September 13-18, 2015; Stockholm, Sweden; Full Report – Draft

Executive Highlights

In this final report (editor’s note – “final report” is our terminology for the complete report on a conference, as opposed to daily reports written at the time of the conference) - we provide our complete coverage of the 51^st Annual Meeting of the European Association for the Study of Diabetes (EASD), held in Stockholm, Sweden from September 13-18, 2015. The conference drew over 15,000 delegates from more than 100 countries, who attended a slate of 264 oral presentations, 30 symposia, 22 corporate symposia, and 1,202 posters – these figures are up slightly from last year’s meeting in Vienna in all categories except oral presentations (which held steady at 264) and posters (which dropped from 1,323).

To help you sort through our detailed full report, we’ve organized our commentary into ten categories: 1) GLP-1 Agonists; 2) Oral Drugs; 3) Insulin Therapy; 4) Outcomes Trials; 5) Diabetes Technology; 6) Novel Therapies; 7) Obesity; 8) Award Lectures and Additional Topics; 9) The diaTribe Foundation Forum: Solvable Problems in Diabetes; and 10) Exhibit Hall. Each section is also available as a separate document. Titles highlighted in blue are new additions that were not mentioned in our daily updates from Stockholm, and those highlighted in yellow represent what we felt were the most notable talks of the meeting – narrowing down this list was a difficult task, to be sure! We congratulate the organizers on a terrific 51^st annual meeting. We’re already looking forward to next year: September 11-16 in Munich, Germany.

Below we outline the key themes that emerged from the conference, followed by nearly 150 pages of detailed reporting. Enjoy!

Themes

Diabetes Drugs

• Speakers and audience members alike appeared very taken by the magnitude of the EMPA-REG OUTCOME results. In a wide-ranging conversation with us following the presentation, Dr. Silvio Inzucchi (Yale University, New Haven, CT) said that he was completely surprised by the results (he joked that his initial reaction was that there must have been some mistake, so strong were the results) and that he had assumed the trial would not be long enough to reveal any beneficial effects. Panelists in a Lilly/BI-sponsored symposium following the presentation seemed similarly flabbergasted. Dr. Naveed Sattar (University of Glasgow, UK) stated that “most of us were blown away” by the results and that no one could have predicted this outcome – we were “gobsmacked” he said. Like Dr. Inzucchi, Dr. Sanjay Kaul’s (Cedars-Sinai Medical Center, West Hollywood, CA) initial reaction was that the “unexpected and unprecedented” results seemed too good to be true, though he stressed that they were statistically robust. Count our team among those who were extremely surprised by the magnitude of the reduction in death and hospitalization from heart failure – particularly after the streak of neutral CVOT results in the past few years, a growing consensus seemed to be that the limitations of these trials (short duration, high-risk population, heavy use of concomitant medications, focus on glucose-independent effects) made it unlikely that they would produce anything other than neutral results. We did not think that would be true for the GLP-1 class though we simply weren’t sure about the SGLT-2 class.
• The mechanism of cardioprotection emerged as one of the biggest unanswered questions from the trial, though the consensus among speakers was that the diuretic effect was the most likely driver of benefit. Most of the past speculation about cardioprotection with SGLT-2 inhibitors has centered around long-term effects due to improvements in blood pressure, weight, HDL, and triglycerides. However, as Dr. Hertzel Gerstein (McMaster University, Hamilton, Ontario, Canada) convincingly argued through comparisons to other cardiovascular outcomes trials, this is not consistent with the immediate, dramatic effect on mortality and heart failure seen in this study – trials demonstrating cardioprotection driven by reductions in blood pressure or lipids have typically taken at least six months to a year to show an effect. As several speakers explained, the lack of an effect on MI or stroke also makes it unlikely that the effect was driven by blood pressure, which we had predicted would be the most likely mechanism. On the other hand, Dr. Gerstein noted that trials evaluating the effect of diuretics in patients with a history of heart failure have shown an effect on mortality almost immediately after randomization, suggesting that a similar mechanism could be at work here. Dr. Inzucchi echoed that hypothesis, suggesting that plenty of participants could have had undiagnosed mild heart failure and that simply removing fluid and eliminating some stress on the heart could have had a profound effect. Panelists in the Lilly/BI symposium (Dr. Kaul, Dr. Lawrence Leiter [St. Michael’s Hospital, Toronto, Canada], and Dr. Lars Rydén [Karolinska Institute, Stockholm, Sweden]) agreed that the results were unlikely driven by improvements in blood pressure, lipids, or weight (or glucose – see below) but also cautioned against attributing them entirely to a diuretic effect. As Dr. Kaul put it in that corporate symposium, “when you see ‘multifactorial’ or ‘multidimensional’ in a journal like New England Journal of Medicine, it’s usually a euphemism for ‘we don’t know.’”
  
  • These results provide yet another indication of the importance of heart failure in CVOTs for diabetes drugs. We have heard a number of speakers in recent years argue that heart failure should be part of the primary endpoint for these trials given its enormous clinical relevance for patients with diabetes, and these results certainly support that argument. In his talk on the implications of the results, Dr. Zinman characterized heart failure as an underappreciated outcome, noting that “if you have diabetes and you have heart failure, the epidemiological data shows you’re not going to do well.” If the hypothesis of a diuretic effect as the main driver of benefit is correct, it suggests that most of the mortality reduction with empagliflozin was due to prevention of deaths from heart failure. Indeed, Dr. Rydén pointed to heart failure as the most likely driver of reduced mortality, and Dr. Inzucchi and Dr. Sattar suggested that patients with heart failure (or at high risk for heart failure) would be a very intriguing population for further studies of empagliflozin.
  • There was a clear consensus that the benefit in this trial was not due to a glucose-lowering effect. While there was a slight difference in A1c (0.3%) between the empagliflozin and placebo groups at the end of the trial, presenters emphasized that the goal was to minimize the effect of glucose-lowering on outcomes in order to isolate off-target effects. This “glycemic equipoise” aspect of CVOT design has emerged as one of the main sources of confusion about interpretation of the results. In particular, we recently heard both Dr. Philippe Gabriel Steg (Université Paris-Diderot, Paris, France) and Dr. Allison Goldfine (Joslin Diabetes Center, Boston, MA) express concern about patients or providers interpreting neutral results from non-inferiority outcomes trials to mean that the drug in question is not efficacious.
• Speakers seemed to agree that a class effect is the most likely explanation for the positive results, though they repeatedly cautioned against over-generalizing from the results of one trial. Dr. Gerstein stated that the benefit is “probably” a class effect but cautioned that it is impossible to be certain. Dr. Sattar agreed that “if you asked us to bet, we’d probably say yes,” it is a class effect, but that the possibility of drug-specific effects has to be considered until the other trials are complete. The SGLT-2 inhibitor class has appeared quite homogeneous in clinical trials thus far and to our knowledge there is no mechanism that would predict a benefit of this magnitude that is specific to empagliflozin though it’s also clear this trial tests empagliflozin only. It would be interesting to think in the future about whether larger CVOTs make sense that use multiple agents (presumably this would be cheaper and faster rather than multiple CVOTs) and where the sub-groups would be large enough to allow analysis by drug. As Dr. Inzucchi noted, the main mechanistic difference between the three approved agents is selectivity for SGLT-2 vs. SGLT-1 (empagliflozin is the most selective for SGLT-2 while J&J’s Invokana [canagliflozin] is the least), but there is no reason at this point to predict that this would lead to a differential effect on CV outcomes. There is some surprise that this drug is third to market but first to emerge with superior CVOT results – it may well be that this is the trial with the sickest patients, of course, so that one that would logically prompt the highest number of cardiovascular events.
• The clinical and commercial impact of the results will be very interesting to watch. Our expectation is that guidelines committees (and payers) will want to wait for results from the other SGLT-2 inhibitor trials before designating the class as the preferred second or even first line option. It is also conceivable that the class could become the treatment of choice only for patients at high cardiovascular risk; while a number of speakers cautioned against generalizing the results to younger, lower-risk patients, it was asked several times in Q&A in the session and the symposium afterwards whether this drug could be considered first line therapy for patients at very high risk of cardiovascular disease. In practice, these results should certainly have some impact on prescribing patterns and will almost certainly help Jardiance gain some commercial and reimbursement ground against its more established competitors. We are also very curious to see if these results have an impact on pricing, as we imagine that some investors will be pushing hard for price increases. AZ fielded a question during an investor event late last year about ways to transition away from the cost-savings program that currently allows most patients with commercial insurance to access Farxiga (dapagliflozin) for free, and we expect that Lilly/BI will be facing similar sentiments. We also wonder whether the results could help boost sales for the companies’ new fixed-dose combination Glyxambi (empagliflozin/linagliptin) or give it an advantage vs. AZ’s saxagliptin/dapagliflozin combination (currently under FDA review) due to the contrast between these heart failure results and the increased risk seen with saxagliptin in SAVOR. From a patient perspective, we imagine those in formularies that favor Lilly and BI drugs will be happy; we wonder whether those that aren’t will be lobbying their HCPs for greater access.
• In light of the positive EMPA-REG OUTCOME results, we heard mixed commentary on broader CVOT policy. During a Lilly/BI-sponsored corporate symposium on the first day of the conference, Dr. Naveed Sattar (University of Glasgow, UK) advocated for more CVOTs in diabetes going forward because they are the only way to fully understand a drug’s cardiovascular risk. Similarly, Dr. Marc Pfeffer (Brigham and Women’s Hospital, Boston, MA) stressed the importance of evaluating hard clinical outcomes rather than relying on surrogate markers such as A1c to judge the effects of diabetes treatments. Following the full reveal of the EMPA-REG OUTCOME results, Dr. Hertzel Gerstein argued that the results represent a “perfect case in point” to prove that the claims that large outcomes trials are not necessary or useful are “really unfounded.” One of the leaders of the trial, Dr. Silvio Inzucchi (Yale School of Medicine, New Haven, CT), stated that he is now prepared to completely revise his previous assessment that these FDA-mandated trials are not worth the investment. We’re very curious whether the many other past opponents of the FDA’s 2008 CV Guidance have had a similar change of heart. This trial did reveal an unexpected and clinically meaningful benefit, and while officially, of course, it’s unknown if Lilly/BI would have undertaken the expense of a CVOT for Jardiance without the FDA mandate, we certainly believe they would have. We also believe that most companies would not have designed and executed the trials in exactly the same way were the CVOTs dictated by FDA – that’s a big part of the reason that we’d like to see CVOTs discussed again among experts and leaders in the field, since so much has been learned since the 2008 Guidance on CVOTs, which we do remember was implemented fairly quickly. As well, we feel that there are still many valid critiques of the current approach, several of which were noted by other speakers throughout the week (see below). We hope to see discussion in the coming years about potential modifications to the guidance that could lead to a more favorable cost-benefit ratio and ensure that these trials are answering the most relevant clinical questions.
  
  • On the more critical side, Dr. Lars Rydén (Karolinska Institute, Stockholm, Sweden) noted the limitations of CVOTs, including their short duration, disproportionately high-risk populations, glycemic equipoise design, lack of attention to postprandial glucose, and endpoints that do not include clinically relevant events like peripheral arterial disease, heart failure, and stable angina. Dr. Steve Bain (Swansea University, UK) cautioned that EMPA-REG OUTCOME’s positive findings should not be generalized to other CVOTs, again pointing to the short duration and high-risk population as factors that limit the potential for a superiority finding. For DPP-4 inhibitors specifically, Dr. Rury Holman (University of Oxford, UK) asserted that much longer trials would be needed to demonstrate a glucose-independent effect on cardiovascular risk with the class, a task that most companies would be unwilling to undertake. We’ll be watching closely as outcomes trials for other drugs report over the next year – we’re looking forward to the results of Novo Nordisk’s LEADER trial for Victoza (liraglutide) in particular.
• GLP-1 agonist/basal insulin fixed-ratio combinations also generated plenty of buzz at this year’s conference. During a Sanofi-sponsored corporate symposium, Dr. Robert Henry (University of California, San Diego, CA) shared brand-new positive topline results from the second phase 3 trial (LixiLan-L) of Sanofi’s LixiLan (lixisenatide/insulin glargine). Dr. John Buse (University of North Carolina, Chapel Hill, NC) presented data on the other major GLP-1 agonist/basal insulin combination on the radar: Novo Nordisk’s Xultophy (insulin degludec/liraglutide). A sub-analysis of phase 3 DUAL I data showed that Xultophy demonstrated broad efficacy irrespective of patients’ baseline A1c or BMI. In a separate talk, Dr. Buse conceptualized Xultophy as a novel drug rather than “just” a combination of the existing drugs and suggested that the product could be positioned as a second-line treatment option within the ADA/EASD algorithm – possibly even replacing basal insulin. Dr. Stephen Gough (University of Oxford, UK) offered similar arguments on the “pro” side of a debate over the utility of these combinations, noting that the benefits of the combination outweigh those of the individual components.
  
  •  We also heard a few points of criticism about this renowned class. Dr. Naveed Sattar (University of Glasgow, UK) questioned the incremental benefits of GLP-1 agonist/basal insulin combinations over GLP-1 agonists alone, citing the inability to titrate the drugs independently, less weight loss and more hypoglycemia than liraglutide alone, and cost as the main drawbacks. Representing the “con” side of the GLP-1 agonist/basal insulin debate, Dr. Leszek Czupryniak (Medical University of Lodz, Poland) similarly supported the option of putting patients on a GLP-1 agonist first and titrating insulin separately. However, even those who were critical of GLP-1 agonist/basal insulin combinations felt that they are appropriate for some populations and have a place among the plethora of available options.
  • GLP-1 agonist/basal insulin combinations have been one of the most-anticipated type 2 diabetes drug classes on the immediate horizon for some time, and the fact that even the “critics” see value in the class says a lot about its potential. Novo Nordisk recently [finally!] submitted Xultophy to the FDA following the approval of Tresiba (insulin degludec), and LixiLan should be submitted later this year. We hope to see this enthusiasm translated into broad payer coverage of the class, and Dr. Buse and Dr. Simon Heller (University of Sheffield, UK) both expressed optimism that payers would recognize the products’ clinical value. We were very disappointed by the recent “no additional benefit” ruling for Xultophy from the German IQWiG and hope this does not foreshadow similar negative assessments in other countries. We do not expect that it will, as the German system has consistently been one of the most conservative in terms of reimbursement for new diabetes drugs in recent years.
• New data on SGLT-2 inhibitors in type 1 diabetes provided more information about the class’ risk/benefit profile in this population. Phase 2 results for J&J’s Invokana (canagliflozin) in type 1 diabetes demonstrated significant placebo-adjusted reductions in A1c (0.3%), body weight (3-5 kg), and insulin doses (4-8 U/day) after 18 weeks but a dose-dependent increased risk of ketoacidosis. All ketone-related adverse events were associated with precipitating factors, and presenter Dr. Robert Henry (UCSD, San Diego, CA) suggested that the risk could likely be reduced in phase 3 with more frequent monitoring, lower doses, less reduction of basal insulin, and/or temporary cessation of treatment during illness or stress. In the same session, Dr. Anne Peters (USC, Los Angeles, CA) framed the DKA risk as significant but manageable and shared her own personal “recipe” for off-label use, which has had a 100% success rate so far. She also pointed to reduced glycemic variability as one of the most meaningful benefits of SGLT-2 inhibitors for her patients, albeit one that is perhaps more difficult to measure in clinical trials (CGM data from this study has not yet been analyzed). We also saw phase 2 results for Jardiance in type 1 diabetes showing similar placebo-adjusted reductions in A1c (0.3-0.5%), insulin doses (10-12%), and body weight (1.6-1.9 kg) after one month. Two participants in that study had extremely high ketone values, both associated with substantial reductions in insulin dose (~30-40%).
  
  • These results confirm that SGLT-2 inhibitors can offer meaningful benefits for many patients with type 1 diabetes, and that more work needs to be done to fully understand how to manage the risk of DKA. We hope that companies will continue efforts to understand how best to maximize the benefits and minimize the risks of this class in type 1 diabetes, perhaps by using lower doses or targeting specific subpopulations such as obese patients – we also believe simple education is needed and should be easy to implement – making sure patients know about ketones, about where ketone levels should be, how they can measure them, etc. Meanwhile, the clinical recommendations that emerge from the upcoming AACE/ACE workshop on DKA with SGLT-2 inhibitors should hopefully give providers more clarity on how best to manage the risk based on current evidence.
• Several studies pointed to glycemic variability as an important endpoint for patients but one that is perhaps difficult to assess in clinical trials. In her talk on the phase 2 results for Invokana in type 1 diabetes, Dr. Peters shared convincing personal accounts of the dramatic quality of life improvements her patients have experienced with the drug, primarily due to reduced glycemic variability. We are very eager to see CGM data from that study to see if those anecdotal accounts translate into clear quantifiable improvements and we believe Abbott’s new Freestyle Libre should be strongly considered to be used in trials along with other CGM technology. Earlier in the week, Dr. Johan Jendle (Karlstad Central Hospital, Karlstad, Sweden) presented CGM data from the AWARD-4 trial showing subtle but promising improvements in time in range and glycemic variability with Lilly’s Trulicity (dulaglutide) vs. Sanofi’s Lantus (insulin glargine) in combination with mealtime insulin. We suspect that those improvements, particularly the reduction in time spent in the hypoglycemic range, are meaningful for many patients, but it is difficult to know how convincing they would be from a regulatory perspective. The issue of glycemic variability also came up in a panel discussion on CV risk, with Dr. Pratik Choudhary (King’s College London, UK) noting that there is circumstantial evidence from studies like ACCORD in favor of increased risk with increased variability. Overall, we are glad to see CGM and glycemic variability being incorporated into clinical trials more frequently (phase 2 results for Biodel’s BIOD-531 presented at this conference also included an assessment of time in range) and hope that this trend continues. We hope that studies like FLAT-SUGAR can better illustrate the impact of reduced variability on patient quality of life and outcomes, though such studies are admittedly very challenging.
• It is clear that the bar for new diabetes drugs remains high. In type 2 diabetes, while we saw some data on entirely new drug classes (such as Teijin Pharma’s glucokinase activator TMG-123 and Isis’ novel insulin sensitizer ISIS-PTP1BRx), there appears to be a greater emphasis on making incremental improvements to existing drugs, such as basal insulins with longer, flatter profiles. This is consistent with what we have seen at major diabetes conferences over the last couple of years after poor results for several promising candidates, namely Takeda’s GPR40 agonist and Pfizer and Lilly’s FGF21 analogs. The positive EMPA-REG OUTCOME results will likely raise the bar for new type 2 diabetes drugs even higher, as candidates with similar efficacy and a neutral effect on CV outcomes could be considered inferior. The bar for new drugs to treat type 1 diabetes is also fairly high despite the relative lack of existing treatment options. Results for GLP-1 agonists in type 1 diabetes, including those from the Lira-1 study presented here, have fallen somewhat short of expectations. While SGLT-2 inhibitors have shown promising benefits, the risk of DKA remains a significant concern. A pre-conference session on immunotherapies for type 1 diabetes reviewed promising results for several candidates but illustrated the many challenges facing the field, particularly the lack of a clear definition of success, which could range from full insulin independence to transient improvements in C-peptide in some patients. We expect the bar for differentiation set by regulatory agencies and payers to only continue to rise in both areas given the increasing focus on reducing costs.
• This year’s agenda had a fairly substantial focus on complications. Cardiovascular complications occupied a substantial portion of speakers’ attention given the buzz around EMPA-REG OUTCOME and other recently reported CVOTs. Our sense is that the diabetes field is increasingly looking beyond glucose and moving toward a more holistic, outcomes-based view of interventions. Several speakers including Dr. Simon Heller (University of Sheffield, UK) and Dr. Stephen Gough (University of Oxford, UK) also referred to the immense amount of diabetes expenditures devoted to complications relative to treatments and expressed hope that payers, particularly in Europe, would take this into account when evaluating the cost-effectiveness of new expensive therapies. While microvascular complications received comparatively less attention, there were still a number of sessions devoted to the topic, including an analysis of the VISTA and VIVID trials of Bayer/Regeneron’s Eylea (aflibercept) showing equal improvements in visual acuity regardless of baseline A1c and on-treatment blood pressure.

Diabetes Technology

• Cambridge’s Dr. Lalantha Leelarathna headlined the artificial pancreas scene at EASD 2015 with results from two three-month, at-home, unsupervised closed-loop studies in tandem with a publication in the NEJM. He presented combined results from two crossover, randomized studies: 24/7 hybrid closed-loop in 33 adults and overnight closed-loop in 25 children and adolescents. Both used Cambridge’s MPC algorithm and compared closed loop to sensor-augmented pump therapy (Abbott Navigator 2, Dana R pump). Day and night time-in-range improved significantly in both studies, with a major ~20-25 percentage point improvement at night and a ~9-11 percentage point improvement during the day. Mean glucose followed a similar pattern, with an ~19-30 mg/dl improvement at night and ~9-11 mg/dl improvement during the day. This translated to an A1c reduction of 0.3% in adults (baseline: 8.5%, post run-in: 7.6%, end of closed-loop: 7.3%; p=0.002) and a 0.3% advantage in children (baseline: 8.1%, post run-in: 7.8%, end of closed-loop: 7.6%; p=0.17). Time spent in hypoglycemia (<50 mg/dl) was very low in both studies, though was still halved in children and adolescents (0.2% CL vs. 0.4% OL) and declined ~55% in adults (median times, 0.3% CL vs. 0.4% OL). The multicenter trials were very scientifically rigorous and included long run-in periods (four weeks and 2-8 weeks), did not have remote monitoring or dietary/activity/geographic restrictions, used sensor-augmented pump therapy as the comparator (harder than MDI), and represent the longest at-home data published to date. The reduction in mean glucose plus less hypoglycemia is an important finding for an insulin-only system. This also marks three straight years of automated insulin delivery trials in NEJM, following the Bionic Pancreas in 2014 and DREAM and ASPIRE In-Home in 2013. We salute the Cambridge team, who has really blazed a trail of ambitious, at-home, free-living closed-loop studies. We’re not sure what the team’s commercialization plans are, though hope there is something in the works. 
  
  • EASD brought yet another Bionic Pancreas vs. Cambridge debate on the merits of bihormonal vs. insulin-only closed-loop systems. This iteration featured Dr. Steven Russell and Dr. Leelarathna, who clashed over the added benefit of a second hormone. Dr. Leelarathna defended the insulin-only approach during Q&A following his lecture, noting that the added benefit of glucagon is incremental and limited to certain patients. His balanced criticism acknowledged the hypoglycemia protection and advantage of glucagon in achieving a  “fully” closed system, but also raised the typical criticisms: higher cost, complexity, and burden. Dr. Russell responded that the added benefit of glucagon will become much more apparent in the real world, given that patients in clinical trials tend to be motivated and very tech-savvy. The real test is how the average type 1 patient will handle the added demands of insulin-only systems (that require carb counting) and whether the impressive glycemic benefits and safety seen in insulin-only clinical trials will still be seen in these patients. Ultimately, we felt that both sides raised valuable points and that the debate speaks to the need for more comparative studies of single vs. dual-hormone systems. The Bionic Pancreas team is embarking on these studies now, and hopefully we’ll see data on this front next year. 
• Now one year on the EU market, talk of Abbott’s FreeStyle Libre turned to real-world use. Clinician and patient enthusiasm for the product is still sky high. It was valuable to see data from a 91-patient, ~9 month observational study of Libre users at a high risk for developing complications (baseline A1c = 10.1%). The data was strong for a device – especially in a tough and very real-world group – with three- to nine-month follow-ups from baseline demonstrating a mean A1c improvement of 1.4%. [Hypoglycemia was not reported, but presumably it declined or stayed the same.] These out-of-control patients are exactly the group that we hope FreeStyle Libre can make a real difference in. Abbott’s symposium also featured two conversations with current users; kudos to Abbott for putting patients on the podium. The device’s convenience was a recurring theme, with panelists highlighting the speed (vs. BGM) and discretion (vs. CGM) as significant advantages. Interestingly, Mr. Stephen Dixon – a type 1 patient – characterized his decision to choose Libre over traditional CGM as a “no-brainer,” highlighting the information availability (“I swipe 15 times per day and get 20 times more information than I would with 15 fingersticks”) without the “nightmare” alarms. On accuracy too, Mr. Dixon provided a stirring endorsement of Libre, noting that he has not done a fingerstick in ~12 months: “People say you must check Libre values against SMBG, but real life is real life.” We’ve heard that from a lot of FreeStyle Libre users. The two big questions on Libre are whether Abbott can scale to meet current demand (we continue to hear it’s hard to get), and when the consumer version will come to the US. We’ve never heard a public timeline on submitting FreeStyle Libre to the FDA; the blinded Pro version is currently under FDA review, with a launch expected next year. 
• Dexcom had an eventful EASD, announcing G5 European approval with a replacement claim, offering a first glimpse at the new sensor with partner Google, soft-launching the new web-based Clarity software, and announcing a direct G5 integration with diasend. At the time of the CE Mark announcement, launches in several European countries were expected in the “coming weeks.” Notably, the EU version of G5 has a replacement claim in the label: “The G5 Mobile System is designed to replace fingerstick blood glucose testing for diabetes treatment decisions.” Though G5 still requires two fingerstick calibrations per day, the move is important as Dexcom seeks to compete with Abbott’s factory calibrated FreeStyle Libre in the EU. Dexcom’s symposium also showed a first-ever picture of the prototype sensor with partner Google – it was the size of penny and a tiny bandage (see the picture below – actually smaller than we had imagined on the body). The partnership was only announced a month ago, though the pressure is certainly on to hit the goal of commercializing within ~ two to three years. EASD also saw a soft-launch of Dexcom’s new web-based Clarity software, featuring more robust pattern recognition and a better interface than the previous PC-based Studio offering. We love the “Best Glucose Day” report and the software’s minimalist interface. Last, Diasend announced integration with Dexcom’s G5, enabling CGM data to seamlessly flow into the data management platform (no cables!). Dexcom’s pipeline does not seem to be slowing down one bit!
• A brilliantly designed human factors study compared use of Locemia’s intranasal glucagon powder to a standard glucagon emergency injection kit in a simulated episode of severe hypoglycemia (a mannequin). The study included two groups to mimic realistic scenarios: (i) people with diabetes that taught a caregiver how to use the glucagon device a week prior to the simulation; and (ii) untrained participants with no connection to diabetes, who were shown the device and then asked to use it on the spot. In the key analysis, 94% of caregivers (15/16) correctly gave a full dose of glucagon with the intranasal device, and it took just 16 seconds on average. Conversely, only 13% of the same caregivers (2/16) delivered a full dose with the injection kit and 38% gave a partial dose (6/16); the average time for these eight individuals was 1 minute and 53 seconds (seven times longer than intranasal delivery). Shockingly, 50% of diabetes caregivers (8/15) failed to deliver any glucagon at all with the injection kit vs. just 6% (1/16) with intranasal. Even more frighteningly, two caregivers in the injection group mistakenly used insulin for the hypoglycemia rescue (cleverly included in the diabetes supply bag alongside the glucagon, to simulate a realistic hypoglycemia rescue situation), as they were confused about which injection to use. Whew. The results were equally strong for Locemia in the untrained acquaintance group. Overall, the data seem like a slam-dunk for Locemia’s needle-free device, especially as it seeks regulatory approval and future reimbursement relative to existing devices. We’ve always said that injected glucagon kits are burdensome for caregivers, but this is just dismal. The study also revealed an unexpected concern: is an injected route of glucagon delivery too easy to mix up with injected insulin? (Could that be a strong marketing advantage vs. glucagon competitors Xeris and Biodel, who both have pens?) Locemia has now reported phase 3 adult and pediatric data, showing equivalence to injected glucagon; we assume a submission could happen sometime early next year.

Obesity

• Similar to last year, we saw a minimal presence of obesity this year, with Novo Nordisk being the sole representative on the commercial front. Novo Nordisk’s two corporate symposia seemed to make up the majority of the conference’s discussion around obesity, with both symposia unsurprisingly focusing on GLP-1 agonists. Notably, these presentations have signified a greater move toward research surrounding the class’ mechanisms of action within the brain, as highlighted by Dr. Niels Vrang’s (University of Copenhagen, Denmark) talk on Novo Nordisk’s Saxenda’s (liraglutide 3.0 mg) actions on the brain’s GLP-1 receptors. Other than the discussion of obesity within the framework of prediabetes and prevention (see theme below), the meeting featured little additional material on obesity – this was also demonstrated by a lack of obesity’s presence in the exhibit hall, as Novo Nordisk did not even promote Saxenda at its booth (it is possible that obesity companies are saving their resources for meetings like Obesity Week – it’s also likely that resources have been reduced).
• The conference featured some focus on the latest research in how we can personalize prevention efforts in prediabetes and obesity. Two award lectures (the Claude Bernard and Minkowski lectures) examined the different phenotypes of those with obesity and prediabetes, stressing the need to better understand how to individualize prevention and early intervention efforts. Specifically, Dr. Hans-Ulrich Haring (University of Tubingen, Germany) noted that those with metabolically unhealthy obesity (vs. metabolically healthy obesity) are more likely to have fatty livers while Dr. Matthias Bluher (University of Lepzing, Germany) discussed how adipocyte size, visceral fat distribution, and adipose tissue macrophage infiltration are differentiated in the insulin resistant obesity phenotype. In addition, both lectures emphasized the importance of intervening early: Dr. Haring pointed out that early brain insulin resistance (as early as in utero) may contribute to obesity and Dr. Bluher echoed similar sentiments, suggesting that developmental genes may have an important role in differentiating adipocyte size and distribution. In understanding what mechanisms of action and “comorbidities” are driving certain conditions, the science in these lectures is critical in identifying which unique patient populations are most at risk. As we have repeatedly heard speakers call for better “prevention and early intervention” at various meetings, we were glad to see EASD feature the research that is tackling the biggest questions on how we can most effectively engage in these efforts. When thinking about the bigger public health implications, this new research can also make important waves in bringing us closer to developing targeted prevention and treatment of both obesity and type 2 diabetes, as scalability with such work remains a significant challenge.

Exhibit Hall

• The exhibit hall provided first looks at two new pumps: startup Kaleido’s colorful patch pump and Ypsomed’s own durable touchscreen, prefilled YpsoPump. Ypsomed plans to launch the YpsoPump in Germany and the Netherlands in 1Q16, with a broader EU launch to follow. We had a chance to demo the device, which felt slightly smaller than a MiniMed 530G with an iPhone-like, black-and-white, fully icon-driven touchscreen. We really liked the 160-unit prefilled insulin cartridge and wonder who Ypsomed’s insulin partner is. We might guess it is Novo Nordisk, who has a non-exclusive partnership with Roche for 160-unit prefilled NovoRapid cartridges for the Accu-Chek Insight pump. Overall, the combination of touchscreen, prefilled, and icon-driven could differentiate YpsoPump from other pump offerings in Europe. Speaking of, we unexpectedly came across Kaleido, a new patch pump company that debuted in Stockholm. The pump and paired handheld are currently in the CE Mark process, and the UK and Netherlands are the first planned launch markets “soon.” The approach resembles Cellnovo, giving patients two reusable pump units, a wireless controller handheld, and an insulin cartridge that connects to a short on-body infusion set (5 cm or 30 cm). The body-worn pump and iPod-like handheld are both quite slim, and the company has put a major emphasis on customizable color offerings. The pump cartridge holds 200 units, and the pump body is rechargeable, waterproof, and lasts for two years (the rep wasn’t positive on the latter). The handheld doesn’t have cloud/app connectivity or a built-in meter, downsides vs. Cellnovo’s handheld and the upcoming next-gen OmniPod PDM. We like the focus on making pumps cooler, though the key differentiator seems to be color – is that enough to distinguish Kaleido from everything else out there and coming along? The company making Kaleido is ViCentra, co-founded by Dr. Joesph Cefai, a principle founder of Cellnovo. We’re not sure about the IP and trade secret implications of that history.
• On the drug side, Novo Nordisk won the award for most forward-looking approach to the exhibit hall, with a booth devoted entirely to new arrivals Tresiba (insulin degludec) and Xultophy (insulin degludec/liraglutide) – the company is clearly going all in on products that it believes have transformative potential. Lilly/BI’s massive booth reeled attendees in with videos of baby animals accompanying the promotional materials for the newly launched Abasaglar (biosimilar insulin glargine). We were a bit surprised to see such heavy promotion for the biosimilar insulin, though this is consistent with Lilly’s past statements that it intends to market Abasaglar as it would any new branded product. Sanofi’s booth had a clear focus on Toujeo (insulin glargine U300), though it also reminded attendees that Lantus (insulin glargine) is still king with displays urging clinicians to “choose the one you know.” In this season of CVOTs, cardiovascular safety was a theme of the day: Merck’s booth was devoted almost entirely to the positive (aka neutral) TECOS results for Januvia (sitagliptin), and AZ’s booth emphasized the reassuring primary results from SAVOR for Onglyza (saxagliptin) and the beneficial effects on CV risk factors with Farxiga (dapagliflozin). 

GLP-1 Agonists

Oral Presentations: Growing Experience with GLP-1 Receptor Agonists

Once-Daily Liraglutide vs. Lixisenatide as Add-on to Metformin in Type 2 Diabetes: A 26-Week Randomized Controlled Clinical Trial

Michael Nauck, MD (Diabeteszentrum Bad Lauterberg, Germany)

Dr. Michael Nauck presented results from Novo Nordisk’s LIRA-LIXI study (n=404) demonstrating significantly greater A1c reductions with Novo Nordisk’s Victoza (liraglutide) vs. Sanofi’s Lyxumia (lixisenatide) as an add-on to metformin in patients with type 2 diabetes after 26 weeks (1.8% vs. 1.2%; baseline = 8.4%; p<0.0001). In addition, a greater percentage of patients in the liraglutide group achieved A1c targets of <7% (74% vs. 46%; p<0.0001) and <6.5% (55% vs. 26%; p<0.0001). As expected, liraglutide led to greater reductions in fasting plasma glucose compared to lixisenatide (51 mg/dl vs. 31 mg/dl; baseline = 187 mg/dl; p<0.0001). Lixisenatide had a greater effect on postprandial glucose immediately following the meal at which it was dosed, but there was no significant difference between the groups in terms of average postprandial excursions for all three meals. Liraglutide and lixisenatide had comparable effects on body weight (weight loss of 4.3 kg vs. 3.7 kg [~9.5 lbs vs. 8.2 lbs]; baseline = 101-102 kg [~223-225 lbs]; p=0.23) and blood pressure (treatment difference of 1.21 mmHg; p=0.37). Only the liraglutide group experienced a significant increase in heart rate, but Dr. Nauck attributed that difference to the fact that heart rate was measured at morning clinic visits when lixisenatide was no longer present in the blood. Liraglutide appeared to produce greater improvements in beta cell function (estimated by HOMA-B), likely due to the more continuous exposure. Rates of total adverse events and GI side effects were similar between groups. Liraglutide was associated with a 17% greater increase in lipase, which could potentially indicate an increased risk of pancreatic adverse events, though no cases of pancreatitis or pancreatic cancer occurred in the trial.

• These results certainly look good for Victoza, though as was discussed during Q&A, the relative benefits of the two products likely depend on the patient population. In particular, we would love to see a head-to-head study of liraglutide vs. lixisenatide as add-ons to basal insulin, where targeting postprandial glucose is the main goal. This is a very timely question for clinicians who will soon be able to choose between the two products as part of fixed-dose combinations with basal insulin (Novo Nordisk’s Xultophy [insulin degludec/liraglutide] and Sanofi’s LixiLan [lixisenatide/insulin glargine], respectively). However, these results should help cement Victoza’s position relative to Lyxumia for patients initiating injectable therapy; we see Lilly’s Trulicity (dulaglutide) as its main competitor in that population.

Questions and Answers

Q: Some would suggest that in patients with a lower baseline A1c, reductions in postprandial glucose are more important. Could including patients with a lower baseline have changed the results?

A: The relative importance depends on the fasting glucose. The question applies to those where you’ve fixed the fasting glucose with a long-acting insulin. There the results may look different. Here we’re talking about patients who are not well controlled at 8.4% on orals. There the effect on fasting glucose is very important.

Q: How do you explain the increased tachycardia with liraglutide?

A: That was not reported as an adverse event. We can’t rely on these clinical trials where the pulse rate is taken when patients come in to check blood pressure, etc. We now have several published studies using 24-hour monitoring and the data indicate that you have a rise in heart rate with any GLP-1 agonist as long as the patient is exposed to the drug. It’s transient for a couple of hours with lixisenatide and permanent with a long-acting agent that’s present all day.

Q: Lixisenatide seems to have a shorter half-life. Has it been dosed twice daily in any trials?

A: I know of one trial comparing once- and twice-daily dosing. There was a little trend toward twice-daily being better but the company decided to market it as a once-daily agent after that.

Q: What do you think the results would be for lixisenatide twice daily compared to liraglutide?

A: I shouldn’t speculate on that.

Continuous Glucose Monitoring in Type 2 Diabetes Patients Treated with Once Weekly Dulaglutide or Once Daily Glargine, Both Combined with Insulin Lispro (AWARD-4 Substudy)

Johan Jendle, MD, PhD (Karlstad Central Hospital, Karlstad, Sweden)

Dr. Johan Jendle presented data from a CGM sub-study of the AWARD-4 trial showing subtle but promising improvements in time in range and glycemic variability with Lilly’s Trulicity (dulaglutide) vs. Sanofi’s Lantus (insulin glargine) in combination with mealtime insulin. As a reminder, primary results from AWARD-4 (the first study to explore use of a GLP-1 agonist with mealtime insulin) demonstrated superior A1c reductions and less weight gain with Trulicity vs. Lantus in combination with Lilly’s Humalog (insulin lispro) after 52 weeks. This sub-study aimed to evaluate the products’ effects on time in range and glycemic variability in 144 participants who wore CGM for four 24-hour periods (baseline, week 13, week 26, week 52). 24-hour CGM traces at 26 and 52 weeks showed a reduction in blood glucose from baseline for all three treatment arms (insulin glargine and two doses of dulaglutide) but no significant differences between the groups. There was also no significant difference between groups in the primary endpoint of percent time with blood glucose between 70 mg/dl and 140 mg/dl. However, the higher 1.5 mg dose of dulaglutide did lead to a significant increase in percent time between 70 mg/dl and 180 mg/dl at 26 weeks compared to insulin glargine, though the difference had disappeared by 52 weeks. Both doses of dulaglutide also significantly reduced time with blood glucose <70 mg/dl at 52 weeks vs. insulin glargine. The higher dose led to a greater reduction in glycemic variability measured by within-patient standard deviation at 26 weeks, but there were no significant differences at 52 weeks.

• While perhaps not as conclusive as one might have hoped, these results do suggest that GLP-1 agonist/rapid-acting insulin therapy could lead to clinically significant improvements compared to basal/bolus therapy for some patients – we see the reduction in time spent in the hypoglycemic range as particularly meaningful. More broadly, we are always glad to see CGM data incorporated into clinical trials and hope that continued research in this area will lead to a better understanding of the impact of time in range and glycemic variability on quality of life and patient outcomes.

Questions and Answers

Q: With glargine did you actually teach people the fasting targets? Because the measurements demonstrated that they reached 7 mmol/l (126 mg/dl) but the target was 5.5 mmol/l (100 mg/dl). I wonder whether they actually would’ve gotten to target.

A: Both for the lispro doses and glargine the algorithms used titration to target. It was the Riddle and Bergenstal algorithm. They were titrated to the same target.

Q: I was slightly surprised to see hypoglycemia rates higher with dulaglutide 0.75 mg. Can you speculate why?

A: There is lower risk. It’s been shown in many studies, including a meta-analysis in the Lancet last year showing that is consistent for trials that combine insulin with a GLP-1 agonist.

Oral Presentations: Incretin-Based Therapy – Novel Agents, New Indications

A Randomized, Double-Blind, Placebo-Controlled, 39 Week Trial of ITCA 650 as Add-on Therapy in Type 2 Diabetes

Michelle Baron, MD (Intarcia, Boston, MA)

Intarcia Chief Medical Officer Dr. Michelle Baron reviewed the FREEDOM-1 results for Intarcia’s ITCA 650 first presented at ADA and shared a few new details. The trial (n=460) demonstrated ~1.1% placebo-adjusted A1c reductions and 2% placebo-adjusted weight loss with ITCA 650 after 39 weeks, with stronger glycemic efficacy in patients not on sulfonylureas. In this presentation, we saw hypoglycemia data for the first time: as expected, rates were low overall (2.6%-9.2%; all minor events) and driven primarily by the patients on sulfonylureas. While it was not included in the formal presentation, Dr. Baron noted during Q&A that ITCA 650 reduced systolic blood pressure by 2-3 mmHg, increased heart rate by 2-3 bpm (consistent with results for other GLP-1 agonists), and produced significant reductions in triglycerides with the higher 60 mcg/day dose; there were no differences in cholesterol between the groups. We are waiting with bated breath for full results from the FREEDOM-2 trial, which we assume will likely be presented at next year’s ADA – the topline results looked quite impressive, showing significantly greater A1c reductions (1.5% vs. 0.8%; p<0.001) and weight loss with ITCA 650 vs. Merck’s Januvia (sitagliptin). 

Questions and Answers

Q: Did you have a chance to look at blood pressure, heart rate, and lipid levels?

A: Yes. Systolic blood pressure was reduced by 2-3 mmHg. Heart rate was increased by 2-3 bpm, consistent with the rest of the GLP-1 agonist class. There were significant reductions in triglycerides in the 60 mcg arm and no changes in cholesterol.

Q: I’m always fascinated about delivery technology. Were there any problems about the devices migrating?

A: We have not had any migration. When the device is placed, some scar tissue forms around it and fixes it in place.

Q: You have equal efficacy on glycemic control but see dose-dependent efficacy on weight. Are there plans for advancing higher doses into obesity?

A: We’re certainly considering obesity.

Efficacy and Safety of Liraglutide Added to Insulin Therapy in Patients with Type 1 Diabetes: The Lira-1 Study

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

Dr. Thomas Dejgaard of the prestigious Steno Diabetes Center presented results, first presented at ADA, from the Lira-1 study of Novo Nordisk’s Victoza (liraglutide) in type 1 diabetes. The trial randomized poorly controlled, overweight patients with type 1 diabetes to liraglutide + 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 insulin-only group had caught up by 26 weeks (-0.6% vs. -0.4%; p=0.15). This is consistent with some anecdotal reports suggesting that the effect of liraglutide may “wear off” in some people with type 1 diabetes over time, perhaps necessitating cycling on and off it. Liraglutide did lead to significant reductions in body weight at 26 weeks (-6.1 kg vs. +0.23 kg; p+0.015), significantly less need for additional insulin (+4 units vs. +14 units; p=0.02), and a non-significant trend toward less hypoglycemia.

• Novo Nordisk recently declined to pursue a type 1 diabetes indication for Victoza following similarly modest results from the phase 3 ADJUNCT ONE and ADJUNCT TWO trials. In ADJUNCT ONE (n=1,398), liraglutide led to ~0.2% placebo-adjusted A1c reductions and 4-5 kg placebo-adjusted weight loss after 52 weeks, with no significant improvements in hypoglycemia. In ADJUNCT TWO (n=835), liraglutide produced 0.2-0.3% placebo-adjusted A1c reductions in the context of a lower insulin dose and 2-5 kg placebo-adjusted weight loss after 26 weeks. We suspect this may be a case of a mismatch between what is clinically meaningful for patients and the bar set by the FDA and especially payers. We imagine that this level of weight loss, hypoglycemia advantages that we suspect may be greater in a real-world setting, and possible reductions in glycemic variability likely add up to meaningful benefits for at least some patients. However, Novo Nordisk’s assessment is likely correct that such incremental benefits are unlikely to pass muster in an increasingly cost-conscious payer environment. We believe applications like oral GLP-1 may well work for type 1 patients and that the company will put its focus there.

Questions and Answers

Q: Was carotid IMT measured?

A: We don’t yet have those results. We did do the measurements but haven’t looked at the statistic yet. There will be a paper soon.

Q: Were these patients all IDDM?

A: Yes.

Q: From your clinical reasoning, what would be the indication to add a GLP-1 agonist in an overweight patient with type 1 diabetes? Would the anticipated weight reduction be a clinical reason by itself or would you anticipate other advantages?

A: Weight loss is very important. However, looking at glycemic variability, there could be something about patients who have difficulty with high and low sugars, they could have more stability with a GLP-1 agonist and reducing insulin.

Q: The side effects were similar to what we know for type 2 diabetes, but nausea was slightly higher in this study – more than 55%. Did you force everyone to go to 1.8 mg or to the maximum tolerated dose?

A: Only one patient didn’t tolerate 1.8 mg and they did the study on 1.2 mg. Patients were allowed to prolong the injection period so if they had nausea after decreasing to 1.2 mg they could do more at a lower dose for a maximum of six weeks.

Q: Were there increased hypoglycemic episodes? Did you measure glucagon?

A: We did measure postprandial glucagon. It was reduced over time but there was no difference between groups. We didn’t see increased rates of hypoglycemia.

Q: Were any patients on metformin?

A: No.

Oral Presentations: Incretin-based Therapy – On and Off Conventional Targets

Upper and/or Lower GI Adverse Events with Long- vs Short-Acting GLP-1 Receptor Agonists: Incidence, Co-Incidence, Effects on HbA1c and Weight

Michael Horowitz, MD, PhD (University of Adelaide, Australia)

Dr. Michael Horowitz presented results from an investigation of gastrointestinal tolerability of long- vs. short-acting GLP-1 agonists, an area that has not been well characterized to date. The study looked at differences in GI adverse event location (upper vs. lower GI tract) along with whether adverse events were associated with A1c or weight reductions. The analysis examined pooled safety data (n=1223; baseline A1c=8.5%) from three studies comparing once-weekly exenatide to twice daily exenatide (DURATION-1, DURATION-5, and NCT00917267) along with a single study (DURATION-6) that compared exenatide once weekly vs. liraglutide once daily (n=911; baseline A1c=8.4%). Results indicated that upper GI adverse events (e.g., nausea, vomiting) are more common with shorter- vs. longer-acting GLP-1 agonists (37% vs. 24% in the pooled analysis and 33% vs. 17% in DURATINO-6; p<0.001) and are more common in females relative to males (p<0.05). The incidence of lower GI adverse events (e.g., diarrhea, constipation) did not differ between GLP-1 agonists nor were GI adverse events associated with changes in glycemic control. Findings did suggest that the presence of upper GI adverse events may lead to weight reductions, though changes in weight were modest and were only observed in the pooled analysis. Ultimately, the findings are notable food for thought though we would love more insight into the mechanism that might be responsible for these differences – perhaps simply the differences in the pharmacokinetic profiles?

• The classification of GI adverse events was based on “standard terminology.”
  
  • Upper GI: Nausea, vomiting, regurgitation, gastro-esophageal reflux disease, impaired gastric emptying, hyperchlorhydria
  • Lower GI: Constipation and diarrhea
• We would point out a couple limitations in the study design: (i) DURATION-6 was conducted in a predominantly Caucasian population; (ii) and NCT00917267 was conducted in a predominantly Asian population. Considering these biases, we find it difficult to draw population-level conclusions from the data.

Questions and Answers

Q: I wonder about your interpretation of DURATION-6, specifically liraglutide vs. exenatide once weekly. Those are different in terms of the concentration when you inject them. I would interpret any differences as substance related. The doses might make a difference here.

A: You could be right.

Q: Did you notice any differences between ethnic groups?

A: Certainly GI agents are used in different concentrations in different populations, so we know that there are ethnic differences.

Posters

Efficacy and Safety of IDegLira (Combination of Insulin Degludec + Liraglutide), in Insulin-Naïve Patients with Type 2 Diabetes Uncontrolled on GLP-1 Receptor Agonist (GLP-1RA) Therapy (075-P)

S Linjawi, BW Bode, LB Chaykin, J-P Courreges, Y Handelsman, LM Lehmann, A Mishra, RW Simpson

This phase 3 trial found that the glycemic control of IDegLira (combination of insulin degludec + liraglutide) was superior to only GLP-1 therapy (liraglutide once daily or exenatide twice daily) in people with type 2 diabetes. In this open-label study, adults with type 2 diabetes who were uncontrolled on maximum GLP-1 therapy + metformin (and pioglitazone and sulfonylurea) were randomized 2:1 to IDegLira once-daily (n=292) or continued unchanged GLP-1 therapy (n=146). The results found that at 26 weeks, the IDegLira treatment group achieved significantly greater A1c reduction than the control group (-1.4% vs. -0.3%) from baseline A1c levels of 7.8% and 7.7%, respectively. With regards to the percentage of participants who achieved A1c levels <7%, 75% of the IDegLira group met this goal vs. 36% of the unchanged GLP-1 group (p<<0.0001); similarly, 63% of patients on IDegLira achieved A1c ≤6.5%, whereas 23% did so on unchanged GLP-1 combination therapy (p<0.001). A mean weight increase of 2.0 kg vs. a mean weight reduction of 0.8 kg occurred in the IDegLira and control groups, respectively (p<0.001). Hypoglycemic episodes occurred more frequently in the IDegLira group at 2.82 per patient year of exposure vs. 0.12 in the control (p<0.001), but both values represented relatively high tolerability. Overall, these results corroborate with previous studies on GLP-1 agonist intensification to supplement insulin therapy in demonstrating superiority over standard GLP-1 therapy.

Achieving the Composite Endpoint of HbA1c <7.0% (53 mmol/mol), No Hypoglycaemia, and No Weight Gain in the Once Weekly Dulaglutide AWARD Program (068-P)

J Fahrbach, I Raz, Z Skrivanek, W Sealls, K Dungan

This post-hoc analysis of the phase 3 AWARD program (all trials except AWARD-4) evaluated the efficacy of Lilly’s Trulicity (dulaglutide; 1.5 mg and 0.75 mg doses) vs. a range of placebo and active comparators with regard to the composite endpoint of A1c <7% with no weight gain or hypoglycemia. Results showed that significantly more patients achieved the composite endpoint at 26 weeks with 1.5 mg Trulicity than with metformin, Merck’s Januvia (sitagliptin), AZ’s Byetta (exenatide twice daily), or Sanofi’s Lantus (insulin glargine) (p<0.05 for all). There was no significant difference between Trulicity and Novo Nordisk’s Victoza (liraglutide). The 0.75 mg dose of Trulicity was superior only to Januvia and Lantus (p<0.001). These results provide a nice illustration of Trulicity’s holistic efficacy profile compared to other therapies, though it would have been interesting to see an SGLT-2 inhibitor included as a comparator as well. We would love to see such composite efficacy endpoints used more frequently as primary or key secondary endpoints in randomized trials of diabetes drugs, as we believe the field’s current A1c-centric view can overlook the enormous importance of weight gain and hypoglycemia for patients.

Symposium: Combination of Insulin Degludec/Liraglutide (IDegLira) – Key Results from the DUAL Programme

The Concept of Combining Metabolic Hormones/Proteins

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

Dr. Juris Meier suggested that it may be worthwhile to pivot GLP-1 combination therapy research toward newer therapies (e.g., secretin, cholescystokinin, and gastrin) and away from existing avenues of development (e.g., GIP and glucagon agonists). The commentary came during a presentation on GLP-1 combination therapies during which Dr. Meier acknowledged the class’s efficacy and tolerability relative to type 2 alternatives. Given this potential, Dr. Meier highlighted the interest in additive effects when co-administering GLP-1 agonists with PYY, GIP, and glucagon, summarizing the host of literature in this field. In particular, Dr. Meier highlighted the additive impact on energy intake of PYY and GLP-1 co-administration and the “interesting” combination of GLP-1 and glucagon co-agonists. On the latter, Dr. Meier expressed healthy skepticism based on a number of theoretical concerns: (i) the stimulation of hepatic glucose by glucagon; (ii) the fact that glucagon antagonists are also being explored in type 2 diabetes treatments; (iii) the synergistic effects on the induction of nausea; (and (iv) the synergistic effects to increase heart rate. Dr. Meier raised similar theoretical concerns about combination of GIP and GLP-1 co-agonists. He pointed out that GIP has already proven ineffective in patients with type 2 diabetes and that the drug counteracts the suppression of glucagon by GLP-1. Alternatively, Dr. Meier discussed the potential of exploring other hormones in the GI tract that he sees as far more promising and synergistic with incretin-based therapy: secretin, cholescystokinin, and gastrin. We haven’t heard about a lot of those and would like to know more. In closing, despite the progress that has been made in GLP-1 combination therapy (with respect to GIP, glucagon, and PYY), Dr. Meier argued that it may be worthwhile to refocus our efforts on other research areas moving forward.

Optimising Individualised Therapy and Improving Outcomes

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

Dr. John Buse opened his lecture on therapy optimization by discussing patient preferences. He shared a meta-analysis of “what is important to the patient about drugs,” showing that treatment benefits (e.g., glycemic control, weight loss) top this list followed by side effects (e.g., nausea, diarrhea) and burden (e.g., route of administration, frequency). In an echo of his presentation from day #1 of EASD, he then introduced Novo Nordisk’s Xultophy (insulin degludec/liraglutide) as a novel alternative that exceeds expectations on all these fronts. He presented sub-analyses (new to us) from the phase 3 DUAL-1 extension trial showing broad efficacy irrespective of patients’ baseline A1c, BMI, or pre-trial medication: (i) improvements in glycemic control across all A1c categories vs. component parts; (ii) improvements in hypoglycemia rates across all A1c categories vs. insulin degludec; (iii) improvements in glycemic control across all BMI categories vs. component parts; (iv) improvements in hypoglycemia rates across all BMI categories vs. insulin degludec; and (v) equivalent improvements in glycemic control regardless of baseline medications. See below for the detailed breakdown. Dr. Buse acknowledged that these across-the-board benefits make it difficult to identify a population of type 2 patients who would be ill-suited to treatment with Xultophy. It’s hard to argue with these data (though Dr. Leszek Czupryniak did just that in a morning debate on the same day), and we agree that this combination class is one of the most exciting advances on the near-term horizon for type 2 diabetes. We expect that cost will be the most significant barrier to widespread adoption of the class, and the inability to titrate components individually could also be frustrating for some patients.

• Xultophy led to improvements in glycemic control across all A1c categories vs. component parts. As Dr. Buse pointed out, this was just as true for patients in good control.

• Xultophy led to improvements in hypoglycemia rates across all A1c categories vs. insulin degludec. This was true even in patients with low A1cs where we would expect relative parity.

• Xultophy led to improvements in glycemic control across all BMI categories vs. component parts.

• Xultophy led to improvements in hypoglycemia rates across all BMI categories vs. insulin degludec.

• Xultophy led to equivalent improvements in glycemic control regardless of baseline medications.

Commentator

Naveed Sattar, MD (University of Glasgow, UK)

Dr. Naveed Sattar shared frank commentary on IDegLira’s phase 3 DUAL program, questioning the incremental benefits of the combination over GLP-1 alone. Dr. Sattar acknowledged the advantages of IDegLira (one injection instead of two, slower GLP-1 titration, less hypoglycemia and weight gain than insulin, ~0.5%-0.9% lower A1c than the individual drugs), but focused mostly on his view of the drawbacks: the inability to titrate the drugs independently, less weight loss and more hypoglycemia than liraglutide alone, and cost. Dr. Sattar called for a trial comparing the fixed-combination of IDegLira to a free combination of the drugs (start with liraglutide and titrate up basal insulin to target) – in essence, minimizing insulin to preserve the weight and hypoglycemia advantages of liraglutide as much as possible. Of course, this view also ignores the burden of two injections, which Dr. Sattar seemed to underestimate. In the excellent Q&A (see below), Drs. John Buse and David Russell-Jones tended to agree with Dr. Sattar in broad strokes, though Dr. Buse noted what is perhaps the most remarkable stat in the DUAL program: ~80% of patients got to an A1c <7% with IDegLira. A GLP-1 alone is clearly a great option when possible, but for all those patients failing GLP-1 alone, failing basal insulin alone, or stuck with two injections per day, IDegLira seems like an excellent option (assuming cost is not prohibitive). Dr. Sattar was less convinced, concluding that IDegLira “makes sense” and “has a role in a modest number of patients,” but more studies are needed to judge it.

• Dr. Sattar complimented IDegLira’s nicely conducted registration trials, an excellent faculty, and robust quality of life/patient-reported outcomes. He said the combination of degludec and liraglutide “makes sense,” and recommended reading an editorial from Dr. Stefano Del Prato (Lancet Diabetes & Endocrinology 2014).
• Is IDegLira a means to put degludec “back in play?” Dr. Sattar called insulin degludec “simple too expensive,” an opinion many of his colleagues also share. In our view, the focus should be on the benefits of the dual therapy rather than pricing of one – we believe the pricing is high merely because Novo Nordisk knew it wouldn’t be covered in most places anyway but could start a set of conversations.
• Dr. Sattar summarized IDegLira’s “potential benefits” and what he finds “less convincing.” The below summarizes both his slides and talking points.

Potential Benefits	What is Less Convincing
One injection instead of two	“Two is better than one, but yet, two is nearly always better than one in terms of glucose lowering, surely?
Slow titration of GLP-1 (less nausea)	Unable to alter basal insulin dose independent of liraglutide dose. “Our diabetes patients vary vastly in age, sex, weight, ethnicity – it’s hard to individualize therapy, and some clinicians and patients find this confusing.”
Less weight gain than insulin alone	IDegLira has more weight gain than liraglutide alone
Less hypoglycemia than insulin alone	IDegLira has more hypoglycemia than liraglutide alone
Patient preferences appeared strong / done well	Patient preference and quality of life done in open studies – potential for bias in reporting. Did the active group perceive they were on better treatment and this then influenced their responses?
Lower glucose levels than either component used alone (But modestly so – 0.5%-0.9% vs. each alone – fair comparison?	Cost, cost, cost. “If this was cheap as chips, it would have a bigger role.”

• Dr. Sattar proposed an “alternative clinical strategy,” starting with GLP-1 first and adding basal insulin independently. He reminded attendees that a few GLP-1s are now available, including once-weekly options. For those who do need basal insulin, Dr. Sattar recommended starting on top of GLP-1 and up-titrating the insulin – thereby minimizing hypoglycemia and maximizing weight loss (vs. the fixed-combination, which presets the insulin/GLP-1 doses). Dr. Sattar said IDegLira could be considered for those with persistent nausea on a GLP-1.
  
  • Dr. Sattar called for a trial comparing the fixed-combination of IDegLira to a free combination (start with liraglutide and titrate up basal insulin to target). Such a trial would compare all the standard outcome measures, including glucose, weight, nausea, hypoglycemia, and patient-reported outcomes. Dr. Sattar cautioned that this trial “requires some thought on how you make it fair” between the two arms.
• “Many require injectable agents at some point. Things have changed in my mind with EMPA-REG outcome. Where do we place SGLT-2s?” Dr. Sattar said that many are using SGLT-2s third and fourth line right now, but with empagliflozin’s positive CVOT results, the class may be used even earlier. Consequently, once patients get to injectables, they may be older and have more co-morbidities.

Questions and Answers

Dr. Buse: I generally agree with you. The advantages in an algorithmic way are much clearer vs. just insulin alone. That’s in opposition to GLP-1 alone as a choice. In the trials, 80% on IDegLira ended with an A1c <7%. The number that didn’t do well on IDegLira was quite small. But for those who go up 50 dose steps, what do you do then? That’s another remaining question. I think your comments are fair. There is likely a continued role for all three approaches. Starting with GLP-1, starting with insulin, and starting with the combination. Insulin alone is the weakest choice.

Dr. Sattar [responding]: I think that’s fine. [Laughter]

Dr. Russell-Jones: I agree with all. The use will vary country by country according to where it fits in. Speaking on the UK, what impressed me the most was people uncontrolled on basal insulin. This is a real potential way to go with intensification. The other group is the GLP-1s failures going to add insulin. This seems a sensible way to do it with lower hypoglycemia rates, etc. Those are the two areas in which this will have utility.

Dr. Buse: The other area I haven’t really thought about is when I see a patient that is very reluctant to go to the next step. This might be a patient where you might say – “This is the next step. You are very likely to get to where you want to be: below or near 7% without a lot of stumbles. For patients that are much more willing and adventurous, you could try one and switch to another. But if I only get one shot on goal, I do think this is the single best shot we have. Pun not intended.

Q: How many patients made it to the maximum dose?

Dr. Russell-Jones: In the first trial, it was around 50%.

Q: What do we do about that?

Dr. Russell-Jones: About 70% reached the target for those on the max dose. The number not reaching the target is small. There is an ongoing trial to look at a higher dose, or possibly a different combination.

Dr. Buse: I’m not sure if they were smart or lucky in the ratio of insulin and GLP-1, but it has worked out for the majority of patients. Some have wondered about a leaner ratio with more GLP-1, or a stronger ratio with more insulin for more powerful glucose lowering. Still, 80% of people getting to target is pretty good.

Q: I totally agree with Dr. Sattar on the trial design and outcome. But you might be forgetting one simple reason for the trials: there are a growing number of patients on insulin and GLP-1 taking two injections. Patient preference is a major player.

Sattar: You might be right, but you need to do that study. We’ve got more orals and more time between diagnosis and thinking about injectables. People are getting picked up earlier. They usually have some other co-morbidities. You’re right that patient preference might be one advantage of the combination. But until you do that trial, you don’t know if that is definitely the case.

Q: In Denmark, the Diabetes Association says that only a small fraction of spending is on drugs, and only 1.3% is on insulin. Sometimes we just fool ourselves in talking about cost. It just lets us say we don’t need to do anything, “It’s so costly...” As doctors, we are costly to the system. We need to be wider in our views.

Dr. Sattar: I agree. Costs, as a proportion, are modest. But the number of people with diabetes is going up. People are living longer. Drugs prices are going up. We can’t let this run away. What are the outcomes, and what do patients prefer? We don’t have enough data on outcomes. I would love to see long-term outcomes. If there is more hypoglycemia and less weight loss compared to liraglutide alone, what does that mean for long-term outcomes? I don’t know.

Michael Berger Debate: Do We Need Fixed Combinations of GLP-1 Agonists and Insulin?

Yes

Stephen Gough, MD (University of Oxford, UK)

This debate on the utility of GLP-1 agonist/basal insulin combinations featured familiar arguments in favor of the class and some less often cited points against it. Dr. Stephen Gough argued for the use of these fixed-ratio combinations, noting that they are “more than the sum of the component parts” in terms of efficacy, tolerability, safety, and quality of life. Specifically, he reviewed the positive safety and efficacy data from the DUAL trials of Novo Nordisk’s Xultophy (insulin degludec/liraglutide), pointed to the GI side effect disadvantages of free-mixing GLP-1 agonists and insulin, and noted the simplicity of the fixed dose combination for patients. These points echo those from Dr. John Buse in multiple presentations during this conference, and those we have heard repeatedly at conferences over the past few years as the DUAL trials have reported impressive results.

No

Leszek Czupryniak, Dr Hab N Med (Medical University of Lodz, Poland)

Dr. Leszek Czupryniak was tasked with what he acknowledged was the more difficult task of arguing against these combinations, but he joked that he had almost convinced himself by the time he was done. He suggested that the pathophysiological rationale for the combination is somewhat questionable since both components act at least in part by increasing insulin levels. He believes it would be more logical to start with a GLP-1 agonist and then add insulin if necessary; in our view, the answer likely varies depending on the patient (for example, the preferred approach would be different for someone with a very high baseline A1c vs. someone for whom weight loss is the main goal). Dr. Czupryniak also noted that the A1c reductions achieved in some trials of these combinations were fairly modest (~0.5%) and claimed that “you can do that with lifestyle in 90% of patients” for a fraction of the cost. Ugh – theoretical arguments like this make little sense to us – all that is needed is to look at the data to see how many patients are successful with lifestyle alone (maybe Dr. Czupryniak could let us know how he does it). Cost was one of the main drawbacks Dr. Czupryniak cited, and the one that we think will be most relevant for patients – of course the ROI of the drugs are rarely discussed (because ROIs are not calculated that we know of). Ultimately, while landmark study DPP shows he is correct that a successful lifestyle intervention can be more effective than the best new drug, the problem lies in implementation – we’d love to see routine implementation be programs that integrate therapy, technology, and lifestyle such as Omada or other behavioral programs.

Panel Discussion

Dr. Stephen Gough: I want to thank my colleague because I think it was a really entertaining talk. I hadn’t realized what a comedian you were. To bring it back to clinical science, I think you twisted the facts because the title was fixed-ratio combinations. The best way to treat diabetes might be to give a cup of tea but it doesn’t work. How many do achieve control when they titrate insulin? Maybe in your practice it’s different, but my patients don’t do it.

Dr. Leszek Czupryniak: Thanks for the compliment. That opens the door for my comedy career, though I would rather you say you were killed by my arguments and I have the finest mind in diabetes research. Seriously, I think we in central Europe and the UK differ in one measure and that’s the possibility of patient education. We like nurses, we like educators, people who work with patients on insulin and the mode of titration. The major barrier is initiating insulin. I was lucky enough in the past to spend time with Dr. Rury Holman and when I saw him working there he said “you need insulin,” and the patient probably knew who he was and said ok. In Poland we start negotiations that take weeks or months. Once they do it, we manage quite well to titrate insulin, especially basal analogs. Clearly we could do better with more nurses and education. I don’t see it as a major problem that we don’t get to targets with insulin. The next step is adding more prandial insulin, or we have GLP-1 agonists but the price is high. I did twist the facts a bit and used manipulation techniques, but that’s what debate is all about.

Q: What I don’t like is fixed-dose combinations. Why don’t we use once-weekly GLP-1 and have our hands free to titrate insulin?

Dr. Gough: It’s a good question. One of the things that we’re not saying is that one size fits all. What I’m saying is that we need to have a range of therapies so we can individualize the patient in front of us. While you may be right that fixed-dose combinations can be inflexible, clinical studies show that they work. The DUAL I study showed that 80% could get to target without weight gain and hypo. Of course, that won’t suit everybody but I think it’d be wrong to dismiss FDCs just because we can’t titrate separately.

Q: Do you think doctors should push more on the lifestyle side before entering the pharmaceutical realm?

Dr. Czupryniak: To be a bit more impartial, since we were playing our assigned roles here, I also think fixed-dose combinations have some benefits. One we haven’t mentioned is that patients take one injection with two agents. You can’t overlook that. It has nothing to do with individualization. I think we all feel a bit wary that we want to increase insulin or the GLP-1 agonist but we have to do the same with the other. We can’t compare it directly to a fixed-dose combination of oral drugs.

Q: What remains obscure is the side effects of the combination. The crucial point is whether it is paralleling those of insulin.

Dr. Gough: I’m not quite sure. In terms of side effects, we know there are side effects with insulin and with GLP-1 agonists, and if you take both together you are likely to get the side effects of both. When you take them the way they have been administered in trials, the side effects of each are less. You get the benefit of insulin and a GLP-1 agonist but you see less of the GI effects than with the GLP-1 agonist alone. It’s similar with basal insulin, where you expect to see weight gain and you know hypoglycemia is increased, and both of those are reduced or mitigated when they’re combined.

Q: Is there a logical explanation for that?

Dr. Gough: First of all, the final dose is less. From a GI point of view, there are probably lots of problems related to dose escalation, and it’s a simple titration algorithm with the fixed dose combination, so it’s a slow titration. We know there’s a glucose-sensitive mechanism with the GLP-1 agonist, which clearly offers a protective role when patients would be taking high doses of insulin.

Q: In a separate scenario, side effects would probably be bearable while free mixing?

Dr. Gough: It might be, but that’s not how we use them. We go in with a starting dose and then we go up to the bigger dose. Maybe we should be using GLP-1 agonists in a different way.

Q: Can you do any subtle titrations with GLP-1?

Dr. Gough: That’s where we tend to see more side effects.

Q: What about compliance and price?

Dr. Gough: I think compliance is good. There’s not clear data on that, but if you look at early patient-reported outcome data, it suggests it is well tolerated and patients prefer it to the individual components. On price, unfortunately the discussions always revert to drug acquisition costs. We don’t talk about the treatment costs of diabetes. We spend lots of money on diabetes and about 80% of it is on complications. Of course the acquisition costs are higher, though they’re not quite as high as you’ve explained because we don’t necessarily use those doses. But we should look at the treatment costs.

Dr. Czupryniak: The costs are substantial, and from a practical point of view we care more about the money spent by the patient, not the government. The cost will remain high because the drugs are effective and they’re new and you have to cover the expenses for development. Compliance is probably better, though I’d still argue that these are not necessarily drugs to use together in the majority of patients. I think it should be a sequential thing. It would be better for many patients to do earlier initiation of a GLP-1 agonist and maintain it further. In some of them some insulin will be necessary, and they might be eligible for a fixed combination. But a tight, fixed titration that doesn’t allow any changes is something where you might have serious doubts.

Corporate Symposium: Evolving Perspective in Treating Diabetes and Obesity (Sponsored by Novo Nordisk)

A New Choice for Diabetes Treatment: The Dual Approach

Stephen Gough, MD (University of Oxford, UK)

Dr. Stephen Gough reviewed the impressive results from the phase 3 DUAL program for Novo Nordisk’s Xultophy (insulin degludec/liraglutide; IDegLira) showing A1c reductions of 1.3%-1.9% with final mean A1cs below 7%, weight loss or weight neutrality, and low rates of hypoglycemia across all five trials. In addition, Dr. Gough noted that the DUAL I extension study supported the durability of Xultophy’s effects and the clinical applicability of its straightforward titration algorithm. Excitingly, Xultophy has finally moved a step closer to reaching patients in the US, having just been submitted to the FDA following the approval of Tresiba.

The Clinical Potential of the Dual Approach

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

Dr. John Buse offered a ringing endorsement of Novo Nordisk’s Xultophy (insulin degludec/liraglutide), suggesting that it may be more appropriate to conceptualize it as an entirely novel agent rather than a combination of existing drugs. The majority of his talk was spent reviewing some of the less-cited data from the DUAL phase 3 program for Xultophy, including patient-reported outcomes, safety of switching from basal insulin, efficacy stratified by baseline characteristics, and GI side effects. The results favored Xultophy across the board, in most cases compared to its individual components. He closed by explaining that he is increasingly conceptualizing Xultophy as a novel drug that offers greater tolerability/quality of life enhancements than either component and unparalleled efficacy among type 2 diabetes drugs rather than simply as a combination of two existing drugs. He suggested that while cost could be a significant barrier for some patients, there does not appear to be any clinical reason why any subset of patients would be a poor fit – that’s a big deal. We believe this therapy could just result in less “noise” and patients doing better for a longer duration – that would be excellent from a public health perspective, personal perspective, health professional perspective, etc. He suggested that Xultophy would be well placed as a second-line treatment option after metformin in the ADA/EASD algorithm, either in addition to the six existing options or even as a replacement for basal insulin – a provocative but logical argument given the greater efficacy and reductions in hypoglycemia and weight gain compared to basal insulin in clinical trials.

Panel Discussion

Q: Can you explain the mechanism of bradycardia in hypoglycemia?

Dr. Simon Heller (University of Sheffield, UK): I can’t entirely. In our paper we looked at sympathetic and parasympathetic tone during nocturnal hypoglycemia. When you’re asleep, sympathetic tone is suppressed. Our working hypothesis is that if you’re suppressing sympathetic tone, you get bradycardia due to unrestrained vagal action. That’s what we think is happening. That opens up the possibility of treatment or screening for the type 2 diabetes population to see if that is happening.

Q: What is the mechanism behind the lower hypoglycemia with IDegLira?

Dr. Stephen Gough (University of Oxford, UK): We know we see lower hypoglycemia with liraglutide, where clearly there’s a glucose-dependent effect on insulin and glucagon, so you’re reaping the benefits of liraglutide in the combination. They’re both important. There’s a great expectation that the mechanism through glucagon helps, so in type 2 diabetes we’re probably seeing that.

Q: Why do we see better GI tolerability with IDegLira?

Dr. Christopher Sorli (Billings Clinic, Billings, MT): From a clinical perspective, dosing and titration makes a big difference. We’re used to the GI effects of standard liraglutide dose increases, and with IDegLira we have the advantage of more precise, slower dosing over time. In most GLP-1 agonist studies it’s about a two-month phenomenon. Most GLP-1 agonists have rates close to placebo after then.

Q: What if we’re not at target with maximum IDegLira? What then?

Dr. John Buse (University of North Carolina, Durham, NC): Physicians are very creative, and we have lots of options of additional agents. I don’t think we have approval for adding insulin to IDegLira; that study hasn’t been done but it could be considered. Rapid-acting insulin is not approved for combining with liraglutide but it has been used with other GLP-1 agonists. There are lots of things that aren’t approved. Adding another oral agent is approved. In this program, the patients who didn’t get to 7% were only about 20% of the population. In general they were pretty well controlled. The other idea is to reinforce lifestyle and recognize that if you have an A1c of 7.3% or 7.6% maybe you’re doing as well as you can, and just reinforce adherence.

Q: What about adding an SGLT-2 inhibitor?

Dr. Buse: That’s what I was just thinking. We will hear very exciting results later. That’s an exciting combination. That combination of an SGLT-2 inhibitor and a GLP-1 agonist has not been extensively reported at all and for much of the population the SGLT-2 inhibitor is contraindicated because of its relative lack of efficacy in renal disease.

Q: A lot of people now talk about the titration period vs. the maintenance period and where to look at hypoglycemia. Where should we do it?

Dr. Tim Heise (Profil, Neuss, Germany): Both matter. The titration period is important for a patient going on a new insulin. If they experience hypoglycemia early, that’s frightening and it doesn’t strengthen trust. If you look at overall treatment duration, the titration period is 12-16 weeks and patients are usually on insulin for decades or many years, so that’s probably what counts more for the overall outcome.

Q: In Denmark we’re battling against other diseases like hepatitis C having expensive drugs. We just had a new report showing only 4% of money in diabetes is used on medications. The rest we give to cardiologists and nephrologists. What is the clinical value of fixed combinations?

Dr. Heller: We spend a small amount of money on medications compared to a huge amount on complications. In the UK, we spend 10% of the NHS budget on diabetes and it’s largely complications. There’s a perception that new drugs are too expensive to be used, and we struggle with reimbursement in the UK to persuade people that combinations are important. What we’ve seen this afternoon is pretty impressive results. NICE has bad press outside the UK and within, but they do take into account many things we talked about, like improvements in A1c and complications. We’ll wait for those evaluations but I have a sneaking hunch that when that stacks up, even though it’s extra money, they’ll come down in favor, particularly because the vast majority of patients have an A1c below 8%, which in the UK is unusual.

Dr. Buse: In the US the gloves are off as far as fighting about prices. It occupies a huge part of a doctor’s day making phone calls. I think this is a product that seems to have across-the-board potential. It is uniquely efficacious and extremely well tolerated. For patients who can’t take other therapies, this might be the last best hope. It’s not available in the US yet, but I’m hopeful the clinical value will be recognized and the price won’t be too high. We’ll see.

Corporate Symposium: Different Patients, Different Needs – Towards an Integrated Care Approach to Diabetes (Sponsored by Sanofi)

When It’s Time to Intensify: What are the Options?

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

Dr. Robert Henry presented an informative and opinionated view of options to intensify insulin therapy in type 2 diabetes, reviewing the data behind rapid-acting insulin and GLP-1 agonists in postprandial glucose lowering and presenting hot-off-the-press positive topline results from the second phase 3 trial of Sanofi’s LixiLan (lixisenatide/insulin glargine). Dr. Henry opened with a discussion of when intensification is necessary, noting that more than half of patients who initially achieve an A1c <7% can’t sustain it; the average time to failure is about 400 days. While these patients may be at target in terms of their fasting plasma glucose (FPG), their postprandial plasma glucose (PPG) may be high and using basal insulin is not sufficient. Dr. Henry demonstrated a clear preference for adding a GLP-1 agonist rather than rapid-acting insulin in such situations, noting that in head-to-head comparisons between GLP-1 agonists and rapid-acting insulins, the GLP-1 agonist arm demonstrated non-inferior A1c reductions, superior PPG changes, weight loss instead of weight gain, and less hypoglycemia. Dr. Henry concluded his talk by giving attendees a sneak peek at the GLP-1 agonist/basal insulin combinations on the horizon (LixiLan and Novo Nordisk’s Xultophy [insulin degludec/liraglutide)..

• Dr. Henry shared positive topline results released just hours earlier from the phase 3 LixiLan-L trial. The combination produced statistically superior A1c reductions vs. Lantus (insulin glargine) after 30 weeks in 736 patients with type 2 diabetes on basal insulin, with a safety profile reflecting those of the components. Secondary endpoint results were not shared, but we eagerly await details on LixiLan’s effect on weight, hypoglycemia, and GI side effects. We see basal insulin/GLP-1 agonist combinations as one of the truly exciting type 2 diabetes drug classes on the immediate or near to medium term horizon and look forward to seeing how the detailed results for LixiLan compare to those for Novo Nordisk’s Xultophy (insulin degludec/liraglutide), which have been very impressive.
• The positive LixiLan-L results follow the announcement of positive topline results from the phase 3 LixiLan-O trial, announced in July. LixiLan-O compared A1c reductions with LixiLan vs. Lyxumia or Lantus in 1,170 patients with type 2 diabetes on background metformin. As with LixiLan-L, the announcement shared only that the combination produced statistically superior A1c reductions compared to the individual components and did not comment on the secondary endpoints. Full results for the trials will be presented at a future conference.
• In its announcement, Sanofi confirmed its expected timeline of 4Q15 for a US LixiLan regulatory submission and 1Q16 for an EU submission. This is consistent with Sanofi’s guidance since its 1Q15 update. While Xultophy has a significant head start in the European market, the two may well launch in the US at around the same time, as we expect an FDA submission for Xultophy in 4Q15 as well (assuming a Tresiba [insulin degludec] approval in October as expected).

 

Oral Agents

Oral Presentations: Incretin-Based Therapy – Novel Agents, New Indications

Omarigliptin, A Once-Weekly DPP-4 Inhibitor, Provides Similar Glycemic Control to Sitagliptin in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin

Ira Gantz, MD (Merck, Whitehouse Station, NJ)

Dr. Ira Gantz presented results from Merck’s phase 3 O-QWEST program showing similar efficacy and safety of once-weekly DPP-4 inhibitor omarigliptin in comparison to once-daily Januvia (sitagliptin). The head-to-head, randomized, double-blind, non-inferiority trial administered 25 mg omarigliptin or 100 mg sitagliptin over a 24-week period to people with type 2 diabetes (n=642) who experienced inadequate glycemic control, despite being on metformin. The primary endpoints were non-inferiority of omarigliptin to sitagliptin in terms of A1c-lowering efficacy, number of participants who experienced at least one adverse event, and number of participants who discontinued the study following an adverse event. Secondary outcomes included change in fasting plasma glucose (FPG) and number of participants achieving A1c goal of <7%and <6.5%. The omarigliptin treatment group saw an A1c reduction of 0.47% while the sitagliptin group had an A1c reduction of 0.43% (baseline A1c was 7.5%), demonstrating no significant difference in A1c efficacy between the two groups (p=0.561). In addition, there was no significant difference in terms of proportion of participants achieving an A1c target of <7.0% or <6.5% (p=0.619 and p=0.212, respectively), change in FPG (p=0.069), and weight loss. Regarding the safety endpoints, there was no difference between the two groups in terms of hypoglycemia incidence and other adverse event measures including diarrhea, influenza, upper respiratory tract infection, urinary tract infection, lipase increase, and back pain. While the data is not particularly groundbreaking, these findings are reassuring as once-weekly formulations were not particularly expected to be superior to current once-daily inhibitions. In addition, a once-weekly DPP-4 inhibitor will likely reduce pill burden, providing greater convenience for patients, promote adherence, and – if priced right – lower copays and patient out-of-pocket expenses.

• In an accompanying press release, Merck reaffirmed its plans to submit omarigliptin for regulatory approval in the US by the end of 2015. Merck’s management first shared this timeline in the company’s 2Q15 update. Omarigliptin will be the first once-weekly DPP-4 inhibitor to market in the US, as Takeda opted to discontinue development of its once-weekly DPP-4 inhibitor Zafatek (trelagliptin) in the US and EU last year due to prohibitive development costs. Zafatek launched in Japan in June, however, making omarigliptin second-to-market in that market (as a reminder, omarigliptin was submitted in Japan in November 2014).
• According to ClinicalTrials.gov, the expected end date for the cardiovascular outcomes trial (CVOT) for omarigliptin has been pushed back to December 2020. This marks the third time the estimated completion date of the trial has been changed by several years; the original expected end date of 2019 was moved up to 2017 late last year. In addition to the CVOT, the phase 3 program for omarigliptin contains several trials projected to end in 2015 to early 2016. As a reminder, positive phase 3 results for head-to-head comparison of omarigliptin and sitagliptin in a Japanese population were presented at EASD last year.

Questions and Answers

Q: Apart from once-weekly administration, what’s the unique selling point here? Are there any advantages when it comes to kidney function?

A: I think a major selling point is that it provides options for patients as far as a weekly administration and allows a patient-centered approach. To answer your question about renal function, this does allow a bit of a broader dose adjustment than our other daily compound, sitagliptin. When you get into renal insufficiency and dialysis, a dose adjustment is possible.

Q: What is the mechanism of the increased half-life of this drug?

A: I think it is its affinity for the molecule and its low renal elimination – that’s basically the reason for its long half-life.

Oral Presentations: Management of Cardiovascular Risk Factors

Increased Risk of Cardiovascular-Related Events Associated with Sulfonylureas Compared to Other Antihyperglycaemic Drugs: A Bayesian Meta-analysis of Survival Data

Steve Bain, MD (Swansea University, UK)

Dr. Steve Bain presented results from a review of randomized control trials (RCTs) and observational studies that compared the risk of cardiovascular-related outcomes (all-cause mortality, cardiovascular-related morality, myocardial infarction, and stroke) associated with sulfonylureas vs. outcomes with all other antihyperglycemic drugs. The study examined 84 RCTs (n=36,573) and 26 observational studies (n=1,553,856), employing a “complementary-log-log link model” to obtain comparative hazard ratios for SUs (or SU + metformin therapy) vs. metformin, DPP-4 inhibitors, GLP-1 agonists, TZDs, and insulin. Findings from the RCT analyses demonstrated that treatment with SUs significantly increased the risk of all-cause mortality and cardiovascular-related morality (HR=1.26 and HR=1.46, respectively) when compared to every single alternative treatment. The suggestion of harm was not unexpected, and analyses of observation studies confirmed the trend. On the other hand, analysis of myocardial infarction was less demonstrative of harm – RCTs showed that the risk of MI for patients on SUs or SUs + metformin was significantly higher than patients on DPP-4 inhibitors and SGLT-2 inhibitors only (HR=2.54 and HR=41.80, respectively). We were surprised not to see a trend for GLP-1 agonists, in particular, though we believe the small sample size (the researchers only looked at two RCTs that examined GLP-1 agonists) impacted the results. Lastly, the analyses of stroke again supported the idea of harm from SUs – RCTs showed that the risk of stroke was significantly higher for SUs relative to DPP-4 inhibitors (HR=9.40) , GLP-1 agonists (HR=45.40), TZDs (HR=1.75), and insulin (HR=1.46). Ultimately, Dr. Bain noted that the findings confirm the risks associated with SUs – not particular surprising – and encouraged providers to be careful in utilizing these drugs in patients with elevated cardiovascular risk.

• Dr. Bain also cautioned that the positive findings from EMPA-REG OUTCOME (full results coming tomorrow evening!) should not be generalized to other CVOTs, specifically calling out Novo Nordisk’s LEADER trial for Victoza (liraglutide). He positioned the remarks not as a critique but as a realistic take based on CVOT trial designs that “are simply not powered to detect cardioprotection.” Dr. Bain pointed to the short duration of CVOTs and enrollment of high-risk patients (including in LEADER) as factors that limit the potential for a superiority finding. We have heard similar opinions from a range of thought leaders, though we wonder if the consensus will shift at all if EMPA-REG OUTCOME is able to demonstrate a substantial benefit. For LEADER in particular, Novo Nordisk Chief Scientific Officer Dr. Mads Thomsen has repeatedly expressed cautious optimism regarding the trial’s ability to show superiority. That said, the trial is powered for non-inferiority, not superiority, and the greater patient exposure relative to other CVOTs (mandated minimum exposure of 3.5 years per patient and total exposure of over 30,000 patient-years) may not be enough to illuminate a subtle benefit. In this sense, Dr. Bain’s remarks came as a valuable reminder of the importance of managing sky-high expectations in the coming days and weeks and resisting the temptation to over-generalize from a single study.

Second-Line Treatment with Sulfonylurea Compared to DPP-4 Inhibitors is Associated with Risk of Cardiovascular Disease, All-Cause Mortality and Severe Hypoglycemia

Jan Eriksson, MD, PhD (Uppsala University, Sweden)

Dr. Jan Eriksson presented data from a Swedish nationwide observational study that suggested that combination with sulfonylureas (SFUs) compared to DPP-4 inhibitors (with metformin) is associated with increased risk of severe hypoglycemia, fatal/non-fatal cardiovascular disease, and all-cause mortality. Data was collected from the mandatory Swedish Prescribed Drug Register linked with National Patient and Cause of Death registers between 2006 and 2013, with a median follow-up time of 3.1 years (n=40,736 for metformin + SFU; n=12,024 for metformin + DPP-4 inhibitor). Results demonstrated hazard ratios (adjusted for age, gender, fragility) for combination therapy with SFU vs. DPP-4 inhibitors at 2.1 for severe hypoglycemia, 1.2 for fatal/non-fatal cardiovascular disease, and 1.3 for all-cause mortality. In addition, the results found an association between severe hypoglycemia and fatal/non-fatal cardiovascular disease with a hazard ratio of 1.5, of which Dr. Eriksson suggested that hypoglycemia may be contributing to the increased cardiovascular risk associated with SFUs. Notably, baseline characteristics and the patient populations show a larger and older population on SFUs with greater proportions having a history of cardiovascular, kidney, and microvascular disease. With such limitations of observational data (although risk factor adjustments were completed), we hope to see greater research into the possible causal relationships between these treatments and observed complications.

Oral Presentations: Understanding the effects of SGLT inhibitors

Empagliflozin Reduces HbA1c with Lower Insulin Doses in Patients with Type 1 Diabetes: A 4-Week Placebo-Controlled Trial (EASE-1)

Thomas Pieber, MD (Medical University of Graz, Austria)

This randomized, double blind, placebo-controlled, phase 2 trial examined the effect of Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin 2.5 mg, 10 mg, and 25 mg) as an adjunct to insulin in type 1 diabetes over one month. CGM data was first presented in poster form at ADA in June (1241-p), and this abstract shared encouraging A1c results. After just four weeks on drug, A1c declined a significant 0.5% for empagliflozin 2.5 and 10 mg (baseline: ~8.3%; p<0.01) and 0.7% for empagliflozin 25 mg (baseline: 8.2%; p<0.01) vs. a 0.2% drop in the placebo group (baseline: 8.2%) Weekly mean insulin dose in the fourth week of treatment dropped 12-14% in the empagliflozin groups and 1.5% in the placebo group (p<0.05). Notably, the risk of hypoglycemia did not increase with empagliflozin. As would be expected, weight dropped 1.4-1.7 kg in the empagliflozin groups vs. +0.2 kg in the placebo group (p<0.001). No cases of DKA were reported, though the empagliflozin group saw slight increases (non significant) in beta- hydroxybutyrate levels. Two participants had extremely high values, one in the empagliflozin 2.5 mg group and one in the empagliflozin 25 mg group. Dr. Pieber noted that both participants had a substantial reduction in insulin dose (~30-40%) – perhaps that will emerge as a risk factor to identify type 1 patients at risk.  

Questions and Answers

Q: Well performed, interesting study. I have great reservations about use of this class in type 1 diabetes.

A: We have to do the clinical trials to see if there is a benefit. A dose finding study led to a phase 2 program. That will lead to a phase 3 program. Keeping the results in mind that empagliflozin in type 2 diabetes can reduce cardiovascular outcomes, I would hold against your statement. If something works in type 2 diabetes, we should definitely test it in type 1 diabetes.

Q: Did you look at those two cases with marked increases in ketones? What was going on? Was there a vigorous reduction in insulin doses?

A: Both subjects had higher ketone levels at baseline. Both subjects had a substantial reduction of insulin dose and risk of hypoglycemia. I agree with you. Later on when we will use this drug in type 1 diabetes, we must come up with defined guidelines on how to reduce insulin but avoid too much reduction to avoid the risk of DKA. Both subjects had a 30-40% reduction. Both had higher ketone levels at baseline. Maybe that’s a biomarker.

Q: You included people with a normal BMI. What is the rationale for making them lose weight? Insulin is important to maintain lean mass.

A: We did not plan the study to test the hypothesis that SGLT-2s are weight loss drugs. We do know that in most cases, if you intensify insulin therapy in type 1 diabetes, you inevitably see a weight increase of 2-10 kg. Those patients see an increased weight, increased blood pressure, higher lipids, and other increased cardiovascular risk factors. This could be good choice for patients with a weight problem. We saw data at a past EASD that those who gain weight with type 1 have a worst prognosis. This could be an options for those with weight problems that are unable to get better glycemic control.

Sotagliflozin, A Dual SGLT1 and SGLT2 Inhibitor, Improves Glycaemic Control in Type 1 Diabetes Mellitus in a Randomised, Placebo-Controlled, Double-Blind Study

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

Dr. John Buse presented phase 2 data on Lexicon’s SGLT-1/SGLT-2 dual inhibitor sotagliflozin (LX4211), first shown in detail at the ADA 2015 Diabetes Care symposium. 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 suggested that both the SGLT-1 inhibition in the gut and SGLT-2 inhibition in the kidney contributed to efficacy. There were two cases of DKA on sotagliflozin, and both were assessed as pump-related and not to study drug. Lexicon’s sotagliflozin for type 1 diabetes is currently in phase 3, with study completion expected in September 2016.

Dapagliflozin Reduces Albuminuria on Top of Renin-Angiotensin System Blockade in Hypersensitive Patients with Diabetes

Hiddo Lambers Heerspink, PharmD, PhD (University of Groningen, the Netherlands)

Dr. Hiddo Heerspink presented 12-week data demonstrating that dapagliflozin reduce albuminuria in patients with type 2 diabetes with hypertension. The meta-analysis pooled data from two studies for patients with type 2 diabetes, who were treated with dapagliflozin 5 mg (n=87), 10 mg (n=167), or placebo (n=189). All patients were on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy. At 12 weeks, DAPA resulted in greater reductions vs. placebo in patients’ albumin:creatinine ratio (ACR). Investigators also observed reductions in A1c, systolic blood pressure, and the estimated glomerular filtration rate (eGFR), though the latter was readily reversible after the last dose. Notably, dapagliflozin’s ACR-reducing effect was also present after adjusting for changes in HbA1c, SBP and eGFR, suggesting that the treatment effect was independent of changes in those variables. On the adverse event front, Dr. Heerspink noted that there were no serious renal-related events in any group, though there were five discontinuations overall (two in the placebo group; one in the 5 mg group; two in the 10 mg group). Ultimately, he concluded that dapagliflozin reduces ACR in type 2 diabetes patients using renin-angiotensin system blockade without increasing serious renal adverse events. The remaining question pertains to the mechanism of this action: Is it a class effect? Does dapagliflozin reduce inflammatory processes? Does it affect the glycocalyx (as Dr. Heerspink postulated)? Only additional studies will tell …

Questions and Answers

Q: If the impact on albuminuria was independent of changes of A1c and everything else, what’s your explanation?

A: It could be that the effect relates to a reduction in inflammatory processes, because experimental studies have shown that dapagloflozin can have anti-inflammatory effects at the tubular level. Or perhaps dapaglifloin has an effect on the glycocalyx and, thereby, reduces the albumin level.

Q: Is dapagliflozin renal protective?

A: We can’t say until we’ve done larger clinical trials. However, what we are seeing here suggests that it is renal protective. However, we have to take this into broader perspective, because we’ve seen other studies show changes in albuminuria that have been due to other effects that ultimately impact renal outcomes. We need long-term outcomes trials.

Posters

A Randomized, Double-blind Trial of Saxagliptin Add-on to Dapagliflozin + Metformin (802-P)

D Catrinoiu, S Matthaei, A Celinski, E Ekholm, W Cook, B Hirshberg, N Iqbal, L Hansen

This poster presented the efficacy and safety results of a randomized, double-blind trial of saxagliptin (AZ’s Onglyza) versus placebo as an add-on to dapagliflozin (AZ’s Farxiga) and metformin in adults with type 2 diabetes. Patients (n = 315; baseline A1c = 7.9%; mean age = 55 years; duration of diabetes = 7.7 years; mean BMI = 31.4 kg/m²) on stable metformin therapy (≥1,500 mg/day) for ≥ 8 weeks received open-label dapagliflozin 10 mg/day in addition to the metformin for 16 weeks. After the open-label period, patients with poor glycemic control (A1c 7%-10.5%) were randomized to receive either placebo or saxagliptin 5 mg/day as an add-on to the dapagliflozin and metformin therapy. The addition of saxagliptin resulted in significantly greater improvements in glycemic control after 24 weeks. A1c reductions were 0.51% with saxagliptin vs. 0.16% with placebo (p<0.0001), and 35.3% of patients in the saxagliptin group achieved an A1c <7% vs. 23.1% in the placebo group (p-value not given). Reductions in fasting and postprandial glucose were similar between the two groups, and both experienced a 0.5 kg weight loss.  The triple therapy was well tolerated, with adverse events balanced between groups. Hypoglycemia was infrequent in both groups and there were no cases of major hypoglycemia (symptomatic episodes requiring assistance) or discontinuation due to hypoglycemia. AZ highlighted this trial (and its counterpart presented at ADA evaluating the addition of saxagliptin to dapagliflozin + metformin) during an Investor Day late last year as part of an overall push toward early, aggressive combination therapy for type 2 diabetes. Management suggested that the results could eventually support a triple fixed-dose combination that would be submitted in 2017 at the earliest.

Symposium: Trending Topics in SGLT-2 Inhibition

Efficacy and Safety of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, as Add-on to Insulin in Patients with Type 1 Diabetes Mellitus

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

Dr. Robert Henry presented phase 2 results for J&J’s Invokana (canagliflozin) in type 1 diabetes demonstrating reductions in A1c, body weight, and insulin doses but a dose-dependent increased risk of ketoacidosis. The double-blind trial (n=351) randomized patients to receive one of two doses of Invokana (100 mg or 300 mg) or placebo as an adjunct to insulin for 18 weeks. A higher percentage of patients achieved the composite primary endpoint of A1c reduction ≥0.4% and no weight gain with both doses of canagliflozin vs. placebo (41% and 37% with the higher and lower doses, respectively, vs. 15% with placebo; p<0.001). Placebo-adjusted weight loss was 5.4% and 3.4% with the two respective doses of canagliflozin (baseline weight = 83-84 kg; baseline BMI = 28 kg/m²), and both doses produced placebo-adjusted A1c reductions of 0.3% (baseline = 7.9%-8%). Canagliflozin also significantly reduced insulin doses (by 8U/day for the 300 mg dose and 4 U/day for the 100 mg dose) and led to numerical but not significant reductions in fasting plasma glucose (placebo-adjusted reductions of 11 mg/dl and 9 mg/dl with the two respective doses; baseline = ~180 mg/dl).

• In terms of adverse events, there were no significant differences between groups for any hypoglycemia parameters, though the rate of severe hypoglycemia was numerically increased in the 300 mg canagliflozin group (7% vs. 3% with 100 mg canagliflozin and 2% with placebo). That is definitely not a positive though we assume that over a longer period of time as insulin dosing changes are managed better, this would go down. We would guess however that an FDA Advisory Committee would need a lot of advocates (who would show up) to get around this. We’d love to know how many severe hypos caused hospital visits. As expected, female genital mycotic infections were increased with canagliflozin (10 events and 9 events with the two respective doses vs. 6 events with placebo) though not by that much. Notably, there was a significant increase in ketone-related adverse events (11 events and 6 events with the two respective doses vs. none with placebo), including serious DKA (6 events and 4 events with the two respective doses vs. none with placebo). All events were associated with precipitating factors such as pump failure, missed insulin doses, or concurrent illness.
• Dr. Henry suggested that rates of DKA could be lower in future type 1 diabetes trials based on lessons learned from this study. While participants were educated about the risk and advised to test ketones in this trial, the full extent of the concern was not widely known when the study began, and future trials will likely include more extensive education for both patients and investigators. Investigators in this study were also advised to down-titrate patients’ basal insulin (by 10% for baseline A1c <8% or 20% for baseline A1c >8%) prior to initiating treatment, which will likely not be part of the protocol in future trials now that the association between reduced insulin doses and DKA risk is better understood. Dr. Henry also pointed to more frequent ketone monitoring, temporary cessation of treatment during illness or stress, and lower doses (such as 25 mg or 50) of canagliflozin as additional potential mitigating factors in future studies.
• We remain optimistic (perhaps it’s just hopeful) that J&J will choose to advance Invokana into phase 3 for type 1 diabetes. While it is debatable whether the benefit/risk profile would meet the FDA’s standards based on these results alone, Dr. Henry suggested during Q&A that one of the main goals of this study was to determine the most effective design for phase 3, and we suspect that with some alterations (such as lower doses of canagliflozin or a more obese study population), the benefits might more clearly outweigh the risks. We are also very eager to see the CGM data from this trial (patients wore CGM for a week before randomization and during the final week of the study), as reduced hypoglycemia and hyperglycemia may be among the most meaningful benefits of SGLT-2 inhibitors in type 1 diabetes from a quality of life perspective even if A1c isn’t different. 

Questions and Answers

Q: The conclusion might be that SGLT-2 inhibitors in type 1 diabetes work. They will improve A1c and quality of life, but you have to learn something. I think the approach of reducing the basal dose and not reducing the bolus dose so much was not right. We’ve seen in our studies, if you reduce the bolus dose you reduce the rate of hypoglycemia as well. The bolus dose was too high and the basal was too low in this case. It’s good to have experience for handling exercise. With acute exercise, you can cover it with carbohydrates or reduction of the bolus dose, but with the refilling phase of muscles we have no experience. It works but we have to learn.

A: The intention of the phase 2 study was to find out factors and features to modify before a definitive registration trial. This started before the whole concept of DKA in type 1 diabetes was recognized as an issue. We thought it might be but not at the level it became, in the 5-6% range. We learned a great deal, which will allow the development of additional studies to answer questions more clearly. I agree with your comment about not primarily reducing basal insulin, but that’s what we learned from this study. Most of the reduction if not all should be postprandial. From previous experience we thought basal reduction was appropriate. That’s the reason for doing studies, so you can design the next set to be more accurate. I’m confident we’ve learned a great deal. The paper with further details on DKA is under review now.

Q: Were adverse events any different between MDI and CSII treatment?

A: There was no difference. I think 38% of patients were on basal-bolus and about 62% on CSII and people on both types got DKA.

Q: Lexicon has presented data on its dual inhibitor with no DKA or no euglycemic DKA reported. Here we do see it. Do you think canagliflozin could be more prone to produce DKA than the dual inhibitor? Could it be mechanism based?

A: Canagliflozin’s SGLT-1 effect is transient in the first one to two hours when the concentration gets high in the proximal duodenum, but the effect is transient, not systemic. The concentration is very low to inhibit SGLT-1 in other parts of the body. I don’t believe there is any relationship between the contribution of SGLT-1 and ketoacidosis. There could be, but the SGLT-1 inhibition is so rapid and short-lived, it seems unlikely. Empagliflozin in short-term studies did develop ketoacidosis, though there were excessive reductions in insulin doses. The point is that empagliflozin is a pure SGLT-2 inhibitor and they got DKA. I don’t believe SGLT-1 is a component. It’s primarily an effect on glucagon and insulin in people with a precipitating factor.

Update on Ketoacidosis with SGLT-2 inhibitors

Anne Peters, MD (USC, Los Angeles, CA)

Dr. Anne Peters’ presentation focused specifically on the DKA results from the phase 2 trial of Invokana presented by Dr. Robert Henry, and on anecdotes from her patients about the less quantifiable benefits of SGLT-2 inhibitors in type 1 diabetes. She opened her talk with convincing personal accounts, including a video of one of her patients, about the dramatic improvements in quality of life Invokana can produce for people with type 1 diabetes, primarily due to reductions in glycemic variability. She noted that even some of her patients who have experienced ketoacidosis have begged to resume treatment afterwards and are able to manage the risk by testing ketones regularly and being aware of precipitating events. Based on the results from this study and her clinical experience, Dr. Peters framed the risk of DKA in type 1 diabetes as significant but manageable. She emphasized that every event in this study was associated with a precipitating event but also noted that the participants were all educated about the risk and how to manage it, suggesting that patient education is not a cure-all. In type 2 diabetes, she noted that rates of DKA have been very low in clinical trials, including EMPA-REG OUTCOME, and that all of the cases she has seen clinically have occurred following surgery. She closed by sharing her personal clinical protocol for off-label use of SGLT-2 inhibitors in type 1 diabetes (see below). Our take-home message was that successful off-label use of SGLT-2 inhibitors in type 1 diabetes is clearly possible when the patient and the provider are both very engaged and well educated about the risk. However, we suspect that the FDA will require a more robust body of evidence and a clearer understanding of the contributing factors and mitigation strategies before it would be willing to approve a broad type 1 diabetes indication.

• Dr. Peters shared her personal protocol for off-label use of SGLT-2 inhibitors in type 1 diabetes. She stated that she has not seen any cases of DKA since developing this “recipe,” but stressed that this is her personal approach and that it is key to continue doing trials to fully characterize the class’ risks and benefits.
  
  • Demonstrated adherence to treatment is a prerequisite. Dr. Peters stressed that she does not prescribe SGLT-2 inhibitors to patients who have not been adherent to insulin therapy and SMBG in the past. She also asks patients to do fingerstick ketone testing every day for a week before initiating the SGLT-2 inhibitor to ensure that they will continue to do so once they are on the drug.
  • Start the SGLT-2 inhibitor at the lowest dose possible. Dr. Peters will often prescribe doses of 25 mg or 50 mg and tell patients to break their pills in half or in quarters. Depending on future clinical trial results, we could imagine such low doses becoming the standard for type 1 diabetes.
  • Reduce basal insulin by 10% and adjust the dose based on glucose and ketone levels. Dr. Peters said that in most cases, patients’ glycemic control will improve with no change in ketones but that it is important to test regularly in this initial phase to be sure.
  • Stop the SGLT-2 inhibitor and test ketones in the case of illness, intensive exercise, or other potential precipitating events. Dr. Peters does not require that her patients test ketones regularly once they are stable on the drug, but she advises them to test if they get sick, reduce their insulin dose, start training for a marathon, etc., and to hold the SGLT-2 inhibitor if ketones are high.
  • If ketones are high in the context of normal blood glucose (<150 mg/dl), treat with carbohydrates, insulin, and liquids. She stressed that patients need to consume enough carbohydrates to be able to take enough insulin dose to correct the ketosis without becoming hypoglycemic. She also advises patients to have a sports drink or other sugary beverage on hand to replenish fluids and glucose in case they become nauseous or start vomiting.

Questions and Answers

Q: DKA in type 2 diabetes is a misdiagnosis. DKA in type 1 diabetes is related to illness. The problem you reported was that the first patient reduced insulin during inflammation, and the person in the video reduced insulin by 25%. I think it’s a mistake to reduce basal insulin because ketoacidosis is a sign of insulin deficiency and the treatment is insulin. If you’re taking an SGLT-2 inhibitor, it’s a clear prandial approach, and the problems with ups and downs come from bolus insulin. Remember the hypoglycemia rate from bolus insulin is 8-10 times higher than at night. It comes from miscalculation of carbohydrates and corrections. If you treat type 1 diabetes with an SGLT-2 inhibitor, you should reduce the bolus only. Don’t reduce the basal, especially in cases of illness.

A: I used to reduce prandial insulin as well. In the trial they reduced basal insulin, which I find slightly easier since you don’t get hypoglycemia at night. All of my patients were self-adjusting their prandial insulin, so they are reducing both. You have to reduce both because otherwise you get hypoglycemia. That’s why I give more insulin and carbohydrates when patients get sick. You have to balance carbohydrates and insulin. I monitor ketones as patients reduce the insulin dose, to avoid ketosis. It’s all a balance. These are well-educated patients, and even doing the best they can when they take the drug variability improves. To me it’s about patients finding their lives easier to manage because there’s a more predictable response to each prandial dose. I’ve found an approach that works for me, but there’s far more than one way.

Q: There were some cases with empagliflozin and sotagliflozin with fairly draconian reductions in insulin doses. Was that also true for the canagliflozin cases?

A: That’s a good question. We’ve submitted a paper with the details. It wasn’t quite as draconian but there was a trend toward higher risk with greater reduction. That’s why I stressed that it’s a balance. You have to eat enough carbohydrates to give enough insulin. It’s education.

Q: In patients with type 2 diabetes with DKA, have you measured lactate?

A: I’ve measured lactate in patients I’ve seen with type 2 diabetes and it was elevated but not highly elevated. I’m not as familiar with what lactate levels are supposed to be in DKA. It was also higher in patients with type 1 diabetes. I’m not sure what to make of the data. That’s why we need to systematically collect data.

Q: What advice would you give to a patient with type 1 diabetes who exercises heavily? Do they have to reduce basal insulin?

A: I had a patient who went to Disneyland where you walk like crazy and it’s hot, and she went into DKA because she needed so much less insulin. It is the same with any unexpected exercise. I tell people don’t take the drug if you are going to suddenly increase your exercise. If you’re running a marathon, hold the drug. I’ve trained people not to take it on a hike because you don’t want to be at risk. DKA resolves quickly once you don’t take the drug. Not taking it for a day or two is far wiser.

Q: So it’s not a drug for very active patients?

A: That’s why I get baseline ketones. These patients are active, so I thought I would see a lot more ketones at baseline. I take care of lots of athletes. I’m not sure I would give it to patients if they were doing triathlons, but in the off-season they could take it. It can vary depending on the circumstances.

Dr. David Matthews: I want to make it clear that we’re talking about off-label use. That’s important because otherwise manufacturers get into trouble.

A: My slides said off-label every time. I take all responsibility for off-label use and fully document what I do. That’s why I keep stressing that we need clinical trials. If you follow what I say, you can’t say I recommended it per se, but I am sharing what I do to help others if they choose to use SGLT-2 inhibitors in an off-label manner.

Symposium: DPP-4 Inhibition – 20 Years of Research

Translation into Clinical Practice

Carolyn Deacon, PhD (University of Copenhagen, Denmark)

In an evening presentation on DPP-4 inhibitors, Dr. Carolyn Deacon noted that once-weekly DPP-4 inhibitors are unlikely to have greater efficacy compared to once-daily formulations, but may improve patient adherence. She stressed that the once-weekly inhibitors are distinct chemical entities with inherent long durations of action, rather than solely molecular reformulations of currently available DPP-4 inhibitors. Showing some of the recent data from Merck’s omarigliptin and Takeda’s trelagliptin, Dr. Deacon explained that once-weekly formulations cannot inhibit the enzyme by more than 100% and thus will likely not exceed the efficacy currently seen in once-daily inhibitors; instead, she pointed to potential for patient adherence as the greatest value of these new developments. The degree of this advantage remains difficult to determine (and will likely also be influenced by cost); but as a reminder, a Merck-sponsored discrete-choice study has suggested that patients (particularly those who are younger) value the convenience of a once-weekly formulation. In our eyes, reducing pill burden could not only help with patient adherence but could also certainly help take away some of the psychological burden and consciousness of living with a disease for people with diabetes. However, we have heard commentary on once-weekly drugs ranging from the concern of patients forgetting to take their medications to the simplicity of changing to a “this is my Sunday pill” system – a decision on once-daily vs. once-weekly will likely ultimately depend on each patient’s individual preferences including age, lifestyle, and more.

Corporate Symposium: Lessons Learned from the TECOS CV Safety Trial and the Evolving Role DPP-4 Inhibitors in the Treatment of Patients with Type 2 Diabetes (Sponsored by MSD)

DPP-4 Inhibitors: What is the Latest Science?

Carolyn Deacon, PhD (University of Copenhagen, Denmark)

Dr. Carolyn Deacon presented some of the emerging data on DPP-4 inhibitors’ mechanisms of action, suggesting that the drug class may be acting through novel pathways other than the known effects through incretins. She briefed attendees on the history of DPP-4 inhibitors, stating that it has now been 20 years since the hypothesis of using DPP-4 inhibition in diabetes was published, with much of the class’ good tolerability derived from nine years of clinical experience and CVOTs. While acknowledging that much of the biology behind DPP-4 inhibitors’ anti-hyperglycemic effects is known, Dr. Deacon explored other potential mechanisms of action as she pointed to recent research showing that not all of the effects appear to be mediated through GLP-1. Specifically, some research has suggested that there are other substrates (non-incretins) that may be protected by DPP-4 inhibition – Dr. Deacon pointed to SDF-1 proteins as potential substrates as well as the diuretic and natriuretic effects that seem to be preserved without GLP-1 receptors. As the learning around this drug class continues, she noted that DPP-4 inhibitors’ actions may involve a wider range of endocrine, paracrine, and/or neural pathways than previously understood. Such research is certainly intriguing to pursue, as identifying these additional pathways can provide clues for novel targets in type 2 diabetes treatment.

Questions and Answers

Q: Do you see differences in the selectivity in various DPP-4 inhibitors?

A: Differences in selectivity have been shown in in vitro studies. This may be related to off-target inhibition. So there’s an interesting in vitro difference but we have no evidence yet of clinical impact.

Q: Do you confirm the benefits of DPP-4 inhibitors on bones?

A: A few studies have shown a small favorable effect on bone. But this is mostly in rodent studies. In clinical studies, there are no adverse effects but there are also no beneficial effects. It appears to be neutral in humans.

 

Insulin Therapy

Oral Presentations: Insulin Analogues – Is Newer Always Better?

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

Tim Heise, MD (Profil, Neuss, Germany)

Dr. Tim Heise presented data, first presented at ADA, from a randomized, open-label, 14-day study (n=75 patients with type 1 diabetes) comparing the PK/PD variability of Lilly’s basal insulin peglispro (BIL) and Sanofi’s Lantus (insulin glargine). Overall, the results suggested that peglispro had a flatter time-action profile than Lantus with a more evenly distributed glucose-lowering effect; the daily variability of both the PK and PD profiles was significantly lower for peglispro than for glargine. Dr. Heise suggested that this may result in easier titration, improved glycemic control, and reduced hypoglycemia with peglispro and that it may have contributed to the superior efficacy and reduced nocturnal hypoglycemia seen in phase 3 trials. We are glad to see more attention being paid to glycemic variability, which we see as an issue that is meaningful for patients but often overlooked by the scientific and regulatory communities. However, the translation to clinical practice remains unclear, - we do not know whether lower variability is linked definitively to improved outcomes since that is a major multi-year randomized control trial – we do think important first steps are making sure continuous monitoring of some kind, as it gets easier, is used in more trials and that observational data is also collected and analyzed. .

Questions and Answers

Q: The doses were 0.5 U/kg for both groups. Based on the previous talk you would expect BIL’s glucose-lowering effect to be less. How was glucose the same?

A: In general the doses were higher than the doses patients were used to because they needed a higher dose in the clamp study. There was not a lot of difference in glycemic control because we adjusted prandial insulin. There was a reduction by about 40% in either arm and no pronounced difference.

Dr. Larry Hirsch (BD, San Jose, CA): What did you use to do the injections?

A: They were done by site personnel who used syringes.

Q: What length needle was used?

A: That would be a good question for BD. I think 8 mm.

Q: I ask because your subjects had BMIs down to 20-30 kg/m², and based on data on skin thickness and subcutaneous fat, unless it was done carefully some injections probably went into the muscle, which could affect the kinetics of insulin and your entire findings. Most people don’t think so, but I’m wondering if it was a factor. It wouldn’t explain the flat profile of BIL but it might contribute to the change in kinetics for glargine.

A: That’s a good point. We trained nurses carefully and did the skin fold technique. From the PK results we didn’t have the impression that there were IM injections, but it’s hard to exclude completely.

Q: You explained that you’re switching off glucose production from the liver, but now you’re looking at uptake in muscle and there’s variability in switching it on and off. What’s happening in hepatic tissue?

A: We don’t have data. The study was done without a tracer. It would be worth doing in the type 2 diabetes population for which the impact on hepatic glucose production is most important, but we don’t have that.

Greater HbA1c Reduction with Basal Insulin Peglispro (BIL) vs. Insulin Glargine (GL) in an Open-label, Randomized Study in Type 1 Diabetic Patients: IMAGINE 1

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

Dr. Satish Garg presented results from the phase 3 IMAGINE 1 study (n=455 patients with type 1 diabetes) of Lilly’s basal insulin peglispro (BIL) first presented at ADA. The results showed strong efficacy but significant safety concerns consistent with those seen in other IMAGINE trials. Peglispro led to significantly greater A1c reductions (0.69% vs. 0.33%; baseline = 7.9%) after 26 weeks, and the difference was largely preserved out to 78 weeks, with glycemic control deteriorating slightly in both groups. There was a significant 22 mg/dl difference in fasting glucose at week 26 and a modest but significant reduction in between-day fasting glucose variability (p=0.026). There was also a 1.9 kg difference in body weight in favor of peglispro; the improvement began at six weeks and continued throughout the trial. At 26 weeks, there was a significant 36% reduction in nocturnal hypoglycemia but a significant increase in total and severe hypoglycemia with peglispro – we assume this would certainly raise concerns at the FDA, though Dr. Garg stressed that aggregate data from multiple phase 3 studies in type 1 diabetes showed no significant difference. Dr. Garg also attempted to provide reassurance about the significant increases in triglycerides, liver enzymes, and liver fat with peglispro, stressing that the magnitude of the difference was small and that there were no cases of Hy’s Law. While this data is certainly compelling in some respects, at this point the candidate’s future is uncertain – much will depend on the additional liver safety studies Lilly is conducting in lieu of an FDA submission this year.

Questions and Answers

Q: Was there a difference in dropouts between groups? Was there a difference in bolus dosing?

A: Guidelines were given in the protocol but it was up to investigators to adjust the insulin dose. There were more patients who dropped out because of local site reactions but not a significant difference. 80% completed the 78 weeks and the primary endpoint was at 26 weeks.

Q: A1c reductions were superior but I understand the rate of hypoglycemia was more frequent in the peglispro group, so if there was lots of hypoglycemia I suppose the results for A1c are due to the frequency of hypoglycemia and not the efficacy of the insulin. The dose of lispro decreased and there was more hypoglycemia despite less nocturnal hypoglycemia, but the frequency was too high. Please explain.

A: I wish I had more time to discuss this. Nocturnal hypoglycemia was significantly lower. Yes, overall hypoglycemia during the day was higher and that was partly due to prandial insulin. Even though the dose was reduced, the overall dose was lower so despite that, only during the day total hypoglycemic episodes were higher but not at night.

BIOD-531 Demonstrates Superior Prandial Glucose Control, Post-Meal Dosing Flexibility, and Less Insulin “Stacking” Compared to Marketed Prandial/Basal Insulins

Marcus Hompesch, MD (Profil Institute for Clinical Research, San Diego, CA)

Dr. Marcus Hompesch presented results, first announced in January, from a phase 2a trial (n=12) of Biodel’s BIOD-531 (U400 ultra-rapid-acting human insulin) in patients with type 1 or type 2 diabetes and severe insulin resistance. Results showed that BIOD-531 administered pre- or post-meal led to superior glycemic control vs. Lilly’s Humalog Mix 75/25 pre-meal and comparable control vs. Lilly’s Humulin R U500 pre-meal over a 24-hour period. Glycemic control was measured by mean glucose concentration and the percentage of measurements within the target range of 70-180 mg/dl – we were very encouraged to see “time in range” incorporated. In terms of postprandial control, pre-meal BIOD-531 was superior to both comparators given pre-meal (the primary endpoint of the study) and post-meal BIOD-531 was equivalent to both comparators given pre-meal. As Biodel has emphasized, the opportunity for flexible dosing without loss of efficacy is one of the product’s main selling points, as this aligns with how many patients dose their prandial insulin in a real-world setting. Another phase 2a trial in moderately insulin-resistant patients showed superior postprandial control and higher time in range with pre-meal or post-meal BIOD-531 vs. both Humalog Mix 75/25 and Humulin R U500 given pre-meal. Unfortunately, Biodel announced in its F3Q15 update in August that an ongoing phase 2b study of BIOD-531 had been temporarily placed on hold due to an FDA request for additional data on the company’s novel U400 syringe. This delay is certainly frustrating, but the issue appears to be manageable – as of the August update, Biodel had completed the required testing and planned to submit data to the FDA within the next few weeks.

	Average Postprandial Glucose (0-5.5 hours)	Average Overall Glucose (0-24 hours)	Percent in Range (70-180 mg/dl; 0-24 hours)
Pre-meal BIOD-531	165 mg/dl**	156 mg/dl*	70%*
Post-meal BIOD-531	178 mg/dl	150 mg/dl*	72%*
Pre-meal Humalog Mix 75/25	180 mg/dl	173 mg/dl	56%
Pre-meal Humulin R U500	178 mg/dl	154 mg/dl	70%

Questions and Answers

Q: The PK profile is biphasic but was C-peptide collected?

A: The hypothesis is that some of the formulation is readily available in a monomeric state, so there is a rapid onset of absorption and then it’s biphasic?

Q: Do you have CGM downloads?

A: We didn’t have CGM.

Oral Presentations: A Glimpse at Future Diabetes Therapy

Improved Postprandial Glycaemic Control with Faster-Acting Insulin Aspart in Individuals with Type 1 Diabetes Using CSII

Marek Demissie (Novo Nordisk, Soborg, Denmark)

Novo Nordisk presented a randomized, crossover, phase 1 study comparing 14-days of faster-acting insulin aspart to insulin aspart in 43 adults on Medtronic insulin pumps. The primary endpoint was two-hour postprandial glucose following a meal test, though patients also wore blinded CGM throughout the two weeks. Faster aspart showed an ~18 mg/dl postprandial advantage at two hours following the meal test (+55 mg/dl vs. +72 mg/dl; p=0.04), a clinically meaningful improvement in our view. The advantage at one hour was a bit lower at 9 mg/dl (+34 mg/dl vs. +43 mg/dl; p=0.08), a bit odd considering prior PK/PD studies showing a solid advantage for fast aspart in the first 30 minutes post-injection. Using blinded CGM over the 14 day treatment period, faster aspart was significantly better at both one at two hours after all meals, particularly after breakfast – the postprandial increase was ~10-12 mg/dl lower with fast aspart for all meals (p <0.005), and ~16-20 mg/dl lower with fast aspart following breakfast (p<0.02). Breakfast is where faster insulin will really shine in our view, setting up patients for more time-in-zone through the morning and middle of the day. On hypoglycemia (measured by CGM), faster aspart demonstrated encouraging results, reducing time below 70 mg/dl by 25 minutes per day (2.5 hours vs. 2 hours; p=0.008); overall event rates were not significantly different. There were slightly higher adverse events (99% vs. 79%) in the faster aspart arm, though the cause was not specified. Novo Nordisk reported topline phase 3a results for fast aspart in March, and in 1Q15, announced plans to submit in the US and EU around the end of 2015. We assume this would include a pump indication, but aren’t sure.

• If approved, how will the label for faster-acting aspart compare to Afrezza? As a reminder, Afrezza’s label does not currently include a faster-acting claim or a hypoglycemia advantage. Will Novo Nordisk be able to obtain either?
• Mr. Demissie suggested that the advantage of faster aspart vs. aspart may be of similar magnitude to the advantage of insulin analogs over human insulin. A study published this year (Heise et al., Diabetes Obes Metab 2015) showed fast aspart increases insulin action by at least 48% within 30 minutes of subcutaneous injection. The same comparison between aspart and human insulin yielded a similar advantage of 38%.

Oral Presentations: Optimizing the Insulin Treatment Paradigm

Effectiveness of Intensification Therapy in Patients with Type 2 Diabetes Who Used Basal Insulin Only

Reimar Thomsen, MD, PhD (Aarhus University, Aarhus, Denmark)

Dr. Reimar Thomsen presented data from a Novo Nordisk-sponsored observational investigation of how intensification therapies are used in the real-world setting. The study employed population-based hospital, prescription, and laboratory database to examine all patients who received their first basal insulin prescription in Northern Denmark between 2000-2012 (n=2,081). Findings revealed a number of interesting insights into basal insulin usage and the effectiveness of different intensification therapies: (i) that intensification with premixed insulin or a GLP-1 agonist reduced the median A1c by ~1%; (ii) that 22% achieved an A1c < 7.0% within 3-6 months; (iii) that 38% achieved an A1c < 7.5% within 3-6 months; (iv) that a similar number of patients on bolus and premixed insulin met A1c targets of 7.0% and 7.5%; and (v) that a greater number of patients on GLP-1 agonists met A1c targets relative to other intensification therapies. We would be cautious in generalizing the results of the latter findings considering that the strict time criterion (3-6 months) may have decreased the likelihood of achieving glycemic targets. However, as we have heard time and again, the results provide valuable perspective on the proportion of patients that do NOT achieve their glycemic targets even with treatment intensification (which speaks, in a big way, to the reality of clinical inertia).

• Ultimately, our biggest takeaway came from a slide depicting providers’ very “rational” approach to treatment intensification. As we would hope, providers only intensified treatment when patients’ A1c rebounded to high levels following an initial reduction on basal insulin. On the other hand, when patients responded to basal therapy, we saw that providers were unlikely to prescribe additional medications. Of course, these results are entirely consistent with what we would expect … though the fact that we see this in reality speaks to the utility of real-world guidelines and individualized therapy.
• Intensification with premixed insulin or a GLP-1 agonist reduced the median A1c by ~1%. Patient who intensified to bolus insulin did not see as significant of a reduction in A1c (~0.4%) – however, we do wonder whether these difference in glycemic improvement are associated with the different baseline A1cs as opposed the efficacy of therapy. After all, patients who intensified to a GLP-1 agonist, bolus insulin, or premixed insulin were relatively similar in achieving A1cs between 7.5%-8.0%. See below for details.

Results of Therapy Intensification

	Patients who intensified to GLP-1 agonist	Patients who intensified to bolus insulin	Patients who intensified to premixed insulin	Patients who intensified to > 1 drug
Sample size	326	893	1,798	59
Median A1c (before)	8.4%	8.2%	8.8%	8.9%
Median A1c (after)	7.6%	7.8%	7.9%	7.7%

Questions and Answers

Q: Do you know the financial standing of patients in the study?

A: No. Those data were not recorded.

Q: One thing you want to know when you choose between a GLP-1 agonist and basal insulin for a patient is BMI data. Do you have that? Also, if you use bolus insulin, you can titrate in a way that you can’t with a GLP-1 agonist. Do you have titration data?

A: Sorry. We don’t have either of those. BMI data are becoming increasingly available, but we didn’t have it for the full time period so couldn’t use it. For the titration data, they are just very difficult to get if you work with prescription data.

Oral Presentations: A Glimpse at Future Diabetes Therapy

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

Nina Wronkowitz, Dr. rer. nat. (German Diabetes Center, Düsseldorf, Germany)

Dr. Nina Wronkowitz presented mechanistic data, first presented at ADA, on Hanmi’s novel basal insulin analog HM12470, which has the potential for once-weekly dosing. The candidate was advanced into phase 1 earlier this year under the new name LAPSInsulin-115. In this study, HM12470 showed a similar receptor dissociation rate compared to regular human insulin in a rat cardiomyocyte (heart cell) line overexpressing the human insulin receptor. HM12470 also had similar mitogenic and metabolic activity compared to human insulin – this should help allay any fears of cancer-inducing activity with the candidate due to its long half-life and the insulin receptor’s role in cellular proliferation. Unlike regular insulin, HM12470 did not induce insulin receptor downregulation with chronic exposure (>24 hours), supporting the potential for a more prolonged effect.

Questions and Answers

Q: What is the linker? Does it play a role in the duration of action or timing?

A: The flexible linker is a peg linker, it has a size of 3.4 kD and is not responsible for the long duration. That is mainly due to the linkage to the non-glycosylated FC region.

Q: Does the compound bind to the IGF-1 receptor?

A: We have not done those experiments but Hanmi has prepared data and didn’t find increased binding to IGF-1 vs. regular insulin.

Q: Does binding require the insulin to be detached from the linker or is it the entire compound?

A: To our knowledge the complex stays stable. It’s not that the insulin is cleared.

Q: Is it because of the structure?

A: We can speculate but we think the high molecular weight will influence it.

Posters

Reduced Hypoglycemia is Observed With Inhaled Insulin Versus Subcutaneous Insulin Aspart in Patients with Type 1 Diabetes Mellitus (932-P)

E Nikonova, B Bode, J Gill, J Stewart, L Blonde

This poster presented the results of a retrospective analysis of a 24-week, phase 3 randomized study (n=339) of Sanofi/MannKind’s inhaled insulin Afrezza versus subcutaneous insulin aspart (Novo Nordisk’s NovoLog) added to basal insulin in patients with type 1 diabetes. The study looked at annualized hypoglycemia rates in the total population, patients taking more than one supplemental postprandial dose, and those taking no supplemental dose during both the dose adjustment period (0-12 weeks) and the stable dosing period (12-24 weeks). Several hypoglycemia parameters were evaluated, including total (all events), confirmed (blood glucose <49 mg/dl), nocturnal (12-6 AM), and severe (assistance required). Overall, results showed significantly reduced hypoglycemia rates (events per patient/year) for patients treated with Afrezza versus NovoLog. This was true for all categories of hypoglycemia in the overall study population (total 55.2 vs. 81.1; confirmed 9.0 vs. 15.0; nocturnal 5.9 vs. 8.8; and severe 0.5 vs. 0.9; all p < 0.05) and the subpopulation of patients taking ≥ 1 supplemental dose (total 96.3 vs. 60.9; confirmed 18.6 vs. 9.8; nocturnal 11.5 vs. 6.5; severe 1.1 vs. 0.6; all p < 0.05). In those not taking a supplemental dose, total hypoglycemia rates were reduced with Afrezza compared to NovoLog (46.0 vs. 64.9 events per patient/year; p= 0.016), but there was no significant difference in the other parameters. There was no significant difference in the number of supplemental doses taken between the two treatment arms.

• Afrezza’s current label does not include any formal hypoglycemia claim or any hypoglycemia data in type 1 diabetes. We were surprised and disappointed by this and know that it may be one of factors behind the product’s slow initial commercial uptake and reimbursement. We hope that the companies will conduct other trials in the future that could more definitively support such a claim, though our understanding is that the FDA’s standards in this area are very challenging to meet. Some of the FDA’s post-marketing trial requests do nt even make sense to us, such as the request for Afrezza to be used in heavy smokers – is that even an ethical trial to hold, or should those patients merely be advised not to take Afrezza? (We also can imagine this trial is challenging to execute – it is things like this that prompt small companies to move away from or not enter diabetes.)

Patient-Level Meta-Analysis of 1-Year Phase 3a EDITION T2DM Studies: Glycemic Control and Hypoglycemia with Insulin Glargine 300 U/ml (GLA-300) vs Glargine 100 U/ml (GLA-100) (975-P)

R Ritzel, R Roussel, A Giaccari, J Vora, M-L Grisoni, C Brulle-Wohlhueter, S Glezer, H Yki-Järvinen

This poster presented the results from a patient-level meta-analysis (n=2,496) of the phase 3a EDITION 1, 2, and 3 studies of Sanofi’s Toujeo (insulin glargine U300) vs. Lantus (insulin glargine U100) in a broad type 2 diabetes population. Both products produced equivalent A1c reductions of ~1.2% after six months (baseline = ~8.3%), but Toujeo provided more sustained glycemic control after 12 months compared to Lantus (A1c reductions of 0.91% vs. 0.8%; p=0.0174). The mean basal insulin dose at 12 months was 14% higher with Toujeo vs. Lantus (0.89 U/kg/day vs. 0.78 U/kg/day), due mainly to greater up-titration during the first 12 weeks. There were hints of reduced hypoglycemia risk with Toujeo, though whether the difference reached statistical significance depended on how the data was sliced. Fewer participants experienced ≥ 1 confirmed or documented symptomatic hypoglycemic event with Toujeo vs. Lantus during the night at the threshold of ≤70 mg/dl; the benefit was significant regardless of threshold (≤70 mg/dl or <54 mg/dl) for confirmed or documented symptomatic hypoglycemia at any time of day. Annualized rates of nocturnal confirmed or documented symptomatic nocturnal hypoglycemia were also significantly lower with Toujeo at the ≤70 mg/dl threshold but were not significantly different in any other categories. The extent of the hypoglycemia benefit is one of the main unanswered questions with Toujeo. The product’s label does not include a hypoglycemia claim, but feedback from clinicians has suggested that there is a clinically meaningful advantage for some patients in the “real world.”

Rapid-Acting Insulin Lispro Products SAR342434 and US-and EU-Approved Insulin Lispro Solution Show Similar Pharmacokinetics and Pharmacodynamics in Subjects with Type 1 Diabetes Mellitus (087-P)

C Kapitza, I Nowotny, A Lehmann, H Khatami, K Bergmann, B Rotthaeuser, R Becker

This study rendered SAR342434 as a biosimilar candidate, as exposure and pharmacodynamics activity of three formulations of insulin lispro – SAR342434, Lilly’s Humalog (US-approved), and Humalog (EU-approved) were shown to be similar. The study assessed 30 male participants with type 1 diabetes and a baseline A1c of 7.6% in a double-blind randomized trial, with each participant subject to each formulation with a 5-18 day wash-out period between treatments. Endpoints for the trials consisted of pharmacokinetic and pharmacodynamic profiles over a 12-hour 100 mg/dL glycemic clamp. Data from the trial demonstrated that the SAR342434 formulation had substantially similar profiles to the US and EU Humalog formulations in both pharmacokinetics, pharmacodynamics, and safety profiles. Specifically, the ratios of mean insulin concentrations over time for SAR343234, US Humalog, and EU Humalog fell within the 0.95-1.03 intervals. In addition, the ratios of mean weight-standardized glucose infusion rates for the same three formulations fell within the 1.00-1.07 intervals. The similarities in endpoints coincide with similarities in safety profiles, as all formulations posed no safety concerns nor tolerance issues, thus supporting the candidacy for SAR342434 as a biosimilar in the EU.

Superior Reduction of HbA1c in a Double-blind, Randomised Study of Basal Insulin Peglispro (BIL) vs Insulin Glargine (GL) in Patients with Type 1 Diabetes: IMAGINE 3 (967-P)

H Lunt, R Bergenstal, E Franck, F Travert, J Mou, M Hartman, M Rosilio, E Bastyr

This phase 3, double-blind study evaluated the efficacy of Lilly’s basal insulin peglispro (BIL) versus Sanofi’s Lantus (insulin glargine) in patients with type 1 diabetes (n=1,114). Patients were randomized 3:2 to peglispro or insulin glargine. From a baseline A1c of 7.9% in both groups, the peglispro group achieved a mean A1c of 7.4% after 52 weeks vs. 7.6% in the insulin glargine group (p<0.001). In addition, the peglispro group achieved a higher percentage of patients with A1c <7% (p<0.001) and weight loss instead of weight gain (-0.6 kg vs. +1.2 kg; p<0.001). Rates of total hypoglycemia were significantly higher with peglispro vs. insulin glargine (15.3 vs. 13.9 events per patient per 30 days; p<0.05), but nocturnal hypoglycemia rates were significantly lower (1.3 vs. 2.5 events per patient per 30 days; p<0.001).  The peglispro group also had unfavorable changes in lipid levels (higher triglycerides, total cholesterol, and LDL cholesterol and lower HDL cholesterol), higher ALT and liver fat levels, and a modest (<2 mmHg) increase in blood pressure vs. the insulin glargine group. This combination of impressive efficacy but significant safety signals is consistent with the results seen across the IMAGINE program for peglispro, which has always appeared to be a “high-risk, high reward” candidate. The additional liver safety studies that Lilly is currently conducting for peglispro in lieu of an FDA submission this year should be key in determining the product’s future.  

Superior A1C Reduction With Basal Insulin Peglispro (BIL) vs Insulin Glargine (GL) and Preprandial Insulin Lispro in a Double-Blind Study in T2D Patients: IMAGINE 4 (972-P)

AM Chang, T Blevins, TR Pieber, GC Vega, S Zhang, EJ Bastyr III

In this phase 3 randomized, controlled, double-blind study, Lilly’s novel basal insulin peglispro (BIL) vs. insulin glargine (GL), in combination with insulin lispro, provided a superior A1c reduction with less nocturnal hypoglycemia and weight gain. The study randomized people with type 2 diabetes previously on insulin therapy to either bedtime BIL (n=691) or GL (n=678) and used a wireless electronic diary system to facilitate communication of SMBG, hypoglycemia, and insulin dosing for 26 weeks. The results found that at 26 weeks, those in the BIL group achieved a mean 1.7% A1c reduction from a baseline of 8.4% while the GL group achieved a mean 1.5% A1c reduction from a baseline of 8.5% (p<0.001 for between-treatment difference). While the BIL group experienced about half as much nocturnal hypoglycemia than the GL group (12% vs. 24%; p<0.001), the BIL group also experienced more day-time hypoglycemia (not quantified in poster). On balance, total hypoglycemia trended slightly higher in the BIL group (RR=1.06, p=0.312 from 0-12 wks; RR=1.15, p=0.011 from 12-26 wks; and RR=1.10, p=0.53 from 0-26 wks). It seems like the excess hypoglycemia during the 12-26 week timeframe could be explained by higher doses of BIL administered during that time compared to GL. Severe hypoglycemia rate and incidence was similar between groups. As previously reported for BIL, it was associated with less weight gain than GL (1.3 vs. 2.2 kg, p<0.001) and elevations in liver enzymes (as in other IMAGINE trials, no participants met the criteria for Hy’s Law). BIL treatment was also shown to be associated with higher triglycerides (0.27 vs. -0.04 mmol/l, p<0.001) and similar LDL-C to GL treatment, with no difference in cardiovascular or severe adverse events. Finally, BIL provided marginally better glucose variability (~3-4 mg/dl advantage over GL in terms of standard deviation for both within-day and between-day variability).

Superior HbA1c Reduction with Basal Insulin Peglispro (BIL) vs Insulin Glargine in Type 2 Diabetic Patients Previously Treated with Basal Insulin: IMAGINE 5 (971-P)

C Serrano, J Buse, H Rodbard, J Luo, T Ivanyi, J Bue-Valleskey, M Hartman, M Carey, A Chang

This phase 3, open-label study (n=466) aimed to demonstrate non-inferiority between Lilly’s basal insulin peglispro (BIL) and Sanofi’s Lantus (insulin glargine) in patients with type 2 diabetes previously treated with basal insulin. Patients were randomized 2:1 to receive either peglispro or insulin glargine for 52 weeks.. In addition, 162 patients underwent MRIs in order to evaluate liver fat content, which has emerged as a potential safety concern with peglispro. The peglispro group experienced significantly greater A1c reductions after 52 weeks: -0.6% versus -0.2% from a baseline of 7.4% (p<0.001). Hypoglycemia rates also favored peglispro over insulin glargine, with a risk ratio of 0.40 for nocturnal hypoglycemia (p<0.001) and 0.77 for total hypoglycemia (p<0.05). Between-day fasting glucose variability and within-day six-point SMBG variability were also significantly lower with peglispro vs. insulin glargine. However, the peglispro group saw significant elevations in triglycerides (~170 mg/dl versus ~155 mg/dl; p<0.05), and liver fat (14.9% versus 9.6%; baseline = 10%; p<0.001). This study, like the other IMAGINE trials, supports the characterization of peglispro as a “high-risk, high-reward” candidate, though it is reassuring that the increases in total and severe hypoglycemia seen in the type 1 diabetes trials were not present here.

Corporate Symposium: Evolving Perspective in Treating Diabetes and Obesity (Sponsored by Novo Nordisk)

What is New in Insulin Treatment?

Tim Heise, MD (Profil, Neuss, Germany) and Christopher Sorli, MD (Billings Clinic, Billings, MT)

Dr. Tim Heise and Dr. Christopher Sorli reviewed data on Sanofi’s Toujeo (insulin glargine U300) and Novo Nordisk’s Tresiba (insulin degludec), emphasizing the reductions in certain hypoglycemia and glycemic variability parameters seen in clinical trials. Dr. Heise noted that Novo Nordisk initiated a head-to-head study of the two products just the week before the conference. The small trial (n=60 patients with type 1 diabetes; currently recruiting) aims to compare the pharmacodynamic and pharmacokinetic properties of the two insulins at steady-state conditions. The primary endpoint is area under the glucose infusion rate curve during a 24-hour period at day 6, 9, and 12. Primary completion is expected in April 2016. This study will provide the first direct comparison between the two products, which will likely be each other’s most direct commercial competitors in the medium-term future. Based on data from previous studies (including that presented during this talk), we would predict a slight edge for Tresiba in terms of duration of action and variability; we assume Novo Nordisk made a similar assessment to conclude that the study was worth the investment. From a clinical perspective the two products appear to be relatively comparable, both offering incremental improvements over their predecessors but potentially clinically meaningful advantages in terms of hypoglycemia and reduced variability. We assume reimbursement will be the main determinant of the products’ success, and positive results from comparative studies like this one could certainly be a useful tool in negotiations with payers. While this talk focused mainly on new basal insulins, Dr. Heise also highlighted the recent positive results for Novo Nordisk’s Faster aspart, noting that the improvement over NovoLog (insulin aspart) in the first 30 minutes is comparable to the improvement with NovoLog over human insulin.

Corporate Symposium: Different Patients, Different Needs – Towards an Integrated Care Approach to Diabetes (Sponsored by Sanofi)

When It’s Time to Intensify: What are the Options?

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

Dr. Robert Henry presented an informative and opinionated view of options to intensify insulin therapy in type 2 diabetes, reviewing the data behind rapid-acting insulin and GLP-1 agonists in postprandial glucose lowering and presenting hot-off-the-press positive topline results from the second phase 3 trial of Sanofi’s LixiLan (lixisenatide/insulin glargine). Dr. Henry opened with a discussion of when intensification is necessary, noting that more than half of patients who initially achieve an A1c <7% can’t sustain it; the average time to failure is about 400 days. While these patients may be at target in terms of their fasting plasma glucose (FPG), their postprandial plasma glucose (PPG) may be high and using basal insulin is not sufficient. Dr. Henry demonstrated a clear preference for adding a GLP-1 agonist rather than rapid-acting insulin in such situations, noting that in head-to-head comparisons between GLP-1 agonists and rapid-acting insulins, the GLP-1 agonist arm demonstrated non-inferior A1c reductions, superior PPG changes, weight loss instead of weight gain, and less hypoglycemia. Dr. Henry concluded his talk by giving attendees a sneak peek at the GLP-1 agonist/basal insulin combinations on the horizon (LixiLan and Novo Nordisk’s Xultophy [insulin degludec/liraglutide).

• Dr. Henry shared positive topline results released just hours earlier from the phase 3 LixiLan-L trial. The combination produced statistically superior A1c reductions vs. Lantus (insulin glargine) after 30 weeks in 736 patients with type 2 diabetes on basal insulin, with a safety profile reflecting those of the components. Secondary endpoint results were not shared, but we eagerly await details on LixiLan’s effect on weight, hypoglycemia, and GI side effects. We see basal insulin/GLP-1 agonist combinations as one of the truly exciting type 2 diabetes drug classes on the immediate or near to medium term horizon and look forward to seeing how the detailed results for LixiLan compare to those for Novo Nordisk’s Xultophy (insulin degludec/liraglutide), which have been very impressive.
• The positive LixiLan-L results follow the announcement of positive topline results from the phase 3 LixiLan-O trial, announced in July. LixiLan-O compared A1c reductions with LixiLan vs. Lyxumia or Lantus in 1,170 patients with type 2 diabetes on background metformin. As with LixiLan-L, the announcement shared only that the combination produced statistically superior A1c reductions compared to the individual components and did not comment on the secondary endpoints. Full results for the trials will be presented at a future conference.
• In its announcement, Sanofi confirmed its expected timeline of 4Q15 for a US LixiLan regulatory submission and 1Q16 for an EU submission. This is consistent with Sanofi’s guidance since its 1Q15 update. While Xultophy has a significant head start in the European market, the two may well launch in the US at around the same time, as we expect an FDA submission for Xultophy in 4Q15 as well (assuming a Tresiba [insulin degludec] approval in October as expected).

 

Outcomes Trials

Symposium: Results of the EMPA-REG OUTCOME Study

Effectiveness

Christoph Wanner, MD (University of Würzberg, Germany)

Dr. Christoph Wanner presented the results for A1c and other surrogate parameters in EMPA-REG OUTCOME, which were consistent with those seen in previous trials of SGLT-2 inhibitors. After the initial 12-week period when investigators were not allowed to alter glucose-lowering medications, placebo-adjusted A1c reductions were 0.54% and 0.6% with the 10 mg and 25 mg doses of empagliflozin, respectively. The difference between groups narrowed after week 12, when investigators could adjust medications at their discretion. At the end of the 206-week study period, the placebo-adjusted reductions were 0.24% and 0.36%, reflecting the goal of achieving glycemic equipoise between groups. Both doses of empagliflozin led to ~2 kg placebo-adjusted weight loss and a ~2 cm reduction in waist circumference shortly after study initiation that were largely sustained throughout the trial. Empagliflozin also produced a sustained ~4 mmHg placebo-adjusted reduction in systolic blood pressure – Dr. Wanner cryptically noted that he would leave it to the audience to make judgments on the magnitude of that effect. Diastolic blood pressure initially decreased by ~1.5 mmHg with empagliflozin vs. placebo, but the difference had essentially disappeared by the end of the study. Heart rate (measured by ECG and in outpatient visits) was stable throughout the trial and comparable between groups. LDL cholesterol increased slightly with empagliflozin from the beginning of the trial, consistent with other SGLT-2 inhibitor studies. HDL also increased with empagliflozin such that the HDL/LDL ratio remained balanced between groups.

Outcomes

Silvio Inzucchi, MD (Yale University, New Haven, CT)

Clearly enjoying himself, Dr. Silvio Inzucchi presented the much-anticipated primary results from the trial, building up the suspense for each finding by pausing dramatically before the Kaplan-Meier curves slowly appeared, often to gasps and applause from the audience.

• Primary outcome: The hazard ratio for the primary outcome of three-point MACE (non-fatal MI, non-fatal stroke, and CV death) was 0.86 (95% CI = 0.74-0.99), translating to a 14% risk reduction that just met the threshold for statistical significance (p=0.038 for superiority; p<0.001 for non-inferiority). Dr. Inzucchi noted that the curves began to diverge after only about three months, which he described as very unusual for a cardiovascular trial. The results were consistent between the two empagliflozin dose groups (10 mg and 25 mg) with a hazard ratio of 0.85 for both, though the p-values did not reach statistical significance because of the smaller number of patients in each group. On-treatment and per-protocol analyses to test the robustness of the results found the same results.
• Individual components: It soon became clear that the overall risk reduction was driven entirely by a 38% reduction in CV death (HR = 0.62; 95% CI = 0.49-0.77; p<0.0001), which drew the first applause and gasps from the audience. The effect was again consistent between the individual dose groups, and in this case significance was maintained despite the smaller number of patients. There was no significant difference in non-fatal MI (HR = 0.87; 95% CI = 0.70-1.09; p= 0.22) or non-fatal stroke (HR = 1.24; 95% CI = 0.92-1.67; p = 0.16) between groups. Dr. Inzucchi offered some reassurance about the numerical increase in stroke, noting that the majority of events occurred more than 90 days after discontinuation of treatment and that the hazard ratio was much closer to unity (1.04) in a prespecified on-treatment analysis that included events only up to 30 days after discontinuation.
• Key secondary outcome: Adding hospitalization for unstable angina (which was balanced between groups) to the primary composite endpoint pushed the results just below the threshold for statistical significance for superiority (HR = 0.89; 95% CI = 0.78-1.01; p<0.001 for non-inferiority; p=0.08 for superiority).
• Subgroup analyses: There was some heterogeneity in the subgroup analyses for the primary endpoint, with nominal differences based on age (more of an effect for people under 65) and A1c (more of an effect for people with A1c<8.5%). However, Dr. Inzucchi stressed that no interactions met the threshold for statistical significance (p=0.0022) in this analysis. Results of the subgroup analyses for CV death were much clearer, with absolutely no heterogeneity and a clear benefit for all groups analyzed.
• Heart failure: Dr. Inzucchi really built up the suspense for this endpoint, prefacing the results with a discussion of the enormous relevance of heart failure for patients with diabetes and the ongoing controversy over the DPP-4 inhibitor class. The audience once again burst into applause when the highly significant 35% risk reduction was presented (HR = 0.65; 95% CI = 0.50-0.85; p=0.002). The results for the individual dose groups were similar, though the curves were not quite as superimposable as those for CV death.
• All-cause mortality: Dr. Inzucchi closed on a high note with the results for what he described as “probably the most important outcome.” Results demonstrated a 32% reduction in all-cause mortality with empagliflozin (HR = 0.68; 95% CI = 0.57-0.82; p<0.001) with no difference between the two doses.

Safety

David Fitchett, MD (St. Michael’s Hospital, Toronto, Ontario, Canada)

Dr. David Fitchett presented the results for adverse events, which were generally reassuring. There was a slight increase in drug-related adverse events with empagliflozin, largely due to increased genital infections, which occurred in 6.4% of all patients and 10% of female patients on empagliflozin vs. 1.8% and 2.6%, respectively, with placebo. There was no difference in serious adverse events between groups. There was no increase in urinary tract infections with empagliflozin, though there was a very slight increase in discontinuation due to such infections. Hypoglycemia was common (28%) in both groups, reflecting the fact that half the participants were on insulin. There was no increase in overall hypoglycemia or hypoglycemia requiring assistance with empagliflozin vs. placebo, including when patients were stratified based on insulin therapy. Notably, given recent concerns, there was no increase in DKA or bone fractures with empagliflozin. There was also no increase in acute kidney injury, events associated with volume depletion, venous thrombotic events, hepatic injury, or hypersensitivity. There was a 4% absolute increase in hematocrit and a 0.9 g/l increase in hemoglobin with empagliflozin, which Dr. Fitchett described as a result of the drug’s osmotic diuretic effect. There was no difference in serum creatinine, eGFR, or electrolytes between groups. Overall, Dr. Fitchett stated that empagliflozin appeared to be well tolerated, with the only risk being an increase in genital infections that rarely resulted in discontinuation.

Commentator

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

Dr. Hertzel Gerstein provided valuable context for the EMPA-REG OUTCOME results, endorsing the robustness of the study, emphasizing the value of large outcomes trials, and offering some hypotheses as to the mechanism of benefit. He argued that “this trial has really performed well,” noting that it met all of his criteria for a useful, reliable outcomes study. He also described it as a “perfect case in point” for why large outcomes trials are necessary and cannot be replaced with large epidemiological studies or meta-analyses of small RCTs. While the mechanism of benefit remains unknown, Dr. Gerstein suggested that a diuretic effect was the most likely driver based on comparisons to past trials, though it could also be a combination of multiple factors. One of Dr. Gerstein’s endorsements of the trial was that it raised more questions than it answered, and he outlined several of those questions during the talk, mostly related to the mechanism of action and the generalizability of the results. In terms of the clinical implications, he predicted that the benefit is likely to be a class effect and suggested that empagliflozin could become the first-line treatment for middle-aged people with type 2 diabetes at high cardiovascular risk.

• EMPA-REG OUTCOME met all of Dr. Gerstein’s criteria for a good outcomes trial: it had a good protocol, answering an important question in a high-risk population; it had high adherence and event ascertainment, with a higher event rate than anticipated; the investigators delivered a clear analysis and presentation of the results; and it “definitely” raised more questions than it answered. As he summed it up, “this trial has really performed well.”
• Dr. Gerstein described EMPA-REG OUTCCOME as a “perfect case in point” for why large outcomes trials are needed. He argued that the claims (fairly widespread in the field in recent years) that large outcomes trials for diabetes drugs are not necessary or valuable are “really unfounded.” He stressed that relying on a drug’s mechanism of action to predict its effects is not sufficient, as “biology can be used to justify any findings.” As in past talks, he expressed skepticism about the use of large epidemiological studies in place of randomized trials, arguing that the results will always be confounded since it is impossible to adjust for confounders you aren’t aware of. He also cast doubt on the validity of meta-analyses of small RCTs that are not powered to evaluate outcomes, noting that the biases present in each individual study are only compounded when the results are combined. Few would argue against large, randomized outcomes trials as the gold standard of evidence; the main question facing the diabetes field is whether the information gained from such trials as they are currently designed is worth their substantial cost.
• Dr. Gerstein suggested that empagliflozin’s diuretic effect was the most likely driver of benefit, though it could also be a combination of multiple factors. He convincingly argued through comparisons to other cardiovascular outcomes trials that the immediate, dramatic effect on mortality and heart failure seen in this study was not consistent with a benefit driven by improvements in blood pressure or lipids, which typically takes at least six months to a year to become evident. The lack of an effect on stroke makes it especially unlikely that the improvement was driven by blood pressure, which we had predicted would be the most likely mechanism. Dr. Gerstein also suggested that the improvement was very unlikely to be a glucose effect, as the A1c difference between groups was too small and the benefit too immediate. Similarly, he suggested that weight loss was not the culprit, as there is currently no evidence linking weight loss to CV risk reduction and the difference between groups was not huge. He did note that past trials evaluating the effect of diuretics in patients with a history of heart failure have shown an effect on mortality almost immediately after randomization, suggesting that a similar mechanism could be at work here.
• Dr. Gerstein outlined several important questions raised by the results:
  
  • Are the findings generalizable to all patients with type 2 diabetes?
  • Why were the results different for different MACE components?
  • Does empagliflozin or other SGLT-2 inhibitors reduce ischemic heart disease or stroke over the long term?
  • What is responsible for the benefits?
  • Why did the benefits appear so quickly?

Corporate Symposium: EMPA-REG OUTCOME – Implications for Management of Patients with Type 2 Diabetes (Sponsored by Lilly/BI)

Panel Discussion

Lars Ryden, MD, PhD (Karolinska Institute, Solna, Sweden), Sanjay Kaul, MD (Cedars-Sinai Heart Institute, Los Angeles, CA), Lawrence Leiter, MD (St. Michael’s Hospital, Toronto, Canada), Naveed Sattar, MD (University of Glasgow, UK)

Q: Should SGLT-2 inhibitors replace metformin as the first choice for type 2 diabetes with high cardiovascular risk?

Dr. Lawrence Leiter: There’s a lot to include in this answer. These are fantastic results that show a dramatic benefit in the population that was studied. What was seen was a benefit in people with known cardiovascular disease. What is yet to be shown, though there are other SGLT-2 inhibitor trials ongoing, is the benefit in people without known cardiovascular disease. Also, the drug was given on a background of metformin therapy, so we know it has a benefit on top of metformin. It’s premature to replace metformin with SGLT-2 inhibitors.

Dr. Naveed Sattar: Most of us were blown away by the results. I don’t think anyone could have predicted the results. It is a bit confusing – the difference between dying from CV event and nonfatal events. Things that prevent nonfatal disease is lipid lowering and blood pressure and metformin is part of that. Metformin is cheap, safe, and it works.

Dr. Sanjay Kaul: It’s too premature to jump to this particular drug as first-line therapy. Metformin was tested in new onset diabetes and we haven’t tested this in that. The mortality benefit found is profound and early but we need to admit that it’s unexpected and unprecedented. At first glance, it seems too good to be true. That said, there are cogent reasons as to why I don’t believe this is an implausible benefit. It was statistically persuasive, based on a large number of events, and was seen with both doses; so there was internal consistency. Thus, it wasn’t a play of chance. Nonetheless, I would like to see it replicated by another drug within the class.

Dr. Lars Ryden: The trial has been done in certain settings in certain patients. They were treated with many things and the results are based on adding this on top of other treatments. You have to use clinical experience and skills to choose the patient you’re putting on this. Another study will give us an answer to other types of patients.

Q: Many of the other cardiovascular outcome trials since December 2008 have addressed patients within 60 days of an index event. EMPA-REG had patients more than two months from a prior cardiovascular event. Did that difference allow a better opportunity?

Dr. Ryden: Maybe. Heart failure was influenced and it takes some time to develop.

Dr. Kaul: For chronic disease, it’s very important to carefully choose the time of ascertainment of events. If you enroll patients early after an ACS event, you’ll likely get a lot of noise and dilute a potential treatment benefit. The timing of enrollment more than two months after an acute event was quite appropriate..

Dr. Leiter: In the completed ACS studies, none of them included patients right after the event. ELIXA is yet to be published and uses at least 60 days after event. Even EXAMINE used from 15 days on. There just weren’t many patients with events that early. It’s not that dissimiliar from prior studies.

Q: Can you provide any comments on the finding that most of the treatment benefits were in the age group above 65 years old?                                                                                            

Dr. Ryden: When looking at differences between subgroups, none of them was actually statistically significant. All went in the same direction. We cannot draw conclusions above or below as they were all very consistent. The hazard ratios were narrow or wide depending on the number of people in a specific subgroup. The results are consistent for all patients studied.

Dr. Kaul: Subgroups are tempting, but often treacherous. Prestigious journals are demanding nominal unadjusted interaction p-values that can be potentially misleading.

Dr. Ryden: There was a related question to gender and it’s the same answer.

Dr. Sattar: The fact that nonfatal disease didn’t change is perhaps because we’ve treated processes for nonfatal disease very well. The process for treating fatal disease is another pathophysiology that we haven’t fully considered.

Dr. Leiter: With regards to MI, remember that it was non-significant but had a 13% reduction. What is remarkable is the CV death benefits that allowed the study to finish with sufficient events.

Q: When thinking about mechanisms of action, was there reduction in the non-diuretic treatment patients?

Dr. Sattar: Could it be diuretic events alone? Probably not. Is it having some kind of diuretic event or background of weight and blood pressure and glucose? I don’t know. I don’t think anyone has the precise answer.

Dr. Kaul: The mechanism of action is tempting to speculate, but we simply don’t know the exact mechanism.

Dr. Ryden: If you look at the rapid onset, SGLT-2 leads to volume depletion, which could unload the heart. There are many other aspects, including less remodeling, less fibrosis, and less coronary vascular stiffness. We need to do very specific trials with this drug to get a more detailed explanation to the mechanisms behind the effect. There certainly will be a number of studies. This study opens up to many thoughts.

Dr. Kaul: We cannot tell what the exact mechanism of action is. What we can tell with some degree of confidence is what it is not related to. It is not a blood pressure effect. Why would stroke go in the wrong direction? It’s not related to weight loss. This has never been shown with 2%-3% weight loss. We know this is not a glycemic effect. The glycemic differential is too modest to translate into an outcome benefit. That’s all we can say. We could consider a hemodynamic effect or a membrane stabilization effect? Ask yourself: when was the last time a hemodynamic or an antiarrhythmic intervention had such a profound and early treatment benefit? I’m not aware of it.

Dr. Leiter: I’d like to provide a note of caution. The danger in trying to come up with an explanation is that we try to generalize. If it’s glucose lowering, then we say that the benefit would be seen with any glucose lowering agent. If it’s blood pressure, then we say that for anything. If it’s diuretic, then we put everyone on Hydrochlorothiazide. But that’s not what the study showed. Empagliflozin showed a dramatic benefit and it’s not appropriate to generalize these results to drugs with other mechanisms of action.

Q: Regarding the possibility of a class effect, are any SGLT-2 inhibitors valid in this sense?

Dr. Kaul: What is common to all SGLT-2 inhibitors is a favorable impact on cardiometabolic risk factors. But we saw that the outcome benefit in this trial was unlikely to be attributable to blood pressure lowering, weight loss, or improved glycemic control. So, the question of whether this is a class effect is now difficult to answer. We need to await the results of ongoing CVOT with other drugs within the class.

Dr. Ryden: Another example is the first study of DPP-4 inhibitors, SAVOR, which showed an increase in heart failure in the group receiving saxagliptin. Subsequent studies did not reveal anything similar eg. in TECOS testing sitagliptin. However, in the DPP-4 inhibitor class of drugs, the molecular structure of each is quite dissimilar. Thus we cannot just say that all drugs in the class is safe even if I personally believe that the findings in SAVOR was a play of chance

Dr. Leiter: Despite everyone dumping on FDA and EMA regulations, we don’t need to wait five years now to see what happens with other studies underway. We’ll have an answer in a few years.

Dr. Sattar: If you asked us to bet, we’d probably say yes. But we have doubt in our mind about whether or not it’s drug specific, so we can’t say until other trials complete.

Q: For the first month, treatments could not be changed. There was a clear drop in A1c. Would this affect the blinding of the study?

Dr. Ryden: It’s a good question. If you administer a drug that is glucose lowering it has an effect. That does not necessarily mean it flaws the results especially since the impact was relatively small.

Dr. Leiter: I don’t think so. What was seen in the EMPA-REG outcomes was seen in previously completed DPP-4 and GLP-1 trials. There was a very similar delta at three to four months, which gradually diminished over time. In each of these studies, investigators were encouraged to treat per local guidelines. The average A1c was still far above what we would recommend. I don’t think it was a result of glycemic benefit.

Dr. Sattar: The end result was 0.3% for A1c, which was almost identical to previous trials. It cannot be that.

Dr. Ryden: A total of 7,000 patients were recruited at almost 600 centers. The responsible physicians cared for the patients as they were instructed and each of them had of course a limited number increasing the chance to guess which arm their patients were allocated to.

Dr. Kaul: It would be a mistake to interpret these results as a validation of the hypothesis that improved glycemic control results in improved cardiovascular benefits. This is simply not what the study shows.

Q: Because the heart failure outcome may have accomplished an important role, what happened with BNP? Was this not yet analyzed?

Dr. Sattar: When thinking about the patients beyond those studies – beyond people with diabetes and existing vascular disease – people with a high risk of heart failure may have a role. Their BNP may have a role. BNP is an excellent predictor of cardiovascular events. That analysis needs further interrogation.

Q: The Kaplan-Meier curves for MACE diverge almost immediately and then are parallel. For deaths, they diverge and continue. Does that mean strokes and MI increase after six months?

Dr. Kaul: The KM curve for stroke shows delayed separation not in favor of empagliflozin.  The ITT hazard ratio was 1.24 for nonfatal stroke, so that’s a potential concern.

Q: Would it be interesting to analyze people with risk factors for MACE but no previous cardiovascular events?

Dr. Leiter: In DECLARE, 60% of participants have multiple risk factors but no previous events so that will help answer that question.

Q: The results adjudicated cause of death and all deaths by treatment. Empagliflozin did not reduce risk of acute MI and stroke. What drove that reduction?

Dr. Rydén: A decrease in heart failure is a probable reason as emphasized during the presentation of the study. Heart failure, particularly of ischemic origin, and diabetes is a very deadly combination.

Dr. Kaul: The 2.2% absolute risk reduction in cardiovascular mortality was driven primarily by unknown cause of deaths that by protocol were classified as cardiovascular followed by sudden cardiac death and worsening heart failure. This raises an interesting hypothesis of a potential heart failure effect that is ripe for validation in future trials.

Q: What might be the mechanisms for hospitalization for heat failure? You know you get volume depletion. You know if you have a burdened or stiff heart, volume depletion in one way or another would unload that heart. You should also know that in animal experiments, if you look at their structure, they’re less fibrotic in the myocardium. Perhaps the vessels dilate easier and preserve the myocardial blood flow reserve.

Dr. Sattar: Many of us have seen the data with this drug and the kidney and something about the cardio-renal axis. There’s a recent paper published in the UK that shows that the most common CV presentation in current times is heart failure, no longer myocardial infarction. 

Dr. Kaul: The risk reduction in mortality seen in EMPA REG OUTCOME trial was virtually double the mortality benefits seen with a recently approved heart failure drug called Entresto which was studied in high-risk patients with systolic heart failure. Entresto impacts the renin angiotensin aldosterone system. So, the effects of empagliflozin might go beyond this.

Dr. Sattar: Ten percent of the patients had known heart failure, but it’s possible that many others had subclinical heart failure. 

Dr. Kaul: The obvious next step is validating this finding and determining whether there is a treatment benefit in heart failure in people with and/or without diabetes.

Q: Can anyone explain why hypoglycemia was not increased, as in earlier reported diabetes event trials?

Dr. Ryden: This drug does not cause hypoglycemia.

Dr. Leiter: SAVOR was the only outcomes trial that showed more hypoglycemia. Patients in that trial had entry A1c levels as low as 6.5%. It was patients with a low A1c and on insulin that showed hypoglycemia in SAVOR.

Dr. Sattar: If you’re on insulin and showing an A1c of 6.5%, some are in good control, but some are quite sick and losing weight.

Q: What about fractures and osteoporosis?

Dr. Ryden: That has not been analyzed yet.

Q: Dr. Gerstein suggested the possible influence of SGLT-2 on cardiac arrhythmia. I don’t think he really said that. He referred to arrhythmia trials, but I don’t think so?

Dr. Sattar: He did say that, I think.

Dr. Kaul: There is a laundry list of potential reasons. When you see “multifactorial” or “multidimensional” in a journal like the New England Journal of Medicine, it’s usually a euphemism for we don’t know.

Q: What about use of SGLT-2s if the GFR is <45? Are you concerned about off-label prescriptions for patients older than 60 years with impaired renal function?

Dr. Ryden: No, according to the outcome of this study.

Dr. Sattar: It would be nice to see the microvascular outcomes as well.

Dr. Leiter: With impaired renal function, efficacy falls off. But the effect on blood pressure seems to be the same.

Q: What about the imbalance between men and women? There were more males than females in the study.

Dr. Ryden: The disease which made patients available for the study is much more common in men. There was no imbalance in events between men and women. The subgroups all went in the same direction and magnitude. You can use the drug in both genders.

Q: Was QT interval influenced?

Dr. Ryden: We don’t know yet. But this drug does not act that way.

Q: How does randomization of empagliflozin and placebo influence statistical calculations?

Dr. Ryden: That was discussed by the study statistician. It is a perfectly fine way of looking at events.

Q: How many patients had new heart failure and how many had worsening heart failure? It will probably come later on, but is not yet known.

Dr. Kaul: We don’t have systematically collected information on heart failure.

Dr. Sattar: This is in part because we didn’t expect these results. It’s a hypothesis generating observation that needs to be validated.

Q: Should SGLT-2 inhibitors be tested in people without diabetes and heart failure?

Dr. Ryden: If you carefully investigate people with ischemic heart failure, the majority is dysglycemic. If you want to isolate those without any disturbance in glucose, then you have to really screen them with an OGTT. To test the drug in patients with heart failure and diabetes is something that should and reasonably will be done. This can be done in a straightforward, large clinical trial but also in small mechanistic investigations .

Q: Regarding dosing, would you give 10 mg or 25 mg? Or something in between?

Dr. Kaul: I would give 10 mg.

Dr. Kaul: There was no difference in cardiovascular outcomes between the 2 doses. I was underwhelmed by the glycemic difference between the 2 doses. I would start every patient at 10 mg and stop there. In the paper, it was mentioned that dose should be individualized based on glycemic efficacy. However, the outcome benefit is unrelated to glycemic control.

Dr. Leiter: There is a cardiology vs. endocrinology divide here. The cardiovascular benefit was no greater at 25 mg. Looking at the other side of it, the harm was no greater. We know from prior studies with empagliflozin that the higher dose is associated with a little bit more A1c reduction and a little bit more blood pressure reduction. There’s a little bit more weight loss. We haven’t discussed the kidney, even though there was no dose response with cardiovascular benefits. We want to individualize therapy. If patients are doing well on 10 mg for their cardiovascular needs, there’s no need to go up. If you want greater metabolic benefit, then there’s no harm in going up to 25 mg.

Dr. Sattar: 10 mg is clearly the starting dose. You get the most bang for the buck. You’re pretty much getting 90% of the effect. That’s on average. There might be some patients who get additional benefit at 25 mg, but 10 mg works well for the vast majority.

Dr. Ryden: I would go with 25 mg, which was safe. We want to take as much as possible out of the drug. In my practice, we start with 10 mg and follow the patient.

Dr. Sattar: I’m involved in some CVD prevention guidelines. We will have to consider these results very carefully and I am sure the community would expect this of us. Other guidelines committees will have to do the same. 

Q: What hyperkalemia was observed during the study?

Dr. Ryden: There was obviously no problem with that so you can be assured.

Q: If CV deaths were lowered, doesn’t this mean that there should have been a rise in nonfatal MI and stroke?

Dr. Sattar: It’s a good point.

Dr. Ryden: If you follow the study  population let us say during 20 years, you might find something and you can figure out how long life was prolonged?

Dr. Kaul: It’s a legitimate question. We would generally expect patients with diabetes to die mostly from atherothrombotic events. That’s why there’s a composite of CV death, nonfatal MI or nonfatal stroke. Nonfatal MI is the largest contributor to the composite but there was a modest but not statistically significant benefit. When nonfatal stroke doesn’t move in the same direction as CV death, it begs the question whether this composite is really the best outcome for these trials. Perhaps there are other things besides atherothrombotic events such as heart failure, arrhythmic events, etc., which may be equally, if not more, important.

Dr. Sattar: It would be nice to have quality of life for these studies as well.

Q: Why did A1c increase by the end of study?

Dr. Ryden: It’s quite frequent that if you follow people with diabetes for a long time HbA1c increases due to the progression of the disease.

Q: Can you provide any comments on the Latin population?

Dr. Ryden: It was a small population, but in principle, the results went in the same direction and were of similar magnitude.

Q: What about this drug in African Americans?

Dr. Ryden: Since they made up a very small proportion of the patients this is a question that is difficult to give a firm reply to

Q: Regarding CANVAS and DECLARE, some may claim that these ongoing trials should be stopped in view of the placebo arm.

Dr. Kaul: I hope that DSMBs (safety committees) of ongoing cardiovascular outcomes trials don’t take any decision in haste. We need to allow other studies to be completed to replicate the mortality benefit and rule out a potentially concerning stroke hazard. Diabetes drugs have a very checkered history when it comes to cardiovascular outcomes. We have seen a large treatment effect which is unexpected and unprecedented. There’s the concern of the stroke signal. If we were to stop those trials, we would lose the opportunity to reliably assess the stroke signal. Dapagliflozin CVOT will accrue nearly twice the number of events thereby providing ample opportunity to refute or confirm the stroke signal seen in EMPA REG OUTCOME trial. Many patients and physicians will consider a disabling stroke as perhaps a worse outcome than death. A drug or class of drugs that reduces mortality but increases disabling stroke would be a wash in my opinion. I hope that they will not do that. CETP inhibitor, torcetrapib, had a highly significant 58% increase in cardiovascular mortality in the pivotal trial. Did the IRBs and DCMs recommend trials evaluating other drugs in the class be stopped? No. I would say it is imperative that we allow those studies to continue to replicate the mortality benefit and clarify the stroke signal. 

Dr. Leiter: It will also depend on what happens to guidelines. If our standard of care changes, one may have to look at the studies and ask for consent from patients again. There will be a lot of conference calls over the next few weeks.

Dr. Ryden: These are very important questions for DSMBs but also for the trial physicians and the patients. They will read about the results in newspapers and start to wonder if they should have the drug rather than be in a study in which they may get placebo. Ongoing studies will be disturbed if the participants want to be on an active drug and leave the study. Studies addressing other than the present population should proceed. An example is a large trial of dapagliflozin in which a lot of the participants have a high risk for cardioavscular risk but no established cardiovascular disease. We need to know if SGLT2 inhibition works in these patients as well as in the just studied population

Symposium: Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)

Update on TECOS Safety Data

Robert Josse, MD (St. Michael’s Hospital, University of Toronto, Canada)

Dr. Robert Josse presented an update on TECOS safety data, suggesting a possible class effect with increased risk for acute pancreatitis with DPP-4 inhibitors. As we learned at ADA, TECOS had an imbalance in acute pancreatitis with 23 vs. 12 cases (p=0.065) not in favor of sitagliptin. Dr. Josse presented a deeper analysis into the data, showing that severe or fatal pancreatitis occurred rarely, with four severe cases and 19 mild/non-severe cases. The median number of days from randomization to pancreatitis was 517 for the sitagliptin group vs. 528 for placebo. Regarding etiology, ten were of unknown etiology while two were alcohol-related, eight were biliary-related, and four were related to a prior pancreatitis history. Notably, Dr. Josse presented a meta-analysis of the three DPP-4 inhibitor CVOTs (SAVOR, EXAMINE, TECOS), which suggested a statistically significant increased risk of acute pancreatitis with an overall hazard ratio of 1.58 (p=0.033). However, he stressed to attendees the need to interpret these results with caution, noting that the trials had differences in follow-up duration and enrolled patient populations as well as variation in the adjudication procedures. As for pancreatic cancer (9 vs. 14 cases in favor of sitagliptin), Dr. Josse showed that a meta-analysis of SAVOR and TECOS (EXAMINE was not included as no cases were reported) suggested no difference in the risk of pancreatic cancer, despite the fact that the rates were numerically lower with the DPP-4 inhibitor group in both trials (HR=0.54; p=0.066). With the acute pancreatitis risk, we would suspect that these numerical imbalances in favor of DPP-4 inhibitor therapy are likely just due to chance, especially with the low number of cases. Yet increasingly, it appears that acute pancreatitis risk may be a class effect, although so far, we have heard most speakers playing the safety signal down. For example, Dr. Josse emphasized that it may not be a major clinical risk, noting that further post-marketing surveillance will help to determine the clinical relevance despite the meta-analysis’ findings;  Dr. John Buse (UNC, Chapel Hill, NC) similarly suggested at ADA that such a risk would be rare and acceptable within the class’ otherwise strong safety profile. While in the aftermath of EMPA-REG, this information on pancreatitis risk is not the most compelling in terms of CVOT findings, we believe that it could still be somewhat useful for providers when individualizing second-line therapies for patients with a history of pancreatitis (although the evidence is likely not sufficient to drastically change current guidelines quite yet).

Corporate Symposium: Getting to the Heart of Type 2 Diabetes (Sponsored by Lilly/BI)

The Broken Hearted – CV Risk and T2D Management

Kausik Ray, MD (Imperial College London, UK), Naveed Sattar, MD (University of Glasgow, UK), and Nikolaus Marx, MD (University Hospital Aachen, Germany)

Lilly/BI’s corporate symposium tantalized the audience with frequent references to the big reveal of the EMPA-REG OUTCOME full results later in the week. Upon entering the packed auditorium, attendees were immediately greeted by a huge screen flashing a continuous loop of the words “SGLT-2,” “CVOT,” and “CVD,” interspersed with EKG-style heartbeats and set to upbeat music. If that display had not already put attendees in the frame of mind to be thinking about the EMPA-REG OUTCOME trial, every seat in the room offered an invitation to the Lilly/BI-sponsored symposium on EMPA-REG OUTCOME immediately following the results presentation (really!). As a reminder, Lilly/BI released topline results from the trial last month stating only that Jardiance (empagliflozin) demonstrated cardiovascular risk reduction vs. placebo. Lilly and BI are definitely building up big interest up the full results – we certainly hope they live up to the publicity, though we believe even a fairly subtle effect, which may well be the result, would still be a big deal given the number of reduced deaths this would still indicate.

• In his presentation during the symposium, Dr. Naveed Sattar (University of Glasgow, UK) asserted that the diabetes field needs more CVOTs moving forward because they are the only way to understand drugs’ full effect on cardiovascular risk. In the case of SGLT-2 inhibitors, he pointed out that the class is known to decrease blood pressure and weight (good in terms of cardiovascular risk), but it also raises LDL cholesterol (for unclear reasons but potentially a concern).  During the ensuing panel discussion, fellow presenter Dr. Kausik Ray (Imperial College, London, UK) echoed this point, stating that superiority (rather than non-inferiority) trials require investigators to be absolutely sure there are no off-target harmful effects first. We agree that outcomes trials certainly provide invaluable information about products’ safety and efficacy but believe that the current FDA paradigm has important limitations that may prevent the trials from demonstrating the most clinically useful information (see below for more).
• During the panel discussion, Dr. Ray and Dr. Sattar speculated on the potential drivers of the positive EMPA-REG OUTCOME results. Dr. Ray was clear that he expects the blood pressure-lowering effect of SGLT-2 inhibitors to be the main driver of reduced cardiovascular risk, while Dr. Sattar suggested that it might be a composite effect of lower blood pressure, weight, and glucose.

Panel Discussion

Kausik Ray, MD (Imperial College London, UK), Naveed Sattar, MD (University of Glasgow, UK), and Nikolaus Marx, MD (University Hospital Aachen, Germany)

Q: Should future CVOTs demonstrate superiority rather non-inferiority?

Dr. Nikolaus Marx: From a cardiologist’s point of view: of course, we’d love to see that and lots of cardiologists can’t understand why these aren’t being performed. But it’s important to remember what is required by regulatory bodies. In future I hope to see superiority trials.

Dr. Kausik Ray: It really depends on what it is you want to do. One way to look at this is in terms of on-target benefits and on-target harm. Lower glucose has a cardiovascular benefit. If you change glucose levels, you might get a benefit, but it will take 25 years. On-target harm are things related to hypo. With any new class, we’re worried about the off-target effects, like heart failure. If you’re absolutely sure there are no off-target effects, then you can go straight to superiority trials. That’s the big question, is it safe?

Dr. Naveed Sattar: Glucose and microvascular risk go hand in hand. Glycemic control is used to prevent microvascular complications. If a diabetes drug can also decrease macrovascular risk, that’s an added bonus. That’d be fantastic. But the key issue is if it can do it without other safety issues and long term CVOTs help find that out.

Q: As a professor of public health, what are the most important messages we should be putting across?

Dr. Ray: Probably preventing diabetes in first place. Once you’ve got it, its progression is inevitable. Education is important, starting particularly in childhood - we’re seeing anthropometric measures that are abnormal in the first decade of life.

Dr. Sattar: I think Dr. Ray is completely correct. The big public health battle is to reduce the number of excess calories in the environment. In addition, picking out people with diabetes early or at high risk to instigate lifestyle changes helps. If I can recognize somebody at high risk and I can encourage and help that individual make small sustainable lifestyle changes to delay diabetes for 5, 10 years, that’s significant.

Dr. Marx: I have one simple sentence: don’t forget about blood pressure and lipids.

Q: CVOTs vary considerably in length. Is there likely to be any difference in short-term vs long-term trials?

Dr. Marx: It depends on the intervention. If you look at statin trials, short-term trials already reduce risk. It’s important to see the design of the trial. If the primary objective is non-inferiority, short-term may be appropriate.

Q: Are the effects of SGLT-2 inhibitors on blood pressure and weight reduction likely to account for superiority in CVOT?

Dr. Ray: From data I showed you, we’ve seen such consistent data on blood pressure and lipids that for me, the blood pressure-lowering effect, even if it’s only 5 mmHg, is going to translate to a reduction in CV events. With regards to weight loss and CV risk, we have not really seen major trials that show this relationship. For me, the blood pressure effect is really going to be what’s driving it.

Dr. Sattar: When they report full results, I suggest looking to see if they’re going to show data by baseline blood pressure - that’s going to potentially informative. I think benefits could be mix of glucose, weight, and blood pressure benefits. But let’s see. There may be a surprise in there.

Corporate Symposium: Evolving Perspective in Treating Diabetes and Obesity (Sponsored by Novo Nordisk)

Cardiovascular Outcomes Trials in Diabetes: What Have We Learned and Where Are We Heading?

Marc Pfeffer, MD, PhD (Brigham and Women’s Hospital, Boston, MA)

Dr. Marc Pfeffer stressed the importance of evaluating hard clinical outcomes rather than relying on surrogate markers like A1c to judge the effects of diabetes treatments. He joked that he did not intend to “pick on A1c,” offering a long list of promising hypotheses in cardiology based on epidemiological studies with surrogate endpoints that were later disproven in outcomes trials. However, he did offer some criticism of existing CVOTs for diabetes drugs, particularly the fact that they do not include heart failure as a primary endpoint. This is a sentiment we have heard repeatedly over the past few years, and we suspect that at the very least there will be more efforts to prospectively collect detailed data on heart failure in future trials given the surprises (negative in SAVOR and positive in EMPA-REG OUTCOME) in trials thus far. Dr. Pfeffer closed by urging attendees to treat the whole patient by addressing multiple CV risk factors rather than putting on blinders and focusing only on A1c – another sentiment that is becoming increasingly common.

Mechanisms in Cardiovascular Effects of GLP-1

Mansoor Husain, MD (UHN Research, Toronto, Ontario, Canada)

Dr. Mansoor Husain explored some of the current research behind mechanisms of GLP-1’s effects on the cardiovascular system. He began his presentation by illustrating that obesity is very interconnected with not only type 2 diabetes, but also hypertension, dyslipidemia, atherosclerosis, CAD, and more. However, a significant amount of data on GLP-1 agonists have shown that this drug class can improve survival post-myocardial infarction, can protect isolated hearts and cardiomyocytes, limit hypertension, and bring about other cardiovascular benefits. Delving into the mechanisms, Dr. Husain demonstrated through knock-out rat data that cardiac GLP-1 receptors are likely not required for post-myocardial infarction benefits, while other data suggests that hypertension is reversed through a GLP-1 receptor-dependent mechanism. In addition, GLP-1 agonists have been shown to induce diuresis and natriuresis, increasing atrial natriuretic peptide (ANP) levels in obese individuals with type 2 diabetes. With the recent positive EMPA-REG results, we would not be surprised to see even greater mechanistic research of diabetes drugs in cardiovascular outcomes in the near future.

Corporate Symposium: Lessons Learned from the TECOS CV Safety Trial and the Evolving Role DPP-4 Inhibitors in the Treatment of Patients with Type 2 Diabetes (Sponsored by MSD)

Lessons Learned from the TECOS CV Safety Trial: The Role of Sitagliptin in the Treatment of Cardiovascular Patients with Type 2 Diabetes

Rury Holman, FMedSci (University of Oxford, UK)

Dr. Rury Holman reviewed the results from TECOS (CVOT for Merck’s Januvia [sitagliptin]) presented at ADA and alluded to several limitations of existing CVOTs during Q&A following his talk. Dr. Holman said it would be a “very long time” before anyone can expect clinical data on the neuro-, cardio-, and nephroprotective effects of sitagliptin or other DPP-4 inhibitors. He believes a truly informative study would have to incorporate the glucose-lowering effects of the drug, and it would be difficult to do this ethically as a placebo-controlled trial given the known relationship between glucose control and microvascular complications. He argued that even uncovering any protective glucose-independent effects would require a much longer trial than most companies would be willing to undertake – this is where we believe funding from non-industry sources can play a very useful role since once these agents are generic, it would of course be very useful to understand the true benefit. Given these concerns, he suggested that a head-to-head comparative outcomes study with agents from different classes are the most likely to reveal the true long-term benefits and harms of new drugs. We completely agree and see this as one of the ways in which more flexible FDA policy could enable more informative trials.

Panel Discussion

Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Germany): You showed data showing that higher A1c equals higher heart failure risk. On the other hand, higher A1c should mean more glucosuria and osmotic diuresis, perhaps not enough to compensate, but does it matter?

Dr. Michel Komajda (Université Pierre et Marie Curie, Paris, France): I don’t think so. At a high A1c you usually have alteration of vascular function and vessel changes, usually an increase in stiffness. It’s a multifactorial issue and I don’t think that point could explain a contradiction to the overall finding.

Q: Other DPP-4 inhibitors are approved for advanced impaired renal function. There’s no clear data on sitagliptin having adverse effects in that population. Why wouldn’t you use sitagliptin for this population?

Dr. Nauck: There’s no doubt that sitagliptin can be used safely in renal impairment. You have to reduce the dose to keep exposure in the range we see in patients with no reduction in function. It’s pretty obvious from these trials that sitagliptin doesn’t worsen renal function in patients with a baseline reduction in GFR. And there’s no obvious provocation of side effects that you wouldn’t see in another population.

Q: Which DPP-4 inhibitors are safe in patients with diabetes and preexisting cardiovascular disease?

Dr. Nauck: Saxagliptin and sitagliptin have a neutral effect on macrovascular events. The only difference is an increased heart failure risk with saxagliptin that was not observed with sitagliptin. There was a mild increase in risk with alogliptin. All of these were patients with a chronic condition or all with multiple risk factors in SAVOR.

Q: Small percentages of patients didn’t receive statins. Was that at the time of enrollment or at the end of the trial? Are you planning to do a post-hoc analysis of this subset?

Dr. Rury Holman (University of Oxford, UK): We have shown no difference in the primary outcome by statin therapy. We haven’t pulled them out to see what happens longitudinally. The reasons they’re not taking statins relates to adverse effects. It’s not a randomized comparison.

Q: In heart failure patients, although you don’t have a definition of ejection fraction, if the ejection fraction is below 40 can sitagliptin be indicated? Or is there still doubt?

Dr. Holman: For the study as a whole there was no imbalance and a tight confidence interval. It was a consistent result by whatever subgroup. You’re correct that ejection fraction measurements were not collected. Some may have it in their records, but there wasn’t a consistent proactive collection. I can’t make a statement about it. We have seen complete consistency of the results however we slice the data.

Dr. Komajda: In the subset with previous heart failure, which was more than 2,000 patients, it is likely many had a low ejection fraction, and there was no harmful effect compared to placebo in recurrent heart failure events or cardiovascular mortality.

Q: Is there anything interesting in the BNP data?

Dr. Holman: That was not collected prospectively, but there is a plan for biomarkers that were collected to be measured. Whatever the level of prior heart failure, it doesn’t influence the results. It’s of interest to cardiologists but I don’t expect it to be a differential. It’s an analysis we plan to do but it’s after the event.

Dr. Nauck: There are two roles of BNP: one is as a marker of worsening heart failure and it’s also a substrate for DPP-4, but the action should not alter its biological activity, correct?

Dr. Carolyn Deacon (University of Copenhagen, Denmark): I don’t think it alters its biological activity, but early reports say it might influence the half-life, so indirectly it might.

Dr. Komajda: When SAVOR was presented in the cardiology community there were lots of questions because we believed high BNP was beneficial. Giving a DPP-4 inhibitor reduces the catabolism of BNP, so it should increase it. There’s no real plausible biological explanation why saxagliptin should be associated with increased heart failure risk, unlike what was observed with the TZDs, for instance, which we know induce sodium retention. It remains a question mark that will be addressed in future studies.

Q: The saxagliptin study showed an increase in heart failure. They stopped saxagliptin when they showed development of heart failure, so what happened then? Did it improve or was it the same?

Dr. Holman: We don’t have that information. The study hasn’t published that. But the study was double-blinded, so no one knew which drug they were on. It wasn’t an expected adverse event, so they wouldn’t necessarily have stopped study drug.

Q: Do we know what happens to cardiac performance in animals receiving either sitagliptin or others in the category?

Dr. Komajda: There’s generally a favorable effect on cardiac function and the vasculature, which raised a lot of questions regarding the accuracy of the methods. At the moment we can say from preclinical studies that the consensus is that the effects are beneficial.

Q: What about vildagliptin in heart failure?

Dr. Komajda: That arises from the VIVID trial in patients with previous heart failure. It was a proof-of-concept study, not an outcomes study. They looked at cardiac dimensions 52 weeks after randomization and there was significant cardiac dilation, no real change in ejection fraction, and no increase in heart failure hospitalization. I don’t know. At this point I do not recommend vildagliptin in a patient with overt heart failure or a previous history.

Dr. Nauck: It’s a logical consequence that if you have diversity and there are some compounds that don’t raise any question in that population, you should use those.

Q: How long should we expect to get results in humans to check the neuro-, cardio-, and nephroprotective effects of DPP-4 inhibitors?

Dr. Holman: A very long time. You would have to design trials that allow sitagliptin to be tested with a glucose differential. That’s a problem because you have to treat glucose to reduce microvascular risk. It would be hard to have a glucose difference trial of any magnitude for a long time. So we look for non-glucose-related effects and we are reading between the lines that these are small differences, and I’m not sure a trial of the length of time it takes to see complications emerge is likely to be undertaken. I’d be interested to know if a company is contemplating that.

Dr. Nauck: Often I hear in discussions that these are disappointing results from a safety study, but it’s a proven thing that as long as agents lower glucose, they will reduce microvascular complications. I would like to see proof from studies that show this rather than just assuming.

Dr. Holman: We need to manage glucose control by doing head-to-head comparisons between agents from different classes and truly seeing if there is long-term benefit or harm.

Dr. Komajda: It’s a pity that the companies stopped the pioglitazone vs. rosiglitazone comparison. That kind of study would be helpful with DPP-4 inhibitors.

Dr. Holman: It’s quite clear that in TECOS there was no signal. The question is whether the SAVOR signal is real. This was not an expected result, and we don’t have a biologically plausible mechanism. We may have stumbled on a problem. There’s a degree of uncertainty that’s not explained. There’s clear data for which agent has no apparent effect, but we have a concern raised that has not yet been refuted.

Dr. Nauck: I’m a clinician prescribing glucose-lowering agents. With this information, it’s difficult to justify ignoring it and prescribing a drug in someone with preexisting heart failure that has produced such results. If this is by error, how long will it take us to know better? We have to do even more trials, maybe head-to-head, and we will learn years from now, but we have to behave and prescribe drugs in the meantime. I’m characterizing my justification for prescription behavior based on published evidence.

Dr. Holman: We don’t know for certain but clearly in the meantime we act on the data that’s available.

Q: Have any studies shown a benefit of sitagliptin on neuropathy?

Dr. Holman: I’m not aware of any long-term studies, maybe some short-term ones.

Dr. Nauck: I believe there’s promising animal data showing specific effects in certain models.

Q: Is there a role for DPP-4 inhibitors in type 1 diabetes?

Dr. Nauck: There was an observation from type 2 diabetes where in some trials a DPP-4 inhibitor used with insulin led to a reduction in A1c and reduced hypoglycemic episodes, there was some interest and a hypothesis put forward that it increased alpha cell sensitivity to changes in glucose. If glucose is high, it will suppress glucagon; if it’s low it will increase glucagon. There’s a little bit of evidence. It’s a good idea to be tested but we don’t have trial results.

Q: What happened to blood pressure in TECOS?

Dr. Holman: It was not changed at all.

Corporate Symposium: Different Patients, Different Needs – Towards an Integrated Care Approach to Diabetes (Sponsored by Sanofi)

Getting to the Heart of the Matter: Understanding CV Risk in Diabetes

Lars Rydén, MD, PhD (Karolinska Institute, Stockholm, Sweden)

Dr. Lars Rydén offered a thoughtful take on the limitations of CVOTs after reviewing the current evidence on the relationship between diabetes and cardiovascular disease. He pointed to several commonly cited shortcomings (short duration, disproportionately high-risk populations, glycemic equipoise design) and mentioned others that have attracted less discussion, such as a lack of attention to postprandial glucose and use of primary endpoints that do not include clinically relevant events like peripheral arterial disease, heart failure, and stable angina. He also cautioned that the promising findings from UKPDS have limited applicability to the modern type 2 diabetes patient population because so few patients were on blood pressure- and lipid-lowering drugs – he said the heavy use of such medications is likely one of the main reasons why it is so difficult for current trials to demonstrate superiority (we wonder if it’s more a matter of just short timing). While the tone of Dr. Rydén’s critique was not as strident as some of the commentary we heard recently at ESC, the implication seemed to be that the information gained from these trials may not be worth the enormous investment of patient time and financial resources. As he aptly noted, the design of current trials is driven by commercial and regulatory factors rather than academic research goals – yeah, that’s pretty depressing given the potential impact on public health. We hope the FDA will feel compelled in the coming years to engage in a discussion about how the 2008 Guidance can be modified to encourage more cost-effective studies. We also hope that government, industry, academia, and private foundations can work together to develop creative ways to better answer the most important clinical questions about diabetes drugs and cardiovascular risk, such as through more robust large-scale databases or comparative effectiveness studies.

 

Diabetes Technology

Oral Presentations: Devices Changing Treatment Paradigm

HbA1c Improvement with Less Hypoglycaemia in Patients with Type 1 Diabetes Wearing an Artificial Pancreas for Two Months from Dinner to Breakfast

Hans DeVries, MD (Academic Medical Center, Netherlands)

Dr. Hans DeVries presented encouraging results from a randomized, crossover AP@Home trial comparing two months of dinner-to-breakfast hybrid closed-loop (8 pm to 8am) with UVA’s DiAs to two months of 24/7 open-loop with sensor-augmented pump therapy (Dexcom G4, Roche Spirit). The trial enrolled 35 current insulin pump users, with three dropouts due to poor system acceptance. The headline finding was a significant reduction in A1c: -0.32% on overnight closed loop vs. -0.16% on open loop (baseline: 8.2%; p=0.04). Though that seems small, we see it as an encouraging finding given the sole use of the system at night; a near halving of nocturnal time spent <70 mg/dl (1.7% on HCL vs. 3.0% on open-loop); and use of pump+CGM as the comparator group (harder). Overnight time-in-range (70-180) significantly improved (67% on closed loop vs. 58% on open loop; p<0.0001), though not as much as we would have expected – perhaps the overnight DiAs algorithm was a bit conservative in this home study, or the comparison to pump+CGM simply made improvement more challenging to show. The study is in press in the Lancet Diabetes & Endocrinology, and an extension phase has tested 24/7 use.

• Three of 35 patients discontinued use due to poor system acceptance. Dr. De Vries mentioned the hassle of alarms as a key factor, and one patient had a “trust issue” (a mathematics professor). It was a reminder that even among pump users, first-gen artificial pancreas systems are not going to be for everyone.
• Read the diaTribe experience testing this system at night and 24/7. Kelly and Adam appreciated DiAs’ nighttime algorithm, ability to reduce hypoglycemia, and the power of waking up with a glucose of 120 mg/dl.

Medical Imaging for Performance Characterisation of a Novel Continuous Subcutaneous Insulin Infusion Set

Robert Pettis, MD (BD, Research Park Triangle, NC)

Dr. Robert Pettis presented an investigational study of the new BD FlowSmart infusion set (6mm, side-ported), first presented as a poster (1088-P) at ADA 2015. As expected, there were no new updates on FlowSmart’s commercialization, which is still slated for “2016” in the US, EU, and Canada. The objective of the study was to use medical imaging techniques to evaluate the in vivo flow and deposition performance of the investigational set against control commercialized sets (Medtronic’s Quickset). Dr. Pettis first shared the results of an in vivo fluoroscopy experiment in swine that provided visualization of device placement and depot patterning during a 10U bolus infusion of iodinated contrast media. Notably, two distinct depots were created by the investigation set in contrast to the smaller, condensed diffusion pattern created by the control set. Building on these findings, investigators sought to replicate the preclinical results in humans. A corollary human MRI study of the investigational set in non-diabetes individual (n=8) showed similar depot patterning across multiple saline bolus volumes (2-20U). Comparison of the 6mm investigational set vs. a control 9mm set also demonstrated that the shorter length increased diffusion in areas of thin subcutaneous fat where muscle can occlude single ports. Lastly, a feasibility experiment of intentionally poorly inserted devices demonstrated successful bolus delivery with the FlowSmart set even under “non-ideal,” “real-life” conditions. Ultimately, we continue to be impressed by the preliminary data, though the major question for BD remains whether these differences will translate meaningfully to the clinic: Better insulin absorption? Lower A1cs? Less hypoglycemia? Greater time-in-range?

Questions and Answers

Q: Have you considered adding multiple ports to the catheter?

A: Yes, but it did not provide any additional advantage. It actually provided a disadvantage because the catheter became less stable. We did investigate different versions, but settled on this one.

Q: if you had to choose a side port vs. a main port, which do you think is better?

A: Two is always better than one, and this is all about redundancy. I think that because of the unique delivery characteristics of the side port, I would go in that direction. But that is my opinion.

Q: Have you done studies in clinic?

A: No. We have not done those studies yet.

Oral Presentations: Optimizing the Insulin Treatment Paradigm

Insulin Pump in Difficult to Control Type 2 Diabetes Mellitus

Priyamvada Singh, MBBS (Beth Israel Deaconess Medical Center, Boston, MA)

An observational pilot study (n=13) investigating the utility of insulin pump therapy in type 2 diabetes demonstrated significant improvements in A1c associated with pump therapy (8.9% to 7.7%) over five years. While we would raise questions about the results – retrospective analysis, very small sample size – the findings are directionally interesting given the lack of reimbursement for pump therapy in this population in the US. The data represent the longest observation of the efficacy of pump therapy in type 2 patients that we can recall seeing to date, and the analysis was interesting from a real-world use perspective. (Of course, the Medtronic’s OpT2mise results are the gold standard in this field so far.) That said, we were a bit disappointed to hear some of the commentary during the Q&A from the investigator, who sounded confused regarding the difference between CGM and pumps (she suggested that pumps record glucose data … ) – a big reminder of the importance of education for all those that are in the field, even those that we think of as “on the cutting-edge.”

Questions and Answers

Q: How did insulin doses change when patients were switched from MDI to pump therapy?

A: The total insulin requirements did not change while patients were on pumps. However, the insulin requirements were only about 100 units relative to 200 units on MDI.

Q: Do you have data on glucose variability?

A: There were fewer excursions.

Q: Did you look at CGM data?

A: We did not have to because insulin pumps have a chip you can download to look at glucose data.

Posters

Needle-Free Nasal Delivery of Glucagon is Superior to Injectable Delivery in Simulated Hypoglycemia Rescue (867-P)

J Yale, C Piché, M Lafontaine, R Margolies, E Dissinger, A Shames, N Fink, M Egeth, H Dulude

This brilliantly designed human factors study compared use of Locemia’s intranasal glucagon powder to a standard glucagon emergency injection kit in a simulated episode of severe hypoglycemia (a mannequin; details below). The study included two groups to mimic realistic scenarios: (i) people with diabetes that taught a caregiver how to use the glucagon device a week prior to the simulation; and (ii) untrained participants with no connection to diabetes, who were shown the device and then asked to use it on the spot. In the key analysis, 94% of caregivers (15/16) correctly gave a full dose of glucagon with the intranasal device, and it took just 16 seconds on average. Conversely, only 13% of the same caregivers (2/16) delivered a full dose with the injection kit and 38% gave a partial dose (6/16); the average time for these eight individuals was 1 minute and 53 seconds, or seven times longer than intranasal delivery. Shockingly, 50% of diabetes caregivers (8/15) failed to deliver any glucagon at all with the injection kit vs. 6% (1/16) with intranasal. Even more frighteningly, two caregivers in the injection group mistakenly used insulin for the hypoglycemia rescue (cleverly included in the diabetes supply bag alongside the glucagon, to simulate a realistic hypoglycemia rescue situation), as they were confused about which injection to use. Whew. The results were equally strong for Locemia in the untrained acquaintance group: 93% success (14/15) with intranasal in an average of 26 seconds vs. 0% success for a full-dose (0/15) and 20% success for a partial dose (3/15) with the injection kit in an average of 2 minutes and 24 seconds. Overall, the results are a slam-dunk for Locemia’s needle-free device, especially as it seeks regulatory approval and future reimbursement relative to existing devices. We’ve always said that injected glucagon kits are burdensome for caregivers, but who knew it was this hard to use them correctly and quickly? The study also revealed an unexpected concern with an injected route of glucagon delivery that is easy to mix up with injected insulin – this could be a strong marketing advantage vs. competitors Xeris and Biodel. As a reminder, Locemia has now reported phase 3 adult and pediatric data, showing strong equivalence to injected glucagon; we assume a submission could happen sometime early next year.

• The severe hypoglycemia simulation included a fully clothed adult mannequin representing a person with diabetes. Participants were told that the mannequin was having an episode of severe hypoglycemia and that they had to administer the rescue glucagon as quickly as possible. The glucagon rescue device was located in the patient’s backpack, which also contained a diabetes supply pouch (glucose meter and strips, alcohol swabs, lancing device, insulin vial, and syringe). Sound effects and distractions created a sense of urgency – a nice touch.
  
  • The trained caregiver arm included 16 adult insulin-using people with diabetes and their caregivers. Patients were taught how to use one of the glucagon devices (in random order) and then instructed their caregivers, replicating real-life transfer of information. One week later, caregivers were asked to treat a mannequin during a simulated episode of severe hypoglycemia. The procedure was repeated with the other device.
  • The untrained acquaintance arm included 15 adults with no diabetes connection, but who said they were willing to assist someone in distress. They were not trained on device use and only shown the device prior to the simulation. This group treated two episodes of severe hypoglycemia with the injection kit and intranasal powder in random order, with a delay of about ten minutes between each simulation.
• Two caregivers in the injection group mistakenly used insulin for the hypoglycemia rescue attributed to “form factor confusion.” An additional two caregivers in the intranasal group and three caregivers in the injection group attempted to give insulin in addition to glucagon “due to misunderstanding of diabetes management” (i.e., “insulin helps the patient with their blood glucose, so I should give that too”). The data simply underscores the tremendous educational challenges related to glucagon, even amongst diabetes caregivers!
• It was notable to see that untrained acquaintances were able to deliver intranasal glucagon successfully and at a similar rate as trained caregivers. We agree with the poster’s conclusion that it highlights the ease of use of Locemia’s needle-free nasal glucagon delivery system.
• “Glucagon delivery using a different route and device form than those used for insulin may reduce the risk of confusion and accidental delivery of insulin.” This was a fascinating point we had never thought of, but a realistic one since insulin might be co-located with a glucagon kit. Certainly, this gives Locemia some marketing advantage for injected rescue glucagon competitors Xeris and Biodel.

Psychological Aspects of Evening and Night Closed-Loop Insulin Delivery Under Free Living Conditions: A 2-month Crossover Trial (988-P)

J Kropff, J DeJong, S del Favero, J Place, M Messori, B Coestier, A Farret, F Boscari, S Galasso, D Bruttomesso, C Cobelli, E Renard, L Magni, J DeVries

This multicenter, crossover trial from the AP@Home Consortium investigated the psychological aspects of overnight closed-loop control, finding that patients appreciate the benefits of artificial pancreas technology despite the existing human factors burdens. The study enrolled 35 patients with type 1 diabetes, exposing all to sensor-augmented pump therapy for eight weeks during a control period and overnight-closed loop therapy for eight weeks during an intervention period. Results demonstrated an overall positive attitude towards closed-loop technology (perspective score = 69/90) with many patients acknowledging “positive effects at work,” “improved blood glucose,” and “less worry.” On the other hand, frequent alarms, interference with sleep and social life, and technological issue (e.g., loss of connectivity) all came up as issues and continue to underscore the need to study closed-loop technology in the context of real-life. Clinical setting are instructive from an accuracy and efficacy standpoint, though these findings serve as a reminder that the “most successful” closed-loop devices may not be those that are “most efficacious” but those that offer the “most normalcy” for patients. Patients did not report differences in fear of hypoglycemia during their time on SAP vs. closed-loop technology, perhaps a reflection of how far low-glucose suspend/predictive low-glucose suspend technologies have come in patient’s eyes. We continue to believe that human factors work will be pertinent to artificial pancreas uptake/success and, despite the limited analyses in this study, are big fans of the push to understand the psychosocial aspects of closed-loop technology more closely. Indeed, we can’t hand patients an artificial pancreas and expect them to love it immediately – perhaps we can take a lesson from CGM (which was once heralded as a must-have) and learn to set expectations more appropriately.

Continuous Glucose Monitoring Improved Glycaemic Control in Patients with Type 1 Diabetes During 52 Weeks of Insulin Pump Therapy as well as with Basal-Bolus Insulin Regimen (983-P)

J Šoupal, M Fleka, L Petruelková, J Škrha Jr., J Škrha, M Prázný

This prospective study investigated the efficacy of long-term CGM use in patients treated with CSII and MDI. The trial enrolled 51 patients with type 1 diabetes, dividing patients into three groups: (i) those initiated on CGM (n=17); (ii) those initiated on pumps without CGM (n=17); and (iii) those initiated on MDI and SMBG only (n=17). [In the first group, ten patients were on pumps (i.e., sensor-augmented pump therapy) while seven were on MDI.] After one year, findings indicated that patients on CGM saw a significant improvement in glycemic control (A1c: 8.3% vs. 7.2%, p<0.0001) with both subgroups (patients on MDI and patients on SAP) showing similar improvement in A1c. Patients on insulin pump therapy alone also saw an improvement in glycemic control (A1c: 8.4% vs. 7.9%, p<0.05) – though, we would note, not as great as those on CGM – while those in the control group did not experience a significant improvement (A1c: 8.3% vs. 8.0%). The poster notes that a reduction in time spent in hypoglycemia was only observed in patients with CGM (8% vs. 6%, p<0.01) – however, we’d point out that it’s tough to compare time in hypoglycemia for patients on SMBG and CGM in the first place given the 24/7 data presented by CGM and lack thereof with SMBG. Regardless of this limitation, the findings speak to the value of CGM relative to pumps, suggesting that a combination of CGM + MDI and be just as effective as CGM + pumps in a subset of patients. We look forward to more rigorous studies investigating the relative benefits of pumps vs. CGM in the future.

Long-Term Accuracy Surveillance of a System for Self-Monitoring of Blood Glucose (930-P)

G Freckmann, A Baumstark, N Jendrike, T Leucht, P Wintergerst, D Rittmeyer, S Pleus

This poster examined the real-world accuracy of CE-marked SMBG systems, demonstrating that commercial devices often do not meet the standards by which they were cleared. The findings came as little surprise considering the attention BGM post-market surveillance has received in the past year (see our report on the 2014 AACE/ACE Consensus Conference on Glucose Monitoring). Four individual studies evaluated a total of eleven test strip lots for a single system’s accuracy over 1.5 years. Results were analyzed using both ISO 2003 (at least 95% of results have to fall within ±15 mg/dl at blood glucose values below 75 mg/dl and within ±20% at blood glucose values ≥75 mg/dl) and more stringent ISO 2013 (at least 95% of results must fall within ±15 mg/dl and ±15% for BG values ≤100 mg/dl) criteria. Findings indicated that nine out of the eleven test strip lots fulfilled the ISO 2003 criteria, while only five fulfilled the more stringent guidance. No clear trend in accuracy was observed over time. Ultimately, the findings drove home the need for consensus on issues of quality and safety. As a reminder, we heard much about the DTS’ post-marketing surveillance program last year, though it looks like the major outstanding question – who will fund it – continues to remain unanswered.

Is The Pump Bolus Calculator a Useful Tool or The Man Behind The Curtain? (920-P)

K Miller, D Maahs, J Wong, S Adi, R Beck, A Peters

This human factors study of T1D Exchange data examined the utility of bolus calculators in insulin pumps. Analysis included 1,944 T1D registry patients on pumps who were age ≥ 13 years. Findings suggested that a majority of patients who use an insulin pump frequently report using a bolus wizard/calculator (79%); this was more common in adolescents, females, patients with shorter duration of T1D, and patients with a lower education level (see table below). None of these findings were particularly unexpected. What was surprisingly was that frequent use of the wizard/calculator was NOT a significant factor in the safe and effective use of pumps – e.g., there were no significant differences between frequent vs. infrequent bolus calculator users in terms of the numbers of boluses per day (5.4 vs. 5.3, p=0.23), glycemic control (A1c 8.0% vs. 8.1%, p=0.04), occurrence of DKA in the prior 3 months (2% vs. 1%, p=0.18), and occurrence of SH in the prior 3 months (6% vs. 7%, p=0.56). Indeed, the findings support the notion that bolus calculators are valuable for patients of lesser diabetes literacy (or newly diagnosed), but also underscore the room for human factors/validation studies that could bring improvements in design/feasibility/utility. We assume that in shorter-term, less educated users, the benefits of accuracy outweigh the hassles of the calculator, though with a certain level of literacy, it appears that this added value dissipates. Moving forward, we would love to see a similar study done in a different population – those using BGMs with built-in bolus calculators on MDI, particularly given how many these patients would not otherwise have access to the benefits. We have to imagine that bolus advice would be associated with safer and more effective self-management.

• Adolescents, females, patients with shorter duration of T1D, and patients with a lower education level were more likely to use insulin pump-integrated bolus calculators/wizards.

Product Demos

Dexcom Clarity

Dexcom silently launched its new web-based Clarity downloading software today, an outstanding upgrade over its previous data interpretation offerings. Clarity retains the high and low pattern recognition features from Studio/Portrait on the Web, but has added a much-improved dynamic web user interface, a better one-page snapshot with key information, and our absolute favorite, a “Best Glucose Day” report – we love the focus on the positive, which is too often overlooked for understanding what is working well. The refreshingly minimalist Clarity interface includes just four pages (Overview, Patterns, Data, and Compare), which show key information, mostly rely on graphics, and allow for manageable customization in all the right places. Pattern recognition is the major focus of the software, which should lay a foundation of what will hopefully come in the future – dosing advice. Details below!

• The “Overview” report is the one-pager for the busy patient/clinician, showing estimated A1c, average glucose, hypoglycemia risk (low, medium, high), time-in-range, calibrations per day, and identified patterns during the specified date range (high, low, and Best Glucose Day, with associated time buckets – super useful for problem identification). Dexcom has clearly been thoughtful about including only the most important things on the Overview page, and for once it’s not an overwhelming spaghetti chart or tables full of statistics. Clicking on a pattern gives a deeper dive into the events that triggered its identification.

• The “Data” page shows an AGP-like modal day report with bands to indicate the 15^th/75^th percentile range of values in a particular time slot – the spirit of AGP is there, though Dexcom has not entirely adopted the look and feel of AGP. The 15^th percentile choice is a definite departure from AGP’s 25^th percentile – we assume the goal is to really hone in on low outliers in a time slot.

• “Compare” is a nice screen for examining quarter-to-quarter changes, giving key side-by-side Overview statistics and modal day reports for two specified periods of times.

• The exported PDFs are equally well-designed and clear (pun intended), and we give the upload process high marks too – once we downloaded the uploader program (Mac and PC compatible), it sat in the background, auto-detected the plugged in Dexcom receiver, and uploaded the data to the web-based report in less than 10 seconds.
• Clarity offers the same view for patients and clinicians (Yes!), and will pull data from both G4 Platinum and G5; we assume G5 data will automatically go to Clarity for those using the mobile app.
• According to the user manual, Dexcom Clarity will also be offered in a separate mobile app. Notably, users can generate a code to allow others to view the data – that will be a big asset to caregivers and healthcare providers. 
• The big next step, of course, is EMR integration … some of that is happening in a pilot at Stanford with EPIC.

Diasend Mobile App

We had a chance to play with CGM data in Diasend’s new Mobile app, which has just two main screens: “Scorecard” (a one pager showing average glucose, standard deviation, time in range, and activity levels via popular trackers like Fitbit and Jawbone) and “Reports” (timeline, modal day, and time-in-range). See pictures below. Like Dexcom’s approach with Clarity, the Scorecard view gives a terrific topline look at what’s happening with someone’s glucose levels – the four statistics diasend chose are great selections. The highlight of the “Reports” view is actually coming in two weeks, where Diasend plans to add AGP to visualize CGM data; Abbott has gotten a lot of patient praise with this output, and the app’s current modal day report is a spaghetti chart. We like the super clear time-in-range pie chart at the bottom of the Reports page – the glanceability of color pie charts is really something we hope to see more of. The app’s scrolling timeline view is not particularly useful for identifying patterns. A third tab, “Upload Data,” can only read from an NFC-enabled A. Menarini meter for now, though presumably more devices will come in the future (FreeStyle Libre?). We got data into the Diasend app via a Dexcom receiver downloaded to diasend.com; like Dexcom’s Clarity, this took ~10 seconds with diasend’s uploader. Diasend’s mobile app is really headlined by its disciplined restraint, and it’s hard to discount the platform’s tremendous compatibility (including Dexcom’s G5 at launch). We hope to see the company do more on the pattern recognition front, and to make the web interface more intuitive for problem identification – there are still too many of the overwhelming CGM graphs and statistics right now.

EASD/ADA Symposium: Devices

The Artificial Beta Cell: European Research

Lalantha Leelarathna, PhD (University of Cambridge, UK)

Dr. Lalantha Leelarathna began with unexpected news – two three-month, at-home, unsupervised closed-loop studies were published today in NEJM (a big day for diabetes indeed!). The single publication combines two crossover, randomized studies: 24/7 hybrid closed-loop in 33 adults and overnight closed-loop in 25 children and adolescents. Both used Cambridge’s MPC algorithm and compared closed loop to sensor-augmented pump therapy (Abbott Navigator 2, Dana R pump). Day and night time-in-range improved significantly in both studies, with a major ~20-25 percentage point improvement at night and a ~10-11 percentage point improvement during the day. Mean glucose followed a similar pattern, with an ~19-30 mg/dl improvement at night and ~10-11 mg/dl improvement during the day. This translated to an A1c reduction of 0.3% in adults (baseline: 7.6% post run-in; p=0.002) and a 0.3% advantage in children (baseline: 7.8% post run-in; p=0.17). Time spent in hypoglycemia (<50 mg/dl) was very low in both studies, though was still halved in children and adolescents (0.3% CL vs. 0.6% OL) and declined ~25% in adults (0.3% CL vs. 0.4% OL). See the pictures below, which really underscore the tremendous nocturnal gains (plus reduced variability) in this study. The multicenter trials were very scientifically rigorous and included long run-in periods (four weeks and 2-8 weeks), did not have remote monitoring or dietary/activity/geographic restrictions, used sensor-augmented pump therapy as the comparator (harder), and represent the longest at-home data published to date. The reduction in mean glucose plus less hypoglycemia is an important finding for an insulin-only system. This also marks three straight years of automated insulin delivery trials in NEJM, following the Bionic Pancreas in 2014 and DREAM and ASPIRE in-home in 2013. We salute the Cambridge team, who has really blazed a trail of ambitious, at-home, free-living closed-loop studies. We’re not sure what the team’s commercialization plans are, though hope there is something in the works!

• The modal day plots below really highlight the advantage of the Cambridge system at night – there’s a clear reduction in mean glucose and a dramatic reduction in variability.

• Total daily insulin dose were not significantly different between open and closed-loop in either study. This is consistent with prior Cambridge studies; insulin delivery was clearly more variable, an advantage of closed loop.
• Closed-loop was used for a median of 20 hours per day in the adult study and 9 hours per day in the children/adolescent study. This was excellent considering the device burden, which entailed a smartphone + pump + CGM receiver + transmitter in the adult study, and a receiver + pump + CGM receiver + transmitter in the children/adolescent study.
• Three severe hypoglycemic episodes occurred during the closed-loop phase, though the system was not in use in these cases. One episode of severe hypoglycemia occurred in an adult participant when the closed-loop system was not in use because of loss of connectivity (low battery); the participant was receiving insulin at the rate supplied by the study insulin pump. One adolescent participant had two severe hypoglycemic episodes (seizures) during the intervention period; the closed-loop system was not in use (not turned on and lack of pump connectivity), and the participant was using sensor-augmented pump therapy. It will be interesting to see what severe hypoglycemia looks like once larger artificial pancreas pivotal studies get under way.
• The paper has a balanced criticism about dual-hormone systems: “Dual-hormone systems may provide additional protection against hypoglycemia, but are currently limited by the need to reconstitute glucagon daily and by the use of a second pump to deliver glucagon through a separate infusion set, which increases the burden and complexity.”

Questions and Answers

Dr. Robert Ratner (ADA, Alexandra, VA): What do you think is the additive advantage of a second hormone over insulin alone? Is it cost-effective?

A: I think the single hormone can reduce hypoglycemia burden, and in most studies the actual burden is fairly small. For the majority of patients, we can do a very good job with a single hormone closed loop. I agree with Steven that there are some scenarios where a single hormone alone cannot stop hypoglycemia – exercise, a large enough dose of insulin. There may be some selective groups of people where dual hormone is useful: those with hypoglycemia unawareness or significant hypoglycemia burden. But we haven’t done comparative studies in Europe of single vs. dual-hormone. There was one study from Canada – Dr. Haidar – which showed a further small increment in hypoglycemia reduction with glucagon.

Dr. Steve Russell (MGH, Boston, MA): Do you think it’s possible to do fully closed loop with insulin only? These insulin-only systems require accurate carb counting and bolusing in the way patients typically do. Can insulin-only reduce that burden to the point of not having to do it?

A: In that scenario, dual hormone may have an advantage. You could dose insulin aggressively and treat with glucagon. Perhaps there’s an advantage with a fully closed-loop system. But you have to balance that with additional cost and complexity.

Dr. Russell: Who are the appropriate people to use these systems? Is the larger population of type 1 diabetes sophisticated enough to use insulin only systems, to do carb counting? In our pivotal trial, we will have MDI patients who have no experience with diabetes technology. We believe our system is easy enough that they can use it effectively. Will that be true for an insulin-only system?

A: The cost of these things is important. If you are taking patients who don’t use MDI correctly, there’s a question on reimbursement. What are the long term benefits and reductions in A1c?

Dr. Ratner: The T1D Exchange has documented an enormous degree of burnout among patients on CGM and even on pumps. Clearly all of the volunteers in the study are enthusiastic about participation. What have you seen in terms of discontinuations due to burnout? What do you anticipate in more generalized use?

A: I don’t know the honest answer. I suspect it’s broadly similar to CGM discontinuation rates. Possibly 10-20% of patients? Possibly more. I think it will all depend on the benefit they perceive and see. With early CGMs, patients were pretty frustrated. That’s why they didn’t want to use them. With more accurate devices, patients are telling us they love and want to use them. But there is the inconvenience of having to wear all these things.

The Bionic Pancreas: When Will The Dream Come True?

Steven Russell, MD, PhD (Massachusetts General Hospital, Boston, MA)

Dr. Steven Russell’s (MGH, Boston, MA) talk on the Bionic Pancreas summarized results from the team’s glucagon-only study (first presented at AADE 2015) and mentioned the possibility of using Lilly’s U200 Humalog (insulin lispro) in the dual-chamber iLet device. This was the first we had heard of this prospect, which would theoretically enable a smaller reservoir size. Timing-wise, it sounds like the team’s pivotal is still on track to begin in late 2016 and run through early 2017 with an FDA submission slated for 2018 and commercial launch in late 2018-early 2019. This could be accelerated based on the results of the ongoing glycemic target studies, as Dr. Russell noted that a single hormone iLet is a possibility pending encouraging insulin-only results. He told us after the session that the FDA would only require a three-month pivotal for insulin-only vs. 12 months for bi-hormonal (given the need for a chronic indication for glucagon). The team could then offer glucagon as an upgrade following an FDA chronic use indication (and commercialized stable glucagon).

• The usual verbal jousting on bihormonal vs. insulin-only closed-loop came during Q&A, when Dr. Russell and Cambridge’s Dr. Lalantha Leelarathna debated the merits of full automation vs. higher complexity/cost. Dr. Leelarathna conceded that future bihormonal systems may offer greater control and the potential to achieve “fully” closed systems, though questioned the tradeoffs, namely greater cost and complexity. Dr. Russell countered that insulin-only designs have a ceiling as hybrid systems that will always put some onus on patients to carb count accurately. Both sides have valid points and this is not an either-or situation – patients and their providers will ultimately decide what’s best for them … See the Q&A from this session below.

Questions and Answers

Dr. Robert Ratner (ADA, Alexandria, VA): You mentioned using concentrated lispro moving forward. What about a faster-acting insulin?

A: Yes. Everyone wants a more rapid-acting insulin. After all, the delay is a challenge. We can achieve very good control with currently available insulin, but we can achieve better control with more rapid insulin.

Q: With more rapid-acting insulin, can the algorithm adapt?

A: We have a parameter in the algorithm that is the expected time to the peak of the insulin in blood. We have experimented in our early studies with two settings, and the more aggressive setting worked well for many people. However, there was lots of variability between subjects. For people with slower absorption, we saw some stacking and hypoglycemia. We are currently assuming that the slower insulin for everyone is safe. We could turn the parameters down a bit and could get significant gains in terms of reduction in mean glycemia. We may be able to use less glucagon.

Q: What would the application filing look like for that? Would you need to do more trials?

A: We would have to do an additional trial to do an ultra-rapid-acting insulin. I think it would be significantly shorter and smaller. The size and duration of the current trial relates to obtaining a chronic use indication for glucagon, since it is only approved for an acute indication.

Q: The glucagon-only data looks pretty impressive, particularly at night. Is there any difference in efficacy at the beginning vs. the end of the night?

A: No, we have never seen any differences in the effectiveness of glucagon at beginning or end of the night. Our assumption is that given the amount of glycogen storage in liver and the amount of glucagon that we’re using, we’re not depleting glycogen enough. We do anticipate that if one went long enough – such as during an extended duration of exercise – one could deplete the stores. This would reduce the effectiveness, but not entirely eliminate it.

Q: What is the battery life of your device? What do you advise patients to do in terms of battery failure?

A: That hasn’t been finally determined. What has been determined is that the system will use AA batteries. Those will provide at least a week of battery life, perhaps more. The life will be determined by the ultimate configuration in terms of optimizing it, shrinking it, changing the display to an electronic paper display, and using less power. We have yet to know what it will be. In terms of failure, we have thought about giving every patient two devices. We haven’t decided what the appropriate approach should be. The system could provide advice for self-treatment with syringes or pens based on the behavior of the Bionic Pancreas while on line.

Q: Have you considered a portable battery-charging device?

A: We do use that in current studies with the device. We advise charging every day. For the iLet device and the one we intend to use in the pivotal studies, it will use disposable AA batteries that are available everywhere and easily replaced. They’re cheaper than lithium ion batteries.

ADA/EASD Statement on the Evaluation of Insulin Pumps

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

Dr. Lutz Heinemann presented an overview of the rationale behind and takeaways from the ADA/EASD Position Statement on Insulin Pumps, first presented in February at the EASD Diabetes Technology Meeting. As he noted previously, his remarks focused on the need for more pre- and post-marketing surveillance and for a more systematic and transparent regulatory process. See our February report for all the details from the statement; below, we summarize a few of the more nuanced points that Dr. Heinemann added to his previous commentary.

• “Publishing the manuscript is nice, but what will be the impact of it?” Dr. Heinemann stressed that recognizing the currently flawed system is only the first step in the reform process. We would agree – the Working Group is valuable only as far as the recommendations are acted upon. We continue to wonder how the publication of this statement will actually affect the broader industry. The recommendations are not binding, and it is tough to say how manufacturers in particular will respond. Much of the utility may be determined by how regulatory bodies react: Will the FDA and EU Commission follow up on the statement? Will the ADA and EASD play a role as the Working Group has requested?
• Dr. Heinemann cautioned that a thoughtful approach to regulating insulin pump therapy could pay off and have relevance for the future of artificial pancreas systems. After all, some of the most common errors seen in pump therapy are associated with user error – something that is sure to creep up with closed-loop systems. In this sense, he stressed that proactive thinking about the human factors design of pumps could pay off in a big way down the road.
• We learned that the Working Group is currently discussing a second statement that will examine the performance, safety, and clinical outcomes of CGM.

Corporate Symposium: Dexcom Continuous Glucose Monitoring in 2015 – Clinical Practice, Technology Innovations and Market Access (Sponsored by Dexcom)

Current and Future Dexcom CGM Technology Innovations

Jake Leach (Senior VP of R&D, Dexcom, San Diego, CA)

Dexcom’s Senior VP of R&D Jake Leach started with big news out of the gate: Dexcom’s G5 mobile system has been approved in Europe and will begin launching in select countries in the coming weeks (in tandem with the US launch). This was very unexpected, as Dexcom has never given an official timeline on EU availability of G5. Notably, the EU version of G5 also has a replacement claim in the label: “The G5 Mobile System is designed to replace fingerstick blood glucose testing for diabetes treatment decisions.” Though it still requires two fingerstick calibrations per day, the move is a major one for Dexcom and makes G5 more competitive with Abbott’s factory calibrated FreeStyle Libre. The EU launch of G5 also brings the Share remote monitoring capabilities and the more accurate G4AP algorithm to Europe for the first time (Share was never launched in the EU). In other major news, Mr. Leach showed a picture of the Dexcom/Google prototype sensor for the first time – it was the size of penny and a tiny bandage (see the picture below – smaller than we had imagined on the body). The partnership was only announced a month ago, though the pressure is certainly on to hit the goal of commercializing within ~2-3 years. On the data front, Dexcom is working on real-time therapy support “like an insulin dosing calculator,” and a pilot is ongoing at Stanford Children’s Hospital to seamlessly integrate Dexcom CGM data with notoriously non-interoperable EPIC. More details below on the Google partnership, G5, the data management pipeline, pump partners, and an insightful Q&A.

• Mr. Leach showed a picture of the Dexcom/Google prototype CGM sensor, highlighting the ambitious goals: “develop a simple, low-cost, disposable, body-worn sensor system integrated into an advanced data analytics platform to drive entry into [the] type 2 market and to expand CGM use in [the] type 1 market.” Succinct and lofty – the best kind of goal. In August, the product was envisioned as a bandage the size of a couple of dimes stacked on top of each other, and this looks roughly the same size. Still, seeing it on a human abdomen for the first time really reinforced how small this form factor will be. We wonder if Abbott’s real-time version of FreeStyle Libre will be out at that point in the US.

• “We expect to have a portfolio of multiple products for different groups. The best example is the type 2 product we’re focused on with Google.” Mr. Leach admitted that these products might require tradeoffs on cost and performance. Indeed, we wonder what level of accuracy/reliability the Google/Dexcom product will achieve – could the sensor attain a MARD ~10%? Is 15% more likely? What is the necessary MARD for a type 2-focused product? What is the right accuracy/reliability tradeoff to substantially improve the form factor? Hard decisions!
• “A MARD of 10% is the safety threshold for CGM to replace SMBG.” Mr. Leach highlighted a new modeling paper (Kovatchev et al., DT&T 2015) to underscore this point. The newly acquired replacement claim in the G5 EU label is a major win for Dexcom, and we wonder how such a label will be phrased in the US – per Dexcom’s 2Q15 call, such a claim is expected sometime in 2016 in the US. This has major implications for Medicare coverage, for doctors to prescribe CGM, for the patient experience of using CGM, and perhaps for payer discussions.
• In new news, remote software updating the Share receiver to G5 will be possible on both Mac and PC. This overcomes frustration with the PC-only upgrade from the G4 Platinum algorithm to the G4AP algorithm (Software 505) last fall.
• Fingerstick calibrations entered on the G5 app will be sent directly to the new smart Bluetooth transmitter. We assume from there they would also be sent to the receiver, should a patient opt to use one. This is impressive smart transmitter technology that retains the same form factor as the existing G4 Platinum transmitter. The tradeoff is a shorter battery life, as we have previously covered (three month indication).
• Mr. Leach highlighted the G5 app’s discrete alerts and alarms, which show up on the iPhone lock screen similar to any other notification (e.g., text message). Swiping the notification opens the Dexcom app and shows the alert. The notification sounds can be customized, correcting a long-stated frustrated of CGM users (“I’m used to the alarms!”). Alarms can also be set to vibrate for discretion. Overall, it seems like the mobile interface is going to offer a substantial customization and user experience upgrade over the standalone receiver.

• Dexcom is currently working on real-time therapy support “like an insulin dosing calculator.” The company has historically focused on retrospective data – and that will continue – though Mr. Leach said in Q&A that improved real-time analytics are also in the works. The hope is to add these straight into the G5 app. We could imagine several potential offerings: a bolus calculator that incorporates CGM values and trend information; analyzing insulin pump data from partners Insulet, Tandem, and Animas; projecting CGM values into the future; real-time exercise dosing/eating advice; etc.
• Stanford Children’s Hospital is piloting seamless Dexcom integration with EPIC, the notoriously non-interoperable electronic medical record. Dexcom users’ CGM data will post to HealthKit (via the Share app now, and G5 in the future), and an EPIC app takes the glucose data from HealthKit and puts it into the EMR. “The user and doctor don’t have to do anything at all.” Physicians can log in and see the CGM data within the EPIC program, eliminating the need to go to separate Dexcom software. Stanford plans to roll the pilot out more widely. Mr. Leach urged attendees to contact EPIC for more details on this seamless integration with HealthKit.
• Mr. Leach emphasized Dexcom’s “ecosystem” approach and showed the growing list of data management, app, and pump partners: diasend, EPIC (new!), Glooko, SweetSpot, Tidepool; Databetes (Meal Memory) and Training Peaks; Animas, Insulet, and Tandem. Apple’s HealthKit platform was shown on the slide as the hub of all these partnerships – it will be interesting to see if Android lags behind on this front. 
• Dexcom CGM data currently posts to HealthKit with a three-hour delay. Mr. Leach said it might be reduced over time. Three hours was established as a safe limit with the FDA, preventing real-time use of CGM data by other apps (i.e., making those apps class III medical devices). It’s a nuanced and tricky debate – what constitutes real time data? Is a 20-minute delay sufficiently retrospective? We hope this window declines over time, since there is so much potential to improve care with real-time, contextual feedback. Other apps could do more if the data flowed to HealthKit closer to its acquisition – Mr. Leach acknowledged as much, but it sounds like Dexcom’s classic interim steps regulatory approach will be the strategy here.
• Dexcom is “working towards” G5 integration with its pump partners Animas, Insulet, and Tandem. At this stage, it’s hard to know who will be first-to-market with an integrated pump:
  
  • Insulet’s next-gen OmniPod PDM is expected to launch in 2016, though we don’t think it will include G5 data on the handheld to start – Insulet has maintained that the PDM will be submitted for 510(k) clearance, meaning non-CGM-integrated. Perhaps the next-gen PDM will launch with integration on the app side, allowing the Dexcom mobile app to display Insulet pump data sent through an Insulet app and HealthKit. That is complete speculation on our part, and an open question is whether HealthKit can even handle insulin dose data (it does not have such an entry field to our knowledge).
  • Tandem announced an updated agreement in its 2Q15 call to integrate G5 in the future, but there is no timing on when it could launch.
  • Animas has never talked about a G5 integration publicly, though we assume one is in the works for automated insulin delivery.

CGM: Cost Modeling and Reimbursement

Claudia Graham, PhD (Dexcom, San Diego, CA)

Dr. Claudia Graham provided a 30,000-foot perspective on CGM, arguing that the technology provides greater and more cost-effective benefits vs. pump therapy. Drawing from the literature (e.g., JDRF CGM trial; Soupal et al. [Abstract #983], EASD 2015), she pointed out that A1c reductions for patients on CGM + MDI are actually comparable to (or better than) those on CGM + pump. Dr. Graham supported the clinical assertion with convincing cost-effectiveness data – in her analysis (tables 1A and 1B below), CGM + MDI, saved ~$10,000 vs. sensor-augmented pumping over four years. She also shared a CORE analysis (i.e., a validated cost-effectiveness model) demonstrating that CGM + MDI therapy can be highly cost-effective (“dominant”) from a payer’s perspective in a one-year time frame– see the analysis below, which used pretty conservative values that should improve with more modern CGM devices. The talk continued a Dexcom theme of “CGM first” (i.e., before pumps), along with management’s recent remarks that the pump partnerships won’t be transformative for the company. It makes sense strategically, given the size of the MDI market and the increasingly cost-conscious payer environment. Dr. Graham’s concluding slide was greeted by nods and laughter: “Is using a pump before beginning a CGM like putting the cart before the horse?” In her eyes, investing in CGM before pumps is a no-brainer decision, though the real challenge is getting payers to buy in. In Europe, that seems to be slowly changing, per her country-by-country update – see below.

• In a slide titled “Simple Math,” Dr. Graham compared the four-year cost of sensor-augmented pump therapy (without considering the cost of insulin) vs. CGM + MDI therapy. The results suggested a ~$10,000 savings with CGM + MDI. The data on this front are clearly estimates, and Dexcom has already made moves with the DiaMond study to evaluate this more fully.
  
  • Assumptions: Transmitters = 1.5/year; Assumes CGM sensor use of 80% at an average selling price of $72 per sensor.

1A. Four-Year Cost of Sensor-Augmented Pump Therapy

Year	Pump	Pump Disposables	Transmitter	Sensors
1	$1,150	$1,455	$675	$2,995
2	$1,150	$1,455	$675	$2,995
3	$1,150	$1,455	$675	$2,995
4	$1,150	$1,455	$675	$2,995
	$4,600	$5,820	$2,700	$11,980
Total Cost	$25,100

1B. Four-Year Cost of CGM + MDI Therapy

Year	Receiver	Transmitter	Sensors
1	$400	$675	$2,995
2	$0	$675	$2,995
3	$400	$675	$2,995
4	$0	$675	$2,995
	$800	$2,700	$11,980
Total Cost	$15,480

• Dr. Graham also analyzed how much benefit CGM + MDI therapy would have to deliver in order to be cost-effective over a one-year period. Under relatively conservative conditions (an A1c reduction of 0.5%, two fingersticks/day; patients using the sensor for ~10 days, 50% reduction in hypoglycemia), Dr. Graham suggested that CGM + MDI would be highly cost effective. Her analysis spoke to the value of CGM under pretty minimal assumptions, though we were also reminded of the need for longer studies examining A1c reductions/severe hypoglycemia/quality of life – indeed, she noted that with current data it is impossible to look past one year.

CGM + MDI: Cost-Effectiveness Modeling

A1c Reduction	# SMBG/Day	# sensors/ month	Hypoglycemia (moderate and severe)	Receiver Cost	Quality of Life	ICER/QALY
0.5%	5.5	4	No reduction	$450	0	$130,403
0.7%	5.5	4	No reduction	$450	0	$94,823
0.5%	2.5	3	50% reduction	50% reduction*	+	$16,613
0.5% (and include indirect costs)	2	3	50% reduction	50% reduction*	+	Dominant

*Assuming 50% of patients don’t buy a receiver in the future, due to G5

• Dr. Graham concluded her talk with a valuable summary of general reimbursement status of CGM worldwide.
  
  • She strongly critiqued Medicare’s unwillingness to cover CGM in patients > 65 years: “Medicare’s ruling on CGM is the bane of my very existence. It’s the most asinine thing I have heard of in my life. One out of five seniors are having hypoglycemia and blacking out in a year, but because they ‘rely’ on a SMBG confirmatory fingerstick, Medicare won’t cover it.” While it continues to irritate, she did offer optimism for the future, suggesting the coverage is not a question of “if” but “when.” See our recent coverage of the bills in Congress here.

CGM Reimbursement Status

Country	Type	CGM?
US	T1D Commercial Payers	Yes
US	T1D Medicare	No
UK	NICE Diagnostic Assessment	Pending for SAP
Sweden	Tenders; regional	Yes, majority
Norway	Tenders; regional	Yes, majority
France	HAS; national	In review
Germany	GB-A; national	In review
Switzerland	National	Yes
Slovenia	National	Yes - pediatrics
Netherlands	Regional	Partial
Czech Republic	Patient capitation	Partial
Israel	Regional	Yes - pediatrics

Using Dexcom CGM in Clinical Practice – Education and Medical Management

Peter Adolfsson, MD, PhD (University of Gothenburg, Sweden)

Dr. Peter Adolfsson provided a practical overview of the clinical use of CGM. To be frank, his talk was far too long and lost the audience about halfway through. From optimizing alarms to understanding lag time, Dr. Adolfsson led attendees through the many intricacies involved in proper education, summarizing the highlights of a CGM start guide utilized in Sweden and to be published globally in the near future. Using these guidelines, Dr. Adolfsson’s Kungsbacka clinic has seen impressive CGM penetration (and benefit) in recent years – CGM use has increased from 52% in December 2014 to 70% currently (55% on real-time CGM + 15% on FreeStyle Libre). It was quote notable to see FreeStyle Libre already at 15% in such a short time after commercialization. According to his estimates, glycemic control has improved in 78% of patients and 87% have had a positive experience on the technology. This is exactly the kind of real-world data that lend credibility to a device, and we hope much more of it comes with Big Data from platforms like diasend, Glooko, and Tidepool.

Panel Discussion

Q: What is the lag time for Dexcom G5 mobile?

Mr. Leach: It’s the same as for G4 Platinum – on average 5-7 minutes. There has been lots of study on it. There’s been interesting work on the physiologic lag between venous and interstitial fluid. That ends up being sub-five minutes. There is a little lag based on our system averaging data over five minutes. That’s why you get the 5-7 minute lag time.

Q: Do you see more cost effectiveness in pediatric patients?

Dr. Graham: I haven’t looked at it. However, I would think that the lifetime cost-effectiveness is better in pediatric patients than for adults … especially when we’re talking about hypoglycemia in the moderate and severe range. Plus, when you add in the cost of hospitalizations associated with hypoglycemia, this is huge.

Q: What about acetaminophen and the interaction with G5? Is this unique to Dexcom’s technology?

Mr. Leach: The G5 system can get erroneous readings with high doses of Tylenol. It’s not specific to Dexcom. Other commercial devices have the same potential error if you are taking large doses of acetaminophen. If you are using CGM, we recommend you don’t take Tylenol.

Q: What about non-invasive sensors?

Mr. Leach: We are constantly reviewing them. We love the idea. The reality is we haven’t seen anything that can the meet performance and reliability to manage diabetes properly. It’s a great dream, but we haven’t seen anything we would consider.

Q: Can you talk about the new ISO standards and how those apply to your CGM?

Mr. Leach: There are new ISO standards. As background, that particular method is performed in a laboratory, and it’s a very analytical test. It’s not actual life. Our CGMs are actually measured in patients where we take venous blood and compare the results to the CGM values. The performance you get from a properly run CGM study is very indicative of the performance of a CGM. We don’t believe the ISO standard is really applicable here.

Q: Can you talk about privacy issues?

Mr. Leach: This is a question we asked ourselves when we began working with smartphones. We spent a significant amount of time thinking about how data is transferred. For example, our Bluetooth protocol is proprietary to Dexcom, and we spent time with security consultants ensuring that this is safe. After all, there are a number of different ways people can try to hack your system. We are confident that our system is very secure. In the iOS system, the information is sandboxed and information is not transferred between apps unless we’re using something like HealthKit where it is controlled. The reasons we’re doing Android G5 second is that we’re still working on mitigating these issues with Android. After all, this is a different system. We believe we can fulfill all the requirements, but this is why Android is slightly behind.

Q: What is your confidence of using Dexcom CGM for treatment decisions?

Dr. Adolfsson: We have already started with G4. We use the value together with trends. We do not do it if there is a large difference between the last calibration, or if you don’t have the trend values. But we are using the CGM for treatment decisions.

Q: In your experience, what additional values do you see from low glucose suspend in pump treatment when used with CGM?

Dr. Adolfsson: If the sensor is correct, it’s the perfect system. Previously, we have always longed for a system with a brake instead. The sensor previously worked much better in a normal range. You need to have quite a good sensor to make this work. I really think this is something for the future. We want a brake as well as speeding up.

Q: Can you talk about the timeline for eliminating fingersticks in the US?

Mr. Leach: We are working on it. However, regulatory timelines in the US are hard to gauge.

Q: Do you have plans for a dose advisor?

Mr. Leach: Yes, we are working on real-time therapy support like an insulin dosing calculator – there are lots of things we can do to optimize insulin therapy with CGM, both retrospective and real-time. We hope to add that to the app, so it’s a component of what users already have.

Q: How will the portfolio evolve over time for different patient segments? What future tradeoffs will you make?

Mr. Leach: We expect to have a portfolio of multiple products for different groups. The best example is the type 2 product we’re focused on with Google. That’s a different product. We may need to make tradeoffs on cost and performance to make the right product for the right patients. I see our portfolio becoming larger with different products

Q: Will Dexcom reduce the three-hour delayed post of CGM data to HealthKit? If it cannot be real-time, could it get to an hour or 20 minutes?

Mr. Leach: As background, Dexcom data downloaded to HealthKit currently has a three-hour delay. We established that as a safe limit when we were working with the FDA so that the data could not be used for real-time decision-making. In the future, that could be changed. That was something we mutually agreed to. It’s going to depend on how people get used to real-time data. In the US, real time data is Class III, which is given a strict review. We’ll see what happens over time. We might be able to reduce the time period. I’d love to be able to have real-time data going into HealthKit, but we’ll have to see.

Dr. Ramiro Antuna: In Spain, we have highly motivated patients using CGM, since they pay out-of-pocket. We are having a hard time with patients downloading the system regularly. What is the percentage at your clinic? In my experience, less than 20% are downloading regularly. How do you empower patients to keep downloading?

Dr. Adolfsson: I always download when they come to the office. I never have written logs. I sit in front of the computer with patients, analyzing together and giving advice on what to look for. “These are the pages that are the most interesting for you to look back at home.” Try to motivate them, try to find the positive things about using the data back home. Comparing it to having a knee surgery, the physiotherapist comes to the bed, and tells you to do 15 squats. You do the 15, and it hurts. Then she tells you to do it every morning, lunch, and dinner. When she comes asking, you say, “Yes, I’ve done it,” when you really haven’t. But then she says, “Doing this will prevent you from having a thrombosis, make you go home earlier, etc.” – she’s pointing out the positive things, which makes it much more interesting. Don’t mention A1c; talk about other things like not needing to go into the office, having visits less frequently, doing visits by Face Time or phone. Of course, we also need to make the technology easier to use.

Dr. Ramiro Antuna: What percent of your patients input carb intake and insulin dosing daily into the CGM system?

Dr. Adolfsson: It’s rare.

Corporate Symposium: One Year with Flash Glucose Monitoring – Perspectives From Different Stakeholders in Diabetes Care. What’s Next? (Sponsored by Abbott)

Clinical Experience with FreeStyle Libre

Katarina Eeg-Olofsson, MD (University of Gothenburg, Sweden)

Dr. Katarina Eeg-Olofsson shared new data from a 91-patient observational study of its factory calibrated FreeStyle Libre system. The trial sought to investigate the real-world benefits of Libre in type 1 patients at a high risk for developing complications (baseline A1c = 10.1%). The data was strong for a diabetes device – especially in a tough and very real-world group – with 3-9 month follow-ups from baseline demonstrating a mean A1c improvement of 1.4%. Hypoglycemia was not reported. Dr. Eeg-Olofsson did note that 1% of patients had serious skin reactions forcing them to discontinue use of the sensor, while ~5-7% continued with extra precaution and care. [The numbers are presumably similar to those wearing other adhesive-using devices.] Ultimately, she noted that further investigations into the human factors (e.g., patient satisfaction, skin reactions) are critical and ongoing. Of course, the studies we REALLY want to see are the ongoing reimbursement trials – REPLACE and IMPACT – which have completion dates in December and September 2015, respectively.

The Impact of AGP and FreeStyle Libre on the Patient-Clinician Dialogue in T1 Diabetes

Stephen Dixon (Type 1 patient, UK) and Pratik Choudhary, MD (King’s College Hospital, London, UK)

A conversation between Dr. Pratik Choudhary and Mr. Stephen Dixon (an on-air reporter in Britain and type 1 patient) shared valuable insight into how FreeStyle Libre is being used in the real world. Mr. Dixon spoke in glowing terms about his year on FreeStyle Libre, describing the experience as a “game-changer” for his diabetes. Indeed, the convenience of Libre was a recurring theme throughout the interview with Mr. Dixon, who highlighted the speed (vs. BGM) and discretion/lack of alarms (vs. CGM) as significant advantages. Mr. Dixon called his decision to choose Libre over classical CGM as a no-brainer, emphasizing the oft-overlooked psychosocial benefits of the technology – e.g., not being “tethered” to a receiver, being able to leave the receiver behind and not lose data (assuming it is swiped within eight hours). On accuracy too, Mr. Dixon provided a stirring endorsement of the technology, noting that he has not done a confirmatory fingerstick (as is indicated in certain situations) in ~12 months: “People say you must check Libre values against SMBG, but real life is real life.” Indeed, the remarks echo commentary on the excellent hypoglycemic accuracy we heard at ATTD 2015 and ultimately speak to what continues to be tremendous real-world enthusiasm for Libre.

• Below, we bring you some of our favorite quotes from Mr. Dixon during the session:
  
  •  “I swipe 15 times per day and get 20 times more information than I would with 15 fingersticks. It’s hugely impressive. The amazing thing is that I can take over my own management much more than before. Normally, you go to clinic once a year to get told how to improve your life. Now, you can do that yourself on a daily basis.”
  • “The alarms on CGM are awful. I haven’t met anybody yet on Libre that wishes for alarms. They always seem to be overly sensitive. Not having an alarm is a benefit.”
  • “Having glucose information with Libre has been a game-changer. I’ve always been very careful about my diabetes management. But with Libre, my attitude has changed. I almost feel like I’ve got a different condition.”
  • “Libre can empower those that do not even want to be empowered.”
  • “There is a huge difference on Libre. The key is not where I am, but where I have been and where I am going. I used to have my hands tied behind my back with SMBG. The fact that I’ve got all this information at my fingertips in a few seconds is incredible.”

The Impact of AGP and FreeStyle Libre on the Patient-Clinician Dialogue in T2 Diabetes

Detlef Behring (Type 2 patient, Germany) and Oliver Schubert, MD (Diabetes Care Center Buxtehude, Germany)

“I was asked earlier, ‘Who should use FreeStyle Libre?’ That’s the wrong question. The real question is who should not use it,” said Dr. Oliver Schubert. It was a compelling introduction to yet another enthusiastic interview with a FreeStyle Libre user – Mr. Detlef Behring – who presented Libre and the accompanying Ambulatory Glucose Profile software as valuable tools for patient education and pattern recognition. [We continue to be fans of AGP’s simple output and pattern identification, and as we understand it, other manufacturers are in line to integrate it too. ] Mr. Behring spoke at length about the positive impact Libre has had on his type 2 diabetes, though he admitted to initial reservations about using the device (e.g., too complex, confusing interpretation). He has been surprised by the technology’s ease-of-use and its accessible data has further motivated him to more frequently check his blood glucose. As he concluded, “I learned from Libre that it’s not my doctors’ job to work on my glucose levels. It’s my job.” Indeed!

Corporate Symposium: How Much Can Technology Support Personalized Diabetes Management? (Sponsored by Roche)

First Results of the Accu-Chek Insight EU Study

Julia Mader, MD (Medical University of Graz, Austria)

Dr. Julia Mader presented results of the Accu-Chek Insight EU study, which found that users were mostly satisfied with the pump though some device malfunctions occurred. In this study, people with type 1 diabetes (n=91) on MDI or CSII were switched to the AccuCheck Inishgt insulin pump (which is a pump with an integrated glucose meter and bolus advice) after one or two training sessions. The results found that over six months, there was no significant change in body weight or insulin dose. Participants were able to maintain glycemic control with the system: at six months, the CSII-experienced group saw an A1c reduction of ~0.1% (baseline A1c of ~7.8%) and the MDI group saw an A1c reduction of ~0.5% (baseline A1c of ~7.9%). The study’s most frequent pump malfunctions were electronic errors while few mechanical/rewind errors were recorded. Survey results regarding hypoglycemia fear and well-being appeared to remain relatively stable throughout the study. Notably, the user acceptance analysis showed that participants liked the system’s ease of use, small size, and screen information provided on the pump and handheld; on the other hand, users least liked the speed of the handheld, the large size of the carrying cases provided, and the small size of the cartridge.

• We also learned that Dr. Kerstin Rebrin has been appointed Roche’s Head of Diabetes Management Solutions, a strong indication of the company’s commitment to CGM and a sign that no one should discount Roche on the CGM front. Dr. Rebrin has an impressive resume in diabetes technology, coming over from BD where she ran the CGM program prior to its discontinuation last year as well as early work at Abbott and in academia, where she was very highly respected. We view the signing as a major win for Roche and look forward to seeing how her expertise can translate to R&D progress. Indeed, given the increasingly competitive CGM landscape, we are curious to see how the company can differentiate its product from the market’s more established players – her job won’t be easy! As a reminder, Roche disclosed at its 2Q15 Diagnostic Division Analyst Event that it plans to bring its novel CGM to the market in the “next 18 months” (as of this past July). We were also impressed to learn today from the Roche session that there won’t be any problems with Roche’s CGM and interferents like Tylenol – so excellent they figured out how to address this.

Questions and Answers

Q: Have you been using this for patients in clinic? What is their response?

A: Some patients wanted to keep the insulin pump. There appears to be fewer errors than before but this is also probably because the patients are trained.

Comment: We’ve been using it and people like the pump and cartridge. The feedback is similar. The communication between the handset and pump needs some work. But it definitely offers a lot to our patients.

Corporate Symposium: Optimizing Insulin Pump Therapy: Infusion Set Failures and Silent Occlusions (Sponsored by BD)

Summary

Aaron Kowalski, PhD (JDRF, New York, NY), Bruce Buckingham, MD (Stanford University, Palo Alto, CA), Larry Hirsch, MD (BD Diabetes Care, Franklin Lakes, NJ), Thomas Danne, MD (Kinderkrankenhaus, Hannover, Germany), Lutz Heinemann, PhD (Science & Co., Düsseldorf, Germany), Hans DeVries, MD, PhD (Academic Medical Center, Amsterdam, The Netherlands)

BD’s first corporate symposium dedicated to the FlowSmart infusion set gathered an impressive lineup of speakers to discuss the “Achilles Heel” of insulin pumps and the company’s new set. There were no new major updates on FlowSmart’s commercialization, which is still slated for “2016” in the US, EU, and Canada. Interestingly, exclusive commercial partner Medtronic was not mentioned at all during the 2.5-hour session; this felt odd, since the set will be co-branded BD/Medtronic and sold exclusively by Medtronic. The session provided a valuable overview of infusion sets and the associated subcutaneous biology, and Drs. Bruce Buckingham, Lutz Heinemann, Thomas Danne, Hans De Vries, and Aaron Kowalski expressed a mix of outrage and enthusiasm – outrage at the underwhelming body of research on infusion sets, and enthusiasm for what BD’s new set could offer.

• Drs. Buckingham, Danne, and Heinemann converged on similar points in their clinical experience and the overviews of the infusion set literature: (i) reliable sets matter tremendously from a patient perspective (for pump satisfaction, for insulin absorption, for DKA, for the artificial pancreas); (ii) patients experience many problems with sets (pain, lipohypertrophy, kinking, scarring, unexplained hyperglycemia); (iii) infusion set wear seems to be highly individualized, with a surprising number of patients able to tolerate seven-day wear without much of a problem (Dr. Buckingham said~20-30%); (iv) sensors are better tolerated than sets, suggesting it is insulin – and not the subcutaneous tissue – that is causing a biological response; and (v) there are a tremendous number of factors that affect absorption/action of subcutaneous insulin (23 were listed on Dr. Heinemann’s slide).

New Insulin Infusion Set Technology: BD FlowSmart

Larry Hirsch, MD (VP Global Medical Affairs, BD Diabetes Care, Franklin Lakes, NJ)

Dr. Larry Hirsch’s review of FlowSmart summarized previous presentations (ATTD, Keystone), but did offer a new perspective on the advantages of the dual-port catheter: with insulin flowing out of two places, two distinct depots of insulin form (via imaging studies), potentially offering absorption advantages (better PK/PD must be confirmed in studies). Going forward, a big question is not whether the FlowSmart set reduces “flow interruptions” (that much seems clear from the data), but to what extent the design offers true clinical advantages – better insulin PK/PD, more time-in-range, fewer hospitalizations from DKA, etc. Those are tall orders for sure, and many of the product’s form factor improvements are still meaningful from a patient perspective (smallest gauge insertion needle on the market, multi-position connector, sliding needle shield cover, etc.). The set is still slated for a launch in “2016” in the US, EU, and Canada. FlowSmart will be available through exclusive commercial partner Medtronic for Paradigm and Luer Lock reservoirs (the slide only showed Medtronic, Roche, and Animas pumps, though we assume Tandem pumps will also be compatible).

• Dr. Hirsch reviewed FlowSmart data first shown at Keystone 2015 and presented in poster form at ADA. The expanded study compared BD’s new infusion set to Medtronic’s Quick-set in 60 healthy participants (ADA 2015 Poster: 1071-P) – the previous pilot study shown at ATTD was only in 25 participants. As a reminder, the study had each participant wear two of each set; diluent was used and pressure was tracked for basal and bolus infusion. Consistent with results from the pilot study, the BD set significantly reduced the amount of time with flow interruptions (p=0.002) and reduced the risk of pressure events by ~75%. There were no observed statistical differences in set site leakage upon removal compared to the Quick-set (1 vs. 0 events, respectively).
• A single slide succinctly summarized FlowSmart’s key product features. We got an up-close look at BD’s headquarters earlier this year.

FlowSmart Product Features

Compatible with Paradigm and Luer Lock connections

Compatible with Quick-Serter insertion device

Proprietary side-ported catheter

30G inserter needle and 28G catheter

10mm hub width and flexible base

8 different points of attachment of tubing to infusion hub

Auto-deployed needle shield

Unit package environmentally friendly

New Research: What the Future Holds

Aaron Kowalski, PhD (Chief Mission Officer/VP of Research, JDRF, New York, NY)

Dr. Kowalski provided an overview of JDRF”s near-term, mid-term, and long-term research priorities. Most notable was his summary of artificial pancreas efforts, which has now moved to the commercialization stage. His slide listed nine organizations developing systems: Medtronic; Animas; Bigfoot Biomedical; Type Zero; Boston University; Inreda; Tandem; Insulet; Roche. That was the order they were listed on the slide, though only Medtronic had a timeline attached to it (April 2017, consistent with the JPM timeline). See below for the most recent timelines and updates on all the organizations. Dr. Kowalski devoted a slide to the use of type 2 therapies in type 1, acknowledging that Novo Nordisk is not moving forward with Victoza; still, he is optimistic about SGLT-2s in type 1 and believes the DKA risk can be overcome. In the medium term research pipeline (“7-12 years”), Dr. Kowalski highlighted Merck/SmartCells Smart Insulin (still in phase 1, expected to wrap in December) and ViaCyte’s encapsulation device (still in phase 1/2, expected to wrap in 2017). Similar to his talk at ADA, Dr. Kowalski summarized his “Diabetes Scorecard (Diabetes Care 2015) to judge the value of future therapies and technologies. He commended BD for the new FlowSmart set, which does bring meaningful value in his view.

• “AP systems Are Coming...” – Dr. Kowalski listed nine organizations on the slide in the following order. We found the order highly instructive, and wonder if it was intentional.
  
  • Medtronic: hybrid closed-loop (meal-time bolusing): April 2017 (Editor’s Note: It was encouraging to see Dr. Kowalski include the “April 2017” timeline, which we first heard at JPM 2015. Though Medtronic historically misses its timeline, the 670G is already in a pivotal study slated to wrap up in May 2016)
  • Animas, Hypoglycemia-Hyperglycemia Minimizing System (Editor’s Note: J&J/Animas has never given a timeline on its AP, but said in 2Q15 that it is working on a next-gen CGM-integrated pump. Bigfoot plans to be in a pivotal trial in 2016)
  • Bigfoot Biomedical: hybrid closed-loop (Editor’s Note: Per the June Dexcom agreement, Bigfoot still plans to be in a pivotal study in late 2016.)
  • Type Zero: hybrid closed-loop (Editor’s Note: Type Zero hasn’t given a launch timing, but does have major studies planned for this year and 2016.)
  • Boston University: Dual-hormone with glucagon (Editor’s Note: The Bionic Pancreas team hopes to be in a pivotal study in late 2016 through early 2017.)
  • Inreda: Dual-hormone with glucagon (Editor’s Note: This is a lesser known European group working with Dr. Hans DeVries. We don’t know any study details or timing.)
  • Tandem (Editor’s Note: Per the 2Q15 call, plans to file an IDE by the end of 2015 for its first clinical study.)
  • Insulet (Editor’s Note: No specific details, but definitely committed to a product given remarks in recent quarterly calls.)
  • Roche (Editor’s Note: No artificial pancreas timing. CGM to be commercialized in next 18 months, per July Analyst Event)
• Dr. Kowalski devoted a slide to the use of type 2 therapies in type 1, acknowledging that Novo Nordisk is not moving forward with Victoza. He highlighted potential type 1 label extensions for SGLT-2s dapagliflozin (AZ) and canagliflozin (J&J) – on a positive note, he believe the concerns over euglycemic DKA can be overcome.
• In the medium term pipeline (“7-12 years”), Dr. Kowalski highlighted Merck/SmartCells Smart Insulin and ViaCyte’s encapsulation device. Merck is still in a 74-patient phase 1 PK/PD trial expected to wrap up in December (the page was updated last month). ViaCyte is still in a 40-patient phase 1/2 feasibility trial that recently expanded into Canada and will wrap up in August 2017.
• Longer-term, JDRF is focused on restoration and prevention.
  
  • Restoration: Many people with type 1 diabetes retain residual C-peptide production, even with a long disease duration. Dr. Kowalski hopes that with a very specific immunotherapy and the right stimulation, insulin production could be restored in some people.
  • Prevention: Dr. Kowalski called prevention “a high priority area,” and noted the now-published joint statement with ADA on defining the early stages of type 1 diabetes. Now that type 1 diabetes has been staged, Dr. Kowalski believes there is a framework to think about prevention and proper risk/benefit.
• Similar to his talk at ADA, Dr. Kowalski summarized his “Diabetes Scorecard (Diabetes Care 2015) to judge the value of future therapies and technologies. Scorekeepers are people with diabetes (and loved ones), clinicians, and payers, and the categories are glycemic control, “burden”, and value. Future advances, said Dr. Kowalski, will only be successful if they add value across all three stakeholders. He commended BD in addressing some of these issues with the new infusion set.
• Dr. Kowalski highlighted a new JDRF call for proposals to improve infusion set duration of wear, with ultimate goal to match CGM wear. We first heard of this in August. Expressions of interest were due by September 22, and JDRF will get back to applicants by October 21. More information is here.

 

Novel Therapies

Oral Presentations: A Glimpse at Future Diabetes Therapy

Glucagon Nasal Powder: An Effective Alternative to Intramuscular Glucagon in Youth with Type 1 Diabetes

Jennifer Sherr, MD (Yale University, New Haven, CT)

Dr. Jennifer Sherr presented phase 3 results in 48 pediatric patients (4-17 years old) for Locemia’s intranasal glucagon, showing comparable glucose-raising ability vs. injected glucagon. The results mirrored those shown at ATTD 2015 in 75 adults. The primary endpoint – an increase in glucose >25 mg/dl within 20 minutes – was observed with intranasal glucagon in 47/48 treatments vs. 24/24 treatments with intranasal glucagon. The one exception was a patient who blew his nose immediately after receiving the intranasal dose. Dr. Sherr rightly noted that this scenario would be unlikely during a severe hypoglycemia episode. The study also tested two doses of the intranasal glucagon, revealing that the same 3 mg adult dose can be used across the pediatric population. That’s a manufacturing win for Locemia. The intranasal glucagon had a slightly higher rate of head/facial discomfort (17-24% vs. 13%), though a much lower rate of nausea (39-43% vs. 67%). Given the rescue indication, we don’t see those events as truly impactful on the drug’s chances.

Questions and Answers

Q: You have an attractive device. My issue here is you have administered in conscious patients that are able to inhale powder. How about unconscious patients?

A: In actuality, the glucagon powder is passively absorbed through the nasal mucosa. Patients do not inhale; that does not help in terms of the absorption of medication.

Q: It’s so rare that we have a new innovations in this area. This may really be important. Could it be a useful tool in emergency cars? When will it be on the market?

A: I can’t speak to when it will be on the market. The company has been having discussions with the regulatory bodies. I suggest inquiring with them.

It will absolutely be useful for emergency settings.

Q: What is the stability? Can you store it at room temperature?

A: It is stored at room temperature. I believe it has a two-year shelf life.

Q: From an adult clinician view, this is great. So often glucagon is not given. What do you think is driving the differences in nausea?

A: I cannot say I know. The glucagon concentrations with injected seem to get a little bit higher than intranasal in some cohorts. I don’t know the mechanism behind it.

Q: Have you studied variability of absorption? What about stuffy noise due to a common cold?

A: Actually, the company did conduct a study doing that. They brought in patients with colds and tested it with and without nasal decongestant. In both situations, the powder was well-absorbed.

Q: The insulin infusion was stopped when you reached lower glucose concentrations. How would this affect the response to glucagon, because in a clinical situation, insulin will remain on board?

A: We resumed normal basal delivery. We stopped the higher rates to induce hypoglycemia. If someone was on injections, they had their previous basal injection from the prior day.

ISIS PTP-1BRx, a Novel PTP-1B Antisense Inhibitor, Improves HbA1c and Body Weight in Patients with Type 2 Diabetes on Metformin ± Sulphonylurea

Erin Morgan (Isis Pharmaceuticals, Carlsbad, CA)

Filling in for Dr. Andres Digenio, Ms. Erin Morgan presented full phase 2 results for Isis’ novel insulin sensitizer ISIS-PTP1BRx. As reported in the topline results announcement in February, ISIS-PTP1BRx produced significantly greater mean A1c reductions (-0.7% from a baseline of 8.8%) vs. placebo (-0.2% from a baseline of 8.4%) at 36 weeks (p=0.03). These results attracted some controversy at the time of the announcement because of the discrepancy in timing between the original primary efficacy endpoint (A1c reduction at 27 weeks) and the reported data (A1c reduction at 36 weeks). However, full results showed a separation between the groups beginning at week 13 that was sustained throughout the trial, even after the cessation of dosing at 26 weeks. Ms. Morgan suggested that the product’s unique mechanism (it targets PTP-1B at the mRNA level rather than the protein level) could explain the relatively slow ramp-up in efficacy. More positively, she noted that the sustained efficacy after the end of the treatment period reflects a long half-life and suggests potential for longer-term dosing. ISIS-PTP1BRx also produced significant improvements in short-term glycemic parameters (fructosamine and glycated albumin). We also sa the magnitude of the improvement for the first time in this presentation: a 2.7 kg reduction vs. 1.4 kg with placebo (baseline weight not given; baseline BMI = 34 kg/m²). The drug also led to improvements in leptin and adiponectin levels; Dr. Morgan noted that adiponectin levels rose before weight loss began, suggesting it was a direct result of reduced PTP1B activity in adipocytes. ISIS-PTP1BRx was safe and well tolerated with no serious adverse events or abnormalities in laboratory parameters.

• We suspect that ISIS-PTP1BRx could produce even more impressive effects in longer-term trials. Both the A1c and weight benefits seemed to increase over the course of this study, suggesting that the longer-term effects could be even greater. Even efficacy of this magnitude could become more clinically meaningful if it proves more durable than that of existing drug classes. This would be consistent with the product’s insulin-sensitizing mechanism: for example, head-to-head studies have shown that TZDs initially appear less efficacious than sulfonylureas but ultimately produce much more durable A1c reductions.
• The next step for ISIS-PTP1BRx will be a study in combination with insulin in obese, highly insulin resistant patients. It will involve a higher dose and have a longer duration than this trial, though Dr. Morgan did not disclose any additional details. Isis has stated in the past that it plans to seek a partner before initiating phase 3 trials for this candidate, and this upcoming trial could be an attempt to increase interest from industry by better defining an initial target population and demonstrating durable efficacy.
• Isis has expressed hope that ISIS-PTP1BRx could help “refresh” the insulin sensitizer class after the baggage associated with the TZDs. A successful insulin sensitizer would be a significant advancement in the type 2 diabetes drug arena, as it would address the underlying pathophysiology of the disease to a greater extent than existing drug classes. Other companies developing PTP1B inhibitors include TransTech Pharma (TTP814; phase 2) and OHR Pharmaceutical (trodusquemine; phase 1). Other companies developing novel insulin sensitizers include J&J (JNJ-41443532; phase 2), Metabolic Solutions (MSDC-0160 and MSD-0602; phase 2), Shionogi (S-707106; phase 2), and XOMA (XMetS; preclinical).

Questions and Answers

Q: What you have is a situation where you induce constitutive activation of the insulin receptor. In the end, won’t that lead to a risk of tachyphylaxis? Won’t cells want to downregulate the amount of insulin receptors or their activity?

A: We’re inhibiting the receptor in the liver. We haven’t seen tachyphylaxis with this drug or other compounds.

Q: What is the relative concentration of the antisense inhibitors in fat vs. other organs?

A: They don’t cross the blood-brain barrier. The concentration for most drugs is higher in the liver and kidney. They don’t distribute well to other tissues. I’d say it’s 70-80% in the liver and kidney.

Q: Did you measure liver fat? Was there an improvement in hepatic insulin sensitivity?

A: We measured it preclinically and saw reductions. We didn’t measure it in this study.

Q: You have increased the insulin receptor, so how do you account for body weight loss? Wouldn’t you expect increased glucose uptake in adipose tissue?

A: Preclinically we saw a reduction in lipogenic genes and increased energy expenditure. We plan to measure that in a long-term mechanistic study.

Q: Do you expect that it’s a central effect?

A: No, it’s a peripheral effect.

Pharmacokinetics, Pharmacodynamics and Tolerability of a Novel Glucokinase Activator TMG-123 After Single Oral Ascending Doses in Japanese Healthy Subjects

Tsuyoshi Kimura, PhD (Teijin Pharma Limited, Tokyo, Japan)

Dr. Tsuyoshi Kimura presented results from two phase 1 studies of Teijin Pharma’s glucokinase activator TMG-123. The candidate preferentially targets the liver, and the hope is that it will carry a lower risk of hypoglycemia than other glucokinase activators with more action at the beta cell. The first study (n=64 healthy volunteers) was a single ascending dose study to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of eight doses of TMG-123 (1-160 mg, delivered via 1 mg, 10 mg, and 50 mg capsules) in a fasting state. After unexpected PK observations were seen with the 50 mg capsules, a second phase 1 study (n=32 healthy volunteers) was conducted using only higher doses (80-160 mg) delivered via 10 mg capsules. The second study also evaluated a 40 mg dose in the postprandial setting. Results showed that TMG-123 was well tolerated up to 160 mg, with no adverse events or hypoglycemia. The drug was rapidly absorbed in fasting conditions, and food ingestion had no significant effect on PK parameters. The PK/PD results also confirmed the expected liver-dominant glucokinase activation. Since these studies were completed, Teijin has developed a 40 mg tablet and confirmed that it has a similar PK profile to the 10 mg capsule formulation. The company is now planning a phase 2 study to assess the efficacy, safety, and potential risk of tachyphylaxis with TMG-123 for up to 24 weeks in patients with type 2 diabetes.

Questions and Answers

Q: Can you tell us something about the metabolism or elimination of the agent, because it’s not just stimulation of glucokinase activation that we’re interested in but how quickly it can be stopped when glucose goes down.

A: In the case of TMG-123, glucose uptake in the liver dominates. Maybe glucokinase raises C-peptide too.

Q: What is it that makes it so liver-specific?

A: The compound is not liver-specific, it’s liver-dominant. One reason is the distribution of the compound.

Q: Have you thought about trying this in MODY?

A: No.

Oral Presentations: Incretin-Based Therapy – Novel Agents, New Indications

Efficacy and Safety of Gemigliptin/Metformin Initial Combination Therapy Versus Either as Monotherapy in Drug-naïve Patients with Type 2 Diabetes

Soo Lim, MD, PhD (Seoul National University, Seongnam, South Korea)

Dr. Soo Lim presented results from a phase 3 study of LG Life Sciences’ gemigliptin/metformin combination showing significantly greater efficacy with the combination vs. either component alone. The trial (n=433 drug-naïve patients with type 2 diabetes) demonstrated significantly greater A1c reductions with the combination (2.1%) vs. either gemigliptin (1.2%) or metformin (1.5%) after 24 weeks (baseline = 8.7%) – the A1c reductions in all three groups were surprisingly large, though the baseline was relatively high. The separation between the groups appeared as early as six weeks and was maintained over the course of the study. The combination was superior for both patients with a baseline A1c <8.5% and >8.5%, though as expected, those with worse control at baseline experienced greater reductions. In addition, a significantly greater percentage of patients achieved A1c targets of <7% and <6.5% with the combination than with the individual components; Dr. Lim particularly highlighted the fact that over 80% of patients achieved an A1c below 7% with the combination. Gemigliptin/metformin also led to significantly greater reductions in fasting plasma glucose beginning as early as six weeks, a difference that was maintained through the end of the trial. The combination also appeared to improve beta cell function and reduce insulin resistance (measured by HOMA-B and HOMA-IR), likely driven by the metformin component. All groups experienced improvements in total and LDL cholesterol, but there was no significant difference among the three arms. The combination led to weight loss comparable to that achieved with metformin alone but led to greater improvements in waist circumference. Adverse event rates were similar across the groups and there were no severe hypoglycemic events. LG Life Sciences markets gemigliptin and gemigliptin/metformin in South Korea and other emerging markets in Asia.

Questions and Answers

Q: Is this double-blind? How did you change the dose of metformin? Were there any criteria?

A: The metformin dose was up-titrated based on the fasting plasma glucose level. We used a threshold of 110 mg/dl for up-titration.

Q: In this case did you know which patients were in which group?

A: Yes.

Q: Have you demonstrated that this DPP-4 inhibitor is more potent than sitagliptin?

A: It has a faster on rate and slower off rate compared to sitagliptin. It has a slightly higher association constant and a much lower dissociation constant vs. sitagliptin. This may contribute to more potency; I’m not sure. I speculate that gemigliptin is more potent than other DPP-4 inhibitors.

Q: Do you plan to do head-to-head studies?

A: We do have a head-to-head study with sitagliptin. We found that the A1c reduction was not different between groups but the increased amount of GLP-1 levels and the DPP-4 inhibition rate was greater with gemigliptin. We also found that glycemic variability was significantly reduced with gemigliptin, greater than with sitagliptin.

Q: Did you measure plasma GLP-1 or GIP or insulin secretion?

A: Yes, we measured active GLP-1 and the DPP-4 inhibition rate.

Q: Do you have any comparison between gemigliptin and other DPP-4 inhibitors?

A: Yes, we have been doing many clinical studies with other DPP-4 inhibitors such as linagliptin. Both linagliptin and gemigliptin may have more favorable effects in renal impairment, so we’re doing a direct head-to-head on the renal effect.

Oral Presentations: Biomarkers of Atherosclerosis

RVX-208 Acts Via An Epigenetic Mechanism to Lower Major Adverse Cardiovascular Events (MACE) in Patients with Atherosclerosis and Especially in Those with Diabetes Mellitus

Norman Wong, MD (Chief Scientific Officer, Calgary, Canada)

Dr. Norman Wong provided an overview of Canadian biotech Resverlogix’s BET bromodomain inhibitor RVX-208. The company arrived on our radar at JPM 2015, after it presented early evidence of a marked reduction of cardiovascular disease in a post-hoc analysis of patients with and without diabetes. Dr. Wong presentation shared this data again – a 64% reduction in the incidence of MACE in all patients (n=499) and an even greater 77% reduction in patients with diabetes (n=192). As we have noted before, the implications are intriguing though tough to wrap our head around as the mechanism of the risk reduction remains a question mark. Dr. Wong did note that RVX-208 therapy has been shown to lower glucose, though neither this nor the lipid effects can explain the full MACE benefit. He suggested that an inflammation-mediated effect is plausible, though the jury is still out given that RVX-208 is known to target multiple pathways with known roles in cardiovascular disease (e.g., coagulation). Ultimately, we will look forward to additional clinical data to shed further light on this field. As we learned at JPM 2015, RVX-208 is moving into a large phase 3 trial called BETonMACE that will enroll a pool of type 2 diabetes patients and with a primary endpoint of a 30% reduction in MACE. Showing cardioprotection in phase 2 is one thing; replicating those results in humans on the big stage (phase 3) is an entirely separate challenge. Considering the dire need for any means of cardiovascular risk reduction in diabetes, we have our fingers crossed.

Questions and Answers

Q: Did you perform in vitro studies?

A: We have done ex-vivo studies, but not in vivo studies.

Q: Which pathways are responsible for diabetes effect?

A: I don’t have a lot of data to back up what I’m saying, though research has shown that inhibitors can play a very important role in inflammation mediation. The cascading effect means that a lot of genes affect cardiovascular disease. In our own animal model, using a beta inhibitor decreases atherosclerosis hugely. We think inflammation is one big pathway. And coagulation and complement are others pathways that plays into this.

Debate: Do We Need Triple and Quadruple Therapies?

Yes

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

Dr. Ralph DeFronzo made the case for treating the pathophysiological basis of diabetes through the use of a combination of diabetes drugs that together target the “ominous octet.” After making his case that the current treatment paradigm is a “treat to fail” approach, Dr. DeFronzo presented interim three-year results from a trial evaluating his signature triple therapy (metformin+pioglitazone+exenatide) vs. conventional therapy (metformin followed by sequential addition of glipizide and insulin glargine) in patients with newly diagnosed type 2 diabetes. Participants evaluated thus far (n=155) were diagnosed with type 2 diabetes within the last two years, drug naïve, and had a baseline A1c of 8.6%. The average A1c at 36 months was 6.7% in the conventional group and a striking 5.8% in the triple therapy group (p<0.0001); seven-point BGM data also showed significantly lower and flatter glucose profiles with triple therapy (p<0.0001). In addition, triple therapy led to a 3.1 kg (6.8 lbs) weight loss vs. a 3.7 kg (8.2 lbs) weight gain with the conventional approach (a significant 6.8 kg (15 lbs) difference [p<0.0001]), and it produced significantly greater improvements in glucose and C-peptide responses to an oral glucose tolerance test (OGTT). Notably, the triple therapy group showed a significant improvement in insulin sensitivity (p<0.001) and a 45% improvement in beta cell function (change in C-peptide/change in glucose concentration/insulin sensitivity [p<0.0001]) vs. no change in the conventional group. The most striking data to us were the Kaplan-Meier plots showing the percentage of patients who achieved an A1c <6.5%: the conventional group showed the typical progressive decline, while the triple therapy group remained essentially flat after an initial 10%-12% failure rate (p<0.0001). In terms of adverse events, rates of edema and GI side effects were higher with triple therapy, but hypoglycemia was significantly lower. We hope these striking results will spark a broader conversation about the current approach to type 2 diabetes treatment, though a number of caveats remain. Any paradigm shift toward early, aggressive combination therapy would require buy-in from payers, as current coverage policies heavily favor a “treat to failure” approach (a state of affairs that Dr. DeFronzo frequently referenced throughout his talk). The baggage surrounding TZDs would also certainly pose an obstacle to widespread use of this particular combination – indeed during Q&A, Dr. DeFronzo was put on the defensive regarding his choice to include a TZD in his combination.

• We saw positive two-year results from this trial (ClinicalTrials.gov Identifier: NCT01107717) at ADA 2013; the study is still recruiting participants and expects to report full results (n=600) in December 2017.
• The open-label trial randomized drug-naïve patients to receive either triple combination therapy (metformin+pioglitazone+exenatide) or conventional sequential therapy (metformin, glipizide, and insulin glargine). Patients were evaluated monthly for the first three months and drug doses were titrated to achieve an A1c <6.5%.
• At 36 months, the average A1c was significantly lower in the triple therapy arm (5.8%) than in the conventional therapy arm (6.7%). A graph of A1c results over time showed that the groups began to diverge at three months and continued to separate slightly toward the end of the three-year period. Dr. DeFronzo emphasized that a 0.9% difference in A1c at such a low range is enormous.
• Seven-point BGM data showed significantly lower and flatter glucose profiles with triple therapy. As Dr. DeFronzo noted, triple therapy almost completely eliminated the postprandial excursions seen with conventional therapy. We would have loved to seen CGM or Abbott Libre data to gain an even more complete picture of the changes in glycemic variability.
• Triple therapy led to a 3.1 kg weight loss vs. a 3.7 kg weight gain with conventional therapy. While it is reassuring to see weight loss in a trial with a TZD, we imagine that at least these results could have been even stronger with an SGLT-2 inhibitor used in place of pioglitazone – many patients will prefer agents that don’t cause weight gain, edema, or have associations with congestive heart failure.
• Patients on triple therapy showed a 45% improvement in beta cell function vs. no change in the conventional group. Beta cell function was measured by change in C-peptide/change in glucose concentration/insulin sensitivity. Dr. DeFronzo made the strong assertion that “with triple therapy, you have a normal beta cell three years later” and challenged the audience to show him another regimen that provides these results. He suggested that these results were not surprising, as GLP-1 agonists have demonstrated beneficial effects on beta cell function in other studies. Again, we wonder what the results would have been with an SGLT-2 inhibitor instead of a TZD – Dr. DeFronzo himself is currently conducting a trial to investigate the use of SGLT-2 inhibitors to correct glucotoxicity in prediabetes, with a similar rationale of relieving beta cell stress.
  
  • Dr. DeFronzo stated that, if he were to restart the triple therapy study, he would include SGLT-2 inhibitors as one of the components. His ideal triple therapy combination would include (i) an SGLT-2 inhibitor, (ii) metformin or pioglitazone, and (iii) a DPP-4 inhibitor or a GLP-1 agonist. He also raised the possibility of including an SGLT-2 inhibitor as a fourth drug in combination with his standard triple therapy combination for a quadruple therapy (think of the copays and dosing burdens though!) Dr. DeFronzo acknowledged that he wasn’t sure what the best combination of drugs is and called for future studies to provide more insight.
• In terms of adverse events, rates of edema and GI side effects were higher in the triple therapy group, though hypoglycemia was significantly lower. Dr. DeFronzo stressed that despite the lower average A1c, the rate of hypoglycemia was only 15% in the triple therapy group vs. 46% in the conventional therapy group (not surprising to us given the therapies used). As expected, rates of edema were higher (5.3% vs. 1.3%) in the triple therapy group due to the TZD, and rates of GI side effects were higher (33% vs. 21%) due to the GLP-1 agonist. There were no bone fractures in either group.
• We hope these striking results will spark a broader conversation about the current approach to type 2 diabetes treatment, though a number of caveats remain. As Dr. DeFronzo acknowledged, such aggressive early combination therapy does not currently make sense from an economic perspective, as payers typically encourage the sequential approach used in the conventional group. During a Lilly-sponsored dinner at Keystone 2015, Executive Medical Director for the Diabetes/Endocrine division Dr. Robert Heine suggested that studies of early combination therapy conducted with payer participation could help change this – we would love to see more movement in that direction. We also imagine that there is significant reluctance among some patients and providers to treat the disease so aggressively from the start – for example, we have heard some providers note that they do not advise beginning with three drugs at once because patients will be inclined to discontinue all three if they experience side effects. Finally, the long-term risks surrounding TZDs would certainly pose an obstacle to widespread use of this particular combination, which is why we would love to see if a similar study with an SGLT-2 inhibitor in place of a TZD could produce equally compelling results. We imagine following the EMPA REG OUTCOME study results, there will be this work that is done.

No

Thomas Pieber, MD (Medical University Graz, Austria)

Dr. Thomas Pieber faced an uphill battle as he set out to present an argument against triple and quadruple therapies – at the start of the debate, by a show of hands, only a very small handful of attendees disagreed with the need for triple and quadruple therapies. Dr. Pieber’s argument centered on the argument that (i) triple therapies are unnecessary because tight glycemic control has only a small impact on cardiovascular outcome and survival; (ii) all new anti-diabetic drugs did not improve cardiovascular outcome (with the caveat that that might change with the revelation of EMPA-REG OUTCOME results later today, which, as you know, it did); and (iii) available evidence indicates that polypharmacy in type 2 diabetes might be dangerous. He presented a wealth of data from previous studies to back up each of his central arguments and cautioned against making clinical decisions without a strong evidence base. In particular, he pointed out that drug interactions in triple therapies have not been tested and are unknown and provocatively commented that “taking the famous cocktail Dr. DeFronzo was suggesting could be harming our patients, even killing them.” Dr. Pieber concluded by advancing the need for a “POEM” (patient-oriented endpoints that matter) approach to evaluating new drugs that looks at reduction of mortality, reduction of morbidity, and improvement in quality of life. By the end of the debate, Dr. Pieber had convinced about a quarter of the audience to change their vote to his view. While we believe triple therapy has shown impressive potential, we can see the logic behind the need for caution that Dr. Pieber espouses.

• In his timely discussion of the cardiovascular outcomes trial (CVOT) results of modern diabetes drugs, Dr. Pieber emphasized that he wants new drugs to actually lower CV risk. He noted that current trials are just demonstrating that the drug is as good as existing therapy rather than superiority and asked, “Why use triple or higher therapy if I only lower A1c somewhat without other benefits?” (We’d consider the significantly lower risk of microvascular complications associated with lower A1c a major benefit, however.) Dr. Pieber did acknowledge that this view could change with the release of full EMPA-REG OUTCOME results later in the day – we imagine he is pleasantly surprised now.

Questions and Answers

Q: So Ralph, Thomas has actually questioned effectiveness of the pathophysiologic approach.

Dr. DeFronzo: First, let me make a comment, the debate was supposed to be on control of glucose and not cardiovascular disease. I gave the Claude Bernard lecture in Rome, where I clearly stated glycemic control will not have an effect on macrovascular complications. This was supposed to be a debate of microvascular complications. I’ve gone online saying cardiovascular outcomes trials will all be negative except perhaps those of SGLT-2 inhibitors and GLP-1 agonists. The reason we want to lower glucose is because we don’t want people going blind and we don’t want people going on dialysis. If you don’t control glucose, you don’t prevent the microvascular complications. If you want to treat macrovascular complications, Dr. Pieber has given a very good approach and I agree with it. I would ask that he go back and read my Claude Bernard lecture from over seven years ago.

Dr. Pieber: I refuse to separate the microvascular and the macrovascular outcomes. I want to stimulate a more critical view of the data and not just follow what the pharmaceutical companies are telling us.

Q: Dr. DeFronzo is right for recently diagnosed patients, Dr. Pieber is right for long-term diabetics. If you treat insulin resistance that begins one to two decades before the onset of diabetes, you get better events.

Dr. Pieber: We need a study that demonstrates that for people on diet and metformin in the early stages, using a triple or quadruple approach not only improves A1c but also cardiovascular outcome. That’s what I’m asking for, to base treatment on the evidence we have.

Dr. DeFronzo: Since you’ve obviously never been a nephrologist and I am and you have never been blind and I have, I want to tell you those are important outcomes. I also want to be alive and not on dialysis. We need to treat all of the things in your quartet.

Q: I’m a firm believer in triple therapy, but I’m a skeptic of the TZD use. I question the overall benefit.

Dr. DeFronzo: We didn’t go above 30 mg. At 30 mg, the data are very clear that you get most of the benefit in terms of A1c and few of the side effects. Once you get past 30 mg, there are more side effects and you have to be aware of them. Pioglitazone is the only drug I’m aware of that improves diastolic retention. The fat weight gain is a cosmetic issue. The only major thing to worry about is bone fractures and we only see them in post menopausal women. You need to pick drugs appropriately for the population you’re working in and you need to be aware of the side effects. The TZD class of drugs is only insulin sensitizer class of drugs. Metformin is not an insulin sensitizer; we couldn’t ever show that it improved insulin sensitivity in the muscle. If you don’t have a TZD, you’re leaving out that part of the story.

Q: Let’s agree that insulin is the only answer as far as diabetes control.

Dr. DeFronzo: I would 100% disagree with that. With my approach you won’t need insulin if you start early enough. If you use the correct medications, you’ll have a normal beta cell and patients won’t have to go on insulin therapy. You need to control microvascular complications and you need to control macrovascular complications. Glucose is what’s important for microvascular complications, but as I said in my Claude Bernard lecture, it has a small effect on macrovascular complications. I’m not a fan of what the FDA is making us do, the participants are too advanced in the disease. Hopefully we’ll start to design studies that are a lot more insightful in terms of what these drugs will do in terms of both microvascular and macrovascular complications.

Symposium: Immunotherapy for Type 1 Diabetes – Building on Success

Welcome and Introduction

Colin Dayan, MBBS, PhD (Cardiff University, UK)

Dr. Colin Dayan opened this session with a stark reminder of the unmet need in type 1 diabetes and a pragmatic perspective on the challenges and opportunities for novel immunotherapies. In a familiar refrain for this audience, he explained that despite increasingly sophisticated insulin regimens and technology, many patients are not achieving target. In particular, there is a subset of patients “having a really tough time with diabetes” that is responsible for most of the morbidity and mortality still associated with the disease. Dr. Dayan sees these patients – those with double-digit A1cs and poor adherence to insulin therapy – and those with low A1cs but frequent hypoglycemia, as ideal candidates for immunotherapy. He was frank about the complexity and difficulty of this area, pointing to the narrow target population (mostly new-onset patients), the lack of reliable biomarkers, the likely need for combination therapies, an unusually high bar for safety, and a poorly defined paradigm for evaluating costs vs. benefits as key challenges facing the field. As he put it, it is not currently clear what price the healthcare system is willing to pay to cure diabetes. Dr. Dayan called for greater cooperation between academia and industry to facilitate a more cost-effective path for new therapies from discovery to the market, as academia cannot afford to develop drugs and pharmaceutical companies won’t make the investment if they are not convinced of the benefit. In his view, academia can help by creating more efficient recruitment networks, discovering better biomarkers, sharing assays, and better defining the population with the highest need. For its part, industry can provide funding for later-stage trials and access to agents and engage in more sharing of samples – the benefits of greater collaboration appeared to be the theme of the day.

• Dr. Dayan suggested that sequential therapy, rather than combination therapy, may be where the field needs to go. This is in contrast to one argument we have heard more and more frequently at recent conferences that combination therapy is likely the most effective way to treat such a multifactorial disease – given there is such a heterogeneous population, of course, there’s not any one rule that applies for all patients. As an example of his proposed approach, Dr. Dayan suggested that abatacept could be useful as an initial therapy and then another treatment could be added once its efficacy wears off. This is a somewhat more conservative version of Dr. Jay Skyler’s proposed approach outlined at last year’s EASD, in which certain therapies would be administered chronically while others would be given at specific time points. It also bears some resemblance to current treatment algorithms for type 2 diabetes, which have attracted some criticism as a “treat-to-failure” approach. However, Dr. Dayan emphasized that in type 1 diabetes, every year of preserved C-peptide and insulin production is very clinically meaningful.
• Dr. Dayan highlighted the EE-ASI project that is working to develop antigen-specific immunotherapies for type 1 diabetes. The four-year project is a collaborative effort funded by the European Commission involving eight academic and industry partners from across Europe. The project is about to enter its fourth year and begin a phase 1 trial of an immunotherapy involving tolerance-enhancing elements bound to gold nanoparticles (developed by Midatech) and targeted to epidermal dendritic cells via a microneedle delivery system. We see this as an excellent example of academic-industry-government collaborations that can hopefully produce more fruitful results than any sector alone.

The Future for Anti-CD3

Bart Keymeulen, MD, PhD (University Hospital Brussels, Belgium)

Dr. Bart Keymeulen presented an update on the status of anti-CD3 therapies in type 1 diabetes and thoughts on the future of the field. For background, anti-CD3 therapies were once considered one of the more promising areas of immunotherapy research in type 1 diabetes, but unfortunately encountered a stumbling block with disappointing efficacy results from the phase 3 Protégé trial of MacroGenics and Lilly’s teplizumab in 2010 and the phase 3 DEFEND trial of Tolerx and GSK’s anti-CD3 therapy otelixizumab in 2011. Dr. Keymeulen highlighted both otelixizumab and teplizumab in his talk and discussed aspects of their efficacy, subgroups of responders, their side effects and safety, and potential future combination therapies. In terms of efficacy and differentiation between responders and non-responders, Dr. Keymeulen noted that while lymphocyte depletion was observed with anti-CD3 therapy, immunological changes do not seem to be reflective or predictive of the degree of C-peptide preservation in humans. However, earlier studies did find that higher doses of anti-CD3 therapy were needed to preserve C-peptide. That said, Dr. Keymeulen argued that C-peptide preservation is a meaningless indicator of efficacy unless there is a clear association with metabolic benefits and suggested that reduced insulin dose, A1c, and glycemic variability are more useful endpoints. Dr. Keymeulen identified several subgroups who were clear responders to anti-CD3 therapy in terms of reduced insulin dose and metabolic benefits. These included those who were young (age 6-30) and those who had high residual beta cell function, a disease duration of less than eight weeks (preferably less than four weeks), lower A1c and baseline insulin dose, or high baseline insulin autoantibody status. In terms of glycemic variability, Dr. Keymeulen noted that lack of data presents a challenge when bringing the therapy to market and negotiating with payers, but he suggested that studies of glycemic variability are now possible with CGM – this is why we are so eager to see CGM used more frequently in clinical trials. Dr. Keymeulen concluded by pointing out that, even in responders, the effects of anti-CD3 therapy do not last forever and raised the idea of combination therapy with anti-CD3 and an agent that stimulates beta cell mass.

• In terms of safety data, Dr. Keymeulen noted that all doses of anti-CD3 therapy were associated with elevated cytokine levels. While the elevation was not too high, he acknowledged that it was “annoying” in terms of pushing for reimbursement for anti-CD3 therapy. He shared that GSK has been working on finding a more acceptable dose for otelixizumab over the last year.
• Dr. Keymeulen expressed concerns about the age inclusion criteria of TrialNet’s ongoing type 1 diabetes prevention study with teplizumab. Participants in the trial must be between the ages of eight and 45, but Dr. Keymeulen noted that in the Belgian population, the development of type 1 diabetes does not occur very quickly. He therefore worries that the control group in the study will not rapidly develop clinical hyperglycemia, making it difficult to demonstrate an effect of the anti-CD3 therapy. Overcoming such challenges is one of the main goals of the recently published JDRF/ADA staging system for early type 1 diabetes, which should allow for greater use of intermediate endpoints in clinical trials instead of requiring progression to symptomatic disease.  
• Dr. Keymeulen advanced the notion of using anti-CD3 therapy in the prediabetes population, noting that people with prediabetes have a higher initial beta cell mass and are more likely to find success. This approach would require much more widespread screening for islet autoantibodies and early dysglycemia, as today most patients are not diagnosed until they develop symptomatic type 1 diabetes. While the new JDRF/ADA staging system will help facilitate a shift in focus toward the earlier stages of the disease, it may be controversial who is tested, who is characterized as high risk, etc.
• Dr. Keymeulen repeatedly noted the challenges posed by pharmaceutical companies and reimbursement organizations for the future of anti-CD3. As Dr. Colin Dayan discussed in his introductory talk, it is currently unclear what price the system is willing to pay even for a complete cure for type 1 diabetes, and what level of improvement short of a complete cure would be considered a success.

Alefacept: Evidence of Enduring Benefit

Mark Rigby, MD, PhD (Janssen, Indianapolis, IN)

Dr. Mark Rigby reviewed two-year results from the phase 2 T1DAL trial presented at ADA and recently published in the Journal of Clinical Investigation showing significant preservation of C-peptide and significant reduction in insulin requirements with alefacept vs. placebo in 49 patients with newly diagnosed type 1 diabetes (within 100 days of diagnosis). He particularly highlighted the 50% reduction in major hypoglycemic events with alefacept vs. placebo at two years, suggesting that hypoglycemia reduction could be a useful endpoint to support approval of novel interventions for type 1 diabetes that is more immediate than the surrogate or long-term markers currently required by regulatory authorities. While we do not expect the FDA to disregard improvements in C-peptide or glycemic control entirely, we do hope that hypoglycemia reduction can be given more weight in clinical trials in the future given how meaningful it is for patients and given how much it matters from a benefit/risk perspective. Dr. Rigby also presented new mechanistic analyses showing a substantial decrease in effector and memory T cells with alefacept and no change in regulatory T cells, effectively shifting the balance of adaptive immune cells toward a more inhibitory state. Alefacept also appeared to lead to an increase in PD-1, a molecule that promotes programmed cell death, in specific memory/effector T cells, potentially suggesting a previously unknown mechanism of action. Finally, Dr. Rigby (like many other speakers in the session) spoke more broadly about the need to differentiate between children and adults when evaluating new therapies for type 1 diabetes, as younger participants experienced greater benefit in this trial. The ADA and several other high-profile organizations hosted an informative meeting on this topic early this year, and we hope that this increased attention can translate into paradigm shifts among researchers and regulators.

Questions and Answers

Q: Alefacept may have an enhanced effect in kids. I know you had a small group of patients, but did you try to see any differences related to age?

A: We defined full responders as no change in C-peptide after two years and partial responders as no more than a 50% decrease. The alefacept group did better than placebo. When you look at the percent with 50% beta cell retention, there was a significant difference for participants age 12-21, but not for those age 22-35. The adult placebo group did better than the younger placebo group. The numbers are small but very suggestive. If you look at the percent with total beta cell retention, none of the younger placebo group had it and about 20% of the adult placebo group did. In the younger alefacept group it was 32% vs. 27% in the adult group. It wasn’t significant but it feels right. There are trends that are maybe reassuring.

Comment: You mentioned that in the US they’re taking this crazy attitude that you have to prove something in adults first. You can’t prove it in adults, you have to prove it in the right population. That’s like saying you have to treat cystic fibrosis in adults first. It’s crazy. Adults don’t have the same disease. It’s similar in type 1 diabetes. It’s a consequence of the TrialNet tradition of using people from 3-45 years old. It’s crazy.

Q: The PD-1 story is interesting. With one of the cancer drugs that targets it, type 1 diabetes is a major side effect. In the treated arm, was PD-1 expression any different between responders and non-responders?

A: We have started analyses, but there’s not a clear picture at this point.

Q: What about PD-1 in relation with age?

A: We haven’t specifically looked at that. There are lots of areas to further pursue.

Q: 14% of placebo patients were responders at one year in the younger group. In the older group it’s 40%. If you look at the GAD data from TrialNet that has a wider range, you have a very high responder rate, double the rate seen in other GAD trials. Such a high responder rate in the placebo group can only dampen the effect, so you have to be concerned.

A: There have been discussions about how important it is to always have a placebo group, or can we use historical controls. It’s always important to have some placebo or control group so you have a gut check or a level setting to be sure there isn’t something very different or as therapies change over time or in different subpopulations, you can have something to better directly compare.

Dr. Colin Dayan (Cardiff University, UK): We saw the CTLA4 data; it affects central memory cells but when it stops it stops. This drug is not depletive. Is that different from the CTLA4 blockade? Does that explain the durability? You’re also seeing biomarker durability.

A: We’re actively looking at the timing of depletion of T cells and C-peptide response. We do think it is depleting, but it may not be that easy. It may be some true immune modulation.

Dr. Dayan: Maybe you’re getting rid of effector memory cells. These are the worst, and maybe they’re slow to come back.

A: We’re not affecting Tregs. They’re doing what they would be. It may be multifactorial. We’re getting rid of the bad guys and keeping the good guys. It may take longer for autoreactive cells to get back up to critical mass. After abatacept was stopped there seemed to be a quick increase. This took longer.

Dr. Dayan: It’s slightly reminiscent of anti-CD3, where the ratio was preserved for a year or two.

Low Dose ATG and G-CSF: Combination Therapy to Preserve Beta Cell Function in T1D

Mark Atkinson, PhD (University of Florida, Gainesville, FL)

Dr. Mark Atkinson reviewed the promising results from a study (n=25) of ATG/G-CSF combination therapy (the “Brazil Lite” approach) in type 1 diabetes, originally presented at ADA 2014. He described the study as “a little radical,” as it included a wider age range and patients with more established disease (up to two years duration) than is typical in type 1 diabetes trials near onset. Results showed significant C-peptide preservation after one year with the combination but no difference in A1c or insulin dose between the groups. There were significant side effects, particularly cytokine release syndrome, but Dr. Atkinson suggested that they were treatable and not overly concerning. Dr. Atkinson reviewed some of the factors that predicted response to therapy, with the caveat that the sample size was small: responders tended to be older (the opposite result from other studies presented in this session) and had lower insulin requirements at baseline. He also briefly shared unpublished two-year data from the study showing declining but still significant preservation of C-peptide (p=0.05 for the entire population and 0.043 for responders). Dr. Atkinson closed with several “conjectures” he believes the type 1 cure field should consider as a whole: (i) recent studies of pancreas pathology suggest insulitis is like a “sniper attack” in the prediabetic phase and rises to an “all-out blitz” around the time of diagnosis; (ii) the field needs to focus more on therapies that target beta cells rather than just immune cells; (iii) the field needs to be more creative in thinking about age dependency, sequential treatment, biomarkers, and prevention vs. reversal of disease; and (iv) the field must learn from past mistakes about disease heterogeneity, cost, safety, who will pay, and public perception of failure.

Questions and Answers

Q: In oncology, when you look at efficacy and side effects, therapies that alone don’t have enough effect often work together. You get as much effect as possible and little adverse events. In diabetes, you often take one drug, it’s not effective, then you take another, and it’s not effective. Maybe combinations are a possibility.

A: This is one benefit of the combination we selected, neither of the two individual therapies alone showed much promise but together, they work well. We probably need to be more mechanistically guided and make even smarter choices moving forward, as a field.

Dr. Colin Dayan (Cardiff University, UK): Everyone today is doing mechanistic studies and learning from them. It seems to add up.

Dr. Atkinson: In the past we were guided to a large extent by studies that worked in NOD mice and then we would try them in humans. Now, we’re much smarter as a community, selecting agents on mechanistic insights for the disease.

Q: Often we look at efficacy at a certain level and say this is what we need. It depends on how easy it is. If I have something like a tablet that improves beta cell function 10%, that’s fine. If it’s a lot of heavy treatment with adverse events and it improves it 28%, that’s different. You don’t need a fantastic effect if there’s some effect with an easy, tolerable treatment.

A: I agree, we must find the right balance between safety and benefit. There is also the potential for disruptive technology in the next few years. If the artificial pancreas and encapsulated stem cell therapies are efficacious, will we have competing technologies? I think it is a question we cannot ignore.

Dr. Bart Keymeulen (University Hospital Brussels, Belgium): The age dependence with alefacept and anti-CD3 was the opposite of your study. My interpretation is that the data is not in conflict because you included subjects a year after the development of clinical disease that still had C-peptide. That’s a selected group with less aggressive disease, and low-dose ATG could have an effect. Are you planning studies in recent onset, younger patients?

A: The TrialNet/ITN trial will have a wide age range. With that and 84 patients, we hope to answer that question. Recent pathology studies are giving clues as to why age may be important. For example, if you look at B cells in the insulitis lesion, they present at different frequencies whether you’re diagnosed younger or older. From the first wave of pancreas pathology studies, we learned that type 1 diabetes is likely a cluster of diseases with the commonality of insulin use. Ten years from now we’ll likely know the genes and mechanisms and hopefully better ways of staging it. But, that's pure speculation now.

Dr. Keymeulen: Can you speculate in terms of Tregs? Was that related to the type of population you studied?

A: This was a pilot trial, so we weren’t able to do elegant work with NIH ITN until the end. Hopefully we will in the next trial, which is enrolling pretty well.

Dr. Keymeulen: We like ATG, but we sometimes have seen Graves’ disease afterwards.

A: The longest we’ve followed people is three years and no one has developed secondary autoimmunity or a disease complication. We believe the dose may be important and ours is low.

 

Obesity

EASO Obesity Media Masterclass

The Role of Adipose Tissue in Weight Loss and Weight Maintenance

Mikael Ryden, MD, PhD (Karolinska Institute, Stockholm, Sweden)

Dr. Mikael Ryden discussed the role of white adipose tissue expansion in obesity, noting that the rate of new cell formation is increased in obesity. Specifically, Dr. Ryden demonstrated data showing that upon changes in body weight, the number of fat cells cannot decrease but only increase. He noted that individuals who develop obesity at an early age typically experience an increase in fat cells throughout their childhood development, stabilizing at a high number of fat cells in adulthood and thus forming a high set point of weight. In addition, upon weight loss, specific disturbances in the hormonal regulation of adipose tissue appear to facilitate weight regain. Again, we see this research pointing to the importance of intervening earlier and taking a hard look at what’s going on with weight during development to design and implement the most effective prevention efforts.

Corporate Symposium: Evolving Perspective in Treating Diabetes and Obesity (Sponsored by Novo Nordisk)

Mode of Action of Liraglutide 3.0 mg in Weight Management

Niels Vrang, MD, PhD (University of Copenhagen, Denmark)

Dr. Niels Vrang discussed the research surrounding the mechanisms of action of Novo Nordisk’s Saxenda (liraglutide 3.0 mg), specifically within the brain. In identifying the various GLP-1 receptors within the brain, Dr. Vrang explained how peripheral liraglutide can affect food intake and weight control. He introduced the complexity of hunger signals, noting that hunger has hedonic aspects, humoral feedback signals from the fat and gut, as well as neural feedback signals from the gut. He highlighted that GLP-1 is not only a gut hormone, but also a neurotransmitter used by a small group of neurons in the caudal brainstem that project to the hypothalamus. In understanding where and how peripherally circulating GLP-1 acts, Dr. Vrang reviewed research demonstrating that the GLP-1 receptors on vagal afferents and area postrema are not important for the weight loss mediated by GLP-1 agonists, but that the receptors on the hypothalamus play a significant role within this mechanism. Specifically, GLP-1 receptors on appetite regulating neurons in the hypothalamus are influenced, as GLP-1 activates the arcuate POMC/CART neurons (which inhibit appetite) and inhibit NPY neurons (which stimulate appetite). Additionally, Dr. Vrang walked attendees through brain imaging studies that have shown that peripheral liraglutide administration is taken up into these specific brain areas in a receptor-dependent manner. Looking forward, he posed questions including how paraventricular nucleus activation (also in the hypothalamus) may affect energy expenditure as well as the roles of brainstem and vagal GLP-1 receptors and glucose regulation. A more in-depth look into the brain for weight management has become an increasingly hot topic of research for obesity – for more on this, please see our coverage from ECO of Novo Nordisk’s symposium on Saxenda in the brain as well as our interview with Dr. Kevin Grove (Novo Nordisk, Seattle, WA) on the brain as a new target within obesity.

The SCALE Phase 3a Clinical Trial Program – Benefits on Secondary Outcomes

Luc Van Gaal, MD (Antwerp University Hospital, Antwerp, Belgium)

Dr. Luc Van Gaal reviewed data from the four different SCALE trials (SCALE Obesity and Prediabetes, SCALE Diabetes, SCALE Sleep Apnea, and SCALE Maintenance), with a specific focus on the benefits on secondary outcomes. He opened by highlighting that 5% to 10% weight loss can improve many obesity-related comorbidities and demonstrated from SCALE data that Novo Nordisk’s Saxenda (liraglutide 3.0 mg) was similarly associated with clinical benefits such as glycemic status, blood pressure, and cardiovascular risk factors. In addition, he reviewed the SCALE post-hoc analysis that showed that improvement in these various secondary endpoints were driven by both weight-loss dependent and independent effects of Saxenda. For a more in-depth look at this analysis, please see our coverage of the data at ECO earlier this year.

Personalizing the Choice of Anti-Obesity Medication (Responder Analyses)

Donna Ryan, MD (Pennington Biomedical Research Center, Baton Rouge, LA)

Dr. Donna Ryan walked attendees through four considerations for prescribing weight loss medications in the goal of better personalizing obesity treatment. She opened by stressing the diversity of patients with obesity as well as the heterogeneity of treatment effects. Dr. Ryan specifically pointed out “the trouble with averages” when discussing obesity pharmacotherapies’ clinical data since there is no “average” patient as many individuals will either derive less than or greater than average net benefit or no clinically meaningful effect. She thus pointed to the need to identify characteristics of patients to best target treatments, providing four considerations based on the knowledge of heterogeneity of treatment effects. First, Dr. Ryan stated the importance of “doing no harm” to carefully evaluate each drug’s contraindications and warnings to exclude certain medications. Second, she encouraged providers to consider the added benefits of therapies (such as effects of glycemic improvement and LDL lowering, which are independent of those benefits mediated by weight loss per se). Some pre-treatment factors, including gender and racial differences as well as response differences based on the presence of type 2 diabetes or insulin therapy will predict weight loss response, but they aren’t modifiable. Dr. Ryan also briefly touched on genetic predictors of weight loss, noting that the research here is interesting and promising but not close for prime time – we would agree that genetic understanding for diabetes and obesity remain far behind that of other disease areas such as cancer. Third, she highlighted the value of managing concomitant medications and chronic diseases to ensure that these are not sabotaging weight loss efforts and medication efficacy, as well. She also stressed the importance of supporting approaches to make adherence to lifestyle intervention easier (more use of meal replacements, using tools such as wearables and apps for self-monitoring of food intake, physical activity and weight. Lastly, Dr. Ryan stressed that patients must play a role in choice of medication, so cost, tolerability and dosing methods are considerations.

• Acknowledging these considerations, Dr. Ryan noted that the actual prescription of medications is still more of an art than a science and early response is the best predictor of ultimate success. She reviewed the drugs’ stopping rules and clinical data surrounding responders. This last consideration is the most common one we have heard and while early response seems to be a pretty reliable predictor. She showed liraglutide as an example and for the two out of three patients who met the EU stopping rule, more than 80% will have 5% weight loss at one year and nearly a third will have 10% weight loss at one year. The challenge to prescribers of obesity drugs is a trial and error system. In the case of obesity medications, the efficacy of the drug may be fine, but other factors may thwart weight loss, thus the recommendation to manage medications, chronic diseases, stress, sleep deprivation and other factors that sabotage weight loss. Until cost considerations are addressed by third party payers and more physicians are trained in weight management, uptake of these medications will be slow.

Panel Discussion

Q: Why is it so difficult for patients to maintain weight loss and do you see a difference in age in the studies?

Dr. Vrang: Patients who gain weight and who become obese and who come into any program have been in an environment that is friendly to weight gain and to maintaining higher weight. So environment is important. And physiology has been adapted to promote weight gain. It’s a combination of environmental and biological forces driving weight back up. A simple 15-minute discussion is not ineffective. We need to rethink biology and environment – those who are more successful are those who have been prepared to engage with a management program that understands the principles of cognitive behavioral therapy.

The age question is often raised. Younger people are less good at producing weight loss and maintaining that. But those who can lose 10-15 kg of weight can keep it off for a longer time. We need to learn from those successes and apply them.

Dr. Ryan: Losing weight is hard work and it takes a lot of commitment from patients. Older patients may do better because they have less external commands on their time and energy.

Q: What about the SCALE studies and safety?

Dr. Van Gaal: We know that there have been some GI effects. We looked at this in SCALE diabetes – it’s roughly the same on average. It’s typically occurring in the initial phase of treatment and then it’s flattening out. There’s also the pancreatitis concern. There were four patients with pancreatitis with good outcomes. On average, the safety profile’s good.

Dr. Melanie Davies (University of Leicester, UK): There are slight differences in GI, but overall no differences otherwise.

Q: Any insights on the clinical experience with Saxenda?

Dr. Ryan: It’s been almost a year since it’s been available in the US. Physicians have a lot of confidence in Saxenda because it’s been used in type 2 diabetes. There’s been a big uptake in providers. There’s great interest and uptake in using medications. The success of using this drug depends on overcoming barriers. We’re starting to see third party payers picking up Saxenda.

 

Award Lectures and Additional Topics

Opening Ceremony

Presidential Address

Andrew Boulton, MD (University of Manchester, UK)

EASD President Dr. Andrew Boulton delivered a warm welcome and introduction, providing his insights on how diabetes has evolved since EASD was founded in 1965. Dr. Rury Holman commented on this talk very positively at the diaTribe Foundation’s Solvable Problems in Diabetes – and this was very well-deserved praise. After introducing 2015 as a “year of celebration” (ADA’s 75th year, EDEG’s 50th year [European Diabetes Epidemiology Group], NEURODIAB’s 25th year [Annual Meeting of the Diabetic Neuropathy Study Group of the EASD]), Dr. Boulton illustrated that the “world has come a long way since 1965” when there was no blood glucose monitoring or glycated hemoglobin and with only SFUs and biguanides (i.e. metformin) as the oral agents (and metformin wasn’t approved in the US until 1994). Addressing the present state of diabetes, he pointed to the increasing prevalence of both type 1 and type 2 diabetes, the recent rapid escalation in the number of diabetes drugs, and greater attention toward public health policies such as the soda tax. As he summarized the future of the field, he expressed excitement about the closed-loop system (specifically citing the bionic pancreas work of Drs. Steven Russell and Ed Damiano), immunotherapy for type 1 diabetes, and new drugs for type 2 diabetes. Notably, he applauded the fact that this year is the first time in the UK that diabetes is no longer the leading cause of blindness for people of working age, as he strongly emphasized that “screening and prevention are the future” (a most fitting preamble for the Claude Bernard Lecture). In addition, he made a call to action to governments throughout the world to not ignore diabetes, as he referred to the enormous human and economic costs of the epidemic. We were so struck by Dr. Boulton’s balance of optimism yet clear sense of urgency on the state of diabetes and were especially glad to hear him devote some attention to the bigger-picture public health needs of prevention and policy in diabetes at such a science-heavy meeting. This is his last year as head of EASD and he will be sorely missed – we do look forward to the start of Dr. Juleen Zierath’s reign.

Oral Presentations: Eye on Retinopathy

Effects of Baseline Hemoglobin A1c and On-Treatment Blood Pressure on Outcomes in the VIVID-DME and VISTA-DME Studies

Marc Evans, MD (Cardiff University, Wales, UK)

Dr. Marc Evans presented results from post-hoc subanalyses of the VIVID and VISTA studies of Bayer/Regeneron’s Eylea (intravitreal aflibercept) that evaluated the association between baseline A1c and on-treament blood pressure and visual and anatomical outcomes. There was no association between baseline A1c quartile and improvement in visual acuity in the aflibercept group. By contrast, patients with a higher baseline A1c in the laser photocoagulation control group saw significantly less improvement in visual acuity. The same pattern was observed for mean change in central retinal thickness (CRT). On-treatment blood pressure was not correlated with improvements in either visual acuity or CRT in either group. Benefits were greater with aflibercept than with laser treatment irrespective of baseline A1c or on-treatment blood pressure. During Q&A, Dr. Evans noted that these findings could have significant clinical implications, as many ophthalmologists currently wait to initiate treatment for retinopathy until patients achieve better glycemic control, sometimes contributing to a vicious cycle of inertia.

Questions and Answers

Q: What was the distribution of medications? It seemed like there was a high number on fibrates in the laser group?

A: It was 7.3%, 3.8%, and 4.1%. Remember that there were two different studies. In essence the laser number is the same as the combined cohort of aflibercept. We spent a lot of time looking at the data from that perspective, but when we put the cohorts together the proportion on fibrates in both groups was similar, so you wouldn’t be able to identify the impact. Same with RAS blockers and DPP-4 inhibitors.

Q: I had a similar point about GLP-1 agonists, which was lower in the laser group. The presentation earlier in this session suggested that GLP-1 may have an important effect on retinopathy.

A: They were talking about topical GLP-1. I’m not sure about a systemic impact in terms of retinal changes. The data we have for GLP-1 physiology is in relation to earlier changes, and these are fairly advanced patients.

Q: I’m interested in the age distribution because looking at other data on patients in trials, the average age was 75, but if you look in routine data you find that the average age is 85 and patients are treated well into their 90s. Is there a reason why the patients in trials are so much younger? Was there an age cutoff for inclusion?

A: There was no cutoff. Remember that this is a trial in which people are coming in for monthly intravitreal injections, so there’s a bias in terms of age inclusion driven by investigator perception of acceptability for treatment.

Q In real life patients are about 20 years older. I’m quite worried that these groups are not overlapping. It has big implications for health economics.

A: What do you mean by health economics?

Q: I’ve been to NICE committees when they’re looking at costs and benefits in different groups.

A: Yes, the generalizability for cost in routine practice is different. The utility gain in routine practice is less because life expectancy is less. If you look at it in terms of QALY gains, it’s about 25,000. What tends to drive it is baseline age. We did a similar analysis with baseline A1c – how much is it worth spending to drop A1c by age – and there was a big difference. It’s really driven by life expectancy to experience utility gains. You’re right that the generalizability may not quite be there.

Q: What is the physiopathological interpretation?

A: We discussed that in the investigator group. We didn’t really know, which is always the best way to start. We speculate that the mechanisms by which anti-VEGF impacts ischemia are not as sensitive to the consequences of hyperglycemia in the eye as the laser. I have many ophthalmology colleagues who focus on optimizing A1c before laser therapy, but the acuity changes with anti-VEGF had no relationship. Rather than inertia for initiating treatment while you wait to get A1c down, that’s the most pertinent clinical observation.

Comment: In the old days, delaying to wait for metabolic control was a way of sharing the lack of success. The ophthalmologist could blame the diabetologist.

Q: Have you done an analysis about the potential influence of nephropathy in the evolution of retinopathy?

A: We have looked at UACR and it’s the same sort of thing, but we haven’t presented it in this paper. We see no relationship between UACR quartile and change in visual acuity in either group.

Oral Presentations: The Price of Diabetes Care

Post-Prandial Hyperglycaemia (PPH): Missed Work Time and Reduced Productivity Among People with Type 1 and Type 2 Diabetes in the US, UK and Germany

Annie Nikolajsen (Novo Nordisk, Soborg, Denmark)

Ms. Annie Nikolajsen presented data on the impact of post-prandial hyperglycemia (PPH) on work productivity as she highlighted the importance of managing this condition within the context of its public health consequences. The study collected data through a web survey that was administered to people with type 1 or type 2 diabetes treated with bolus insulin in the US, UK, or Germany (n=906), with the majority of participants having type 2 diabetes. The results found that among the 519 participants who worked for pay, 68% experienced difficulty stabilizing their blood glucose after eating, with 27% reporting missing some work and 10% missing an entire day of work due to a PPH episode. When looking at presenteeism (the act of attending work while sick), 71% reported having some work productivity issues, with 54% reporting difficulty focusing, 45% being less productive, and 44% needing to take a break while at work. Presenteeism was more common among workers with type 2 diabetes than those with type 1 diabetes (p<0.05) and interestingly, respondents from Germany were significantly more likely than those in the US and UK to report presenteeism due to PPH (p<0.01). In conclusion, Ms. Nikolajsen stressed that these results indicate that PPH is not only common, but is also associated with significant absenteeism and presenteeism, highlighting the need for clinical management of PPH. In understanding the magnitude of the diabetes and obesity epidemic, these data are important considerations to recognize as they remind us that these diseases extend beyond the burden on an individual’s quality of life but also to a larger network’s economic burden, in terms of work time and productivity lost.

Questions and Answers

Q: Were there any exclusion criteria?

A: We had some exclusion criteria based on treatment: if patients were not on bolus insulin or if they were not in a healthy state.

Comment: This is an important study. Absenteeism is an easy concept but presenteeism is more difficult to understand. It is not a very popular concept because it implies you are letting your employer down.

Q: Do people with diabetes feel guilty?

A: We have not investigated that in this study.

Award Lecture: 47th Claude Bernard Lecture

Understanding Phenotypes of Prediabetes: Essential to Influencing Progression to Type 2 Diabetes

Hans-Ulrich Haring, MD (University of Tubingen, Germany)

Dr. Hans-Ulrich Haring presented on the phenotypes of prediabetes, discussing the roles of brain insulin resistance, fatty liver, fatty pancreas, and genetics. In reviewing the wide variety of phenotypes presented by people with prediabetes and better understanding their mechanisms, his work was an exciting glimpse into how we can begin to individualize prevention efforts. Dr. Haring first reviewed eight-year follow-up data demonstrating that insulin resistance in people with prediabetes increases over time, although some are able to up-regulate insulin secretion and better prevent the progression to type 2 diabetes. Looking to genetics to identify who was and was not able to compensate, Dr. Haring noted that the gene variant TCF7L2 has appeared to be the strongest variant (with a small per-allele odds ratio of ~1.4), but stated that this genetics approach does not provide an adequate explanation for the differences. However, in examining obesity subphenotypes, he pointed to MRI and MR-spectroscopy data showing the fat distribution differences in those who are metabolically healthy obesity (MHO) vs. metabolically unhealthy obesity (MUHO). He highlighted that those with MUHO are much more likely to have fatty livers as well as increased pancreatic fat, thus stressing the importance of treating fatty liver disease. In addition, Dr. Haring brought up the speculation that brain insulin resistance may be the cause rather than the consequence of obesity and may begin as early as in utero. In developing a model, Dr. Haring therefore hypothesized that early brain insulin resistance may be contributing to obesity, in which there is crosstalk between the fatty liver, pancreatic fat cells, and inflammation that is ultimately accentuating beta cell dysfunction. Moving forward, Dr. Haring emphasized the value in defining subphenotypes and in understanding the pharmacology behind these hypothesized mechanisms to develop new targets and personalize prevention efforts to learn who responds to what and how to effectively intervene as early as possible. We were glad to see such a renowned lecture focus on prediabetes (talk about the growing focus on the need for prevention); and with lifestyle intervention and metformin as really the only mainstream approaches for treating prediabetes, we concur that this research into the progression’s physiological basis will be key to identifying and personalizing a wider array of prediabetes treatment options.

Award Lecture: 50th Minkowski Lecture

Size, Sites and Cytes: Importance of Adipose Tissue in Diabetes and Beyond

Matthias Bluher, MD (University of Leipzig, Germany)

In the esteemed Minkowksi Lecture, Dr. Matthias Bluher discussed how “size, sites, and cytes” contribute to adipose tissue dysfunction and resulting obesity comorbidites. In a lecture filled with appreciation for his family, mentors, and collaborators, a humbled Dr. Bluher opened with the motivation for his research as he highlighted the challenges of weight maintenance and the lack of scientific understanding around this etiology. In stressing obesity as a driving factor of the diabetes epidemic, Dr. Bluher walked attendees through the latest research on the role of adipose tissue in the pathogenesis of type 2 diabetes. He discussed the diversity of processes that adipose tissue signals regulate from the immune system to appetite within the brain, ultimately pointing to the three components of “size, sites, and cytes” in differentiating the insulin resistant obese phenotype (as compared to insulin sensitive or metabolically healthy obesity). Regarding size, Dr. Bluher noted that adipocyte hypertrophy through impaired expandability of subcutaneous adipose tissue may underlie the insulin resistant obesity phenotype. In terms of “site,” he pointed out that visceral fat distribution contributes to the insulin resistance within obesity – a factor that we have commonly heard as a reason to move away from BMI as the sole measure for obesity. Lastly, Dr. Bluher discussed “cytes” in demonstrating that the insulin resistant obese phenotype tends to have higher visceral adipose tissue macrophage infiltration along with evidence of “foam cells” in adipose tissue. With these three aspects, Dr. Bluher raised questions on the mechanisms behind these specific factors, pointing to the potential role of developmental genes in the expandability of subcutaneous adipose tissue and fat distribution as well as the influence of relevant genes within the brain. In our eyes, this lecture reflected themes similar to Dr. Hans-Ulrich Haring’s Claude Bernard Lecture on the need to personalize prevention efforts and to intervene early (as early as in utero considering the role of developmental genes) and is another striking reminder of the potential of understanding obesity’s pathophysiology in its role as a gateway disease.

Dogmata Debate: Is Insulin Resistance Always Bad For You?

Yes

Ele Ferrannini, MD (University of Pisa, Italy)

Dr. Ele Ferrannini argued that chronic insulin resistance is at least “mostly bad for you,” presenting extensive data on the many associated metabolic abnormalities. He explained that while most studies of insulin resistance focus on glucose uptake in skeletal muscle, insulin resistance affects adipose tissue as well, where its main effect is to increase lipolysis and liberate free fatty acids into the bloodstream, leading to oxidative stress. He also noted the links between insulin resistance and cardiovascular risk via impaired endothelial and cardiac function, and the direct impact of insulin resistance on beta cell function. Dr. Ferrannini’s main point was that insulin resistance is associated with worse values for a wide range of metabolic parameters (BMI, heart rate, blood pressure, LDL, triglycerides, and glucose) and is an important part of the broader metabolic syndrome phenotype. He noted that there is likely a genetic component to insulin resistance at least in some cases, as there is a wide distribution of values in the population and insulin resistance has been shown to exert significant effects regardless of weight and waist circumference. Dr. Ferrannini closed by discussing the intriguing new topic of insulin resistance in the brain and its potential links to excess appetite and cognitive dysfunction.

No

David Matthews, DPhil, BM, BCh (University of Oxford, UK)

In a highly entertaining talk complete with cartoons and even singing, Dr. David Matthews argued that insulin resistance in itself is not always pathological, as it is a normally distributed variable and often a physiological adaptation to certain conditions. He noted that unlike most metabolic parameters, insulin resistance varies over orders of magnitude within a population, both for people with and without diabetes – as he put it, the equivalent would be not worrying about a blood pressure of 1200/800 mmHg or a weight of 700 kg. While acknowledging that insulin resistance is associated with metabolic derangements, he stressed that no causal relationship has been shown, in contrast to other conditions like hypertension. He argued that insulin resistance is simply a result of the nature of insulin signaling, which works as an amplitude modulation system (simple, cheap, and noisy) rather than a frequency modulation system (resource-intensive, noise-free, difficult to decode) like the nervous system.

Symposium: Is the Brain the New Pancreas?

Identified Sources and Effects of Insulin in the Cerebral Cortex

Gábor Tamás, PhD (University of Szeged, Hungary)

Dr. Gábor Tamás’s valuable overview of his neuroscience work provided insight – albeit often over our head – into the effect and interaction of insulin with neocortical neurons. The very in-depth presentation concluded with a number of takeaways that will likely be of interest to our basic science readers: (i) that insulin mRNA is expressed by neurogliaform interneurons of the rat cerebral cortex; (ii) that external insulin suppresses excitation in cortical circuits; (iii) that neurogliaform cells release insulin in response to glucose and glibenclamide; (iv) that human interneurons express insulin mRNA and proinsulin; and (v) that insulin expressing subpopulation of inhibitory interneurons are positioned to math neuronal activity and metabolic supply. Whew! You can access the details of Dr. Tamás’s talk here. The clinical implications remain an open question, but we are grateful to Dr. Tamás for opening our eyes to this exciting avenue of work [that has implications for our understanding of the intersection of Alzheimer’s disease and insulin as well].

Questions and Answers

Q: You explained that external insulin suppresses excitatory neurons. How can you explain that insulin deficiency results in brain stimulation? We usually find the opposite.

A: You have to think about the mechanism. What insulin actually does is that it turns up a part of cortical inhibition. This tonic inhibition is not equally well distributed over interneurons and pyramidal cells. You have to think about epileptic discharges work and the suppression of discharges. Epilepsy is not always excitatory overload. It can also be the result of suppressed inhibitory action. In this case, this is one of the scenarios I can think of.

Symposium: Emerging Issues in Diabetes

Does a Proper Diagnosis of Diabetes Make a Difference?

Sanjeevi Carani, MD, PhD (Karolinska Institute, Stockholm, Sweden)

Dr. Sanjeevi Carani provided an unambiguous and positive answer to his opening question: Does a proper diabetes diagnosis actually matter? Yes, indeed! Dr. Carani began by putting in perspective the complex landscape of possible diabetes diagnoses – from type 1 diabetes to LADA to MODY to neonatal diabetes – suggesting that “treating hyperglycemia alone” is not going to help patients. He stressed that identifying subtypes of diabetes is a critical piece of the puzzle, noting that our therapies are more-than-differentiated enough to make a real difference in various subtypes of patients. Indeed, Dr. Carani shared that he tests for autoantibodies in the majority of his adult patients presenting with type 2 diabetes – a sentiment shared by only ~20% of the clinicians in the audience. This is of course a question of financial ROI, though from a patient perspective, Dr. Carani was adamant that doing right by patients inherently means subtyping – for example, he raised the very real potential of mistreating patients (treating LADA patients with SUs; treating neonatal diabetes with insulin). In terms of LADA alone, he estimated that 10-12% of patients would be misdiagnosed with type 1 diabetes without appropriate autoantibody testing. Ultimately, we were glad to hear his effort to raise the level of discussion on these fronts; the ROI argument is certainly not where it needs to be though we are hopeful that growing attention can push this in the right direction.

• Dr. Carani underscored the importance of proper diagnoses by summarizing the variety of early intervention options for various type of diabetes. See his breakdown below.

Treatment Options for Diabetes Subtypes

Diabetes Subtype	Ideal Treatment Option
Type 1 Diabetes	Insulin
Fulminant Diabetes	Insulin
LADA	Insulin, sitagliptin (SUs should NOT be given)
MODY	Insulin, Oral tablets
MMDM	SU in MODY 1 and 3; Insulin in MODY 5
Neonatal Diabetes	SU
Mitochondrial Diabetes	SU
Type 2 Diabetes	Oral tablets

Questions and Answers

Q: Do you measure antibodies in all newly diagnosed type 2 diabetes patients?

A: Yes.

Q: Which of these subtypes are reversible?

A: All of them have some amount of beta cell loss, so they are not truly reversible. However, the earlier we catch them, the earlier it is to save beta cell function to early intervention is important.

Prediabetes – When Is It Worth Treating it?

Mahmoud Ibrahim, MD (Center for Diabetes Education, Atlanta, GA)

Dr. Mahmoud Ibrahim discussed the role of prediabetes and emphasized the value of treating overweight and obesity in the context of prediabetes management. He first reviewed guidelines regarding the definition and algorithm for prediabetes by ADA and AACE and highlighted the high prevalence of prediabetes citing the recent JAMA article on diabetes prevalence and trends through 2012. When discussing treatment and how to manage prediabetes, Dr. Ibrahim noted that we must examine the risk factors rather than just looking at blood glucose values and really target overweight and obesity. Specifically, he reviewed the treatment options for obesity including lifestyle intervention, drugs, and surgery, walked through the NIH practical guide on obesity management, and briefly introduced the CDC’s National Diabetes Prevention Program (see our coverage of Dr. Ann Albright’s keynote on this at AADE). Interestingly, Dr. Ibrahim also mentioned consanguinity as an area to further explore, as prevalence in Arab countries ranges widely – certainly, further examination of the roles of genetics and the environment will help us frame the potential therapy options as well as identify the most high-risk patients.

Statin-Induced Type 2 Diabetes – Should We Worry?

Peter Gaede, MD (Slagelse Hospital, Denmark)

Dr. Peter Gaede discussed statins’ potential to increase blood glucose levels relative to their benefits for preventing CVD. It was comprehensive overview that drew heavily from the literature (Sattar et al., Lancet 2010; Cederberg et al., Diabetalogia 2015) to demonstrate both that statins treatment is associated with new onset diabetes (no surprise there) and that statins reduce CVD (even less surprise here!). Consistent with previous research, he implicated changes in insulin resistance, insulin sensitivity, and GLUT-4 transporter blockage as primary culprits in the pathogenesis though stressed that the full mechanism remains poorly understood. Ultimately, he asserted that the risk of new-onset diabetes on statin therapy was small relative to the benefit of CVD risk reduction, noting that, “there is no reason to worry at all about glucose levels in patients with statins.” Along these lines, he applauded the US’s recent guidelines that further encourage the use of statins, saying that EU regulators could take a lesson from the stateside changes. In conclusion, he noted that there are some patients at risk with statins (e.g., those who already show features of metabolic syndrome) but encouraged their use in a majority.

Questions and Answers

Q: Can you explain the mechanism by which statins increase glucose levels?

A: Statins seem to increase insulin resistance. Studies also seem to show that insulin secretion is going down and that GLUT-4 is being blocked in some way on a cellular level. However, the exact mechanism is unknown.

Q: If you have metabolic syndrome, you are at risk. So if you are young, should you prescribe statins?

A: It’s always a question about the absolute risk reduction. Even if you are young, there is a clear benefit of statins.

Symposium: Beta Cell Imaging

Current Understanding of Human T1D

Mark Atkinson, PhD (University of Florida, Gainesville, Florida)

Dr. Mark Atkinson ambitiously strived to present an overview of the current understanding of human type 1 diabetes in 20 minutes. His fast-paced and informative presentation was structured with eight takeaway “lessons”: (i) the incidence of type 1 diabetes is increasing, but perhaps at different rates at different ages in different populations; (ii) genetics is important but we are far from a complete understanding of how it influences disease risk and progression; (iii) type 1 diabetes is truly an autoimmune disease, despite recent dissenting opinions; (iv) type 1 diabetes is heterogeneous; (v) type 1 diabetes is a disease of the beta cells and islets, and their role in disease pathogenesis has been underemphasized in research; (vi) beta cells can survive long after disease onset; (vii) beta cell replication does not occur very often after the first few years of life, but beta cell mass is significant; and (viii) type 1 diabetes is a disease of the pancreas, with known reduction in pancreas weight associated with onset. Dr. Atkinson frequently referenced and presented images from the Network for the Pancreatic Organ Donor with Diabetes (nPOD), a JDRF-sponsored initiative founded in 2007 that facilitates collaborative research projects using tissue samples from cadaveric organ donors with type 1 diabetes or islet autoantibodies. Dr. Atkinson made the point that human beta cells and islets look different from those of mouse models throughout the progression of type 1 diabetes, especially with regard to insulitis, and that it’s important to develop stages and markers for progression based on human data. This point echoed comments from Dr. Alberto Pugliese (Diabetes Research Institute, Hollywood, FL) at Friends for Life this July, where he explained that animal studies often do not provide an adequate understanding of human disease. The history in the type 1 diabetes cure field of promising preclinical studies that fail to translate into effective clinical therapies is likely in part a reflection of this – too, we’d like patients to understand the math better, that the chance across a range of preclinical trials being successful is relatively low but that it’s critical that the research is pursued.  

Questions and Answers

Q: What are the two or three things this group can do to answer some of those questions and challenges you raised?

A: Number one: help us quantify the number of beta cells in individuals all throughout the history of type 1 diabetes. We need to know numbers before onset – are they low? Are beta cells replicated in the prediabetic state? Second, we need help in quantifying the insulitis rate. Third, there’s a whole lot of effort on preventing or reversing the disease, but we need better tools – any type of imaging here that can give us insight into whether the therapies we’re using are of clinical benefit would be very helpful.

Beta Cell Dysfunction and Death – What Are We Trying to Image?

Decio Eizirik, MD, PhD (ULB Center for Diabetes Research, Brussels, Belgium)

Dr. Decio Eizirik discussed the role of beta cell imaging within both type 1 and type 2 diabetes, highlighting its optimal use and future opportunities. Based on human data, he demonstrated how one can still have a residual amount (usually less than 1-2%) of beta cells after long T1D disease durations and how there is an increased percentage of bihormonal cells (expressing glucagon and insulin) in type 2 diabetes due to increased apoptosis in beta cells, but not alpha cells, and possible transdifferentiation from alpha to beta cells. He noted that those with at least five years of type 1 diabetes tend to have major loss of beta cells. Under these conditions, imaging should be able to detect a 80%-90% decrease in beta cell mass as well as any small improvements (1% to 10%) in beta cell mass – unfortunately we are not there yet, and this is a major challenge to the field. Dr. Eizirik emphasized the wide variability in beta cell mass within the non-diabetic population, stressing that imaging is not effective as a diagnostic tool, but should instead be used for the stratification and follow up of individual patients based on baseline and repeated imaging (pointing to using this approach to test whether GLP-1 agonists’ have or not effects on beta cell mass as an example). In addition, he pointed to the need for discovering surface and intracellular markets that specifically identify beta cells (rather than all islet cells), noting that the present evidence isn’t sufficient to hope that non-beta cells will trans-differentiate into beta cells in sufficient numbers in humans. Dr. Eizirik’s ideal approach is to use beta cell imaging for patient stratification and follow up based on basal and stimulated C-peptide release, analyzed in parallel with imaging based on intracellular insulin and beta cell specific surface markers, as well as with testing of blood biomarkers that detect beta cell death. This should allow better detection of functional and non-functional beta cell mass. He highlighted that bringing together these different types of testing and information can help “direct individualized therapy,” further providing concrete steps as to how we can better personalize medicine within diabetes.

Questions and Answers

Q: How do you think insulin injections will affect beta cell function and mass?

A: The insulin therapy is obviously crucial to keep the patient alive in T1D. It will protect beta cells against “exhaustion” but also reduce their function, which is reversible (as it is the case following removal of insulinomas – there is often a transitory hyperglycemia, and then the endogenous non-tumoral beta cells resume their work and restore physiological glucose level). In conclusion, the information we have today is that insulin therapy is mostly protective to the remaining beta cells. 

Corporate Symposium: Individualized Patient Care in Type 2 Diabetes: Translating Science to Practice (Sponsored by AstraZeneca)

Why Not Combine Earlier?

Jochen Seufert, MD, PhD (University of Freiburg, Freiburg, Germany)

Dr. Jochen Seufert critiqued the traditional stepwise “treat to fail” strategy for type 2 diabetes, noting that it is a progressive disease requiring therapy intensification over time as beta cell function decreases. He suggested that using combination therapy as a first line treatment may allow for faster achievement of A1c targets. Combining treatments with different mechanisms of action may also produce benefits such as improved target achievement, greater weight and blood pressure reduction, reduced risk of hypoglycemia, delayed disease progression, improved long-term glucose control, and reduced long-term complications. He presented medical record data from the UK Clinical Practice Research Datalink showing that a six-month delay in therapy intensification increased the risk of cardiovascular disease by 20% and heart attack by 26% when compared with immediate therapy intensification, furthering the argument in favor of early use of combination therapy. We have heard similar arguments from a number of speakers on the conference circuit in recent years. Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX) has of course been one of the most vocal proponents of early combination therapy, and interim three-year results from his triple therapy trial (metformin + pioglitazone + exenatide) presented here looked quite promising. However, a move toward early aggressive combination therapy as standard practice would require significant buy-in from payers, and we expect that some patients and providers would be hesitant to treat the disease so aggressively from the start due to the risk of side effects.

Treatment Decisions For Our Patients: What Are The Considerations?

Richard Pratley, MD (Florida Diabetes and Endocrine Center, Orlando, FL)

Dr. Richard Pratley offered his take on important treatment considerations in type 2 diabetes, with the discussion driven by an audience vote on what the attendees saw as the most important issues for their patients. He described the current state of type 2 diabetes treatment as “the best of times and the worst of times,” as there more treatment options available than ever before but they come with a great deal of complexity. He urged clinicians to focus on drugs with low risks of hypoglycemia and weight gain (we completely agree), stressing that hypoglycemia has an enormous impact on people’s lives and may be associated with adverse outcomes. He noted the significant overlap between diabetes and renal and cardiovascular disease, suggesting that “we are in the golden age” of understanding the effects of diabetes drugs on CV risk and predicting significant changes in the landscape in the near future. Dr. Pratley closed with a realistic but encouraging message, suggesting that the diabetes field is currently “winning the battle but losing the war.” He congratulated diabetologists on being at the forefront of personalized medicine due to the need for such individualized treatment (an interesting twist on the typical discussion of personalized medicine, which tends to be focused on high-tech gene therapies) and urged them to take a multifactorial approach built on patient engagement and lifestyle changes as a foundation.

Questions and Answers

Q: Can you pin one out of all of those that is the commonest consideration in your practice?

A: One factor I pay a lot of attention to is renal function. It’s important for adjusting medications and it impacts cardiovascular risk and hypoglycemia risk.

Q: What about cost?

A: That’s critically important. They won’t take medications they can’t afford. Patients have to make difficult choices between paying for diabetes medications and other medications. We have discussions about treatment preferences and cost and whether their insurance will pay, and I work with them to find alternatives when something’s too costly. The goal is as much as possible to get good glucose control.

Q: Do we have the cost-effectiveness conversation often enough?

A: No, we focus a lot on A1c reductions and other side effects. I’d like to see a day where we can line up A1c, side effects, and cost-effectiveness to understand how to make the best decisions.

Q: It’s not the biological age but the physical age of the patient. How do we deal with considerations with a frail elderly person?

A: I sat on the ADA consensus statement on treatment in the elderly. We sat around for a couple of days, and it turns out there’s not a whole lot of evidence. Those people are often excluded from trials, so we don’t know the appropriate targets or how to get there. We have to recognize that older individuals are very diverse. Some are very healthy and have a 20-25 year lifespan. Conversely, you can have a 65-year-old with cardiovascular disease, a long duration of diabetes, and many complications, and you would treat them differently. The frail elderly won’t benefit from long-term intensive treatment. The criteria are less stringent, but that doesn’t mean you don’t treat the patients.

Q: Duration of diabetes comes into the discussion. A 70-year-old who got diabetes yesterday is different from one who’s had it for 30 years. Does that enter into your choice?

A: It certainly does. A 70-year-old with a recent diagnosis has an excellent chance of achieving target with one or two therapies. Keep in mind that a healthy 70-year-old has a 15-20 year life expectancy and should be treated that way. It’s different for someone with complications. More and more people with type 1 diabetes are surviving into the elderly years.

Q: How do you deal with adolescents with type 2 diabetes? We’re seeing that more and more.

A: That’s also a special population that has issues around medications, weight, and often genetic factors that predispose them to the disease. There’s less information, so we extrapolate from other trials. We do know when adolescents get diabetes and they’re at long-term risk, they tend to get complications earlier. You need to be aggressive.

Q: Do you have special education programs for adolescents? Does that help?

A: We don’t. It’s a great idea because they won’t sit around in a typical type 2 diabetes group and learn about management in the same way. We should target them and individualize therapy and education.

Comment: If you look at the data from TODAY, adherence rates among 14-17-year-olds drop to 30% after one visit.

Q: Does heart failure increase hypoglycemia risk?

A: Heart failure is an important comorbidity of type 2 diabetes, and it works both ways. Diabetes leads to heart failure and heart failure can lead to diabetes. It is associated with increased hypoglycemia risk, particularly with sulfonylureas and insulin. That’s a particularly dangerous combination because heart failure patients are at increased risk for sudden cardiovascular death. Toss sympathetic activation on top of that and you’re asking for trouble. We have to treat them with particular care.

Corporate Symposium: Evolving Perspectives in Treating Diabetes and Obesity (Sponsored by Novo Nordisk)

Hypoglycaemia Anno 2015: What We Have Learned

Simon Heller, MB BChir DM (University of Sheffield, UK)

Hypoglycemia expert Dr. Simon Heller challenged the conventional wisdom that severe hypoglycemia is on the decline, noting that the rates reported in clinical trials are significant underestimates compared to those seen in real-world practice. He reminded the audience that patients with type 1 diabetes or longstanding type 2 diabetes develop an impaired glucagon response and reset their threshold for sympathetic activation in response to hypoglycemia, meaning they already have significant cognitive impairment by the time they become symptomatic. He reviewed the association between severe hypoglycemia and mortality seen in several studies while acknowledging that this is a very controversial area. In terms of how to address the problem, Dr. Heller pushed back against the assumption that all patients need expensive new technology, noting that studies such as HypoCOMPaSS demonstrated equal improvements in hypoglycemia awareness and prevention with MDI vs. pump therapy provided both groups received equally thorough education and training.

The diaTribe Foundation Forum: Solvable Problems in Diabetes

Quotable Quotes

On Guidelines...

• “Right now, the status of guidelines is like a cookery book with a list of ingredients but no recipes. We don’t have the evidence to make the best choice for the patient in front of you at the right time.” – Prof. Holman
• “In terms of the methodologies to help doctors understand which tools to use for whom, the gaps are enormous. We treat diabetes one case at a time. There’s enormous heterogeneity in this disease – both in type 1 diabetes and type 2 diabetes. It’s bewildering, the degree to which one has to confront a number of questions for which we have very little insight and few tools for clinicians.” – Dr. Gavin
• “On the other hand, relying on guidelines alone isn’t the answer. You don’t want to be a doctor that’s just a robot that brings patients down a path that’s telling you what to do at every fork. Because that would get rid of any exercise of clinical judgment. My younger colleagues are not enthusiastic about that. They’re sitting in their offices with all these charts hanging on the walls. There are guidelines for everything and all they have to do is to take the patient down these paths. That’s true destruction of clinical judgment.” – Prof. Ferrannini

On Investing $500 Million in Diabetes...

• “We’re spoiled for choice with so many treatments, but we don’t know how best to use them. Doing studies that are guideline changing, that put into context their relative merits and benefits, would be helpful. That’s not the sort of money you get from industry, and governments are not keen to fund long-term outcome studies.” – Prof. Holman
•  “I would invest it in prevention, because it’s quite clear to me that we are managing diabetes better than we have in the past.” – Prof. Ferrannini
•  “The Claude Bernard Lecture was timely by emphasizing that preventing diabetes is the way to go. We have a lot of people with diabetes that already need our help but it’s the next generation that faces a diabetes tsunami that needs to be stopped.” – Prof. Holman
• “Prevention is going to be fantastic and we’ll dance in the streets. But it will be a bigger dance when clinicians don’t have to worry about what to do with what and for whom.” – Dr. Gavin

On EMPA-REG OUTCOME...

• “This is truly exciting – getting a superiority trial that is positive ... If you have diabetes, even if you optimally manage the risk factors, you can’t get back to the non-diabetic cardiovascular risk level. That’s extremely unfair and people with diabetes deserve better  – if this drug can help, that’s great.” – Prof. Holman
•  “I think we need to be thoughtful about what the outcomes really mean and not rush to sound bites that more often than not get us into trouble and lead to limitation of thinking, not broadening.” – Dr. Gavin

On Next-gen Therapies...

• “I don’t invest too much hope in any one drug to save us. That won’t happen. And that’s fine, because the complexity of diabetes will defy us. A complementarity of treatments will be required to address the pathophysiological complexity of diabetes ... But there is great hope. Grow the classes, show how they can marry and cohabitate. And there will be great outcomes and glory! And polygamy!” – Dr. Gavin
• “...we have learned so much more about use of insulin in recent years, that insulin has almost become a new drug.” – Prof. Ferrannini
• “I continue to harbor the notion that the inventiveness and creativity of humankind will allow us to master technology, electronics, and gadgetry more quickly than we master biology. My optimism is that there will be strides toward development of effective closed loop systems. My pessimism is that they will be for a very narrow band of patients.” – Dr. Gavin

On a Positive Note...

• "When I started in diabetes, a patient with type 2 diabetes had an estimated loss of life of around 15 years. Now that is probably down to about 3 to 5 years." – Prof. Holman
• “...we don’t have to go all the way. We just have to do it a hell of a lot better than what we’ve been doing.” – Dr. Gavin
• "I’m definitely more optimistic about the future of prevention, not only because we’re beginning to understand the underlying disease processes, but also because society is waking up to the problem and beginning to do something about it.” – Prof. Holman

Themes

• How would panelists invest $500 million in diabetes? Prevention and “guideline-changing” studies:
  
  • Speakers were unanimously negative on current treatment guidelines, citing the major lack of evidence on what to prescribe when and for whom. The most memorable analogy came from Prof. Holman, who described guidelines as being “like a cookery book with ingredients but no recipes.” Prof. Ferrannini was even more frank: “Don’t believe guidelines.” Panelists expressed pleas for studies that can help providers make the best treatment choice for a particular patient at a specific time – not simply yield a list of available medications in a vague order. Unfortunately, said Prof. Holman, these “guideline-changing” studies, as they call them, are unlikely to be funded by governments or industry. Indeed, he believes even the GRADE study is lacking in some respects (notable commentary, given that he was on the trial’s advisory board from the start): “It was a great attempt, but it was too short and not big enough. We need to do that trial but on steroids.” Prof. Ferrannini brought up an additional factor that will become increasingly important as algorithms are further developed and “get smarter” – will analytics erode clinical judgment? For example, if IBM’s Watson can suggest the perfect therapy based on a patient’s entire medical history and all the available literature, where does that leave doctors? An optimist would say smart analytics will augment doctors’ natural abilities and free them to focus on other issues (e.g., behavior, mental health); a pessimist believes computers will largely replace doctors. The truth is probably somewhere in the middle according to the panelists, and given the current shortage of healthcare providers, what are the alternatives?
    • Dr. Gavin captured the complicated politics of guidelines well: “When we have even partial answers, the guidelines constantly tell us to individualize, individualize, individualize. Yet we are sort of trapped by this reductionist narrative in terms of the way the guidelines direct us. They avoid being hierarchical so they don’t offend anyone. If they’re not at all hierarchical, they’re simply a series of options, and I don’t know if that is always the most informative way to help clinicians struggling with the fundamental questions.”
  • There was clear interest in investing in diabetes prevention, and panelists highlighted and emphasized the importance of Dr. Hans-Ulrich Haring’s Claude Bernard Lecture on the phenotypes of prediabetes. As background, the Claude Bernard Lecture is a very big deal – the equivalent of the Banting Lecture at the ADA. Prof. Ferrannini stressed the need to define sub-phenotypes of prediabetes and develop new targets that can personalize prevention efforts. We found this exciting, considering that lifestyle intervention (and metformin to a lesser extent though it’s not approved for this purpose in the US) is really the only mainstream approach for treating prediabetes at present. As Prof. Holman pointed out, we are finally unearthing the scientific evidence necessary to support the prediabetes rhetoric – the challenge now is translating this work into practice (therapies and technologies and behavioral approaches) and convincing payers that the benefits of “treating” prediabetes far outweigh the risks. Panelists did not mention digital interventions for prediabetes or obesity pharmacotherapy, though emerging data suggests potential for both.
• Panelists offered tantalizing predictions of the EMPA-REG OUTCOME full results that – in retrospect – trended slightly on the optimistic side for the primary risk reduction: Dr. Gavin at 30%; Prof. Holman at 18%; and Prof. Ferrannini at 15–25%. The actual figure was a 14% risk reduction for MACE, the primary outcome; in hindsight, we should’ve asked the panelists their opinion on secondary outcomes. Most in the audience concurred with the mid-teens to low-twenties predictions. Speakers agreed that a diuretic effect was a potential explanation for the benefit, though they also cautioned against over-generalizing from the results of one trial and didn’t know ultimately whether the result would indicate a class effect. Dr. Gavin was particularly emphatic on this point: “I think we need to be thoughtful about what the outcomes really mean and not rush to sound bites that more often than not get us into trouble and lead to limitation of thinking, not broadening.” Despite this, panelists did demonstrate some prevailing bias toward a class effect, with both Dr. Gavin and Prof. Holman suggesting that SGLT-2 inhibitors may become the standard second-line therapy and in fact some have asked whether it should be first-line therapy in some populations. Certainly, the clinical and commercial impact of the results will be interesting to watch; unquestionably, the overall sentiment is that guidelines committees (and payers) will want to wait for results from the other SGLT-2 inhibitor trials before designating the class as the preferred second line option.
• Dr. Gavin reflected on the need for a “complementarity of treatments” to address the pathophysiological complexity of diabetes. This was a common refrain throughout the evening: that neither drugs nor technology alone holds the solution to diabetes care. Of course, the task of integrating care is a tall order, though all three panelists were optimistic that we are closer to multifaceted models of care than ever before. We also loved the perspective that for the many challenges in diabetes, the field currently understand what does NOT work for patients better than it ever has before. That’s something to hang your hat on!
• Panelists also debated the progress of closed-loop development, emphasizing to attendees the importance of managing sky-high expectations. As systems near commercialization, we were reminded of the importance of considering the design elements that will maximize benefit and assure safety. Dr. Gavin stressed that artificial pancreas technology will not be appropriate for all patients when it arrives on the market – Will it only be early adopters who try it? For whom will it be financially accessible? There are big psychosocial questions that also remain that were pointed out: how large is the patient population willing to hand over complete control to a device? How much extra equipment will users need to carry? On the latter question, we believe it won’t be much or any at all for current pump and CGM users; for MDI users, on the other hand, a lot of extra stuff at the start!
• Notably, the importance of public-private partnerships in healthcare and diabetes also emerged as a key theme. We appreciated Prof. Ferannini’s reflection on the value of allowing more avenues for industry, academia, and patients to interact with each other. There was clear consensus that increasing collaboration is needed, though still a lot of uncertainty about how to get there … especially in the US. As a reminder, we received an introduction to the Accelerating Medicines Partnership (AMP) in Type 2 Diabetes at ADA 2015 that represents a step in the right direction. We’d love to see more of this kind of approach moving forward.

Panel Discussion

Kelly Close: Thank you so much to all of you for being here this evening. It is so meaningful to us. We salute your families for giving you so much support in your work, as you are true visionaries for our field. Please thank them from us. To start – this is very exciting. What has struck you the most at EASD 2015? What has moved you here in Stockholm?

Prof. Ele Ferrannini: I heard the Claude Bernard Lecture, and I thought Dr. Hans-Ulrich Häring did a superb job. He’s taken the knowledge of the science from the cellular to the genetic and all the way to the phenotypes. He’s begun to identify specific changes in physiology in muscle and brain tissue – he only left out the gut, likely because of time. He’s begun to put this into the scientific terms towards what we are all taking about: individualization. This is what we try to do with our clinical judgment every day.

Dr. Rury Holman: I would say, even preceding the Bernard Lecture, was the address by Andrew Boulton which I thought was amazing and detailed the achievements of the EASD which is just over 50 years old. Andrew demonstrated the power of a group of academics who first met in the small town of Montecatini in 1965 but had the ambition that together they should start a diabetes group. It was slow progress, but what’s come out of it is extraordinary. Now, with the availability of European Foundation for the Study of Diabetes funding we have the power to do research in an academically driven way with the help of industry. The Claude Bernard Lecture was timely by emphasizing that preventing diabetes is the way to go. We have a lot of people with diabetes that already need our help but it’s the next generation that faces a diabetes tsunami that needs to be stopped. I thought what was really interesting was data that goes all the way back to the womb – detecting changes in utero induced by elevated glucose levels. We should be worried at how early these changes are occurring and Dr. Haring now has the science to underpin this process with his scientific expertise.

Dr. James Gavin: Solving the problems of diabetes is no small task. I was in the exhibit hall for a bit today and I was so happy to have time to go in and look around. For example, I went to a session on newer insulins. Some of what I learned there I was already exposed to, such as the research on super rapid-acting insulin and the degree they’re likely to make a difference in patients’ lives. So we can hopefully ultimately approximate what you hope to accomplish with the artificial pancreas. I am absolutely struck and impressed by what I’ve seen in terms of development and capabilities that will allow us not to chase blood sugars but to treat what glucose levels are coming and to avoid them. The coming of new technologies will allow us to engage patients, so people won’t have to be reminded that they have a disease hour by hour, day by day. These technologies will allow people to live their lives and come back occasionally for therapeutic treatment.

Ms. Close: Thank you. I love hearing what’s most exciting to you. And now I’d like to move the conversation in a high-level direction. We saw in the US that the Robert Wood Johnson Foundation gave $500 million to fight childhood obesity – that’s adding on to another $500 million for childhood obesity several years ago. The influence of Dr. Gavin played a major role here. If the three of you could work with any foundation who was set to give $500 million to diabetes, in what area would you advise them to work?

Prof. Holman: I’m biased as a trialist. The issue is we’re spoiled for choice with so many treatments available, but we don’t know how best to use them. Doing studies that are “guideline changing”, that put into context their relative merits and benefits, would be helpful. That’s not the sort of money you get from industry, and governments are not keen to fund long-term outcome studies. I’m not talking about cardiovascular outcomes. I’m talking about which treatment works best for which people, when we should we start, who should use what and in what order. If I were blessed with that money, I would look at guideline-changing trials.

Ms. Close: That’s so interesting, Professor Holman – before we move on to the others, as a quick follow-up, could we ask how you feel about the GRADE study?

Prof. Holman: I must declare a conflict of interest. I was on the original study design team. I think it was a great attempt, but it is too short and not big enough. We need to do that trial but on steroids.

Prof. Ferrannini: I have difficulty in even fantasizing about this kind of money to invest in diabetes. You know, if that became true, I cannot even tell you what I would do with that money [laughter]. Ultimately, I would invest it in prevention, because it’s quite clear to me that we are managing diabetes better than we have in the past. We heard from Dr. Andrew Boulton earlier today that diabetes is no longer the primary cause of blindness; we’ve seen in the New England Journal of Medicine recently (Gregg et al., 2014) that complications have fallen to 50% of what they were; and clearly, the survival and the quality of life for patients have improved. However, we just cannot cope with the number of new cases. For that, we can only use prevention. And for prevention, we have to refine our tools to ensure that the people getting treatment are the ones who need it.

Dr. Gavin: I have had the gratifying experience of knowing that such a fantasy could happen since I spent 12 years on the Robert Wood Johnson Foundation. Seeing us get that funding, I think this can actually happen. Now, I would hope that we would be able to split the $500 million into at least two parts. I think prevention is absolutely one of those frontiers that we need to continue to push forward on. Also, I think we’re getting closer to the point where we can differentiate the different forms and stages of diabetes in ways so that we can use our tools most appropriately. Prevention is going to be fantastic and we’ll dance in the streets. But it will be a bigger dance when clinicians don’t have to worry about what to do with what and for whom. It’s a great conundrum.

Ms. Close: Thank you for these fascinating impressions. On a bit of a different front, Jim, you alluded to different therapies and technology. How much are these helping doctors and nurses? Is that a frontier we’re moving toward? Helping health professionals better understand what therapeutic tools patients need when?

Dr. Gavin: In terms of the methodologies to help doctors understand which tools to use for whom, the gaps are enormous. We treat diabetes one case at a time. There’s enormous heterogeneity in this disease – both in type 1 diabetes or type 2 diabetes. It’s bewildering, the degree to which one has to confront a number of questions for which we have very little insight and few tools for clinicians. When we have even partial answers, the guidelines constantly tell us to individualize, individualize, individualize. Yet we are sort of trapped by this reductionist narrative in terms of the way the guidelines direct us. They avoid being hierarchical so they don’t offend anyone. If they’re not at all hierarchical, they’re simply a series of options, and I don’t know if that is always the most informative way to help clinicians struggling with the fundamental questions.

Ms. Close: That’s so well said. I want our doctors and nurses to feel more successful themselves. Along those lines, can I ask broadly about how you all define success in your own careers? This is so important for all generations here to hear, especially the youngest.

Dr. Gavin: In childhood obesity, defining success has been fairly easy. At the end of the day, we want to see the trend reverse and to see a new level set for the prevalence of childhood obesity. This is about diabetes prevention. This strategy hits multiple touch points – it touches childcare, it touches the messages kids are getting, etc. And all those touch points affect not just kids, but their families. And all those things affect diabetes.

Ms. Close:  That goes back to the Claude Bernard Lecture from this morning about how work with children doesn’t start at zero, it really starts nine months earlier right after conception. Thank you, Dr. Gavin. What would you say, Professor Holman?

Prof. Holman: I think defining success is actually making a difference. I have had the extraordinary opportunity to work with people in so many different countries to try to get definitive answers. It goes back to what Jim was saying about guidelines. I don’t think people are afraid to make comments, but it remains an area of ignorance without the evidence base needed. Right now, I’m striving to move from simple outcome studies to trials that can inform the relative impact of treatment strategies on the person, the payer, and the physician. Meanwhile, we need to pull together all the information in our rich toolbox, including digital tools and computers, to make it more accessible to people with diabetes. It’d be great to have a physician with unlimited time who can make wise choices for them, but sadly for many people are lucky if they are able to see a physician. We need something that can help support diabetes management at the patient level – and something that means they don’t have to obsess about managing their diabetes every minute of the day.

Ms. Close: I think it’s great we’re getting help from friends who are in technology. If you look at the innovation over the last couple of decades, that’s absolutely where it’s been. What about you, Professor Ferrannini?

Prof. Ferrannini: I may be less ambitious than you guys. [Laughter] As a researcher, success is when a paper gets accepted. [More laughter] Which doesn’t happen all the time. As a physician, success with a diabetic patient is when I can find the time – not the eight to ten minutes the healthcare system allows. Success is the first time I can spend the time necessary to explain the disease. Patients have probably been on the web, they have all sorts of information, and you can explain what diabetes is about. It shouldn’t be frightening, but you should explain the risks and complications. That initial imprint on the patient and on the family is the time when you are doing all that is possible to put in the most promising premise for future management suggestions. It’s a bit like what you do with infectious disease. You don’t say, “Take some of this antibiotic and then come back in three days.” You treat it aggressively immediately, and I think that’s what needs to be done in diabetes. I think that’s what’s needed to gain adherence, and I feel success when I have that time and he comes back with better control. If he’s obese, my success is if he loses weight because we know obesity is a major risk factor for diabetes and diabetes is the daughter – though not the only daughter – of obesity.

Ms. Close: I’d like to talk about governments around the globe. I’m really curious since you’re all advising them. Who is doing the best job? Who are you most impressed by? What can the EU learn? What can the US learn? Tell us some stories about interacting with policymakers and the biggest payers.

Dr. Gavin: I recently came back from an interesting tour of South Africa and had a chance to speak at length with payers and policymakers about diabetes in particular. At the end of those eight or nine days, I came back home with the conclusion that our doctors are doing a wonderful, fantastic job in the US. I stopped complaining so much because there was resistance from payers to novel therapies in South Africa, the likes of which I hadn’t encountered in a long time. I can’t speak for many governments or payers, but the largest of payers in South Africa have enormous resistance to novel therapies, seeing no benefit in those offerings beyond traditional therapies. Therefore, there’s no chance of achieving the necessary level of patient engagement in diabetes. It’s just not going to be done. It also reminds me that the information and awareness needed to change diabetes is lacking. I think that’s one extreme.

Now I’ll contrast that with a fascinating conversation I had with Dr. Griffin Rogers, the head of the NIDDK. I was just so thrilled to hear about one example of government-industry partnerships, and some of the partners involved are on this board. They’re looking at ways in which to take the burgeoning field of proteomics, genomics, metabolomics and to make big data available in a place that’s accessible. And they want to make it accessible to anybody that needs it for advancing work to continue to move forward on issues like differentiation of diabetes, appropriate phenotyping, staging, and the designation of who needs what. To see what’s happening here, it’s not with the goal of a proprietary outcome but making available all this data that’s already here but organizing it in such a way and presenting it in a way that the public, and I mean the public globally, can access it. That is the kind of thinking and action I’d like to see characterize governments everywhere.

Ms. Close: We look really forward to hearing more about that. On a different front, it is also so instructive in diabetes to look at what’s happening in other therapeutic areas. Interestingly, when other areas are having breakthroughs like hepatitis C for example, it is effectively hurting diabetes because payers are stressed about investing in their most significant ROIs – the ROI for diabetes spending effectively goes down when there are breakthroughs in other areas. So I love the point about presenting things more compellingly in diabetes, and ideally with more focus on systems and behavior change, we can see more of that.

Dr. Gavin: One of the things I would emphasize is on public-private partnerships. Because when I think about the amount of data we’re getting in, it’s too big. Someone other than the government is going to have to take the lead in gathering that information and making sure everyone’s interests are appropriately tamed – so that people do not feel they are giving in to someone else – for the greater good. It’s up to someone other than government to take the lead in that.

Prof. Ferrannini: I would have a word of caution with that. Big data can be used for different purposes and should be for the benefit of the people. And there are already striking examples of that. On one hand, it’s good to pull data and to have some way of accessing and analyzing it. But I believe that this is a process that should be controlled. Perhaps by the government, but even better by a synergy with all different stakeholders, including industry, academics, payers, patient reps, and insurance companies. I’ve had a brief experience thinking about this shared risk approach to developing new drugs because industry takes a lot of risks. Perhaps stakeholders should be part of this process very early on. Reps of patients, for example, would say that this injectable would not go far. The biology is interesting and the data can be promising and a therapy can lower A1c. But patients may not take it up as people would think. So I think big data should be controlled.

Dr. Gavin: I share your caution. My point on the government taking the lead is very different from the government taking control. I think the trouble is when there isn’t appropriate input, we need appropriate input from all stakeholders. Big data needs to be seen as a potentially enormously valuable resource and it needs to be harvested. But as with every resource, there is potential for great good and for great harm. We need to learn from the lessons of being burned badly.

Ms. Close: It’s interesting to think about how to bring people into government. Many leaders in tech in the private sector who’ve done very well are being asked by President Obama to come work on technology in the government – this was true for example of the great Megan Smith at Google who is now the White House’s Chief Technology Officer and basically “on loan” to the government if I understand it right. It is a great example of service that high tech is giving the US government. There was a piece in Wired about this that was quite a compelling model for healthcare although our sector just doesn’t yet have the health that high tech does; yet and still, with all the incredible commitment and mission-driven approach by young leaders today, I think there’s a lot of really good models we can think about with government on people moving to work for even a short time in the public sector on healthcare.

Prof. Holman: Back on systems, there are many examples I could give you from different countries, but I’ll talk about China. We’ve worked there for nearly eight years, and in that time while we’re concerned about the diabetes epidemic in US, they’re racing ahead. It’s interesting to see how they choose to deal with it. It intrigued me that they understand that type 2 diabetes is a societal problem, not just a medical one. They have perhaps a more balanced view, which some may feel is less empathic, but is realistic with concerns for potential problems for both the health and the wealth of the country. In a one-parent family society, the impact of diabetes can be greater if the only child has to take time off work to care for a parent. Diabetes management may have to be driven more by economics than some would like but that’s the reality.

The conversations we’re tiptoeing around in the UK at present are about whether we should pay more for cancer drugs that give a slightly extended period of life for very sick people, or to invest more in other disease areas. This is becoming a stark choice in China where over 35% of people are diabetic or have pre-diabetes and there are few primary care physicians. The Chinese government is now taking a robust approach, driven by the metrics, to come up with a three or five year plan to address the diabetes issue.

Ms. Close: That’s amazing to hear. In China, what will we see on that three to five year trajectory? What’s different there about the approach?

Prof. Holman: I think the perspective over there is realistic. They have the data and they see the problem. You know, there was a publication in the NEJM a few years back (Yang et al., 2010) that was a bit of a wakeup call with regard to the prevalence of diabetes. Instead of just worrying about it, they repeated the study (Xu et al., JAMA 2013) and found that the number of people at risk had gone up! Managing the emerging number of people with diabetes poses a major problem given that healthcare is provided mainly through hospitals. In the face of their diabetes epidemic, China is exploring alternative strategies with a greater emphasis on more locally provided care – something that is being trialed by the Beijing Diabetes Community Study which I help support.

Ms. Close: Thank you so much for that. Now, I want to move to thinking about EMPA-REG. I wonder what you think of the potential impact of therapies that are cardioprotective and renoprotective. When I saw the original press release a few weeks ago about empagliflozin and cardioprotection, I started to weep because I thought about what this could actually mean and what the impact could be. All of these therapies will be generic one day (at least the orals, presumably) and we won’t have to be worried about access and patients could do significantly better globally. Can the three of you speak to these results? What are major things you’ll be looking for? Are these class effects? Will these therapies be disruptive? And specifically, on Thursday, what kind of risk reduction are you looking for? [Note – it wasn’t specified but “primary risk reduction” was understood.]

Dr. Ferrannini: I think that the press release has already made a big splash, so one can only be disappointed [joking]. And I have no idea because it’s two doses so we’ll just have to wait to see whether it’s just the higher dose, if it’s due to a subgroup, or whether it’s because of effect size. And I presume that most people would think that the results would be applied to the class rather than a single agent. And clearly, they’re going to make a lot of noise about it. This is the first CVOT that has shown protection. One must say that there was biological plausibility, which was probably better than the other single drugs that have been tested. The intrinsic changes with weight loss and blood pressure are major players and they’re convincing.

Prof. Holman: This is truly exciting – getting a superiority trial that is positive. Until we see the data, it is difficult to generalize about the results. Presumably the effect size is going to be larger than the usual 15%. We have seen UKPDS data before for metformin that demonstrated cardiovascular positivity. We did see in the PROactive study that their secondary endpoint suggested a cardiovascular benefit. When we simulated their results using the UKPDS Outcomes Model, the cardiovascular benefit was fully explained the pioglitazone induced changes in multiple risk factors. We need to understand how an SGLT-2 inhibitor can have a beneficial cardiovascular effect and whether, as is most likely, it is a class effect. Improving glucose control has led to a massive reduction in microvascular disease – triggered by DCCT and UKPDS. Retinopathy is no longer a major cause of blindness. Optimising glucose control goes a long way to stopping microvascular complications but there is only a modest impact on macrovascular complications. The EMPA-REG data are exciting because people with diabetes remain at twice the risk for macrovascular disease even when treated to target with current therapies. If an SGLT-2 inhibitor can help even up these odds, that’s great.

Dr. Gavin: I have very little to add. I’m obviously as excited as anyone about the data, and I hope that whatever they are, they don’t diminish the importance of us continuing other conversations in diabetes. This in no way implies that we don’t continue to push as hard as we can on the prevention front. The fact is that the need for individualization of therapy will remain. Everybody affected by this disease has higher risk, and they’re not all appropriate candidates for this class. Many other therapies with potential will continue to develop data on their contributions to outcomes. I think we need to be thoughtful about what the outcomes really mean and not rush to sound bites that more often than not get us into trouble and lead to limitation of thinking, not broadening.

Ms. Close: I can’t wait for Thursday and to hear the results across the board. Thank you for these comments. We are going to start the “Lightning Round” (quick answers to quick questions) now, while all of you in the audience think about your next questions to our experts.

Lightning Round

Ms. Close: How would you rank your enthusiasm for the artificial pancreas on a scale from 1 to 10?

Dr. Gavin: 5.

Prof. Ferrannini: 5.5.

Prof. Holman: 6.

Ms. Close: What is most likely to become the standard second line therapy?

Dr. Gavin: SGLT-2 inhibitors.

Prof. Ferrannini: GLP-1 agonists.

Prof. Holman: I think GLP-1s are in a favored position. You did mention the Intarcia implantable device earlier. With that being by design a 100% compliant therapy, their data there could be become persuasive especially if the ongoing GLP-1 outcome studies are positive.

Ms. Close: For combination therapy, which combination are you more excited about? Basal + GLP-1? Or GLP-1 + SGLT-2?

Dr. Gavin: GLP-1.

Prof. Holman: Depends on the stage of disease. If it’s in the middle or end stage of the disease, I think both combinations have great promise.

Prof. Ferrannini: I agree.

Ms. Close: What risk reduction percentage is most likely in the EMPA-REG Outcome Study?

Dr. Gavin: 30%.               

Prof. Holman: 18%.

Prof. Ferrannini: In the range between 15%–25%.

Ms. Close: What do you think is the right first injectable for patients who are not at target? Basal insulin and GLP-1 combined? Once weekly, injectable, or basal only?

Dr. Gavin: I say incretins before insulin. This is all based on where you get the patient and at what stage. You lose none of the subsequent options, but incretins before insulin.

Prof. Holman: For a patient with reasonable beta cell function, use an incretin first. If they don’t have that, then insulin.

Prof. Ferrannini: I think that starting with a combo early would be promising, if the data shows they need it.

Ms. Close: Would you say that you are more or less pessimistic about strides that could be made on the prevention front relative to five years ago?

Dr. Gavin: I’m more optimistic. I guess that makes me less pessimistic [laughter].

Prof. Holman: I’m definitely more optimistic, not only because we’re beginning to understand the underlying disease processes, but also because society is waking up to the problem and beginning to do something about it.

Prof. Ferrannini: And I agree!

Ms. Close: Let’s go back to the closed loop that we spoke about briefly at the start of the Lightning Round. How optimistic should we be about automating insulin delivery and the future of the closed loop?

Prof. Ferrannini: Well the idea of closed loop has been around for very long. I think there are some fundamental problems with it, so I don’t have the highest levels of optimism. There’s the difficulty of monitoring for long periods of time and accurately, but also because one way or the other, you’re going to be providing insulin in the peripheral circulation and that is not the physiological route. There is very little that can be done with other transplantations. So I’m moderately optimistic.

Prof. Holman: So it’s been a battle for years. We worked on it and other people worked on it. Insulin is one of the drugs with the narrowest therapeutic window. It’s got to be ultra-safe 24/7, 365 days a year. I think we’re some way off from doing it. I don’t think it’s impossible, but the current technology is not robust enough – maybe five to ten years down the line.

Ms. Close: Well, we’re going to have to go back and talk to technology companies about what they can do.

Dr. Gavin: I continue to harbor the notion that the inventiveness and creativity of humankind will allow us to master technology, electronics, and gadgetry more quickly than we master biology. My optimism is that there will be strides toward development of effective closed loop systems. My pessimism is that they will be for a very narrow band of patients.

Ms. Close: I’m curious if you say that meaning narrow for those that can benefit or narrow for those that can access it? We’ll come back to you on this! Professor Ferrannini?

Prof. Ferrannini: There are also some promising developments in dual hormone control because the major problem with insulin is obviously hypoglycemia. And also the fact that a lot of patients with type 2 diabetes don’t need insulin – they’ve got plenty of it. They just can’t put it out in a timely fashion.

Ms. Close: I remember when CGM was just in its nascent days. I saw JDRF really encourage companies to work together. That was when technology was so much worse than it is today. A lot of things had to go right to make improvements happen. Sensors were not accurate; algorithms were not good enough; and insulin was too slow. Now, we’ve got better sensors and smarter algorithms, but the speed of insulin has not changed. How do you feel about smart insulin, technically speaking? Of course, we know access is always a big issue.

Dr. Gavin: Part of the session I was in today had presentations about smart insulin. I think it will align well with the technology and newer algorithms that we’re trying to implement without the serious limitations on the effectiveness of other developments.

Prof. Holman: Smart insulin is a closed loop system in a syringe. In people with type 2 diabetes the insulin dose is less critical, any insulin is better than none, but the challenge is in type 1 diabetes – you need to have the dose precisely right at all times. Smart insulins are probably also going to struggle with rapid responses to meals. I think we’re always going to be in a situation where type 1 diabetes will have different challenges.

Ms. Close: What technology will be the biggest game-changer in the next ten years in developing countries?

Prof. Ferrannini: Making management more accessible. There are large areas in Africa where the situation is completely different from China. I don’t know much about China other than that I don’t like their food. [Laughter] But in Africa, I’m told that the major problem is access to treatment, even just basic treatment like insulin or any oral. I think technology would be like eating dessert before dinner.

Prof. Holman: Access to treatment is a much greater issue than technology. In some parts of Africa if you do a consult on a patient for insulin, often the choice is not what regimen is preferred but what if any insulin there is in the pharmacy that week. We’re not even at the stage of discussing technology, it’s having people and resources to provide what is in fact a lifesaving drug.

Ms. Close. Thank you, such fantastic insights. We’ll now open up the floor for Q&A.

Audience Q&A

Q: I want to return to the closed-loop discussion. Could you elaborate? Do you think algorithms will overrun the need for glucagon? How do you see insulin evolving? How do you see the technology developing in this space?

Prof. Ferrannini: The basic algorithms have been there for quite a long time. We can account for every drop of glucose in the blood. What we can’t do is change the way we deliver insulin and the onset and offset time of insulin. Remember, it takes time not only for insulin to be absorbed but to exert its primary effects at the cellular level. Even If you reduce the dose, it takes time for the insulin at the receptor to stop working. It has to do with complicated cellular kinetics. That’s why, I think, having glucagon available is a sound idea. Whether it’s workable, I’m not sure.

Prof. Holman: The delivery of insulin is always a tricky problem. The best insulin will never be perfect. People do strange things and they can outwit the algorithm. Having glucagon as backup helps in those life or death situations. I think it’s really important to have that back-up system but do understand that it does add complexity and cost. If you have insulin in the right place with instantaneous algorithms, that could be perfect but for now we continue to give insulin peripherally. There is also a medical and legal issue – if things go wrong with an automated delivery system, who gets sued? The software engineer, the physician prescriber or the educator? It’s a difficult area.

Prof. Ferrannini: I also think that we have learned so much more about use of insulin in recent years, that insulin has almost become a new drug. The contrast between long-acting and short-acting insulin, and not to speak of the possibility of smart insulins – that would be transformative.

Dr. Gavin: The partnering of insulin with other molecules has enormous potential.

Dr. Robert Vigersky (Medtronic, Los Angeles, CA): The title of this was “Solvable Problems,” and I’m heartened by the optimism of the panel. But are we going to solve it before it bankrupts the economy?

Ms. Close: I’m going to defend our title. We were going to call it addressable problems, but it doesn’t quite have the same ring to it as solvable problems! [Laughter] Listening to you talk about cardioprotection, that’s such an exciting approach and could be lifechanging – but we’ll always hear complaints about expensive drugs or technology as if those are the major problem areas. It’s the heart attacks and strokes and patients being in and out of the hospital driving the cost curve up!

Prof. Ferrannini: The problems are solvable to the extent that we understand the potential for the solvable better than we did years ago. The research efforts ongoing in -omics that you mentioned are very helpful. Whether it’s actually solved depends on money. We had heated discussions in Italy where the healthcare system is public and regional. The discussion was if you had a monoclonal antibody that cured hepatitis C, every citizen will raise their hand and say I demand to be cured, and that would run the system bankrupt. Another example is cancer. Cancer drugs are extremely expensive and on top of what the old drugs do, any new drug only guarantees an extra week of life. What if it rains that week? [Laughter] This is in contrast to the notion and the data we’re accruing that we can actually prolong the survival and quality of life in diabetes but we have to wait 20 years. The metrics to allocate resources here or there are not there. You can’t compare the metrics of a cancer drug with a statin, the benefit of which will be seen 20 years down the line. It becomes a societal problem, an economic problem.

Prof. Holman: It’s a very real problem. There is a limited size cake and different countries cut it differently. We have NICE in the UK, and some people feel we weigh cancer vs. diabetes patients somewhat unfairly. However, I’m optimistic because all this effort means we’re developing new drugs that will be cheaper over time. The onus is on us to weigh outcomes appropriately. When I started in diabetes, a patient with type 2 diabetes had an estimated loss of life of around 15 years. Now that is probably down to about 3 to 5 years. We need to find a way to give a fair share of the funding for the facilities and strategies that work. There is never enough money for everybody, but this is about getting the playing field level. For people with diabetes, it has not been as favorable as it should be.

Prof. Ferrannini: The only thing is that we have to be careful of the economists because they’re very good at predicting things past. I haven’t seen many reasonable cost analyses. If that 15% reduction in cardiovascular outcomes were calculated, what would the cost savings of that be?

Prof. Holman: We have the UKPDS Outcomes Model that was developed with the help of health economists. What the model does is predict reasonably well what complications will occur in which people over time. If we did have a drug that reduces heart attacks or strokes, then you could simulate its impact over a longer time to estimate the cost reductions that might accrue. Governments, however, don’t like to think about five to ten years down the line because they’ll be out of office; so short-term thinking remains a big problem. If you think in the longer term, you can ultimately save money or not spend as much.

Ms. Close: One thing on that point: Let’s get the data. It’s much easier to get that data today. Being able to show how people with diabetes are really doing is so important.

Dr. Gavin: It’s a critical question, and I do have optimism that we can bring some solvability and some solution to these problems before they bankrupt us. Because we don’t have to go all the way. We just have to do it a hell of a lot better than what we’ve been doing. We need more pressure, and we need to get rid of the drain these problems are causing us. If we can achieve cardioprotection, stroke protection, delay of dialysis or transplantation … that’s something that is possible with our tools and with algorithms appropriately used. Something like that would go an enormous way in terms of the economic stress. And in many of those instances, we can get there.

Prof. Holman: Don’t lose faith, the problems are solvable. The strides being made are phenomenal. For instance, it’s been two years since I have sent a patient to a renal unit. Things have gotten better but also more complicated. There are more battles to fight and we do need more money. I think collaboration is the word for me – we need industry, academia and clinicians to work collectively to solve the problems.

Q: We talked about microvascular complications, and we’ve made great progress. Is NASH a disease that should be adopted by the diabetes community as a non-paradigmatic diabetes complication and a problem of endocrinologists and diabetologists?

Prof. Holman: I’ll declare an interest because the last person we appointed to our Unit is a NAFLD expert. I think the concern about with NASH moving to hepatic cirrhosis may have been overstated but for the diabetes community we heard this morning that ectopic fat in the wrong place can create havoc. I suspect it generates more problems in the metabolic sphere than a few cases of cancer downstream. It’s enormously important.

Prof. Ferrannini: I think steatosis is relatively speaking no problem because it’s a consequence of insulin resistance in many cases. There are polymorphisms of some genes that produce accumulation of fat in the liver without insulin resistance, but it’s a very small fraction of the general population. It’s what causes the next step, fibrosis, that’s interesting. As I was discussing this afternoon, it’s crucial for research to understand the cases where you have fibrosis without steatosis. That will point in the direction of the second hit that will transform steatosis into NASH, which is at risk of progressing to cirrhosis and in a few cases cancer.

Dr. Gavin: And that brings us back to the question of the resources necessary to do that.

Prof. Ferrannini: The imaging tools we have are not good enough for fibrosis. They can tell us how much fat there is in the liver, but not how much fibrosis there is.

Prof. Holman: In our Unit, we are exploring a urinary proteomic test that will screen and stage NAFLD more effectively. It’s a new technology that does not require a biopsy.

Ms. Close: My last question is if you had just one single biggest advice for all of our amazing supporters, what would that be?

Prof. Ferrannini: Don’t believe guidelines. [Laughter] You know, I have a problem with guidelines because like it was said earlier, they give you the ingredients but not the recipes. And those recipes can’t be given because the evidence isn’t there. But they give a lot of info on the ingredients. You don’t want to be a doctor that’s just a robot that brings patients down a path that’s telling you what to do at every fork. Because that would get rid of any decisions of clinical judgment. My younger colleagues are not enthusiastic about that. They’re sitting in their offices with all these charts hanging on the walls. There are guidelines for everything and all they have to do is to take the patient down these paths. That’s true destruction of clinical judgment.

Dr. Gavin: I’ve developed an enormous respect for those working in diabetes. I don’t invest too much hope in any one drug to save us. That won’t happen. And that’s fine, because the complexity of diabetes will defy us. A complementarity of treatments will be required to address the pathophysiological complexity of diabetes. We’re now developing a pathway for a conundrum. But there is great hope. Grow the classes, show how they can marry and cohabitate. And there will be great outcomes and glory! And polygamy! [Laughter]

Ms. Close: What an amazing way to end this intriguing and very rich discussion. Thank you so much, Dr. Gavin and Professors Holman and Ferrannini – your thoughts on all of these complex subjects have been remarkably valuable. And thank you so very much to all of our supporters for tonight and to our teams – this would not have been possible without you.

Exhibit Hall

Abbott

Abbott’s distinctive yellow booth was packed with attendees’ enthusiasm for FreeStyle Libre, now one year out on the EU market. We did not glean any new insights, though tried our very best to learn about the US timeline for a consumer version – no dice (and not really any surprise). Much like last year, promotional videos and posters advertised the simplicity and convenience of the factory-calibrated technology: “You can do it during a movie”; “You can do it in a meeting”; “You can do it in public”; “You can do it on the dance floor”; “You can do it without lancets”; “You can do it anytime, anywhere”. Clever with a twist of innuendo – this company has really nailed the marketed on this product. A smaller component of the booth promoted the Ambulatory Glucose Profile software, which clinicians and patients both praised in Abbott’s symposium yesterday and which has impressed us quite a lot – boy has Dr. Rich Bergenstal worked hard on this and we’d LOVE to see this taken up by more so we can get more standardization going on. This lounge-like area featured a large-screen video presentation of the product and generated a surprising amount of interest in its own right. Yeah. They’ve got it going on. We also heard by the way that reimbursement in Germany (!!) was going quite well – that’s from our German blogger friends.

AstraZeneca

AZ boasted a sizable booth featuring its full diabetes portfolio and several interactive challenges for attendees, including the “type 2 diabetes challenge” (a delightfully tough quiz on diabetes statistics and pathophysiology that we thought was a very smart way to engage attendees) and a series of case studies complete with action figures to represent patients. Perhaps because attendees are on the competitive side (so many are doctors!), the booth was quite well attended. In what we thought was an intelligent approach, the positive (aka neutral) primary results from SAVOR were featured heavily in the promotional materials for Onglyza (saxagliptin), with large posters trumpeting the “demonstrated cardiovascular safety profile.” While the primary safety data was reassuring, the heart failure signal could hurt Onglyza to some extent relative to others in the class (particularly Januvia), especially since label updates are likely on their way. Consistent with most of AZ’s displays at recent conferences, the new Bydureon (exenatide once weekly) pen occupied the most space in the booth, with plenty of opportunities for demonstrations. SGLT-2 Forxiga (dapagliflozin) had a substantial presence as well; perhaps in anticipation of the upcoming positive CVOT results for competitor Lilly/BI’s Jardiance (empagliflozin), the promotional materials emphasized Forxiga’s positive effect on CV risk factors and reassuring safety data from phase 2 and 3 trials. In keeping with the cardiovascular theme, AZ also devoted a small portion of its booth to its anti-platelet drug Brilique (ticagrelor) – this is further evidence that focus on cardiology is building (good!) and the responsibilities for how to take care of patients and what a healthy patient looks like are becoming more critical (it’s about healthy hearts as well as healthy glycemic levels).Some would say the lines between diabetes and cardiology are growing blurrier – that may be, but we welcome the focus on all the components of a healthy “whole” patient (including mental health) and how to help get them there.

Bayer

Bayer was conspicuously absent from the Exhibit Hall floor, the only one of the Big Four BGM companies that did not invest in a booth at EASD 2015. The absence was not particularly surprising considering the company’s absence at ADA 2015 and the divestment of the Diabetes Care business to Panasonic Healthcare for ~€1.0 billion (~$1.2 billion) in June 2015. But we hope KKR will get with the program and invest some very needed R&D dollars into the next-generation technology. Although valuable Medtronic customers make up a lot of their users now, Medtronic wants to pull all of them toward CGM.

Dexcom

Dexcom’s booth in the far back of the hall advertised the newly CE-Marked G5 mobile system (“First fully mobile CGM”), which was announced yesterday in the company’s symposium (launching in the coming weeks in Europe). Signage highlighted the EU approval down to age 2 and the newly acquired replacement claim. Though G5 was under glass and not on formal hands-on display, a Dexcom rep let us play with a demo version of the new app. We’re very psyched for this. Our trial suggested a simple menu structure (Home, Trends, Alerts, Setup Wizard, CGM Scenarios) and reinforced the great use of color for glanceability, valuable lock screen notifications (like a text message), and the highly customizable alarms (22 different sounds, with lots of timing options). The demo version did not let us enter a calibration or see any data analytics, so we’ll have to wait until we try G5 in the US (also slated to launch in the coming weeks). Dexcom has done some subtle but meaningful things with the G5 app user interface – for example, the trend graph screen background dynamically changes color based on whether the current value is in-range (gray) or out-of-range (bright red or yellow). On the previous G4 receiver, the background remains black while only the individual glucose points change color. It’s another small but meaningful reminder of how much more is possible on a mobile app! Dexcom is highly highly valued but in stirring shape from what we can see – lots of things need to go right to sustain the valuation and so far so good.

Diamesco (POCTech)

POCTech advertised a new seven-day CGM requiring just one calibration at startup. A handout boasted a 10.8% MARD vs. fingersticks in an unconvincing 15-patient study (10 had type 2 diabetes, only 250 paired points vs. fingersticks). The rep told us a larger 110-patient study was just completed, showing a 10-12% MARD. There was no handout on the new study, and the rep was unable (or didn’t want) to answer our questions. Diamesco expects a CE Mark in early 2016 and Chinese FDA approval by the end of 2016. The company hopes to return to EASD 2016 announcing a launch. We are skeptical at this stage, particularly because the CGM flyer made several shifty data mistakes – for example, showing a graph with only one patient’s (!)data; using type 2s, who have lower glycemic variability and don’t provide a true test of the system; not using YSI as the comparator.

Diasend

Diasend announced integration with Dexcom’s G5 system. Excellent timing - it will be available right when G5 launches this month. Dexcom CGM data will now seamlessly flow into Diasend (no cables!), allowing combination with insulin pump and activity data (Fitbit, Jawbone). It’s a strong integration: patients will link their Dexcom G5 Mobile account with their diasend Personal account (from within diasend) to establish a permanent link (cloud-to-cloud). This makes the diasend integration low hassle for patients, platform agnostic, and immediately ready for Android once G5 launches next year. Like Apple’s HealthKit, diasend will still come with a three-hour delay between the CGM data acquisition and posting. Patients will be able see their Dexcom data in the diasend app, but are not required to, since G5 will also synchronize to their web-based diasend patient account (and linked healthcare provider account). The news also marks the launch of diasend’s new mobile app, which will be on display here at EASD.

Intarcia

As at ADA, Intarcia’s booth was centered around a plastic demo model with representatives demonstrating the insertion procedure for the ITCA 650 exenatide mini-pump. The procedure looked relatively straightforward to perform, although we imagine some patients and non-specialists could find it intimidating – word of mouth will, of course, be very important on both the patient and health professional side. Said one doctor who self-identified as an independent doctor, who is taking part by helping run some of Intarcia’s trial: “I’ve done this a few times and it’s easy – and my nurse has done it 300 times!”  Several members of Intarcia’s management team were present at the booth and noted that the company has seen a great deal of interest following the recent positive FREEDOM-2 results vs. Januvia; potential applications to insulin have apparently been the most common line of questioning from attendees. The company appeared to be open to this possibility, noting the current mini-pump could hold about three months’ worth of insulin. Management also pointed to SGLT-2 inhibitors as another intriguing option – as we see it, a co-formulation of a GLP-1 agonist and either insulin or an SGLT-2 inhibitor would also be very intriguing. Outside of diabetes, the team also mentioned potential future interest in obesity, other metabolic diseases, or oncology, though they emphasized that Intarcia is “here in diabetes to stay.”

J&J/Animas

Animas was positioned in the middle of the J&J booth. The area was packed despite occupying a small sliver of the expansive J&J layout. Attendees crowded around an educational display on the features of the Animas Vibe integrated with Dexcom G4 Platinum CGM. Reps expressed big-time enthusiasm for the product, talking at length about how positive the patient response has been – indeed, it saw 32% operational growth in the US per J&J’s most recently quarter update. We did not see any reference to the recently announced partnership with Tidepool. We were dreaming and hoping to see a next-gen artificial pancreas offering on demo, but that was wishful thinking ... for now!

J&J/Janssen

In addition to a rainbow and a light-up model of the kidneys, the cheery half of J&J’s booth devoted to Invokana (canagliflozin) featured a very heavy emphasis on the clinical trial data demonstrating superiority vs. Januvia. This is in contrast to the displays at recent US conferences, where strong access and reimbursement have been the main themes, reflecting the benefits of Invokana’s first-in-class status there. Vokanamet (canagliflozin/metformin) also received comparatively little attention in this booth compared to those at recent US conferences, where it has occupied an increasing share of real estate at Janssen’s booths.

J&J/LifeScan

LifeScan’s portion of the J&J exhibit captured a significant portion (~25%) of the booth’s real estate, one of the larger investments we can recall seeing in some time. The company brought a pair of BGM announcements to EASD: (i) LifeScan has updated its data downloading software (the “Reveal” app that pairs with the VerioSync); and (ii) the company recently received FDA 510(k) clearance for its Bluetooth-enabled OneTouch Verio Flex meter.

• LifeScan debuted its new Reveal mobile app and web portal. The company has given a facelift to the software (which, as a reminder, pairs to LifeScan’s VerioSync meter and now the Flex meter) while retaining many of the positive features of the original software: a colorful time-in-range chart (blue for hypoglycemia, green for in-range, red for hyperglycemia); pattern recognition for any high or low glucose patterns; easy sharing of results via email or text message. We wonder if the data will now post to HealthKit on the iPhone, a complaint in reviews of the app. We are fans of more seamless and automatic blood glucose data upload, though hope the results can also flow freely to other platforms.
• We learned today that LifeScan recently received FDA 510(k) clearance for its Bluetooth-enabled OneTouch Verio Flex meter. The device has been available in the EU “for some time,” though we cannot recall having seen it previously. The meter is sends blood glucose data wirelessly to the Reveal mobile app on an iPhone, iPad, or iPod touch. See pictures here. Reps did not provide a timeline for a US launch or pricing. It’s good to see movement from LifeScan on the BGM pipeline front (especially considering the very challenging US BGM market), and the company has trickled out a few new meters over the past year. The compelling advantage of the Flex over the VerioSync seems to be the addition of a color range indicator and a few buttons (the VerioSync is very slim and stripped down). This meter marks the third smartphone-connected BGM commercialized by a Big Four company, following LifeScan’s OneTouch VerioSync and Roche’s Accu-Chek Connect. We like that they are moving faster of late.

Kaleido

In the rear of the hall, we unexpectedly found Kaleido, a new patch pump company that debuted here at EASD (website). The pump and paired handheld are currently in the CE Mark process, and the UK and Netherlands are the first planned launch markets “soon.” The approach resembles Cellnovo, giving patients two reusable pump units, a wireless controller handheld, and an insulin cartridge that connects to a short on-body infusion set (5 cm or 30 cm). Unlike Cellnovo or the OmniPod, the handheld doesn’t have a built-in blood glucose meter. The body-worn pump and iPod-like handheld are both quite slim (measurements here), and the company has put a major emphasis on customizable color offerings. The pump cartridge holds 200 units, and the pump body is rechargeable, waterproof, and lasts for two years (the rep wasn’t positive on the latter). The handheld doesn’t have cloud/app connectivity, a downside vs. Cellnovo’s handheld and the upcoming next-gen OmniPod PDM. We asked the rep what separates Kaleido from OmniPod, and he emphasized the personalized colors and the ability to remove the pump (though it is waterproof, so this is not required). The rep had not heard of Cellnovo and was unable to compare the devices – this was odd and not confidence inspiring. We like the focus on making pumps cooler, though the key differentiator seems to be color – is that enough to distinguish Kaleido from everything else out there and coming along? The company making Kaleido is ViCentra, co-founded by Dr. Joesph Cefai, a principle founder of Cellnovo. We’re not sure about the IP and trade secret implications of that history.   

Lilly/BI

Lilly/BI’s massive booth commanded attention with its placement in the center of the exhibit hall – this booth combined with Lilly’s adjacent display easily claimed the largest amount of floor space of any company in attendance. Approaching attendees were immediately greeted by an attention-grabbing display (complete with videos of baby animals interspersed with the phase “do we have your attention?”) for Abasaglar, Lilly/BI’s newly-launched (though only in ex-US markets) biosimilar version of Sanofi’s Lantus (insulin glargine). The marketing surrounding Abasaglar acknowledged that “first times can be awkward” and emphasized easing the initiation phase for Abasaglar. Walking further into the booth, attendees entered a rustic-yet-modern refreshment area that exuded warmth with its wood-paneled walls and coordinating wood floors. On the other side of the refreshment area, attendees found a variety of interactive trivia games based on Lilly/BI’s impressively broad portfolio of products (the broadest around). One game focused on Jardiance (empagliflozin) and Synjardy (empagliflozin/metformin) had participants tossing beanbags into different holes to answer multiple-choice questions about their dosing, mechanism of action, and more. For Tradjenta (linagliptin) and Jentadueto (linagliptin/metformin), visitors to the booth could try their hand at a Mario Kart-style video game in which questions about the products were peppered into the driving experience. Not to brag, but we placed 5^th on the leaderboard during our visit.

Lilly

Lilly’s booth came across almost as an extension of the massive Lilly/BI booth next door, with a prominently-displayed reprise of the baby animal videos and photos for Abasaglar. We were a bit surprised to see such heavy promotion for the biosimilar insulin, though this is consistent with Lilly’s past statements that it intends to market Abasaglar as it would any new branded product. Biosimilar insulin glargine has been highly anticipated, largely due to hopes that it could represent a reprieve from skyrocketing insulin prices. So far Abasaglar has only been priced at a 15-20% discount relative to Lantus [insulin glargine]), though we expect that the discount could be steeper in the US (where full approval is on hold pending the outcome of a Sanofi lawsuit). New arrivals Trulicity (dulaglutide) and Humalog U200 KwikPen were also on display, though Trulicity’s exhibit hall presence continues to be relatively subdued for what is arguably a best-in-class product.  The booth also included a corner devoted to Lilly initiatives including diabetes books for kids and the company’s NCD [non-communicable diseases] Partnership in developing countries.

Medtronic

Medtronic’s booth was mostly devoted to the new MiniMed 640G with predictive low glucose management. The pump launched at ATTD 2015 in Europe, and a demo today reminded us of the design improvements over the MiniMed 530G – e.g., a larger color screen, four way arrow navigation, more customizability for alarms, insulin-on-board right on the home screen with sensor information, the ability to stop a bolus mid-delivery, etc. We had two new learnings from our ATTD test drive: (i) the pump indicates boluses on the trend graph screen with a blue dot (helpful to quickly understand when a last bolus was given and how it affected the glucose trend); and (ii) the history menu includes more robust analysis, such as CGM pie charts showing time-in-zone. The rep told us that patients love the system at night, especially because the alarms can be turned off (allowing the system to work in the background with disturbing sleep). 

Medtrum

Our red flag alarms went wild in Medtrum’s booth, who advertised a predictive low glucose suspend artificial pancreas complete with its own CGM (9% MARD, Bluetooth-enabled) and patch pump. What! The company plans to launch in Europe later this year. The reps freaked out when we started asking hard questions about the CGM data (comparator, in-clinic days, paired points, type of patient), and the vague posters around the booth were of little (read: no) help. We have low confidence this is the real deal.

MSD

MSD (Merck’s international equivalent) was very clearly all about the recent results from its CVOT TECOS for Januvia (sitagliptin), which demonstrated resounding neutrality. The booth’s posters exclaimed, “now even more reason to choose Januvia first as a partner to metformin,” with summaries of the TECOS safety evidence. MSD has even scheduled Meet-the-Expert sessions (three times a day!) focused on the CVOT’s data. A “Wall of Discovery and Development” in the back of the booth walked attendees through the history of DPP-4 inhibitors and highlighted the date of the release of the full TECOS results at ADA as the most recent milestone in the class’ journey. While the majority of the booth focused on TECOS, the booth also had a few standard posters on Janumet (sitagliptin and metformin HCl), a corner on the company’s LDL-lowering drug Atozet (ezetimibe/atorvastatin), along with iPads that gave attendees the chance to experience hypoglycemia virtually. Overall, we are not surprised at all that the company is making the most out of TECOS’ positive results, as management suggested it would do so in its last company update – these data will very likely maintain, if not bolster, Januvia’s dominant position within the DPP-4 inhibitor class, due to provider familiarity with the drug as well as the slightly more questionable results from SAVOR (for AZ’s Onglyza [saxagliptin]) and EXAMINE (for Takeda’s Nesina [alogliptin]).

Novartis

Novartis’ booth had an impressively large amount of real estate that promoted Galvus (vildagliptin) and Lucentis (intravitreal ranibizumab), with less attention focused on Eucreas (vildagliptin/metformin fixed-dose combination). On one side of the booth, tall touch screens featured images of various patient profiles, promoting the idea that Galvus is appropriate for a wide range of patients, specifically focusing on its renal safety and low hypoglycemia risk. On the other side, Lucentis was the star of the booth’s more interactive activities, branded as “designed to save sight” and as the “most prescribed licensed anti-VEGF therapy to help improve vision for diabetic macular edema patients.” Touch screens featured interactive quizzes that included questions regarding patients’ most feared complication (which was unsurprisingly problems with vision) and Lucentis’ mechanism of action. The booth featured other activities surrounding Lucentis including a retinopathy screening station (which used a telemedicine approach by sending your retina images to a remote ophthalmologist, perhaps hinting towards Novartis’ greater attention towards digital health) as well as a virtual reality simulation of diabetic macular edema. In addition, the booth promoted a strong sense of urgency around the diabetes epidemic, with the text “It’s time to do more about diabetes” on its overarching floating ring (alongside the logos of Galvus, Lucentis, and Eucreas). Several touch screens and videos were devoted to a theme of “Time2DoMore” with statistics from the IDF Atlas and calls to action, as well as ellipticals coupled with screens that attendees could use to learn more about the movement while getting their daily dose of exercise. With Galvus’ declining revenues and Novartis having even explicitly stated its reallocation away from Galvus, we were very surprised to see the larger size of the company’s booth, although we would guess that the larger European demographic (Galvus is only marketed ex-US) and the losses from the German market are strong motives to more aggressively market the drug.

Novo Nordisk

Novo Nordisk won the award for the most forward-looking approach in the exhibit hall, as its booth was devoted entirely to new arrivals Tresiba (insulin degludec) and Xultophy (insulin degludec/liraglutide). The Tresiba displays advertised the ability to “get A1c down with control,” accompanied by pictures of hot-air balloons “falling” along with A1c. The hot pink and grey displays for Xultophy spoke of “taking progress a step further” next to pictures of patients confidently descending a staircase. The new products certainly seemed to attract interest among attendees, as representatives were quite busy offering demonstrations of the new pens (both of which looked similar to the Levemir [insulin detemir] FlexTouch pen) when we swung by. Novo Nordisk is clearly going all-out for products it believes will have transformative potential, and we are very curious to see if this disproportionate emphasis continues at future conferences (particularly once Tresiba and Xultophy are approved in the US). Aside from product-specific displays, Novo Nordisk’s booth also took the prize for promoting a healthy lifestyle, with a refreshment stand offering salads instead of the usual coffee and members of Team Novo Nordisk in full cycling gear recruiting participants for the EASD 5K.

Roche

Roche’s booth was decked out in its classic navy colorway and located toward the right side of the hall, advertising a host of Accu-Chek products from the Mobile (one of its older BGMs) to the Insight (its insulin pump with prefilled cartridges) to the Connect (its newest BGM). Roche launched the Connect BGM and paired smartphone app (with a bolus calculator!) in the US in early August, and we learned today that 2015 launches have also included Australia, Turkey, and Brazil. The system hit the market in the EU in September 2014 with availability in South Africa, Italy, and Germany. Roche hopes to launch the Connect in four additional territories in the upcoming six months: Austria, Canada, Luxemburg, and France. Whether the company can establish reimbursement (especially in the tough French market) will be a key to accessibility, though regardless, the fuller scale launch is an important move toward reducing the hassle of downloading and insulin dose calculation for patients and providers. See diaTribe’s test drive here.

Sanofi

Toujeo (insulin glargine U300) was the clear focal point of Sanofi’s exhibit hall booth, with half of its outer perimeter taken up by the product’s distinctive green and purple logos. The materials on Toujeo heavily emphasized its flat action profile, with the slogan “the insulin of today for a steady tomorrow.” We liked that - it is what it is!  Sanofi also reminded attendees that Lantus (insulin glargine) is still king with displays urging clinicians to “choose the one you know” despite the prominent displays for the new biosimilar version (Lilly/BI’s Abasaglar) and Novo Nordisk’s next-generation Tresiba (insulin degludec) a few steps away. Lyxumia (lixisenatide) was also allocated some booth space (its “award-winning” pen was emphasized), as was Amaryl (glimepiride). Aside from drug products, Sanofi also showcased its blood glucose meters, its “Every 1 Matters” initiative,, and a quiz game that donated up to €15,000 to the Swedish Diabetes Association. We think the GLP-1 combo with Lantus will be extremely successful – they may need another ratio eventually – and we will be excited to see this become an offering.

Ypsomed

The bright green booth debuted the company’s in-house developed, touchscreen, durable, prefilled insulin pump, YpsoPump. Launch is slated for Germany and the Netherlands in 1Q16, with a broader EU launch to follow. We had a chance to demo the device, which felt slightly smaller than a MiniMed 530G with an iPhone-like, black-and-white, fully icon-driven touchscreen. We LOVED the prefilled cartridge and thought all this was very easy. The pump will launch with prefilled insulin cartridges (160 units), and we can’t wait to hear who its insulin partner is. We might guess it is Novo Nordisk, who has a non-exclusive partnership with Roche for 160-unit prefilled NovoRapid cartridges for the Accu-Chek Insight pump. Overall, the combination of touchscreen, prefilled, and icon-driven could differentiate YpsoPump from other pump offerings in Europe. From our view, it’s more about expanding the market and all the companies should be getting far better data on this fron than pumps have had in the past. There’s lots of competition vs. the MiniMed 640G, Insulet’s OmniPod, Animas’ Vibe, and Roche’s Accu-Chek pumps – but the brand here has reined supreme. More details following our demo are below.

• Notably, the YpsoPump user interface is entirely icon driven and navigated by swiping left to right – there are no words to distinguish anything in the menus, a bold design choice that walks a fine line between simple and potentially confusing but we liked it. At points it may err towards the latter, making it hard to know what different buttons do without some training (e.g., we kept entering the history and priming and rewind menus, which have non-obvious icons). Of course, once someone learns what the icons mean, it would probably be quite liberating to navigate a pump in this way. In a major positive, the icon-driven interface makes the pump language neutral, a brilliant choice for a European product that clearly drove the design.
• The pump does not have a bolus calculator, though Ypsomed will give patients a companion smartphone app with this feature. YpsoPump has Bluetooth built-in, but in talking to the rep, it will not communicate with the smartphone app, so the calculator-to-pump transfer will be manual.
• Ypsomed also plans to launch a self-filling reservoir after the prefilled version. The rep would not disclose any timing. We assume the prefilled version will be the focus, given the marketing advantages to patients and HCPs.
• The Orbit infusion set will be marketed alongside the pump. The set offers 360 degree rotation and both steel and Teflon cannulas.
• As far as cannibalizing the OmniPod, a banner above the booth proclaimed “Freedom of choice in pump therapy,” flanked by icons of the YpsoPump and OmniPod. Both Insulet and Ypsomed have maintained that the pumps will not compete against each other, and there are certainly some points of differentiation. Still, much of the YpsoPump marketing sounds like the OmniPod – “Enjoy simplicity,” “Easy to learn,” “Easy to operate,” “simply discrete” – so it will be interesting to see what happens once both are available side-by-side next year.  

 

-- by Melissa An, Adam Brown, Helen Gao, Varun Iyengar, Sarah Odeh, Emily Regier, Ava Runge, and Kelly Close

-- The authors thank Jessica Dong, Sam Haque, and Stephanie Kahn for additional help with conference writing