 0.91 (95% CI 0.70-1.19, p=0.49) for unstable angina, 0.98 (95% CI 0.82-1.16, p=0.81) for coronary revascularization, 1.02 (95% CI 0.89-1.17, p=0.73) for cardiovascular hospitalization, and 0.98 (95% CI 0.87-1.10, p=0.72) for a composite endpoint of cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization. Dr. Shimada concluded that alogliptin does not increase risk of cardiac ischemic events or cardiovascular hospitalization in a high-risk post-acute coronary syndrome population.

• This analysis examined data on incident rates of myocardial infarction and unstable angina, coronary revascularization, cardiovascular hospitalizations, and composites of these ischemic endpoints from all 5,380 patients randomized in EXAMINE. As a reminder, EXAMINE was a randomized, double-blind, placebo-controlled trial of alogliptin plus standard of care versus placebo plus standard of care in patients with type 2 diabetes and recent acute coronary syndrome with mean follow-up length of 18 months.
• No significant differences were found between the alogliptin- and placebo-treated groups for any of the cardiac ischemic endpoints in the analysis. HR for myocardial infarction was 1.07 (95% CI 0.87-1.31, p=0.53), 0.91 (95% CI 0.70-1.19, p=0.49) for unstable angina, 0.98 (95% CI 0.82-1.16, p=0.81) for coronary revascularization, 1.02 (95% CI 0.89-1.17, p=0.73) for cardiovascular hospitalization, and 0.98 (95% CI 0.87-1.10, p=0.72) for a composite endpoint of cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization. By treatment allocation, there was no difference in rates of PCI with stent or CABG though a near significant difference was found in rates of PCI without stent (HR 1.47, 95% CI 0.96-2.25, p=0.08); Dr. Shimada cautioned that we should not overinterpret this finding as this was likely due to low event rates rather than treatment effect. Median length of stay for patients hospitalized for cardiovascular events was six days in both groups (p=0.85).
• Dr. Shimada concluded that alogliptin does not increase the risk of cardiac ischemic events or cardiovascular hospitalization in a high-risk acute coronary syndrome population. Conversely, in the Q&A, he noted this also suggests no apparent cardiovascular benefit to alogliptin use in this population.

Questions and Answers

Q: Does this mean alogliptin also shows no cardiovascular benefit?

A: This was the conclusion of the main trial. When you took a more detailed look at the endpoints I’m afraid I have to say that it seems there is no apparent benefit during this period of time.

Q: Participants were all likely on other protective regimens, such as anticoagulants. Do you have any breakdown by medication use?

A: Patients on statins and anti-platelet therapies were so high (>90%) that you could not meaningfully compare them to the relatively small proportion of patients not on standards of care.

Oral Presentations: Recent Advances in Diabetic Macrovascular Disease

Cardiovascular Risk of Polyvascular Disease in Diabetes—Insights from SAVOR-TIMI 53 (56-OR)

Antonio Gutierrez, MD (UCLA, Los Angeles, CA)

Dr. Antonio Gutierrez presented a new analysis of SAVOR-TIMI 53, the cardiovascular outcomes trial for AZ’s Onglyza (saxagliptin), comparing rates of major cardiovascular events based on disease site and number of diseased vascular beds. In the analysis, two-year rates for the primary endpoint (CV death, myocardial infarction, and ischemic stroke) were similar for patients with isolated coronary artery disease (CAD; 7.8%), cerebrovascular disease (CVD; 6.6%), or peripheral arterial disease (PAD; 7.0%) (p=0.09) but increased in patients with two (15.7%) or three (23.9%) diseased vascular beds vs. patients with one diseased bed (7.6%) (p<0.001). Those with isolated PAD had increased rates of CV death (4.0%) vs. those with isolated CVD (1.8%) or CAD (3.3%) (p=0.02). Dr. Gutierrez concluded that patients with type 2 diabetes and PAD or multiple diseased beds have the highest risk of cardiovascular and overall mortality.

• In this analysis of SAVOR, rates of major cardiovascular events were compared based on disease site (CAD, CVD, and PAD) and number of diseased vascular beds. As a reminder, SAVOR was the cardiovascular outcomes trial for AZ’s Onglyza (saxagliptin). The trial evaluated the effects of saxagliptin versus placebo in patients with type 2 diabetes at risk or with a history of cardiovascular events. This analysis included 12,641 patients with atherosclerosis for the analysis of number of diseased beds and 11,249 patients with atherosclerosis in one site alone for the analysis of disease sites.
• Two-year rates for the primary endpoint (CV death, myocardial infarction, and ischemic stroke) were similar for patients with isolated CAD (7.8%), CVD (6.6%), or PAD (7.0%) (p=0.09) but increased in patients with two (15.7%) or three (23.9%) diseased vascular beds vs. patients with one diseased bed (7.6%) (p<0.001). Those with isolated PAD had increased rates of CV death (4.0%) versus those with isolated CVD (1.8%) or CAD (3.3%) (p=0.02). Rates of CV death were also increased in patients with two (6.3%) or three (11.5%) diseased beds versus those with one diseased bed (3.2%) (p<0.0001). Isolated PAD patients had the highest rates of all-cause mortality (6.5%) vs. those with CAD only (4.5%) or CVD only (4.5%) (p=0.03). Overall, for every additional diseased vascular bed, there was an increased risk for the primary endpoints (CV death, myocardial infarction) and secondary endpoints (hospitalization for coronary revascularization, hospitalization for heart failure).
• Dr. Gutierrez concluded that patients with type 2 diabetes and PAD or multiple diseased beds have the highest risk of cardiovascular and overall mortality. He also commented that SAVOR highlighted the additional insights large-scale CV outcomes trials can yield in our understanding of CV disease, beyond evaluating the safety of a particular drug.

Questions and Answers

Q: If you took those with two vascular beds and compared the different possible combinations sites, what would they look like?

A: We do have that, but it will be broken out in the future.

Q: You mentioned duration of diabetes and smoking rates were higher in patients with PAD. I wonder if you took those away what the data would look like.

A: We are working that – but you also have to include medication use and adjust for these other variables too.

Q: Can you comment on heart failure results?

A: I think the approach we’re tossing around if you are to use saxagliptin bring them back at three months to make sure they’re not having symptoms of heart failure. There were groups more susceptible for heart failure. That question is being tossed around.

Corporate Symposium: CV Outcomes with T2D Agents (Sponsored by Merck)

Applications of New Data and Key Takeaways for Your Type 2 Diabetes Practice

Jennifer Green, MD (Duke University, Durham, NC), Deepak Bhatt, MD, MPH (Brigham and Women’s Hospital, Boston, MA), Jaime Davidson, MD (UT Southwestern, Dallas, TX), and John Anderson, MD (The Frist Clinic, Nashville, TN)

Merck hosted a well-timed corporate symposium/CME with valuable commentary and a review on CVOT data, including (impressively) the TECOS results presented just two hours previously – we’ve never seen scientific learnings reported and then a CME program in place virtually simultaneously! We learned later that the CME program director had been on hand to make it happen with such quick turnaround. Though not as packed as we thought it would be, the symposium featured a rockstar panel, including TECOS lead author Dr. Jennifer Green and a particularly highly-regarded SAVOR investigator Dr. Deepak Bhatt. A bold case study prompt asked how the panel would advise a group of insurers looking to consider the DPP-4 inhibitor outcomes data in the context of formulary decisions. Dr. Bhatt suggested that differences in price (including generic status) trumped any of the differences between results from TECOS, SAVOR, and EXAMINE, although if he was starting a patient de novo (price being equal) he thinks sitagliptin (Merck’s Januvia) comes out slightly ahead. Dr. Green suggested that payers look into their own data, as non-RCT studies of DPP-4 inhibitors and heart failure have not shown major differences. She acknowledged that it is not clear whether (and how) to apply TECOS data to sitagliptin alone vs. to the entire class. For more on the valuable commentary from the panel, see our transcript below.

Case and Panel Discussion

Case Prompt: Several insurers are meeting to discuss formulary decisions for DPP-4 inhibitors in the context of data from recent cardiovascular outcomes trials. What guidance would you provide?

Dr. Deepak L. Bhatt (Brigham and Women’s Hospital, Boston, MA): If there was a difference in price, and one was cheaper, and all were available, I’d go with the cheapest. If one was generic, and I’m not sure which one goes generic first, I’d go with that one. If a patient was already on a DPP-4 inhibitor, I wouldn’t switch it based on any of these data. I don’t think the differences in these cardiovascular outcome trials would really influence my decision-making. If starting de novo and if all of them were equally priced, sitagliptin looked pretty good in TECOS. There was no signal at all for heart failure. You could argue that the other trials were smaller (EXAMINE) or had shorter median follow up (SAVOR-TIMI 53), and in different types of patients. But in that respect, I guess sitagliptin would win.

Dr. Jaime Davidson (UT Southwestern, Dallas, TX): Sometimes in our institution, one year it’s one agent, and another year it’s another agent. What we prescribe is not necessarily what the pharmacy has available. We haven’t had endocrinologists in our pharmacy committee for some time.

Dr. Anderson: So it’s a consideration but it’s not the only consideration, nor is it the highest priority?

Dr. Bhatt: I think it’s a tough thing when you’re comparing across trials, not to mention it is not intellectually legitimate.

Dr. Jennifer Green (Duke University Medical Center, Durham, NC): As a payer, you could look at your own population data. Studies like that have been done and have seemed to show no real impact between the different agents.

Case prompt: Patient who asks about safety risks with DPP-4 inhibitors

Dr. Green: We have to be judicious with patients at higher risk, but for the average person, yes risk is increased, but it doesn’t appear from the results of the trials we have so far that giving patients at DPP-4 inhibitor is going to dramatically increase their risk of pancreatic complications. This data is very new and the recommendations may change, but at least from first glance it’s safe to say that there were more events of pancreatitis occurring in the DPP-4 inhibitor groups. From a clinical perspective, however, it doesn’t seem to be a major concern.

Dr. Davidson: We don’t have data for the older agents like we now have for these newer agents. We have over 30,000 patients worth of data in clinical trials with DPP-4 inhibitors and we don’t see any noise on pancreatitis and pancreatic cancer. I feel very comfortable with these agents, and the FDA has not actually sent any warnings out about heart failure and pancreatitis.

Dr. Bhatt: For pancreatitis we have three studies showing that in large populations, it’s not as frequent as it might have felt before. In SAVOR, pancreatitis was very carefully adjudicated. The cancer data are fascinating but of course the follow-up is relatively short. I think it’s at least reassuring that there is no signal emerging. Larry Leiter from the SAVOR steering committee shared data from a cancer perspective here showing no signal we can see, again with the caveat of brief follow-up. For the heart failure issue, in SAVOR we saw a statistically significant excess in hospitalization for heart failure, but the absolute risk excess was very small and not associated with excess mortality. There was no change in BNP levels and other biomarkers; we couldn’t find a mechanism. It was one of multiple comparisons made for a secondary endpoint, which therefore needs to be viewed cautiously. In EXAMINE there was no significant excess in hospitalization for heart failure. In TECOS, which was very well powered and the longest duration of the three, there doesn’t seem to be any signal for hospitalization for heart failure.

 [Chair] Dr. John Anderson (The Frist Clinic, Nashville, TN): Before TECOS, the biggest concern with this class was heart failure. Does neutrality in TECOS help the class?

Dr. Green: I think the jury is out. There is lots of debate on whether we should apply this information to the group as a whole, or whether we only feel confident in the information we have as individual agents. Certainly people will be interested in performing meta-analyses of these findings, but we have to understand whether it is valid to compare info across trials. It’s probably only optimal to compare when you’re testing drugs against each other. The FDA so far has received recommendations that the info about heart failure be included in the product labeling. Whether or not the will go beyond that, to make recommendations or restrictions for the use of these drugs, remains to be seen. It will be challenging to determine whether this calls for concern for individual drugs or the whole class.

Case Prompt: In a patient with new onset heart failure who has taken a DPP-4 inhibitor for years, do you stop the DPP-4 inhibitor?

Dr. Bhatt: This is a very common scenario in the emergency department. Heart failure has been underappreciated in patients with diabetes. In this case it’s hard to know what to do. Metformin’s labeling has changed for heart failure, TZDs we know cause edema, and the data on sulfonylureas changes every year, it seems. By the time we’re done with this symposium, someone will have done a meta-analysis of these three DPP-4 inhibitor CVOTs and submitted it for publication. I would take the 30,000-foot view and say that DPP-4 inhibitors seem safe. If a patient needs a DPP-4 inhibitor as part of their overall regimen, I would not stop it based on the CHF issue.

Dr. Green: Based on this presentation, how many of you in the audience think that the heart failure here is caused by the DPP-4 inhibitor?

[Very few hands]

Dr. Green: I don’t see many hands. There are many other reasons for heart failure. Also, you have to think about what you are going to give her instead. You will have to choose something else, possibly another drug that increases the risk of heart failure or which may have limited outcomes data. We know a lot about DPP-4 inhibitors, while the alternatives are somewhat unknown.

Dr. Anderson: What would you say about the heart failure data in SAVOR, Dr. Bhatt?

Dr. Bhatt: There was an imbalance in hospitalization for heart failure in the trial between the two treatment arms. However, the rates of hospitalization for heart failure were high overall, trumping the low incremental risk with the study drug. I think that is the bigger message. Patients with diabetes have other risk factors for heart failure. The theory has been put out there that hyperglycemia serves as an osmotic diuretic, promoting diuresis when blood sugars are out of control. Whether that is seen in a given study may depend on baseline A1c. It’s interesting to note that baseline A1c was 1% lower in TECOS than in SAVOR. I think the bigger issue is that we need to pay more attention to heart failure in diabetes patients in general.

Dr. Davidson: Every one of these trials is totally different by average patient age, A1c, and diabetes duration. What I see is that none of these trials really show increased risk of heart failure, and I feel comfortable. However we must remember that these were patients with very advanced cardiovascular disease in these trials – not your average diabetes patient.

Q: Is it OK to use a DPP-4 inhibitor in a patient with a family history of pancreatitis?

Dr. Bhatt: It wouldn’t bother me.

Dr. Green: It wouldn’t bother me, but the patient needs to be part of that decision.

Q: Why did SAVOR show an increase in heart failure?

Dr. Bhatt: No mechanism has been identified. We’ve looked at biomarkers, although we didn’t do echo or MRI substudies. We couldn’t find a plausible mechanism.

Q: TECOS started before the instruction from the FDA. One criticism is that these trials cost a lot and increase the cost of medication. Do we need to continue doing them?

Dr. Green: What can cost the most is a lack of knowledge. Having gone through the entire experience with rosiglitazone, I can say that the maelstrom it introduced into my clinical practice cost me personally and cost my patients with regards to concern raised. Those costs are very poorly appreciated. Costs associated with doing these trials are finite. I don’t know the dollar amount, and yes it is likely that these costs are translated to those who use these medications. In a sense, you’re buying a bit of peace of mind. I think the expenditure may be worth it. In the future, I hope we have a way to collect data in a more robust, reliable, and efficient way, perhaps from daily clinical practice. But I don’t want to go back to what we were doing before.

Dr. Davidson: The only problem I see with these trials is that what we learn does not apply to the majority of patients we see in our everyday clinical practice. I had the money, I would spend them to follow younger patients for a longer time. The reason higher-risk patients are enrolled in these trials is that nobody can afford to follow patients for 25 years. The data you heard today only applies to the patients in the trials: 55 years and older, who had acute events or had risk factors for heart disease. The answer is great because we can now feel comfortable about using these drugs in that group of patients. It’s expensive – we pay and patients pay – but research is always good for the future of medicine.

Dr. Bhatt: I would agree with those points. There are consequences to a lack of knowledge, when patients are learning from what they see on the internet. Patients stop taking their medicine when they see noise on TV and the internet. Going from having very little to having lots of cardiovascular outcomes data is good for patient care. Even the other information, on pancreatitis, cancer, and fractures, is useful. We can provide patients with reassurance when they come in with questions such as about bladder cancer. Non-inferiority is not the sexiest concept, and many doctors don’t fully know how to best interpret it. We’re watching out for drugs that can cause harm. The paradigm has spread to other chronic disease areas like COPD and arthritis. Finally, I think there might be value in doing longer term studies to look for cardiovascular benefit, long-term harm, or even cancers, but we would need to embrace the concept of large simple trials from the regulatory perspective.

Dr. Anderson: Do you have any concluding thoughts?

Dr. Bhatt: I think lots of good things have come out of cardiovascular trials in diabetes. Another benefit is collaboration across disciplines, which will help care immensely. Getting primary care, cardiologists, endocrinologists, nephrologists, and others together has a collateral benefit.

Dr. Davidson: There was no increase in events with these trials. That is enough for me.

Dr. Green: I’m definitely in favor of continuing to carefully scrutinize these agents for lots of effects, definitely including cardiovascular safety. Please remember that when we looked at the preliminary data on these agents, it suggested that the drugs reduced rates of cardiovascular complications. We didn’t see that, but these longer-term trials give you the real answer compared to previous studies that were not designed to assess cardiovascular safety. It confirms the validity of doing these long-term cardiovascular outcomes trials. The information presented today is just the tip of the iceberg. There is so much more information that can be collected, especially with regards to rare events. We’re going to learn much more than just the effect on MACE.

Novel Therapies

Oral Presentations: ADA President’s Oral Session

Induced Pluripotent Stem Cells Converted to Myotubes Mirror In Vivo Insulin Resistance in Humans (380-OR)

Salvatore Iovino, PhD (Merck Research Labs, Boston, MA)

In a fascinating presentation, Dr. Salvatore Iovino discussed a human model of insulin resistance in muscle cells. To create this model, he generated and analyzed induced pluripotent stem (iPS) cells from individuals with a genetic form of insulin resistance (IR-Mut) and from healthy individuals of a similar age.  These cells were differentiated over 35-40 days into functional myotubes (early-stage muscle fibers). Myotubes derived from IR-Mut patients showed defects in insulin signaling, insulin-stimulated metabolism, and transcriptional dysregulation that mirrored the defects observed in the patients in vivo. Thus, iPS cells differentiated in vitro to muscle provide a novel model to study the molecular mechanisms of insulin resistance in skeletal muscle.

• Myotubes derived from IR-Mut individuals showed significant genetic differences compared to the control group. Myotubes derived from IR-Mut patients showed impaired insulin signaling with reduced levels of the insulin receptor (IR) protein and reduced activation of IR, IRS-1, AKT and ERK1/2. These defects led to impairments in insulin-stimulated 2-deoxyglucose uptake, glycogen synthase activation and glycogen accumulation. Expression of insulin-regulated metabolic genes, including HK2, GLUT4 and RAD1, was also significantly reduced in IR-Mut compared to the control myotubes. Furthermore, while control myotubes responded to insulin with significant increases in the expression of the early growth response genes EGR1, cFOS and JUN, these insulin-stimulated transcriptional changes were impaired in IR-Mut myotubes.

Oral Presentations: Combining Basal Insulin and GLP-1 Agonists

LAPS GLP/GCG Dual Agonist, HM12525A, Confirmed Prolonged Pharmacokinetics in Healthy Volunteers: A First-in-Human Phase 1 Study (173-OR)

Marcus Hompesch, MD (Profil, Chula Vista, CA)

Dr. Marcus Hompesch presented results from a phase 1 trial of Hanmi Pharmaceuticals’ long-acting GLP-1/glucagon dual agonist HM12525A showing a positive safety/tolerability profile and the potential for once-weekly dosing. The trial enrolled 40 healthy volunteers who were randomized to one of five dose groups (0.25-4.0 nmol/kg) and received a single subcutaneous injection of either HM12525A (n=6 per group) or placebo (n=2 per group). The primary objective was to evaluate safety and tolerability, with pharmacokinetic (PK) parameters as a secondary endpoint; the total study duration was 56 days. Results showed that HM12525A was well tolerated up to a dose of 2.0 nmol/kg. GI side effects were the most common adverse event, and they tended to occur early and in a dose-dependent fashion. Mean heart rate also increased in a dose-dependent manner, with significant elevations vs. placebo at the two highest doses; Dr. Hompesch cautioned that it is difficult to draw meaningful conclusions about this effect from such a small study and that the signal would need to be assessed in larger trials. Anti-drug antibodies were detected in six subjects, but there were no neutralizing antibodies and there did not appear to be any interference with PK. There were no other significant safety observations, including any clinically relevant changes in blood pressure. HM12525A demonstrated a half-life of 131-178 hours, which Dr. Hompesch said should support at least a once-weekly dosing regimen. Hanmi is currently conducting a multiple ascending dose trial of the candidate in patients with type 2 diabetes (we did not find any trials currently listed on ClinicalTrials.gov).

Oral Presentations: New Concepts and Treatments of Diabetic Dyslipidemia

Evaluation of the Glycemic Effects and Efficacy and Safety of Evolocumab (AMG 145) in Subjects With or Without Dysglycemia or Metabolic Syndrome (258-OR)

Rury Holman, FMedSci (The Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK)

Dr. Rury Holman continued the session’s discussion on PCSK9 inhibitors by reviewing the results of the DESCARTES study, which examined the glycemic effects, LDL-lowering efficacy, and safety of evolocumab (Amgen’s Repatha) in 901 patients stratified by glycemic status. After 52 weeks, no significant differences were seen between the evolocumab and placebo groups in measures of glycemic control. Additionally, no notable differences were seen between groups in weight, BMI, waist circumference, blood pressure, or heart rate. As background, the DESCARTES study randomized patients (following optimization of lipid-lowering therapy) 2:1 to 52 weeks of monthly evolocumab or placebo. Baseline glycemia was categorized as type 2 diabetes (n=120), impaired fasting glucose (IFG, n=293), metabolic syndrome (MetS, n=289), or none of these (n=393); 194 had both IFG and MetS. Overall, evolocumab showed encouraging lipid efficacy and safety at 52 weeks in subjects with or without dysglycemia or MetS, with no notable changes in glycemia, incidence of new onset type 2 diabetes, or key safety parameters.

• Notably, results also showed that incidence of new onset type 2 diabetes (defined as HbA1c ≥ 6.5% at any post-baseline visit) in those without diabetes at baseline was 4.6% (evolocumab) and 5.4% (placebo). No notable differences in dysglycemia were seen among subjects on various statin doses. Encouragingly, evolocumab also reduced LDL-C by >50% in all groups, with favorable effects on other lipid parameters as well. Adverse events in combined type 2 diabetes, IFG or MetS groups were 73% for evolocumab vs. 70% for placebo.
• Given these positive results, Dr. Holman emphasized the major potential of PSCK9 inhibitors, especially for patients who cannot achieve LDL-C targets with statins. These results are particularly reassuring given the concerns about increased diabetes risk with statins. Of course, as noted during Q&A, price will likely be one of the more significant obstacles to broad access, and we imagine that this class’ success will be heavily dependent on the level of reimbursement.
• For more on the DESCARTES study, see our coverage of Dr. Dirk Blom’s (University of Cape Town, South Africa) presentation of primary results at ACC 2014.

Questions and Answers

Q: How will providers decide the criteria that will motivate $50,000/year treatment? How will you tell your patient to undergo a massive weight loss or this will cost you $50,000?

A: It’s interesting that you start with cost. This is remarkable science, and I am more interested in the mechanism that this can help people who are pre-diabetic. I can’t justify the price and I don’t know how this will pan out. For those who can’t currently achieve LDL-C safely, this drug offers a valuable alternative. I agree though that the cost may be difficult to justify.

Q: Is it possible to figure out how low LDL-C can go on this drug?

A: We know that there is no change in the decremental improvement in risk as you go lower and lower with LDL-C. However, how low you can go with evolocumab wasn’t a question addressed by the DESCARTES study, but I’ll be interested in exploring it in future studies.

Q: 52 weeks is pretty short and the sample size is pretty small, so we’ll need to power this out in a longer term study. Have you looked at patients with high risk factors and family history of dyslipidemia?

A: It is a relatively small trial but was not intended to be an outcome study. Nevertheless I think these are still pretty definitive results with no evidence of worsening glycemia, compared to data in our AFORRD study that showed a 0.3% A1c rise with atorvastatin. The evolocumab data to date has been very consistent and we would not expect any different results in patients at even higher risk. If you have an opportunity for a reasonable cost PSK9 inhibitor, that would likely have better adherence than a statin long-term, then this drug would have value in patients not achieving LDL targets.

Efficacy and Safety of the PCSK9 Inhibitor Evolocumab (AMG 145) in Patients with Type 2 Diabetes (257-OR)

Naveed Sattar, MD (University of Glasgow, Glasgow, United Kingdom)

Dr. Naveed Sattar presented encouraging efficacy and safety data on Amgen’s PCSK9 inhibitor Repatha (evolocumab) in patients with type 2 diabetes. In a pooled analysis of four phase 3 studies (MENDEL-2, LAPLACE-2, RUTHERFORD-2, and GAUSS-2), LDL-C was reduced by 57% and 60% from baseline, respectively, in patients on biweekly or monthly evolocumab. Results were comparable in patients without diabetes: 61% reduction with biweekly dosing and 62% with monthly administration. Additionally, reductions were comparable among all type 2 diabetes subgroups (baseline statin intensity, insulin use, A1c, eGFR, and existing CVD), which Dr. Sattar argued is a promising sign for the drug’s efficacy and safety in a wide range of patients with type 2 diabetes. These results are very timely in light of the recent FDA Advisory Committee meetings for Repatha and Sanofi/Regeneron’s PCSK9 inhibitor Praluent (alirocumab). Both meetings ended with strong votes in favor of approval, but it appears that the initial indications will likely be quite narrow, with broader approvals placed on hold until the ongoing cardiovascular outcomes trials report results.

• This analysis of the MENDEL-2 (monotherapy), LAPLACE-2 (combination therapy), RUTHERFORD-2 (HeFH), and GAUSS-2 (statin intolerant) phase 3 studies examined the lipid effects and safety of 12 weeks of evolocumab treatment in patients with type 2 diabetes (n=417) vs. patients without (n=2729). Overall, evolocumab significantly lowered LDL-C by 55 to 75%. LDL-C reduction was also comparable among all type 2 diabetes subgroups (baseline statin intensity, insulin use, A1c, eGFR, and existing CVD).
• More specifically, 88% (biweekly dosing) and 87% (monthly dosing) of patients with type 2 diabetes on evolocumab achieved LDL-C <70 mg/dl compared with only 36% (biweekly) and 29% (monthly) of patients on ezetimibe plus placebo and only 23% (biweekly) and 16% (monthly) of patients on placebo alone. Dr. Sattar also noted that reductions in Lipoprotein(a) (25-30%) and triglyceride (8-15%) levels were comparable in evolocumab-treated patients with and without type 2 diabetes.
• In terms of safety, 41% of patients with type 2 diabetes on evolocumab experienced adverse effects, compared to 47% of patients on ezetimibe and 35% of patients on placebo. Additionally, only 2% of patients with type 2 diabetes on evolocumab experienced serious adverse effects compared to 4% of patients on ezetimibe and 4% of patients on placebo. 0.4% of patients on evolocumab experienced an adverse effect that led to discontinuation of the study drug compared to 2.7% of those on ezetimibe and none on placebo.
• For background, evolocumab is a member of the exciting new PCSK9 inhibitor class, which lowers plasma LDL cholesterol by preventing endocytosis of LDL receptors, thus enabling more cellular uptake of LDL cholesterol. For further reading on the PCSK9 inhibitor class, see our coverage of Dr. Marc Sabatine’s (Brigham and Women’s Hospital, Boston, MA) presentation of results from a phase 3 trial (not a dedicated outcomes trial) that found a statistically significant 53% reduction in CV events with evolocumab vs. standard of care alone. Similarly promising 18-month phase 3 results for alirocumab recently published in NEJM found a 48% reduction in CV events. We eagerly await results from the ongoing outcomes trials of these candidates, which are expected to complete in late 2017 to early 2018. Additionally, Pfizer’s PCSK9 inhibitor phase 3 bococizumab remains on track to have outcomes data on pace with Amgen and Sanofi’s candidates. To our knowledge, there are ~10,000 people with diabetes in these trials collectively, and we believe this class will eventually hold great potential in this population.

Questions and Answers

Q: These are not unexpected results. The interesting test will be at the FDA level. I’m curious about patients with new onset diabetes, what do we see in patients with A1c’s of 6 and 6.5?

A: Right. In terms of statin use, most guidelines have come to the conclusion that risks are outweighed by the benefit. Statins may have a specific effect, but they do increase weight.

Comment: Is it potentially that statin weight gain though modest is able to cause that new onset diabetes?

A: I think it could be part of the cause. The new onset diabetes might actually disguise the slight gain of fat, but I’m just speculating. The effect of statin tolerance needs further study. Most people accept that this is part of the therapy and must take lifestyle changes seriously. There is no such thing as a free lunch. [Audience laughter].

Q: Do PSCK9 inhibitors have a significant effect on HDL?

A: ApoB will have come down, so HDL is altered, but predominately because ApoB is altered. I think ApoA1 may have only a trivial effect on HDL. We know that the effect on LDL is causal, but there’s still debate over the effect on HDL. I don’t think that’s a major issue though.

Oral Presentations: Diabetes—A Mixed Bag

Metabolite Profiles Heralding Diabetes Incidence in the Diabetes Prevention Program (DPP) (151-OR)

Geoffrey Walford, MD (Massachusetts General Hospital, Boston, MA)

Dr. Geoffrey Walford presented a study investigating the connection between metabolite profiles and diabetes risk in the Diabetes Prevention Program (DPP) cohort. Previous studies had indicated that increased circulating branched chain and aromatic amino acids (BCAA/As) and decreased glutamine/glutamate predicted type 2 diabetes in white, European populations with an average risk for type 2 diabetes. This analysis paired 427 participants in the DPP study who developed diabetes with 427 participants who did not, matching them based on age, sex, race/ethnicity, treatment, fasting plasma glucose, body mass index (BMI), and hypertension. They profiled 84 different metabolites at baseline and after two years of either intensive lifestyle, metformin, or placebo intervention. The results found that, when adjusted for age, sex, fasting glucose, hypertension status, and BMI, the traditional metabolite markers were no longer significantly associated with type 2 diabetes risk. He also noted that BCAA/A levels were not influenced by the intensive lifestyle therapy or metformin, suggesting that these traditional markers are not part of the causal pathway for diabetes among individuals who are already at a certain risk level. However, four novel metabolites were associated with type 2 diabetes risk in the DPP population:  betaine, serine, methionine sulfoxide, and propionylcarnitine. Dr. Walford focused on betaine as a novel metabolite marker and noted that it has been linked to a beneficial metabolic state and associated with lower triglycerides, adiposity, and blood pressure and higher insulin sensitivity.

Questions and Answers

Q: You’ve tested quite a few metabolites. How did you address the issue of multiple hypotheses?

A: So the concern with our analyses is that we may get false positives. We feel we guard against this using a Bayesian approach. All of the metabolites we explored do have a non-null pre-test probability. Showing nominal significance in this data is at least highly suggestive that they are true findings. The other argument against using a perhaps more strict threshold is the intercorrelation of the metabolites. I didn’t note this but among the branched chain amino acids there is high intercorrelation of metabolites. Although we test eight metabolites the number of independent hypotheses is likely much less than that.

Q: What is the key factor that affects the betaine levels?

A: There’s some very interesting mechanistic work that is being done in animal studies, this will come out shortly we hope. In terms of betaine levels within the plasma, betaine is an essential metabolite; it comes from the diet. The betaine in the plasma is also somewhat affected by your urinary excretion of betaine, this is variable among individuals who are at risk for or have diabetes. Effective betaine levels in the tissue are likely modified by regulated transport of betaine into the tissues as well. Plasma markers are I think a very important biomarker, but more work has to be done in terms of how we understand the influence of the markers.

Prospective Study of N-terminal-proBNP and Risk of Diabetes in Older Adults: The Cardiovascular Health Study (153-OR)

Erika Brutsaert, MD (Yeshiva University, Bronx, NY)

Dr. Erika Brutsaert presented on the potential connection between B-type natriuretic peptide (BNP) and diabetes risk in older adults. BNP plays a role in heart and vascular function and has recently been shown to induce lipolysis. Higher levels of BNP have been linked with decreased diabetes risk in middle-aged adults, but it was unclear if this association persisted in older populations. This study measured a cleavage product of proBNP, N-terminal (NT)-proBNP, in a population of healthy adults 65 and older in the 1992-93 visit of the Cardiovascular Health Study. Existing diabetes, prevalent cardiovascular disease, and history of congestive heart failure were among the exclusion criteria. Primary outcomes of interest were fasting glucose ≥126 mg/dL, non-fasting glucose ≥200 mg/dL, use of anti-hyperglycemic agents, or Centers for Medicare & Medicaid Services (CMS) claims for diabetes. Results were adjusted for traditional risk factors, including age, sex, race, BMI, systolic blood pressure, anti-hypertensive treatment, smoking, alcohol use, and LDL. After 12.6 years of follow-up, the study found that each doubling of NT-proBNP was associated with a reduced risk of incident diabetes (HR=0.91 [95% CI: 0.84-0.99]). However, this association was attenuated when adiponectin was controlled for and abolished with control for HOMA-IR. This led Dr. Brutsaert to suggest that they may play a role in the connection between BNP and diabetes risk. Dr. Brutsaert emphasized that these findings suggest that the natriuretic pathway may be a potential future target for diabetes prevention.

Questions and Answers

Q: What do you think are the therapeutic implications? 

A: That’s an interesting question. There was a recent study that came out looking at neprilysin, which breaks down natriuretic peptide. This was shown to improve mortality in people with heart failure. It also raises natriuretic peptide levels. So this may be an avenue to look into therapeutic benefit. Some researchers have looked into IV natriuretic peptide and have shown some metabolic benefits with that. The problem with that is I think natriuretic peptide has been shown to worsen renal function and lower blood pressure in people with heart failure.

Oral Presentations: Concepts in Nutrition and Diabetes Prevention and Treatment

Different Phyla Composition of Gut Microbiota in Vegetarians and Non-vegetarians Associated with Inflammatory Status (89-OR)

Ana Moraes, MS (University of Sao Paulo, Brazil)

Ms. Ana Moraes presented her findings on differences in gut microbiota in vegetarians compared to non-vegetarians. Previous evidence suggests that the ratio of firmicutes to bacteroidetes is higher in obese individuals, that there is a correlation between abundance of proteobacteria and a high fat diet and C-reactive protein (CRP) concentration, and that vegetarians have less adiposity and a more favorable metabolic profile. This study analyzed the gut microbiota of vegetarians and non-vegetarians (n=230). The only significant difference in microbiota phyla composition was a higher proportion of Proteobacteria (1.1% in vegetarians vs. 1.9% in non-vegetarians; p=0.007) and Actinobacteria (0.1% in vegetarians vs. 0.3% in non-vegetarians; p=0.002). Ms. Moraes connected these results to the possibility of a pro-inflammatory condition in non-vegetarians. The Q&A session touched on whether the length of vegetarianism could affect gut flora and thus the results, the potential effect of fiber intake on the results, and whether BMI or waist circumference was corrected for, but analysis concerning these factors was not yet available.

Questions and Answers

Q: Can you say the length of time that people were vegetarian in this study?

A: For at least one year.

Q: Is there any data on gut flora in terms of length of being vegetarian?

A: No, we don’t have this kind of data.

Q: Could that affect your findings? Let’s say that the proportion of people who have been vegetarian for a short period of time – say one year or two years – would have a different gut flora than someone who has been vegetarian for longer?

A: We don’t have this kind of analysis comparing time with this diet.

Q: Is there any information about how gut flora changes over time?

A: For our study, no. But we have some papers that were already published with this kind of information.

Q: Did you also record things like fiber intake? Because how can you say that it is actually the consumption of meat and not the absence of fiber that might make a difference in the gut microbiota?

A: We just finished our data collection so we don’t have, yet, this kind of analysis with kinds of diet, but we will have it soon. Maybe there will be some kind of analysis on the specific composition of diet, maybe analysis of high-fat diet and fiber.

Q: Did you correct for BMI or waist circumference in any way in looking at your markers?

A: No not for this kind of analysis, not yet.

Posters

Efficacy and Safety of Alirocumab in Individuals with Diabetes: Analyses from the ODYSSEY LONG TERM Study (1296-P)

H Colhoun, H Ginsberg, L Leiter, U Chaudhari, R Pordy, J Robinson

An analysis of the phase 3 ODYSSEY LONG TERM trial found significant LDL-C reductions with Sanofi/Regeneron’s PCSK9 inhibitor Praluent (alirocumab) in people with diabetes, similar to the reductions seen in people without diabetes. As a reminder, the trial enrolled 2,341 patients with and without diabetes, who were either heterozygous familial hypercholesterolemia (HeFH) patients or high CV-risk patients on maximally tolerated doses of statins. Thirty-six percent of individuals in the Praulent group and 35% in the placebo group had a history of diabetes at baseline. People with diabetes experienced a 59% least squares mean placebo-corrected reduction in LDL-C at week 24. This level of LDL-C reduction did not significantly differ from that seen in people without diabetes (p=0.1155): 63% vs. placebo. Most people with (78%) and without (80%) diabetes achieved an LDL-C level <70 mg/dl at week 24 (p<0.0001 vs. placebo). The mean LDL-C reductions maintained significance over 78 weeks in people with and without diabetes, though the ITT analysis showed that the LDL-C level gradually crept up from a nadir of ~55 mg/dl at week 4 to ~80 mg/dl in people with diabetes and ~75 mg/dl in people without diabetes at week 78. The researchers explained this was due to premature treatment discontinuation in both treatment groups, and that the on-treatment analysis showed greater durability. Turning to safety, no increases were seen in adverse events in people with diabetes compared to those without; adverse events that occurred in ≥5% of people in all subgroups were nasopharyngitis, upper respiratory infection, influenza, and urinary tract infections. Injection site reaction happened in 3.4% of people with diabetes on Praulent vs. 3.2% on placebo, and myalgia occurred in 3.1% vs. 2.5%, respectively. The poster noted that treatment with Praulent’s ability to prevent CV events is currently being studied in ODYSSEY OUTCOMES, which will include a “sizeable” proportion of people with diabetes. In a post-hoc analysis of ODYSSEY LONG TERM, Praulent was associated with statistically insignificant reductions in CV events in people with and without diabetes.

• The PCSK9 inhibitor class has had quite a presence at this year’s ADA with numerous corporate symposia and product theaters, indicating the significance of the class’ implications in the diabetes patient population – we look forward to learning more about how the FDA will respond to these drugs at this week’s EMDAC meetings on Praulent as well as Amgen’s Repatha (evolocumab).

Leucine Synergizes with Phosphodiesterase 5 (PDE5) Inhibitors and Metformin to Reverse Hepatic Lipid Accumulation and Inflammation and Treat Nonalcoholic Fatty Liver Disease (NAFLD) (260-LB)

L Fu, F Li, Q Cao, X Cui, B Xue, H Shi, A Bruckbauer, M Zemel

This NuSirt-sponsored preclinical study provided evidence suggesting that triple combination therapy with leucine, metformin, and the phosphodiesterase 5 (PDE5) inhibitor sildenafil could hold promise in nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). Mice were fed a high fat/atherogenic diet to induce NASH and insulin resistance and randomized to receive treatment with combinations of leucine, low dose metformin (<20% therapeutic dose), and low dose sildenafil (<10% therapeutic dose). Each of these drugs has been found to interact with the AMPK-Sirt1 pathway to decrease lipid accumulation in hepatocytes, and NuSirt recently announced the publication of promising preclinical results with the leucine/PDE5 inhibitor combination in type 2 diabetes and NAFLD/NASH. In the study, the triple combination demonstrated significantly greater stimulation of hepatocyte fat oxidation (~60%, p<0.01) and inhibition of triglyceride accumulation (~70%, p<0.001) compared to either leucine/metformin or leucine/sildenafil. The triple combination also led to greater reductions in alanine aminotransferase, liver mass, and liver fat than either dual combination. NuSirt has stated that it plans to initiate a phase 2a trial of this combination in NAFLD/NASH in the near future pending regulatory feedback, and we are glad to see the company working to address such a great unmet need.

• Another NuSirt-sponsored study (1237-P) found that leucine/metformin combination therapy improved glucose and fat utilization and increased median lifespan in C. elegans and provided additional mechanistic insights. This combination is currently in a phase 2a trial in type 2 diabetes that is expected to complete this month.

Leucine-Metformin Synergy Activates the AMPK/Sirt1 Pathway to Increase Insulin Sensitivity in Skeletal Muscle and Glucose and Lipid Metabolism and Lifespan in C. elegans (1237-P)

M Zemel, A Bruckbauer

This NuSirt-sponsored study presented recent results in C. elegans on the mechanisms behind leucine/metformin synergy. Previous data has found that adding leucine to metformin improved insulin sensitivity and glycemic control while achieving an ~80% reduction in metformin dose in diet-induced obese mice. These results showed that leucine (0.5 mM) and low dose metformin (50-100 µM) synergistically activate Sirt1 (p<0.001) at low (<100 µM) NAD⁺ levels typical of energetically satisfied states. This activation of Sirt1 increased insulin-independent glucose disposal in myotubes (~50%, p<0.002) and reduced insulin EC₅₀ (half-maximal effective concentration) by 60%. Furthermore, the increased glucose disposal in myotubes was associated with an increase in AMPK and IRS1 phosphorylation. Normally, in the C. elegans model, exposure to high glucose impaired glucose utilization and shortened lifespan by ~25%. However, when administering leucine and metformin to these high glucose-treated worms, median and maximal lifespan were increased by 29% and 15%, respectively (p=0.023). Additionally, the leucine + metformin administration restored normal glucose utilization and increased fat oxidation almost two-fold (p<0.005). In contrast, metformin alone exerted no independent effect at any concentration (0.1 – 2.0 mM). Leucine and metformin’s synergistic activation of Sirt1 at low NAD+ concentrations may prove to be an exciting target to improve energy metabolism and insulin sensitivity.

• As background, Sirt1 is a key sensor of energy status and regulator of glucose and lipid metabolism. Insulin resistance and diabetes are associated with impairment of Sirt1, and activation of the AMPK-Sirt1 axis improves hyperglycemia and insulin sensitivity. The amino acid leucine has been shown to activate Sirt1 by lowering the activation energy of NAD+, thus mimicking the effects of caloric restriction, and enabling coactivation and amplification of other AMPK/sirtuin activators like metformin.
• NuSirt is currently investigating this leucine/metformin combination approach in a phase 2a trial in patients with type 2 diabetes. The goal of the trial, the first in humans, is to determine whether adding leucine to metformin can lead to equivalent A1c reductions at a lower metformin dose, potentially making the drug more tolerable for the approximately 20% of patients who experience serious GI side effects at standard doses. Study completion is expected this month, and NuSirt has suggested that the drug should “hopefully” be available to patients by 2017.

Special Lecture: Banting Medal for Scientific Achievement Lecture

The Multifaceted Roles of Adipose Tissue: Therapeutic Targets for Diabetes and Beyond

Philipp Scherer, PhD (University of Texas Southwestern, Dallas, TX)

Dr. Philipp Scherer gave an engaging and informative Banting Lecture on potential therapeutic targets for the metabolic syndrome related to adipocyte health. As with last year’s Banting lecturer, Dr. Daniel Drucker (Lunenfeld Tanenbaum Research Institute, Toronto, Canada), Dr. Scherer attempted to highlight the clinical relevance of an emerging area of basic and preclinical science. Synthesizing years of rodent data, Dr. Scherer detailed the role of adipocytes in (i) the release of protein factors that impact systemic metabolism, with special emphasis on adiponectin (a protein that plays a key role in both glucose and lipid regulation); (ii) the buffering of critical lipid mediators; and (iii) the release of metabolites that impact one’s basal metabolic rate. First, Dr. Scherer described how adiponectin can be anti-apoptotic (protecting the heart, beta cell, and kidneys from complications of the metabolic syndrome), proangionic (protecting expanding adipose tissue from hypoxia and dysfunction), anti-atherogenic (reducing CV complications), anti-inflammatory, proadipogenic (helping adipose tissue to expand in a healthy manner), and improve hepatic insulin sensitivity. Thus, he expressed confidence that adiponectin-receptor agonists can be a clinically useful new drug class. Second, he dove deeper into how adipocytes, through adiponectin, can influence the levels of beneficial (namely sphingolipids) and harmful (especially ceramides) lipids in the body. Through this mechanism, adiponectin can drive rapid improvements systemic insulin sensitivity. Lastly, he described how uridine biosynthesis (a key metabolite secreted by adipocytes, and building block for a large number of biochemical reactions) could be targeted by the transcription factor xbp1s to increase a person’s basal metabolic rate. This influence on basal metabolic rate would be similar to the promise of therapies of brown fat therapeutics. However, Dr. Scherer hypothesized xbp1s could be safer than brown fat targets because calories would be burned through biosynthetic pathway rather than the generation of heat.

Symposium: ADA Diabetes Care Symposium — Novel Clinical Interventions in Therapy That Impact the Management of Diabetes

The Use of Anti-Anginal Agent Ranolazine for Glycemic Control in Patients with Type 2 Diabetes: Phase 3 Trial Results

Robert Eckel, MD (University of Colorado, Aurora, CO)

The highly respected Dr. Robert Eckel presented phase 3 results on the glucose-lowering effects of the anti-angina drug ranolazine (Gilead’s Ranexa). For background, anti-hyperglycemic properties of ranolazine were first noticed in post-hoc analyses of its angina trials. The studies Dr. Eckel presented were specifically designed to evaluate glycemic endpoints for ranolazine as monotherapy and as an add-on to metformin or glimepiride. From a baseline A1c of 8.0-8.5%, ranolazine provided a 0.56% placebo-adjusted reduction as monotherapy and a 0.50% placebo-adjusted reduction as an add-on to glimepiride. There was no observed A1c reduction with ranolazine as an add-on to metformin, likely because patients’ metformin dose had to be lowered after ranolazine addition because ranolazine interferes with metformin metabolism. Ranolazine’s suspected anti-hyperglycemic mechanism is lowering glucagon. We have not heard updates from Gilead on ranolazine in some time; the company has completed three phase 3 trials of the drug in type 2 diabetes and is currently conducting a phase 4 trial in diabetic peripheral neuropathic pain. We assume the regulatory path to a diabetes indication would be fairly straightforward given that ranolazine is already on the market; that said we are also thinking that the next step may be to explore combination therapy rather than bringing this out as monotherapy.

Questions and Answers

Q: If ranolazine acts like a glucagon antagonist, does it have any effect on the liver? The glucagon antagonists in development were stopped in the early phases because of liver problems.

A: There was no apparent change in liver function.

Symposium: The Accelerating Medicines Partnership in Type 2 Diabetes — A Pharma/NIH Collaboration

Overview: Rationale, Goals, and Implementation

Philip Smith, PhD (NIDDK/NIH, Bethesda, MD)

Dr. Philip Smith, co-chair of the Accelerating Medicines Partnership (AMP) in Type 2 Diabetes, provided an introductory overview of this industry/NIH partnership. The members include: NIH as the government member; Janssen, Lilly, Merck, Pfizer, and Sanofi as the industry members; and ADA and JDRF as the nonprofit members. Dr. Smith opened his presentation by stressing the many challenges and inefficiencies that currently exist in R&D and drug development. With this background, he explained that the AMP strives to bring the private and public sectors together to work on these issues by integrating better targets with emerging technologies, extensive human data, and big data tools. Importantly, the research supported by AMP is meant to be precompetitive and shared broadly, helping make the program as accessible and effective as possible. The AMP has three major focus areas: type 2 diabetes, Alzheimer’s disease, and rheumatoid arthritis (and related autoimmune disorders), each with its specific aims and approaches. In the five-year, $40 million type 2 diabetes program, Dr. Smith explained that the disease area has a significant amount of human genetic data, which AMP aims to link to risk and phenotypes to better identify and enhance therapeutic targets. He briefly introduced the Type 2 Diabetes Knowledge Portal as a groundbreaking tool to achieve this. Looking forward, Dr. Smith stated that the portal will undergo continuous enhancement with plans to develop new analytics and gain new cohorts.

The Type 2 Diabetes Knowledge Portal: A User-Friendly Window into Genomics Data

Mary Carmichael (Broad Institute, Cambridge, MA)

Ms. Mary Carmichael walked attendees through recent screen shots of the Type 2 Diabetes Knowledge Portal (http://www.type2diabetesgenetics.org), noting its capabilities. She described the Portal as a “resource for the community, by the community.” The Portal currently contains 28 very large datasets on the genetics of type 2 diabetes and related traits (e.g., fasting glucose). Functionalities of the Portal include, but are not limited to, helping users visualize data, survey prior findings across all available datasets, and hunt for genetic variants that may support or refute their biological hypotheses. Users can also view summaries of current knowledge on genetic variants associated with type 2 diabetes – or volunteer to draft their own summaries. Future directions for the Portal include (i) automated association tests for variants across user-selected sets of samples; (ii) new data, including large exome sequence data sets and annotations from public databases; (iii) new analytical methods for the pipeline; and (iv) new content and features that allow users to directly contribute and annotate information in the portal. Email t2dgenetics@broadinstitute.org to join the Portal’s mailing list that will communicate updates (the hope is new features will be rolled out each month).

How the Type 2 Diabetes Knowledge Portal Can Advance Your Science: Genetic Determinants of Insulin Resistance

Geoffrey Walford, MD (Massachusetts General Hospital, Boston, MA)

Dr. Geoffrey Walford took an in-depth look at the Type 2 Diabetes Knowledge Portal, walking attendees through how to make the most out of the tool through the example of investigating insulin resistance. By illustrating that continued understanding of the genetics of insulin resistance is important in advancing therapeutic targets and enhancement, Dr. Walford showed that the portal can help explore insulin resistance’s known genetic architecture and examine the impact of gene variants on various traits. More specifically, he demonstrated the portal’s efficiency in exploring GWAS findings, identifying what findings are novel, and testing new theories. Looking forward, after pointing out the incredible progress that the portal has made (even within the past week), Dr. Walford stated that goals include integrating other datasets over time and developing testing capabilities for genetic risk scores. We are overall impressed with this new collaborative tool that is accessible and applicable to users of all different backgrounds and believe that this can be very powerful in moving type 2 diabetes research forward with its joint, open source philosophy.

Type 2 Diabetes Knowledge Portal: A Call to Action, Community Participation, and Future Directions

Michael Boehnke, PhD (University of Michigan, Ann Arbor, MI)

Dr. Michael Boehnke called for investigators to contribute their data to the Type 2 Diabetes Knowledge Portal. He argued that adding data to the Portal is the right thing to do, given the trust placed in investigators to advance science by study participants who donate their time and DNA and by the government and charitable organizations that fund the work. He also emphasized that submitters will benefit due to the visibility the Portal will give to their research and the opportunities for collaboration, including with pharmaceutical companies, it will create. Additionally, some grant funding is available to help investigators integrate their data into the Portal. Lastly, he stressed that we will all benefit from the Portal containing more data because it offers simplified access to a wider range of genetic results based on large, well-phenotyped, multiethnic studies. Notably, during Q&A multiple attendees took the microphone to urge pharmaceutical companies to contribute the genetic and phenotypic data they collect during trials to the Portal, especially because it may enable companies to more quickly identify the next blockbuster drug. One attendee suggested if pharmaceutical companies are concerned about sharing data associated with proprietary agents, they could instead only upload data from patients who took generic agents. This data could still help researchers make meaningful progress in identifying genetic markers predictive of who will respond to which generic agent. Dr. Philip Smith noted that one of the pharmaceutical companies financially supporting the Portal (Janssen, Lilly, Merck, Pfizer, Sanofi) is already collaborating on data to some extent, and that he hopes others will do the same as the Portal proves its value.

Symposium: Triple G — Genes, Gut, and Glucose

The Bugs Within: The Human Gut Microbiota and Metabolism

Oluf Pedersen, MD, DMSci (University of Copenhagen, Copenhagen, Denmark)

Dr. Oluf Pedersen’s presentation explored the relationship between the gut microbiome and common metabolic disorders. Several observational studies suggest that obese individuals have reduced bacterial diversity. Furthermore, metabolically unhealthy individuals tend to have a low gut bacterial gene count (LGC; defined by <380 K-genes). According to Dr. Pederson, LGC individuals are more likely to be obese, insulin resistant and have elevated markers of low-grade inflammation. Dr. Peterson described a study in which obese recipients were given duodenal infusions of allogenic gut microbiota from lean donors. Six weeks after infusion of gut microbiota, the insulin sensitivity of obese recipients was increased. While such an approach is unlikely to become a widely accepted strategy to improve insulin sensitivity now, it may prove to be an interesting therapeutic alternative in the future. Dr. Pederson concluded his presentation with a discussion of gut microbiota and diabetes. Like individuals with obesity, individuals with type 2 diabetes also have gut microbiota imbalances. In a trans-national study, Dr. Pederson confirmed that patients with type 2 diabetes suffered from a depletion of butyrate producing taxa. In addition to endogenous microbiota deficiency, patients with type 2 diabetes often are prescribed four to 10 medications that also influence their gut microbiota. For example, the metformin-associated gut microbiome was closer to the healthy gut microbiome compared to the microbiome of patients with type 2 diabetes who had never been on metformin. An important remaining question in Dr. Pederson’s exploration is whether gut microbial signatures are valid biomarkers of type 2 diabetes.

Symposium: Adipose Tissue – Local and Systemic Influences on Metabolism and Insulin Resistance

Brown Adipose Tissue in Humans: Relevant or Much Ado About Nothing?

Eric Ravussin, PhD (Pennington Biomedical Research Center, Baton Rouge, LA)

Dr. Eric Ravussin began his presentation by cutting to the chase, saying, “I will begin with my conclusion. I don’t think there’s much hope for curing diabetes or obesity with brown adipose tissue.” He argued for a frame-shift in how we think about BAT, acknowledging that “chasing drugs that stimulate energy expenditure” has not been “fruitful.”  He emphasized that while previous studies of activation of brown adipose tissue (BAT) have proven unsuccessful in initiating weight loss alone, Dr. Ravussin believes that BAT may be useful in weight loss maintenance, specifically via cold-induced thermogenesis. In his opinion, the energy balance equation is misleading and the static weight change rule does not account for a new steady state that is reached after weight loss. Instead, this metabolic adaptation stage could be fertile ground for the induction of a possible second drug that increases energy metabolism, i.e. where BAT could be a target for weight loss maintenance. In his team’s study of competitors from the TV show “The Biggest Loser,” researchers found that the metabolic rate after 30 weeks of weight loss was 500 calories per day below what was expected for their new body weight and body composition. He referred to this as a metabolic adaptation – a stage after losing weight in which BAT activation may help maintain a healthy weight in our “obesogenic” environment.

• Expanding on BAT activation’s potential for weight loss maintenance, Dr. Ravussin presented data from his group’s study with participants from the TV show “The Biggest Loser” (Johannsen et al., JCEM 2012). On average, after 30 weeks, participants lost 38% ± 9% of their initial weight, of which only 17.4% was the loss of fat-free mass (FFM). Notably, researchers found that after 30 weeks of weight loss, the actual resting metabolic rate (RMR) was 500 calories below the predicted RMR based on weight loss of fat mass [predicted RMR= 1.241 +19.2 FFM + 1.8 FM – 9.8 age + 405 (male)]. Even after only six weeks of weight loss, participants had an RMR 244 calories below the predicted RMR.
• Dr. Ravussin concluded that stimulating energy expenditure, e.g. via leptin replacement, might result in more successful weight loss maintenance. He reviewed data showing that metabolic adaptation, i.e. the unexplained decrease in RMR, was related to a decrease in leptin (Knuth et al., AJCN 2014). Specifically, the larger the drop in leptin concentration, the larger the metabolic adaptation.
• Dr. Ravussin also reviewed new data showing that people with type 2 diabetes had no defect in cold-induced thermogenesis (CIT) with well-controlled cold exposure compared to lean subjects and age-matched controls (Blondin DP, et al. Diabetes 2015). Additionally, shivering response and BAT volume of F-fluoro-deoxyglucose (FDG) activity was inversely proportional. Dr. Ravussin translated these results as support for the potential of BAT activation specifically with well-controlled cold exposure, since people with type 2 diabetes did not differ in cold-induced oxidative metabolism and total energy expenditure compared to young healthy controls, despite these patients having smaller BAT volume and lower glucose uptake per BAT.

Questions and Answers

Q: Do older patients with type 2 diabetes have significant amounts of brown fat?

A: Older patients have much less brown fat than younger people for sure. Studies in Japan have shown this inverse relationship with age. Brown fat is something we progressively lose, unfortunately for you and I [laughter].

Symposium: Diabetic Dyslipidemia — Where's the Action in 2015?

Metabolic Effects of Bile Acid Sequestration

Bart Staels, PhD (University of Lille, Lille, France)

Dr. Bart Staels described how bile acid sequestrants lower LDL, increase HDL, and improve glycemic control. While bile acid sequestrants improve lipid homeostasis by increasing bile acid synthesis through the deactivation of FXR, they improve glycemia through the TGR5 pathway. Citing several mouse studies for support, he explained that bile acid sequestrants improve glycemia by stimulating the TGR5 pathway, which activates the GLP-1 receptor and eventually suppresses glycogenolysis. Although the majority of this research relies on animal models, bile acid sequestrants have also been demonstrated to induce GLP-1 secretion in humans. In fact, several drugs in this class are already on the market or in development: Daiichi Sankyo markets the bile acid sequestrant Welchol (colesevelam), and GSK has an ileal bile acid transport inhibitor in phase 2.

Professional Interest Discussion Group: Professional Interest Group Discussion on Exercise

A Debate on Exercise Resistance in Diabetes: Pro

Lauren Sparks, PhD (Translational Research Institute, Orlando, FL)

Dr. Lauren Sparks presented evidence in support of the existence of exercise resistance in a pro-con debate on the topic. She began by reviewing data suggesting that while many individuals with type 2 diabetes benefit from exercise, a significant percentage do not achieve the same metabolic results. Much of Dr. Sparks’ talk focused on establishing that different individuals and populations respond differently to exercise, providing support for the existence of a non-responder population. Dr. Sparks then went on to suggest that genetics or epigenetics may play a role in differentiating non-responders from responders. She concluded by presenting the setup and preliminary results from her RESIST study, which examines exercise resistance at the cellular level in a small population with type 2 diabetes.

• Dr. Sparks proposed that some individuals may be resistant to exercise and may not experience its typical benefits. She emphasized that there is a lack of research into exercise resistance, but that current data does suggest significant variation in responses to exercise.
• Retrospective data suggests that significant numbers of individuals with diabetes do not respond positively to exercise as expected. Dr. Sparks highlighted the findings from the STRRIDE trial demonstrating variation in insulin sensitivity, muscle mitochondrial density, and muscle lipid content in response to exercise in overweight and obese individuals. A meta-analysis suggested that up to 15-20% of individuals with type 2 diabetes may be resistant to exercise, which could have serious implications for how treatment plans are prescribed and individualized for patients (we do not think they are too individualized as it stands). Dr. Sparks also cited a meta-analysis conducted by Bouchard et al. (PLOS, 2012) indicating that 7% of individuals actually exhibited an adverse response to exercise.
• Dr. Sparks suggested that there may be a genetic or epigenetic component to exercise resistance. Dr. Sparks pointed to responders and non-responders having distinct basal molecular profiles of muscle tissue, with different genes expressed in responders and non-responders, as evidence for a pre-determined component to exercise resistance. Dr. Sparks postulated that, typically, exercise may lead to gene expression promoting fuel utilization in muscle, which in turn increases insulin sensitivity, oxidative capacity, and mitochondrial content. In her model of exercise resistance, some individuals may have epigenetic control at the muscle cells that inhibits the gene expression response to exercise.
• Dr. Sparks’ RESIST study examined exercise resistance at the cellular level in a small, homogenous, Caucasian male population. The study conducted exercise training for 10 weeks with 24 males with type 2 diabetes, measuring mitochondrial ATP synthesis and function. The results of the study indicated that there were high and low responders to exercise within the participant group. Looking forward, Dr. Sparks hopes to address whether the described non-responder phenotype in muscle fibers is intrinsic and retained when exercise is mimicked in vitro.

Questions and Answers

Q: What can you tell us about how muscles look under the microscope? We have responders vs. non-responders – does one have more glycogen than the other?

A: So quantitatively, I can tell you we haven’t done anything on that. In that previous study I showed, we weren’t geared towards measuring any of that so I don’t have any data on glycogen content. But I can tell you that in the current study that we’re doing, we are preparing the tissue for immunochemistry and we will look at some of those things.

Q: And what about responders vs. non-responders in terms of strength or endurance?

A: We did do a strength test and there were no differences between the groups, nor in VO₂ max responses in those two groups. It seemed to be more at the level of muscle substrate utilization.

Q: Is there something clinical (not a muscle biopsy)? I’m a responder because I work very hard; I’m very religious in what I do. So I would hypothesize that some physical characteristics, some nutritional factors, and environmental factors may be very important.

Dr. Sheri Colberg-Ochs (Old Dominion University, Norfolk, VA): Hey, hey that’s mine. [Laughter]

Q: So I would hope that you’re getting some of those basic fundamental characteristics in your studies. Since it’s the older population that that are trying to get the exercise, that are prediabetic, it may well be sleep apnea or other clinical characteristics that are more relevant than what’s going on in muscle.

A: I completely agree. I can tell you that this study right now is pretty small, so it’s only 24 subjects. Because of my background and because of the data I had to go on, I am still focusing pretty much solely on the muscle and not necessarily environmental factors, which is why the cohort is what it is. So it’s males only, Caucasian only, because we’re looking at this at a more of a molecular level. In the future, I would like to open this up to a much more epidemiological style, public health approach that can compare different types of exercise.

Q: But there’s no reason you can’t get that information in the 24 people. You have all the resources to do that?

A: Yes, I could.

Q: One of the challenges of this kind of study is that if the group is very homogenous in terms of the mechanism that is giving rise to exercise resistance, then this might work out. But if there are 24 people and 30 different mechanisms, it may be challenging. So I’d like to get your thoughts on how likely do you think it is that it’s a homogenous group with respect to the mechanism? Because you can certainly think of many different points in the pathway that could give rise to exercise resistance and that could be a challenge.

A: Yes, it’s definitely a limitation of this study. The reason we’re focusing on this particular mechanism – and like you said, we may not find it – is the precedent we had to go on, the data pointing out these changes in these promoters of these three genes, which is why we chose to focus on them. But we will be doing these methylation arrays as well and hopefully we can tease something out of the data to get more of a clear direction. Because I agree with you, we could totally miss it if we just focus on this part of the pathway.

Q: Has anybody done anything younger to try and get a sense of if it’s possible exercise resistance sets in later because of some factor or is it an inherent defect that you’re born with? I’m think about one study that was done in mice and swim training that showed if they started the training when they were really young, they did much better than if it was brought in later. Is it possible that the non-responders are people who did something different earlier in life or is it always going to be there?

A: As far as I know, it hasn’t been looked at directly, but I would love to take this into kids. I have this memory of these presidential fitness tests when I was a kid and every year there were always those kids who couldn’t run the mile in 10 minutes or couldn’t do the 100 sit-ups. So I truly think that it is something that probably is starting very early. Maybe if you could interfere earlier, then maybe that could change the outcome so that they’re not necessarily always a non-responder.

Q: One of the things I was curious about is your proposed study where you’re looking at diabetes vs. athletes? How are you defining your diabetics? The reason I ask that is that we had tried to tackle some of this exercise resistance question by looking at different phenotypes of impaired fasting vs. impaired glucose tolerance or a combination of both. What we find is that the combination actually don’t seem to respond as well in comparison. And going back to the question about clinical outcomes, it seems to really directly impact their improvement in glucose tolerance and two hour blood glucose.

A: So the way we’re defining these guys, again because we’re focused on the molecular mechanisms and keeping it as clean as possible, we decided to go with their A1c range from 6.5-8.5%, and we’re also doing oral fasting glucose. The biggest thing is because of this exercise and medication factor, we want them on monotherapy so that they can wash off of or they’re just not on medication at all. So we’re trying to keep that as clean as possible. We also know that the duration of diabetes relates to the exercise response as well, and we looked at that in a previous study. There are lots of issues around this; it’s not a magic bullet or one single answer for exercise resistance. I think it will be many different answers from many different people. As cleanly as we can, that’s how we’ve chosen to approach this study and hopefully we can get some answers. But I know that previous hyperglycemia can also have an effect on the exercise response.

A Debate on Exercise Resistance in Diabetes: Con

Sheri Colberg-Ochs, PhD (Old Dominion University, Norfolk, VA)

Dr. Sheri Colberg-Ochs raised important considerations in the exercise resistance debate based on her own experiences conducting exercise-related research on individuals with diabetes. She began by questioning the relevance of many of the animal and in vitro studies that suggested processes for exercise resistance. She then questioned whether the clinical studies that concluded that some individuals with diabetes do not experience the usual metabolic benefits of exercise had adequately controlled for a multitude of confounding factors. In her own experience, despite best intentions, there are often variations in training intensity, daily energy expenditure, and diet that are not adequately taken into account in exercise studies. Dr. Colberg-Ochs also suggested that studies that saw exercise resistance in individuals might have simply not continued the training long enough to see results. Ultimately, the theme of her arguments was that one should never assume all factors are adequately controlled for and that this may have severe repercussions for the results.

• Dr. Colberg-Ochs questioned the relevance of much of the current evidence supporting the existence of exercise resistance. She pointed out that studies in rats involve successive breeding for certain traits that results in a homogeneity not seen in the human population. In addition, she questioned the extrapolation of findings at the myotubule level to the whole human body and argued that the way muscle cells respond in vitro may not necessarily be the same as how whole muscles or the whole body responds.
• Dr. Colberg-Ochs argued that many confounding factors are not adequately accounted for in exercise resistance studies. For example, the setup of exercise-based studies involves initially setting a maximal aerobic capacity. However, despite best intentions, many participants may underestimate their maximal aerobic capacity if they did not push themselves hard enough because they are unused to physical activity, lack motivation, or experience localized muscle fatigue or other limitations. As a result, training intensity throughout the study may then be based on an artificially low maximal aerobic capacity. Dr. Colberg-Ochs also suggested that non-training daily energy expenditure and diet are not adequately accounted for in many of these studies and these factors can have a large confounding effect on the observance of exercise resistance.
• Dr. Colberg-Ochs proposed a handful of alternate explanations for observed exercise resistance. These included a failure to fully control for diet, variation in the amount of training done by some subjects, variation in daily activity energy expenditure, factors affecting insulin action and glycemic balance, medication effects, and failure to take body fat composition into account in BMI measures.

Questions and Answers

Q: I want to follow up on one of the points you made about setting up your training intensity based an initial exercise capacity test. Is this something that we all have to deal with? It’s very easy to get athletic people to push through, and then you struggle with people who are unaccustomed to exercise or have limitations. So what kind of solutions have you worked through to resolve that issue?

A: I wish I had a good response to that. I’ll tell you what I did one time. I did a study and we had one guy who was a lean type 2 and he did a lot of running and that stuff. He wanted to be in the study so I went ahead and included him. But when we got to the end and we looked at the data, he was such an outlier, we threw the data out. That was my response: I can’t include this person because he’s just not like all the others and it’s going to skew all the means. I think we might need a better way of initially assessing what would be a starting point, and I don’t know what that is.

Q: Have you taken data on the participants’ readiness measure? I know in other studies that I’ve done, that’s a variable to consider – their readiness to participate.

A: Do you have a particular physical readiness thing that’s more physiologic? We have a physical activity readiness questionnaire that asks questions like “do you have chest pain when you exercise?” I’m not aware of a really effective one other than that. We don’t have anything else.

Q: I think you made a very important point that if people don’t exercise or exercise as much, they may appear to be non-responders. I’m not sure that that’s evidence against genetics. Could there be genes that affect people’s tolerance for exercise or the amount of exercise they’re interested in?

A: I totally agree. I wasn’t trying to rule that out entirely. Likely there are some people who truly don’t respond. Maybe you have someone who doesn’t respond to aerobic training but responds to resistance training. It may be that what we’ve been doing for years is prescribing exercise for people and saying you need to do this, you walk for 30 minutes, instead of letting people gravitate to activities that they prefer to do. Maybe for genetic reasons they like to do one activity more than another. We certainly know that there is different muscle fiber typing that might affect how people respond.

Comment: You pointed out correctly that if you take this sedentary person and try to do an aerobic capacity on them it’s hard to get them to the point where they will have increasing heart rate. So what you end up with is peak exercise rather than anaerobic capacity. I highly recommend that you plot on the horizontal axis work load and on the vertical axis the heart rate and you look at the slope. As the person becomes more fit, the slope will become flatter and flatter. You don’t have to worry about this problem of getting them to plateau.

Point two is that at least four decades ago, the Danes pointed out in their research that if you prevent the core temperature from going up, there will be no improvement in aerobic capacity.

And the last point is that about three decades ago the Norwegians showed that if you train just below your anaerobic threshold, you can get much better improvement in aerobic capacity than if you go above the anaerobic threshold. And that’s controversial because there’s a whole group of people, myself included, that believe you need to go above anaerobic threshold for three minutes, and then below anaerobic for three minutes to recover. But the point is that somewhere above and below the anaerobic threshold is where the optimal exercise needs to be and as they improve that anaerobic threshold, the exercise load has to follow to keep them in that prime spot.

A: Right, so basically training is a moving target and I think it moves faster for some people.

Comment: So when you take the highly fit mice, and you train them, they don’t get any fitter and they don’t improve metabolically. Maybe we all have an inherent gene that makes it such that we can’t improve any further. We haven’t identified that. The only way real way we can do that is have the DNA and have the VO₂ max measure on the people to look for those genes in genome wide scans and that would be very interesting. In contrast, when unfit mice put on treadmill and made to run, they do get fitter and they do improve metabolically, although they cannot reach the level of fitness of the mice bred to be fit. That’s a very interesting model that provides some very intriguing possibilities for these two approaches to defining who’s a responder and who’s not a responder. It comes down to collecting all the data you can possibly think of and what is great is you have this opportunity to look at that.

I think some of the answers may be in studies of master athletes. Back in the 1990s in my lab, we were able to raise the VO₂ max of the master athletes substantially with training and when we de-trained them, we uncovered dyslipidemia and then we looked at genes that might predict that. So there are interesting things that can be found out from just working to get that volunteer who’s interested in their training responses to get the data we want and need to make those analyses possible.

A: I agree, thank you for that comment.

Corporate Symposium: Novel Mechanisms and Advancing Therapeutic Paradigms for Optimizing LDL-Focused Management and Cardioprotection in the Diabetic Patient (Sponsored by Sanofi/Regeneron)

ADA and ACC/AHA Guidelines for Improved LDL-Targeted Atheroprotection in Diabetic Patients: Unique Considerations and Target Goals in the Setting of T2D: What Works? How Well? What Doesn’t Work? How Low Should We Go? Why?

Vivian Fonseca, MD (Tulane University, New Orleans, LA)

The renowned Dr. Vivian Fonseca discussed the link between diabetes and cardiovascular risk, emphasizing current gaps in our knowledge and potential future therapeutic strategies. Following a review of the complex data behind glycemic control and cardiovascular risk, he suggested that moving forward, modifying multiple risk factors concurrently may be a more effective approach than focusing solely on A1c. He touched on the potential role of inflammation in the development of cardiovascular disease, asking whether newer agents may also play a role in modulating that risk factor. He concluded by asking what the optimal goal for LDL is in minimizing cardiovascular risk.

• Dr. Fonseca opened by noting the current gaps in our knowledge with regard to diabetes and cardiovascular risk. While LDL and blood pressure control have demonstrated beneficial effects on cardiovascular outcomes, he noted that results with various diabetes therapies and glycemic control have been less clear. While the UKPDS took roughly a decade to show cardiovascular benefit, researchers expected improvement in outcomes in ACCORD and ADVANCE over shorter time periods. Moving forward, he suggested that modifying multiple risk factors concurrently (hyperglycemia, hypertension, and dyslipidemia) may be a more effective approach than focusing on lowering A1c alone.
• With regard to ACCORD, Dr. Fonseca noted a recent study (Hempe et al., Diabetes Care 2015) demonstrating increased hypoglycemia and mortality in subjects with high glycation indexes. These patients have a higher A1c than would be predicted by their blood glucose levels, which could potentially lead to overly intensive treatment that increases hypoglycemia risk. Therefore, taking hemoglobin glycation index into account may enable providers to identify subpopulations at higher risk and better optimize their diabetes management.
• Dr. Fonseca reviewed the potential role of inflammation in the development of cardiovascular disease. He noted multiple therapies with possible effects on inflammation, including a low fat diet, aspirin, statins, and insulin sensitizers. He questioned whether newer agents may also affect inflammation.
• Dr. Fonseca concluded by asking what the optimal goal for LDL is in minimizing cardiovascular risk. With the idea that lower is better, he noted that current trials may not have gone low enough. He hoped new trials would help uncover the optimal goal for patients moving forward. The ongoing cardiovascular outcomes trials of PCSK9 inhibitors, which can bring some patients down to very low LDL levels, should hopefully provide more clarity on this issue – as we understand it, this and neurocognitive effects represent the main safety issues at presents. CVOT outcomes must come before approving the drug, except for the most needy patients, e.g., those with hypercholesterolemia. .

Evolving Clinical Paradigms for LDL Lowering: Focus on Efficacy, Implications, Side Effects, and Safety Results of Landmark Trials Evaluating PCSK9 Inhibition, ApoB Suppression, and Other Novel Targets – Implications for the Diabetic Patient

James McKenney, PharmD (Virginia Commonwealth University, Richmond, VA)

The wonderful Dr. James McKenney gave a thorough overview of the clinical studies supporting the PCSK9 inhibitors in development, discussing optimal indications for their use. Dr. McKenney opened with encouragement, suggesting “we may be on the front edge of another era in cardiovascular therapies.” Following a review of the mechanism of action of the drug class, he underlined three potential populations for which these drugs could be most useful: familial hypercholesterolemia patients, patients with high CV risk uncontrolled on statin therapy, and patients intolerant to statin therapy. In addition to strong effects on LDL reduction, he praised the minimal adverse event profile of the class. He concluded by noting the ongoing long-term outcomes trials of the class – while he suggested results from these studies were necessary to draw definitive conclusions, he felt the early evaluation of adjudicated CV events with PCSK9 inhibitors provided reason to be hopeful for positive results.

• Dr. McKenney opened with encouragement, suggesting “we may be on the front edge of another era in cardiovascular therapies.” He highlighted the numerous new mechanisms being researched, including PCKS9 inhibitors, Apo B antisense, MTTP inhibitors, and CTEP inhibitors. Focusing on the PCSK9 inhibitors, he reviewed the candidates in development, including Sanofi/Regeneron’s Praluent (alirocumab; under review), Amgen’s Repatha (evolocumab; under review), Pfizer’s bococizumab (phase 3), Lilly’s LY3015014 (phase 2), Alnylam’s ALN-PCS siRNA (phase 1), and AFFIRIS AG’s peptide-based vaccines (preclinical).
• Dr. McKenney briefly reviewed the mechanism of action of the PCSK9 inhibitors, correlating it with their downstream clinical effects. He noted that the inhibitors that produce an initial 100% blockade of PCSK9 result in a maximum reduction in LDL-cholesterol of about 60%. The body continues to secrete PCSK9 and so increasing the dose of the PCSK9 inhibitor prolongs the effect but does not increase the reduction. Looking at single ascending dose studies, this was demonstrated with a roughly 60% decline in LDL-cholesterol with both alirocumab 150 mg SC Q2W and evolocumab 140 mg SC Q2W. At the selected doses for market, alirocumab 75 mg every two weeks produces a roughly 50% decline in LDL-cholesterol and 150 mg every two weeks produces a decline of 66%; evolocumab 140 mg every two weeks produces a 66% decline while 420 mg every four weeks produces a 50% decline. In Dr. McKenney’s clinic, he suggested about half of his patients prefer bimonthly administration as opposed to monthly.
• Dr. McKenney underlined three potential populations for which these drugs could be most useful: familial hypercholesterolemia patients, patients with high CV risk uncontrolled on statin therapy, and patients intolerant to statin therapy. He reviewed positive results for PCKS9 inhibitors in these populations, with a 61% decline in LDL-cholesterol in heterozygous familial hypercholesterolemia patients with evolocumab 140 mg every two weeks and a 55% decline with 420 mg monthly dosing (baseline LDL 155 mg/dl). For high-risk patients on maximum tolerated statin therapy, he noted the 51% decline in LDL-cholesterol in patients treated with 75 mg alirocumab every two weeks in the ODYSSEY COMBO II study (baseline 109 mg/dl). Lastly, for statin intolerant patients, he showed the 45% decline in LDL-cholesterol in patients unable to tolerate two different statins in the ODYSSEY Alternative study (baseline 191 mg/dl).
• With regard to the safety profile of the class, looking to the Osler (evolocumab) and ODYSSEY Long Term (alirocumab) studies, he noted no signal for elevation in transaminase levels, myalgias, GI side effects, or neoplasms. At the planned FDA Advisory Committee meetings on the drugs, he suggested the agency would be interested in the effects on neurocognitive events/disorders, which occurred infrequently in these studies but showed  a slight increase relative to control groups – he suggested large outcome studies would be needed to elucidate this further. Neurocognitive events did emerge as one of the main safety-related discussion points in the meetings for Praluent and Repatha, along with the unknown effects of very low LDL levels, and (surprisingly to us) a potential risk of diabetes comparable to that seen with statins.
• Dr. McKenney concluded by noting the ongoing long-term outcomes trials in the class. These included ODYSSEY Outcomes for alirocumab (estimated completion January 2018), SPIRE-1 (estimated completion April 2018), and SPIRE-2 (estimated completion January 2018) for bococizumab, and FOURIER (estimated completion October 2017) and GLAGOV (estimated completion July 2016) for evolocumab. While he suggested results from these studies were necessary to draw definitive conclusions, he felt the early evaluation of adjudicated CV events with PCSK9 inhibitors provided reason to be hopeful for positive results.

Panel Discussion

Vivian Fonseca, MD (Tulane University, New Orleans, LA), Deepak Bhatt, MD (Harvard Medical School, Boston, MA), Michael Davidson, MD (University of Chicago, Chicago, IL), James McKenney, PharmD (Virginia Commonwealth University, Richmond, VA)

The corporate symposium concluded with a fascinating panel discussion that addressed a notable question: Would panelists use PCSK9 inhibitors prior to cardiovascular outcomes trial data being available? The discussion turned particularly animated on this point, as three of the four panelists were in favor of prescribing the class - Dr. Vincent Forlenza was the sole holdout: “I don’t know.” The others cited impressive cholesterol data that was “too compelling” to ignore in patients at an already high risk for a coronary event. All three, however, qualified their statement by noting that in patients with low or medium risk of a cardiovascular event, the decision was more nuanced and required a unique benefit-risk assessment per individual. Last, all four panelists agreed that the bigger question was on the reimbursement front: Would payers jump on board without CVOT data? We heard healthy skepticism in response and a consensus that coverage and cost would pose some of the greatest challenges for the class moving forward. Based on the discussion and votes at the recent FDA Advisory Committee meetings for Praluent and Repatha, it appears that the initial indication for the products will likely be quite narrow (possibly just for patients with familial hypercholesterolemia) and that broader labels more applicable to patients with diabetes will likely be placed on hold until CV outcomes data is available.

Q: Let’s assume things go well and PCSK9 inhibitors are approved … should we use them prior to CVOT data being available? Would you use them in someone at high risk for cardiovascular disease?

Dr. Fonseca: I would use them in statin intolerant patients. With patients with diabetes, I would discuss the consequences and costs with them. I would say that I couldn’t promise that the therapy will reduce the risk of cardiovascular events, but the LDL data is so strong that I might still use it. Cost and coverage will be important.

Dr. McKenney: I would use them in people with high CV risk and elevated LDL-cholesterol levels in spite of statin therapy. The question will be ultimately answered by the payers. Payers are likely to say that they want to see CVOT data.

Dr. Davidson: I don’t know the answer but I think it’s going to be about who can afford it. We’re going to want to use it in all patients.

Q: If cost isn’t an issue – in someone’s who LDL at a mid-level, but has had three myocardial infarctions in the past year – would you use a PCSK9 inhibitor in the absence of CVOT data?

Dr. McKinney: Yes.

Dr. Davidson: Yes.

Dr. Fonseca: I don’t know.

Q: Is there any data on prediabetes being a risk factor for cardiovascular disease?

Dr. Fonseca: There is a continuum, but it’s not a straight-line relationship. There are very few clinical trials on pre-diabetes being linked to cardiovascular risk. There’s just not enough data here.

Q: Statin adherence for primary prevention is suboptimal. Given the more invasive nature of PCSK9 antibodies how do you foresee adherence?

Dr. Bhatt: In the real world we’ll have to see. Of course in clinical trials it’s closely monitored. I can see adherence being worse in clinical trials. In the other hand I can see it being better given it’s an injection every two weeks or month versus a pill every day. So it may depend on the patient.

Q: Can you talk about the relationship of PCSK9 inhibitors on CRP levels?

Dr. Davidson: It does not lower CRP levels. That has been thought about statins. No evidence of that with PCSK9 antibodies.

Dr. McKenney: I agree that PCSK9 inhibitors do not alter hsCRP. However, the key biomarker for risk reduction is LDL-cholesterol. And I would remind everyone that we have gone through a slow process of determining what the optimal LDL-cholesterol should be. Our treatment guidelines recommended <130 mg/dl in 1988, <100 mg/dl in 1993, and <70 mg/dl in 2004 for high risk patients. The goal has changed with time to become lower and lower because of outcome trial results. The ongoing outcome studies with PCSK9 inhibitors are going to result in mean LDL-cholesterol levels in the 30s or so. I suspect, if they are positive, we will redefine what our desirable level should be again.

Q: Please comment on the functioning beyond liver.

Dr. McKenney: PCSK9 only targets LDL receptors. Even though PCSK9 is made by the liver and kidneys, the only target is LDL receptors. So a monoclonal antibody that binds to PCSK9 to allow the LDL receptors to pull more circulating cholesterol into the liver is the unique effect of these drugs. There are no other biological targets. That’s why, in my opinion, these therapies seem so safe.

Q: Can you talk about antibody production with PCSK9 inhibitors? Is there a loss of efficacy?

Dr. Davidson: Difference between the different types of antibodies. Evolocumab and alirocumab are fully human. They both show some evidence of antibody production. There has been maybe on or two cases where there was a loss of efficacy, but that’s it. As of now, the rate of antibody production is very low. There is no evidence of safety issues.

Q: What about in type 1 diabetes?

Dr. Fonseca: I’m pleased to see this question. Guidelines suggest a statin for patients after a certain age, though there are no trials in a type 1 population. There is actually no PCSK9 trial in diabetes, only sub-analysis in diabetics. There may be some type 1s in trial; I really don’t know. We’ll have to look at that.

Q: Is there anything that compels you to stop treatment?

Dr. Bhatt: The epidemiological data with PCSK9 inhibitors seems pretty safe.

Q: Do PCSK9 inhibitors actively do anything good?

Dr. Davidson: It is a counter regulatory protein that maintains cholesterol homeostasis.

Dr. Bhatt: To date with statins, they have been very safe. There might be some benefits of statins in terms of dementia that could extend to PCSK9 inhibitors. We’ll get a definite answer in some years.

Q: There is also a question about children.

Dr. McKenney: PCSK9 monoclonal antibodies have been found surprisingly effective in children with homozygous familial hypercholesterolemia. These patients have loss of function LDL-receptor mutations inherited from both parents. Their mutation may be negative, which means that the receptor has no function, or defective, which means it has 2-25% of function. Patients with a negative/negative profile don’t respond at all to PCSK9 inhibition. But patients with any other combination of defective/negative or defective/defective experience a 25-40% reduction. This outcome was not expected but was a very welcome result.

Q: Have you seen any data about patients that don’t respond to treatment with PCSK9 inhibitors?

Dr. McKenney: I haven’t seen any. Everybody seems to respond. In fact, compared with the standard deviation of cholesterol values around a mean in an untreated population, the standard deviation after PCSK9 inhibition is substantially compressed.

Q: I have questions about other drugs.

Dr. Fonseca: Cycloset had a one-year diabetes safety trial; they didn’t continue the trial unfortunately. We have nothing with metformin. Tadalafil with chronic low-dose use may well have a beneficial effect, but it was never tested for that with its so-called side effect. You may not live longer but certainly a lot happier according to the commercials.

Dr. Bhatt: You’re right normally it was an anti-anginal – it wasn’t effective. It can be used in pulmonary hypertension.

Q: If these are approved, is there room for other agents with other mechanisms of action? Will it be ethical to do these studies?

Dr. Bhatt: There is always room for innovation. We have to see how PCSK9 inhibitors fair in CVOTs. We’ll have to look at how the drugs do in patients with low LDL cholesterol levels? I have not been very concerned, but we really have to see how these drugs fair. I wouldn’t dismiss innovation, especially ones that are complementary to this pathway. It would be ethical but the study might have to include PCKSK9 inhibitors.

Q: Is there a possibility for an oral therapy?

Dr. Davidson: It’s very difficult with protein and protein interactions in the liver for it to work orally. One big question is when to use these drugs – I think that will be big in FDA panel next week. It will be a regulatory question and an insurer question. I think there will be lots of patients not having success on statins that will be using it frequently.

Q: Why should we keep statin therapy around?

Dr. Bhatt: All the data I showed you were of PCSK9 inhibitors acting on top of statins. So, the effect is additive. We have studied PCSK9 inhibitors as a monotherapy, and you don’t see the same benefit.

Q: Where would you put these in the algorithm for therapies?

Dr. McKenney: I believe these are statin-plus therapies out of the gate. Their use will be for patients with high CVD risk or recurrent events while on statins, patients with intolerance to statins, and patients with familial hypercholesterolemia. When the outcome studies are complete and demonstrate substantial CV risk reduction when added to a statin, I suspect we will then see studies to demonstrate similar utility as monotherapy.

Q: Can you talk about gene therapy to knockout PCSK9 inhibitors?

A: There is a whole separate set of issues there, but I’d like to see how that plays out.

Q: How will physicians distinguish between evolocumab and alirocumab?

A: I don’t know. Some will like the idea of having doses to choose from. Some might like to start at a higher dose. Some might like the once-a-month approach vs. every two weeks. Cost is going to be a big factor.

Q: Would you use these in metabolic syndrome versus statins given the effect on insulin?

Dr. Fonseca: I think the effect of statins on glycemia is very small. But I think there’s a clear benefit in cardiovascular outcomes, so I would still use them. We need to do more analysis on this subset from outcomes trials.

Corporate Symposium: Managing the High Risk Patient – LDL and Beyond: Contemporary and Future Approaches (Amgen)

Understanding Pathophysiology of Lipid Disorders, Focusing on the Role of PCSK9 in LDL-C Homeostasis

Jorge Plutzky, MD (Brigham and Women’s Hospital, Boston, MA)

The renowned Dr. Jorge Plutzky reviewed the pathophysiology of lipid disorders and the involvement of PCSK9, setting the stage for the rationale of using PCSK9 as a therapeutic target. After opening his presentation by labeling PCSK9 inhibitors as “one of the most clear-cut approaches” in medicine, Dr. Plutzky walked attendees through much of the preclinical, genetic, and therapeutic data on the relationship between LDL levels and CV risk. He reviewed the mechanisms of cholesterol transport and explained PCSK9’s role as a secreted protein that targets the LDL receptor for degradation. Specifically, he discussed genetic models of PCSK9 showing how people with gain of function PCSK9 mutations have higher LDL levels and increased CV risk while loss of function PCSK9 mutations confer lower LDL levels and protection against CV risk. With these data, Dr. Plutzky concluded that PCSK9 inhibitors are a new class of therapies backed by a strong body of evidence.

Cardiovascular Disease and the High-Risk Person: Epidemiology, Pathophysiology, and Contemporary Guidelines

James Underberg, MD (NYU School of Medicine, New York, NY)

Dr. James Underberg discussed the current guidelines for managing patients at high risk of developing cardiovascular disease. Although in the past, there was some controversy regarding the value of using statins in reducing atherosclerotic cardiovascular disease (ACSVD) events, Dr. Underberg advocated for their use at moderate or high levels in high-risk individuals. According to Dr. Underberg, individuals at high risk are those with clinical ACSVD, those with LDL levels ≥ 190 mg/dl and/or patients between the ages of 40-75 with type 1 or type 2 diabetes. In terms of treatment, Dr. Underberg did not indicate which guidelines he thought were most helpful; however, he noted several common themes from ACC/AHA, ADA, NLA, and AACE/IAS guidelines for high-risk patients. These are as follows: (i) patients with established ASCVD should be aggressively treated; (ii) statins should be used as the first line therapy for these high-risk patients; and (iii) moderate to high intensity statins should be used if they can be tolerated by the patient; however, side effects such as muscle pain and damage should be considered.

Addressing the Residual Risk

Howard Weintraub, MD (NYU School of Medicine, New York, NY)

In his presentation on addressing residual risk for patients at high risk of cardiovascular disease, Dr. Weintraub outlined several trials that failed to show a benefit of increased HDL concentrations in reducing atherosclerotic cardiovascular disease (ACSVD) risk. For example, even though HDL concentrations increased in individuals in the AIM-HIGH trial, there was no evidence of ACSVD risk reduction. Furthermore, in the ILLUMINATE trial, patients receiving torcetrapib, a cholesterol ester transfer protein (CETP) inhibitor had a 72% increase in HDL concentration after 12 months; however, the trial was stopped early due to an increase in major cardiovascular events and overall death. Despite the current very limited evidence that increased HDL concentrations improve cardiovascular outcomes, companies such as Merck and Lilly have CETP inhibitors (anacetrapib and evacetrapib, respectively) in phase 3 trials.

Emergent Options for the Management of Lipid Disorders: Clinical Data from Novel Classes of Drugs

Lawrence Leiter, MD (University of Toronto, Toronto, Canada)

Dr. Lawrence Leiter provided an overview of clinical data on the value of LDL reduction and the role of PCSK9 inhibitors as a treatment option for patients who have not achieved their LDL targets. He shared data showing an ongoing treatment gap including a study that revealed that 43% of Canadian patients with diabetes are not at their LDL target. He noted that there are many reasons for this, including overreliance on diet, use of insufficient starting doses of statins, complacency, and lack of follow-up for up-titration. Dr. Leiter thus emphasized the need for additional lipid lowering agents, as statin monotherapy may not allow many patients to achieve their targets. He pointed to PCSK9 inhibitors as promising therapies that are close to market and reviewed clinical data on Amgen’s Repatha (evolocumab), Sanofi/Regeneron’s Praluent (alirocumab), and Pfizer’s bococizumab, showing relatively consistent LDL reductions in the range of 50%-60%. While acknowledging that there are not yet much data in people with diabetes, he highlighted the OSLER study findings showing that the diabetes population experienced very similar reductions in LDL despite their differences in glycemic status. We certainly believe that PCSK9 inhibitors can have huge beneficial implications for diabetes care, though the initial approved indications will likely be narrow until the ongoing cardiovascular outcomes trials report results – please see our coverage of the FDA EMDAC meetings on Praulent and Repatha for more.

Product Theater

The Prevalence of Elevated LDL-C in Diabetes: Cholesterol Management and the Role of PCSK9 in Cholesterol Homeostasis (Amgen)

Harold Bays, MD (Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY)

Dr. Harold Bays presented his “clinical researcher” perspective on the role of PCSK9 in cholesterol homeostasis. He opened by stressing the high prevalence of elevated plasma LDL levels in people with diabetes and the low percentage of patients who achieve their LDL treatment goals. Dr. Bays elaborated on the many barriers to achieving LDL goals. In an informal poll of the attendees, ~30% responded that they manage patients with statin intolerance. Dr. Bays proceeded to discuss the mechanisms of how PCSK9 maintains cholesterol homeostasis by regulating the recycling of LDL receptors, with the rest of his presentation focusing on the genetic models of PCSK9 function in people with either gain of function or loss of function mutations. He ultimately concluded that from a scientific standpoint, PCSK9 plays an important potential role in cholesterol homeostasis, which may include patients with diabetes. We certainly agree – see our coverage of the recent FDA EMDAC meeting on Sanofi/Regeneron’s Praluent (alirocumab) and Amgen’s Repatha (evolocumab) for more.

Type 1 Diabetes Cure Therapies and Pathophysiology

Oral Presentations: Interventions in Inflammation and Diabetes

Durable Efficacy of Alefacept in Type 1 Diabetes (231-OR)

Mario Ehlers, MD, PhD (Immune Tolerance Network, San Francisco, CA)

Dr. Mario Ehlers presented new, two-year data from the phase 2 T1DAL (n=49) trial testing the efficacy and safety of the anti-CD2 agent alefacept in early type 1 diabetes (within 100 days of diagnosis). As a reminder, participants were randomized 2:1 to receive two 12 week courses of either alefacept or placebo. ADA 2013 featured the disappointing news that alefacept did not meet its primary efficacy endpoint of comparative C- peptide AUC from a two hour mixed meal tolerance test at week 52. Fortunately, at two years, alefacept had significantly slowed the decline in C-peptide; the alefacept group’s 4 hour C-peptide AUC fell ~0.1 pmol/ml, compared to the control group’s drop of ~0.35 pmol/ml (p=0.002). The alefacept group required significantly less insulin at two years in order to achieve the same A1c as the placebo group (~7.5%): ~0.4 U/kg/day vs. ~0.6 U/kg/day (p=0.005). Notably, patients in the alefacept group also experienced significantly fewer major hypoglycemic events than those in the placebo group over the course of the study (~9 vs. ~19 episodes/participant years; p<0.001), and this was expanding at year 2 (~8 vs. ~20; p<0.001). In terms of safety, Dr. Ehlers reported that no drug associated SAEs occurred during the trial and that there was no significant difference in AE rates between the treatment groups at year two. During Q&A, an attendee remarked that alefacept seemed too good to be true, and indeed, there is currently a catch. Alefacept had been on the market for psoriasis until a few years ago when it was removed for “business reasons.” Dr. Ehlers reported that work is ongoing to develop a biosimilar, since the Immune Tolerance Network would like to try the agent in combination with a tolerogenic agent (an agent that promotes immune tolerance like anti-IL-6 or abatacept) with or without an antigen-targeting agent.

Questions and Answers

Q: It appears that you have two populations of people in the responders and non-responders. Have you looked at if there were differences in the populations that could explain this?

A: How they differ remains unclear. We think it could be a different group of responders in each study depending on the drug that is used. It could be that with each particular drug there is diversity in the autoimmune processes and some will respond and some won’t. We are performing a responder analysis now. There was a portion of the treatment group that had higher C-peptide than they had at baseline. We’re trying to learn why that happened.

Q: This drug is quite effective and well tolerated. So I am sure you are familiar with the too good to be true rule. Can you comment on what side effects you were expecting and what you saw?

A: In the psoriasis experience there was a small excess of infections. There was some controversy over increased rate of malignancy but they were skin related so it was hard to tease out with a skin condition like psoriasis where there is a higher risk for skin cancer risk to begin with. This was a small study – smaller than we wanted due to the drug being removed from the market. In terms of the tolerability, it was very well tolerated compared to anti-CD3.

Q: I was very impressed with your hypoglycemia data. Did the responders in terms of C-peptide correlate with the responders in terms of hypoglycemia?

A: There was some correlation but only partly. It’s an interesting observation that we don’t fully understand.

Oral Presentations: Making a Difference with Behavioral Science

Impact of Child Antibody Results on Parent Anxiety in the Environmental Determinants of Diabetes in the Young (TEDDY) Study (217-OR)

Suzanne Johnson, PhD (Florida State University College of Medicine, Tallahassee, FL)

Dr. Suzanne Johnson spoke on the impact of positive antibody test results on the anxiety levels of parents in the long-running TEDDY study cohort. The TEDDY study follows 8676 children who were determined to have genetic risk factors for type 1 diabetes at birth and regularly screens them for autoantibodies in order to determine potential environmental triggers for type 1 diabetes. The study also collects psychosocial information and administers the Spielberger’s State Anxiety Inventory (SAI) at least once a year. Dr. Johnson looked at SAI scores of parents whose child never had a positive antibody test, of parents before and after a positive antibody test, and of parents who had completed at least two SAI tests after a positive antibody test. The study also determined whether parents underestimated or had an accurate perception of their child’s diabetes risk. They found that parents of children who never tested positive had decreased anxiety over time. If a child tested positive once, anxiety increased regardless of whether or not the parents correctly estimated the risk of developing type 1 diabetes. Over time, parents who correctly estimated the risk maintained increased anxiety. Those who underestimated the risk and had a child with only one positive test had decreasing anxiety levels over time.

Questions and Answers

Q: I have a couple of questions. Number one is about the ones who are underestimating. What is going on there? Is that simply a denial thing? Number two, did you repeat that assessment or is that a single baseline assessment?

A: No we repeat it. So the first thing we might be interested in is how we even determine that. We use a question – we simply ask the parents “Do you think your child’s risk for type 1 diabetes is the same as, greater, or less than the other children that are not in the TEDDY study. And of course the correct answer is “greater than,” but a remarkable number of people say it’s the same as and even some say less than. This very simple measure turns out to be very powerful – it predicts drop out rate in the study, it predicts compliance, it predicts all kinds of things. But we really spend a lot of time on trying to make sure parents understand the risk. Mothers do seem to understand it better than the fathers. And we repeat it every time their kid gets their antibody test results back: if it’s negative, we say your risk hasn’t changed. I will say in other studies I’ve done, the underestimation actually increases over time. We’re not seeing an increase; it’s very stable across the TEDDY study. So whatever we’re doing is not getting worse. People just have trouble with risk perceptions and understanding risk, it’s very complicated, and it’s a very difficult thing for us to adequately communicate and for people to understand.

Q: Do you have information on who the first generation relative [with type 1 diabetes] was and is there a difference in anxiety level if mom has type 1 or if dad has type 1 diabetes or if it’s a sibling who has type 1 diabetes. Should we be giving these results if there is such a high degree of anxiety and there’s nothing we can do about it.

A: We do know who the first degree relative is. We haven’t seen a lot of difference in anxiety based on who that is yet. I think the question of whether we should tell people or not is an interesting one and something that people wrestle with all the time. I think that in TEDDY, we ended up feeling that in terms of informed consent, people had to really understand what they were getting into and that their children were being selected because they were high risk for type 1 diabetes. We just didn’t feel that not telling them was adequately informing them. Particularly since this is an observational study, this is a study to find a trigger. There are a lot of demands placed on these people and I just don’t think it would be fair to ask them to be in this study without realizing why their child was selected. And I think it might actually be a motivator. I think many people who joined TEDDY did so because they actually are hoping the study will answer that question, find trigger, and result in some better prevention strategies that so far we have been unable to find.

Posters

Effect of Cell-Free Mesenchymal Stem Cells Microvesicles (MVs) and Exosomes Therapy on ß-Cell Mass in Type 1 Diabetes Mellitus (T1DM) (1099-P)

W Nassar, M El-ansary, T Shehab, M Hameed, A Saad, W Essa, S Shawki, M Mohamed, M Temraz, H Adel

This study evaluated the efficacy of treating newly diagnosed type 1 diabetes patients with cell-free cord blood mesenchymal stem cell-derived microvesicles. Because these microvesicles are harvested from umbilical cord blood, which remains in the placenta and the attached umbilical cord after childbirth, the authors suggest that this method offers several key advantages, including no risk to the donor, easy availability, and no ethical issues (perhaps in contrast with other approaches using embryonic stem cells). The study divided 29 patients with type 1 diabetes into two groups; 20 were treated with two doses of microvesicles spaced one week apart, while nine received placebo infusions. After 12 weeks of follow-up, patients receiving microvesicle treatment exhibited significant improvements in A1c levels, fasting C-peptide levels, and C-peptide response, likely due to increased beta-cell function and mass. Significant increases in plasma levels of transforming growth factor beta 1 (TGF-ß1) and interleukin-10 (IL-10) were also observed, suggesting a reduction in autoimmune response. As always, larger studies with longer follow-up are needed to distinguish this treatment from other promising stem cell therapies with proven benefits only in the short term. Surprisingly, no safety data was explicitly provided for this trial, though the authors claim to have found the technique to be safe.

• Out of “more than one hundred patients who were willing,” 29 young, recently diagnosed type 1 diabetes patients were chosen for the study. All patients were diagnosed fewer than five years prior to study entry and had a blood test confirming the presence of at least one autoantibody. Exclusion criteria included clinically significant liver, kidney, or heart disease; pregnancy; immunosuppressive medication; viral diseases; or diseases associated with immunodeficiency and previous treatment with mesenchymal stem cells.
• 20 participants received two doses of microvesicles one week apart, with 9 participants receiving normal saline infusions. The first dose of microvesicles was administered intra-arterially over 10 minutes and the second by intravenous infusion over one hour. The second dose was thought to be important to overcome the expected complexity of cytokine interference in autoimmune modulation. Participants were followed for 12 weeks.
• Participants receiving the microvesicles exhibited improved beta cell function and glycemic control at 12 weeks. A1c levels improved significantly from baseline (6.7% vs. 8.2%; p < 0.034), as did fasting C-peptide levels (1.1 ng/ml vs. 0.2 ng/ml, p < 0.003) and the C-peptide response following an oral glucose tolerance test (1.8 ng/ml vs. 0.5 ng/ml, p < 0.004).
• Plasma levels of IL-10 and TGF-ß1 also significantly increased from baseline at 12 weeks in the treatment group, suggesting a modulation of the autoimmune response. Plasma IL-10 levels rose from 3.9 pg/ml to 13.3 pg/ml (p < 0.001). Plasma TGF-ß1 levels also rose significantly from approximately 3 pg/ml at baseline to 26 pg/ml at 12 weeks (specific numbers and p-value not provided.) Both are cytokines known to play an inhibitory role in autoimmune diseases.

Symposium: Pediatric Dysglycemia—It’s Not All Type 1 or Type 2

Immune Resistance Plus Autoimmunity: Double Diabetes or Type 1.5?

Ingrid Libman De Gordon, MD, PhD (Children’s Hospital of Pittsburgh, Pittsburgh, PA)

Dr. Ingrid Libman De Gordon explained that endocrinologists have used the nomenclature of type one and two diabetes mellitus ever since Etienne Lanceraux first recognized two different types of diabetes in 1877. By comparison, ‘double diabetes’ or ‘type 1.5’ is a new term, first referenced in 1991. Double diabetes has no strict definition, but functions more as a clinical concept in patients with type 1 diabetes who have the characteristics of type 2 diabetes: obesity, a positive family history of type 2 diabetes, high daily insulin requirements, and signs of insulin resistance. Type 1 diabetes is not immune to broader public health trends, and obesity rates at onset have risen along with overall obesity rates across the country — 40% of youth with type 1 diabetes are now overweight or obese. These children with type 1 diabetes present with a typical type 2 diabetes phenotype but with higher insulin sensitivity and lower insulin secretion; they also tend to have high systolic blood pressure and low HDL cholesterol levels. To better understand how to treat ‘double diabetes,’ Dr. De Gordon conducted a study with the T1D Exchange investigating the use of metformin to treat overweight children with type 1 diabetes; results were presented at ENDO in March. Though the trial failed to reach its primary endpoint of significantly greater A1c reductions with metformin at 26 weeks, it did show reductions insulin requirements and in LDL cholesterol (in male children). Ultimately, Dr. De Gordon questioned the usefulness of the type 1 diabetes/type 2 diabetes classification scheme, as all types of diabetes require individualized treatment and, as he put it, “neither diabetes nor obesity cares about nomenclature.”

Symposium: Next Generation of Beta Cell Replacement

Human Pluripotent Stem Cells

Douglas Melton, PhD (Harvard Stem Cell Institute, Cambridge, MA)

In a packed session (even the overflow room was full), Dr. Doug Melton provided updates on his lab’s progress following the publication of its widely heralded beta cell differentiation protocol last fall. Dr. Melton devoted the first half of his talk to the extensive research that went into developing the protocol and the published results showing successful generation of large quantities of insulin-producing beta cells that can successfully ameliorate hyperglycemia in animal models. Excitingly, he shared that the group has made progress even since Dr. Melton’s keynote address at the GTC Diabetes Summit slightly over a month ago: they have now successfully modified the protocol to produce cell clusters with predominantly alpha or delta (somatostatin-producing) cells rather than beta cells. This is an important step toward Dr. Melton’s stated goal of making “an islet of any composition you want” within a few years – a potentially critical achievement for a future cell replacement therapy, as some in the field have suggested that simply implanting cells will not be sufficient from a clinical perspective. Dr. Melton also reiterated his goal of making the 40-day, $6,000/flask procedure faster and less expensive, stating that his team is very confident that this is achievable and has already made advances since the October publication. He concluded by reminding the audience that the long-term goal is to use this differentiation protocol as a drug screening tool and a clinical therapy – the Melton group has reported several key developments on this front in recent months, including a $44 million financing round for startup Semma Therapeutics and partnerships with Novartis and AZ.

Questions and Answers

Q: What is the immune status of the cells?

A: They are identified by the immune system and killed. Even if you make a cell from a type 1 diabetic, their immune system will kill it. Maybe not in type 2 diabetes, but in type 1 diabetes it will be fully immunogenic.

Stem Cell Transplantation for Type 1 Diabetes

Richard Burt, MD (Northwestern University, Chicago, IL) and Carlos Eduardo Barra Couri, MD, PhD (University of Sao Paulo, Sao Paulo, Brazil)

Dr. Richard Burt and Dr. Carlos Couri gave a tag team talk on early clinical data for hematopoietic stem cell transplantation (HSCT) in patients with type 1 diabetes. Dr. Burt first introduced the concept of using HSCT for type 1 diabetes, highlighting preclinical work that suggested improvement in type 1 diabetes in a mouse model following HSCT. Dr. Couri went on to discuss early results from a small and uncontrolled study (n=25) of HSCT in patients with type 1 diabetes conducted in Brazil. In all 25 patients in the study, C-peptide area under the curve (AUC) during a mixed meal tolerance test increased for a period of roughly six years before returning to baseline. Eighteen patients became transiently insulin independent for a mean period of 2.5 years and three patients became continuously insulin independent for a mean period of 9.6 years. Dr. Couri concluded that HSCT may prolong insulin independence or reduce the insulin requirements of patients with newly diagnosed type 1 diabetes, with relapse potentially due to the reinfusion of autoreactive T-lymphocytes.

• Dr. Burt introduced the use of HSCT for type 1 diabetes, highlighting preclinical work. He noted that engraftment of hematopoietic stem cells derived from embryonic stem cells prevented clinical diabetes and induced tolerance to GAD in NOD mice, an animal model for type 1 diabetes (Burt et al., J Exp Med 2004). On the clinical front, he showed that protocols for HSCT in various autoimmune diseases such as multiple and systemic sclerosis have demonstrated strong results, with the suggestion that results may be disease-, patient selection-, conditioning regimen-, and even center-specific. Thus far, clinical studies of HSCT for type 1 diabetes have occurred primarily in Brazil, largely due to difficulties with insurance approval and controversies over embryonic stem cells in the US.
• Dr. Couri presented early results from a small and uncontrolled study (n=25) of HSCT in patients with type 1 diabetes. Patients in the study were <6 weeks from diagnosis, age 12-35, and had positive serum anti-GAD levels. HSCT was performed using a non-myeloablative protocol (that preserves more of the patient’s cells) in hopes of preserving pancreatic functional reserve and maintaining endogenous insulin secretion.
• In all 25 patients in the study, C-peptide AUC during a mixed meal tolerance test increased for a period of roughly six years before returning to baseline. Eighteen patients became transiently insulin independent for a mean period of 2.5 years and three patients became continuously insulin independent for a mean period of 9.6 years. The percentage of patients with peak stimulated C-peptide >0.2 nmol/L (correlated with fewer complications and less hypoglycemia) was 100% at 84 months but dropped to 50% at 96 months. Dr. Couri noted that after adding sitagliptin, three patients who had returned to insulin dependence became insulin independent again, and 11 patients only required a once-daily dose of basal insulin in combination with sitagliptin. Four patients never became insulin independent; three of them presented in diabetic ketoacidosis and one required glucocorticoids during the conditioning regimen. Adverse effects included nausea, vomiting, and alopecia in all individuals in the acute setting, with two patients developing bilateral pneumonia. Late adverse effects included five patients with Grave’s disease, one patient with hypothyroidism, and three patients with oligospermia.
• Dr. Couri concluded that HSCT may prolong insulin independence or reduce the insulin requirements of patients with newly diagnosed type 1 diabetes, with relapse potentially due to the reinfusion of autoreactive T-lymphocytes. Future avenues to reduce relapse will include modifying the regimen to enhance selection and providing a source of beta cell mass, possibly through embryonic stem cells.

New Materials for Islet Transplantation

Daniel Anderson, PhD (MIT, Cambridge, MA)

Dr. Daniel Anderson provided an engineer’s perspective on the design criteria involved in developing a durable islet cell replacement therapy. The key challenge as he presented it is designing semipermeable encapsulation devices that can protect cells from immune attack while still allowing nutrients, oxygen, and insulin to cross in and out. He explained that microencapsulation efforts (forming bubbles around small sets of cells) have traditionally relied on alginate capsules, but those devices have typically prompted an immune response leading to significant scarring and rapid cell death. However, Dr. Anderson’s lab has developed modified alginate devices that can be successfully implanted into mice without attracting significant immune attention. He shared promising new preliminary data from studies in nonhuman primates showing that cells encapsulated in the new devices maintained glucose-responsive behavior for four weeks after transplantation with no signs of an immune response. By contrast, cells in conventional alginate capsules had all died after four weeks and showed significant fibrosis.  Dr. Anderson closed his talk by referring to promising early results from his group’s collaboration with Dr. Doug Melton’s (Harvard Stem Cell Institute, Cambridge, MA) lab: cells produced by the Melton protocol and encapsulated in the Anderson devices successfully corrected diabetes in a mouse model for 175 days.

Questions and Answers

Q: This data was with no immune suppression?

A: Correct.

Q: Your results are very promising in terms of avoiding fibrosis. Does putting capsules in the animals cause chronic inflammation?

A: You can detect the presence of neutrophils after implanting the capsules but you don’t see any toxic inflammation.

Q: Can you share what the new material is?

A: Soon, not yet. We don’t think the key is permeability; we think it’s how the immune system recognizes the device and reducing that response.

Q: We have made capsules for 30 years using conventional alginate and found in patients with type 1 diabetes, soon after retrieval after five years of graft, capsules free of fibrosis. I don’t think it’s a matter of the specific machinery to make the capsules. The problem is the purity of the alginate and the purity of the polymers you use. In the paper you referred to, the capsules were made of barium alginate, which is a very dirty alginate. Our capsules are made with the appropriate composition and I swear they are clean, but you need many years to get them very pure. Your method might be good, but if conventional alginate is purified, it can yield clean capsules.

A: Thank you for the feedback. My advisors are looking at alginate in primates and our own data suggest that conventional alginates don’t lead to clean capsules. I’m not aware of compelling human data yet, but my understanding is there’s a lot of fibrosis. I’m happy to talk about this later.

Q: What is the size of the capsules?

A: The size of the capsule can affect the fibrotic response. These are on the larger side at 1.5 mm.

Dr. Norma Sue Kenyon (University of Miami, Miami, FL): Your group had a paper come out on this just this month that was maybe counterintuitive.

A: Yes, we thought smaller would be better but that was not the case.

T Regulatory Cells

Penelope Morel, MD (University of Pittsburgh, Pittsburgh, PA)

Dr. Penelope Morel detailed the role of T regulatory cells (Tregs) in the development of type 1 diabetes, highlighting novel approaches to using Treg cells to treat and prevent the disease. She opened with a review of the role of Treg cells in the immune system, noting their ability to both directly (via effects on antigen-presenting cells) and indirectly (via cytokines acting in the periphery) mitigate the effects of autoimmune T cells. She underlined the relationship between Treg cells and type 1 diabetes, noting the reported defects in number and function of Treg cells in patients with diabetes and the possible genetic variants contributing to these defects. Preclinical studies aimed at increasing Treg number and function via low-dose antigen exposure have demonstrated a preventive effect in mouse models of type 1 diabetes. In terms of therapeutic strategies, she noted various methods for increasing Treg activity, including injecting antigen to induce antigen-specific Treg cells and performing ex vivo expansion of Tregs to administer to patients. Of the ongoing clinical trials, she felt those using low-dose anti-CD3 and low-dose IL-2 showed the most promise. Moving forward, she suggested studies would evaluate immunological endpoints and biomarkers rather than purely clinical outcomes in order to optimize dose and effect. As a reminder, two examples of ongoing projects in this area, the BCG vaccine and NeoStem’s autologous Treg infusion therapy, were discussed recently in our GTC Bio report.

Questions and Answers

Q: There are concerns about use of in vivo use of Treg cells and loss of function. Do you have any comment?

A: I think it is in the way the Tregs are generated. In the ex vivo studies growing the cells with cytokines we have found that some Tregs are only stable in continued presence of these cytokines. If you use intrinsic T cell receptor signaling pathways you may be able to generate more stable Tregs. That’s one of the main reasons it hasn’t taken off as much.

Symposium: The Gut Microbiota and the Islets – A Toll Road to Diabetes

The Role of Intestinal Microbiota and Innate Immunity in Development of Type 1 Diabetes

Danny Zipris, PhD (University of Colorado Denver, Aurora, Colorado)

In several mouse studies, Dr. Danny Zipris sought to identify bacterial communities potentially linked to type 1 diabetes and elucidate their interplay with toll-like receptors (TLRs) that play a role in the immune response. In the first study, he found that the TLR3 pathway, not the TLR9 pathway, was crucial in the development of diabetes. In the second study, Dr. Zipris proposed a new model for how manipulating gut microbiota may induce regulation and prevent disease development. Several lines of evidence support this model, such as the observation that certain gut microbiota profiles have protective roles in the RIP-B7.1 strain of mice. In addition, mouse strains susceptible to diabetes have different gut microbiota profiles than mouse strains resistant to diabetes.  Although these results present strong evidence of a two-way link between gut microbiota and diabetes, the specificity of the mouse strains, the small sample sizes, and the scarcity of human trials make us cautious about drawing sweeping insights.

Questions and Answers

Q: What about gut microbiota in humans? Can manipulation of the bacterial genera produce results?

A: We have conducted several human studies in Colorado and Europe. Although there are promising results regarding gut microbiota manipulations, the data are not similar across the two regions. There may be several factors, such as geography and diet, which influence these differences. As a result, we must conduct more studies to discern these differences.

Defining the Autoimmune Microbiome in Type 1 Diabetes

David Endesfelder, PhD (Helmholtz Zentrum Munchen, Munich, Germany)

Dr. David Endesfelder made the case that the gut microbiota communities associated with early islet autoimmunity development might be tied to the early introduction of solid foods. The BABYDIET study enrolled 150 infants with a first degree relative with type 1 diabetes. Of these infants, 22 developed islet autoantibodies. These children were matched by date of birth with 22 islet autoantibody negative children. Dr. Endesfelder found that islet autoimmunity development was most common in a subgroup of children with high abundance of Bacteroides (a bacteria that has repeatedly been associated with type 1 diabetes in the literature) and low abundance of Akkermansia. About 60% of children with this gut composition (who also tended to have high risk HLA genotypes) developed islet autoantibodies over the first two years of life (HR=2.8 [1.1-7.1], p=0.021). Unsurprisingly, microbial community composition was strongly influenced by dietary factors, particularly whether the child was breast fed or eating complex foods (i.e., a diet of varied soft or solid foods). In particular, the early introduction of solid foods was associated with the increased abundance of Bacteroides and decreased abundance of Akkermansia that was associated with an increased risk for developing islet autoantibodies. Of note, the timing of gluten introduction was not significantly associated with the children’s gut microbiota composition.

Questions and Answers

Q: How were samples collected?

A: They were collected at home. Stool samples were collected at home and shipped by express courier overnight to the clinical study center where they were processed and immediately frozen. Transport times tended to be lower than 72 hours, but sometimes were higher. That could have had an impact.

Q: Did you find any correlation with number of autoantibodies?

A: No we did not find anything, but I know other studies did.

Q: Do you have an inference for the impact of HLA genotype on your findings?

A: We did not find an association with HLA genotype. All of the kids in the study have high-risk HLA genotypes. Maybe we need larger sample sizes. We only had 22 kids, and among them there were three different HLA genotypes.

Q: Did you find an association with the introduction of gluten?

A: We did not find an association with gluten introduction.

Gut Microbiota, Incretins, and Glucose Metabolism

Patrice Cani, PhD (INSERM/UCL, Brussels, Belgium)

Dr. Patrice Cani explained how, in rodents, prebiotics (compounds that induce the growth and/or activity of specific gut microorganisms and have a beneficial effect on health) help to decrease fat mass and increase glucose tolerance in part through their indirect stimulation of GLP-1 secretion. Prebiotics help to drive the production of short chain fatty acids, which in turn increase the production and secretion of GLP-1. Further, rodent knockouts suggest that the insulin sensitizing effects of prebiotics are largely dependent on this GLP-1 pathway. Additionally, Dr. Cani presented rodent data suggesting that the bacterium Akkermansia muciniphila has a beneficial impact on glucose tolerance and fat mass gain. He also noted that NAPE-PLD enzymatic activity, which plays a role in the conversion of specific bioactive lipids into chemical messengers, influences rodent metabolism.

Symposium: Non-Insulin Adjunct Therapies in Type 1 Diabetes

Targeting Hyperglucagonemia in Type 1 Diabetes (Pramlintide, GLP-1 Agonists, DPP-4 Inhibitors)

Nitesh Kuhadiya, MD (University at Buffalo, New York, NY)

As part of a packed symposium on non-insulin adjunct therapies, Dr. Nitesh Kuhadiya explored therapies that can target hyperglucagonemia in type 1 diabetes. He opened by first discussing the role of glucagon in uncontrolled type 1 diabetes, stressing that even patients with decent A1c values can experience excessive postprandial glucose fluctuations and nocturnal hypoglycemia due to excessive postprandial glucagon not corrected by exogenous insulin. Dr. Kuhadiya examined the potential of pramlintide, GLP-1 agonists, and DPP-4 inhibitors as strategies to target this phenomenon. He noted that pramlintide reduces postprandial glucagon and slows gastric emptying but did not frame it as an ideal choice due to the need for injections at every meal and the association with nausea. He also presented data suggesting that DPP-4 inhibitors produce relatively unimpressive effects that diminish over time. On the other hand, Dr. Kuhadiya highlighted GLP-1 agonists as a class with significant potential to reduce postprandial glucagon levels with much less nausea compared to pramlintide. He stated that liraglutide (once daily injection) and exenatide (twice daily injection) have been the most studied GLP-1 agonists with regard to hyperglucagonemia but that once-weekly formulations need to be better studied in type 1 diabetes. Notably, Dr. Kuhadiya ended by briefly referring to insulin/GLP-1 agonist/SGLT-2 inhibitor triple therapy, which he believes needs further investigation but may have significant potential to reduce glycemic excursions in type 1 diabetes. We saw encouraging results from a small retrospective study of this combination at this conference and look forward with great interest to future randomized controlled trials.

Questions and Answers

Q: I was wondering about the different types of GLP-1 agonists based on half-life.

A: There have been studies done on liraglutide and exenatide. Both have shown clinical benefit. One is shorter-acting. You also get other good benefits on liraglutide. Preliminary studies conducted on once a week in type 1 diabetes have shown reductions in A1c and insulin requirements. What needs to be looked at is the suppression of glucagon with once-a-week GLP-1 and I don’t think that’s been done so far yet.

Q: Can you comment on the adverse event profile in type 1 diabetes vs. in type 2 diabetes?

A: It’s very similar for GLP-1 in both. There’s nausea at the time of initiation of the study and for two to three days of escalation. It’s very similar to what we’ve seen in patients with type 2 diabetes.

Symposium: Clinical Updates and Looking to the Future in Beta Cell Replacement

Clinical Islet Transplantation Update

Camillo Ricordi, MD (University of Miami, Miami, FL)

Dr. Camillo Ricordi spoke to a full room about new developments in islet transplantation. Though traditional islet transplantation techniques have improved slowly over time, there are many regulatory and cost impediments to the development of a cure. Unfortunately, after the initial creation of the Edmonton Protocol, it was realized that islet function eventually decreased and beta cells failed.  The Clinical Islet Transplantation Consortium is making steady progress advancing islet transplantation through clinical trials and obtaining licensure for an islet product for use in patients with type 1 diabetes and severe hypoglycemia, glycemic lability, or a kidney transplant. The CIT-07 islet transplantation protocol is currently being investigated in a single-arm, multi-center phase 3 study in 48 patients with type 1 diabetes. Patients will receive up to three separate infusions of islets within eight months and will be followed for at least 24 months. Dr. Ricordi reported that all 48 subjects have reached the one-year follow-up point for primary endpoint evaluation, though he did not present any of the primary results since the manuscript has not yet been published. We saw a sneak peek of some data from this trial at Rachmiel Levine in March showing significant reductions in insulin dependence, hypoglycemia, and glycemic lability after one year; publication of the full results is expected in mid-2015.

• Throughout the course of the trial, 18 patients experienced 29 serious adverse events (SAE); however, no SAE resulted in death or disability. Of the 29 events, only five were directly related to the transplant procedure. The majority of complications resulted from immunosuppression (n=13) or were unrelated entirely (n=11).

Islet Transplantation: Critical Pathways Forward

James Shapiro, MD PhD, (Alberta Diabetes Institute, Edmonton, Alberta, Canada)

Dr. James Shapiro spoke to a packed audience on novel approaches to islet transplantation. According to Dr. Shapiro, persufflation (gaseous oxygen perfusion) during pancreas preservation is important to maximize viable islet yield for each organ. As this technique is not widely used in current practice, there is a scarcity of suitable human pancreases available for islet transplantation. In addition to new techniques in pancreas preservation, Dr. Shapiro also discussed novel sites for islet graft implantation. Up to this point, the vast majority of islet transplants have been performed percutaneously into the portal vein system. Although this system approximates physiologic insulin delivery, it also exposes islets to an instant blood mediated inflammatory reaction (IBMIR).  Anticoagulation therapy with heparin has helped to reduce the impact of IBMIR and improved the success rate of islet engraftment. Still, while the portal site remains the most common islet habitat, it is certainly not without complications such as bleeding and portal vein thrombosis. Researchers are exploring other promising transplantation sites such as gastric submucosal space (GSMS), where after endoscopic placement, islets would benefit from a rich blood supply. According to Dr. Shapiro, islet encapsulation devices may be another approach to successful islet implantation. Both micro- and macroencapsulation devices could provide a secure oxygen and nutrient-rich environment for islets, while potentially affording a degree of immunoisolation. Such efforts have met with little success up to this point, but several projects including ViaCyte’s VC-01 and Beta-O2’s bAir device have shown promise and are currently undergoing clinical trials.

Closing the Loop and Insulin Delivery

Working Group on the Psychosocial Aspects of the Artificial Pancreas

This valuable workshop on the artificial pancreas was headlined by patient-friendly optimism from FDA’s very impressive Dr. Stayce Beck; caution from the renowned endocrinologist Dr. Anne Peters; a balanced industry perspective from consultant Marie Schiller; and a surprising and distressing lack of payer awareness about type 1 diabetes and what severe hypoglycemia actually costs. Though the workshop was technically focused on the psychosocial aspects of the artificial pancreas, it really hit on a wide diversity of perspectives addressing the real world challenges as products advance to commercial readiness.

Payer Perspective

Aaron Davis (Partner, Jupiter Life Science Consulting, Los Angeles, CA)

Mr. Aaron Davis gave one of the most insightful closed-loop presentations of ADA, summarizing primary payer research (n=10 US payers, medical and pharmacy) from Metabolic Markets (2014). The results were fascinating, indicating virtually non-existent payer understanding of severe hypoglycemia (mostly anecdotes, since there is no real data); major lack of consensus on unmet needs in type 1 diabetes; considerable payer frustration over type 2 diabetes; and little understanding of the different insulin pumps. Mr. Davis said that payers are in a challenging spot right now, as spending has increased but outcomes have only modestly improved. From our recent conversations with payers, we know the challenge has increased from some elements of healthcare that have nothing to do with diabetes, such as the unexpected costs of drugs related to other illnesses like hepatitis C. Notably, Mr. Davis urged the audience to more effectively communicate who is likely to benefit the most from a new technology. A direct payer quote on the type 2 slide was particularly striking: “[The] unmet need is not more therapies. Our problem is getting patients to comply and doctors not letting patients “alibi” out of it.” [While we wouldn’t put it exactly like this, we do believe that lack of attention to behavioral elements of diabetes, along with mental health challenges (not just depression but “distress” as characterized by Dr. Bill Polonsky and friends) make it very challenging for patients to adhere to a complex set of drug, technology, exercise, and food goals. We are not particularly surprised to hear HCPs say they can’t control all of this, though we haven’t heard the phrase “alibi out of it” before – that’ll go down in our books! We do think creating more resources for coordinated and integrated care is critical, and technology-related tools could play an important role in scaling the success of HCPs.]

• “Payers recognize hypoglycemia risk, but don’t know the details very well.” Mr. Davis said that payers understand severe hypoglycemia is dangerous and costly, but there is no data beyond anecdotes to understand the issue. Payers believe the severe events in type 1 are likely small in numbers, but can be a significant cost per event. Direct quotes from the research:
  
  • “Plans may underestimate hypoglycemia. I led a team looking at the issue a few years ago. We were asking what hypoglycemia events cost, and we really don’t know.”
  • “There is more hypoglycemia risk in type 1, but I don’t have any data for type 1s. I appreciate that it can be disastrous, but I don’t know what we can do about it.”
  • “Hypo is a big risk, which is where education comes in. But what is my absolute risk. If I have a million member plan, how many severe hypo events will I see in a year?”
  • Payers sound like they do not speak to patients or HCPs very much, or assess records from emergency rooms. It also sounds like they are not aware of the T1D Exchange research on this issue.
• Mr. Davis believes there is “low payer understanding” of type 1 diabetes. We were glad he was so candid about this; in particular, he cited primary payer research (n=10 US payers, medical and pharmacy) from Metabolic Markets (2014) that asked, “When thinking about type 1 diabetes, what are the unmet needs?” Notably, more payers said “no unmet need” (n=3 mentions) than “no cure” (n=2) – a stark reminder of the lack of consensus and knowledge around type 1. The rest of the responses were equally distributed across the board: closed-loop (n=3); better insulins (n=2); postprandial glucose issues (n=2); need to simplify (n=2); avoid hypoglycemia (n=2); improved infusion sets (n=1). He did not offer many details on the methodology, but presumably the 10 payers could make more than one choice, as there were 17 responses. We were quite surprised to see that 30% of the payers actually said there is “no unmet need” in type 1 diabetes, despite all the spending on total cost of care. It was also notable to see three votes for the closed loop as an unmet need – though we would love to see an artificial pancreas, we’re not sure it fits the category of “unmet need” at this point. To the list we would add clinical decision support (e.g., how much insulin to take), mental health/distress, and overworked/underpaid healthcare providers.
• In type 2 diabetes, “the payer community is more direct, but they are challenged.” Regarding a similar question– “What are the unmet needs in type 2 diabetes?” – responses bucketed into just three areas: compliance (n=6); clinical inertia (n=4); and arresting the disease (n=2). Again, it was distressing to see what was not mentioned: medication side effects, overworked/underpaid HCPs, the behavioral challenges/stigma for type 2 patients, or lack of access to care.  Mr. Davis noted that this payer view of type 2 diabetes has been very consistent over the years. However, payers are now grappling with increased spending and only modestly improved outcomes – presumably they are also not feeling great about the increased exposure (much higher number of patients) and the fact that patients overall are living longer and costing the system a great deal of money. Overall, Mr. Davis said there is “considerable payer frustration in type 2 diabetes.” From this conversation, we understand why payers would be nervous – just the number of patients – but to say there is “considerable frustration” is unfortunate, since there is no shortage of ideas to try.  
• Payers want to know more about advances in insulin delivery beyond features/benefits. However, there is said to be generally a limited (or low!) understanding of the different pumps available today, and payers see little differentiation among pumps from an outcomes perspective. The latter is unsurprising to us, since most of the companies have not done studies to show the different outcomes. Some verbatim quotes from the payer research included one that was quite enthusiastic about the closed loop:
  
  • “I’m very interested in what’s going on with the artificial pancreas. We will be wiling to pay for it with a few caveats: like proper patient selection and knowing who are the right doctors to support it.”
  •   “The usual key questions come to mind: do we get better outcomes than with the existing technology – my hypothesis is yes, but what’s that incremental benefit vs. the increased cost?”
  • “We recently did a survey of our insulin pump patients. 50% didn’t understand key pump features. We want to know more about what is going on with this technology.”
•  “Payers are under an assault of new technologies all the time. If we don’t communicate who are the best patients, they will take the path of least resistance: I get to choose.” Mr. Davis urged the audience to communicate who is best for a new technology. Payers will base coverage decisions on who benefits the most based on the available clinical data.

Artificial Pancreas – The Regulatory Approvals Perspective

Stayce Beck, PhD, MPH (FDA, Silver Spring, MD)

FDA’s Dr. Stayce Beck gave a very positive talk on the potential of incorporating patient perspective into approval of artificial pancreas systems. She highlighted a new Draft Guidance on Patient Preference Information (released in May) – notably, such information could support labeling claims and meaningfully affect the risk-benefit assessment of closed-loop systems. The document explains what manufacturers should consider when choosing to collect patient preference information, as well as how such information can be incorporated into device labeling for patients and HCPs. It sounds incredibly exciting the direction that this could take; Dr. Beck said there are “lots of ways” to incorporate such information into regulatory decisions – for example, scared parents waking up multiple times at night to test blood glucose vs. an automated system that eliminates overnight hypoglycemia but raises A1c by 0.5%. It’s fantastic to hear the FDA speaking this language, which parallels the Agency’s highly encouraging February blog post on the approval of EnteroMedics’ implantable obesity device (“Listening to Patients’ Views on New Treatments for Obesity.”) We had been encouraged by that approach, though do not see that as a product that will be embraced by HCPs or patients – the AP is of course much different. We believe patient-reported outcomes will be key for closed-loop devices, since burden reduction is a major benefit of AP systems that should be incorporated into regulatory reviews – to what extent it will be weighed vs. harder outcomes will be interesting to see. Dr. Beck also said in Q&A that the FDA doesn’t have any preference on whether an artificial pancreas algorithm runs on a phone or pump; the former is more challenging, however, since the software mitigation and testing is much greater – still, this represents another sign of a forward-thinking FDA, for which we are very happy. It’s also another sign to us how the FDA drug side is so much different from the device side.

• “We are interested and open to incorporating patient preference information. But it must be done in a validated, quantifiable way.” There’s often a lot of “anecdotal evidence” on patient preferences, which is challenging for the FDA – “We’re a science-based agency, and we must make decisions that are defendable and based on scientific, quantified, validated data.” Interestingly, she said that companies sometimes don’t meet their endpoints, and at the last minute, appeal to patient preference information. Dr. Beck cautioned against collecting such information after studies end. To aid sponsors in collecting valid patient preference information, the agency has released three guidance documents:
  
  • May 2015: Draft Guidance on Patient Preference Information. 
  • November 2013: Draft Guidance on Medical Device Development Tools (MDDTs). This is a pilot program for FDA qualification of tools like patient-reported outcome assessments. MDDTs can be qualified for a specific context of use, and the Agency is currently accepting proposals.
  • December 2009: Final Guidance on Patient-Reported Outcome Measures.
• Dr. Beck highlighted the recent approval of EnteroMedics’ implantable weight loss device as an example of incorporating patient preference information – see our detailed report on the Blog Post, “Listening to Patients’ Views on New Treatments for Obesity.” We were impressed at the time, as the device lacked efficacy, but patient perspective played an important in getting approval. We don’t know enough about the advocacy effort, however, we don’t expect this product to be particularly commercially successful – we would want to make sure that patients do not receive any blame for the product not doing well.

How Can We Manage Expectations And Support HCPs To Provide Optimal Support For AP Systems In Routine Care?

Anne Peters, MD (USC, Los Angeles, CA)

Dr. Anne Peters provided a cautious HCP perspective on closed-loop systems (not hers), fearing clinicians may not be equipped to handle the technology: “Why adopt a largely unproven, highly complicated, very expensive, potentially dangerous technology” when most patients turn down CGM, when most providers don’t download BGMs, and when many people with type 1 are doing okay on current therapies?” Dr. Peters showed a metaphor to illustrate the point – a humorous video of a self-driving car that goes awry (an artificial pancreas), leaving the car’s passenger (the HCP) completely helpless and frightened. It was a hit with the crowd and accentuated two of her final points: (i) lack of fellowship training in diabetes technology; and (ii) a responsibility question mark when things go wrong with systems (Device manufacturers? AP researchers? Endocrinologists? CDEs?). Dr. Peters’ concluding thought in Q&A summarized her experience fighting for patients, but also caring for the underserved in LA: “I’ll offer the artificial pancreas to everyone once we have it. I’ll fight like crazy for them to get it. The magic is in the people who will need it the most. But they’re not going to be the first to get it.” We do ask what “doing okay on current therapies” means and whether that is using A1c only or other points as well. 

Challenges and Opportunities from an Industry Perspective

Marie Schiller (Schiller Advisors, Boston MA)

Type 1 advocate Marie Schiller shared an industry perspective on closing the loop, discussing key challenges and opportunities. On the bright side, the technical/development/regulatory risk is starting to decline, she said, though companies seem to be struggling with the business/revenue model. Ms. Schiller does not believe closed-loop systems will command a premium – “You either have to be at par or charge less.”

• Key opportunities:
  
  • Technical/development risk is starting to decline: The regulatory path is “more fleshed out,” she said, in large part thanks to efforts from JDRF and HCT.
  • Ability to have a greater impact. “Management teams get it – they see patient views.”
  • Capture MORE patients for longer periods of time: If closed-loop systems are prescribed right upon diagnosis, companies can put patients on systems sooner. Ms. Schiller ballparked US pump penetration at “somewhere in the 35-50% range” in type 1 (we haven’t heard that high end before), and “not at all” in type 2 (at DTM 2014, Dr. Bruce Bode estimated that there are ~100,000-150,000 type 2 pumpers in the US). Ms. Schiller estimated a potential artificial pancreas market of ~ 8 million patients on basal-bolus MDI regimens in the US, Canada, and the EU markets combined (“A big opportunity”).
  • Increased revenue from new components: Ms. Schiller used the term line extensions” to suggest companies adding new closed-loop products to what they currently offer.
  • New business models: As an example, Ms. Schiller highlighted Medtronic’s recent split into three business units: one is service and solutions, while the others are intensive- and non-intensive diabetes management. Closed-loop systems bring an opportunity to create new business opportunities beyond just selling hardware, she said. This is also how the Bigfoot Biomedical team has talked about their automated insulin delivery system.
• Key challenges:
  
  • Technical: CGM accuracy, concentrated insulin, risk mitigation.
  • Cost of goods sold and business models: Ms. Schiller characterized “the ideal product” as a system with the lowest possible cost that can provide the most value. She said closed-loop systems will “probably not” command a premium. Though medtech has made money on premiums in the past, “We cannot do that any more. You either have to be at par or charge less.” Ms. Schiller said that building a revenue model is extremely challenging and “industry is struggling a bit” with it.
  • Regulatory and Integration: Bringing all the components together is challenging, as the FDA considers artificial pancreas products a “system” – pump, CGM, algorithm, meter, human interaction. Aside from Medtronic, this is not something that companies have the infrastructure to internally take on. Later, Ms. Schiller called the necessary collaborative effort “one of the biggest hurdles.”
  • Portfolio considerations: Drug delivery units in companies are often not specific to one therapeutic area. For instance, an infuser could be used in rheumatoid arthritis, cirrhosis, and other disease areas. Something that is best for diabetes might not be best for other areas. This is an interesting perspective we had not heard before, though we’re not sure it applies to most of the pure-play diabetes organizations working on the artificial pancreas – the exception is Medtronic, though they clearly have a very specific roadmap ahead. 
  • Greater competition. More than ever, there are a range of companies looking to bring hybrid closed loop system to market in the 2017-2018 time frame.
  • Features and IP: Closed-loop algorithms are complicated, and companies must decide how they’re going to design from user and IP perspectives. 
  • Outcomes: Payers go by A1c only, unless companies can prove why other outcomes matter. We’d note that this has changed on the regulatory side, as the final artificial pancreas guidance does accept time-in-range as a valid endpoint.
  • System/Physician economics: Going into a physician’s office, there must be a clear value proposition as to how the economics of an office will change once automated insulin delivery is available. “We need to go out and do a full systems review. We need to build those outcomes into our studies. For example, when I go out on Ed’s system, I spend 10 minutes with a patient instead of 20 minutes. The system costs 10% more, but we just saved you 30%. Every time we ask a clinical question, we need to ask an economic question.”
  • Distribution models. Ms. Schiller highlighted that regional differences are especially key.

Panel Discussion

Dr. Henry Anhalt (T1D Exchange, Boston, MA): I really enjoyed your presentation, Stayce. How do you balance scientific evidence vs. patient preference information? Does that just come down to a label discussion? If you talk about change in A1c going up, but a decrease in psychosocial burden, how do you weight one against the other?

Dr. Beck: We haven’t approved an artificial pancreas device, so we haven’t put it into practice. We’re talking a lot internally. It depends on what the study is and what the investigator is saying the device can do. Are you saying that with an artificial pancreas, you don’t ever have to think again about diabetes? Or just that it can minimize hypoglycemia? We’re having conversations and talking about it before hand. I always recommend to sponsors, “Come early, be loud, and stay late. Come talk to us about it before you start the study, so you really are actively looking at it.”

Dr. Katherine Barnard (University of Southampton, UK): data. What data do you need?

Dana Ball: We recognize that we need validated standardized tools to measure what we think we’re going to need to get approval. We need to build a body of evidence to support patient and clinician needs. The Trust has projects to fund the development of quality of life scales across all stages – the pediatric setting, young adults, and older adults. We have to think very carefully and tailor tools – it’s not going to be a one-size fits all approach. It’s a two-prong approach – collect the data in a good enough way, and at the same time, work as a community to create new tools.

Q: There is a balancing act between usability and cost. Would the FDA approve anything less than perfect?

Dr. Beck: Definitely. Let’s not let perfection be the enemy of good. We don’t expect this will be a perfect device. We do want to look at the risk profile. When it isn’t going to work, are there mitigations that can be incorporated into the device? For instance, when the device goes offline or when devices aren’t communicating, it slips to open loop and maintains basal levels. We need to build that into the system to keeps disaster away. But it doesn’t have to be perfect.

Dr. David Kerr (Sansum Diabetes Center, Santa Barbara, CA): I’m nervous that the artificial pancreas is going to be a California hipster technology. And the majority of people who will benefit will struggle to access it.

Dr. Anne Peters: The most needy patients are my underserved patients, and they don’t have access. The mortality rate is much, much higher. People don’t have enough money for food. The ones who are going to use it [artificial pancreas] are the early adopters – they fight me for technology. One of my patients was in the LA Times in an article about Afrezza. She loves it. She’s a type 1 on an insulin pump and has an A1c of 6.8%. There is nothing about her that makes me to put her on another drug. She convinced me that she wanted it. She believes it helps her life. I cannot predict who that’s going to be. People self-select. I’ll offer this [artificial pancreas] to everyone once we have it. I’ll fight like crazy. The magic is in the people who need it most. But they’re not going to get it first.

Dr. Kerr: Who is the ideal population for a pivotal study?

Dr. Beck: Everybody. We don’t necessarily want you to pick people with a 7-9% A1c, no complications, and no cardiovascular problems. In a study, you see who it does and doesn’t work for. Maybe it’s not appropriate for someone with a low A1c. Maybe it is, but that’s part of the purpose of the pivotal study – to determine who should use the device and if there are certain populations that shouldn’t. You would label the device with that information and why it shouldn’t be used in those populations.

Mr. Davis: From a payer perspective, the payer world is looking for guidance about who is the right patient for this type of technology. Absent guidance from industry and thought leaders, they get to define it. The opportunity right now, as data is developing, is identifying who is the best fit. We need to start to decide now who is the most appropriate population. Otherwise, the payer community gets to decide that for you.

Q: What are you current thoughts or concerns on phones controlling artificial pancreas systems?

Dr. Beck: We get asked this a lot. The FDA doesn’t have any preference on whether the algorithm is in a phone or the pump. What we do have preference for is that whatever is controlling it is tested and looked at in different ways. The phone has different risks than the pump. There might be a technological way to deal with the risks, but we do have to think about a lot more things. What about a phone call? What if I’m playing Candy Crush? What if i don’t get text messages – that would be a problem. The artificial pancreas system needs prioritization in the phone. Some of that has to be worked out with phone companies. It’s thinking through those situations and ways to address it.

Dr. Jill Weissberg-Benchell (Children's Hospital of Chicago, IL): I have a patient needs question. If I’m a three-year old, what I might want is fundamentally different from a 13-year-old, from a college student, from a 60 year-old. How do we move forward if everyone needs something different?

Ms. Schiller: We’re not looking at the label as an approved artificial pancreas for kids 6-9 years old, females, with an A1c 8-9%, and both parents at home. [Laughter] But Aetna might. That’s what industry is doing – obviously looking at target product profiles and target patient populations. Sometimes you start seeing it fall to the lowest common denominator.

Mr. Davis: It’s a very good question, and a very important one. One example of payer policies is what I showed for BCBS Alabama and Aetna. For sensor-augmented pumps, it said if you hit our pump and CGM policy and you’re over 16, we’ll approve this. They probably pulled age 16 out of the air. Somewhere, someplace, 16 seemed right. Is that the right person? There might be no guidance and no data to support it. Back to the original question – if it’s approved for people with type 1 diabetes, it’s on the manufacturers and community to say, “This is the right technology for everybody.”

Dr. Firas El-Khatib (Boston University, MA): I’m struggling with the idea that the FDA could potentially approve an artificial pancreas driven by a phone, provided risk is mitigated on the phone. How do you deal with that? We all have phones. But this is a fluid situation. The phone gets approved and risk is mitigated, but then the phone changes if it is personal phone. If it’s not and you lock and freeze the phone, how useful is it to carry another phone? This can turn tragic quickly if another app fringes on one, or there is an update to the phone, or the phone company releases the next phone.

Dr. Beck: I didn’t say it was easy. We’re open to the idea. Personally, I would prefer to carry around one phone. I agree that there are lots of challenges, and how the realities of it would work or not. There are ways that you could work with the phone companies to do some testing. If you’re one of their developers, there is some way to go through a pre-specified test program. We are open to that idea of setting a pre-specified test plan. A lot of it is about system setup. I still haven’t updated from iOS 6 to 8 – I don’t have enough memory on my phone left to do it. Maybe there is a way to make it so it stops working and can only do open loop.

Dr. Aaron Kowalski: This is an important topic. We’re going to butt up [i.e., max out] on the ability to improve glycemic control with artificial pancreas systems. The driver will be form factor and minimizing the burden of wear. The phone is an obvious component. Marie and I often discuss this, “Where will people with diabetes be willing to take the risk for the benefit of a reduction in burden?” I think we coddle people with type 1. Bryan Mazlish’s wife and son have been using an artificial pancreas running on a phone for two years. How much do people with diabetes want it? What are the mitigations you can build in? The person with diabetes should have some voice in there.

Ms. Schiller: Today, I’m all open loop. If I can have four hours and then the phone shuts down, it is incremental benefit.

JDRF/NIH Closed-Loop Consortium Meeting: “The Last 100 Yards”

This invite-only annual meeting brings together closed loop researchers and industry for learnings and nuanced discussion on the state of the field. The evening began with JDRF’s Chief Mission Officer/VP of Research Dr. Aaron Kowalski, who shared a comprehensive overview of AP highlights from the past year. Subsequently, Drs. Roman Hovorka (Cambridge), Boris Kovatchev (UVA), Steven Russell (MGH/BU), and Moshe Philip (Schneider Children’s Medical Center) presented their plans for large efficacy studies of artificial pancreas systems – these proposals are summarized in a table below. A panel discussion followed, including added representation from FDA, Medtronic, Animas, and Dexcom. A panel of providers, patients, and payers closed out the night, sharing perspectives on expectations and adoption of artificial pancreas systems.

The Last 100 Yards

Aaron Kowalski, MD (JDRF, New York, NY)

Dr. Aaron Kowalski opened the annual JDRF/NIH closed-loop night (“The Last 100 Yards”) with an inspirational, gracious, and passionate lecture. His impressive 20-minute review provided a comprehensive summary of closed-loop progress from ALL the major players in the field – Stanford, UCSB, Barbara Davis Center, Bionic Pancreas, DREAM, UVA, and Cambridge, just to name a few! He turned to running for an analogy, opening his presentation suggesting that a commercialized hybrid closed-loop has the finish line in sight and must make the most of its final adrenaline rush to drive at the nuanced questions that remain. The field, in his view, has demonstrated technical feasibility in all six stages of the JDRF roadmap, but is left with commercialization questions regarding adoption and reimbursement. His words were a reminder that improving patient outcomes – reducing burden and simultaneously improving glycemic control and hypoglycemia – is both the great challenge and the great promise of this technology. Dr. Kowalski declared emphatically that “the standard of care right now is completely unacceptable!” He cited very impactful data on overnight PLGS presented by Dr. Bruce Buckingham earlier at ADA – the 3,000+night study showed that those in the control arm were spending 5% and 8% of nights (depending on the age group with a glucose <60 mg/dl for two hours or more. PLGS reduced that to just 1% and 3%, respectively. Said Aaron, “This data has really motivated me. It is really powerful.” There are major hurdles ahead, but Dr. Kowalski was optimistic in thinking about the challenges that remain ... or in his words, this footrace’s “last 100 yards.”

• Dr. Kowalski provided a comprehensive look of closed-loop progress from ALL the major players in the field. He broke down his analysis both by the academic groups involved in closed-loop research and the major sites playing home to studies. We bring you his summary below:

Major Players in Closed-Loop Research

Group/Site	Recent Work/Progress
UVA (DiAs)	12 research centers around the world 3 control algorithm implemented: USS Virginia, RCM (Pavia); Zone MPC (UCSB) 320 people with type 1 diabetes participating in multi-center clinical trials 118,470 hours (14 years) of DiAs system use Overnight CLC in Outpatient and Home Setting (with NIH) Multicenter Outpatient Control-to-Range (JDRF CTR3)
Stanford	Hotel based studies to evaluate initial settings in the Medtronic MiniMed 670G hybrid closed-loop system Detection of Sensor and Infusion Set Failure Control-to-Range Multicenter study of prolonged outpatient use of a closed-loop system Predictive Low Glucose Suspend Bionic Pancreas DiAs Advisor to restore hypoglycemia unawareness Use of CGM, Closed-loop systems and Behavioral Support in Toddlers Probabilistic Closed-loop Control (MMPPC) to Handle Unannounced Meals Control-to-Range Closed-loop in a Diabetes Camp Setting Development of a drug eluting infusion set 670G in a diabetes summer camp – 2014 (Medtronic) 640G for predictive low glucose suspend (Medtronic) Extended wear infusion set (Dexcom)
UCSB/Sansum	Semi-automated artificial pancreas with MannKind’s technosphere insulin Control to Range @ Home PID vs. MPC Clinical Trial Risk Mitigation and Fault Study Fault Detection with Stanford RO1-DK085628: Exercise detection and classification DP3-DK104057: Pediatric design and evaluation (UCSB & Yale) DP3-DK101068: Implantable artificial pancreas AP Database
Yale	Closed-loop work with: Insupatch; hyaluronidase; liraglutide; SGLT2 inhibitors, dual SGLT1/2 inhibitors; Hotel Study (with Stanford and BDC) Exercise/Snacking Study Young Child closed-loop study (with UCSB) Collaborations in Development: Princess Margaret Hospital; Schneider Children’s Hospital; University of Cambridge; Illinois Institute of Technology
Montréal/McGill	Pump vs. dual hormonal vs. single hormonal Dual hormonal vs. single hormonal Closed-loop and carbohydrate counting
Oregon Health and Science University	Bihormonal artificial pancreas research
Illinois Institute of Technology (Ali Cinar)	CGM fault detection Exercise classification module Module for detecting rapid glucose increases and insulin bolusing
Cambridge	Three free living studies completed Two home studies underway One home study in preparation
DREAM	Closed-Loop Studies At Home Over the weekend 60 hours at home study ongoing Two weeks 24/7 closed-loop at home ongoing 3 Months overnight closed loop study at home ongoing
Australia (Dr. Tim Jones)	Australian at Home Overnight Closed Loop Study Predictive Low Glucose Management RCT Home Trial Hybrid Closed Loop (Medtronic) in free living conditions at home
AP@home	2x2 month dinner-to-breakfast home trial 2x3 month 24/7 home trial
Bionic Pancreas	Insulin + glucagon vs. insulin-only set-point study (MGH) Insulin-only set-point study (Stanford) 12-month Pivotal Study

Large Efficacy Studies for Artificial Pancreas Systems

Moshe Phillip (Schneider Children's Medical Center, Petah Tikvah, Israel), Steven Russell (MGH, Boston, MA), Roman Hovorka (University of Cambridge, UK), and Boris Kovatchev (UVA, Charlottesville, VA)

Rapid-fire presentations from Drs. Moshe Phillip, Steven Russell, Roman Hovorka, and Boris Kovatchev shared updates on each group’s future efficacy studies that are coming soon. We heard never-before-details from each speaker and were impressed to see how actively and ambitiously the academic groups are thinking about large-scale efficacy studies (in some cases with an eye towards FDA approval). Competition is really pushing the thinking and dialogue forward aggressively, and we can hardly wait for the host of real-world data the coming 12-24 months will hold. It is going to be a truly exciting couple of years for the artificial pancreas. Please note that some of these studies have already begun (Project Nightlight), some are planned for the near future (Bionic Pancreas pivotal, IDCL), and some do not have public timelines (DREAM pivotal). We summarize updates from each group below:

Planned Large Closed-Loop Efficacy Studies

	Study Length/Size	Design	Comparator	Endpoint	Commercialization plan
DiAs – “Project Nightlight”	n=84; 11 months	Patients will cycle through SAP therapy, nighttime, 24-hour, and nighttime (a second time) closed-loop control	SAP vs. overnight vs. 24/7	A1c, risk of hypoglycemia, patient preference	Established a company, TypeZero to commercialize algorithm either on a smartphone or built into a pump
DiAs – “International Diabetes Closed-Loop Trial” (IDCL) Pivotal trial of commercial grade artificial pancreas built by Type Zero and in collaboration with pump companies	N=240; 6 months	Randomized patients 2:1 to closed-loop control vs. SAP; stage one: control-to-range vs. SAP; stage two: enhanced control-to-range vs. SAP	SAP therapy	A1c, incidence of hypoglycemia
Bionic Pancreas Pivotal Study To obtain FDA approval for the device and a chronic use indication for Xeris’ glucagon	12 months; n=480 Xeris glucagon Dual-chamber Pump	Randomized 2:1, parallel Bionic Pancreas vs. usual care arms; no remote monitoring or restrictions on foods/exercise	Usual care (CSII or MDI)	A1c, % time spent < 60 mg/dl during the last three months of each arm	???
Cambridge	12 months; n=130	Randomized patients 1:1 on 24/7 closed-loop control vs. SAP therapy; no remote monitoring or restrictions on foods/exercise	SAP therapy	???	Working with pump and CGM companies
DREAM pivotal study	6 months; n=?	“Parallel studies looking at both safety and efficacy”	SAP therapy	% of readings < 70 mg/dl; time within 70-180 mg/dl; A1c at six months	Licensed to Medtronic
Medtronic US pivotal study	3 months; n=150 Now Recruiting	Single arm study; two-week run-in on pump+ CGM followed by 3 months on the 670G	SAP therapy (during run-in period)	Safety; A1c; insulin dose; weight; time spent with closed-loop on vs. off; time spent in different glucose ranges	Commercialize internally

Panel Discussion – Large Efficacy Studies for Artificial Pancreas Systems

Roman Hovorka, PhD (University of Cambridge, UK), Boris Kovatchev, PhD (UVA, Charlottesville, VA), Steven Russell, MD, PhD (MGH, Boston, MA), Moshe Philip, MD (Schneider Children's Medical Center, Petah Tikvah, Israel), Stayce Beck, PhD (FDA, Silver Spring, MD); Chip Zimliki, PhD (Medtronic, Los Angeles, CA), Krishna Venugopalan, PhD (Animas, West Chester, PA), Tomas Walker (Dexcom, San Diego, CA)

Dr. Aaron Kowalski: Steven, you laid out the clinical trial design. When we did the JDRF CGM trial, we thought about this a lot. You’re going for a dual outcome – it’s bold. You’re shooting for the moon, and I commend you. The preliminary data suggests you can do this. The concern is that you have people that are already there, so you’re already putting yourself behind the eight ball. You may be treating people with an A1c of 6.5%. You have an A1c outcome, which is logical. But can you talk about that decision?

Dr. Steven Russell: Quite a few people in our trials have already had good glucose control. In most of the trials, half had an A1c <7%. So it’s primarily those in poor glucose control who see a reduction in mean glucose. For those in good control, we reduce hypoglycemia. Our population of patients so far has been pretty sophisticated folks at the time of enrollment. We think when we can enroll a much more general population and people with higher A1cs – not necessarily those who hear about the trial and fly across the country to participate. That will make it easier to see reductions in mean glucose. In terms of a reduction in hypoglycemia, that’s what takes more power. In the multicenter home use study, we reduce time in hypoglycemia from 1.9% in usual care to 0.6%. It was still a very large reduction and highly statistically significant.

Q: Do you have any reactions to that? Any aspects of this that you don’t think they are capturing with the studies they have described?

Dr. Krishna Venugopalan: I think it’s good to see longer-term studies being driven by academic investigators. It allows us to understand what the true solutions are going to provide. Extended data is essential to access, not just approval. It’s very exciting to see that. We’re very excited to be working with some of these individuals that are moving this forward.

Mr. Tomas Walker: I’m happy to see the focus on reducing hypoglycemia. The impact of hypoglycemia cannot be overstated. Despite the focus on severe hypoglycemia, the impact we’re seeing on non-severe hypoglycemia at night is really validated by trials. I’m happy to see addressed.

Dr. Stayce Beck: Everybody talked about how they are willing to talk to us. Each system might have different efficacies, but each of them will be able to show what their system can do.

Dr. Chip Zimliki: I applaud Stayce and the FDA for being so flexible. Medtronic has taken an aggressive approach to accelerating our artificial pancreas. We are focused on safety endpoints – the critical factors such as DKA and severe hypoglycemia. While I applaud those looking at long-term trials, we want to get a first generation product out as soon as humanly possible.

Ms. Hutton: Can you talk about the user interface and how important that is? In these large efficacy studies, how are you capturing the importance of the patient perspective in designing such systems and capturing that in clinical studies?

Dr. Roman Hovorka: I think that for the success of closed-loop systems, human factors are as important as the algorithms. If people are not willing to use the systems, you are not going to get the benefits. We are working with psychologists and human factors engineers. I think the challenge is that we don’t have the right metrics to capture some of these things. We’re trying to do the best we can, but I don’t think we have the best tools to understand how people perceive these systems.

Dr. Boris Kovatchev: We have had the advantage of using a relatively unchanged interface in ten different centers across the world. The interface was originally designed using focus groups and psychologists and human factors engineers. In these three years of use, we’ve collected a lot of data. We’ve figured out what people would like to have changed and are aiming for a refined version.

Dr. Moshe Phillip: You don’t need many studies to understand that patients want these systems as simple as possible and want systems that minimize the number of devices.

Q: You used the metaphor of the last 100 yards. As we get closer, could we run into the paradox where you keep halving the distance and not quite getting there? What are the barriers and potential pitfalls that we might run into?

Dr. Kowalski: Very, very good point. I think I see that question from both sides. I do commend industry – Medtronic really threw down the gauntlet. Medtronic is really pushing the entire industry towards these first systems. But it’s just one finish line, and there are going to be multiple. The other side of that equation is that I worry about being overly conservative. One of the interesting things, as we approach that goal line, is whether we are going to alarm too much. Are we not going to give people enough control, or be too conservative and risk averse? The expectation setting is critical. How much do you alarm?

Dr. Beck: I think what we talk about is the clinical study. What are the endpoints? And then there is manufacturing. We’re working with JDRF on different manufacturing models for different component systems; it’s not a small part, and it’s not nearly as exciting. But we need to start shifting our conversations.

Mr. Walker: From the standpoint of a CGM in the artificial pancreas, the alarm has to be actionable. We need to change how we think about them: alarms vs. action alerts. Alarms lose value when you cannot do anything about the alarm. It’s well reported in the literature across aviation and healthcare. Alarms have to mean something. It’s an action alert.

Dr. Kowalski: You know this very well at Dexcom. If you give too many action alerts, particularly in teens and young adults, it really becomes an issue. Where is the balance between safety and dis-incentivizing people from using these systems?

Dr. Zimliki: We use a risk-based approach. That’s what Medtronic is doing. You need a prioritization of alerts, so that some will supersede others. That needs to be done automatically. That’s the purpose of what we are trying to do.

Dr. Russell: However, even if these systems are actionable, it would be better if you had a system that would prevent the low from occurring in the first place.

Mr. Brandon Arbiter (Tidepool, Palo Alto, CA): Some of the questions we talk about at Tidepool are: who are the early adopters of this technology? How do we manage the chasm between early adopters and everyone else? I think it’s interesting to consider whether certain people are predisposed to certain systems.

Dr. Russell: I do think that we’ve seen early adopters enrolling in these trials so far. We’re trying to avoid that now by making sure one-third of our pivotal trial patients are MDI users. If you make a system that is simple enough, then you should be able to draw in people that are more than early adopters. You’d have to think that a simple system would be more attractive than a sensor-augmented pump.

Mr. Venugopalan: Let the user determine the extent of control and the extent of sharing. A key part with these solutions is disrupting the pump business model of sticking with something for 4-5 years. It becomes something with upgradeable features and remote upgrades. More diagnostics. You may be able to tailor solutions to individuals and iterate much more rapidly. It’s not just innovation from an algorithm perspective – it’s innovation from a business model perspective.

Dr. Kovatchev: The system will have to be adaptable in real time. One person may want something today and a different configuration tomorrow. You need to provide a different solution at different times. That has to be embedded in system design.

Dr. Hovorka: I think the design of clinical studies is difficult. I think it’s interesting to consider those who are putting pregnant women on closed-loop bot during and following delivery. That’s very real life.

Adam Brown (Close Concerns, San Francisco, CA): What is the appropriate comparator group in a closed-loop pivotal study? Is it MDI users on SMBG – the majority of people with type 1 – or is it the best that we have right now: sensor-augmented pump therapy?

Dr. Phillip: I would say that you have to design the control group in a way that allows you to test the primary outcome of your study. If you have a control group that is two steps removed – such as Dr. Russell’s that adds a sensor and closed-loop – then you don’t know if final effect is because of the sensor or because of the closed-loop system. You’ve got to make sure your outcome reflects what you want it to reflect.

Dr. Russell: This is not an academic exercise. We give people systems to improve their diabetes control. We don’t want to limit ourselves to the people using pumps – that’s only 1/3 of the people with type 1 diabetes. People have chosen not to use a pump or a sensor, or maybe their HCPs believe they are not good candidates. Those are exactly the people who need an automated system to take care of them. Most people with type 1 diabetes are on MDI. I don’t think we should take that person and give them a run in on sensor-augmented pump therapy – they never felt they wanted it in the first place. You try and do that and you have a very long run in period, and you still don’t know how to implement that therapy. To use that as a comparison group doesn’t make sense. What benefit could you provide to patients that are actually candidates to use the devices? It’s not an academic question about which part is due to the control algorithm. What if people don’t want to use sensors and pumps because they don’t get enough benefit?

Dr. Kowalski: Steve, Steven. I know you’re a reviewer. You know that all the major journals will critique that approach. Medtronic faced this in their NEJM paper.

Dr. Russell: This has been a major concern. But if we want to get approval for this device in the general population, we need to include MDIs. We do our studies for patients, not peer reviewers.

Comment: Steve, we’ve done exactly what you’ve said. We took patients on MDI or on pump or on SAP, and we gave them a seven-day run-in. We saw no difference in time-in-range or adaptation whether they used a pump, a sensor, or MDI. If you look at the published data, you cannot tell which is which.

Dr. Hans De Vries (Academic Medical Center, Amsterdam, The Netherlands): I think both are right. If you just look at CGM development, we’ve seen initial trials in CGM looking at pump users in the control group and then we saw comparisons to sensor-augment pumps in the control group. We’ll see the same thing again here. You might need to convince the payers by comparing to the optimal treatment. After all, why would they pay for something new if they don’t have the optimal treatment? But you’ll also have patients who aren’t on pumps and CGMs, but want to get on the whole package.

Dr. Roy Beck (Jaeb Center for Health Research, Tampa, FL): We’ve worked with two groups here. I could write a point-counterpoint on this, because I think you could do both scientifically. What we really want it a three-arm study. But ultimately, I come around to Steve’s point. In the T1D Exchange data, at most 15% of people at the top centers are using sensor-augmented pump therapy. The reason for that is not all about insurance. It’s because of the reasons we’re all alluding to – the hassle factor. If you could pop this on and use it, there’s a really expanded population for it.

Dr. Yogish Kudva (Mayo Clinic, Rochester, MN): What lessons have we learned and not learned from the past year? Let’s think about the use of STAR 3 to approve devices. It has been sub-optimal. I think that there are issues of making sure providers are educated. The other issue is the payer issue. One of the payer issues is that when you have a refusal that has come back from the insurance company, it is an opinion that has come from someone in the middle. That is the real world in the US. There is a middle-man. I think in the US that’s an important issue. The third point is that we know a lot about patient factors with regard to device use. But what about the MDI use? I don’t think we know enough about that yet.

Dr. Kowalski: I think you are right. All of this sums up into patient access and improved outcomes. The components of patient access are very complex but these studies play a very important role, as my team will attest. We sit with these payers and they will criticize the design of these trials and that does have downstream affects on decisions. So those are important clinical questions. I think the glass-half-full view is that the collaboration between this community helps, and I’m convinced that these systems are the tipping point in terms of improved control and reducing burden concomitantly. I have to believe payers will catch on.

Panel Discussion – Adoption of Artificial Pancreas Systems

Jessica Roth (JDRF, Washington, DC); Adam Brown (Close Concerns, San Francisco, CA); Kenneth Snow, MD (Aetna, Boston, MA); Paul Radensky, MD (McDermott Will & Emery, Washington, DC); Jill Weissberg-Benchell, PhD (Feinberg School of Medicine, Chicago, IL); Brian Herrick (JDRF, New York, NY)

JDRF’s Jessica Roth and Close Concerns’ Adam Brown co-moderated this panel of payers, providers, and patients, who discussed expectations for and adoption of various artificial pancreas systems. The payers on the panel – the very articulate endocrinologist-turned-payer Dr. Kenneth Snow of Aetna and Dr. Paul Radensky of McDermott Will & Emery (a law firm specializing in reimbursement) – had crystal clear advice for the entire room: artificial pancreas systems may prompt benefits on A1c, hypoglycemia, and burden, and to get it reimbursed, the data must clearly show that. Dr. Snow used the analogy of buying a mouse trap – there are $3, $5, and $30 mouse traps, but when you go to buy a mousetrap at the store, there is no data to point out which is better. In that case, the consumer probably just buys the cheapest one. The same is true with the artificial pancreas: Aetna will pay for the “better mouse trap” if there are data to clearly suggest that. Psychologist Dr. Jill Weissberg-Benchell and type 1 patient Brian Herrick emphasized the artificial pancreas’ quality of life benefits (e.g., less worry, a parent that doesn’t have to wake up at night), and the payers made it clear that those softer endpoints are indeed seriously considered in the payment decision; however, the data must be rigorously collected with validated instruments to prove it’s true (we are not sure how this will be done, though HCT has funded a group of researchers to develop such approaches). Adam pointed out the challenge in that tradeoff – capturing powerful, transformative stories about the impact quality of life and summarizing them with what can seem like cold, quantitative statistics (e.g., an 8.6 on a 1-10 worry scale). Both payer representatives cautioned against being deemed a “convenience” benefit alone, a weak argument to justify payment.

• This panel emphasized that engaging payers early and often will be critical for properly designing artificial pancreas pivotal studies. And this time is now. Indeed, Dr. Roman Hovorka wondered whether any learnings from the JDRF CGM study could be applied to reimbursement for artificial pancreas technologies – Dr. Kowalski agreed that they could, highlighting how hard JDRF worked early to seek input from payers in planning the study. What was interesting to hear, however, was that different payers weighed different endpoints more heavily (e.g., A1c vs. hypoglycemia). That suggested that any ultimate study design is really going to be a compromise, meaning it may not satisfy all stakeholders (patients, payers, clinicians) or goals equally.
• We left the panel and the entire evening with a strong appreciation of the nuances in pivotal study design; we hope academic investigators and companies are heavily leveraging JDRF’s expertise and network to do this properly.

Quotable Quotes

• Dr. Kenneth Snow (Aetna): “Does technology improve outcomes? If it does, please prove it to me – we’re happy to cover it if you do. Lower A1c, les hypo, less distress – we all know what needs to be shown. If you can’t show me, I won’t cover it.”
• Brian Herrick (JDRF, type 1 patient): “For the first system that works, I’m going to do everything in my power to get it. And I’m not the only one that feels that way.”
• Dr. Paul Radensky: “Through the work with Medicare and Medicaid we’ve seen a willingness to accept quality of life outcomes. However, it’s tough if you do not come first with science outcomes. Time in range is something they are willing to look at – I looked before a home anti-coagulant monitoring, where having numbers in range was important. I don’t think it’s an either/or – it’s both sets of outcomes that you need.”
• Dr. Jill Weissberg-Benchell: “I think we first need to improve the lives of people that live with diabetes, which means a real-time everyday perspective. And that’s not A1c, because that’s not a real-time everyday perspective. Can a child sleep through the night? Can a parent sleep through the night? Is there less conflict between parents and children? Is the child a better friend? That to me is the most powerful thing that a closed-loop system can provide.”
• Dr. Snow: “A disclaimer. I’m an endocrinologist. I’ve had patients die in the middle of the night. So that does hit home and I understand the issue. But I’m not going to claim that all of my colleagues will and that all payers will. There is a significant value that goes beyond A1c and beyond hypoglycemia. All of these things are very important and should be quantified as part of a study. Provide me with the evidence.”
• Dr. Carol Levy: “I’m the person who has to fill out the forms to get reimbursement. But no one ever asks for psychological factors. They always ask for numbers.”
• Dr. Snow: “I think the harder challenge is when the innovation is moving faster than the literature. You might have four studies that are in print and coming out eventually, and yet the data that is currently out there is outdated; that is much harder to do. Some people come to us and say, ‘Hey here is the result of the study before it is in print.’”

Joint ADA/JDRF Symposium: Closed-Loop Technology in Youth – Real Estate, Alarms, and Challenges

The Artificial Pancreas Road Map Update – Too Slow, Too Fast, When Does My Child Get an Artificial Pancreas?

Aaron Kowalski, PhD (Chief Mission Officer/VP, Research, JDRF, New York, NY)

Dr. Aaron Kowalski’s AP roadmap presentation mixed outrage with optimism, highlighting what he characterized as incredible unmet need and the very promising status of artificial pancreas systems (including multiple slides on Bigfoot, Bryan Mazlish). Part one of his presentation used T1D Exchange data to highlight how few people with type 1 are meeting glycemic goals – this data is still quite sobering, and Dr. Kowalski made a major point that it’s not due to “compliance” (i.e., patients even testing 7-8 times per day are still struggling). Part one concluded with a stark slide centered on two big bolded words to summarize how quickly artificial pancreas efforts are moving: “TOO SLOW!!” Dr. Kowalski was optimistic, however, and deliberately did NOT show his six-step roadmap – “We’ve achieved technical feasibility across all steps,” he said, and now it’s time for (i) commercial development; (ii) regulatory approval; (iii) reimbursement; (iv) clinical adoption; (v) people with diabetes access/benefit; and (vi) improved outcomes. JDRF sounds very focused on all these buckets, particularly reimbursement. Dr. Kowalski noted that “multiple companies” are in commercial development and are targeting 2017-2018 launch of hybrid systems (he did not specify, but we know of at least Medtronic, Bigfoot, Bionic Pancreas, Tandem, and potentially Insulet, Animas, TypeZero, Cambridge, and Roche). Dr. Kowalski was equally positive about the FDA pathway to market, which he characterized as “very favorable.” Moving forward, Dr. Kowalski has proposed a “Diabetes Scorecard (Diabetes Care 2015) to judge the value of artificial pancreas systems beyond A1c – scorekeepers are the people with diabetes (& loved ones), clinicians, and payers, and the categories are glycemic control, “burden”, and value.

• Dr. Kowalski’s Diabetes Care paper  now proposes a three-step roadmap to artificial pancreas systems, with a bifurcation occurring at step three: automated insulin delivery (AID) vs. multi-hormone (MH) systems. The first two steps – low glucose suspend and predictive suspend – are already available and commercialized as the MiniMed 530G/Veo (Worldwide) and MiniMed 640G (EU, Australia). This is in contrast to the initial model: (i) low glucose suspend; (ii) predictive low glucose suspend; (iii) hypoglycemia/hyperglycemia minimizer; (iv) automated basal (hybrid closed loop: manual meal bolus); (v) fully automated closed-loop (insulin-only); and (vi) fully automated closed-loop (multi-hormone).
  
  • The “next steps” column (see below) makes it clear that multi-hormone approaches still have much to prove. Overall, the paper takes a somewhat skeptical eye towards bi-hormonal systems, particularly glucagon. This is not that surprising, as Dr. Kowalski has long questioned the incremental benefit that glucagon might add over insulin-only systems. We look forward to head-to-head trials that will bring data to the discussion.

Dr. Kowalski’s Revised AP Roadmap
System	Next Steps
1. Suspend	Clinical adoption
2. Predictive Suspend	US approval, reimbursement, clinical adoption
3a. Automated insulin delivery (AID)	Faster insulin action, miniaturization, integration, individualized control
3b. Multi-hormone (MH)	Glucagon: soluble, pumpable glucagon; chronic glucagon exposure studies; dual-chamber pump development, algorithm finalization, head-to-head vs. AID Amylin: co-formulation vs. dual-chamber pump, ratio determination, algorithm finalization, head-to-head vs. AID

• Dr. Kowalski devoted two slides to a Diabetes Mine guest column by Sarah Mazlish (Bigfoot), which underscored the reduced “burden” artificial pancreas systems can provide (even to those in very good control like Sarah). Though he acknowledged artificial pancreas systems might be more expensive than other therapies, Dr. Kowalski believes their “value” will be worth it, since outcomes will be so much better. [We’d note that it’s still hard to know how the cost of commercialized artificial pancreas systems will stack up to current therapies; what the clinical data will look like vs. current therapies; and what fraction of patients will switch to closed loop systems. We do believe the value will be there for many patients, but it’s hard to know what fraction of type 1s that is, and how it will change over time with subsequent generations.]

Pediatric Patient Safety and Patient Products – The FDA Perspective

Stayce Beck (FDA, Silver Spring, MD)

The FDA’s Dr. Stayce Beck provided strikingly optimistic commentary on the pathway to a pediatric closed-loop system – “[We want] a fully approved system available for anyone that needs it.” We would like her to advocate before CMS when the time comes! Dr. Beck opened her presentation emphatically, noting that closed-loop approval in adults and pediatrics can – and should, in the FDA’s eyes – occur in parallel. She acknowledged the widely held misconception that an adult approval must precede pediatric approval – indeed, she stated that “that is the opposite of what we want.” Dr. Beck stressed a host of differences that introduce nuance into the transition of closed-loop systems into pediatric populations: differences in body fat, activity level, glucose variability, hormones, and capacity for decision-making between adults and children. In light of these differences, she suggested that closed-loop systems must be tested separately in children in order to pave the way for approval – and also that the FDA is very willing to consider this need. Of course, she acknowledged the FDA’s view that appropriate mitigation techniques, such as remote monitoring, are paramount in this more vulnerable population. She also stressed that such safety measures do not devalue the data in the FDA’s eyes, quelling concerns that the use of such techniques could hamper confidence in results or imply a distrust of the system. Dr. Beck advocated for more minimal exclusion criteria for pivotal studies in general, stressing that the FDA would rather identify patient sub-populations that should not use closed-loop systems through clinical trials, as opposed to off-label use leading to disastrous results in the real world. We’re pretty much ready to start a Stayce Beck fan club – she just continues to impress in public presentations with her patient-friendly perspective.

Pathway to the Pediatric Bionic Pancreas

Ed Damiano, MD (Boston University, MA)

Dr. Ed Damiano’s comprehensive overview of the Bionic Pancreas in pediatrics shared an updated timeline on the group’s pre-pivotal studies – notably, two glycemic set-point studies will take place starting in August. An MGH study will test insulin-only and bi-hormonal configurations of the bionic pancreas head-to-head – the same participants will use both configurations for at least one set-point (130 mg/dl), though the team will also expects to test other target levels (insulin-only 145 and possibly 115 mg/dl; bi-hormonal: 100, 115, 130 mg/dl). A separate Stanford set-point study will test an insulin-only version of the Bionic Pancreas at several algorithm set points, and will do so over a longer period of time. [We first reported the insulin-only news in less detail at GTC Bio in April – though we had been fairly surprised at the time, it makes complete sense given the uncertainty around multiple elements of glucagon.] We see this as a necessary move to counter the group’s critics, especially those asserting that the system doses insulin and glucagon too aggressively and would be unable to fail safely. It also speaks to the team’s willingness to let the data speak for itself – they could easily just move ahead to the bi-hormonal study, assuming glucagon availability. Last, we believe it could be a mitigation strategy in case an approved stable glucagon does not come in time for the Bionic Pancreas pivotal study (2016-2017). ADA certainly continued the fascinating insulin-only vs. bi-hormonal debate, and we’ve heard a range of opinions in recent months (e.g., Keystone 2014, DTM 2014, ATTD 2015, ENDO 2015); ultimately, true head-to-head data is needed to show what incremental value glucagon adds to the equation. Our favorite commentary came from Yale’s Dr. Stuart Weinzimer in Q&A: “I think it’s a false argument to compare one against the other. What I would like to see are options for patients with diabetes and clinicians. I want to see an insulin-only system and a bihormonal system on the market. Then clinicians can choose and help patients choose what is best for them. So let the market decide.” Amen to that.

• As a reminder, the Bionic Pancreas team still hopes to conduct its pivotal study in 2016-2017, with FDA premarket approval slated for 2017-2018 and commercial launch in 2018. We saw results from the recently completed 11-day multicenter study for the Bionic Pancreas at AACE 2015; Dr. Damiano showed these again at ADA, but we did not see anything new.

Practical Translation of Closed-Loop Technology to the Pediatric Clinic – The Clinical Diabetes Educator's Perspective

Laurel Messer, RN, CDE (University of Colorado, Aurora, CO)

Ms. Laurel Messer shared updated results from a predictive low-glucose suspend study (PLGS) in adults and children. (This was not Medtronic’s MiniMed 640G but rather a custom algorithm replacing the Veo’s low-glucose suspend feature.) The study enrolled patients 3-45 years old (n=unknown) who were randomized to either CGM alone or PLGS overnight for 42 days. Results indicated that PLGS reduced clinically significant hypoglycemia (for > two hours) by 74% (patients 15-45 years old), 62% (11-14 years old), and 53% (4-10 years old). Ms. Messer attributed the difference in efficacy to disparities in adherence – 4-6 year olds wore the sensor almost one fewer day than other age groups due to skin issues and CGM usability. Within the same group, 64% experienced skin reactions and 36% had moderate/severe reactions to the device. Ms. Messer stressed that such human factors have big implications for the penetration of closed-loop technology in this younger population and called for more dialogue on this front.

• Broadly, Ms. Messer stressed that there is very little information about the usability of closed-loop technologies in children and that expectations are unrealistically high. As an example, Ms. Messer cited a survey in which a majority of patients reported feeling reluctant to start pump therapy (58%), but also reported that they would have “no barriers” to using closed-loop technologies (79%). Ms. Messer suggested that such irony is presently par for the course and that the field needs to start thinking harder about the human factors side of artificial pancreas technologies.
• Ms. Messer stressed that different pediatric subpopulations have unique needs in terms of closed-loop human factors design. In the youngest children (patients 3-10 years old), she noted that the artificial pancreas will not be able to decrease the care burden until trust with parents is established. There are also needed CGM improvements to better deal with skin sensitivity. In older adolescents, Ms. Messer suggested that there are challenges associated with increased autonomy in this age range that tends to lead to more frustration and greater burnout risk, highlighting that education around calibration is key (for all patients, we would add).

Panel Discussion

Q: What is the status of a soluble glucagon? And is there potential to integrate an accelerometer into the pump? Could that be integrated into the pump to avoid hyperglycemia for a 10-second sprint and hypoglycemia with prolonged exercise?

Dr. Ed Damiano (Boston University, MA): I’ve never been a big fan of using an accelerometer for automatic glucose control. In my own personal experience, if my son is playing basketball in practice, his blood glucose will go down. If he’s doing the exact same thing but competing in a game, his blood glucose goes up – he is tense, excited, and there’s hormonal activity. These are the same scenario – the accelerometer wouldn’t know the difference. There is such variability that it’s not a good read. The ultimate signal we want to control is glucose – that should be the only read. And the results reading only glucose seems to bear that out.

The soluble glucagon is a big one – it’s a challenge that there’s no stable, pumpable glucagon that is FDA approved. There are some platforms out there that have shown stability out to more than a year, and some up to two years. Xeris is one; Zealand is working on an analog. There are other groups out there. What we’re doing right now has no commercial path forward – we have no expectation of using reconstituted Lilly glucagon. It’s not chemically stable long enough. The challenge can be solved in more than one way, and there are good candidate drugs out there. We have talked about the roadmap with the FDA and what it would look like for one of the drugs out there. Some are into phase 3, some are just in phase 1. I’m optimistic we’ll see them coming along very quickly.

Q: Is it necessary to have glucagon? Even in young kids? Can the Bionic Pancreas work insulin-only?

Dr. Ed Damiano: We have yet to test insulin-only, so I would say to come back to me in a few months. My intuition is that in kids, more than anyone else, we need glucagon. We’ve evolved to use glucagon. To preserve the spontaneity in life, we have to preserve glucagon. We use it. And it is the first line of defense for people without diabetes. So it is definitely something I want to see in an automated system in the future. We could introduce insulin-only systems to bridge the gap to glucagon systems.

Dr. Aaron Kowalski (JDRF, New York, NY): I think this is an important area that we need to focus on: the benefit of insulin alone vs. bihormonal systems. What we are seeing is that insulin-only approaches will work. And they will work very well. One of the things I just wrote abut is that we need to be careful about the comparator when we think about diabetes. Some have been critical about artificial pancreas systems because they claim that these systems won’t be like islet cells. If you’re comparing against islets, you are doomed to fail. But if you are comparing against the standard of care today, you can do better. Insulin-only systems can do better and the data bears that out. I do think that glucagon can add a level of control. I just think that there is a level of dysregulation that we need to understand.

Dr. Damiano: It’s not like it’s one or the other.

Dr. Kowalski: No I agree. It’s not one or the other.

Dr. Stuart Weinzimer (Yale University, New Haven, CT): I think it’s a false argument to compare one against the other. What I would like to see are options for patients with diabetes and clinicians. I want to see an insulin-only system and a bihormonal system on the market. Then clinicians can choose and help patients choose what is best for them. So let the market decide.

Q: Do you think faster insulin would help your systems? And second, if I just ate at a restaurant and don’t want to wait for a cab and decide to walk to a hotel, I would often get hypoglycemic. That’s one of the variables that really frustrates people. In your population, were you seeing that glucagon was enough to rescue patients in that situation? I know people were trying all crazy kinds of things. Do we just need faster insulins?

Dr. Damiano: I really want faster insulin. It is going to make our system better. However, I would agree that what we have now is good enough. It’s good enough not just for hybrid systems but even for a fully automated system. What we have is good enough for really good glucose control. We published a paper to show exactly that. We took an adolescent population and looked at half without meal announcements and half with meal announcements. The difference between the groups was only ~13 mg/dl. So even if you forget meal announcements, we have a system that works to bring adults to ~7.0% and teens to ~7.5% without hypoglycemia. Despite that, I do want to see insulin get faster. It makes bihormonal systems better. It makes insulin-only systems faster. It makes these systems more realistically approximate physiological conditions.

Q: Can you talk more about whether an accelerometer would help?

Dr. Damiano: I don’t think an accelerometer is predictive of glycemia. There is nothing more challenging than our summer camp setting. In Beacon Hill, we had one woman walk 35 miles in five days. In the multicenter study, people could use gyms as much as they wanted. Our system dealt with active people just fine.

Q: Have you ever followed up with patients who were very active the following week and seen how the system adjusts to less activity? Can it adapt again?

Dr. Damiano: The timescale of adaptation is about 18 hours. However, this varies depending on the insulin usage. For example, we had one patient who was receiving 0.5 units/kg/day and adaptation was almost instantaneous. However, in patients that received more insulin, adaptation took a bit longer. It adapts pretty darn quickly. I think it handles dramatic changes quite well.

Q: As a camp doctor, I’m interested in how much down time there was during your studies when a site was out?

Dr. Damiano: Typically, if we lost a sensor – which happened a lot – you would have a two-hour period, maybe up to three hours, with no CGM data. The system learns the normal basal rates and invokes those even when the CGM sensor is offline.

Q: Can you predict any differences in parental buy-in between insulin-only and bi-hormonal systems?

Dr. Messer: We’re excited to work in the future with insulin and glucagon in the Bionic Pancreas. My initial concern was the burden of two pumps. The hassle was very concerning. More studies need to be done in pediatrics, with insulin-only systems, and with bihormonal systems.

Dr. Damiano: I don’t know of any studies that have compared the buy-in of insulin-only vs. bihormonal systems. I just want to clarify that the system we use now uses two infusion sets. However, we’re building a dual-infusion set that you would have to change every 72 hours. It will be stainless set; it will have separate catheters that will use separate paths. It will require no more skin real estate than a current infusion set.

Dr. Messer: Still, it’s actually the CGM that causes the most problems with body real estate. The CGM is still really a major player here in terms of burden.

Dr. Weinzimer: Looking at user factors and quality of life, there’s some great data that Kat Barnard collected, but we have to be very cautious. Most studies are 5-10 days per patient at most. No matter how burdensome it is the device is, 5-10 days is very different from 3-6 months. We’re going to get a much better idea of the burden when we start doing pivotal studies.

Dr. Kowalski: it’s a very, very important point. You’ll see the insulin-alone systems come to the market first. I’m almost certain. I believe we’ll have to do the studies on incremental benefit of bihormonal control to see whether the glycemic benefit is distinguishable from an insulin-only system or liraglutide or amylin. We’ll have to look at the glycemic benefit, the severe hypoglycemia, the mean blood glucose, the time-in-range. Are those endpoints distinguishable enough from insulin-alone, given the greater cost and size? Where do we put effort in the future to drive systems that are more adoptable? Part of that is glycemic control, but part of that is burden. Glucagon systems may mean blood glucose is the mean, but patients have a much lower risk of severe hypoglycemia. It could be tremendously beneficial and very much worth the cost. These first systems are going to set the benchmark. We’ll have to drive from there.

Q: Such a gap exists between the patients that do and do not have access to technology. Dr. Kowalski, I wonder where you see the JDRF’s role in advocating for payers to come to the table?

Dr. Kowalski: The ultimate metric for the success of closed-loop technologies is the number of patients that achieve better outcome. This is not just a tool for wealthy people. It’s for everyone. The JDRF has evolved quite a bit since I first joined. We are just about to kick off a major initiative with the Helmsley Charitable Trust that focuses on downstream issues for the artificial pancreas: clinical adoption and access. We’ve already had a number of discussions with payers on closed-loop technologies. I’m cautiously optimistic. I do think that we’re going to pivot from therapies that are driving incremental improvements to a big step forward in glycemic control. If you look at the changes in these studies, they are quite dramatic. We’re going to see both the burden and glucose control improve concomitantly. Just remember, CGM has only 10% penetration because of the many barriers. Patients do not think the incremental benefit is worth it. But with closed-loop systems, the incremental benefit is worth it. This is going to be a multifaceted campaign, because the ultimate metric is people with diabetes getting better.

Q: In pediatrics, there is very little real estate. Were any bionic pumps inserted in lipohypertrophic areas?

Dr. Damiano: No, not intentionally.  We inserted in the abdomen. Dr. [Bruce] Buckingham [Stanford University, Stanford, CA) suggested that sensors work well even in lipohypertrophic areas.

Dr. Laurel Messer (Barbara Davis Center, Aurora, CO): We actually found that sensors worked better in those hypertrophic areas.

Dr. Damiano: However, skin real estate is definitely a concern for pump therapy, whether automated or not. Closed-loop systems are only a bridge to a cure; they can’t solve all the problems of pump therapy. You have to be connected to a device. It’s a contraption. I’d love to see Doug Melton step up and show us a cure tomorrow. But this is a much better solution than what we have today. And this handles everyone. It’s an umbrella for everyone with type 1.

Q: In adult studies, did you look at food intake? If didn’t have hypoglycemia and hyperglycemia, were they just eating less?

Dr. Damiano: The 9,000 calorie-anecdote was on the bionic pancreas, which wasn’t usual care. We did not capture data on calorie intake. In the real-life setting, you don’t want to capture all the data or it’s not real-life. We did in Beacon Hill, and there wasn’t any difference compared to usual care. We have no reason to believe that subjects ate less.

Q: I work on closed loop tech for pregnant women in the UK. I completely agree with Dr. Beck that children and other marginalized groups need to be part of the studies. This includes children, pregnant women, and people with multiple co-morbidities. I understand that the FDA’s view is to focus on low-risk populations first in safety studies, but I worry this delays technology. How can we fast track this technology and make sure it gets from research to the clinic to the people who need it most?

Dr. Stayce Beck (FDA, Silver Spring, MD): We’ve been working a lot with different investigators to design studies that best protect patients but are also as real-world as possible. There will always be a need for some in-clinic studies first to make sure people are protected. This includes testing with more vulnerable populations before going to market. We do want to ensure that once the device is on the market, it can be safely prescribed off-label for anyone an HCP chooses. We want to make sure the device is studied to some extent in those populations.

Symposium: Diabetes Devices and Technologies – The Patient Experience

How a Device Becomes a Device

Adam Brown (Close Concerns/The diaTribe Foundation, San Francisco, CA)

Please see Adam’s slides here, which pinpoint five principles that helped the iPhone succeed, apply them to diabetes devices, and discuss key barriers – the visuals and stories really make the outline below come to life.

• Adam highlighted five key principles that helped the iPhone succeed: (i) Makes my life easier, solves a need, subtracts hassle; (ii) User-experience-obsessed, iterative, feedback-driven design; (iii) No instructions needed; “it just works”; (iv) Significant improvement over existing options; and (v) Fun, addictive, “awesome!”
• Adam applied this five-part framework to two diabetes device case studies – Insulet’s OmniPod and Cygnus’ GlucoWatch, discussing why one has largely succeeded commercially (despite recent business challenges for the US OmniPod business) and why the other failed quickly following launch.
• In the second half of his presentation, Adam shared seven principles why devices often fail to meet all five criteria: (i) Device development often focuses only on safety/efficacy to pass the FDA (Necessary, but not sufficient!); (ii) The regulatory bar is much higher for solving really important problems (e.g., like how much insulin to take); (iii) Not enough attention is paid to making it fun, addictive, and awesome; (iv) Lots of focus on “high tech” – sometimes the simplest solution is profound (e.g., BD’s AutoShield Duo Pen needle); (v) an over-reliance on outdated business models. Companies must disrupt themselves. (e.g., example of Kodak inventing the digital camera in 1976 and burying the technology); (vi) First gen devices aren’t great in any domain. We may be in the early days of where devices could go...(i.e., we must have patience); (vii) Too much focus on incremental instead of game changing improvement. (How about 10x better?).
• To build a great device, Adam told attendees to remember the acronym PLANE: Patient and Provider Feedback (early, often, and relentlessly); Life Easier, Less Hassle; Addictive, Awesome; No instructions needed; Exceed Existing options (10x!).

The Human Side of the Artificial Pancreas

Jill Weissberg-Benchell, PhD, CDE (Northwestern University, Chicago, IL)

Dr. Weissberg-Benchell discussed very interesting psychosocial research on the 40 participants in the multicenter trial of the bionic pancreas. Most notable were the slides qualitatively documenting patient perceptions – the take was overwhelmingly positive on less worrying while sleeping, greater peace of mind, relaxing, and trust in the device – see the data below. We’re very excited to see so much more work going into the real-world, human factors, psychosocial side of the artificial pancreas, and as Dr. Weissberg-Benchell mentioned, it’s fortunately happening before these products are on the market. Along with Drs. Katherine Barnard and Korey Hood, Dr. Weissberg-Benchell has a grant to examine closed-loop human factors in greater detail. We hope the learnings are leveraged as pivotal studies take place to make products as great as they can be, to manage sky-high provider expectations, and to make clincians’ lives easier.

Table 1: Experience of Bionic Pancreas – Positive Aspects

	% Agree or Strongly Agree
It helped me worry less about having a low while sleeping	78%
I had greater peace of mind while wearing the device	73%
It helped me to worry less about high blood sugars	73%
IT helped me to relax, knowing that unwanted change in blood sugar would be addressed automatically	73%
It helped me worry less about low blood sugars	73%
By the end of the study, I trusted the device to manage my blood glucose	68%
I found it hard to trust that the bionic pancreas could control my blood sugars	17%
Using the device was more trouble than it was worth	33%

Table 2: Experience of Bionic Pancreas – Negative/Bothersome Aspects

	% Agree or Strongly Agree
It was a big bother having to change the glucagon every day	78%
Carrying around all of the equipment was a burden	75%
It was uncomfortable to wear all of the necessary equipment	60%

Questions and Answers

Q: Will we always need glucagon?

A: Only 2 of the artificial pancreas studies are bi-hormonal. As a psychologist, I don’t have an opinion of which is better; a single system won’t meet the needs of everyone; so let’s get them all to market and give people a choice.

Q: What did the caregivers say?

A: We didn’t interview them yet, but have a Helmsley grant to do further studies.

Q: What did you think about the results of the WHO-5 (that quality of life did not improve much)?

A: It’s not really a sensitive enough measure (only 5 questions).  The more specific questions about impact of the APs are probably more relevant.  We now have an opportunity to define what will be used to define success for APS systems: it shouldn’t be just A1c.

Q: Interesting that people express so much frustration with alarms, even though they are what keep people safe.

A: We haven’t done enough to figure out how to give patients information and control they need to make the alarms work well for them.

Q: Can you give some more background about people who don’t continue use of pumps and CGM?
A: I can show you what data I’m citing – there’s a lot published about discontinuation rates of pumps, especially related to body image.

Q: In the 40 people in the study, was there a difference in people who have had diabetes for different lengths of time?

A: Outcome differences were not changed by duration of diabetes.

Symposium: Novel Clinical Interventions in Therapy That Impact the Management of Diabetes

Predictive Low Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children without Increasing Ketosis

Bruce Buckingham, MD (Stanford University, Stanford, CA)

Dr. Bruce Buckingham shared encouraging results from an in-home predictive low glucose suspend study (not Medtronic’s MiniMed 640G), which spoke to the promise of this technology in an impressively large and well-conducted RCT in pediatrics – the 81 participants (4-14 year olds) were blinded to whether PLGS was turned on (n=1,724 nights) or off (n=1,696 nights). The percentage of nights with a glucose <60 mg/dl for 120 minutes declined from 8% to 3% (p<0.001) during PLGS in 11-14 year-olds, and from 5% to 1% (p<0.001) in 4-10 year-olds. The magnitude of benefit rose considerably as the duration of nocturnal hypoglycemia increased (e.g., in 11-14 year olds, nights with hypoglycemia episodes >30 minutes declined 36%, while nights with an episode >180 minutes declined 68%). Mean overnight glucose was slightly higher (+7-8 mg/dl) during PLGS in both groups (152 vs. 144 mg/dl and 160 vs. 153 mg/dl), but the tradeoff for hypoglycemia was unquestionably worth it. This is now published in Diabetes Care. It was truly striking to see that patients spent more than 1 out of 20 nights hypoglycemic for more than two hours – Dr. Aaron Kowalski repeatedly highlighted this data through ADA.

Day and Night Closed-Loop Control Using the Integrated Medtronic Hybrid Closed-Loop System in Type 1 Diabetes at Diabetes Camp

Trang Ly (Stanford University, Stanford, CA)

Stanford’s Dr. Trang Ly shared a bit more about the Medtronic MiniMed 670G’s adaptability, courtesy of a deeper dive on the camp study first presented at ATTD. Dr. Ly presented the efficacy of the system by day of wear, which actually showed solid adaptability – overall time-in-range (70-180 mg/dl) rose from ~62% on day one to ~83% on day six, including an impressive jump from ~68% to 96% time in range overnight. Regarding the algorithm, Dr. Ly shared that the system is tailored to adapt “slowly, gradually” to the median over the previous six days, and we look forward to longer studies that will, perhaps, show even greater improvement relative to standard care (As a reminder, the ATTD data showed no statistically significant differences in any of the glycemic parameters between the 670G and 530G groups). As we noted at ATTD, the algorithm is still a work in progress, with future slated improvements to include flexible insulin:carb ratios, changing the correction threshold and target, and more aggressive tuning overall. This is now published in Diabetes Care.

Questions and Answers

Q: In the camp setting, how do you account for physical activity? Isn’t that a huge variable?

A: It is. Physical activity in camp is very different from activity at home. That’s why you have a control group. All the groups participate in all the activities. The biggest challenge is that the insulin delivery is supervised in camp. That really impacts the control and generally helps patients avoid hypoglycemia.

Q: How often are patients disconnected from their pumps? Overall, how long does it take for adaptation to occur? Could longer studies show a greater effect?

A: These are great results for six-day study but longer studies will show where adaptation works over time. It takes the median of previous six days, weighted toward more recent days. It’s tailored to be a slow, gradual adaptation over time.

Meet the Expert Sessions

Patient Perspectives on Closed-Loop Systems and Studies – Panel Discussion

Chris Aldred (The Grumpy Pumper, Southampton, UK) and Kelly Close (The diaTribe Foundation, San Francisco, CA)

A patient-centered panel discussion – led by Stanford’s great behavioral psychologist Dr. Korey Hood and featuring Mr. Chris Aldred (Southampton, UK) and our very own Ms. Kelly Close (The diaTribe Foundation, San Francisco, CA) – brought a healthy dose of both realism and optimism to the closed-loop conversation. Mr. Aldred, a very respected blogger in the UK (“The Grumpy Pumper”), lived up to his name by pointing out some of his concerns that the artificial pancreas may not live up to its billing right out of the gate. Indeed, he pointed out the risk that early on, there may well be unrealistically high expectations and advocated for more conservative optimism in light of the number of questions remaining to be answered. The words served as a strong reminder that not all patients will be automatically excited to use artificial pancreas technology when it arrives, particularly those happy with their current therapies or unwilling to wear something on the body. Kelly shared a few of her thoughts on the challenges of human factors design, acknowledging that connectivity issues have been meaningful in certain studies (this is a solvable problem, she stresses, although not one that was often discussed before last year) and that closed-loop systems in the research setting are of course in “debugging” mode – this is what research is for! With all that in mind, she spoke in glowing terms of the benefits already apparent in these first-gen systems – being brought to a soft landing from hyperglycemia (“virtually no hypoglycemia”) and the huge benefits of overnight control (“I wake up and I have a fair shot at my day … my husband says he always loves me, but he likes me more on the closed loop because of how I can start all these days …”). She posed the question at the end, “is it worth it?” and answered that it was worth it for the right patients – not the ones with particularly high expectations, for example. Ultimately, Mr. Aldred thought that the closed loop would be worth it too. The nuanced discussion underscored the importance of setting patient expectations moving forward: closed-loop technology will be a welcome prospect for many, but presentation in the early days will be important, as will patient selection.

Mr. Chris Aldred: I have had type 1 since I was 25. That was 21 years ago now when I was diagnosed. I’m really keen on technology of many sorts, things that’ll help me make better judgments and make life easier. I haven’t been a part of any trials yet. I have read about this stuff and I’m into thinking about what the right thinking is. To be honest, I’m a bit skeptical. I just won’t use any old thing that’s out there. Technology has got to help my diabetes live with me.

Ms. Kelly Close: I write for a newsletter called diaTribe, which is funded by the renowned Helmsley Charitable Trust – I’ve written many pieces in diaTribe about my experiences on the artificial pancreas. It’s so cool to have patients up here talking about our experience and we thank ADA and Korey for asking for our patient perspectives. I’ve been in the Bionic Pancreas and DiAs trials, and they have both been instrumental – but in the Bionic Pancreas trial, I had a nurse helping me 24/7, so that perceived “hassle factor” was lower than it would be in real life. The DiAs study was a little closer to what reality would look like. Of course I would want it for many patients who could benefit, especially those for whom acute short- or long-term complications could be avoided. I think getting patient access to this technology is a pretty big question and not one that is easily answered. If I can quickly ask, what does the audience think is the biggest benefit of the artificial pancreas?

A (CDE): Makes lives easier.

A (CDE): I think the answer is twofold. One of them is from a patient perspective: the relief of the burden of day-to-day diabetes management. The second is the glycemic control portion of it. Patients who have recurrent hypoglycemia or who have A1cs that are 9.0%, 10.0%, or 11.0% might be able to tighten down. There are about 20 other reasons I can think of, but those are the top two that come to mind.

Kelly: Thank you. So from my view, having been lucky enough to try several systems, I can say, the biggest benefit of automated insulin delivery is that it gives me a fair shot at my day. I don’t know how many of you have read Gretchen Rubin’s The Happiness Project, but she speaks about the importance of making your bed every day. Something so simple makes you feel better and have a better day. For me, the artificial pancreas gets me back to zero. That’s where everyone else starts their day. You wake up and you have a fair shot at your day. It makes you feel more normal. We are often – in spite of ourselves – somewhat grumpy. I called my family when I was on the Bionic Pancreas, and I spoke to my husband who said, “you sound more like my Kelly.” We have no idea how much we don’t get to be us because diabetes creates a lot of noise – we’re so busy just thinking about how to deal with our diabetes all the time. We joke about this all the time - my husband says that he always loves me and that he likes me much more on automated insulin delivery.

Q: If you were on a long-acting insulin overnight, how often do you find that you have glucose excursions?

Kelly: Personally, all the time. When you’re on CGM, you ultimately get to fix it and you’re much safer. Diabetes for sure is less costly and less dangerous with CGM, but patients don’t always hear all the alarms, and many still find it challenging to use, and HCPs can find it hard to use. But personally, all the time. CGM lets you fix it much of the time, but you don’t avoid it.

Ms. Aldred: I like my sleep way too much to wake up at night. Because I didn’t grow up with diabetes, I didn’t have a lot of those worries as a kid. Now I know that if I have had certain foods, I will go high. However, I don’t test a lot at night.

Kelly: One of the hardest things about diabetes is that you can be really high and not even realize it. Then you take a rage bolus (I learned that term from the great Kerri Sparling Morrone of Six Until Me, who is sitting right here in the front row) and you are at 40 mg/dl and it’s a huge spiral. Automated insulin delivery has eliminated that. Closing the loop is not going to change whether or not you go high if you eat too much pasta or pizza – of course you will go high! It’s not going to keep your glucose in range 24/7. However, what it does is it creates an amazing soft landing from hyperglycemia, where you get to avoid hypoglycemia. Period. It’s interesting because in my first trial I had a nurse with me 24/7 and I raved about it. In my second trial on the DiAs, it was “in the wild” (a research house). And the one I’m on right now is even tougher – it’s all me taking care of it (and John!). It’s tougher without a nurse right there for sure. So there are some bumps. However, if you remember the days of [Dexcom’s] STS, it was really challenging and few of us felt it was an advanced product. But look how far we’ve gotten. The STS enabled Dexcom’s G4! As research subjects, we have to do trials like the STS. Frankly, current closed-loop systems are pretty hard to use right at this moment; there are connectivity problems and all sorts of other things that nurses took care of in the first bionic pancreas trial I was part of. It’s hard, because researchers are trying to get these systems to work and ensure that they are safe enough and as patients we need to focus on helping de-bug them.

To the question, are they worth it? OF COURSE! Of course they are worth it. For anyone who’s been in a trial, there is no question.

That said, as a community, our expectations are much higher than they used to be. We should be in debugging mode right now. We want patients to be in trials who want to work on making the systems better. I think that’s the stage that we’re in.

Dr. Korey Hood (Stanford University, Palo Alto, CA): What are people skeptical about? There are people who are skeptical and are a little bit worried.

Mr. Aldred: Just to touch on a previous question, I want to address the notion of the burden of diabetes. I think the burden is quite personal. Here’s a hypothetical: If you had a fully working artificial pancreas and users do not have to do anything and its free, but it is the size of a backpack, how many people would actually wear it? Not many, because the burden of the backpack outweighs the burden of diabetes. We can’t treat everyone the same way. Is it worth it? I think so. But my skepticism sits in knowing all the variables that are needed to control my diabetes. How can a system understand all those difference preemptively? How is it going to distinguish an adrenaline high from a carbohydrate high? The former doesn’t require as much insulin. I’m not saying it won’t get to the point where it can do this successfully, but how do we get to that actual end game?

One of the other concerns I have is that we’re going to have first, second, and third gen systems. In the UK, we’re lucky enough to get our pumps funded. However, we don’t get to change our pumps for the next four years. So, if I have one artificial pancreas before the next gen comes out, then I’m stuck with that version for the next four years. This needs to be iterative like our phones, where we can upgrade them. There are lots of challenges here.

Q: Do you wear a CGM? Is it paid for?

Mr. Aldred: Yes. I can’t wear it for more than two days without getting a rash, but I wear it. And if you’re self-funded, you’re going to wear it until it dies and catches fire.

Q: How does a sensor affect your life day-to-day?

Mr. Aldred: I really like it. I wouldn’t wear it if it didn’t outweigh the hassle. I get more benefit than I get from not wearing it and I wear it as long as possible. I tend to know when it’s coming to the end of its useful life. Until it is unreliable, I will leave it on. Whereas with a cannula, I’ll rip it out and change it immediately even if it’s a bit uncomfortable.

Q: Kelly, what systems have you used in these trials and what day-to-day issues have you faced?

Kelly: I think automated insulin delivery is going to be the killer app for CGM. I think the data that can come from CGM and how we can be in zone a lot more of the time can be really powerful. I’ve been in the DiAs study and the Bionic Pancreas. On the latter, I know there has been some controversy about glucagon. However, that was my first exposure to glucagon and it was incredible. It seems to enable a faster recovery from hyperglycemia as it might be a more aggressive algorithm.

People want to know whether I would take that risk: I will take that on. I think making sure your family feels good about that is really important. DiAs does not have glucagon and it had a slower reaction. At night, DiAs is an absolute dream. And during the day, issues like connectivity do come up. However, when I’m out of range, it does bring me down softly. You’re not worried about hypoglycemia and that’s hugely powerful for someone who has experienced a lot of severe hypoglycemia.

Q: Can you talk about the decision to be on MDI vs. a pump?

Mr. Aldred: That’s a very difficult question. I got offered a pump back in the day and I said I don’t want one. But after 15 years of starting days out of range, I gave in.

Kelly: I agree that the bar for using this equipment is high. I only wore a pump when my boss – back in finance – made me do it! We needed to know if MiniMed was a good investment, so she made me wear it for a week. I’ve been on a pump ever since. Would I have gone on that on my own? No way! The perceived hassle in my head was completely different from knowing what it was like to wear it! Also, I’ve been on a CGM and I know the value in it, but again, it is a big hurdle for many, many patients to get over, to put this thing on. We know diabetes is associated with depression, but it’s good to remember that in addition to this, there is also a lot of distress. Patients need to talk to each other about this technology and talk about changes CGM is making in patient’s lives. It’s important to recognize that pumps aren’t perfect. Maybe it will take until the third generation to convince a lot of the hardcore MDI patients. However, in the long run, these devices are going to make life less expensive for payers and less dangerous for patients, when the studies are done that gives data to show that.

Dr. Hood: Some people have asked me whether there is a glycemic benefit to pumps. For some MDI users, they don’t want to move to pumps it’s because they are achieving the kind of control they want without one. They don’t see the value added of going to some other system. When there is a closed-loop system, I think people will see more value added. Hopefully, we can leverage that enthusiasm around it.

Mr. Aldred: I think one of the other issues for me is that the decision was talking about as a “move” from MDI to pump. It was talking about like there was no going back. There will be some people out there, who do not get to “try” a pump and that dissuades them. We don’t give people the change to test drive pumps. I wouldn’t buy a car without test-driving it.

Kelly: I was made to go on a pump, pretty much. I think as patients, we are not really encouraged to, as, say, a civic duty, do the right thing and to keep our glucoses in zone. We all have a responsibility to society, to ourselves, and to our families. I am definitely not blaming patients – not ever! – but I think a little bit more of that responsibility will help.

Q: Kelly, how much SMBG are you doing on closed loop?

Kelly: You do have to do SMBG to calibrate the system, but it is pretty accurate. When I was on the Bionic Pancreas, I think it was 12 times a day. It is a lot less on DiAs, maybe once or twice a day.

Q: Are you not more worried because a computer is doing what it wants to do?

Ms. Close: Oh no! No! I have this pump that has a basal rate and an insulin sensitivity factor and an insulin to carb ratio and all this math. For example, how many of us in the room with diabetes believe our basal rates are perfect? [No one in the room raises their hand.] Right! This is math. Complicated math. This should be done by a computer. This shouldn’t be done by us. We have enough trouble counting carbs. I’m not more worried on these systems. I feel safer. I’m much more worried about access to having the system, and we’ll all have to work hard to address that.

Dr. Hood: At Stanford, we are running an artificial pancreas trial and we ask that question to our patients. By the end, most say that feel more confident in the system across the board. We’re still under 100 patients but that’s still a sizeable population.

Audience comment: I recently just completed the Bionic Pancreas trial. What I found was that does cause some negatives. I was rocking a fanny-pack with a lot of gear, but when it gets commercialized, all that will be gone. You can also physically hear the insulin and glucagon being injected which is nice. It’s really nice to see your glucose come up without you doing anything. I did have some nausea on day one, but that was minimal. It’s still early, but it was a pretty cool concept that is only going to get better and better.

Q: I’ve been a type 1 since 1989. I’m also a tech geek. However, I find that when I’m a switching patient from MDI to pump, diabetes management goes from something that’s been on a shelf and to something that is a part of their lives. It connects them more with their diabetes. What is your experience with that?

Kelly: What was life changing on closed-loop was not having to worry about hypoglycemia. I didn’t think I normally did that. But it is totally different, being on closed loop. I did have to worry about connectively, and we do need to reframe closed-loop conversations to understand that this is going to be a lot of work. I do think we need more people funding this so research can continue to move quickly.

Dr. Hood: The data on CGM in general suggests that there are mixed results. Some people find that it raises their worries and burden, but many think that there’s a great benefit to it.

Q: Have you found that patients gain weight on MDI?

Mr. Aldred: Yes. I’ve put on weight. I probably eat more now that I’m on a pump because I eat when I want to because I feel like I can. MDI was restrictive. In that sense, maybe the technology has helped me put more weight on. But if I did whatever I wanted to and didn’t have diabetes in the first place, then I probably would have put on a lot more weight already.

Q: Can you speculate on certain personality traits and whether they lend themselves to closed-loop?

Kelly: The more worried a patient feels about severe hypoglycemia, that would be a driver to the closed-loop. I think some people feel psyched to be a pioneer and to be a part of change. What I don’t think is a good profile is people who think closed-loop development should move as fast as consumer electronics. That’s just not going to happen. People who should go on the closed loop are people who will be given and who will have reasonable expectations early on and people who want to help move technology forward – also, people with significant needs (e.g., lots of severe hypoglycemia) that the closed loop can address.

Pumps and Continuous Glucose Monitoring in Youth – From Research to Clinical Use

Bruce Buckingham, MD (Stanford University, Stanford, CA)

After highlighting some of the findings from the T1D Exchange dataset, Dr. Bruce Buckingham provided a whirlwind tour of diabetes technology use in children and adolescents. As we have heard more broadly, Dr. Buckingham emphasized that infusion sets are currently the weak point in insulin delivery. He also discussed data from several studies investigating whether insulin brand or needle type affects infusion set health, concluding that there was no difference. On the closed-loop front, Dr. Buckingham explained that an artificial pancreas system will need to be able to detect infusion set failures, and that ideally, infusion sets would need to last for (at least) a week for use in such systems. 

• Dr. Buckingham found no meaningful difference between Novolog and Humalog, or between steel and Teflon needles in a handful of exploratory studies that explore the duration of use of infusion sets. Anecdotally, he commented that there is a strong sentiment among patients that Novolog makes infusion sets last longer and causes fewer occlusions than Humalog. However, the two rapid-acting insulins fared equally well in infusion sets in a small study of 20 subjects; there was no meaningful difference in infusion set survival at one week when either insulin was used and insulin precipitation occurred in every catheter to some degree. Similarly, Dr. Buckingham and his colleagues have also found no difference in infusion set survival at one week in their own studies. Notably, a group of their patients were able to use each infusion set successfully for 6-7 days, with no deterioration in glucose values.

Questions and Answers

Q: Could you tell us about the Bionic Pancreas? How long will it be until it is available?

A: The way we were using it was you had this brick, which had an iPhone and Dexcom and two Tandem pumps. It was a little clunky. Most of the homegrown systems are fairly clunky. People are moving toward making one integrated system. It will receive a signal from the Dexcom. There will be separate cartridges for insulin and glucagon, and they’ll be delivered at one infusion site. It will be much more integrated. The key is to get glucagon approved for pump use. No one has delivered glucagon long-term continuously. I think it’d be great if we could be fairly aggressive with insulin and have glucagon on the back end … the whole key in closed-loop control is adaptability. Everyone is different, so having a system that adapts is going to be key.

Q: We have had poor luck with CGM and getting patients to continue using it. Do you have any thoughts on how we can improve those numbers?

A: I think it’s always a matter of training and expectations and what they can expect out of this system. I think if you have a lot of false alarms and it becomes annoying, it tends to detract from use. Start out where you don’t get a lot of unnecessary alarms, and tell them how to use it so it’s functional for them. The Dexcom does very well in the hypoglycemia range, which has been a problem in the past. I think it’s a real improvement. One case I was going to show was an adolescent using a Dexcom, who was doing two blood tests a day – just enough to calibrate it. The patient based all boluses on the Dexcom. It’s not indicated, but that tends to make people use it more. The Abbott Libre is factory calibrated. In a few years, I think you’re going to see Dexcom and Medtronic have factory-calibrated products. If you have an accurate sensor, you can really use it to a large extent.

Oral Presentations: Moving Towards a Closed-Loop System

First New Year’s Night on Closed-Loop Control (CLC) at Home: Case Reports from a Multicenter International Trial of Long-Term 24/7 CLC (223-OR)

Stacey Anderson, MD (University of Virginia Health System, Charlottesville, Virginia)

Dr. Stacey Anderson presented data from an impressive six-site, multinational, at-home trial testing two weeks of overnight closed-loop and two weeks of 24/7 closed-loop using UVA’s DiAs (Dexcom G4, Roche pump, Android phone). Sensor-augmented pump (SAP) was the comparator, and she showed data from 24/30 participants. Her conclusion summed up the data in seven words – “SAFE during the day. HIGHLY EFFECTIVE overnight.” The primary endpoint of hypoglycemia (time spent <70 mg/dl) was halved overall (4% during SAP vs. ~2% during closed loop; p<0.05); the improvement was very marked at night, where time spent in hypoglycemia improved by more than two-thirds (3% to ~0-1%; p<0.05). Overall 24-hour time-in-range (70-180 mg/dl) improved a bit (66% in open-loop vs. ~73% in the two closed-loop phases of the study), as did overnight time-in-range (62% to ~71-74%). Overall, we would caution that this study was not randomized (the intervention was applied sequentially, pump only, SAP, overnight-only, 24/7 closed-loop), so it’s tough to draw conclusions about how well it works vs. a parallel control group; UVA’s ongoing Project Nightlight study will allow for that comparison. We’d also note that patients were doing fairly well at baseline (mean A1c 7.3%, range: 5.9-8.6%), meaning the ability to improve on open-loop control in terms of time-in-range was probably limited. The hypoglycemia data is certainly impressive.

• You can read Adam and Kelly’s personal experience in this study here – they found that the overnight algorithm was excellent (it treated to a target of 120 mg/dl by 7 AM), and the daytime algorithm erred on the side of conservative in this feasibility study. They both loved the overnight system and were glad to see the daytime version being tested to identify and work out bugs.
• Notably, the study has obtained a five-month extension, which will give longer-term, real-world data on the 10 subjects currently participating. The trial is now using the Share Receiver.

Outpatient Glycemic Control with a Bionic Pancreas in Preadolescents with Type 1 Diabetes (222-OR)

Steven Russell, MD, PhD (MGH, Boston, MA)

Dr. Steven Russell provided a deeper dive on data from the Summer Camp 2014 in pre-adolescents (first shown in October at CMHC 2014) – the findings were very consistent with other camp and adult studies. Full 24-hour data suggested an improvement in mean glucose (168 to 137 mg/dl; p<0.001), a significant reduction in hypoglycemia (time <60 mg/dl: 2.8% to 1.2%), and a strong improvement in time-in-range (70-180: 58% to 81%). Dr. Russell shared – for the first time we can recall – stratified overnight results (11 PM – 7 AM) from the study that showed very impressive nocturnal efficacy: A mean glucose of 122 vs. 168 mg/dl, a dramatic reduction in hypoglycemia (0.6% vs. 2.8%), and a striking 92% time-in-range (vs. 59% in open-loop). Mean insulin usage was identical in the two arms (0.68 u/kg/day) and mean glucagon usage was 0.29 mg/day. On the pivotal study front, Dr. Russell shared a new plan to pursue an indication for the Bionic Pancreas in patients eight years and older.

• His slide deck also featured a prominent picture of a six-year-old (!) on the Bionic Pancreas, reminding us of how ambitious the camp study really was – the bionic pancreas brick was the size of her chest!
• On the pivotal study front, Dr. Russell shared that the group’s new plan is to pursue an indication for the Bionic Pancreas in patients eight years and older (Dr. Damiano had previously guided for 10 and older). This is great to hear considering that the technology will likely be used off-label in populations where it is not indicated. It’s impressive to see the team going this young – certainly, it’s a population whose families will benefit tremendously from this technology.

Artificial Pancreas Improves Glycemic Control in a Multinight Outpatient/Home Study of Patients with T1D (224-OR)

Sue Brown, MD (UVA, Charlottesville, VA)

Dr. Sue Brown summarized new data from a multicenter overnight study of UVA’s DiAs closed-loop system. The randomized, crossover trial included 44 patients (baseline A1c 7.4%) and compared five nights of overnight (11 PM – 7 AM) closed-loop control in a hotel supplemented by daytime sensor-augmented pump (SAP) therapy to five days of SAP therapy. As hypothesized, analysis of the study’s primary arm demonstrated that overnight closed-loop control did manifest in improved 24-hour glycemic benefits - time-in-target increased from 71.5% on SAP to 78.3% on closed-loop therapy (p = 0.003). This finding was accompanied by a reduction in hypoglycemia as time <70 mg/dl dropped from 4.3% on SAP to 2.5% on closed-loop (p=0.004). Dr. Brown also summarized the results of an extension study in ten patients, who experienced five subsequent nights of overnight closed-loop control at home – Dr. Brown stressed that this was the first time DiAs was taken home in the US! In the home setting, overnight closed-loop marginally increased time-in-target from 71% to 75% and more than halved hypoglycemia from 4.9% to 2.2% (p < 0.05).

• As expected, both primary (n=44) and secondary (n=10) study sub-analysis showed that the 24-hour benefits were driven by the more impressive performance of the closed-loop system overnight.
  
  • Primary: In the multicenter study, mean blood glucose dropped from 155 mg/dl to 137 mg/dl (p<0.001), time-in-target increased from 68% on SAP to 86% (p<0.001), and time < 70 mg/dl dropped from 3.2% on SAP to 0.9% on closed-loop (p<0.001). See Table 1 below.

Table 1: SAP vs. Closed-loop Therapy under supervision

	Overnight			24 Hours
	SAP Therapy	Closed-loop therapy	P-value	SAP Therapy	Closed-loop therapy	P-value
Mean blood glucose	155 mg/dl	137 mg/dl	p<0.001	--	--
Time-in-range (70-180 mg/dl)	68%	86%	p<0.001	72%	78%	p=0.003
Time < 70 mg/dl	3.2%	0.9%	p<0.001	4.3%	2.5%	p=0.003

• Secondary: In the home study, mean blood glucose dropped from 161 mg/dl to 151 mg/dl (ns), time-in-target increased from 63% on SAP to 85% (p=0.07), and time < 70 mg/dl dropped from 3.7% on SAP to 0.6% on closed-loop (p=0.03). See Table 2 below.

Table 2: Overnight SAP vs. Closed-loop Therapy at home

	Overnight			24 Hours
	SAP Therapy	Closed-loop therapy	P-value	SAP Therapy	Closed-loop therapy	P-value
Mean blood glucose	161 mg/dl	151 mg/dl	ns	--	--
Time-in-range (70-180 mg/dl)	63%	85%	P=0.07	71%	75%	ns
Time < 70 mg/dl	3.7%	0.6%	P=0.03	4.9%	2.2%	p<0.05

• Ultimately, the findings are impressive, though not altogether surprising given where the field is now. Overnight closed-loop has been outstanding for year – the big question is whether any first-gen hybrid closed loop will actually be night-only – from what we saw at the JDRF night, it appears unlikely.

Day and Night Closed-Loop Insulin Delivery in Young People with Type 1 Diabetes: A Free-Living, Randomized Clinical Trial (221-OR)

Martin Tauschmann (University of Cambridge, UK)

Dr. Martin Tauschmann presented new data from the Cambridge group’s day and night study of closed-loop insulin delivery in adolescents. The randomized, crossover trial included 12 adolescents (10-18 years of age) and compared seven-days of closed-loop control to seven-days on CGM alone with a goal of assessing safety and efficacy. The findings were very comparable to prior results seen in Cambridge’s adults studies – the intention-to-treat analysis showed that mean time in target (70-144 mg/dl) increased from 53% to 71% and time <70 mg/dl decreased from 2.9% to 1.7%. Much of this improvement was attributed to the nighttime period – said Dr. Tauschmann, “The algorithm was very impressive overnight.” Indeed, mean blood glucose overnight on closed-loop control was 140 mg/dl vs. 175 mg/dl on CGM alone. Differences between the groups during the day were non-significant (169 mg/dl [closed-loop] vs. 185 mg/dl [SAP]) and Dr. Tauschmann was quick to acknowledge, “there is room for improvement” – we point out that much of the reason why the day doesn’t show significant changes is likely due to food, exercise, stress, etc – things the AP can’t meaningfully change due to the slow speed of insulin.  

• Dr. Tauschmann stressed that there were no differences between the groups in terms of total daily dose of insulin - 57.3 units/day (closed-loo) vs. 56.6 units per day (SAP). He noted, however, that there was a shift in distribution with the closed-loop system delivering more insulin as basal relative to SAP therapy.
• Dr. Tauschmann noted that the study was not powered to study hypoglycemia – that said, neither group experienced significant time < 70 mg/dl: 3.3% (SAP) vs. 3.7% (closed-loop). It was a big surprising to see that hypoglycemia was that high in the closed-loop arm, though we imagine most occurred during the day.
• We were impressed with the durability of the group’s closed-loop system, which was active for 91% for the study period. Dr. Tauschmann reported one closed-loop interruption per patient per day that was typically due to connectivity issues. He did acknowledge, however, that patients were asked not to use closed-loop control during strenuous exercise – the group’s goal long-term is to address this though, “[they] are not there yet.” His commentary certainly lends perspective to the impressive results the Bionic Pancreas has seen in the unpredictable camp setting.

Glycemic Control in a Large Cohort of Patients with Type 1 Diabetes (T1DM) Treated with Continuous Subcutaneous Insulin Infusion (CSII) (226-OR)

Lalantha Leelarathna, MD (Central Manchester University Hospital, UK)

Dr. Lalantha Leelarathna presented the results of a recent retrospective study that sought to: (i) evaluate the effectiveness of glycemic control in patients with type 1 diabetes in pumps; (ii) investigate the demographic factors associated with positive A1c changes; and (iii) compare the penetration of different pump models. The study used data from 422 patients at a single center in the UK, who primarily used pumps from Medtronic, Insulet, Animas, and Roche. Results indicated, unsurprisingly, that pump use was correlated with an improvement in glycemic control – the proportion of patients achieving an A1c < 7.5% increased from 19% to 32% after initiating pump therapy. There was also a significant correlation between pre-pump A1c and glycemic improvements. What was unexpected, in Dr. Leelarathna’s view, was the number of patients in poor control – notably, more than a third of patients had an A1c >8.5% and 11% had an A1c >10%. In our eyes, the findings highlight the challenges of managing type 1 diabetes in the real world and provide valuable perspective on the non-representative patients we see in clinical trials.

• Dr. Leelarathna highlighted a handful of additional findings that were thought were notable. We summarize those below:
  
  • Results indicated that there were no differences in A1c change between different pump users (p=0.22) or between those using durable pumps vs. the OmniPod (p=0.54). However, a higher percentage of patients using traditional pumps saw A1c improvements > 0.5% relative to those on OmniPod.
  • The breakdown of pump use by brand was: Medtronic: 42%; Insulet: 30%; Animas: 14%; Roche: 13%. These numbers are skewed significantly away from Medtronic relative to our worldwide full-year 2014 estimates – Medtronic (68%), Roche (10%), Animas (10%), Insulet (10%), and Tandem (2%). We assume whether this is a regional or center-specific preference – Dr. Leelarathna did not offer any commentary on this point.
  • 83 patients changed pumps during the study period with the majority switching from Medtronic to OmniPod. Dr. Leelarathna attributed this trend to the launch of second-gen OmniPod in late 2011 that, in his view, brought a big convenience factor to a lot of patients.

Questions and Answers

Q: When patients were switching from Medtronic to other models, they must have been going from an integrated CGM to another device. Did you account for this at all?

A: Unfortunately, the NHS does not routinely fund CGM. So there was extremely limited CGM use in our population. I don’t think that explains much difference in these patients.

Q: Do you have demographic data on what kinds of patients change to a patch pump from a traditional pump?

A: I can’t answer that at the moment. We are collecting more data though. We’re not sure whether there was a fundamental difference in these groups, and either way, it’s difficult to be sure in a retrospective study.

Q: Did you collect any data on hypoglycemia?

A: Because this was a retrospective study, we were not able to collect hypoglycemia data.

MD-Logic Closed Loop Control (ClC) for Automatic Type 1 Diabetes Meal Management (219-OR)

Revital Nimri (Schneider Children's Medical Center, Petah Tikvah, Israel)

Dr. Revital Nimri summarized new data from two DREAM consortium studies that aimed to optimize meal announcements in the group’s MD Logic closed-loop system (licensed to Medtronic). The first study (n=9) evaluated the safety and efficacy of four different insulin doses (0%, 70%, 100% and 120% of the meal bolus calculated according to the patient’s carbohydrate ratio) on glycemic control, while the second (n=9) determined if increasing the meal bolus by adding a dose equivalent to two hours of basal insulin can improve glycemic control further (known to patients as a “super bolus”). The unsurprising findings of the first study revealed that the optimal dose for an announced meal bolus is between 70% and 100% of the calculated pre-meal bolus – these brought patients’ mean blood glucose to 138 mg/dl and 131 mg/dl, respectively, while minimizing hypoglycemia. Time-in-range was maximized for the normal bolus (> 80% time-in-range) followed closely by the 120% bolus (though this was accompanied by hypoglycemia) and the 70% bolus. Moving to the second study, Dr. Nimri noted that the combined two-hour basal plus bolus dose significantly improved the postprandial glucose profile at both meals tested: breakfast (251 mg/dl vs. 199 mg/dl, p=0.03) and lunch (155 vs. 140, p=0.05). In conclusion, she suggested that the MD-logic bolus calculator should incorporate the two-hour basal profile into its algorithm, though acknowledged that the ideal bolus dose will be more variable depending on multiple day-to-day variables: meal-time, exercise, health, etc.

• Study Design: The two studies included 13 patients total (baseline A1c: 8.0%) with some overlap (nine in each trial). The first study included four sessions of 12 hours for each patient each with two meals, while the second study included two similarly organized sessions. The glycemic index of the breakfast meal was high (40) and that of lunch was low (14).

Questions and Answers

Dr. Roman Hovorka: How much insulin is 80% plus the two-hour basal dose? Does it come to 90%?

A: I don’t have a definite answer.

Dr. Bruce Buckingham: The one thing I’d point out is that at the lunch test in your studies you still have some insulin left over from breakfast bolus. That’s a confounding factor to take into account.

Q: Was carbohydrate done in a supervised manner? I just want to make clear that carbohydrate counting in real life is often less accurate than in studies.

A: We found that the controller can overcome 20% of errors for under- and over-bolusing, so I don’t think the precise accuracy is as important.

Oral Presentations: ADA Presidents Oral Session

Outpatient Overnight Glucose Control with Dual- and Single-Hormone Artificial Pancreas Systems in Type 1 Diabetes: Randomized Controlled Trials (383-OR)

Ahmad Haidar, MSc (Ecole Polytechnique de Montreal, Quebec, Canada)

Mr. Ahmad Haidar presented never-before-seen pooled results of two randomized crossover trials comparing overnight dual-hormone closed-loop therapy to single-hormone closed-loop therapy to conventional pump therapy, showing superior avoidance of hypoglycemia with the dual-hormone approach. The first study – published in The Lancet – compared three nights (11 PM – 7 AM) of each intervention in 33 pediatric patients (ages 9-17) in the camp setting. The second crossover study compared two nights of each intervention in 21 adults and seven pediatric patients at home. Dual-hormonal overnight therapy resulted in significantly less time < 72 mg/dl compared to both alternative treatment paradigms (1.0% vs. 3.1% [single-hormonal] vs. 5.1% [pump]). Perhaps more notably, the dual-hormonal approach resulted in only one hypoglycemic episode requiring intervention in 150 treatment nights (!) relative to 11 events and 29 events in the insulin-only closed-loop and pump therapy arms, respectively. Mr. Haidar showed traces demonstrating that the improvement in dual-hormonal glycemic control came largely during the first-half of the night when glucagon was heavily utilized to counterbalance the insulin stacking of the daytime – indeed, though the single-hormonal systems essentially suspended insulin delivery early on, it was often not sufficient to prevent hypoglycemia. In terms of glycemic control, Mr. Haidar noted that both closed-loop systems achieved mean blood glucoses of 122 mg/dl vs. 140 mg/dl for the conventional pump therapy arm. The findings are notable as the first “pseudo” head-to-head trials comparing insulin-only to insulin+glucagon closed-loop. Certainly, the overnight period is a testing ground, and the really interesting work will occur during the day. We look forward to seeing even more comparative data once the Bionic Pancreas team conducts its two glycemic set point studies (insulin-only and bi-hormonal) starting this August.

• Mr. Haidar stressed that there was not excessive glucagon usage (0.03 mg per night) or adverse symptoms reported in the dual-hormonal arm.
• Notably, there was not perfect parity in the trial designs or in the equipment used – Dexcom sensor + Roche pumps in the pediatric study vs. Medtronic sensor + pumps in the second study – though we still find the results very directionally interesting. Note that these are solely academic systems as opposed to technologies in commercial development.

Questions and Answers

Q: You noted that 35% of nights in the dual hormonal arm did not require glucagon. Do you have predictors for those nights?

A: No. But we wonder if the duration of diabetes was associated with that.

Q: What do we know about the nighttime snack schedule?

A: During the camp, the campers were snacking about one hour before sleeping. Most of the hypoglycemic we saw during the early night hours was related to the snacking bolus. In the home study, we provided a 120 g meal slightly before bed with a bolus on one night. But we did not have the daily snack in home study – that was only in the camp study.

Q: Do you think current insulin is too slow? It seems like patients have to have glucagon in order to compensate for the insulin.

A: When we looked at individual hypoglycemic events, we found that we get decreased insulin delivery before hypoglycemic episodes. We weren’t able to prevent hypoglycemia from previous boluses. However, when you look at the second half of the night, the stacking effect of insulin was not there anymore.

Q: The highest risk for hypoglycemic events was during the first half of the night. Did you try to help patients optimize their insulin delivery during the daytime? 

A: For the camp study, we tried to optimize the basal overnight rates for patients. One limitation is that both studies were using different settings. There was not parity between the camp study and home study.

Oral Presentations: Cardiovascular and Other Clinical Effects of Hypoglycemia

Restoration of Hypoglycemia Awareness and Prevention of Recurrent Severe Hypoglycemia in Long-Standing Type 1 Diabetes: Sustained Benefit and Improved Overall Glycemic Control Over 2 Years following Recruitment into the HypoCOMPaSS Multicenter RCT (352-OR)

Stuart Little, MBBS (Institute of Cellular Medicine, Newcastle University, Newcastle, UK)

Dr. Stuart Little presented impressive two-year follow-up results from the HypoCOMPaSS trial, a 24-week 2x2 factorial randomized control trial (RCT) conducted in 96 adults with type 1 diabetes and impaired awareness of hypoglycemia (IAH). The objective of the study was to compare analog MDI vs. insulin pump therapy, as well as to compare SMBG vs. real-time continuous glucose monitoring in patients with impaired hypoglycemia awareness. At the end of the 24-week period, patients returned to routine care – potentially switching back from MDI to CSII or vice versa – though access to CGM was provided to all initially randomized to this monitoring regimen. Two-year follow-up results demonstrated that – provided equal education and attention – hypoglycemia awareness in all patients has continued to improve following RCT completion. Impaired awareness has fallen from 5.1 at baseline to 4.1 at six months and, further, to 3.7 at 24 months (p<0.01 vs. baseline). Significant improvements have also been seen in the severe hypoglycemia rate – 8.9 episodes per patient-year during the 12 months preceding the study to 0.4 over the 24-month study period (n=69; p<0.01). Even more impressively, only 36% of patients have suffered a severe hypoglycemic event over the study period relative to 92% in the preceding 12 months. Despite the reductions in hypoglycemia, A1c still improved at 24 months (7.7% vs. 8.2% baseline; p<0.01). Overall, the findings speak to the value of education and better therapies – what is unclear is how the CGM compared to pump therapy in terms of driving the improvement. Dr. Little concluded that IAH can indeed be improved and that recurrent severe hypoglycemia can be prevented through strategies targeted at avoiding hypoglycemia while improving overall glycemic control. As a reminder, we saw one-year results from the HypoCOMPaSS trial at ADA 2013.

Questions and Answers

Q: Your randomized control trial was run for roughly half a year. However, the results at the end of the half-year persisted for up to two years. What do you think was the mechanism that led to this? Were the pumps the big difference-maker?

A: Yes. Patients avoided recurrent severe hypoglycemia because of the pumps. I wouldn’t say severe hypoglycemia was eliminated, but I do think that the education on hypoglycemia avoidance helped. It’s honestly impossible to tell the impact of pump therapy.

Q: Do you think the results were a consequence of the technology or a behavioral intervention?

A: A mixture of both. I think it was the holistic care.

Q: Some people have the technology and fail nonetheless. We tend to think the techno