International Diabetes Federation: World Diabetes Congress 2015

November 30-December 4, 2015; Vancouver, Canada; Full Report

Executive Highlights

In this final report, we bring you our full coverage of the International Diabetes Federation (IDF) World Diabetes Congress, held at the Vancouver Convention Centre from November 30 to December 4, 2015. This year’s conference drew over 8,000 registrations, significantly down from the ~10,000 registrations at the last IDF Congress in Melbourne in 2013.

To help you sort through this year’s detailed full report, we’ve organized our commentary into six categories:

We’ve highlighted in yellow any presentations and commentary that we found particularly notable. Our full report includes over 100 talks that were either not published in our daily highlights reports or have been expanded in the past three weeks – these titles are highlighted in blue. We congratulate the organizers on a terrific IDF 2015; we’re already looking forward to the next congress in 2017 in Abu Dhabi, United Arab Emirates.

Below we outline the key themes that emerged from the conference, followed by 104 pages of detailed reporting.

Table of Contents 

Themes

Diabetes Drugs

  • We heard plenty of commentary on cardiovascular outcomes trials (CVOTs) at IDF 2015, including discussions on the EMPA-REG OUTCOME results, other recently-reported or soon-to-report trials, and broader CVOT policy. Lilly/BI continued to highlight the cardioprotective benefit associated with Jardiance (empagliflozin) in a corporate symposium on the first day. During the symposium, Dr. Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) spoke from a regulatory perspective and argued that empagliflozin’s risk/benefit profile justifies a Class I recommendation (meaning the benefit greatly outweighs the risk and the treatment should be administered). In the same symposium, Drs. Silvio Inzucchi (Yale University, New Haven, CT) and Eugene Wright (Cape Fear Valley Health Affairs, Fayetteville, NC) noted in a panel discussion that the results are convincing enough to change their clinical practice, but noted the limitations of the trial in terms of minority representation and suggested that professional organizations may want to wait for the other SGLT-2 inhibitor CVOTs to report before changing treatment guidelines.
    • Part of this hesitation likely comes from the uncertainty behind the mechanism driving the cardioprotective benefit. Indeed, while acknowledging their strong validity, Dr. Kaul also stressed the need for replication of the results given their “unexpected and unprecedented” nature. In a separate session, nephrologist Dr. David Cherney (University of Toronto, Canada) pointed to the differences between empagliflozin and thiazide diuretics to suggest that sustained, reduced plasma volume associated with empagliflozin use could be behind the benefit. Most of the speculation we have heard about the mechanism of benefit has centered around empagliflozin’s volume effects, as its effects on glucose, weight, and blood pressure appear unlikely to be responsible. That said, we are still very partial to Dr. Kaul’s statement from EASD that “when you see ‘multifactorial’ or ‘multidimensional’ in a journal like NEJM, it’s usually a euphemism for we don’t know.”
    • While the EMPA-REG OUTCOME results proved that it is possible to demonstrate CV superiority under the current CVOT paradigm, some speakers urged caution about extrapolating the results to other upcoming trials. Professor Neil Poulter (Imperial College London, UK) in particular cautioned that, despite very positive pooled MACE analyses from pre-approval trials of Novo Nordisk’s Victoza (liraglutide), we should not get our hopes up too high that LEADER will demonstrate a cardioprotective benefit. While EMPA-REG OUTCOME has made us more optimistic that other SGLT-2 inhibitor trials will have positive results, it does not change our overall assumption that most of these trials are likely to be neutral. While there is certainly reason to believe that GLP-1 agonists could be cardioprotective due to their favorable effects on weight, blood pressure, and lipids, a benefit mediated through these mechanisms may not become apparent in relatively short trials that enroll very high-risk patients.
    • The divergent heart failure results in the three DPP-4 inhibitor CVOTs remained a source of much consternation and discussion. Dr. Stefano Del Prato (University of Pisa, Italy) suggested that head-to-head studies of DPP-4 inhibitors are needed to better understand the increased risk for heart failure seen with AZ’s Onglyza (saxagliptin), though Dr. Daniel Drucker (Lunenfeld-Tanenbaum Research Institute, Toronto, Canada) pointed out that the very rare nature of this adverse event makes the mechanisms behind it very difficult to study. Dr. Rury Holman (University of Oxford, UK) presented a meta-analysis of the three DPP-4 inhibitor CVOTs (SAVOR-TIMI, EXAMINE, TECOS) that demonstrated no statistically significant difference in the risk of hospitalization for heart failure for the class – this was largely driven by the neutral results from TECOS, the largest of the three studies. In the absence of head-to-head studies or a clear mechanistic explanation of the SAVOR results, we assume the most likely practical consequence of these results is that clinicians will opt for Merck’s Januvia (sitagliptin) over Onglyza for patients at high risk of heart failure. Of course, Jardiance or other SGLT-2 inhibitors may become the favored option for these patients in any case following the EMPA-REG OUTCOME results.  
    • Several speakers proposed broader changes to how CVOTs are conducted. Dr. Eberhard Standl (Diabetes Research Group e.V. at Helmholtz Zentrum München, Munich, Germany) suggested that a large number of participants in CVOTs have undiagnosed heart failure. He argued strongly that future CVOTs should capture all cases of heart failure at baseline with BNP measurements to more carefully investigate the issue. Dr. Julio Rosenstock (UT Southwestern Medical Center, Dallas, TX) called for a closer look at the adjudication process for the pancreatitis results of ELIXA (the CVOT for Sanofi’s Lyxumia [lixisenatide]). Dr. David Matthews (Oxford Center for Diabetes, UK) argued that CVOTs may not be the most appropriate approach to answering questions in a huge epidemic disease such as diabetes, considering that they only enroll a tiny fraction of the affected population, only take into account the mean or median outcome, and may be too short to be useful. On the other hand, Dr. David Nathan (Harvard University, Boston, MA) argued that CVOTs still have a place since we don’t have adequate biomarkers for macrovascular risk in diabetes. While the criticism of the CVOT paradigm on the conference circuit has been muted to some extent post-EMPA-REG OUTCOME, these statements suggest that there is still plenty of room for improvement to ensure that these trials are as cost-effective and broadly valuable as possible.
  • We heard several speakers point to the cost of insulin as a major factor affecting clinical decision recommendations. Dr. Matthew Riddle (Oregon Health and Science University, Portland, OR) highlighted the 10-factor price differential between human insulins and newer insulin analogs and shared that some patients in his clinic are going back to human insulin due to cost issues. As a result, he suggested that, of the many newly available insulin formulations (“next-generation” basal insulins, concentrated insulin, inhaled insulin, and biosimilars), biosimilar insulin has the most potential to benefit the greatest proportion of patients. He argued that only a rather small percentage of patients will benefit from the relatively incremental efficacy or dosage improvements with the other new formulations, but upwards of 50% of patients would benefit from presumably lower-cost biosimilars. Going one step further, Dr. David Beran (Geneva University Hospitals, Switzerland) encouraged patients and health systems to move away from analogs and even insulin pens and switch back to human insulin via syringe delivery. He cited the comparatively high cost of insulin analogs and pens and the WHO’s position that analogs offer no clinical advantages beyond human insulin to support his point. While human insulin and syringes may have a lower upfront cost, we do not see a wholesale return to human insulin as an ideal solution due to the significantly increased risk of hypoglycemia and potential for lower patient adherence.
    • The issue of insulin cost in general is quite complex – while the list price of insulin has certainly gone up in recent years, rebating has also increased as pharmaceutical companies wrestle with pharmacy benefits managers over exclusive formulary contracts. Thus, it’s hard to say to what degree insulin costs have changed for payers and insured patients. Uninsured and under-insured patients are most directly impacted by higher list prices, though many companies do offer patient assistance programs for those in this situation. In addition, the manufacturing process for biologics like insulin is much more complex and expensive than small molecule oral diabetes drugs. As a result, even biosimilars are not likely to offer enormous discounts (Lilly/BI’s biosimilar insulin glargine Abasaglar is discounted at 15%-20% relative to Lantus in the European markets where it has launched, while small molecule generics are typically priced at a 50%-80% discount relative to their brand-name counterparts). A recent New York Times op-ed noted that it is 100 times more expensive to reverse-engineer a biologic than a small molecule – up to $200 million vs. about $2 million. Thus, it’s clear that insulin manufacturers are facing a variety of pressures and that more innovative, multidisciplinary solutions that engage industry, payers, providers, patients, and policymakers will be needed to reverse the current trend in insulin prices.
  • New data from ACCORDION and ADVANCE-ON reinforced the clear legacy effect of intensive glycemic control on microvascular outcomes and the lack of clarity around the connection to macrovascular outcomes. Dr. Hertzel Gerstein (McMaster University, Hamilton, Ontario, Canada) presented primary results from ACCORDION (observational follow-up to ACCORD; n=8,601) showing a neutral effect of previous intensive control on cardiovascular outcomes after a median of almost nine years of follow-up (HR = 0.95 for the primary MACE outcome; 95% CI: 0.87-1.04; p=0.27). Importantly, the increase in mortality that caused ACCORD to be stopped early resolved quickly after the end of randomized treatment, though there was still a significant difference in CV mortality by the end of ACCORDION. The most positive news from ACCORDION came from a retinopathy sub-study (n=2,856) showing a significant legacy effect of intensive control on retinopathy progression after eight years (HR = 0.42; 95% CI: 0.28-0.63; p<0.0001). We also saw a new analysis from ADVANCE-ON (observational follow-up to ADVANCE) showing that the legacy effect of intensive control on renal outcomes was greater for patients with lower systolic blood pressure and less advanced kidney disease at baseline.
    • Taken together, the two studies support the clear benefits of even a short period of intensive control on microvascular outcomes. We feel it is crucial for the field not to lose sight of this in the midst of the worthwhile debate over the relationship between glycemic control and macrovascular outcomes. Complications like blindness and end-stage renal disease are incredibly important from a patient quality-of-life perspective, and a treatment approach that reduces the risk of those complications while having a neutral effect on CVD could still be considered a success.
    • The results only add more fuel to the debate on the macrovascular outcomes side. Based on the totality of the evidence (from DCCT/EDIC, UKPDS, ACCORD, ADVANCE, and VADT), there appears to be a hint of a relationship between glycemic control and macrovascular outcomes, but it likely takes many years to emerge and is weaker than the link for factors like blood pressure and LDL cholesterol. Unfortunately, we do not expect to gain much more clarity on this subject in the near future given the expense and difficulty of these studies. We also do not anticipate a clear resolution of the most worrisome finding from these trials: the increased mortality in the intensive group in ACCORD. In his presentation, Dr. Gerstein stated that no explanation has emerged for that signal despite years of extensive analysis. We would speculate that the answer most likely lies in the fact that the patients who were treated intensively and did not achieve target were the ones at higher risk. This is supported by an analysis of SMBG data presented at ADA 2011 showing that mortality in both groups was linked with divergence from glycemic targets.
  • The concept of individualizing therapy – and the debate over how best to do so – remains a major theme in the diabetes drug arena. We were glad to see individualized care emphasized as a major priority in the new NICE guidelines for type 2 diabetes published during the conference. Of course, as was frequently acknowledged in a session on clinical practice guidelines, the real challenge lies in translating a statement like “individualized care” into effective clinical practice. Some of those dirty details were evident during an AZ-sponsored symposium in which panelists were asked how they would treat their own type 2 diabetes. While oral combination therapy seemed to be the consensus favorite approach, there was quite a range of views on the best specific agents, the benefits of initial combination therapy vs. aggressive sequential therapy, and the role of lifestyle intervention. We found it interesting that while lifestyle intervention often receives only a cursory mention in most type 2 diabetes drug-focused talks, a majority of panelists suggested that it would be a cornerstone of their own treatment plans. Farther down the treatment algorithm, Dr. John Buse (University of North Carolina, Chapel Hill, NC) raised several questions about the best place for GLP-1 agonist/basal insulin combinations vs. their individual components or basal-bolus insulin regimens. As with oral therapies, the answer is likely different for different patients. Both discussions illustrate the extent to which clinical judgment and the “art of medicine” often determine which patients are actually treated with which drugs. This will certainly continue for the foreseeable future given the wide range of (imperfect) choices in type 2 diabetes and the lack of comparative effectiveness research.
    • Another dimension of personalization is the question of how generalizable clinical trial results are to the larger patient population. This came up several times in the context of EMPA-REG OUTCOME, as several speakers cautioned against over-generalizing the results beyond the high-risk population enrolled in the trial but also acknowledged that the findings have already had an impact on their clinical practice. As one attendee put it, it is unlikely that there will ever be a properly powered outcomes trial of Lilly/BI’s Jardiance (empagliflozin) in lower-risk patients, and “are we really going to say you need to have a heart attack first?” before prescribing it.
  • PCSK9 inhibitors generated quite a buzz as a potential therapy (albeit an expensive one) for the many patients with diabetes who are not at their LDL cholesterol targets. The first two PCSK9 inhibitors – Sanofi’s Praluent (alirocumab) and Amgen’s Repatha (evolocumab) – were approved this past summer. While their indications are fairly narrow at the moment (individuals with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease [ASCVD] on maximally-tolerated statin therapy), the indicated population nonetheless includes a significant number of patients with diabetes. Dr. James McKenney (National Clinical Research, Richmond, VA) emphasized that both PCSK9 inhibitors are functionally the same, but the two companies chose to emphasize different options with their dosage strategies, with Sanofi emphasizing flexibility in efficacy and Amgen emphasizing flexibility in dosing schedule. Both Dr. McKenney and Dr. Harry Ginsberg (Columbia University College of Physicians and Surgeons, New York, NY) expressed excitement over the phase 1 RNA interference (RNAi)-based methods of PCSK9 inhibition that may support twice-yearly dosing. They also both noted that PCSK9 inhibitors can – and should – be used on top of statins, with additive (though not synergistic) effects. Dr. Christoph Wanner (University Hospital of Würzburg, Germany) emphasized that more and more individuals with diabetes and/or obesity are entering PCSK9 trials, suggesting that the drugs are appropriate for many within the diabetes patient population. Indeed, in a comparison, Dr. Wanner found the participant population of one of the phase 3 trials for Praluent to be quite similar to the participant population of EMPA-REG OUTCOME. If the ongoing cardiovascular outcomes trials for PCSK9 inhibitors produce positive results and lead to much broader indications, we would expect their relevance for patients with diabetes to increase even further.

Diabetes Technology

  • Enthusiasm for Abbott’s FreeStyle Libre has not abated after passing the one-year mark on the EU market. The corporate symposium stayed packed till the very end as Abbott shared new accuracy data in China, a reimbursement studies update, and real-world experience with Libre Pro in India. On the data front, Dr. Linong Ji (Peking University People’s Hospital, Beijing, China) shared new findings from a 40-patient, 14-day Chinese pivotal trial of Libre that demonstrated a MARD of just 10.7% vs. YSI, very consistent with the EU pivotal trial (MARD: 11.4%). It was a testament to this technology’s impressive design, though once manufacturing scales up as more countries come online, Abbott will of course need to maintain those results at scale – factory calibration is certainly not easy! As of Abbott’s 3Q15 call, capacity constraints persisted in Europe (patient want this technology!), though were expected to resolve soon. On the reimbursement front, we learned that the two six-month studies – REPLACE (n=210 type 2s on MDI, A1c>7.5%) and IMPACT (n=225 type 1s on MDI or pumps, A1c <7.5%) – will be presented at ATTD and ADA 2016, respectively. These studies were a very big investment and will be highly informative for obtaining broad reimbursement, especially in Europe where patients are less accustomed to paying out of pocket for healthcare.
    • The legendary Dr. Viswanathan Mohan provided insight into the strong reception FreeStyle Libre Pro has seen in India – he has used the blinded 14-day sensor in ~1,000 patients in just nine months. Dr. Mohan spoke in glowing terms about the value in optimizing patients’ therapy by helping providers feel more successful and – most importantly – making the invisibility of diabetes more tangible to patients. One of Dr. Mohan’s most fascinating comments was that Libre Pro makes patients “trust SMBG more” because now they see single values in the context of broader patterns. The strong reception bodes well for the Libre Pro sensor that is expected to launch in the US next year (submitted in 2Q15).
    • Management separately shared with us that the consumer version of FreeStyle Libre has been submitted to Canadian regulatory authorities. This is the first we had heard of this news. An approval timeline was not provided and we are still not sure how recently it was submitted. Still, it is big positive to see Abbott pushing its geographic footprint forward, and we hope to see the consumer version make its way to the FDA in the near future too. The news could also signal management’s confidence that the manufacturing capacity constraints will be rectified soon.
  • IDF was lighter on closed-loop discussion than even EASD 2015, though a talk from Harvard’s Dr. Frank Doyle provided a major highlight: an NIH grant will fund the International Diabetes Closed Loop (IDCL) trial, a six-month, 240-patient study comparing a commercial-grade version of UVA’s DiAs to sensor-augmented pump therapy. It’s not clear, but it’s possible that the award represents the part of the NIH’s $20 million AP initiative that was not awarded this fall – as a reminder from DTM 2015, the winners were Cambridge ($6.4 million), the DREAM consortium ($2 million), and Boston University/Mass General ($1.5 million), accounting for half of the original allotment. It is not clear whether the group will use this study to support a regulatory submission of the DiAs system, though Dr. Doyle’s language – “to generate the safety and efficacy data needed to satisfy regulatory agency requirements and to demonstrate the clinical effectiveness to facilitate reimbursement” – absolutely hinted at this possibility. Dr. Doyle said the trial will begin in 2016 at ten international study sites – UVA, Harvard University, Mount Sinai School of Medicine, Mayo Clinic, Barbara Davis Diabetes Center, Stanford University, William Sansum Diabetes Center, Academic Medical Center Amsterdam, University of Montpelier, and University of Padova. We assume Dexcom CGM will be a key part of the system, though are not sure what pump will be used or where the control algorithm will reside. Presumably startup TypeZero (who aims to commercialize the DiAs system, per our June 2015 coverage) would be responsible for the FDA submission and commercialization, though that’s not clear either. To be clear, the consortium – as opposed to TypeZero itself – received the award. We’re very glad to see a long-term, large closed-loop study funded; this trial is both longer and larger than the US pivotal study of Medtronic’s MiniMed 670G (n=150, three months).
    • The tough questions surrounding automated insulin delivery were not answered at IDF, though we look forward to meatier discussion at ATTD. What’s the appropriate control group in a pivotal study, if any (e.g., the 670G pivotal has no control group!)? What is the incremental benefit of glucagon over insulin alone?  How will patients trade off the level of automation (hybrid, full) vs. the level of glycemic control (low average, high time-in-range) vs. the device form factor (size, hassle factor)? New data is needed to advance the conversation on many of these issues, while others will be addressed once products get on the market. The field certainly seems increasingly comfortable with the idea that artificial pancreas systems are going to look and function differently and provide a spectrum of risk vs. benefit tradeoffs for different patients. No question about it – it will be an exciting couple of years for automated insulin delivery!
  • The incremental clinical benefit of pumps was questioned in REPOSE, a two-year randomized study comparing pumps to MDI in very poorly controlled type 1 diabetes (baseline A1c: ~9.2%). To address limitations of prior studies, education was held equal between the groups. At 24 months, pumps showed a very modest 0.2% A1c advantage over MDI (p=0.12) in those with a baseline A1c >7.5% and data from all four study visits (n=208 of the total n=267). Numerical A1c changes were not shown for all participants, but categorically, only 29% of the entire pump group and only 25% of the entire MDI group achieved an A1c <7.5% (p=0.5) – a testament to the poor control these patients were in at baseline (A1c: ~9.2%), and why neither education nor a pump is a magic bullet. Pumps offered no benefit on severe hypoglycemia (it was halved in both groups) and actually led to more DKA. It was disappointing to see so little benefit to pump therapy in this study, and unfortunately, SMBG or CGM data were not collected to supplement the A1c data. On the positive side, pumps did show significantly higher diabetes specific quality of life for diet restrictions and daily hassle, a finding Dr. Simon Heller called “real” and “sustained.” Dr. Heller was not negative on pump use, however – he concluded that care for adults with type 1 should start with MDI and structured training (e.g., DAFNE), with pumps offered later to those limited by MDI. In a follow-up conversation, Dr. Irl Hirsch pointed out a few important caveats to the data: the starting A1c’s were too high to expect a benefit, SMBG data was not collected at all, and based on the results, was not used effectively at the interim visits to titrate insulin.
    • Still, the data prompt many important questions. Do we know the true clinical benefit of pumps? If not, how should a pump study be conducted to show the true benefits? Pumps are not like taking a drug – they are totally different therapy for patients AND clinicians. What is fair way to assess the incremental benefit of the technology over MDI? As basal and bolus insulins continue to improve, will the advantages of pump technology decline? How will patients and payers tradeoff CGM vs. pump use? What patients are most likely to benefit from pumps and how should we identify them? We strongly support offering pumps and CGM and closed-loop to those likely to benefit from them, but technologies will increasingly need to demonstrate their value to become widely adopted.
  • Integrity introduced its non-invasive ear lobe clip device for spot monitoring glucose in type 2 and prediabetes. While the device itself was unimpressive, it did beg many thought provoking questions for the field: What level of glucose monitor accuracy is good enough for type 2 diabetes and prediabetes? How should companies trade off accuracy vs. improved form factor vs. cost? When does the output from a less invasive glucose monitor cross from useful to dangerous? (Integrity’s MARD is 23% - is that good enough for type 2?) These questions have important implications not just for Integrity, but type 2-focused glucose monitors from Abbott, Dexcom/Google, Medtronic, Novartis/Google, and wellness CGM companies like Echo and Sano. (Abbott is arguably the leader right now on the composite profile, having achieved a great form factor with FreeStyle Libre, a lower cost, and accuracy safe enough to dose insulin with factory calibration. But there is clearly a spectrum on the cost, accuracy, and form factor dimensions of any product.) Not every glucose-monitoring device needs to be accurate enough for dosing insulin, but there is presumably some threshold that must be hit. What is that threshold, and how should that be weighed against a smaller or less invasive or less costly device in different patient populations? For instance, if the Novartis/Google contact lens has a MARD of 20% (total speculation on our part), is that good enough to drive therapeutic change in type 2 diabetes and prediabetes? At what point does the device’s clinical inaccuracy outweigh any potential benefit of more frequent monitoring? Tough questions indeed, and ones that will likely be solved only with prototypes tested in clinical trials. We left this session with low overall confidence in Integrity’s product, though perhaps the company can improve with future generations (more details below).
  • Hearing about global disparities in care, we continue to wonder if digital health – particularly text messaging – can scale to meet a wide variety of challenges in diabetes: growing patients, a shortage of providers, and limited access to care. IDF did not share major new data on this front, though we appreciated Dr. Ambady Ramachandran’s overview of using text messaging to potentially prevent diabetes. His lab’s ongoing two-year study includes 1,050 patients in India and the UK, with one group receiving three personalized lifestyle modification texts per week. Results are currently pending (estimated completion this month)! His talk also reviewed a previous study published in Lancet in 2013, demonstrating a 36% risk reduction in the incidence of type 2 diabetes in the intervention group (text messages; n=271) compared to control (usual care; n=266). The number needed to treat to prevent one case of type 2 diabetes was only 11 patients! We hope to see more focus on scaling behavior change through interventions like text messaging – the low cost, low side effects, and high scalability seem like winners all around. A downside, of course, is patient annoyance factor, and hopefully smart phones can take text messaging to the next level with more personalized and interactive content.
    • Who is doing the most exciting and scalable things in type 2 diabetes prevention and care? Will Omada Health eventually scale to help millions? Why hasn’t WellDoc’s BlueStar – which started as a text messaging intervention – scaled faster in its rollout in the US? How can established diabetes drug and device companies help bring low-cost, proven diabetes prevention and lifestyle change technology to market? We continue to hear about isolated attempts to change behavior in diabetes, but the ecosystem is arguably fragmented and siloed – where can collaborations form to change things at a population level?

Obesity

  • Perhaps as expected given how the commercial market is going, we saw very little on obesity pharmacotherapies, with Novo Nordisk’s Saxenda (liraglutide 3.0 mg) as the only product represented on the commercial front. Regarding corporate symposia, Novo Nordisk held the one obesity-related corporate symposium at the beginning of the meeting, which was sprinkled with discussions around the clinical data and mechanisms of action of Saxenda. In the exhibit hall, Saxenda was also the only obesity pharmacotherapy present with a  separate Novo Nordisk booth highlighting the product. Additionally, very little on the scientific agenda focused on obesity pharmacotherapies, although we saw some presentations around the increasingly discussed topic of metabolic surgery as well as the “obesity paradox” seen in certain ethnicities (likely due to the global nature of this meeting). Certainly the lack of  momentum surrounding obesity drug manufacturers (see our recent updates from Arena and Vivus) has factored into some of the slowdown of this area’s research, reminding us of the importance of the role of healthy industry in driving innovation. We also note there was virtually no presence from obesity devices. Given that the rates of obesity are continuing to rise worldwide, we are disappointed to not see more focus from a public health perspective on how to drive personalized therapy – theoretically there seems to be support but we do not see it in any commercial numbers.
  • That said, of the minimal obesity discussion we heard, there seemed to be a little bit more focus on efforts to better personalize obesity treatment – just not enough. During the Novo Nordisk symposium, Dr. Carel Le Roux (University College Dublin, Ireland) highlighted responder analyses of obesity drugs’ clinical data, noting that early weight loss remains our best predictor. This symposium’s panel discussion also featured various KOLs’ insights on the heterogeneity of treatment responses, as panelists touched on hypotheses in genetics/epigenetics, lifestyle variations, and more. In addition, Dr. Jeanne McCaffery (Alpert School of Medicine, Providence, RI) pointed to the latest genetics research and promising alternative “biomarkers” in the potential for precision medicine in obesity treatment, not only for pharmacotherapies but also for lifestyle intervention. Similar discussions were also featured at this past EASD, with regards to prediabetes and obesity prevention. “Personalized medicine” has certainly become a buzzword for many disease areas and while the topic has gained slightly more attention within obesity, we are wary of how close the field really is to identifying the right patients for the right treatments, given the complex genetic, behavioral, and environmental components of obesity.

Big Picture

  • IDF 2015 brought the full publication of the Seventh Diabetes Atlas, now posted online in full at www.diabetesatlas.org. An estimated 415 million adults have diabetes in 2015, a 9% increase from 382 million in 2013 (the Sixth Atlas), and an unbelievable trajectory from 30 million people with diabetes in 1985. IDF now estimates 642 million people could have diabetes by 2040, a 55% increase from 2015. The new 2040 projection of 642 million substantially revises the Sixth Atlas’ 2035 projection of 592 million. In 2015, one in eight global healthcare dollars ($673 billion) were spent on diabetes, rising a remarkable 23% from $548 billion in 2013 (compared to a 9% increase in diabetes cases over that time). Costs are projected to exceed $802 billion in 2040 (19% growth, which seems like a big underestimate given the projected 55% growth in diabetes). One person now dies from diabetes every six seconds (5.1 million deaths per year), which makes diabetes a bigger killer than HIV, tuberculosis and malaria combined. The three countries with the highest number of people with diabetes are still China (110 million, +11% from 2013), India (69 million, +6% from 2013), and the US (29 million, +20% from 2013). By 2040, IDF projects 151 million diabetes cases in China (+38% from 2015), 124 million in India (a shocking +78% from 2015), and 35 million in the US (+20% from 2015- a major underestimate in our view).
    • The conference’s high-level session on the Atlas offered some nuanced perspective on the topline data published in November: (i) how conservative the 2040 estimates might be (they assume no change in diabetes prevalence and only reflect expected population growth – in particular, the US 2040 estimate for 35 million people with diabetes is highly, highly conservative in our view); (ii) how much uncertainty comes with all these estimates (data is often old or just doesn’t exist in many cases, particularly for mortality); and (iii) how much the US disproportionately contributes to global spending on diabetes (48% of all global dollars spent on diabetes, despite having just 7% of global cases!).
    • On a broader note, the IDF Atlas session was disappointing from an attendee perspective. The speakers communicated little sense of urgency, and the Atlas’ main data were presented with a half-empty room right at 8:30 am (it later filled up around 9 am, during the cost talk). For such a major IDF and diabetes community-wide project, the prioritization of this talk was baffling. Why wasn’t this a standalone, unopposed session? Why wasn’t it later in the day when more people would have attended? Why wasn’t there a greater sense of alarm in the presentation delivery? We heartily salute IDF for the tremendous effort in putting together each Atlas – this is a massive undertaking and so critical – and we hope future Congresses give this session more priority. It deserves it. We also hope IDF involves more of the diabetes community in building the next Atlas, as there is room for collaboration on numbers as important as these.
  • IDF 2015 also gave us a sense of the growing focus on addressing the psychological needs of people with diabetes to improve glycemic control and quality of life. We heard a number of speakers discuss diabetes distress and its connection to fear and the provider-patient relationship, as well as the psychological responses to hyper- and hypoglycemia. Dr. Lawrence Fisher (UCSF, San Francisco, CA) called for more empathetic provider-patient conversations to improve adherence to insulin regimens, asking doctors to talk to patients about why they stop using insulin to better understand the complex emotions involved in treatment. On a similar topic, Dr. William Polonsky (Behavioral Diabetes Institute, San Diego, CA) shared that a striking 39% of patients with type 1 diabetes and 35% of those with type 2 experience diabetes distress (a fatalistic attitude and feeling of being defeated by diabetes and self-care), and advocated for moving away from “blame and shame” and scare tactics to strategies that help people flourish with diabetes and overcome distress. Earlier in the week, Ms. Riva Greenberg (Huffington Post, New York, NY) dedicated the entirety of her presentation to this topic, and stated that flourishing with diabetes requires focusing on the successful aspects of a patient’s diabetes management and working to expand these strengths to other components of care. Later in the week, Dr. Jessica Browne (The Australian Centre for Behavioral Research in Diabetes, Melbourne, Australia) spoke about the work her team is doing in Australia to understand the social stigma surrounding diabetes (type 1 and type 2) and highlighted that campaigns to raise awareness of diabetes (and risk of type 2 diabetes) in the community need to be designed with attention to minimizing the harmful impact they can have on people already living with the condition. We are always glad to hear these issues addressed and hope that future discussions can move beyond describing the problem to proposing actionable solutions: for example, a script to guide providers through the process of discussing insulin initiation with their patients. 
    • Additionally, in a symposium on hypoglycemia, Professor Jane Speight (The Australian Centre for Behavioral Research in Diabetes, Melbourne, Australia) introduced the concept of “hyperglycemia avoidance”, arguing that fear of long-term complications is one of the foremost factors driving recurrent hypoglycemia. She underscored this point by sharing data showing that people with diabetes have significant concerns about developing complications. Furthermore, those who have severe hypoglycemia remain more concerned about the long-term complications than about hypoglycemia. This is often driven by the well-intentioned messages provided by health professionals. Importantly, she highlighted that real-world studies (unlike the major clinical trials of the past) now demonstrate no relationship between optimal A1c and hyoglyaemia risk. Professor Speight indicated that this means people should no longer feel that they need to accept hypoglycemia risk as a “necessary evil”. She pointed out the UK’s new NICE guidance which, for the first time, recommends that hypoglycemia, awareness of symptoms, and strategies to reduce risk are part of the clinical conversation.  In the same symposium, Professor Stephanie Amiel (King’s College London, UK) noted that despite the destructive intrusion of hypoglycemia in many aspects of life (reliance on others, loss of driver’s license, loss of employment, psychological distress, etc.), only four in 17 people with impaired awareness of hypoglycemia are concerned about it. This is a testament to the heavy psychological burden of the threat of future complications, which affects many people with diabetes and is often exacerbated by doctors’ attitudes towards glycemic control. We were pleased to see an increased focus on the psychological factors driving outcomes in people with diabetes, and expect to see further interest on the topic in future meetings as more rigorous data become available.
  • Lastly, we were glad to see the IDF agenda focus on population-level issues within diabetes and obesity, including discussions around the influence of urban areas as well as lessons from experiences with health policies. Specifically, a session during the meeting exclusively focused on the relationship between urbanization and diabetes, which featured speakers from around the world discussing their respective hometowns’ trends in diabetes. Notably, we loved hearing from Dr. Avi Friedman (McGill School of Architecture, Montreal, Quebec, Canada) on innovative community designs as well as a presentation on the IDF’s Diabetes Prevention Score to help assess urban areas for increased risk. In addition, IDF brought attention to relevant policies, as one open forum featured insights on how the soda tax in Mexico was designed and implemented, with specific commentary on how to gain support and work with stakeholders on industry-related policy issues. As a reminder, IDF recently called on world leaders to use sugar taxes – with IDF’s global influence, we believe the organization can certainly bring some momentum to these issues and also has unique expertise in helping share lessons across different regions. For additional insights on this sort of work, check out our highlights (days #1 and #2) of Novo Nordisk’s Cities Changing Diabetes Summit.

Exhibit Hall

  • This year’s exhibit hall was smaller and less busy than other conferences in 2015, though we bring you a few updates on both the tech and drug sides. Abbott drew an enthusiastic crowd of many non-European attendees (and probably some Europeans!) eager to watch FreeStyle Libre demos, while J&J/Lifescan held its own by announcing the Canada launch of its OneTouch Verio Flex Bluetooth-enabled BGM. We hear many continue to be excited about the Finesse as well. Bayer made an appearance after its absence from ADA and EASD 2015, with a corner of its exhibit devoted entirely to Eylea (aflibercept for diabetic retinopathy/diabetic macular edema) for the first time in our memory. We also got a closer look at what Taiwan-based VigiPen is doing on the smart insulin pen front. On the drug side, newer offerings included Lilly/BI’s Basaglar (biosimilar insulin glargine), advertised with entertaining baby animal videos, and Sanofi’s Toujeo (insulin glargine U300). Novo Nordisk emphasized Tresiba (insulin degludec) and Xultophy (insulin degludec/liraglutide), though not to as great an extent as at EASD 2015, where they were the only products featured. We were struck by the SGLT-2 exhibits, which stood as a clear reminder that IDF 2015 was an ex-US conference: J&J/Janssen’s booth devoted to Invokana (canagliflozin) was much smaller than at conferences such as the ADA, and AstraZeneca stressed Forxiga’s status as the first-to-market SGLT-2 inhibitor. Please see below for detailed coverage of each exhibit hall booth.

Diabetes Drugs

Symposium: Cardiovascular Outcome Studies and Glucose-Lowering Therapies

TECOS

Rury Holman, FMedSci (University of Oxford, UK)

Dr. Rury Holman presented an update on TECOS safety data, suggesting that the hint of renal dysfunction observed in sitagliptin-treated patients is “hardly of clinical significance.” He reviewed and expanded on the previously published renal findings: (i) the marginally improved mean urine albumin to creatinine ratio (UACR) values seen with sitagliptin compared with placebo (-1.0 mg/g) in the subset of 3,669 patients with data available; and (ii) the marginally worsened mean estimated glomerular filtration rate (eGFR) values seen with sitagliptin than with placebo (-1.3 ml/minute/1.73 m2) for the entire population. Dr. Holman suggested that both of these minor differences could be linked to the difference in A1c between the groups (glycemic equipoise was not quite achieved). To exclude the possibility that the small difference in mean eGFR values may mask larger differences in patients with reduced renal function at baseline, Dr. Holman shared new subanalyses indicating that the minor differences seen in mean eGFR values were similar across all chronic kidney disease (CKD) categories. Coupled with the fact that the changes were fairly weak to begin with, Dr. Holman concluded that it is unlikely that sitagliptin has a clinically significant impact on renal function. We fully concur. While in the aftermath of EMPA-REG, this information on renal risk is not the most compelling in terms of CVOT findings, we believe that it could still be somewhat useful in putting providers at ease when individualizing second-line therapies for patients with a history of chronic renal disease.

  • Dr. Holman also revisited the trial’s heart failure data to provide further clarity on the question of a DPP-4 inhibitor class effect; the study’s preliminary answer was reassuring with a neutral hazard ratio of 1.00. Dr. Holman stressed that further analyses of recurrent hospitalization for heart failure are just as encouraging, resulting in an unchanged hazard ratio of 1.00 after accounting for first+recurrent hospitalizations along with no evidence that patients in the sitagliptin arm had a differential outcome to heart failure (e.g., cardiovascular and all-cause morality in patients with one or more hospitalization for heart failure events did not differ). Notably, Dr. Holman also presented a meta-analysis of the three DPP-4 inhibitor CVOTs (SAVOR, EXAMINE, TECOS), demonstrating no statistically difference in the risk of hospitalization for heart failure when the studies are pooled (an overall hazard ratio of 1.14 [p=0.178]). He stressed the need to interpret these results with caution, echoing the lingering uncertainty around the mechanism behind the differential effects and suggesting that the increased heart failure result seen with saxagliptin may be due to chance, its trial’s patient population, adjudication process, or even a drug-specific effect.

ELIXA

Julio Rosenstock, MD (UT Southwestern Medical Center, Dallas, TX)

In this presentation, Dr. Julio Rosenstock reviewed the study design and outcomes of ELIXA, the CVOT for Sanofi’s Lyxumia (lixisenatide) – see full results (which demonstrated neutrality regarding CV risk) from our coverage at this past ADA and the recent publication in NEJM. Notably, when discussing the trial’s pancreatitis results, Dr. Rosenstock called for the need to more closely investigate the adjudication process for a more nuanced assessment of this safety signal. As a reminder, the results of ELIXA showed no significant increase in pancreatitis (8 events vs. 5 events). However, Dr. Rosenstock expressed skepticism of how the adjudication of these events was completed, noting that the process is based on only “classical criteria.” He highlighted that he would also like to see the “mild cases” reported, which are likely not captured through this adjudication process; specifically, he pointed to the value of identifying participants with higher lipase levels even if they do not technically represent a form of pancreatitis. Ultimately, we feel that acute pancreatitis is being increasingly acknowledged as a side effect for incretin-based therapies – although an acceptably small one – and a more granular analysis of this nature can help dissect the magnitude of the signal – we feel the tradeoff in using them is positive given how much benefit they give patients and given that the risk can be managed.

Questions and Answers

Q: I’m skeptical about this study since the efficacy was so modest – the weight reduction and blood reduction were very modest. Would you agree that the increase of heart rate is related to the very low dosage? Similarly, the neutrality around hospitalization due to heart failure may also be because dosage is so low. Would we see different results with higher doses?

A: First of all, 85% of people reached the standard dose of 20 micrograms. One of the important things of the study is that we’re testing the drug for CV events; we’re not testing for the impact on blood glucose. Its true efficacy is not that impressive but the intent is to get equipoise between the two groups. The placebo group was also receiving much more medication for glucose control. Also, I don’t think this drug’s purpose is to lose weight. This is something we’ll see and I look forward to other trials to see if weight loss can be maintained over two to three years. In terms of heart rate, here we didn’t really see an increase in heart rate. I don’t think this CVOT needs to be assessed for glucose control because the study design is to get equipoise between two groups.

Q: Can you speculate on the heart rate aspect a little bit since the measure was taken one day after drug was given the last time? The drug has a half-life of three to four years. Can you really expect to find anything at this point?

A: There may be long-term effects of GLP-1 – maybe through the autonomic system or another mechanism, but we don’t know if it’s a direct action on the heart or if it’s related to the autonomic system. Part of Juris Meier’s study showed that it was clear that the increase of heart rate was sustained over 24 hours with liraglutide but over a shorter time with lixisenatide. It was maintained overnight without a dip of heart rate. Whether this has any implications on CV outcomes, we don’t know.

Cardiovascular Outcomes with Empagliflozin: Results from EMPA-REG OUTCOME

Bernard Zinman, MD (Mount Sinai Hospital, University of Toronto, Ontario, Canada)

Dr. Bernard Zinman reviewed the EMPA-REG OUTCOME results and offered some speculation on the potential mechanism of benefit. He stressed while explaining baseline characteristics that the trial participants had longstanding diabetes and received “what most of us would accept is state of the art” treatment for all CV risk factors. He also emphasized that the trial aimed to maintain glycemic equipoise – this seems to be one of the main points of confusion with this and other CVOTs for diabetes drugs, as some have interpreted the lack of an A1c difference between groups as a sign that the drug is not effective. Discussing the results, Dr. Zinman stressed that the dramatic effects on CV death and heart failure occurred very early in the trial. He expressed particular excitement about the significant reduction in all-cause mortality, which he described as the “holy grail” for any cardiovascular study. He also provided interesting granularity on how cardiovascular death is adjudicated in these trials, noting that a large portion of that category consists of deaths without a clear cause – “if you go to sleep and wake up dead, that’s called a cardiovascular death.” While this is standard practice in CVOTs, that lack of clarity around the cause of death could make investigation of the mechanism of benefit more complicated. After noting that he would “leave it to someone else” to refer to EMPA-REG OUTCOME as a landmark study, Dr. Zinman closed by naming a number of factors that could have contributed to the benefit, including sympathetic tone, weight and visceral fat reduction, oxidative stress, and others in addition to volume change. However, during Q&A he seemed to agree with the prevailing hypothesis that a hemodynamic effect was most likely responsible.

Questions and Answers

Q: Why not do a study on people with heart failure or heart conditions without diabetes?

A: That’s an excellent point. I’m sure various companies are thinking about that. It may be as effective in people with heart failure without diabetes. You’ll still get some glucosuria and an osmotic effect.

Q: If there’s not much difference between the 10 mg and 25 mg doses, why not use only the 10 mg dose?

A: That’s something the NEJM reviewers insisted we comment on. As far as cardiovascular outcomes go, there was no difference. If the metabolic targets aren’t met with the 10 mg dose we have the option of going to 25 mg, but I mostly use 10 mg.

Q: What do I tell my patients who ask why I didn’t give them this drug?

A: You didn’t know the results. Now that you do, you should give it.

Q: To all people with diabetes?

A: No, it should be people who meet the entry criteria for the trial, then you can extrapolate to some extent.

Q: Many patients don’t meet the inclusion criteria but have subclinical ischemia or heart failure. Could you consider earlier use?

A: Many patients have type 2 diabetes with underlying heart failure. DECLARE has a large subset that is basically primary prevention, so we’ll know more. For now it’s left to the individual.

Q: There was an impressive nephroprotective effect. Do you believe that was related or independent?

A: The relationship between renal and cardiovascular outcomes is an interesting concept. We will do a mediation analysis to see what relates to what. We know intra-glomerular pressure is reduced, which makes ACE inhibitors work much better. The development of doubling of serum creatinine was reduced nicely and progression from microalbuminuria to macroalbuminuria was reduced significantly. We don’t know the relationships but it’s nice to see it happening.

Q: It’s a landmark study to me, but I’m not sure I agree with the conclusion. Based on the statin trials I don’t think the mechanism was atherosclerotic, since there was no effect on MI and stroke.

A: I agree 100%. We chose MACE because that’s what the FDA wants. This effect was not atherosclerosis, it’s a hemodynamic effect. Eventually there may be benefits, but the immediate response occurred so quickly that it has to be a hemodynamic response, not an atherosclerotic effect.

Q: Could it be a direct effect on the heart?

A: It could be. It has to be studied. There are no SGLT-2 receptors on the heart.

ADVANCE-ON

Sophia Zoungas, MD, PhD (University of Sydney, Australia)

Dr. Sophia Zoungas first reviewed the primary results from ADVANCE-ON, the long-term observational follow-up of the ADVANCE study. Those results, presented at EASD 2014, found a significant legacy effect of glucose lowering on end-stage kidney disease (HR = 0.54; 95% CI: 0.34-0.85) but no impact on macrovascular endpoints or retinopathy. This latest analysis demonstrated that the effect on renal death was not significant, though the point estimate did go in the right direction (HR = 0.85; 95% CI: 0.45-1.62). It also found that the benefits on end-stage kidney disease were greater for patients with lower systolic blood pressure (<140 mmHg) and less advanced kidney disease (no CKD or CKD stage 1/2) at baseline. Importantly, unlike in ACCORD, there was no evidence of increased harm with intensive glucose control in patients with any stage of CKD at baseline. The relative risk of severe hypoglycemia was also comparable across CKD stages, though the absolute risk was greater with more advanced disease. As Dr. Zoungas noted, these results highlight the benefits of achieving intensive control earlier in disease progression. It also suggests that glucose-independent mechanisms of nephropathy may predominate over glucose-dependent mechanisms in later stages of the disease. As for why the overall results were less impressive than those from UKPDS or VADT, Dr. Zoungas pointed to lower baseline A1c (7.5% in this trial), an insufficient difference in A1c during the randomized period, or an insufficient trial duration as potential explanations. The point was also made at the original results presentation that UKPDS enrolled a much younger, more recently diagnosed cohort; the participants in ADVANCE may have passed the window in which intensive glucose lowering can have a benefit on outcomes.

Symposium: New Views On Incretins

GLP-1 and Type 1 Diabetes: Sufficient Efficacy and Safety?

Urd Kielgast, MD, PhD (Hvidovre University Hospital, Copenhagen, Denmark)

Dr. Urd Kielgast offered a middling take on GLP-1 agonists in type 1 diabetes: positive on safety and more pessimistic on efficacy. On safety, she concluded that there is no increased hypoglycemia risk, impairment of counterregulatory mechanisms, or other serious or unexpected side effects associated with the class in type 1 diabetes. However, she did note that gastrointestinal side effects are more common and that the long-term implications of the increase in heart rate and reduced systolic blood pressure are unknown at this point (we assume the blood pressure effect would be positive if anything but clearly need long-term trials to be sure). The question of efficacy is more complex. Dr. Kielgast pointed to promising early-stage data showing substantial reductions in postprandial glucose with GLP-1 agonists regardless of beta cell function. The drugs also led to A1c reductions, lowered insulin doses, and weight loss in uncontrolled proof-of-concept studies. As we have unfortunately learned over the past few months, the results from placebo-controlled trials – Novo Nordisk’s phase 3 ADJUNCT ONE and ADJUNCT TWO studies for Victoza (liraglutide) being the largest – were less encouraging. Novo Nordisk subsequently decided not to pursue a type 1 diabetes indication for liraglutide – a disappointing but understandable decision in our view although we do question what sub-group analysis in a very large trials . We imagine other GLP-1 agonist manufacturers will now be more reluctant to pursue type 1 diabetes indications as a result. However, Dr. Kielgast noted that she would like to see studies in new-onset patients and studies of short-acting GLP-1 agonists, which have a greater effect on gastric emptying. We also think benefits like weight loss and potentially reduced glycemic variability could be meaningful for at least some patients, but we are fairly pessimistic that there will be a regulatory path forward in the near future.

  • Dr. Kielgast shared results from an unpublished study (n=12) of liraglutide vs. placebo to support the safety of GLP-1 agonists in type 1 diabetes. The 12-week trial found no difference in gastric emptying rate or glucagon response during hypoglycemia between the liraglutide-treated and placebo-treated groups. There was also no difference in cortisol, growth hormone, adrenaline, or noradrenaline levels.
  • Dr. Kielgast presented results from two placebo-controlled trials suggesting modest efficacy with liraglutide in type 1 diabetes. A randomized, double-blind, placebo-controlled trial in normal-weight patients with type 1 diabetes (n=40) found no significant difference in A1c reduction, glycemic variability, 24-hour glucose profiles, hypoglycemia event rate, or diastolic blood pressure with liraglutide vs. placebo after 12 weeks. However, the liraglutide-treated group did experience a significant 3.1 kg mean weight loss (compared to a 1.1 kg weight gain in the insulin monotherapy group; p<0.0001), a significant reduction in bolus insulin dose (p=0.02), and a reduction in systolic blood pressure (p=0.04). Similarly, the Lira-1 study in patients with type 1 diabetes and obesity observed no improvement in 24-hour glucose profiles or glycemic variability among patients treated with liraglutide. While there was a significant difference in A1c reduction after three months, the effect was lost at six months due to the A1c plateauing in the liraglutide group and continuing to decrease in the insulin-only group. There was a significant difference in body weight reduction (p=0.015) and bolus insulin dose (p=0.02), however.

New Incretin Therapies: Is Longer Acting Always Better?

Jack Leahy, MD (University of Vermont College of Medicine, Burlington, VT)

Dr. Jack Leahy emphasized the differences between short-acting and long-acting GLP-1 agonists – particularly with regards to postprandial glucose control – and identified the patient populations who may benefit most from the less popular short-acting versions. He acknowledged that long-acting GLP-1 agonists (such as Novo Nordisk’s market leader Victoza [liraglutide]) are better in most cases due to their superior A1c-lowering efficacy in head-to-head studies against short-acting products. However, Dr. Leahy highlighted the effect of short-acting GLP-1 agonists (such as Sanofi’s Lyxumia [lixisenatide]) on mealtime glucose, calling the postprandial glucose suppression their “defining feature” and comparing them to native GLP-1. Delving into the potential mechanisms a bit, Dr. Leahy attributed the effect on postprandial glucose to delayed gastric emptying, which disappears with chronic administration of long-acting GLP-1 agonists but persists with short-acting agents. Ultimately, Dr. Leahy concluded that long-acting GLP-1 agonists are best for patients with both fasting and mealtime hyperglycemia, while short-acting versions are best for those who primarily have difficulty with postprandial glucose control. He suggested that patients who are on basal insulin already, are elderly, or eat high-carb diets are possible candidates for short-acting GLP-1 agonist therapy. He also speculated that individuals with prediabetes or early type 1 diabetes may benefit from short-acting GLP-1 agonists as well. We’ve previously heard from several speakers on the potential of short-acting GLP-1 agonists for postprandial glucose control, particularly in combination with basal insulin. This may offer a potential niche for the relatively late-to-market Lyxumia in the US and may be a point of differentiation between the two GLP-1 agonist/basal insulin fixed-ratio combinations Xultophy (insulin degludec/liraglutide) and LixiLan (lixisenatide/insulin glargine).

GLP-1 and Insulin: When and How?

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

Dr. John Buse expressed characteristic excitement about GLP-1 agonist/basal insulin combinations and raised several unresolved questions about their optimal use. He reviewed clinical trial data on Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s LixiLan (lixisenatide/insulin glargine), emphasizing their “clear dramatic effect” on glycemic control and significant hypoglycemia and weight benefits compared to basal insulin alone. He believes it remains uncertain how the two products will differ in clinical practice. We have generally assumed they will have fairly comparable clinical profiles, but Novo Nordisk indicated in its 3Q15 update that it believes Xultophy will be highly differentiated. Dr. Buse also suggested that GLP-1 agonist/basal insulin combinations (fixed-ratio or otherwise) come out on top in the arguably more relevant comparison to basal-bolus insulin. He noted that while the available evidence has suggested a modest advantage at best in terms of glycemic control, the significant weight and hypoglycemia benefits and the convenience of a single injection are very clinically meaningful. The major remaining questions for Dr. Buse are (i) where these combinations should be positioned in treatment guidelines; (ii) whether adding basal insulin when patients have failed on a GLP-1 agonist is as effective as the reverse; and (iii) whether GLP-1 agonists could be an alternative to basal insulin as an add-on to rapid-acting insulin. He believes the last two questions remain unresolved and require further study. While the answer to the first is complex, Dr. Buse believes that absent concerns about cost and the long-term safety of GLP-1 agonists, “you could make a very strong argument that the combined approach is clearly superior to basal insulin” as an add-on to oral therapy.

Symposium: Long-Term Effect of Intensive Glucose Control in Type 2 Diabetes – The ACCORD International Ongoing (ACCORDION) Study

Cardiovascular Outcomes

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

Dr. Hertzel Gerstein presented primary results from the ACCORDION study (observational follow-up to ACCORD) showing a neutral effect of previous intensive control on cardiovascular outcomes and an attenuation of the increased mortality risk seen during randomized treatment. ACCORDION followed 8,601 ACCORD participants (90% of those eligible) through up to seven phone calls and clinic visits following the end of the randomized treatment period, for a median total follow-up time of 8.8 years. As expected, the A1c difference between the intensive and standard control arms had disappeared by the end of follow-up, with an average A1c of ~7.7% in both groups by month 57 after the end of ACCORD. There was no difference between groups in the primary MACE composite outcome (CV death, non-fatal MI, non-fatal stroke) 14 years post-randomization (HR = 0.95; 95% CI: 0.87-1.04; p=0.27). Importantly, the increase in mortality that caused ACCORD to be stopped early quickly resolved after the end of randomized treatment, with a hazard ratio of 1.01 (95% CI: 0.92-1.10; p=0.91) after 14 years. There was no heterogeneity for either outcome in any subgroup analyzed. Unfortunately, the significant reduction in non-fatal MI at the end of ACCORD was not maintained through ACCORDION (HR = 0.89; 95% CI: 0.79-1.02; p=0.09). The results for non-fatal stroke were also neutral (HR = 0.87; 95%CI: 0.73-1.04; p=0.11). The increase in CV mortality was still significant (HR = 1.20; 95% CI: 1.03-1.40; p=0.02), but Dr. Gerstein stressed that it was attenuated over time and that there was no increased risk in the post-randomization period – this seemed to be a point of confusion during Q&A.

  • The original ACCORD results published in 2008 demonstrated no effect of intensive vs. standard glucose control on overall CV outcomes but a worrisome increase in mortality. The trial randomized 10,251 patients with type 2 diabetes and high CV risk to intensive (target A1c <6%) or conventional (target A1c 7-7.9%) glucose-lowering therapy. It also evaluated intensive vs. conventional blood pressure- and lipid-lowering therapy in a factorial design. Patients were followed for a mean of 3.7 years before the trial was stopped early due to increased mortality in the intensive group. The intensive group achieved a significantly lower A1c at one year (6.4% vs. 7.5% in the conventional group; baseline = 8.1%) and the difference was maintained throughout the study. The results for the primary composite outcome were neutral (HR = 0.90; 95% CI: 0.78-1.04; p=0.16). The risk of non-fatal MI was lower in the intensive group (HR = 0.76; 95% CI: 0.62-0.92; p=0.004), but there was an increased risk of both CV death (HR = 1.35; 95% CI: 1.04-1.76; p=0.02) and all-cause mortality (HR = 1.22; 95% CI: 1.01-1.46; p=0.04).
  • ACCORDION passively followed 8,601 ACCORD participants for a total median follow-up time of 8.8 years. Dr. Gerstein emphasized that this represents 90% of eligible participants, and 98% of patients who did not experience a MACE event or die during the trial, meaning it should provide a robust estimate of the long-term effect. As one might expect, patients who chose to participate in ACCORDION were somewhat healthier than those who did not (younger age, lower BP, less prior CVD, fewer smokers). Patients were treated at the discretion of their personal providers and followed up with study investigators by phone or in person up to seven times in a 3.5 year period. Outcomes were reported by study investigators, but a random 10% of outcomes were adjudicated for quality control.
  • A1c was comparable between groups by the end of ACCORDION, though a difference persisted for some time after the end of randomized treatment. A1c in the intensive group rose to ~7.4% but remained (non-significantly) below that of the conventional group (~7.8%) at the end of the five-year study period (randomization in the blood pressure and lipid arms was maintained even after the glycemic aspect of the trial was stopped). The difference had dwindled to ~0.2% by the beginning of ACCORDION and was essentially gone by the end of follow-up. The confidence intervals were quite wide at all points during and after the study.  
  • Results for the primary MACE composite and all-cause mortality were completely neutral, with no heterogeneity between subgroups. The hazard ratio for MACE (CV death, non-fatal MI, and non-fatal stroke) was 0.95 (95% CI: 0.87-1.04; p=0.27) 14 years after randomization. The hazard ratio for all-cause mortality at 14 years was 1.01 (95% CI: 0.92-1.10). We would note that the number of patients dropped off considerably after ~10 years. The neutral results held true when patients were stratified by sex, age, race/ethnicity, history of CVD, baseline A1c, blood pressure, and lipids.
  • Results for non-fatal MI and non-fatal stroke were both neutral, while the increase in CV death was attenuated but still significant. The hazard ratio for MI was 0.89 (95% CI: 0.79-1.02; p=0.09) and the hazard ratio for stroke was 0.87 (95% CI: 0.73-1.04; p=0.11). The risk of CV death was still significantly elevated in the intensive group (HR = 1.20; 95% CI: 1.03-1.40; p=0.02), but Dr. Gerstein stressed that this was attenuated over time and that the curves were parallel after the end of randomized treatment. This seemed to be a point of confusion during Q&A, as some questioners assumed this meant there was an increased risk in the post-randomization period alone.
  • Dr. Gerstein stated that no explanation has emerged for the excess mortality in ACCORD despite years of extensive analysis. He noted that the risk was not related to the degree of glucose lowering, cardiac autonomic neuropathy, hypoglycemia, weight change, or specific drugs. It was statistically correlated with neuropathy, aspirin use, and higher baseline A1c, but Dr. Gerstein argued that these are most likely surrogates for sicker patients. He also referenced the recent paper suggesting differences in hemoglobin glycation index as an explanation but argued that it did not provide a conclusive answer. Other than a chance finding (which Dr. Gerstein also raised as a serious possibility), we would speculate that the answer most likely lies in the fact that the patients who were treated intensively and did not achieve target were the ones at higher risk. This would suggest that providers should closely monitor high-risk patients and back off on treatment if they are not responding, but that those who succeed in reaching intensive targets are at no increased risk.

ACCORDION Eye Study Results

Emily Chew, MD (National Eye Institute, Bethesda, MD)

Dr. Emily Chew presented results from the ACCORDION Eye Study (n=1,268) demonstrating a significant legacy effect of intensive glycemic control on retinopathy progression after eight years. The original ACCORD Eye Study (n=2,856) found that a significantly lower percentage of patients in the intensive group experienced progression of retinopathy compared to the conventional group after four years (7.5% vs. 10.4%). Outcomes were also better in patients treated with fenofibrate in addition to statins compared to those treated with statins alone. There was no difference between the intensive and conventional blood pressure arms. ACCORDION aimed to evaluate whether the beneficial effects of intensive glucose control and fenofibrate persisted after the end of randomized treatment and whether blood pressure had more of an effect with long-term follow-up. The legacy effect of intensive glycemic control was clear: 5.8% of patients in the intensive group experienced progression of retinopathy after eight years vs. 12.7% in the standard group (HR = 0.42; 95% CI: 0.28-0.63; p<0.0001). The effect of fenofibrate disappeared after treatment discontinuation, and no significant blood pressure effect emerged. Given the fairly low retention in the study (58% of eligible patients participated), Dr. Chew presented sensitivity analyses bolstering the validity of the results. An analysis restricted to sites with >80% retention also demonstrated a favorable hazard ratio, though the benefit was not significant due to the small numbers. A post-hoc analysis using a composite outcome of retinopathy progression or death (a way to account for competing risks) also demonstrated a significant benefit.

Brain Structure And Function

Anne Murray, MD (Hennepin County Medical Center, Minneapolis, MN)

Geriatrician Dr. Anne Murray presented results from the ACCORDION MIND study demonstrating no significant legacy effect of intensive control on cognitive decline or total brain volume. The original ACCORD MIND study (n=2,977) found no significant difference between groups in change in DSST scores (an assessment of cognitive function) or other cognitive measures. It did find a significantly lower decline in brain volume with intensive glycemic control and standard blood pressure treatment, but it also found significantly higher abnormal white matter volume with intensive control, leaving the overall conclusions unclear. Participants in ACCORDION MIND (n=1,328) underwent a fourth cognitive assessment and a third brain MRI at 80 months post-randomization. Results showed no significant difference in mean change in DSST score (p=0.32), total brain volume (p=0.91), or abnormal white matter volume (p=0.41) between groups at 80 months. Dr. Murray suggested that patients’ long duration of diabetes, the short and transient difference in A1c between groups, healthy survivor bias, and younger age could be possible explanations for the lack of an effect. Our sense is that efforts to understand the link between diabetes and cognitive dysfunction remain at an early stage, and we hope that better mechanistic understanding will inform more targeted studies and therapies in the future.

Panel Discussion

Q: It’s difficult to understand why there is still increased mortality since patients who died already are no longer patients. How can you exclude the complexity of drug treatment in the intensive group as a factor behind the increased mortality?

Dr. Hertzel Gerstein (McMaster University, Hamilton, Ontario, Canada): There was absolutely no long-term mortality effect at all. Mortality from cardiovascular causes persisted but was attenuated. It’s impossible to disentangle the many different drugs and combinations and figure out whether one or the other was responsible for the mortality signal that was originally observed or the persistent CV mortality signal. There have been many analyses looking at specific drugs and combinations and nothing emerged as significant. That doesn’t mean there is no answer. We just can’t find it. A few papers suggested it was maybe a random finding. It was not seen in other studies. We just don’t know.

Q: Were the drugs used in the two arms similar or different?

Dr. Gerstein: The drug cocktail in the intensive group was much more complex. During follow-up it was the same.

Q: Then cardiovascular deaths should also be the same?

Dr. Gerstein: It was attenuated. The curves diverged at two years and stayed exactly the same after. That may be why we see an attenuation of the long-term effect from 35% to 20%.

Q: Should we change practice according to these results that show no big difference in mortality in all studies? Do patients need all these medications we’re giving?

Dr. Gerstein: That’s a philosophical question. We know that ACCORD had a short period of treatment of 3.7 years. We know from all the trials that long-term legacy effects on CV events may take longer. VADT had five years of treatment and at the end there was no effect on CV outcomes. That required another five years. Metabolic interventions probably take longer to have an effect if they have an effect. There is a clear unequivocal eye benefit. During the active period there was also a benefit on brain volume that went away.

Dr. Emily Chew (National Eye Institute, Bethesda, MD): That’s an important point. You can read lots of conclusions on what to do after ACCORD, but the eye findings are important. If you look at the public and ask what senses they value, 70-80% would give anything up for vision. Vision is incredibly important for quality of life. To prevent people from getting an injection in their eyes or laster photocoagulation every month is a big deal. Retinopathy is not to be forgotten. A legacy effect of only 3.7 years is pretty powerful. This is very important for care and quality of life.

Q: It’s reassuring that total mortality was resolved. For CV mortality, during the follow-up did they look at the total time duration or just the follow-up duration?

Dr. Gerstein: All of these trials are analyzed from the day of randomization to the end of follow-up. They look at whether a specific period of intensive control has a ten-year effect on whatever. If you analyzed just the follow-up that’s an epidemiological study. If it’s a long-term effect you’ll see it that way. If it goes away, it’s not a long-term effect.

Q: It’s disappointing that the original signal of improved nonfatal MI was not continued. What does this tell us about the role of intensive therapy on atherosclerosis?

Dr. Gerstein: My personal belief is that the data in total say you maybe need three to five years of intensive intervention to see any long-term effect on outcomes like ischemic heart disease. In ACCORD there was a benefit but it was modest and probably takes a long time. In the DCCT it took a long time.

Q: If we have no mortality difference but still an increase in CV mortality, what is it protecting against?

Dr. Gerstein: There was slightly less non-CV mortality but the numbers change up and down. The difference in numbers is small, 10-20 people. I wouldn’t over-interpret it. You have to look at the totality of the evidence. The ADA got it right with their recommendations.

Symposium: Do We Need New Insulins for the Management of Diabetes?

Why Do We Need New Insulins? An Overview

Philip Home, DM DPhil (Newcastle University, Newcastle upon Tyne, UK)

Dr. Philip Home discussed why we need new insulins and which advances on the horizon are most promising. He believes the main flaw of current insulins is the high variability of action resulting from subcutaneous administration – they cannot achieve the minute-to-minute control of blood glucose that endogenous insulin can. This means that new therapies that provide feedback control, such as smart insulin, closed loop systems, or transplanted islets (including those derived from stem cells), will represent the largest advances. However, he stressed that even the closed loop will have limitations because the glucose sensing and insulin delivery still occur subcutaneously. One therapy Dr. Home believes will not solve the problem is oral insulin, as the poor bioavailability and erratic absorption will make it very difficult to replicate the correct physiological profile in his view. The same constraints apply to insulins with buccal, nasal, or pulmonary absorption. While we believe some patients will see oral insulin as a major success even if it is just able to match the efficacy of current analogs, it sounds like that will be a high bar according to Dr. Home. In terms of more incremental improvements, Dr. Home argued that we have likely optimized basal insulin analogs as much as possible, as Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (insulin glargine U300) have essentially flat profiles. He believes there is still some room for improvement with mealtime insulin. Products that offer a faster onset of action like Novo Nordisk’s faster aspart (just submitted in the EU and the US), Lilly/Adocia’s BioChaperone Lispro, and Biodel’s BIOD-531 will be improvements over current options, though still unlikely to match physiological control.

New Formulations: How Will They Change Therapy?

Matthew Riddle, MD (Oregon Health and Science University, Portland, OR)

Dr. Matthew Riddle suggested that potentially lower priced biosimilar insulin will benefit more patients than other new insulin formulations for type 2 diabetes. Dr. Riddle estimated that over 50% of patients, for whom cost is a leading concern, could benefit from biosimilar insulin glargine. He shared that he sees some patients coming off insulin analogs and returning to normal human insulin due to cost issues, as he noted the 10-factor price differential between human insulins and newer analogs, which is likely to only go up. As a result, he believes that cost considerations will drive use of the biosimilar version of insulin glargine. We’ve been hearing increasing concerns over the high cost of insulin and it seems that many providers are putting great hope in biosimilar insulin glargine as a potential source lower priced insulin. That said, biosimilar insulin glargine has been priced at only a 15%-20% discount in the markets it has launched in, begging more and bigger questions on how we can resolve this growing challenge (i.e. patents, who’s funding innovation, etc.).

  • In contrast, Dr. Riddle estimated only about 25% of patients would benefit from the longer and flatter profiles of next-generation basal insulins such as Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (U300 insulin glargine). He argued that while these products can reduce hypoglycemia risk, the advantage over standard of care Lantus (insulin glargine) is not as great as the hypoglycemia risk difference between older insulin analogs and human insulin. Thus, he suggested that since the relative benefit is more incremental (an unsurprising view given that Lantus in particular was a “once a generation” product in terms of improvements for patients, in our view), providers need to know who will get the most benefit. Specifically, he speculated that, based on data showing especially marked improvements in hypoglycemia and body weight with Toujeo vs. Lantus in Japanese populations, people with lower BMIs and lower insulin requirements may benefit the most.
  • Dr. Riddle estimated that 5% of patients would benefit from concentrated insulin and suggested that the main appeal of concentrated insulins such as Lilly’s Humulin U500 is the possibility of fewer injections for individuals with very high insulin doses, which may promote better adherence. More specifically, Dr. Riddle felt that concentrated insulins only made sense for patients with a dosing requirement >80 units per day (at which point it becomes impossible to deliver other forms of insulin with a single injection). Lilly’s increased attention to Humulin U500 over the past year and the launch of the Humalog (insulin lispro) U200 KwikPen in May suggests that the company clearly believes there is a significant market for these products, though we have heard some complaints from HCPs about the price increases for Humulin U500 that have been part of that increased attention.
  • Finally, Dr. Riddle rather pessimistically suggested that inhaled insulin (Afrezza) would only benefit his estimated 1%-10% of patients with true, complete needle phobia. Inhaled insulin’s (Afrezza) main strengths, in Dr. Riddle’s view, include its injection-free delivery mechanism and rapid onset, which he suggested may translate into better adherence and mealtime control. However, he noted that he doesn’t think there are that many patients with complete, true needle phobia. While this is likely true, we have assumed there would be a broader population of patients who would find these advantages meaningful. We hope a continued focus on educating HCPs, improving reimbursement, and reducing administrative hurdles can help reveal how broadly appealing Afrezza’s clinical profile is.

Yes, If We Are to Avoid Hypoglycemia and Mortality

Simon Heller, MD (University of Sheffield, UK)

Dr. Simon Heller delivered his signature talk on the dangers of hypoglycemia, focusing on the connections to CVD and mortality. He opened with a very sobering discussion of the “dead in bed” syndrome, citing the many epidemiological studies showing a link between hypoglycemia and sudden death in people with type 1 diabetes. While the mechanism of this phenomenon is not entirely clear, Dr. Heller suggested that arrhythmias, particularly long QT intervals, could be responsible. Dr. Heller also discussed the ever-controversial question of the increased mortality in the intensive group in ACCORD. He notes that rates of hypoglycemia were higher in the intensive group but cautioned that there are “undoubtedly other things going on.” For example, he suggested that hypoglycemia could function as a marker for overall frailty that can be used to identify people at risk. Dr. Heller then turned to the many potential mechanisms by which severe hypoglycemia can increase the risk of CVD, including blood coagulation abnormalities, inflammation, endothelial dysfunction, and sympathetic activation. He also stressed that the risk seems to be present in type 2 diabetes as well, citing studies that found high rates of asymptomatic nocturnal hypoglycemia in type 2 diabetes that was associated with arrhythmias. Returning to the central topic of the symposium, Dr. Heller argued that better insulin delivery is necessary to overcome these serious risks. While the exact hypoglycemia benefits of the newest insulins are not entirely clear, we are always glad to see the importance of hypoglycemia thrown into such sharp relief, as we fear the issue is sometimes overlooked in the current A1c-centric, cost-conscious environment.

Questions and Answers

Q: We’ve discussed the realities of NPH use in your country and the US because of cost. With the lack of CGM availability for type 2 diabetes, there’s a high incidence of nocturnal hypoglycemia that we presumably don’t identify. Are there any biomarkers you can think of to identify people at cardiac risk?

A: We haven’t done that. My hypothesis is that C-peptide might be a biomarker. We speculated in a previous study that it would be a marker for risk of severe hypoglycemia. The problem is it’s asymptomatic. If we are using NPH or even analog insulin, it would behoove us to persuade our patients to at least once or twice a month set an alarm and measure their glucose at 3 am. There might well be a considerable benefit. It could drive changes in insulin prescriptions if people are having hypoglycemia.

Dr. Irl Hirsch (University of Washington, Seattle, WA): We presented a poster from the T1D Exchange showing that after 40 years of diabetes, quite a few patients were C-peptide positive, and it did protect them from severe hypoglycemia. Your point about the lasting effects of inflammation from hypoglycemia is almost like talking about metabolic memory for hypoglycemia. I’m not exactly sure of the mechanism, but do you agree with the metabolic memory analogy?

A: Clearly studies in newly diagnosed patients have demonstrated that early intensive control produces benefits. That’s clearly indicated from DCCT and UKPDS. If we can get it right early, there are benefits. Whether repeated hypoglycemia – this isn’t severe, this is what all patients experience every day – whether those effects accumulate, I have no idea. It’s a great hypothesis and extremely difficult to test. It would explain the surprising results with intensive therapy.

Novel Ways to Deliver Insulin: Which Routes for Which Patients?

William Cefalu, MD (Pennington Biomedical Research Center, Baton Rouge, LA)

Dr. William Cefalu discussed the challenges facing alternative modes of insulin delivery, including those in the pipeline and recent arrivals to the market. He primarily touched on intranasal, buccal, oral, and inhaled insulin delivery, though he noted that sublingual and intraperitoneal insulin are also being investigated. Dr. Cefalu noted that intranasal and buccal insulins have faced significant bioavailability challenges due to the thicker mucosa and lower surface area of the upper airways. Dr. Cefalu was more optimistic about oral insulin, but noted that there are still significant hurdles to overcome within the GI tract and stated that he would withhold judgment until larger trials are complete. As a reminder, Novo Nordisk has an ongoing phase 2a trial for its primary oral insulin candidate expected to complete in January 2016; Biocon and Oramed are also in the oral insulin game. In contrast to other delivery methods, Dr. Cefalu was more positive about the theory behind inhaled insulin delivery, noting the inherent advantages of delivering insulin through the thin, high-surface-area alveolar membrane. Regarding Sanofi/MannKind’s Afrezza in particular, Dr. Cefalu suggested that the product’s distinct PK/PD properties, more convenient and patient-friendly delivery devices, diminished lung toxicity concerns, and greater acceptance of aerosolized medicines may allow it to succeed where previous inhaled insulins have failed. That said, Dr. Cefalu concluded that while inhaled insulin does offer distinct advantages, it still cannot fully challenge the current injectable insulins. He suggested that the most appropriate patients for inhaled insulin might be: (i) those with type 1 diabetes who want to improve glucose control but face issues with hypoglycemia; (ii) individuals with type 2 diabetes with needle phobia who are otherwise reluctant to take insulin; and (iii) patients with either type 1 or type 2 diabetes who are on  basal-bolus therapy but want to reduce their number of daily injections. However, Dr. Cefalu noted that in this last case, replacing a rapid-acting insulin with an inhaled insulin may prove unpredictable since the PK/PD profiles are not exactly the same. For more insights on inhaled insulin, please see our coverage of Dr. Anne Peters’ (USC, Los Angeles, CA) thoughts on the “hybrid” use of this mode of insulin delivery.

Symposium: Type 1 Diabetes – Avenues for New Approaches to Therapy

Disease Modifying Therapy in Type 1 Diabetes

Carla Greenbaum, MD (Benaroya Research Institute, Seattle, WA)

Dr. Carla Greenbaum delivered a passionate talk on the need for disease-modifying therapies for type 1 diabetes – and for endocrinologists to overcome their fear of immunotherapy. To those who argue that advances in current treatment will make disease-modifying therapies unnecessary, Dr. Greenbaum responded that “we’re not as good as we think we are.” She pointed to T1D Exchange data showing “pretty lousy” glucose control across the board, significant rates of severe hypoglycemia, and declining but still prevalent rates of complications. She argued that the best place for disease-modifying treatments is before clinical diagnosis, at stage one of the recently published JDRF/ADA staging system (multiple autoantibodies with normal blood glucose). She also emphasized that children need to be considered as an independent group, as they experience a much faster rate of disease progression than adults. Dr. Greenbaum has been a staunch advocate of this point and co-chaired a consensus conference on the topic earlier this year. In terms of specific therapies, Dr. Greenbaum highlighted teplizumab, rituximab, abatacept, and alefacept as the four candidates that have demonstrated efficacy and a reasonable safety profile in clinical trials. She made the important point that the level of efficacy seen in those trials (~20-25% benefit vs. control) is comparable to that produced by approved immune therapies for other diseases – the trick is figuring out how best to use them. The issue of expectations is perhaps one of the biggest challenges facing this field: there has been so much hope and hype around a “cure” for type 1 diabetes that an immunotherapy or cell replacement approach could be perceived as a disappointment even if it produces real clinical benefits.

Symposium: Hypertension and Diabetic Complications

SGLT-2 Inhibitors and the Regulation of Vascular Function in Diabetes

David Cherney, MD, PhD (University of Toronto, Canada)

Dr. David Cherney speculated on the potential mechanisms driving the heart failure benefit in EMPA-REG OUTCOME. While the suggestion that Lilly/BI’s Jardiance (empagliflozin) may be acting as a diuretic is a popular theory, Dr. Cherney emphasized that there are significant differences in the clinical effects of thiazide diuretics and empagliflozin. Like empagliflozin, thiazide diuretics are associated with lower diastolic and systolic blood pressure and reduced plasma volume. However, the volume contraction effects are attenuated over time, with plasma volume returning to normal by eight weeks. Thus, Dr. Cherney hypothesized that the blood pressure lowering observed may be related to systemic vasodilation rather than plasma volume. In contrast, SGLT-2 inhibitors appear to produce long-term, sustained reductions in plasma volume. The finding that the hospitalization for heart failure risk curves separated very early on in the trial – within 3-4 months – suggests to Dr. Cherney that an acute hemodynamic or volume-mediated effect is at play. He also suggested that the reduced plasma volume could contribute to reduced myocardial stretch, which in turn can reduce arrhythmias. Arrhythmias could have been counted within the category of sudden cardiac death in the trial, so Dr. Cherney hypothesized that the reduced plasma volume could contribute to the reduction in cardiovascular mortality risk. Another hypothesis Dr. Cherney raised included a potential role for metabolically active epicardial adipose tissue (which has been shown to suppress myocardial contractility). Dr. Cherney also suggested that SGLT-2 inhibitors could increase renin levels, thereby activating the renin-angiotensin system. Since many of the participants in EMPA-REG OUTCOME were already on an ACE inhibitor, the angiotensin I from the system may be shunted over to the vasodilatory pathways. Dr. Cherney also hypothesized that the risk reduction could be due to multiple pathways or a potential renal protective effect of SGLT-2 inhibitors.

Symposium: SGLT-2 Inhibitors in Treating Diabetes

Clinical Role

Per-Henrik Groop, MD (University of Helsinki, Finland)

Dr. Per-Henrik Groop focused on the profound nature of the EMPA-REG OUTCOME results, using the HOPE study of the ACE inhibitor ramipril as a point of comparison. He first synthesized the pre-EMPA-REG data on the SGLT-2 inhibitor class, highlighting the durable weight loss and blood pressure reductions and expressing slight concern about the increase in LDL cholesterol. He argued that in marked contrast to the situation for DPP-4 inhibitors (a lot of hope for cardioprotection followed by neutral outcomes trials), the EMPA-REG OUTCOME results completely exceeded expectations for the SGLT-2 inhibitor class. While we would argue that there was some optimism in the field for cardioprotection with SGLT-2 inhibitors, we agree that the magnitude of the results and the specific parameters affected were a complete surprise. Dr. Groop highlighted the similarity of the EMPA-REG OUTCOME results to those in HOPE, which led to the establishment of ACE inhibitors as standard treatment for people with diabetes. With the caveat that this was not intended to be a head-to-head comparison, Dr. Groop noted the similar relative risk reduction for all-cause and CV mortality in both trials. He also noted that the risk reduction in EMPA-REG OUTCOME occurred in the context of much lower absolute risk, which he attributed to a higher standard of care. Several questioners pushed back against Dr. Groop’s excitement during Q&A, noting that HOPE included a much broader patient population than EMPA-REG OUTCOME and stressing the need to avoid over-extrapolation of the results. Dr. Groop agreed that the data should not be over-generalized but stressed that he made the comparison to emphasize the landmark nature of the study and the prediction that it will lead to a similar paradigm shift.

Questions and Answers

Q: I hope people are applauding your graphics, not your conclusion. We have a very high-risk population and your extrapolation is out to generality. The HOPE trial had a mix of people. I think we’re moving out into unsafe waters with enthusiasm for this idea that this should be generically differentiated.

A: These were not head-to-head comparisons. I’m trying to show what we’ve learned from big studies. We learned from HOPE to treat people with diabetes with ACE inhibitors. Now we have new medications that on top of standard of care have similar effects. That’s the take-home message to bring to the clinic.

Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX): We have a very select population who’s incredibly sick and very high risk. I’m not convinced at all that if you take newly diagnosed diabetics you’ll see the same results. If you have patients who fit these characteristics, they should be on empagliflozin. To extrapolate to other populations, who probably make up 80-90% of the total population, is hazardous.

A: I agree, but I’ll give the same answer. I’m trying to show more of a paradigm shift. The data for empagliflozin was shown in a high-risk population. We don’t know if it can be translated to those without established CVD. DECLARE will hopefully show that. I totally agree with you. I’m just saying we should consider that this was a landmark study, and I think it will lead to a paradigm shift.

Q: We saw the comparison between SGLT-2 inhibitors and ACE inhibitors. Do we have a comparison with metformin?

A: I tried to squeeze out what I could from HOPE. I don’t know how many were on metformin. This was not head-to-head; I’ll stress that again. I’m saying that with 15 years of time difference, the two trials showed a very similar effect. The absolute risk reductions were the same and on top of standard of care. Don’t go home and try to translate everything to a patient not shown to have a benefit.

Q: HOPE studied people out to 4.5 years. EMPA-REG was two years. What are your thoughts on the implications of two years vs. five years?

A: Again, EMPA-REG enrolled very sick patients. In HOPE you also had people with risk factors. In EMPA-REG everyone had established disease. In HOPE, 31% just had risk factors. If you have established CVD, then the time to treat is shorter.

Clinical Safety

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

Dr. Stefano Del Prato reviewed the various safety parameters of SGLT-2 inhibitors, providing commentary on the class’ various suggested safety concerns. After demonstrating that the class can provide good durable glycemic control, he presented data around hypoglycemia, concluding that the drugs’ risk is low in various treatment regimens (added on to insulin and other medications) likely due to the class’ indirect mechanisms of action on insulin sensitivity and secretion. With regards to urinary tract infections, Dr. Del Prato noted that this has become less of an issue while mycotic genital infections remain the most common side effect in females, although events tend to diminish over time and episodes are mostly mild and manageable. However soon after this presentation, the FDA added new warnings and precautions on DKA and urinary tract infections to all SGLT-2 inhibitors’ labels – the recent reporting of serious UTI cases may thus bring this signal back to the forefront. Regarding kidney function, he noted that no evidence yet suggests that the drug class can accelerate loss of kidney function, although certain patient populations (i.e. older age, use of loop diuretics) may be at higher risk for hypovolemia. Dr. Del Prato also reviewed the evidence around bone fractures, as canagliflozin but not dapagliflozin has shown an effect on bone mineral density, thus begging the question as to if this is a drug effect or class effect. However ultimately, Dr. Del Prato pointed to the EMPA-REG results when assessing the class’ risk/benefit balance, concluding that the class’ potential risks are worth taking in exchange for cardioprotection. However, he shared the important message that amidst the great enthusiasm surrounding these CVOT findings, we must not forget to remain wary of any safety signals that emerge – in light of EMPA-REG, DKA, and recent additional FDA warnings, we believe this class has certainly received attention from all sides.

  • On DKA, Dr. Del Prato shared his belief that SGLT-2 inhibitors must be properly used by their indications – a view that we hear shared by many other KOLs. He stated that SGLT-2 inhibitors may predispose individuals to ketoacidosis with most of published cases resulting from insulin deficiency in type 1 diabetes while type 2 diabetes cases were typically with patients already on insulin or under stressful conditions.
  • Interestingly, he pointed to SGLT-2 inhibitors’ possible role as a technique to identify tumors in cancer. Dr. Del Prato highlighted that the data in diabetes show a non-significant increased risk, but noted that recent research has utilized the functional expression of sodium-glucose transporters in studying cancer – an intriguing area that we’ll keep our eye out for to see if this brings any insights to type 2 diabetes.

Questions and Answers

Q: Why should there be increased bone fracture risk in one drug but not the others?

A: I have no clear cut explanation why the risk of bone fracture should be increased with one of the drugs in the class but I have to acknowledge that FDA has revised the label for canagliflozin. Data recently published have shown a decrease in bone density with canagliflozin, while similar studies have not found such an effect with dapagliflozin. No increase in bone fractures has been reported over the 4-year follow-up of the EMPA-REG with the use of empagliflozin. However, there’s no way to get a final answer unless head-to-head trials are carried out.

Q: Looks like this mostly has to do with bone density, which may possibly be explained by lack of calcium?

A: No imbalance in calcium or magnesium concentration have been reported in the registration trial. And data on biomarkers of bone absorption and formation have not been found to be significantly affected by the use of SGLT2 inhibitors.

Symposium: Diabetes in Youth

The SEARCH for Diabetes in Youth Study: Overview and Results

Elizabeth Mayer-Davis, PhD (University of North Carolina, Chapel Hill, NC)

After a review of the published data from the first two phases of the SEARCH for Diabetes in Youth Study (SEARCH 1 and 2; latest results published in 2014), Dr. Elizabeth Mayer-Davis noted that the investigators are currently analyzing the latest data from SEARCH 3 and have submitted an abstract to ADA for presentation at ADA 2016. The SEARCH 3 data will cover incidence trends for type 1 and type 2 diabetes from 2002-2012. It will be the first SEARCH dataset to report incidence trends for type 2 diabetes and for racial/ethnic groups other than non-Hispanic whites. The next prevalence data will be collected in 2017. The group is also launching the SEARCH 4 registry and cohort studies, which will complete in 2020. The registry study will investigate incidence and prevalence trends for type 1 and type 2 diabetes. It will also look at whether the alarmingly high rates of DKA seen in previous SEARCH studies (28-29% at diagnosis for type 1 diabetes) have declined and whether the surveillance process itself can become more cost-efficient. The cohort study will evaluate the incidence and progression of complications in a group of youth (n=1,464 with type 1 diabetes, n=384 with type 2 diabetes) who had in-person visits early in the study (2002, 2006, and 2008). It aims to identify the risk factors driving development of complications and understand why complications seem to occur earlier in youth with type 2 diabetes compared to type 1.

Symposium: Islet Transplantation vs. Embryonic Stem Cells – Where Does The Future Lie?

Summary

Kevin D’Amour, PhD (ViaCyte, San Diego, CA), Timothy Kieffer, PhD (University of British Columbia, Vancouver, British Columbia, Canada), James Shapiro, MD, PhD (University of Alberta, Edmonton, Alberta, Canada), Ian Rogers, PhD (Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada)

Speakers in this symposium offered a strong vision of a future in which stem cell-based therapies are a mainstay of type 1 diabetes treatment. Dr. Kevin D’Amour first reviewed the preclinical studies of ViaCyte’s VC-01, currently the most advanced cell replacement therapy in development. He noted that investigators are still enrolling the first cohort of patients in the ongoing phase 1/2 trial of the device. Ten patients have been treated to date, and a few have now reached their one-year anniversary with the product. Dr. D’Amour declined to provide specifics on how those patients have responded but emphasized that this first phase is intended to evaluate safety and optimize the device – in other words, impressive efficacy results were not expected at this point. Dr. Tim Kieffer then discussed his group’s protocol with BetaLogics to produce functional beta cells (more mature than the pancreatic progenitor cells produced by ViaCyte’s protocol) from embryonic stem cells. That project remains preclinical, as investigators are exploring how environmental factors like diet or thyroid hormone levels could influence the cells’ efficacy. Dr. James Shapiro discussed recent advances in protocols for islet transplantation.  He concluded on an optimistic note, saying it is “clear that cell transplantation will become mainstream treatment in the future…I firmly believe the nuts and bolts of a cure are in play.” Finally, Dr. Ian Rogers explained the science behind iPS cells, which could potentially serve as a less controversial replacement for embryonic stem cells as a cell source for these treatments.

Symposium: The Alpha-Cell – Learning from the Past and Building for the Future

Blocking Glucagon Action: Ready for Prime Time?

David Kelley, MD (Merck, Rahway, NJ)

In a detailed presentation on glucagon receptor (GCGR) antagonist therapy, Dr. David Kelley stated that the worrisome dose-dependent elevation in plasma LDL cholesterol associated with the class is mechanistic, and can therefore be mitigated pharmacologically. For example, he shared preclinical results demonstrating that co-administration of the cholesterol drug ezetimibe inhibited the rise in LDL cholesterol associated with Merck’s discontinued GCGR antagonist MK-0893. Dr. Kelley also contextualized current GRA therapy research by providing background on MK-0893, which was discontinued in 2011 due to safety concerns (weight gain and increased liver transaminases in addition to elevated LDL cholesterol). Indeed, this drug class has encountered a few recent stumbling blocks, though the companies with candidates still in development have expressed great excitement about the potential efficacy. Lilly recently discontinued its development of its phase 2 candidate LY2409021 after a phase 2 blood pressure trial failed to meet its primary endpoint. Further, at this year’s AACE, Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX) expressed skepticism about the class, cautioning that though GCGR antagonists boast exciting glucose-lowering efficacy, the long-term impacts are largely unknown. However, Isis and Ligand both have GCGR antagonists in early clinical development and have offered very positive commentary on the class. Isis recently initiated a new phase 2 trial of its candidate ISIS-GCGRRx and Ligand shared in its 3Q15 update that it plans to initiate phase 2 for its candidate LGD-6972 in mid-2016.

Symposium: Pipeline Therapies For Type 2 Diabetes

GPR Agonist: Ready for Prime Time?

Fiona Gribble, DPhil, BM, BCh (University of Cambridge, UK)

Dr. Fiona Gribble discussed G-protein coupled receptors (GPCRs) as potential therapeutic targets in type 2 diabetes. For context, she opened by explaining that GPCRs are a massive class of receptors found in hormone-secreting enteroendocrine cells (EECs) that can produce GLP-1 and promote insulin secretion while sending satiety signals to the brain. However, as opposed to other targets, GPCRs are particular attractive because they are easy to activate (or block) with specificity. Dr. Gribble also pointed to the great diversity of GPCRs – GPR30, GPR40, GPR119, GPR120 – that are often found only in particular tissues, thus reducing the potential for off-target side effects. As such, she positioned interest in GPCRs as appropriate despite relatively poor results seen with some recent candidates (e.g., Takeda’s GPR40 agonist) and argued the lack of efficacy seen in clinical trials is more likely to reflect our relatively limited understanding of the class vs. the insignificance of GPCRs as a whole. She noted that the co-action of various GPCRs may offer the best potential solution in the future or that combinations with our drug classes, such as DPP-4 inhibitors, are needed for greater efficacy. Ultimately, Dr. Gribble suggested that there are far too many unanswered questions for the field to lose interest in this approach. Indeed, we felt that she remained very optimistic as she stressed that raising gut hormone levels is one of the hallmarks of gastric bypass surgery – in her view, drugs that boost gut hormone levels must reasonably be expected to mimic some of the beneficial effects of bypass surgery. She did acknowledge that the challenge is mimicking the scale (a 10-fold increase in hormone secretion) of the effect we see after surgery, suggesting that perhaps targeting the distal gut in addition to the proximal gut offers one avenue for increasing hormone secretion more significantly.

FGF-21 as a Potential Therapeutic Approach

David Moller, MD (Lilly, Indianapolis, IN)

Dr. David Moller summarized research examining the promise of fibroblast growth factor-21 (FGF-21) as a therapeutic approach to treating type 2 diabetes. He began by walking through the history of the molecule’s discovery and development, speaking in glowing terms about the vast potential. He noted, though, that some of this enthusiasm has diminished in recent years given clinical findings from Lilly and Pfizer that the analog did not show statistically significant reductions in glucose. Despite these negative results to date, Dr. Moller remained convinced that the net relevance of these potential effects in humans has yet to be fully described. He suggested that other lines of evidence also point toward indications in fields other than diabetes or obesity (such as in dyslipidemia or NASH) as possible alternative therapeutic uses. Indeed, we heard Dr. Hans-Ulrich Haring (University of Tubingen, Germany) discuss the importance of fatty liver disease as a driving factor within diabetes at this past EASD. Several critical questions remain to be addressed, though overall, Dr. Moller seemed cautiously optimistic that FGF-21 based therapies could potentially be harnessed in the future as novel approaches to prevent and treat a variety of metabolic disorders.

  • FGF-21 mechanism of action: Unlike other members of the FGF family, FGF-21 is not mitogenic (does not promote cell division), which suggests that it would not be carcinogenic. Preclinical studies suggest that FGF-21 exerts its positive metabolic effects by increasing metabolic rate (increasing energy expenditure). With regards to its molecular mechanism, FGF-21 binds to FGF receptors, of which FGF-1R is of primary interest. β-Klotho (KLB) is an obligatecofactor for FGF-21 binding to FGF-1R, and is also sufficient for FGF-21 stimulation of glucose uptake in adipocytes where it is not normally expressed. Downstream, FGF-21 increases adiponectin levels, reduces levels of free fatty acids, increases leptin sensitivity, and potentially causes “browning” of white adipose tissue (a very exciting prospect).
  • Adverse events: Notably, Dr. Moller acknowledged that there has been a signal of bone-density reduction associated with FGF-21 treatment in mouse studies though stressed that the relevance of this data in humans has yet to be examined.

IDF Award Lecture: Basic Science

Cellular Communication, Insulin Resistance and the Pathogenesis of Type 2 Diabetes

C. Ronald Kahn, MD (Joslin Diabetes Center, Boston, MA)

IDF Award Recipient Dr. C Ronald Kahn delivered an in-depth presentation on the pathogenesis of type 2 diabetes and obesity, highlighting several key underlying mechanisms: protein kinase C (PKC) δ expression, adipose tissue inflammation, concentration of brown/beige fat, and external (diet) and internal (microbiome) environmental factors. He reviewed relevant data from a series of studies on two mouse models, the B6 mouse (prone to obesity and type 2 diabetes) and the 129 mouse (resistant to obesity and type 2 diabetes). One study found that the disease-prone mice had a higher concentration of liver PKCδ, an enzyme known to promote insulin resistance, than the resistant mice. Further, the overexpression of the PKCδ gene induced fatty liver disease in mice, while knocking it out reduced signs of ectopic fat in the liver. Dr. Kahn noted that humans with obesity and obesity-associated diabetes also have higher levels of PKCδ. He described additional research on the same mouse models, which revealed that leukocyte markers of inflammation in white adipose tissue are higher in B6 mice compared to 129 mice, while 129 mice are resistant to inflammation. 129 mice also have more inducible brown/beige fat than B6 mice, which may also play a role in their resistance to obesity. Next, Dr. Kahn discussed outcomes of two studies using separate 129 mouse cohorts from different vendors, echoing comments he made at last year’s Research Symposium on Diabetes and the Microbiome. The two groups of 129 mice were raised in different environments, leading to significant changes in the gut microbiome that altered their propensity for glucose tolerance and obesity: both displayed strong glucose tolerance, but one was obesity resistant while the other was obesity prone. Dr. Kahn’s lab found that many of the differences were eliminated when the two lines were bred for three generations in the same environment, but each strain still retained a unique microbiome. Notably, after three generations the two 129 strains had very similar and low levels of weight gain. This suggests that the difference in microbiome contributed to the discrepancies in weight gain observed in early generations, highlighting how simple changes in the external environment can meaningfully alter the the microbiome and influence metabolic outcomes.

  • Additional research attempting to modify the gut microbiome revealed that transplanting a B6 microbiome into a germ-free mouse led to weight gain and high blood glucose. Moreover, administration of antibiotics caused dramatic changes in the microbiome, radically decreasing diversity across all mouse strains. In B6 mice, antibiotics decreased the expression of liver inflammatory genes and improved insulin resistance, thought these changes were not observed in the 129 mice. Dr. Kahn emphasized the need to understand how the whole bacteria community contributes to metabolic syndrome phenotypes, rather than the contribution of individual bacterial species.

CDA 2015 Young Scientist Award

Toward a Complications-Free Life: Early Detection and Intervention Strategies in Type 1 Diabetes

Bruce Perkins, MD (University of Toronto, Canada)

In the heartfelt CDA Young Scientist Award lecture, University of Toronto’s Dr. Bruce Perkins shared optimism for use of SGLT-2 inhibitors in type 1 diabetes. His team plans to test SGLT-2s as an adjunct to dual-hormone closed-loop. Dr. Perkins specifically mentioned the ongoing phase 3 study of empagliflozin in type 1 diabetes (EASE2), which follows positive proof of concept studies of SGLT-2s in type 1. He admitted that euglycemic DKA is a concern in type 1, but it should not prevent use of the drug in his view – we just need to be proactive about preventing later-stage DKA. Dr. Perkins shared that his team is planning to add an SGLT-2 inhibitor on top of insulin-glucagon closed-loop, which could really helpful attenuate postprandial spikes. There was no timeline on when this study could begin, but we certainly can’t wait to see those results, especially because adjunctive liraglutide and pramlintide have shown only modest benefits in the closed-loop setting. Cost is also a concern with any adjunct to insulin-only closed loop ... (As an aside, Dr. Perkins seemed less optimistic on insulin-only closed-loop – he noted a larger improvement in time-in-range with the Bionic Pancreas vs. the Cambridge system, and highlighted Dr. Ahmad Haidar’s data from ADA 2015 showing an advantage insulin+glucagon to insulin-only overnight. This debate will have much better data once the Bionic Pancreas team completes its head-to-head insulin-only vs. insulin+glucagon studies next year).

  • More broadly, Dr. Perkins talked about ongoing validation of Corneal Confocal Microscopy (CCM) to predict future neuropathy, and work on nephropathy through the PERL study. The former was new to us and is currently in a 1,040-patient study with 6-8 years of follow-up. The goal is to establish the diagnostic thresholds for future prediction of neuropathy before patients show any signs of the complication. That would be big indeed. Notably, CCM could be combined with retinal screening visits, offering a more integrated approach to complications screening.

Debate: Do We Still Need More Outcome Trials In Diabetes?

Yes, Nothing Else Truly Suffices

David Nathan, MD (Harvard University, Boston, MA)

Arguing in favor of outcomes trials, Dr. David Nathan asserted that while observational studies can raise important questions that inform future trials, only controlled experimental studies can sufficiently control for bias and confounding, properly assess risk, and demonstrate causal relationships. This is evidenced by the list of prominent discrepancies between epidemiological and experimental studies in the past. Dr. Nathan did acknowledge the concerns about cost and generalizability with RCTs and noted the recent push for “pragmatic trials” to help bridge the gap to real-world practice. He did not explicitly endorse this approach, but we believe it could be a very promising way to strike the right balance between scientific rigor and clinical relevance. Dr. Robert Califf, President Obama’s nominee for FDA Commissioner, has been an advocate of pragmatic trials in the past, suggesting that this could become a priority for the FDA if he is confirmed. On the more specific question of whether outcomes trials are needed for diabetes drugs, Dr. Nathan argued that while there is strong evidence in favor of A1c as a surrogate for microvascular benefit, the lack of clarity in the macrovascular arena means that outcomes trials are still required. Even if that is the case, we believe there is still plenty of room for revision of the current guidelines for these trials, potentially including more flexible endpoints, longer durations, or use of active comparators. We look forward to watching results emerge for GRADE, a trial that Dr. Nathan is helping lead.

No, There Are Other Good Alternatives

David Matthews (Oxford Centre for Diabetes, Oxford, UK)

On the opposing side, Dr. David Matthews argued that while RCTs are the gold standard for answering explicit, limited questions, “the truth from an RCT can be very thin.” He showed a pie chart illustrating the tiny fraction of the total type 2 diabetes population enrolled in most CVOTs and argued that this is often not sufficiently acknowledged when interpreting results. He also noted that trial results only refer to the mean or median outcome of an intervention, and the wide distribution of individual responses is often forgotten when interpreting the data. As many others have noted, he argued that most current CVOTs may be too short to provide useful information: UKPDS would also have been neutral if it lasted 18 months to three years.  Most importantly, Dr. Matthews believes that conducting RCTs of specific drugs in patients with advanced diabetes is not the smartest approach to tackling the epidemic. He argued that it is very clear from epidemiology that rising obesity prevalence is driving rising diabetes prevalence and that it would be more prudent to focus on large-scale prevention efforts comparable to those in the infectious disease field. Dr. Matthews also made the oft-cited point that these trials are very expensive, estimating their cost at $8-$16 billion by 2020.

  • “Could we do something more useful with $16 billion?” We thought this was an excellent thought-provoking question – while the information gained from CVOTs has clearly been valuable, it is less clear whether it has been worth the cost. Dr. Matthews’ proposed alternative topics for investigation:
    • Scaling up community prevention interventions
    • Primary pathology of the beta cell
    • Effects of calorie labeling and soda taxation
    • Optimizing retinopathy screening and prevention of blindness
    • Biological solutions like stem cells and transplantation

Debate: Incretin Therapies and Cancer

We Still Need To Be Cautious

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

Dr. Daniel Drucker urged caution in the debate over cancer risk with incretin therapies, focusing primarily on the potential risk for colorectal cancer. He argued that there is a “paucity of excellent data” on any type of cancer with incretins, as clinical trials (including CVOTs) are too short to properly evaluate the risk and retrospective analyses can’t correct for confounding variables. He did not express an enormous amount of concern over the risk of medullary thyroid carcinoma (MTC), as the incidence is extremely low (1 in 25,000) and the only concerning signals have come from rodents, which have very different physiology from humans in this area (only rodents have GLP-1 receptors on thyroid C-cells). Dr. Drucker predicted that registry studies should provide more color on whether any clinical imbalance exists. He also offered fairly reassuring commentary on pancreatic cancer, noting that the only hints of an imbalance in CVOTs of incretin therapies have favored the active treatment group. As he has in other recent talks (most extensively at Rachmiel Levine in March), Dr. Drucker expressed the greatest concern about the risk of colorectal cancer, as preclinical studies have consistently shown that GLP-1 acts as a growth factor in the bowel. While there is no conclusive human data on the risk, there are some concerning signals. Human biopsy data has shown increased proliferation of epithelial cells in the colon following bariatric surgery (when GLP-1 levels rise), colorectal cancer was the only type of cancer with an increased incidence after bariatric surgery in the Swedish Obese Subjects study, and the ELIXA CVOT of Sanofi’s Lyxumia (lixisenatide) found a 17-10 imbalance in colorectal tumors with the drug. Dr. Drucker was careful to emphasize that this does not constitute conclusive evidence but reminded the audience that “the absence of evidence is not the evidence of absence.”

There is Little to Worry About

Michael Nauck, MD (Diabeteszentrum Bad Lauterberg, Germany)

Dr. Michael Nauck argued that concerns about cancer with incretin-based therapies have been overstated. He cautioned that the FDA adverse event reporting system, from which most concerns about pancreatic and thyroid cancer have arisen, is highly susceptible to reporting bias. He also noted that the best animal studies – involving long-term exposure and careful histological analysis in non-human primates – have found no signs of increased risk of either pancreatic or thyroid C-cell cancers with incretins. Dr. Nauck shared data from a new meta-analysis he conducted (not yet published), which he believes constitutes the most reliable human data on the subject. Using clinical trial data from over 40,000 people on GLP-1 agonists and over 80,000 on DPP-4 inhibitors, it found a risk ratio of 0.96 with a tight confidence interval (0.90-1.03) for all neoplasms. The incidence of MTC was too low to draw any statistical conclusions, but the results for all other types of thyroid carcinomas were neutral (HR = 0.67; 95% CI: 0.37-1.21). The same was true for colorectal cancer (HR = 0.84; 95% CI: 0.57-1.24) and pancreatic cancer (HR = 0.82; 95% CI: 0.57-1.19). Dr. Nauck’s overall practical conclusions were not all that different from Dr. Drucker’s; he even dug up a quote from Dr. Drucker stating that the hypothesis of increased cancer risk with incretins was not supported by the evidence. The main point of disagreement seemed to be on the degree of concern around colorectal cancer, though when pressed during Q&A, both agreed that frequent screening is the most appropriate clinical response to the potential risk at this point.

Panel Discussion

Q: What level of increased cancer risk would be tolerable with drugs that haven’t demonstrated a benefit on cardiovascular or total mortality?

Dr. Michael Nauck: You’ve mentioned the right way to assess risk and benefit. We’re just in the beginning of understanding the benefits. We’ll see results reporting from CVOTs with other GLP-1 agonists soon. One can question whether the design of the studies is suited to bring out the benefits the drugs have under conditions where you allow glucose to be reduce. I think it’s too early now to say given this or that benefit, we can live with this or that increment in cancer risk for rare tumors. We’re not in a position to make that calculation now.

Dr. Daniel Drucker: A lot of drugs don’t show a clear reduction in CV risk in the context of studies. You may be familiar with a drug called insulin; ORIGIN showed no reduction in CV risk but gave valuable information on its negligible effects on tumor formation. We’re not in a position to say yet what is the true risk/benefit ratio. We’re still waiting for most CVOTs to report, and even those studies are likely not sufficient to provide definitive answers for malignancies, even colorectal. We’ll get a dozen or so cases per arm.

Q: Dr. Drucker, can you explain the quote from the paper he dug up?

Dr. Drucker: I still feel the same way for most biology. The reality is that the bowel growth data is newer than two years old. It was just published, and it’s data that was previously replicated in Copenhagen. It’s mouse data. To me it generates a hypothesis and nothing more. In order to test it, you need a much larger, rigorous long-term controlled trial or perhaps a meta-analysis.

Dr. Nauck: I think we have a strategy to reduce risk for colorectal cancer in general since patients at higher risk really should use screening programs. The typical interval between two colonoscopies is three years. I think the duration of exposure that’s been covered comes close to three years. If you do things right and screen, we should be on the safe side.

Q: What about SGLT-2 inhibitors and cancer? Preclinical data did show some signals of renal carcinoma and blood cancer. Is there any potential risk there with long-term clinical use?

Dr. Nauck: That’s an unexpected question. I remember the discussion about dapagliflozin and bladder tumors. Now empagliflozin has reported some beneficial effects on renal outcomes. I think we have to continue to monitor it, but today I don’t know of a strong signal that would lead us to expect increased rates.

Dr. Drucker: I think that data is pretty unconvincing.

Q: The drugs we’re talking about are not first line. Can you comment on the difference in risk with GLP-1-based therapies combined with metformin vs. used separately?

Dr. Drucker: Not really; the dataset is insufficient. There’s huge literature suggesting we should use metformin as an anti-cancer agent. There’s an NIH-sponsored trial with breast cancer that should report soon. Most metformin cancer data is retrospective, not controlled. We will get good high-quality data to see if we need to put metformin in the drinking water.

Dr. Nauck: My clinical conclusion is that these drugs are best used in combination with metformin. That should take care of the cancer risk to the best of our knowledge today.

Q: Do you feel comfortable prescribing incretins for a patient with a history of pancreatitis?

Dr. Drucker: No, I don’t think you should. There’s a very slight risk with incretin-based therapy and there are lots of other ways to treat diabetes.

Q: What about the risk of benign colonic adenomas?

Dr. Drucker: I’ll answer your question with Dr. Nauck’s reminder that if you’re concerned, you should have regular colonoscopies. I can’t answer the question. We don’t make clinical decisions based on mouse data. There’s no compelling human data, so it’s up to the physician.

Q: Given the rarity of events and the difficulty to distinguish them in clinical trials, what is the answer to determining risk? Will registries give us the data we need or will people avoid treatment of those with chronic polyps who are at the highest risk so we’ll never know? Will we rely on post-marketing CV trials that recruit a different population to look for tumors?

Dr. Nauck: I only recommend that kind of activity if there is a real signal in humans that there might be an increased risk. Then to nail that, registries are one way of keeping our eyes open. Adenomas can be managed, and sending continuous data to a database is helpful. I don’t think that’s necessary if there’s no real signal that we have to be afraid of a real increase in risk. I don’t see that now.

Dr. Drucker: I don’t see it either because we don’t have the data.

Non-Industry Satellite Symposium: Joint Symposium of the Diabetes & Cardiovascular Disease EASD Study Group and the Munich Diabetes Research Group e.V.

Antihyperglycemic Drugs and Heart Failure

Eberhard Standl, MD (Diabetes Research Group e.V. at Helmholtz Zentrum München, Munich, Germany)

Dr. Eberhard Standl tackled the complex subject of diabetes drugs and heart failure, calling for greater attention to the topic in clinical trials. Echoing recent comments from CODHy, he noted that a large number of patients in recent CVOTs for diabetes drugs likely had undiagnosed heart failure. For example, he suggested that 25% of participants in SAVOR and EXAMINE should have been worked up for acute heart failure and over 50% for chronic heart failure based on biomarker measurements, yet the actual percentage of diagnosed patients was only ~12.8% and 27.8%, respectively . He argued that future CVOTs should attempt to capture all cases of heart failure at baseline using BNP measurements and include a composite of heart failure hospitalization and CV death as a key secondary outcome. Even if the FDA requirements do not change, we expect there will be increased attention to heart failure in future trials given the growing consensus around its relevance in diabetes and the unexpected results from recent studies. In terms of specific drug classes, Dr. Standl suggested that the story for the TZDs is a complicated one. The shift away from insulin resistance and fatty acid metabolism induced by the class should be beneficial, but the adverse effects of increased fluid retention may outweigh those benefits at least in patients with existing heart failure. He offered no silver bullet explanation for the much-debated discrepant heart failure results from the three DPP-4 inhibitor CVOTs or for the unexpected benefit in EMPA-REG OUTCOME. He did suggest that the contribution of heart failure to the mortality benefit in EMPA-REG OUTCOME may be “getting overrated” because heart failure only accounted for 25% of those deaths. However, as noted in the morning panel, that figure may be a significant underestimate given the potentially high rate of undiagnosed heart failure and the difficulty ascertaining cause of death in many cases.

Corporate Symposium: Getting to the Heart of Cardiovascular Risk in People with Type 2 Diabetes (Sponsored by Lilly/BI)

Take Heart: Contemporary CVOTs and EMPA-REG OUTCOME

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

Dr. Silvio Inzucchi reviewed the now-familiar EMPA-REG OUTCOME results, emphasizing their dramatic and unprecedented nature. He particularly stressed the importance of heart failure as an outcome in diabetes trials now that more patients are surviving heart attacks and living longer with cardiac damage. He also suggested that many EMPA-REG OUTCOME participants likely had subclinical heart failure at baseline. The importance of heart failure in CVOTs for diabetes drugs has emerged as one of the strongest points of consensus in the field since the first trials have begun reporting results. Some have suggested that heart failure should be incorporated into the primary composite endpoint for these trials or at least be evaluated as a key secondary endpoint. The challenges involved in diagnosing and adjudicating heart failure seem to be the biggest practical hurdles, but we expect that this will become a higher priority in future trials given the surprising results (positive in EMPA-REG OUTCOME and negative in SAVOR) that have emerged thus far. On the question of the hour – what drove the benefit in EMPA-REG OUTCOME – Dr. Inzucchi echoed the most common hypothesis that osmotic diuresis seems to be the most likely explanation, though he stressed that there are plenty of other options that need to be investigated. He did argue that the benefit was almost certainly not mediated through atherosclerosis or glucose lowering given the extremely small difference in glycemic control between groups and the lack of a significant effect on MI or stroke.

The Heart of the Matter: CV Risk Reduction in Type 2 Diabetes

Sanjay Kaul, MD (Cedars-Sinai Medical Center, Los Angeles, CA)

Dr. Sanjay Kaul contextualized the implications of the EMPA-REG OUTCOME results from a regulatory standpoint. He began by presenting the compelling benefit-risk profile demonstrated in the trial: 17 fewer MACE events, 22 fewer cardiovascular deaths, seven fewer MIs, 25 fewer overall deaths, and 14 fewer hospitalizations for heart failure vs. 53 excess genital infections and five excess strokes for every 1,000 patients treated with empagliflozin (Lilly/BI’s Jardiance). He argued that this benefit-risk profile justifies a Class I recommendation (meaning the benefit greatly outweighs the risk and the treatment should be administered). The next question is whether further studies must be performed to justify a Class IA designation (sufficient evidence from multiple randomized trials or meta-analyses, vs. a Class IB designation where the evidence comes from a single randomized trial or nonrandomized studies). He argued that the highly significant p-value of p<0.0001 is sufficiently persuasive since it means there is a 91% chance that future studies would replicate the findings. For comparison, the likelihood is only 50% for a p-value of 0.05. Dr. Kaul admitted that when he first encountered the EMPA-REG OUTCOME results, he was skeptical and wondered if the findings were “too good to be true.” However, he now believes that the results are likely to be valid based on the large and early benefit observed, the highly statistically persuasive findings, the large number of events in the trial, and the consistent effect seen with both doses. That said, Dr. Kaul believes that the data do need to be replicated given how “unexpected and unprecedented” they were. He concluded on an uplifting note by stating that if the results hold up to regulatory scrutiny, the long-sought “holy grail” of a diabetes drug that improves cardiovascular outcomes may have been achieved.

  • Dr. Kaul presented a Bayesian analysis supporting the validity of the EMPA-REG OUTCOME all-cause mortality results (32% reduced risk). Even when using a skeptical prior (which assumes a large treatment effect is unlikely), Dr. Kaul found that there is a 92% probability of a 15% risk reduction in all-cause mortality. Using the baseline non-informative prior (which makes no assumptions about the expected treatment effect), the probability of a 15% risk reduction increased to over 99%. Dr. Kaul emphasized that even with skepticism injected into the data, they still hold up to scrutiny and stated that he is very comfortable using this 92% probability when making clinical decisions.
  • Dr. Kaul suggested that it’s a “slippery slope” to attempt to explain the mechanism behind the risk reduction. Like most speakers we have heard over the past few months, he ruled out glycemic control, blood pressure lowering, and weight loss as likely factors. He also dismissed the idea that background medications could have exerted a harmful effect in the placebo group or a cardioprotective effect in the empagliflozin group because there was no significant difference in additional medications between the two groups. He suggested that that volume depletion and antiarrhythmic effects were potential drivers of the risk reduction and repeated his quip from EASD that “multifactorial” is often a euphemism for “we simply don’t know.” Ultimately, he emphasized that future mechanistic studies are required to pick apart the exact mechanism behind the risk reduction.
  • Dr. Kaul suggested that a beneficial SGLT-2 inhibitor class effect cannot be assumed and that the current evidence more strongly favors a cardioprotective benefit for AZ’s Farxiga (dapagliflozin) than for J&J’s Invokana (canagliflozin). Dr. Kaul argued that a class effect is still an unanswered question since the cardioprotective benefit of empagliflozin is unlikely to be mediated by cardiometabolic factors. He emphasized the importance of continuing the ongoing cardiovascular outcomes trials for SGLT-2 inhibitors in order to provide a more definitive answer to the question of a class effect.

Panel Discussion

Dr. Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA): Dr. Wright, is the evidence generated generalizable? Do you think it’s practice changing? What do you think about African-Americans in this trial?

Dr. Eugene Wright (Cape Fear Valley Health Affairs, Fayetteville, NC): Clinical studies like this are informative and potentially actionable to the extent that they represent patient populations we see. In my area, we have a large population of African-Americans, Hispanics, and Native Americans, who were clearly underrepresented in this study. That said, the results we see are very encouraging. I must admit when I first saw them, I was very excited about the benefit. Now we not only have a therapy that gives glycemic benefit, improves markers like blood pressure and reduces weight (which makes patients happy), but now it has an indication that it may actually be saving lives. As the ongoing studies are looked at, I hope we do get to see if this benefit extends to special populations.

Dr. Kaul: What do you make of the mortality data? What’s driving the effect?

Dr. David Fitchett (St. Michael’s Hospital, Toronto, Canada): I can say what does not contribute. I don’t think it’s an atherothrombotic effect and I don’t think it’s the reduction of MI or stroke. I don’t think it’s the anti-hypertensive effect. An early separation of mortality curves was seen in heart failure studies. If we look at eplerenone and beta blocker trials, we see mortality benefits with under three months of treatment. My feeling is it has to do with the myocardial effect or the effect on heart function or metabolism. Certainly the osmotic diuretic effect is probably a reasonable hypothesis. We know that in heart failure patients if you treat to increase hematocrit and reduce circulating plasma volume, patients do better in terms of heart failure symptoms and have reduced mortality.

Dr. Kaul: Dr. Inzucchi, as a practicing endocrinologist, what role do you see for this drug in the therapeutic armamentarium? You wear many hats and one is a writer of guidelines. What impact do you feel this has on future guidelines? Do you feel vindicated that you preempted this to some extent by including SGLT-2 inhibitors in the latest iteration of the ADA/EASD guidelines?

Dr. Silvio Inzucchi (Yale University, New Haven, CT): In 2015, when the ADA and EASD asked us to update the guidelines, we included SGLT-2 inhibitors. There was some discussion among us of whether this was too soon. At that point, the drugs had only been on the market for less than three years. We felt based on the safety data, tolerance, and popularity with patients, they deserved the second-line therapy status and, in retrospect, we were right. I’m certainly glad we included them. I’m not sure if our panel will be asked to write the next iteration; we’re at the behest of the ADA/EASD committees. However, most organizations are conservative in their guidelines. They want good evidence and perhaps a multiplicity of evidence. For me, the data are good enough to change my practice for patients who meet the criteria for inclusion in EMPA-REG OUTCOME. However, it would be major mistake to be overenthusiastic and extrapolate the data to patients who are lower risk. I don’t know the timeline for next set of guidelines, but perhaps the committee will want the data to percolate before rushing to change the guidelines.

Dr. Kaul: If you have a mortality benefit from EMPA-REG OUTCOME, is it ethically justified to conduct another trial with empagliflozin to replicate the mortality results? In terms of an evidence level of A or B: if the FDA allows a superiority claim for empagliflozin for cardiovascular mortality then I think it’s a no-brainer – the evidence should be level A, not B.

Dr. Inzucchi: The ADA/EASD document is a position statement, it’s actually not a set of guidelines. “Guidelines” means it incorporates all levels of evidence. Ours is a position statement because we realized there is no data to make recommendations and no comparative trials. It’s essentially expert opinion, which is the lowest form of evidence we have.

Dr. Wright: In terms of changing practice, from a primary care perspective, it’s hard to deny the benefits vs. the risks. It’s hard to make the argument for not wanting to incorporate empagliflozin into practice. We need to understand the limits of who was included in the study and who was not represented, but when you see this kind of benefit analysis, it’s something I think we all get pretty excited about.

Q: How do you explain the increase in non-fatal stroke 30 days after stopping empagliflozin? Did the data break up in terms of hemorrhagic vs. ischemic stroke?

Dr. Inzucchi: There were few hemorrhagic strokes. They were mostly ischemic, which is what tends to occur in diabetes.

Dr. Kaul: If you look at the pharmacokinetics of the drug, there is very little of it around after day 3, it persists perhaps up to day 7. It’s hard to explain why stroke could be attributable to this drug. There could have been an impact during the phase of active therapy that manifested later. Whenever we have sparse data, the point estimates are very unstable and fragile – they dance around the null. I‘m not putting too much on that, but nonetheless it’s going in the wrong direction and needs to be addressed. The effect was also observed in the canagliflozin program, especially in the early stages. At this point, we’re not sure how to explain it and can only offer an explanation post-facto. If you have volume depletion in a person who is already on a loop diuretic, perhaps it induces watershed infarcts that result in strokes. That information was not captured in the early canagliflozin studies. The short answer is I can’t explain it. If we see a similar effect in other outcome trials, we’ll have to take it seriously.

Q: I’m unfortunately a cardiologist that got involved in preventive medicine. The FDA is mandating billions of dollars in trials in high-risk CV patients. These drugs are easily used and are taking off like crazy. Are we really going to say you need to have a heart attack first to use them? Or how about a stroke or a bypass? At the end of the day, we won’t have a properly powered preventive trial in diabetics. I understand the importance of evidence-based medicine but I also understand logic and imperative of preventing these things. Thoughts?

Dr. Wright: The drug has an indication for glycemia. How you tend to use it and in whom is a decision you and the patient make. The study fuels a different conversation about why you’re giving this drug. Many patients I’ve had on SGLT-2 inhibitors before the outcomes findings had great results. Now, in the appropriate patients, I’m able to have a different conversation about why it’s beneficial.

Dr. Kaul: There’s an art of medicine and a science of medicine component. From a regulatory perspective, the science of medicine trumps art. But as physicians, once a drug is approved, we’re free to use it for the appropriate indications. Here’s where it’s tricky: what is driving the benefit? Is it possible that more than 10% of patients had heart failure at baseline? Because it was not captured in a systematic way, my guess is a fairly larger number of these patients, who had to have prevalent ischemic heart disease, had heart failure. That’s the reason why we can only at this point say people with established heart disease are appropriate candidates because the mechanism of benefit might be mediated through that.

Q: Can you elaborate on the causes of cardiovascular death? You talked about heart failure and sudden death. There was also a significant percentage of unspecified deaths – do we have data on this?

Dr. Kaul: As best as I know, it’s un-assessable. We really don’t know what they were. By convention, “other causes” is anything that has ruled out cardiovascular causes. I’m not aware of any more granularity of deaths.

Q: But there were still a number of deaths that were included under cardiovascular deaths but marked “other.”

Dr. Inzucchi: In all large CV trials, if there is no known cause of death such as hit by a bus or cancer, they are all apportioned to “cardiovascular death – other. Dr. Fitchett, what is your underlying sense regarding heart failure outcomes?

Dr. Fitchett: Certainly patients with pre-existing heart failure had a high event rate and a six-fold increase in mortality. Patients admitted to the hospital with heart failure had something like 18% mortality. There’s no question that patients with pre-existing heart failure or who developed heart failure had a high event rate. Sudden death and heart failure death constituted about 50% of mortality. The others were unspecified and classified as cardiovascular death. I think heart failure, either recognized or unrecognized, is a very important part of it. I want to emphasize that heart failure associated with diabetes is very common. In many trials heart failure events are far more common than vascular events like MI or stroke. It’s an outcome that has been under-recognized until recently.

Dr. Kaul: In a non-heart failure trial it is very difficult to adjudicate heart failure outcomes. That’s one reason why we don’t typically include it as an endpoint. One question is regarding the definition of heart failure at baseline and adjudication. It needs to be scrutinized.

Q: The 10 and 25 mg doses appear equivalent. When do you use 25 mg?

Dr. Wright: I start with 10 mg for glycemic effects. If there’s no effect, I go to 25 mg.

Q: In both the placebo and empagliflozin arms statin use was less than 75%. Were you surprised by that? I would have thought it would be more than 90%.

Dr. Kaul: That’s consistent with other non-ACS trials. Only there do you see compliance rates above 85% or 90%. In heart failure or diabetic trials, like all the DPP-4 inhibitor trials, it’s 70-80%.

Dr. Inzucchi: When we looked at the heterogeneity of response we didn’t find any. It didn’t seem like people on statins had an attenuated response.

Q: The results seem to be driven by people with heart failure. Should it only be used in people with heart failure?

Dr. Kaul: I can only address the results for CV death or hospitalization for heart failure. History of baseline heart failure was not an effect modifier. The results were statistically indistinguishable. I haven’t seen the data for MACE yet but I would not be surprised if history of heart failure was not an effect modifier. That’s probably to some extent because it was not recognized. That feeds into my speculated mechanism.

Dr. Fitchett: I don’t think we should say the drug should only be used in people with a history of heart failure or to prevent heart failure. A lot of people with diabetes have subclinical heart failure, so we shouldn’t target just people with a history. There’s heterogeneity there.

Dr. Inzucchi: I would bet $10 that 30-40% of patients had diastolic dysfunction if we had been smart enough to get an echocardiogram at baseline. They were older, there was lots of insulin, and they all had cardiovascular disease. I can’t imagine 90% had normal ventricles.

Dr. Kaul: We concur.

Changing Heartbeats: Challenges and Patients' Emotional Struggles at Insulin Initiation in Type 2 Diabetes

Lawrence Fisher, PhD (UCSF, San Francisco, CA)

Psychologist Dr. Lawrence Fisher gave an actionable talk on adherence to insulin, suggesting that traditional adherence boosting strategies are too narrowly focused. “Medication use is driven by patient feelings, beliefs, and expectations,” he said, and it all starts with more empathetic provider-patient conversations. Indeed, Dr. Fisher recommended everyone read a short NEJM publication on adherence from earlier this year (Rosenbaum et al., 2015), which concludes, “I want to believe that if patients knew what I know, they would take their medicine. What I have learned is that if I felt what they feel, I’d understand why they don’t.” With no change in adherence after 40 years of research (the conclusion of a depressing 2014 Cochrane Review), Dr. Fisher advocated for taking a step back and asking patients why they stop using insulin. His slide summarizing four such studies really supported the psychological underpinnings of adherence to insulin (e.g., “Makes me feel like a failure”; “It overwhelms me”; “It makes me feel hopeless”). Dr. Fisher concluded with eight actionable tips for improving adherence to basal insulin, including (i) a different, ongoing conversation about insulin from diagnosis; (ii) framing the insulin message accurately (not failure!); (iii) addressing fear of hypos and injection phobia; and (iv) conveying the good news about insulin (more energy, better sleep). See below for all eight strategies and the summary of what basal insulin stoppers said – as well, see Q&A between Dr. Fisher and the very respected Dr. Silvio Inzucchi (we were very impressed by his question and obvious care for patients).

  • Dr. Fisher summarized patient responses from four studies to questions like “What are the very good reasons you have for not taking this medication?” and “What is it like for you to take this medication?” (Polonsky et al., Diabetes Care 2005; Karter et al., Diabetes Care 2010; Fisher et al., Pt. Educ Counseling 2012; Rosenbaum NEJM 2015).

Summary of Common Patient Responses Across Studies

  • “Reminds me I’m sick, that I am not normal”
  • “I don’t like putting unnatural things in my body”
  • “No real benefit”
  • “I can do it myself by exercise and diet” (control)
  • “Make me feel like a failure”
  • “It make me feel ashamed that I have this disease”
  • “I am embarrassed by having to take it”
  • “I am not sure I really trust what they tell me”
  • “It makes me feel hopeless”
  • “It overwhelms me”
  • “I am afraid of the future (complications) – it scares me”
  • “I can’t manage it – it’s too complicated”
  • “I don’t like the idea that I HAVE to take it”
  • Dr. Fisher provided eight practical tips for enhancing insulin use, mostly focused on the language providers use. The strategies definitely came from the perspective of a psychologist, but were based in both scientific literature and Dr. Fisher’s clinical experience. We wonder if scripts could be developed to help HCPs use the right words when talking about insulin.  

1. Have a different, ongoing conversation about insulin from diagnosis

Be an active listener and reflect (hard for HCPs). Label, acknowledge, and accept beliefs, attitudes, and feelings – repeat and summarize. Highlight changes over time. Normalize. Don’t try and change how someone feels or believes – you’ll fail. Ask questions like: “Do you know anyone who is taking insulin? How has it been for them? How would you feel about taking insulin? What troubles you the most about insulin? What might it mean to you to take insulin?”

2. Restore a sense of personal control and choice

Provide options. Try time limited experiments (e.g., measure BGs for one week, then start taking insulin for one week and compare the blood glucose results). Ask how patients might want to test the accuracy of a belief. Distinguish between fears and realities. Point out both sides of the ambivalence (“I can see that you are worried about your diabetes. But you also have concerns about taking insulin. It seems like you are caught in the middle here”). Allow patients to direct the interaction.

3. Enhance self efficacy

Try things in the office. Schedule frequent follow-ups for selected patients. Allow patients to meet with other patients. Send reminders (they work in the short-term).

4. Frame the insulin message accurately

So often insulin has to do with failure and blame. But it’s an expected part of having diabetes, and it’s no reflection on a patient’s management. Tell patient it may be odd at first (anticipate how they might feel). Normalize concerns. Link to A1c or other health-related targets and goals to concretize the experience.

 

5. Address fear of hypos

Address real or imaginary fears. Normalize. Try a brief experiment as a test. Use low doses to start.

6. Address injection phobia

True injection phobia is ~2-3%. What seems like injection phobia is often a cover for other things: low self-efficacy, other beliefs, feelings, and expectations. Do office demos.

7. Convey the good news about insulin

Emphasize potential improvements in sleep, energy, highlight changes in target values, A1c, blood glucose levels, clock changes in mood over time.

8. Repeat frequently because things change

This process is key after diagnosis, when the number or dose of orals increase, and when insulin is first suggested.

  • Dr. Fisher said traditional approaches to improving adherence have relatively small effect sizes, low bang for the buck, and don’t work as well as we would like (“necessary but not sufficient”). These include behavioral (CBT), education, team-based care, social and peer support, different packaging, reminders (successful early on, but waning effectiveness over time), reducing co-pays and cost (“modest results”), and increasing the time between refill or using mail order. Dr. Fisher lamented that there has been no change in adherence after 40 years of research (per a 2014 Cochrane Review).
    • The most effective adherence strategies employ very complex multi-components target interventions. Unfortunately, Dr. Fisher said these are “impractical” and “too expensive” in real-world use.
  • No patient characteristics consistently distinguish between medication takers and non-medication takers across measures or studies (age and gender are possible exceptions). Even within the same subjects, different ways of measuring adherence yield different results (self report vs. medication monitoring with a chip in the pill bottle vs. claims data). Studies generally find a ~20% higher rate of adherence with self-report vs. medication monitoring or claims data. Medication use is also highly variable both within and across subjects, making prediction difficult. Dr. Fisher further noted that most predictors that are significant are not actionable (age, gender).

Questions and Answers

Dr. Silvio Inzucchi: There has been progress in diabetes towards less frequent administration of drugs. We have once-weekly GLP-1 and even once-weekly pills. Is there data that improves adherence?

Dr. Fisher: It improves adherence in some patients, but makes it worse in others. A number of patients wonder if the strength is sufficient to be maintained over the course of a week. They just don’t trust it. So it’s a mixed blessing – it’s helpful for some, and not helpful for others – which speaks to the need for patient-centered care.

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

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

Neil Poulter, FRCP (Imperial College London, UK)

Professor Neil Poulter offered his very candid take on the “misinterpretation and disappointment” that have characterized diabetes cardiovascular outcomes trials (CVOTs) to date. He began by contextualizing the body of epidemiological evidence that has demonstrated a causal relationship between levels of blood glucose and major cardiovascular events, citing the strong dose-response relationship that has been observed in multiple studies (e.g., EPIC-NORFOLK). However, with the exception of the recently published results of EMPA-REG OUTCOME, Professor Poulter noted that the benefits of lowering blood glucose on major cardiovascular events have been disappointing – from the results of ACCORD to more recent CVOTs – and have prompted an important question: How can we rationalize the paradoxical adverse effects of glucose lowering on cardiovascular outcomes? Professor Poulter discussed a number of possibilities: Were trial results wrong due to power or chance? Could harm been caused by other off-target damage? Were interventions too short and too small? Were the wrong populations studied? He noted that the reasons behind the underwhelming effect of glucose lowering on major CV events remain unclear and that the even more unexpected, cardioprotective results of EMPA-REG have only add to the confusion. Professor Poulter labeled the findings “a TOTAL sea change,” stressing more broadly that the unknown mechanism should encourage caution in thinking about the coming results of LEADER – much more on that below!

  • Professor Poulter cautioned that the positive findings from EMPA-REG OUTCOME should not be generalized to other CVOTs, specifically Novo Nordisk’s LEADER trial for Victoza (liraglutide). Indeed, in spite of the very positive pooled MACE analyses of liraglutide to date [HR = 0.56 (95% CI: 0.34, 0.93), Professor Poulter was strikingly adamant. He positioned the remarks not as a critique but as a realistic take based on history of disappointing and paradoxical findings. Professor Poulter pointed in particular to the initial CV outcomes analysis of sitagliptin prior to TECOS that seemed to hint at cardioprotection – an exposure-adjusted hazard ratio of 0.83 – but eventually showed “not even the slightest hint” of a benefit. The remarks came as a valuable reminder of the importance of managing sky-high expectations and resisting the temptation to overgeneralize from a single study. As a reminder, Novo Nordisk Chief Scientific Officer Dr. Mads Thomsen has repeatedly expressed cautious optimism regarding the trial’s ability to show superiority. That said, we’ve heard from many KOLs that 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.
  • On the topic of intensive glucose control, Professor Poulter disagreed with the ADA’s decision to change the recommended A1c target in adults to >7.0% from >6.5%. Said Professor Poulter, “I suspect that this is NOT the right thing to do.” He pointed out that VADT and ADVANCE both showed no increase in mortality with intensive control, suggesting instead that the ADA has reacted too hastily to a single study. He drew an analogy to the FDA and EMA’s response to rosiglitazone adverse event data, suggesting that we may be making the same mistake twice. Certainly, we think there is still much to learn about the tradeoffs of tight vs. lenient glycemic control – e.g., how does glycemic variability play a role? – and we appreciated Professor Poulter’s effort to bring this conversation into the spotlight.
  • We found Professor Poulter’s impressions of FDA clinical trial assessments particular fascinating as he suggested that the Agency has become increasingly lenient (in an ironic sense) in the way it thinks about safety post-rosiglitazone – see image below. He opened by reviewing the various clinical trial result scenarios and the resulting likelihood of approval: (i) upper HR limit of 95% CI<1.0 -> approvable (no need for post-marketing study); (ii) 1.0<upper HR limit<1.3 -> approvable (need for post-marketing study); (iii) upper HR limit>1.8 -> not approvable. He noted that these cutoffs (HR= 1.0 vs. HR=1.3 vs. HR=1.8) are arbitrary, noting that that resulting misguided goal is to ensure no extra harm. However, he reminded us that our original thinking was that “lowering glucose should reduce CV events,” impressing upon the audience how much we have sacrificed in getting to our current conception: “If it doesn’t increase the likelihood of a CV event by more than 29% - probably – then we will take it.” Very interesting food for thought to be sure!

Managing Diabetes in Special Populations

Melanie Davies, MD (University of Leicester, UK)

Dr. Melanie Davies summarized data from clinical trials, demonstrating that GLP-1 agonists and DPP-4 inhibitors enable efficacious and well-tolerated treatment options in two specific populations of patients with type 2 diabetes: those who have concomitant mild-to-moderate renal impairment and those who are fasting during Ramadan. As expected, she drew heavily from the results of two major liraglutide trials – LIRA-RENAL and LIRA-RAMADAN. We reported results from the former at EASD 2014: the 26-week study randomized patients (n=279) 1:1 to receive either liraglutide 1.8 mg or placebo as an add-on to oral agents and/or insulin. The results showed significantly superior A1c reductions (-1.0% vs. 0.4%) and weight loss (-2.4 kg vs. -1.1 kg) with liraglutide 1.8 mg compared to placebo. Very importantly, treatment with liraglutide did not result in worsening of renal function, as there were no significant differences between the groups on change in eGFR and urinary albumin/creatinine levels. As Dr. Davies noted, the confirmation of safety is particularly valuable considering the relative lack of antihyperglycemic treatment options available to patients with renal impairment. Dr. Davies then turned to LIRA-RAMADAN, which – as a reminder – found liraglutide to be superior to SFUs in terms of A1c and hypoglycemia for individuals fasting for Ramadan (see our ADA 2015 coverage for more). The results are especially important in the context of the growing diabetes prevalence in the Middle East, and we applaud Novo Nordisk for considering the needs of this special population in a full-scale clinical trial.

Mechanisms in Cardiovascular Effects of GLP-1

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

In this presentation, Dr. Daniel Drucker illustrated the complexity of dissecting the mechanisms of cardiovascular effects of GLP-1 agonists. He opened by stressing that the class’ “single most important” risk factor is its reduction of blood pressure, as he demonstrated that such reductions have been consistently demonstrated in clinical trials of GLP-1 agonists. However, Dr. Drucker noted that the intricacy of the class’ direct and indirect actions on the heart and blood vessels makes it challenging to identify mechanisms or predict the effects, as he touched on research of GLP-1 agonists’ effects on apolipoproteins, vasodilation, diuresis and natriuresis, and more. While GLP-1 receptors are known to be expressed in cardiomyocytes, blood vessels, and platelets, the localization of these receptors remains ambiguous and it is unclear whether some of the class’ benefits seen in rodents can translate into humans. In addition, Dr. Drucker mentioned that while we can collect human data from CVOTs, the patient population studied is very well-defined and not generalizable in fully comprehending GLP-1 agonists’ cardiovascular effects. While CVOTs may provide valuable information, they certainly leave many questions unanswered as seen by the many circulating theories regarding the mechanism of cardioprotection seen in the EMPA-REG trial for Lilly/BI’s Jardiance (empagliflozin).

Corporate Symposium: New Evidence from the TECOS CV Safety Trial and the Role of DPP-4 Inhibitors in the Treatment of Patients with Type 2 Diabetes

Celebrating 20 Years of DPP-4 Inhibitor Research: The Latest Science and Where Will It Take Us?

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

Dr. Daniel Drucker reviewed the complex mechanistic evidence on DPP-4 inhibitors. He explained that the drugs’ glycemic effects are clearly mediated through GLP-1 and GIP and that they likely do not act directly on the heart, despite demonstrating cardioprotective effects with acute administration under certain circumstances. Intriguingly, he also cited recent preclinical studies suggesting promise for DPP-4 inhibitors in immuno-oncology: the drugs prevent degradation of a substance called CXCL10, which increases the number of activated immune cells directed toward tumors. This is an interesting positive counterpoint to the concerns about increased cancer risk that have plagued this class and the GLP-1 agonists over the years. Dr. Drucker himself has suggested in the past that the potential for a long-term risk of colorectal cancer is something to watch with incretin-based therapies.

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

Lawrence Leiter, MD (University of Toronto, Canada)

Dr. Lawrence Leiter reviewed the design and results of TECOS, the CVOT for Merck’s Januvia (sitagliptin). See the full results of this trial from this past ADA and an update on the safety findings from EASD, which were all presented again by Dr. Leiter. In addition, Dr. Leiter briefly walked attendees through the results of other DPP-4 inhibitor CVOTs including SAVOR-TIMI and EXAMINE, noting that they both demonstrated safety but not superiority. Concluding, he highlighted that the TECOS study was similar to SAVOR and EXAMINE, having demonstrated overall CV safety but not superiority of the DPP-4 inhibitor class in high CV risk patients with type 2 diabetes. However as expected, he noted the apparent difference in risk of hospitalization of heart failure amongst the trials as SAVOR saw a small increased risk (HR of 1.27) and EXAMINE saw a numerical increase (HR of 1.19) while TECOS saw no signal. Looking forward, he pointed to ongoing trials that may help provide additional color on these safety parameters and more for other antihyperglycemic agents.

Questions and Answers

Q: How was the diagnosis of heart failure made and who made the decision to be hospitalized?

A: The decision for hospitalization was at the treating physician’s discretion. The decision was not mandated but adjudication criteria was standardized across the study. It’s very similar across all three CVOTs. They virtually had an identical definition across the trials.

Q: Can you comment on the decline of eGFR?

A: There was a very small diff in eGFR in sitagliptin-treated patients. It’s probably not clinically significant. At the moment, we have no additional info.

Q: There were patients on sitagliptin in EMPA-REG – what did we find in those results?

A: In the EMPA-REG results, 10%-11% of patients had background therapy of DPP-4 inhibitors. The clinical benefit was similar to those on DPP-4 background vs. those who are not.

Q: We saw in EXAMINE that although there was a trend of increased heart failure, it wasn’t statistically significant in those with pre-existing heart failure. Patients without heart failure had a statistically significant increase with heart failure risk.

A: You’re correct. It’s an interesting observation, which you wouldn’t expect. But note of caution – we’re talking very small numbers and we don’t know what that means. In the SAVOR study, the relative risk was the same whether they had prior heart failure or not.

Q: TECOS was designed to be a non-inferiority trial so was it powered to prove superiority?

A: What’s interesting and confusing was that SAVOR was always advertised as a superiority trial and TECOS was advertised as non-inferiority trial. But the statistical analysis plan was identical in both studies because of the regulatory requirement of hierarchical analysis. The first analysis is safety, and the second is superiority. So neither study showed superiority.

Clinical Discussion: What Role Can CV Safety Trials Play in Helping Clinicians to Best Treat Patients with Type 2 Diabetes?

Stefano Del Prato, MD (University of Pisa, Italy); Daniel Drucker, MD, PhD (Lunenfeld-Tanenbaum Research Institute, Toronto, Canada)

The top-rate team of Drs. Stefano Del Prato and Daniel Drucker discussed how to elucidate the lingering uncertainty around heart failure risk in DPP-4 inhibitors. During the panel discussion, the audience was informally polled regarding their sentiments on the class’ heart failure signal: most attendees expressed a belief that there may be differences in the class’ products regarding this risk while no attendees voted that all DPP-4 inhibitors had increased risk or that none of the DPP-4 inhibitors had no increased risk. Comparing data from dQ&A’s Diabetes in Primary Care surveys from 2014 and 2015 shows a slight decline in PCPs’ enthusiasm for DPP-4 inhibitors as a second-line therapy after metformin, concurrent with growing enthusiasm for SGLT-2s. Addressing the differences seen in the various CVOTs for the class, Dr. Del Prato stressed the need for better data as he noted that it is very difficult to make any statements without a head-to-head trial of the class’ drugs, as he suggested that the increased risk seen with AZ’s Onglyza (saxagliptin) may be due to chance or its trial’s different patient population or adjudication process. Regarding how to make clinical decisions without this “better data,” he referred to the use of Merck’s Januvia (sitagliptin) as TECOS demonstrated clear neutrality. Meanwhile, Dr. Drucker expressed that he is unsure if even a head-to-head trial can elucidate this uncertainty, as he pointed out that the very rare nature of this adverse event makes it incredibly difficult to delineate its mechanisms. Ultimately however, providers’ moderate concerns over the class’ safety signal appear to be reassured by Januvia specifically with TECOS’ spot-on neutrality – for more on Januvia’s recent growth, please see our coverage of Merck’s 3Q15 update.

Corporate Symposium: Insulin Resistance – Core Defect in Type 2 Diabetes and Implications for Cardiovascular Disease (Sponsored by Takeda)

Combination of DPP-4 Inhibitors and TZDs: A Synergistic Treatment Approach

Guntram Schernthaner, MD (University of Vienna, Austria)

Dr. Guntram Schernthaner discussed the potentially synergistic therapeutic targets of using DPP-4 inhibitors and TZDs in combination. He argued that the two classes are complementary mechanisms of action. DPP-4 inhibitors increase the incretin effect, increase insulin secretion, and suppress glucagon secretion. TZDs, on the other hand, increase insulin sensitivity, suppress hepatic glucose production, and decrease plasma free fatty acids by suppressing lipolysis. Furthermore, there is minimal risk of hypoglycemia with the two drugs and the combination can be administered with once-daily dosing. Overall, Dr. Schernthaner concluded that the combination addresses multiple pathologies of type 2 diabetes, including pancreatic dysfunction and insulin resistance. Dr. Ralph DeFronzo’s (UT Health Science Center, San Antonio, TX) famous triple therapy involves a TZD and another incretin in the form of a GLP-1 agonist. It’s no coincidence that Dr. DeFronzo is also one of the biggest proponents for using a cocktail of drugs to address the multiple pathologies involved in type 2 diabetes. The concept appears to gaining mainstream acceptance, as evidenced by Dr. Schernthaner’s presentation (and the many other presentations at IDF) advocating combination approaches.

  • TZDs have largely fallen out of favor in the last few years, but Dr. Shernthaner defended the class on the grounds of their effect on improving insulin sensitivity and the durability of their effect (which he argued is unmatched by any other class of diabetes drugs). In addition, he highlighted that the ADA/EASD treatment guidelines continue to include TZDs on equal footing with other drug classes as potential second- and third-line options. In addition, he argued that pioglitazone has demonstrated protective effects on multiple organ, including the heart, the brain, the kidneys, and the liver.
  • Looking to the cardiovascular outcomes trial results for pioglitazone and DPP-4 inhibitor alogliptin, Dr. Schernthaner suggested that the two drugs have complementary effects and are a good option for patients with high cardiovascular risk. Alogliptin demonstrated cardiovascular safety with no increase in heart failure while pioglitazone significantly reduced the combined cardiovascular endpoint of death, MI, and stroke and the associated increase in heart failure was not associated with increased mortality.

Corporate Symposium: The Science Behind Early Combination Treatment for Type 2 Diabetes: Current Insights and Perspectives (Sponsored by AstraZeneca)

What is the Role of Glucagon in Type 2 Diabetes?

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

The highly respected Dr. Daniel Drucker discussed the dysregulation of glucagon in type 1 and type 2 diabetes and how new type 2 diabetes drug classes can potentially target these defects. He cited studies showing dysregulation of glucagon suppression very early in the progression of diabetes and others demonstrating an abnormal glucagon response in type 1 diabetes even when glycemia is normalized. With regard to current drug classes, he noted the paradoxical increase in glucagon and hepatic glucose production that occurs with SGLT-2 inhibitors and suggested that combining them with incretin-based therapies could help ameliorate those effects. The latter portion of his talk focused on the somewhat counterintuitive idea of increasing glucagon to treat type 2 diabetes. Dr. Drucker explained that glucagon can exert favorable effects on energy expenditure mediated through FGF-21, but he cautioned that many basic questions (like dose response, tachyphylaxis, and the differences between humans and rodents) remain to be addressed. He cited a recent preclinical study showing very impressive weight loss and glycemic improvements with a GLP-1/GIP/glucagon receptor triagonist but stressed that it is currently unknown whether this approach is safe or translatable to humans. Dr. Drucker’s greatest safety concern with this compound and other glucagon receptor agonists is the potential for adverse cardiac effects, as there are glucagon receptors on the heart and preclinical studies have shown harmful effects of acute glucagon administration during ischemia. Quite a few companies are developing GLP-1/glucagon dual agonists for type 2 diabetes. The class has demonstrated impressive potential in early clinical trials, but cardiovascular safety will certainly be critical to watch as they move through the pipeline.

Is Early Combination Therapy Essential in Type 2 Diabetes?

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

Dr. Stefano Del Prato advocated for the use of combination therapy early in the progression of type 2 diabetes. Dr. Del Prato characterized type 2 diabetes as a progressive disease, marked by both insulin resistance and ongoing loss of beta cell function. As such, he argued that treatment intensification is needed throughout the course of the disease, but noted that “ treatment intensification” often turns into “treatment procrastination” and clinical inertia. He pointed to UKPDS data to show that no matter which diabetes drug you start with, monotherapy will always eventually fail. As an alternative, he suggested combining two or more diabetes drugs that, together, target more of the dysfunctional organs in type 2 diabetes. Dr. Del Prato emphasized the need for a “rational” drug combination that works together to address more than one pathogenic mechanism. An ideal combination would reduce hyperglycemia, reduce hypoglycemia, and either reduce or maintain body weight. In addition to providing sustained efficacy and a low rate of side effects, Dr. Del Prato suggested that a good combination would reduce clinical inertia and improve adherence, resulting in even greater real-world A1c reductions. In terms of timing, Dr. Del Prato asserted that previous trials suggest intensive combination therapy later in the progression of type 2 diabetes is less helpful since patients often already have complications at that point. In contrast, Dr. Del Prato was optimistic that early use of combination therapy could bend the association curve between duration of disease and risk for complications, with the added benefit of preventing beta cell failure. Use of combination therapy in early-onset type 2 diabetes is gaining real traction among clinicians – at a debate during EASD 2015, the vast majority of attendees voted “yes” to the question of whether or not we need triple- and quadruple-therapies in type 2 diabetes. That said, it’s unclear if payers and more cost-conscious health systems are able and/or willing to finance combinations of fairly expensive therapies.

What is the Physiological Rationale for Early Combination Therapy?

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

Dr. John Buse argued that the rationale for early combination therapy in type 2 diabetes is self-evident given the large and growing number of physiological abnormalities associated with the disease. He began by citing his “favorite study of all time”: a paper by Weyer et al. that identified lack of compensatory insulin secretion as the main differentiating factor between high-risk patients who progressed to type 2 diabetes and those who did not. Insulin resistance increased in both groups over time. For the purposes of this talk, Dr. Buse’s main conclusion was that type 2 diabetes by definition involves at least two physiological defects and that loss of beta cell function seems to be the key driver of progression. He also noted that as new drug classes have been developed, it has become clear that type 2 diabetes almost always involves additional defects like a decreased incretin effect, increased lipolysis, and increased glucose reabsorption in the kidneys. Dr. Buse celebrated the availability of so many new drug classes with complementary mechanisms and advocated for aggressive intensification of therapy if the approach fails. He did caution that more clinical trials are needed to validate the benefits of aggressive combination therapy right at diagnosis. Interim results from Dr. Ralph DeFronzo’s triple therapy study likely represent the best evidence to support this approach at the moment, though it is not directly assessing initial combination therapy vs. aggressive sequential therapy with the newest drugs. In terms of specific combinations, Dr. Buse spoke favorably about the potential synergistic effects of metformin/DPP-4 inhibitor combinations on GLP-1 secretion and noted that combining an SGLT-2 inhibitor with a DPP-4 inhibitor and/or metformin can improve efficacy by blunting the increase in hepatic glucose production.

How Do You Select the Right Early Combination Approach for Best Patient Outcomes?

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

Dr. Julio Rosenstock offered his thoughts on fixed-dose combinations in the early treatment of type 2 diabetes. He focused on the four available combinations: DPP-4 inhibitor/metformin, SGLT-2 inhibitor/metformin, SGLT-2 inhibitor/DPP-4 inhibitors, and GLP-1 agonist/basal insulin. He showcased clinical data for AZ’s Kombiglyze (saxagliptin/metformin) and Xigduo (dapagliflozin/metformin) demonstrating greater A1c reductions for the combination than for each component alone. He also pointed to the only SGLT-2 inhibitor/DPP-4 inhibitor combination on the market, Lilly/BI’s Glyxambi (empagliflozin/linagliptin). However, Dr. Rosenstock noted that Glyxambi is the combination of two expensive drugs, compared to metformin combinations, in which metformin is a relatively inexpensive drug. Thus, he felt that combinations with metformin were more appropriate for the early treatment of type 2 diabetes, but suggested that Glyxambi may be an option for those with metformin intolerance. Glyxambi generated significant buzz for its clinical efficacy, however Lilly has barely mentioned the product since its launch in March. Along with the fact that the product’s sales have not been broken out in the company’s earnings calls since its launch, it seems that Glyxambi has yet to gain significant market traction. Finally, Dr. Rosenstock touched on GLP-1 agonist/basal insulin fixed-ratio combinations, emphasizing that the combination can mitigate the weight gain often seen with initiation of insulin therapy.

  • Dr. Rosenstock emphasized that the ideal diabetes medication changes depending on which factor is most important to a particular patient and his/her provider. He noted that diabetes drug selection should take into account a variety of factors, including glucose-lowering efficacy, safety profile, effect on body weight, cost, and cardiovascular impact. As examples, Dr. Rosenstock suggested sulfonylureas and metformin are best to avoid high costs and GLP-1 agonists and SGLT-2 inhibitors are best for weight loss.

Management of Hyperglycemia: Prospects for Therapeutic Advances

Philip Home, DM DPhil (Newcastle University, Newcastle upon Tyne, UK)

Dr. Philip Home argued that future type 2 diabetes therapies will need to (i) alter calorie balance to achieve greater glycemic efficacy or (ii) offer significant non-glycemic benefits. He argued that most current therapies have been able to achieve only modest A1c reductions (“could I call them pathetic?”) because they either flood the system with insulin or otherwise push glucose into the liver. The liver then “fights back” by reducing postprandial glucose uptake and increasing glucose production, limiting the effect of the therapy. Dr. Home argued that only approaches that affect calorie balance will be able to achieve greater glycemic efficacy. This could include GLP-1/glucagon dual agonists (which he sees as particularly promising), SGLT-1/2 inhibitors, fat/carbohydrate absorption inhibitors (if side effects can be reduced), and potentially metabolism enhancers that target the mitochondria. Therapies Dr. Home believes are “unlikely to get anywhere” are G-protein receptor drugs, insulin receptor agonists, 11-beta HSD1 inhibitors, glucokinase activators, glucagon antagonists, and biguanide mimetics. He also suggested that a drug could still be considered successful if it matched the efficacy of current therapies and offered additional benefits like weight reduction (GLP-1 agonists), heart failure benefits (at least one SGLT-2 inhibitor), blood pressure or LDL reductions, or possibly anti-inflammatory or anti-thrombotic effects. We loved hearing this much granularity on what it will take to meet the increasingly high bar for new type 2 diabetes therapies. The role of next-generation versions (such as oral or longer-acting formulations) of existing drug classes was one aspect of innovation not addressed in this talk. While it is unlikely that such products can offer the same sort of dramatic clinical improvements, they may be able to achieve meaningful quality-of-life and adherence benefits that can themselves improve outcomes.

Corporate Symposium: Type 2 Diabetes – Is There a Benefit in Tailoring Treatment to The Asian Phenotype? (Sponsored by Bayer)

What Will The Acarbose Cardiovascular Evaluation (ACE) Trial Tell Us?

Rury Holman, FMedSci (University of Oxford, UK)

Dr. Rury Holman headlined this Bayer symposium by providing an informative overview of the possible role of the alpha-glucosidase inhibitor acarbose in reducing risk of glycemia-related CV disease. He opened by discussing the association between postprandial hyperglycemia and CV disease (STOP-NIDDM study) – “a significant reduction was seen in CV risk but with very few endpoints ” – though acknowledged that we have yet to understand the relationship in its totality. In particular, he raised the findings of the NAVIGATOR trial (that demonstrated that treatment with the short-acting insulin secretagogue nateglinide nateglinide did not significantly reduce the incidence of either of the trial’s two co-primary cardiovascular outcomes), noting two possible confounders: the relatively short duration for a glycemic intervention and the use of an insulin-promoting agent. With these lurking variables in mind, Dr. Holman suggested that there remains a gap in our understanding of acarbose as a therapeutic agent and introduced attendees to the Acarbose Cardiovascular Elevation Study (ACE), a secondary CV intervention trial currently evaluating the effect of acarbose treatment in patients with impaired glucose tolerance. For context, Dr. Holman shared a study by Kato et al. (Cardiovascular Diabetology 2010) that suggested that acarbose has more beneficial effects on postprandial endothelial function than nateglinide and that these effects are mediated by an improvement of postprandial hyperglycemia without accompanying postprandial hyperinsulinemia. As such, the purpose of this trial is to specifically address the role of postprandial metabolism in CV disease. As a reminder the trial began in 2008 with a goal of enrolling 7,500 patients, though Dr. Holman shared that completed recruitment included only 6,526 individuals. Results are expected in 2018.

  • The Acarbose Cardiovascular Evaluation (ACE) Trial is now evaluating the effect of acarbose on CV outcomes. This multicenter, randomized, placebo-controlled, double-blind secondary prevention CV outcomes study is being sponsored by the University of Oxford, is funded by Bayer Healthcare, and is being conducted entirely in China because of the rapidly increasing incidence of diabetes in China. It will examine addition of acarbose or matching placebo three times a day to fully optimized CV disease care over a period of four years and has enrolled 6,526 patients. Its primary endpoint is time to first occurrence of 5-point MACE (CV death, nonfatal MI, nonfatal stroke, hospitalization for heart failure or hospitalization for unstable angina).

Corporate Symposium: Every Patient Matters – Towards Improving Population Health Care in Diabetes (Sponsored by Sanofi)

Understanding Diabetes Through a Patient and Population-Based Approach

Juliana Chan, MD (Hong Kong Institute of Diabetes and Obesity, Hong Kong)

Dr. Juliana Chan discussed the role of observational studies as a complement to randomized controlled trials, arguing that they can help bridge the gap from investigating efficacy to determining the real-world effectiveness of interventions – we certainly agree. As an example, she focused on her group’s International Diabetes Management Practice Study (IDMPS), a large observational study of diabetes care in the developing world. The ongoing study includes over 72,000 patients and over 5,000 healthcare providers from 48 countries where the diabetes epidemic is expected to explode in the near future. It began in 2005 and includes six “waves” of investigation in different areas: (i) achievement of targets for screening, education, and treatment; (ii) health resource use; (iii) barriers to insulin use; (iv) the experience of hypoglycemia; (v) mental health issues including depression, anxiety, and stress; and (vi) self-management. The group has published a number of papers with results from the first phases of the study. For example, the first phase found that long duration of diabetes and younger age were key risk factors for not achieving A1c targets and that diabetes education led to improvements in almost all parameters measured. The second phase found, as one might expect, that complications and poor control were associated with higher health resource use. The third phase identified several factors associated with severe hypoglycemia in type 1 diabetes, including lower education, complications, and use of premix insulin. Interestingly, it also found that severe hypoglycemia was associated with higher A1c values – the opposite from the relationship in many clinical trials. The fourth phase identified dosing difficulties, risk of hypoglycemia, and side effects as main barriers to insulin initiation; it also noted that patients’ main concerns about insulin change once that initiation barrier has been crossed.

TEENS Study

Lori Laffel, MD (Joslin Diabetes Center, Boston, MA)

Dr. Lori Laffel reviewed results from the TEENS study of type 1 diabetes in US adolescents. She began by describing the difficult transition all adolescents with diabetes face, from a stage where the entire family essentially has diabetes to one where the patient is primarily responsible for daily management. She noted that even the “haves” – children with good access to resources and very involved parents – face significant emotional challenges meeting the demands of diabetes management. Of course, the “have nots” – those who have to worry about basic resources and may not have access to tools like blood glucose meters – face a different sort of emotional burden. These challenges are illustrated by the fact that very few people with type 1 diabetes between the ages of 18 and 25 achieve glycemic targets. In the TEENS study, 72% of patients were not at their target A1c, and one in five had an A1c >10%. The study found that factors associated with a higher A1c included female gender, puberty, and longer duration of diabetes. Relevant family factors included living in a single-parent home, low parental education, high family conflict, and parents who had to stop working to care for the child (though that is more likely an effect rather than a cause of the poor control). Not surprisingly, lower A1c was associated with better quality of life in the study, and many of the same factors associated with better glycemic control were also associated with better quality of life. Many of the risk factors identified were not modifiable, but Dr. Laffel singled out diabetes-specific family conflict as the one that should be the most effective to target.

Corporate Symposium: Novel Mechanisms and Advancing Therapeutic Paradigms for Optimizing LDL-focused Management and Cardioprotection in the Diabetic Patient (Sponsored by CMEducation Resources)

Evolving Clinical Paradigms for LDL Lowering: Focus on Efficacy, Implications, Side Effects, and Safety Results of Landmark Trials Evaluation PCSK9 Inhibitions, APOB Suppression, and Other Novel Targets – Implications for the Diabetic Patient

James McKenney, PharmD (National Clinical Research, Richmond, VA)

Dr. James McKenney reviewed the mechanism of action and phase 3 clinical data for PCSK9 inhibitors to familiarize the non-cardiologists in the room with this exciting new drug class and its potential implications for their patients with diabetes and cardiovascular disease. Dr. McKenney noted that the FDA indication was narrower than the EU indication and suggested that the FDA’s aim was to “get its feet wet” and see what the cost to the health system looks like before expanding to a wider indication. We assume positive results from the ongoing cardiovascular outcomes trials would almost certainly lead to expanded indications. He emphasized that the two PCSK9 inhibitors on the market – Sanofi’s Praluent (alirocumab) and Amgen’s Repatha (evolocumab) – are identical in terms of efficacy. Praluent is slightly behind in the battle for formulary access at the moment, and this will likely be the major determining factor in the two products’ success given the lack of clinical differentiation. However, Dr. McKenney highlighted the different dosing options each company decided to offer. Praluent is available in a 75 mg dose and a 125 mg dose, both taken bi-weekly, and the 125 mg dose has greater LDL-lowering efficacy. On the other hand, Repatha offers flexibility in its dosing schedule with either 140 mg bi-weekly or 420 mg (taken as three 140 mg injections) once-monthly. Looking to the future, Dr. McKenney also whetted the audience’s appetite with a peek at a small interfering RNA (siRNA)-based PCKS9 inhibitor that has demonstrated persistent LDL lowering after four to six months in phase 1 studies, raising the possibility of twice-yearly dosing.

  • Dr. McKenney also emphasized that PCSK9 inhibitors have additive – though not synergistic – effects on top of statins. In a different presentation, Dr. Harry Ginsberg (Columbia University College of Physicians and Surgeons, New York, NY) echoed this sentiment and, like Dr. McKenney, drove home the point that the new class should be used on top of current standard-of-care statin therapy.
  • While PCSK9 inhibitors are not a “diabetes drug” in the strictest sense, Dr. Christoph Wanner (University Hospital of Würzburg, Germany) argued in favor of their appropriateness for many patients with diabetes in a separate talk. He emphasized that more and more individuals with diabetes and/or obesity are entering PCSK9 trials, suggesting that the drugs are appropriate for many within the diabetes patient population. Indeed, in a comparison, Dr. Wanner found the participant population of one of the phase 3 trials for Praluent to be quite similar to the participant population of EMPA-REG OUTCOME.

Posters

Liraglutide vs SGLT-2 Inhibitors in People with Type 2 Diabetes: A Network Meta-Analysis (0266-P)

M Lorenzi, U Ploug, J Langer

In a meta-analysis, Victoza (liraglutide 1.8 mg) demonstrated greater A1c reductions than SGLT-2 inhibitors in patients with type 2 diabetes on metformin. The analysis (n=17 RCTs) found that both doses of Victoza demonstrated greater mean reductions in A1c than any dose of any of the three approved SGLT-2 inhibitors. Victoza was also associated with a greater percentage of patients reaching an A1c goal of ≤7%. However, weight loss was similar between Victoza and the SGLT-2 inhibitors, with the higher 300 mg doses of J&J’s Invokana (canagliflozin) and 25 mg doses of Lilly/BI’s Jardiance (empagliflozin) producing larger weight reductions that the lower 1.2 mg dose of Victoza.

Insulin Degludec/Insulin Aspart Lowers Fasting Plasma Glucose and Hypoglycemia Rates Independent of Baseline HbA1c, Disease Duration, and Body Mass Index (0336-P, 0337-P, 0338-P)

H Rodbard

Three posters showed that Ryzodeg (insulin degludec/insulin aspart) produced lower rates of overall and nocturnal hypoglycemia than NovoMix 30 and/or basal-bolus insulin degludec and insulin aspart. This was true regardless of baseline A1c, disease duration, or BMI. Patients treated with Ryzodeg also had lower fasting plasma glucose vs. both comparators. Ryzodeg-treated patients with a BMI ≤30 or a disease duration longer than 10 years saw significant differences in insulin dose at the end of the trials as well.

Patient/Physician Inertia in Insulin Intensification for Patients with Uncontrolled Type 2 Diabetes Using Basal Insulin; Perceptions of Control Among Type 2 Diabetes Patients Treated with Basal Insulin (1081-P; 0742-P)

M Brod, KM Pfeiffer, AH Barnett

The Perceptions of Control study identified barriers to insulin therapy intensification in patients with poorly controlled type 2 diabetes on basal insulin from the patient and physician perspective. The most common barriers cited by patients in the web-based survey were fear of weight gain (45%), the perception that intensification would signal disease progression (44%), fear of hypoglycemia (41%), and reluctance to add more injections (41%). Overall, 57% of patients surveyed stated they were only somewhat willing or not at all willing to initiate  bolus insulin. The primary source of physician reluctance to intensify was the belief that their patients would not agree to intensification (noted by 62% of physicians). Other top reasons included hypoglycemia concerns (46%), mental illness (48%), poor cognitive skills (46%), and concerns about patient adherence (41%) as barriers to intensification. This study dovetailed nicely with Dr. Lawrence Fisher’s (UCSF, San Francisco, CA) actionable talk on barriers to insulin initiation yesterday. The two together emphasize the need for better provider education on how to talk about insulin, and perhaps better patient-provider communication in general.

Post-Prandial Hyperglycemia and Impact on Healthcare Resource Use, Diabetes Management, Missed Work Time and Reduced Productivity (0720-P, 1074-P, 0956-P, 0721-P)

Four posters examined the physical, emotional, and economic implications of post-meal hyperglycemia. 27% of respondents with recent post-meal hyperglycemia in one survey reported missing work time and a whopping 71% reported decreased work productivity. Another survey found that people with post-meal hyperglycemia had significantly more healthcare visits (5.5 visits in the past year vs. 4.4 visits for patients without post-meal hyperglycemia). The same study found that those with post-meal hyperglycemia also measured their blood glucose more frequently (1.9 extra measurements per day vs. 1.2, p<0.001) and were more likely to report diabetes-related complications. A third study found that contributing factors for post-meal hyperglycemia included stress (in 27% of respondents), eating out at a restaurant (25%), being busy (21%), and feeling tired (19%). Physical and emotional consequences included tiredness, dizziness, and feelings of demoralization, lack of sociability, and irritability.

Efficacy and Safety of Once Weekly Dulaglutide Added on to Sulfonylurea in TYpe 2 Diabetes (AWARD-8) (0219-P)

K Dungan, R Weitgasser, FP Manghi

Lilly presented a new poster from its phase 3 AWARD-8 study, demonstrating that Trulicity (dulaglutide) as an add-on to sulfonylurea is more effective than a sulfonylurea alone. The randomized, double-blind, placebo-controlled trial (n=300) evaluated the efficacy and safety of treatment with dulaglutide vs. placebo in sulfonylurea-treated patients over 24 weeks. From a baseline A1c of 8.4%, participants in the dulaglutide-treated group experienced a 1.3% greater A1c reduction than those in the placebo group (p<0.001). In addition, those treated with dulaglutide were more likely to reach a target A1c <7% (55% of those in the dulaglutide-treated group vs. 19% in the placebo group; p<0.001). Dulaglutide treatment significantly improved fasting plasma glucose over placebo (p<0.001) as well. The dulaglutide group showed some weight reduction (-0.9 kg), although the between-group weight change was not statistically significant. As expected, the most common adverse events associated with dulaglutide treatment were gastrointestinal-related (10.5% nausea and 8.4% diarrhea), leading to six discontinuations in the dulaglutide group vs. none in the placebo group. Hypoglycemia rates were also higher in the dulaglutide-treated group (p=0.025), although the overall incidence remained low at 11.3%. Overall, the trial demonstrated that dulaglutide is a safe and effective treatment when added on to sulfonylureas – while this finding isn’t particularly surprising, it could lend confidence to providers who may have been previously hesitant to prescribe the two together.

Diabetes Technology

Corporate Symposium: One Year of Flash Glucose Monitoring: The Global Clinical Experience (Sponsored by Abbott)

FreeStyle Libre Accuracy China Study

Linong Ji, MD (Peking University People’s Hospital, Beijing, China)

Dr. Linong Ji shared never-before-seen data from Abbott’s 40-patient, 14-day Chinese pivotal trial of its factory calibrated FreeStyle Libre system, which demonstrated excellent accuracy vs.  both YSI and capillary fingersticks. MARD was just 10.0% vs. YSI (the study had 6,969 paired sensor-YSI points) and 10.7% vs. capillary fingersticks (the study had 6,696 paired sensor-YSI points). The data were impressively consistent across the board as 87% of points were in Zone A of the Consensus Error Grid and 13% in Zone B in both environments, a testament to the device’s accuracy as patients would experience it (i.e., relative to fingersticks). Similar to the EU pivotal trial, accuracy did not significantly deteriorate between days 1-7 vs. days 8-14. The data actually represent a slight improvement on what has been achieved in the EU pivotal trial, where Libre demonstrated an overall MARD of 11.4% vs. FreeStyle Precision BGM (n=13,195 paired points) and 11.8% vs. YSI (n=1,238 paired sensor-YSI points). The overall accuracy in these clinical trials is highly encouraging, and once manufacturing scales up, Abbott will need to maintain those results at scale – we have little doubt on that front, but factory calibration is of course not easy. As a final note, Dr. Ji did not share a timeline on China approval of Libre (or whether the device has yet been submitted to regulatory authorities).

  • In a follow-up conversation with management, we learned that FreeStyle Libre (the consumer version) has been submitted to Canadian regulatory authorities. This is the first we had heard of this news publically. A timeline was not provided and we are still not sure when this was submitted. It is positive to see Abbott pushing its pipeline forward, and we hope to see the consumer version make its way to the FDA in the near future. As a reminder, the blinded Pro version is currently under FDA review, with a potential launch in 2016.
  • The Chinese pivotal study was conducted similarly to the US studies with three centers across China in type 1 and type 2 patients on insulin therapy. Patients wore two sensors on the back of their arm for 14 days and were asked to: (i) perform eight capillary blood glucose tests daily; (ii) scan the sensor following each test; and (iii) attend three in-clinic eight-hour YSI sessions. Notably, Dr. Ji shared that patients had a mean baseline A1c = 8.6%, ranging from a low of 5.6% to a high of 13.4% for a nice mix of well-controlled and out-of-control patients.
  • There was one rather significant difference between the China and US data – the mean lag time was 3.1 minutes in China vs. 4.5 minutes stateside. Dr. Ji could not explain the discrepancy though he hypothesized that it may reflect ethnic differences. Indeed, it’s tough to say what’s causing the difference. Sample size? A different batch of devices?
  • MARD was not broken down by glucose range, so accuracy in hypoglycemia is an unanswered question for the Chinese study. Just like the EU, we assume the product label will recommend a confirmatory fingerstick when patients are hypoglycemic.  Still, patients in the real world clearly trust the device enough to never test, so we have little concern about the hypoglycemia data in this study.
  • Dr. Ji shared positive data from user experience studies of FreeStyle Libre in the pivotal study. There was no background on how these questions were asked – we assume Yes/No. Said Dr. Ji jokingly, “This is probably due to the fact that I treat them too well.” Jesting aside, the data do point to why European patient uptake has been so strong in these early days, especially in those that have avoided current CGM due to comfort/wearability:
    • 100% agreed that the sensor was easy to apply.
    • 100% agreed that applying the sensor was less painful than a routine fingerstick.
    • 100% agreed that the system was packaged with sufficient information to use the system.
    • 100% agreed that the amount of pain felt when applying the sensor to the arm was acceptable.
    • 100% agreed that the amount of bleeding experienced when applying the sensor to the arm was acceptable.
    • 100% agreed that the sensor was comfortable to wear.
    • 97.5% agreed that the sensor was easy to wear due to its small size.
    • 100% agreed that the sensor did not get in the way of daily activities.
    • 100% agreed that scanning the sensor is less painful than pricking a finger.
    • 100% agreed that scanning the sensor is easier than pricking a finger.
    • 100% agreed that the amount of erythema on the arm when the sensor was removed was acceptable.
    • 100% agreed that the amount of edema on the arm when the sensor was removed was acceptable.
  • Very few adverse events were reported among patients in the study. Only 9 subjects reported any sort of discomfort related to the sensor insertion and all reports were consistent with what would be expected following insertion of a sensor into the skin. There were no severe adverse events reported and all patients were able to see the trial to conclusion:
    • Moderate erythema – 6 patients
    • Bruising – 2 patients
    • Mild pain – 1 patient
  • Though not indicated for long-term or deep underwater wear, commentary during Q&A suggested that Libre has been used accurately by divers for up to an hour and to a depth of 30 meters. Dr. Genovese summed up his personal experience with such off-label wear quite succinctly: “It works perfectly!”
  • The Chinese Clinical Trial Registry (ChiCTR-OPC-15006147) for the study was last updated in June: A Multicenter Clinical Accuracy Evaluation of the Abbott Sensor Based Interstitial Glucose Monitoring System in Chinese Diabetes Subjects.

Professional Use of FreeStyle Libre Pro: The Clinical Experience in India

Viswanathan Mohan, MD, PhD (Dr. Mohan’s Diabetes Specialties Center, Chennai, India)

A series of case studies presented by Dr. Mohan provided insight into the incredible reception FreeStyle Libre Pro has seen in India. We were floored by his estimate that he has already used the blinded 14-day sensor in ~1,000 patients (whoa!) in just nine months. He spoke in glowing terms about the pattern recognition in Abbott’s Ambulatory Glucose Profile, the value in optimizing patients’ therapy by helping providers feel more successful, and – most importantly – making the invisibility of diabetes more tangible to patients. It sounds like the device has been used far more often in type 2 patients, though Dr. Mohan suggested that the device holds value for anyone on insulin. Especially for patients in India who cannot afford the technology themselves, he impressed upon the audience that two weeks of wear provides a valuable retrospective look to identify trends and can even inform smarter allocation of limited fingersticks. Indeed, we thought that one of Dr. Mohan’s most fascinating comments during Q&A was that Libre Pro makes patients “trust SMBG more” (because now they see single values in the context of broader patterns!). Ultimately, the spectacular reception bodes very well for the Libre Pro sensor that is expected to launch in the US next year (submitted in 2Q15). Abbott did not comment on this timeline (though they were asked) and we assume this is still on track.

  • Although Libre Pro has only approved in adults, commentary during Q&A suggested that providers in India are even taking liberties with the sensor in children. The off-label use does not appear to be affecting accuracy in the slightest. Said Dr. Mohan, “We’ve learned a lot of things. I know it’s not approved, but talk about clinical value … We do it!”
  • As a reminder, Medtronic announced the launch of CareLink iPro Pattern Snapshot yesterday, a new one-page download report for the blinded iPro2 professional CGM. The report prominently shows a patient’s top three glucose patterns and lists up to six possible causes for each one. We do think FreeStyle Libre Pro’s 14-day wear, factory calibration, and slim form factor is a big step up over iPro2’s three-day wear, the need to retrofit the raw sensor data to fingerstick readings, and the larger transmitter.

Flash Glucose Monitoring: Use of AGP in Clinical Practice in the EU

Stefano Genovese, MD (IRCCS MultiMedica, Sesto San Giovanni, Italy)

Dr. Stefano Genovese saved the best for last as the major highlight of his presentation came in his closing sentence with an update on Abbott’s two six-month FreeStyle Libre reimbursement studies – REPLACE (n=210 type 2s on MDI, A1c>7.5%) will be presented at ATTD 2016 and IMPACT (n=225 type 1s on MDI or pumps, A1c <7.5%) will be presented at ADA 2016. Both studies are listed as “ongoing and not currently recruiting” participants on ClinicalTrials.gov with completion slated for December 2015 and September 2015, respectively. As a reminder, the goal of the type 2 study is to show a change in A1c at six months, while the type 1 study seeks to reduce time spent in hypoglycemia at six months. We can hardly express how much we are looking forward this data as reimbursement is critical around the globe, especially in Europe where patients are less accustomed to paying out of pocket for healthcare. [Libre currently has partial reimbursement only in Sweden.] If these studies report positive results and Abbott obtains widespread reimbursement, the company will have its hands full meeting demand.

  • The bulk of Dr. Genovese talk presented the FreeStyle Libre and its accompanying Ambulatory Glucose Profile as clinical tools that can facilitate patient education, improve pattern management, and reduce glycemic variability. Drawing from multiple studies, Dr. Genovese cited glycemic excursions as a driver of microvascular complications and mortality due to the associated oxidative stress. In order to reverse this trend, Dr. Genovese espoused more frequent glucose monitoring – he shared that less than 40% of patients on SMBG in Italy check their glucose more than four times per day whereas ~90% on Libre scan their glucose>four times per day.

FreeStyle Libre Accuracy Study

Timothy Bailey, MD (UCSD, San Diego, CA)

Dr. Timothy Bailey reprised the topline results from Abbott’s 72-patient, 14-day CE Mark pivotal trial – first shared at EASD 2014 – which demonstrated an overall MARD of 11.4% vs. FreeStyle Precision capillary fingersticks (87% of points were in Zone A of the Consensus Error Grid, 13% in Zone B). He opened with a short and sweet introduction to FreeStyle Libre, leading awe-struck attendees through the nuances of flash glucose monitoring: 14-day wear, factory calibrated, approved for wear on the upper arm, etc. Indeed, audiences continue to flock to Libre symposia and this was no exception – the room was packed till the very end! In terms of material itself, the vast majority of Dr. Bailey’s presentation echoed his previous talks on the same topic (ATTD 2015).

Panel Discussion

Q: This is a major paradigm shift to have Libre available. I think the presenters were highly complementary. Can you talk quickly about the various error grids that are used to assess the results?

Dr. Timothy Bailey (UCSD, San Diego, CA): I hate error grids. But they’ve proved to be very useful from a regulatory point of view. They were invented because most glucose monitors were not accurate and it was decided that meters that made less egregious errors were better. However, now in the US, almost 99% of readings are in Zone A and B, so it’s not very useful for comparing technologies.

Q: Bananas and other fruits can cause errors in BGM readings? Do you think that was why there was a higher MARD for Libre vs. capillary?

Dr. Linong Ji (Peking University People’s Hospital, Beijing, China): Yes. Ultimately, we should not interpret just one point though. I like the term “context.” We should use the collective data set to make a clinical judgment.

Dr. Bailey: It’s a good point about bananas and other foods that can interfere with readings. We instructed participants in our trials to do accurate readings. That’s why in reality SMBG may underperform and that’s why the SMBG is different.

Q: Can you talk about the availability and timeline for Libre in Canada and the US?

Mr. Steve Scott (Abbott Diabetes Care, Alameda, CA): The answer to that we’re in the process of trying to get approval for the device in the US, and we’ve submitted the device to Health Canada and can’t really talk about more than that.

Q: Is Libre really CGM in disguise?

Dr. Stefano Genovese (IRCCS MultiMedica, Sesto San Giovanni, Italy): I think it was a good idea of Abbott to design Libre this way. It is a CGM because the sensor continues to measure glucose. However, it is also called “Flash” because the measurement and the possibility to see the measurement is on request. But the actual fact is that the sensor continues to measure everything. It’s the way you use it. The device doesn’t have alarms and this is a problem with CGM, because patients complain about CGM alarms during the night. In the end, Libre gives you all the information a CGM gives you.

Dr. Viswanathan Mohan (Dr. Mohan’s Diabetes Specialties Center, Chennai, India): As far as India is concerned, it is a CGM because we don’t give patients the real-time monitoring capability with the Pro version. We do have Medtronic’s consumer CGM available to patients, but a big difference is the cost. Libre is also less painful and more convenient. No calibrations are VERY convenient. So ultimately, getting Libre for 14 days at lower cost with much less pain is wonderful for us. That’ s why this system has taken off in this country.

Dr. Bailey: I can’t prescribe Libre, but my savvy patients ask about it. SMBG is universally strongly disliked. The big difference is the factory calibration and no fingersticks. I would summarize by saying that CGM and Libre are different technologies, and I have patients that like CGM because it saves them from hypoglycemia at night. But I would say that that’s the minority of patients.

Dr. Mohan: We’ve been saying that Libre replaces SMBG. I have a slightly different take. For us, it doesn’t replace SMBG because we don’t give patients the Pro week after week. That would be too expensive. Instead, we tell them what the problems are and then we tell them when to do SMBG. Most of our patients are type 2s and we tell them that these are the points when you should check – 3 AM, after dinner, their trouble spots, etc. Now patients trust the SMBG a little more and I think Libre and SMBG can be kind of complementary.

Q: Can you talk about the patient experience with and feedback that you’ve received in practice? Are patients seeing a change in lifestyle and outcomes as measured by A1c?

Dr. Genovese: To be honest, I wanted to present some data but I cannot talk about that in a scientific symposium. I can tell you my opinion: the quality of life has DEFINITELY increased. Libre has been used and quality of life has improved a lot. In particular, the number of patients measuring and evaluating their blood glucose more than four times a day has increased to 90% in Italy vs. less than 40% who measure four times a day on SMBG. Libre is increasing the quality of life and changing how patients think about diabetes. I used to say that with SMBG we have a measure of glucose at one point in time. With this approach, you have the trend and the movement of many variables. Patients have much better knowledge about their condition.

Q: Can you talk about the cost in the EU?

Dr. Genovese: The starter kit is something like 150 euros, and it contains the reader plus two sensors. Each sensor is 50 euros, individually. Overall, this comes out to about 4 euros per day. So the cost is higher than SMBG but not so high.

Q: Can a person with an American credit card buy it?

Dr. Genoese: If you go to the website from a particular country, it goes to the country’s website. Another way is if you have a friend in EU.

Mr. Scott: The product is only for sale in those countries and only for use by residents in those countries.

Q: Can you clarify how many times the sensor actually measures glucose?

Mr. Scott: The system measures glucose every minute. Because of limited storage on board, what is put into memory on the body is one data point every 15 minutes. However, the ability to scan and get a reading is available every minute.

Q: Dr. Genovese, have your type 1 patients seen a decrease in the incidence of hypoglycemia?

Dr. Genovese: We are collecting the data. The primary endpoint of the IMPACT study is the time in hypoglycemia. Our expectation is that patients using Libre have fewer hypoglycemic events than those using SMBG because they check their blood glucose far more often. I cannot give you the data in a formal way because we are collecting the data still.

Q: What patients are best for Libre Pro vs. the consumer version?

Dr. Mohan: We have only Libre Pro in India. Certainly, I think it is better in type 2s. In type 1s, I think you need the consumer version because retrospective data itself isn’t as helpful. With a type 1 patient, getting a two-week pattern can be useful but it can also be useless since sometimes there is so much fluctuation that it is quite maddening. For type 2s though, it is fantastic. The majority of our patients have type 2, so it’s fantastic in India.

Q: It’s always really nice to have another tool in the toolbox. Has anyone had any experience with this device in children or women in pregnancy?

Dr. Mohan: Abbott asked me not to talk about this because it’s not approved. But yes, we have used Libre in kids. We did it in a newly diagnosed child recently who travelled to see me from 200 miles away. I was able to identify a lot of hypoglycemia because of Libre and we reduced the night dose. We did a second AGP a few months later. We’ve learned a lot of things. I know it’s not approved, but in terms of clinical value … We do it!

Dr. Genovese: Abbott is doing studies, rest assured. On the use of these instruments, I just want to give an example. Libre is indicated in water for no more than one hour at a depth of no more than one meter. I have a good friend who is type 1 in Italy who loves to diving and he uses Libre diving for one hour at depth of 30 meters. It works perfectly.

Q: Is Libre covered by insurance companies where it is available?

Mr. Scott: Libre has limited reimbursement in Sweden. It is our intention to make the device available to a larger population.

Q: What happens at 14 days?

Mr. Scott: The device ceases to function at 14 days.

Symposium: Closed-loop Devices for Treating Diabetes: What We Have and What We Need

Personalizing the Artificial Pancreas for the Outpatient Setting

Frank Doyle, PhD (Harvard, Cambridge, MA)

Dr. Frank Doyle’s comprehensive overview of closed-loop algorithms was highlighted by big news – the International Diabetes Closed Loop (IDCL) consortium has received an NIH grant to fund its IDCL trial, a six-month, 240-patient study comparing a commercial-grade version of UVA’s DiAs to sensor-augmented pump therapy. It’s not clear, but it’s possible that the award represents the part of the NIH’s $20 million AP initiative that was not awarded this fall – as a reminder from DTM 2015, the winners were Cambridge ($6.4 million), the DREAM consortium ($2 million), and Boston University/Mass General ($1.5 million), accounting for half of the original allotment. (The UC4 AP grant has also been reissued, with award winners to be notified in late 2016.) We do stress that this is speculation on our part and that other grant awardees (or funds allocated) were not discussed. Of course, the DiAs consortium was always a strong candidate, given their experience and encouraging results to date. It is not clear whether the group will use this study to support a regulatory submission, though Dr. Doyle’s language – “to generate the safety and efficacy data needed to satisfy regulatory agency requirements and to demonstrate the clinical effectiveness to facilitate reimbursement” – absolutely hinted at this possibility. We assume Dexcom CGM will be a key part of the system, though are not sure what pump will be used or where the control algorithm will reside. Presumably TypeZero would be responsible for the FDA submission and commercialization, though we’re not sure. To be clear, the consortium - as opposed to TypeZero itself - received the award. Dr. Doyle shared that the trial is slated to begin in 2016 at ten international study sites – UVA, Harvard University, Mount Sinai School of Medicine, Mayo Clinic, Barbara Davis Diabetes Center, Stanford University, William Sansum Diabetes Center, Academic Medical Center Amsterdam, University of Montpelier, and University of Padova –putting a PMA submission in winter 2016/2017 at the very earliest. The news adds to what is shaping up to be an exciting couple of years for commercialized artificial pancreas systems, led by Medtronic’s MiniMed 670G (in a pivotal study slated to wrap up by May 2016)!

  • Dr. Doyle opened his presentation by reminding the audience of the exponential acceleration in artificial pancreas research over the past ten years, citing data from the AP Clinical Trial Database. We’ve seen this before, though were still impressed by the thoroughness of the database (which acts as a store of artificial pancreas clinical studies). The database contains information on trials spanning 11 years (2004-2015) and was established by searching PubMed and Web of Science with a number of keywords including: (i) Closed-loop diabetes; (ii) Artificial pancreas; (iii) AP; and (iv) Bionic Pancreas.
  • The bulk of Dr. Doyle’s presentation described UCSB’s Model Predicted Control algorithm. It was quite math heavy – often over our heads! – though it was clear that the group is moving quickly and rigorously toward safer and more effective systems. This group (like many others) has its eyes clearly on the prize: a real-world system that maximizes safety and efficiency that can be personalized to individuals.

Questions and Answers

Dr. Robert Eckel (University of Colorado, Aurora, CO): I’m interested in UCSB’s model in terms of the insulin on board. Is that based on patient data?

A: We’re using some data from broad standards of care but the algorithm is not based on patient data. However, that’s a thing we could do.

Q: Is there still a place for glucagon in closed-loop systems?

A: If we go to a longer horizon, I think questions about amylin and glucagon will be in the forefront of our minds. Our lab has focused on insulin, but there is work being done by Dr. Ken Ward (OHSU, Portland, OR) and Dr. Ed Damiano (Boston University, MA). I think this a long-term question.

Dr. Irl Hirsch (University of Washington, Seattle, WA): This insulin on board business is a big deal. Personalization is critical because you have to account for variability in a number of factors, such as when the pump catheter was changed. After all, the set is going to deliver insulin differently on day one vs. day three.

A: Without a doubt, these variables are important. In your example, what we would need is a way to quantitatively correlate the day post-insertion with insulin delivery and absorption. If we had a way to quantify that, putting it in the algorithm is very simply.

Q: When will closed-loop systems reach the market? 

A: When we started working on this, people said they were five to ten years out. In the last five years, we’ve continued to say that they are five years out. From talking to companies, I think we’re seeing parts of artificial pancreas systems creep into practice – such as low glucose suspend – and these are rudimentary steps toward an artificial pancreas. If you’re talking about the full system, I’d still say we’re within five years of getting that to market. We’re testing prototypes and getting closer. There is not going to be one solution. There are going to be different solutions from different companies.

New Sensors for Closed-loop Systems

Jeffrey Joseph, MD (Thomas Jefferson University, Philadelphia, PA)

Dr. Jeffrey Joseph gave an enthusiastic overview of glucose sensors, sharing notable optimism on the recent progress (particularly Abbott’s FreeStyle Libre) and disclosing a new startup (Capillary Biomedical) is working on a long-term implantable glucose sensor for the artificial pancreas. He was positive on all currently available and pipeline sensors, though his optimism on FreeStyle Libre stood out – Dr. Joseph called the 11.4% MARD, 14-day factory calibration, and stable sensor accuracy “very exciting” and “amazing.” He acknowledged that the device is not real time (i.e., not for closing the loop), but said, “I’m sure this technology will progress.” Indeed, we wonder if Abbott plans to offer a real-time version at some point down the road. Dr. Joseph optimistically pointed out several companies’ emerging technologies, though didn’t comment on their commercial potential or timing. He devoted slides to implantable CGMs from GlySure (in human studies), Senseonics (90-day data complete; EU launch by end of 2015), BioRasis (UConn, long-term implantable), Microchips (long term implantable), and a notable new company called Capillary Biomedical (more below).

  • Dr. Joseph disclosed that a new startup, Capillary Biomedical, is working on a multi-year implantable optical glucose sensor for the artificial pancreas. The idea leverages original work done at Animas in 1995 on an implantable glucose sensor that optically measured glucose in blood flowing through an artery. The Capillary Biomedical idea takes this concept a step further, measuring glucose in an ultra-filtrate of interstitial fluid drawn from the surrounding tissue. Micro-pumps pull tissue fluid through a network of soft, flexible catheters with micro-porous membranes to create the ultra-filtrate. The starfish-looking device appeared to have several sensors for redundancy. Dr. Joseph did not share any timing, expected accuracy, or clinical trial plans.
    • Capillary Biomedical’s Angel List web page has more details on the idea. Glucose is determined via infrared spectrometry. A physician implants the device under the skin of the abdomen in the subcutaneous tissue. The implant requires an outpatient surgery that uses local anesthesia. The device will send real-time glucose information wirelessly to an external receiver, mobile phone, and insulin pump. The implanted system only requires periodic inductive charging. We’re not sure if it would be factory calibrated or how large the implant would be.
    • The Angel List page notes that Paul Strasma is CEO, formerly VP Marketing & Clinical Trials at GluMetrics. Dr. Joseph is the only other listed employee, Vice-Chairman & Director of Research. The company has not posted any job on its Angel List page. Based on its billboard webpage, it is located in Irvine, CA and has been around since 2014. The LinkedIn page notes that the  “novel approach aims to overcome the twin challenges of sensor degradation and tissue encapsulation.”
  • More broadly, Dr. Joseph noted that current sensors from Abbott, Dexcom, and Medtronic are in the 9-14% MARD range, and importantly for closing the loop, produce fewer large errors. He said the “magic number” for safely closing the loop is a MARD <10%. The “major” recent advance, according to Dr. Joseph, has come in the software realm, where algorithms compensate for sensor drift, detect sensor instability or failure, and optimize calibration. We would point out Dexcom’s work with Dr. Claudio Cobelli’s team as the standout example there, which brought the G4 Platinum’s MARD down to 9.0% with Software 505/G4AP.

Questions and Answers

Dr. Irl Hirsch (University of Washington, Seattle, WA): What about scarring and damage from long-term infusion set wear?

Dr. Joseph: It is a real problem. The damage is likely not from insulin infusion, but from tissue damage when the set is inserted, and then damage from movement. We need to address this.

Adam Brown (Close Concerns, San Francisco, CA): Why hasn’t hospital CGM moved faster? Edwards is out of the game and the Medtronic Sentrino hasn’t done much in Europe. Is this a technological problem or a commercial problem or both?

Dr. Joseph: Hospital administrators want to see a cost-benefit to using the technology. I’m convinced there is a clinical benefit, but there has to be a cost-benefit. In addition, no one knows what to do with the data. The alarm goes off, the nurses does something, but there is not a protocol that has been validated. I think the future is in-hospital closed-loop. But companies have to be convinced they will make money if they invest the resources.

New Insulins and Insulin-Delivery Technologies for Closed-Loop Systems

David Klonoff, MD (Mills-Peninsula Health Services, San Mateo, CA)

Dr. David Klonoff shared a comprehensive overview of new insulins and insulin-delivery offerings for closed-loop systems. He stressed that new insulins or insulin-delivery technologies could revolutionize closed-loop control by both improving glycemic control (greater time-in-range, less hypoglycemia, lower mean glucose levels) and increasing patient convenience. What products are available or soon-to-be available? See below. Dr. Klonoff also discussed Afrezza (seems to be less potent than indicated) and shared optimism for hybrid closed loop systems. His talk reminded us that a lot of things are happening in faster insulin. The bigger question is how much incremental benefit these products will show, and whether they will get paid for.

  • In discussing the utility of Afrezza in the real world, Dr. Klonoff echoed commentary we’ve heard from other KOLs that the formulation often feels slightly less potent than indicated. As a reminder, Afrezza is available in 4-, 8-, and 12-unit doses though Dr. Klonoff reported that patients seem to respond more like the doses are in 3-, 6-, and 9- units increments. Overall, he was very positive on Afrezza’s efficacy, explaining that its faster onset of action compared to rapid-acting analogs should be a significant advantage as an adjunct to hybrid closed-loop systems.
  • Dr. Klonoff expressed a great deal of optimism about hybrid closed-loop systems despite the fact that partial meal announcements are necessary. Indeed, he cited compelling data that hybrid options can provide very effective meal coverage even while insulin action remains slow. He also acknowledged that different patients will view the benefit/hassle tradeoff differently, appreciating that what is tolerable for some may not be tolerable for others. We fully agree that the question of fully automated vs. daytime hybrid vs. nighttime-only systems is one of patient preference – more on that in diaTribe. Ultimately, we believe a range of options is a good thing for people with diabetes, since all systems and products have pros and cons.

Dr. Klonoff’s New Insulin Landscape Overview

Company

Product/Approach

Status (based on previous CC coverage)

Recent Coverage/News

Novo Nordisk

Faster-Acting Insulin Apart

Submitted in the EU and US

FDA submission

Biodel

BIOD-531: U400 ultra-rapid-acting human insulin

Phase 2b

Biodel initiates phase 2b

Thermalin

Flourolog: U500 rapid-acting insulin with onset of action = ~30 minutes

Phase 1

JPM 2015

Lilly/Adocia

BioChaperone Lispro: Multiple formulations include Lispro U100, Lispro U200, Lispro+Aspart

Phase 1b

Adocia/Lilly announce positive phase 1b results

Counter Culture Labs

Grassroots, non-profit biohackers: Approach unknown

Preclinical

Website

Dr. Klonoff’s New Insulin Delivery Technology Landscape Overview

Company

Product/Approach

Status (based on previous CC coverage)

Recent Coverage/News

Sanofi/MannKind

Afrezza: Inhaled Insulin

Available in US pharmacies

MannKind 3Q15

Dance BioPharm

Dance-501: Inhaled insulin

Phase 2b in 2016

DTM 2015

BD

Intradermal microneedles

Unknown, though we’re pessimistic this is even still in development

BD F4Q14

Insuline Medical

InsuPad/InsuPatch: Warms skin by increasing blood flow and helping the body absorb insulin better and faster.

Available in Germany and Israel; US status unknown

Website

Numerous companies (BioJect’s Zetajet; InsuJet;

Jet injectors: Needle free insulin administration that uses high velocity air pressure

“Popular in EU market.” Removed from US market due to little interest

EASD 2013

Roche

DiaPort: Intraperitoneal insulin infusion system

Unknown

Roche 2Q14

Symposium: Late-Breaking CSII vs. MDI study – The REPOSE Trial

Late-Breaking CSII vs. MDI Study: The REPOSE Trial

Simon Heller, MD (University of Sheffield, UK)

Dr. Simon Heller presented late-breaking results from a two-year randomized, parallel group study comparing pumps to MDI in very poorly controlled type 1 diabetes (baseline A1c: ~9.2%), holding education equal between the groups. Both the pump (n=132) and MDI (n=132) groups completed the DAFNE course (dose adjustment for normal eating) at baseline, and were randomized to use a pump (Medtronic) or MDI (Levemir and aspart) over 24 months (median age: 41 years). After adjusting for center, DAFNE course, and baseline A1c, pumps showed a modest 0.2% A1c advantage over MDI (p=0.12) in those with a baseline A1c >7.5% and data from all four study visits (n=208 of the total n=267). Numerical A1c changes were not shown for all participants, but categorically, only 29% of the pump group and only 25% of the MDI group achieved an A1c <7.5% (p=0.5). Pumps fared slightly better in a per-protocol analysis, showing a significant (but modest) 0.3% A1c advantage over MDI (p=0.02). DKA was much more common with pumps – 17 events vs. 5 events (13% vs. 4%) – though that difference was confined to the first year of the study, and most DKAs were due to infections (only 18% from set failure in pumpers). The combined rate of severe hypoglycemia was halved overall, though there was no significant difference between pumps and MDI (a testament to the efficacy of DAFNE). Pumps showed significantly higher diabetes specific quality of life for diet restrictions and daily hassle, a finding Dr. Heller called “real” and “sustained.” Dr. Heller concluded that care for adults with type 1 should start with MDI and structured training (e.g., DAFNE), with pumps offered later to those limited by MDI. It’s good to see a long-term, comparative, well-controlled study of pumps vs. MDI (holding education constant), though in speaking to Dr. Irl Hirsch, this study had some important caveats: the starting A1c’s were too high to expect a benefit, SMBG data was not collected at all, and based on the results, was not used effectively at the interim visits to titrate insulin (see our Q&A with Dr. Hirsch below, followed by Dr. Heller’s response).

Q&A with Dr. Irl Hirsch

ADAM BROWN: Dr. Hirsch, what do you think of this study? Would you have designed it differently?

DR. IRL HIRSCH: I commend them for a well-controlled study that ensured equal education at baseline. But they did not do the study appropriately: they studied insulin delivery and left out glucose monitoring. You cannot uncouple those too! We don’t know what happened after the study started with the interim visits – there were no SMBG downloads. How do you make insulin adjustments without glucose data for either MDI or CSII?

In the US, we would download the glucose meter, download the pump, look at the frequency of testing, make suggestions on when glucose testing should be increased, and make adjustments in insulin based on glucose levels. Dr. Heller gave no information on this. My guess is glucose testing was the same in both groups, and it was probably low in both groups, based on our data from the T1D Exchange and STAR-1.

With CGM, we’ve learned that glucose data is the most important thing. Even with SMBG, our first paper in the T1D Exchange showed a relationship between A1c and glucose testing – and we showed that in every age group. If you’re only testing twice per day, you’re not going to do very well.

ADAM: This was a pretty tough group with a mean A1c over 9%. Any thoughts on that inclusion decision?

DR. HIRSCH: If you’re using A1c as a primary endpoint in an adult type 1 diabetes study, don’t include people with A1cs over 9%. They’re not doing the minimum – they are testing infrequently (maybe twice a day) and they’re missing insulin more often. That is why I believe they saw more DKA in the pump group. We learned this the hard way in STAR-1. CGM significantly reduced A1c by 1% for everybody except those with an A1c >9%. They recommended five SMBG tests per day but based on our previous studies it is doubtful this was the case here. The ideal situation would have been documentation of equivalent SMBG in both groups, and then make conclusions about insulin delivery methods.

ADAM: What are the implications of this data?

DR. HIRSCH: My concern is payers are going to look at this and say, “We shouldn’t cover pumps.” Hopefully, the paper, when published, will note the limitations.

ADAM: What studies are we missing in the pump vs. MDI debate?

Dr. HIRSCH: My biggest concern with pumps and closed loop is that pumpers are running out of on-body real estate due to scarring, lipohypertrophy, etc. None of this may matter if we don’t figure out how to reduce that.

Response From Dr. Heller

Dr. Heller: I agree with Irl’s interpretation of our data, but I would challenge strongly his view that these are limitations. The point of the research question is whether poorly controlled adults should go straight onto pumps or whether they should have proper training in the use of insulin.  Then for those who subsequently go onto self-manage their diabetes effectively and find the limitations of MDI prevent them getting to their glucose goals and impair their quality of life, pumps should be generally available – indeed they need to be strongly encouraged to take advantage of such technology.  I believe our data strongly support such a pathway ,which actually could ease the reimbursement barriers to pump therapy in many countries – the people who would benefit the most would be provided with a pump. In summary, our study results argue strongly for much better skills training for all people with type 1 diabetes followed by the availability of pumps for those who experience limitations.

Other Study Details and Outcomes

  • Patients had a median age of 41 years, were primarily white, had a median diabetes duration of ~15 years, a mean BMI of 27 kg/m2, and more than half (~55%) had microvascular complications. In short, this was a tough group! Importantly, patients could only participate in the study if they had no strong preference for pump therapy vs. MDI. Those who had a clinical indication for pump (e.g., hypoglycemia problems) were excluded from the study.
  • Visits occurred at baseline, six months, 12 months, and 24 months. There were no specifics on what these entailed. The DAFNE education program was only completed at baseline and included three courses with 5-8 participants in each course.
  • In the unadjusted results, pumps showed a 0.4% A1c advantage, presumably because of the higher baseline A1c (-0.8% vs. -0.4%; baseline: 9.3% vs. 9.0%). As noted above, after adjusting for baseline A1c, center, and DAFNE course, pumps showed a more modest 0.2% A1c advantage over MDI (p=0.12).
  • The per-protocol analysis excluded 11 participants that switched from pumps to MDI and seven participants that switched from MDI to pumps. We assume these switches occurred during the trial by patient choice, but it was not specified. The 11 patients that switched from pumps to MDI saw a 0.7% improvement in A1c (10.4% to 9.7% at 24 months), while the seven that switched from MDI to pumps saw a striking 2.0% reduction in A1c at 24 months (10.3% to 8.3%). That could suggest that when patients drive the choice to switch to a pump, the clinical benefit can be much bigger.
  • Dr. Heller was very positive on structured training with DAFNE, noting that it reduces the risk of severe hypoglycemia and leads to modest but long-lasting benefits in A1c (“it should be delivered widely”). DAFNE teaches patients flexible intensive insulin therapy to match insulin doses to foods. NICE supports DAFNE but very few adults in the UK go through the program. This is not surprising to us – DAFNE requires a five-day training course (9am-5pm; Monday to Friday) and is only delivered in person at 60+ UK centers. It is a downside that it is not offered online and we wonder how it can be scaled and made much more convenient.
  • We certainly agree with Dr. Heller’s conclusion that further work is needed to support people in achieving tighter glucose targets. For those in poor control, we need better strategies! The cost-effectiveness of improving glycemia in this group is high – what are the highest ROI interventions that could do so?
  • Said Dr. Heller, “In the UK it is estimated that 6% of adults with type 1 diabetes use pumps compared to 40% in the US.” Dr. Heller did not source these estimates or attempt to explain the discrepancy, though presumably it stems from NICE’s stricter reimbursement criteria for pumps.
  • Why conduct REPOSE? According to Dr. Heller, existing evidence on pumps vs. MDI can be biased, as those allocated to the pump may receive more training and attention vs. those on MDI. This study included comparable training for both groups, something few trials have done. The results are consistent with previous meta-analyses showing an ~0.3% benefit of pumps over MDI (Misso et al., Cochrane Review 2010).
    • How should a pump study be conducted to show the true benefits of the technology? Pumps are not like taking a drug – they are totally different therapy for patients and clinicians. What is fair way to assess the incremental benefit of the technology?

Questions and Answers

Dr. Bernie Zinman (Mount Sinai Hospital, Toronto): Really nice study. Can you tell us about the number on CGM, or were they not allowed to wear CGM?

Dr. Heller: We had no specific policy on CGM.

Dr. Zinman: We did a similar study comparing MDI with pumps. Those that started with a high baseline tended to get a better benefit of pumps than MDI. Did you find that too?

Dr. Heller: We are currently undertaking that analysis. To date, we haven’t seen that effect.

Dr. Irl Hirsch: Very impressive study. You noted the caveats very well. My question has to do with the interim visits. Specifically, what happened with the glucose data – was the data downloaded? Especially with higher DKA in the pump group and not using CGM in general, what was the frequency of home blood glucose monitoring? That’s the key for any insulin delivery. Checking blood glucose enough to make treatment decisions.

Dr. Heller: During training we emphasized the importance of blood glucose and ketone testing. They definitely had the training. Blood glucose monitoring was recommended up to five times per day and more. These were not people with a strong preference for a pump. Some people on pumps didn’t perhaps appreciate it in the way people who want pumps do. Is that a fault of study design? We clearly agonized over that.

Dr. Hirsch: But do you have SMBG data?

Dr. Heller: Only self-report. We don’t have those data.

Q: What about weight gain?

Dr. Heller: We have looked at it, and there were no significant differences in weight gain. I want to emphasize, these patients were poorly controlled, and the majority remained poorly controlled. It’s not surprising they didn’t gain much weight.

Q: Were the MDI patients on analog basal insulin? Were they using it once per day?

Dr. Heller: All these patients were on analog insulin. When funded, the reimbursement in the UK wanted to compare the best MDI practice. All the patients were on twice-daily Levemir and insulin aspart as the bolus insulin.

Q: In people that are physically active, often being on a pump allows them to make smaller adjustments more quickly, leading to overall better control. Did you take that into account?

Dr. Heller: We didn’t take into account physical activity levels. In a surprise to us, when we undertook the study, we thought we would have great difficulty because people didn’t want to risk going low with exercise on MDI. The opposite was true for most centers. When we talked to people on MDI about pumps, they would say, “I think I’m fine, and if I exercise, a pump is going to get in the way.” A lot of the people, such as you describe, who would benefit from a pump during exercise, didn’t think it was going to help them. And some of the people you talk about are probably using pumps already.

Debate: The Pump – Is It for Everyone?

Yes

Betsy Rodriguez, BSN, MSN, CDE (Centers for Disease Control and Prevention, Atlanta, GA)

Ms. Betsy Rodriguez opened this debate by defending her “mixed yes” stance on pumps, stressing that education is one of the most important aspects of successful pump therapy. According to Ms. Rodriguez, “the pump is not for everyone – it just needs to be an option!” She acknowledged that people choose insulin pump therapy for different reasons (better glucose control, more flexibility, fewer needles, etc.), including her daughter, who chose pump therapy because it dramatically reduced the frequency of hypoglycemic episodes. Ms. Rodriguez discussed other benefits of pump therapy, including peace of mind, discretion, and micro-doses for better control, though ultimately concluded that none of this would be possible without adequate pump education. We fully agree, especially considering that cost-effective, scalable education programs for patients are relatively few and far between; the burden of education is often on primary care providers or endocrinologists, who are already overworked and overwhelmed – it is no wonder that education is so often overlooked! Ms. Rodriguez concluded by underscoring value of intermittent “pump vacations”, too, emphasizing that “you can get on it, you can get off it, but at the end it’s about the quality of life.”

No

Dicky Poon (Hong Kong, China)

Mr. Dicky Poon discussed the practical issues that often prevent people with diabetes from using pumps, drawing on his own experience as a person with type 1 diabetes in Hong Kong. His presentation centered on three major factors hindering pump use in Hong Kong: (i) expense (>$600 per month for pump expendables vs. $120 per month for MDI); (ii) very limited tech support; and (iii) the humid subtropical climate, which leads to reliability issues and skin irritation. With these caveats in mind, he asserted quite succinctly that, “it’s too early to say that insulin pump is for everyone.”

Yes

Chuck Eichten (Author, The Book of Better: Life with Diabetes Can't Be Perfect. Make It Better, Portland, OR)

Mr. Chuck Eichten argued in favor of pump therapy, underscoring that it is the best option available for treating diabetes. He began his presentation with a humorous disclosure: “I am absolutely, unequivocally, unapologetically, and at times even hysterically biased in favor of the insulin pump.” He acknowledged that pump therapy is not perfect, but stressed that it provides the better control than MDI and offers major advantages, such as flexibility in eating and sleeping patterns, discretion/privacy, and fewer needles (“1,460 holes vs. 156 holes in yourself”). For those with objections to pump therapy, he offered a compelling analogy: “Remember how afraid you were the first time you met the love of your life and you were so scared to talk and now you are so happy you did? That’s how you will feel about your pump.”

No

Wilf Ruland (Ontario, Canada)

Type 1 father Mr. Wilf Ruland led a moving discussion that focused on Ontario’s inappropriate pump subsidies that practically force patients to use pumps regardless of their insulin delivery preferences. According to Mr. Ruland, the province subsidizes pumps and associated supplies but does not provide health funds for pens, syringes, insulin, CGMs, or pump-equivalent training for those on MDI. He positioned the policy as an inefficient outlay of public health dollars that could also be detrimental to health outcomes. We would add – perhaps most fundamentally – that the policy tactlessly places patient preferences as an afterthought, putting pump vs. MDI decision-making power in the hands of regulators instead of patients. Mr. Ruland alluded to his teenage daughter as an example of a patient affected by the policy, noting that she doesn’t want a pump, but despite excellent management on MDI, is not eligible for funding for her method of insulin delivery or for better pump-equivalent training. We are surprised to hear of this model of targeted subsidies and wonder if outcomes have improved as a result of it. Ultimately, a pump is a tool for insulin delivery, though whether or not it is “useful” can depend on the individual. 

Symposium: Health Information Technology to Prevent, Diagnose and Manage Diabetes

Using Health Information Technology to Prevent and Treat Diabetes

Fran Kaufman, MD (Chief Medical Officer, Medtronic Diabetes, Northridge, CA)

Dr. Fran Kaufman highlighted CGM, online programs, mobile phones, and other health information technologies (IT) as effective solutions for managing diabetes prevention and treatment in large populations. She emphasized the value technology brings to a constrained diabetes healthcare system – providers do not have sufficient time and effort to manage patients with diabetes through 10-minute visits every 90 days. Dr. Kaufman stressed the utility of CGM to enhance diabetes care, whether it’s used real-time, retrospective, integrated into the medical record, or driving closed-loop. We were particularly glad to hear her mention use of CGM in research studies to determine the effectiveness of interventions – we certainly hope to see much more of that in drug studies going forward. Dr. Kaufman expressed optimism for future integration of CGM into fully automated systems for insulin delivery (closed-loop), including systems with multiple data inputs (blood glucose, insulin, heart rate, activity, etc.). Of course, Medtronic is leading the field on closing the loop near-term, with the MiniMed 670G in a pivotal study slated to wrap up in May 2016. More broadly, she discussed the translation of evidence-based intervention programs into online formats, such as the chronic disease self-management programs developed by the Stanford Patient Education Research Center and the Diabetes Prevention Program. These programs were proven effective in prior studies, and online transference has improved their scalability and cost effectiveness. Dr. Kaufman concluded with an example of cell phone monitoring in which an Indian mobile diabetes program sent a series of text messages to one million people, demonstrating efficacy in improving physical activity, increasing consumption of fruits and vegetables, and decreasing consumption of high fat and fried foods. This vividly illustrates the considerable ROI potential of mobile phone technology, in which a vast number of people can participate in a simple, cost-effective intervention. Now that is where diabetes care HAS to go.

Effectiveness of Short Messaging Service (SMS) Using Mobile Phones in the Prevention of Diabetes

Ambady Ramachandran, MD, PhD (India Diabetes Research Foundation, Chennai, India)

Dr. Ambady Ramachandran contextualized his lab’s ongoing study (NCT01570946) evaluating the efficacy of text messaging interventions in type 2 diabetes prevention, providing an in-depth review of several diabetes prevention studies conducted in India. The ongoing study began enrolling participants (n=1,050) in India and the UK in 2011, and results are currently pending (slated to wrap up in December 2015). According to Dr. Ramachandran, the study is based on findings from a series of studies demonstrating that (i) lifestyle intervention is effective at preventing the progression to diabetes; and (ii) mobile phones can allow this intervention to be scalable and reach large populations via simple short messaging service (SMS). As an example, he shared results from the first Indian Diabetes Prevention Program (IDDP-1) in the early 2000s, which followed 531 participants with impaired glucose tolerance for three years to evaluate the effectiveness of lifestyle management and metformin on preventing progression to type 2 diabetes. Study results showed that 55% of the control group developed diabetes, while the lifestyle modification intervention reduced diabetes conversion by 28.5%. There was no additional benefit of using metformin. He noted that compared to DPP studies in the US and Finland, the IDDP-1 showed diabetes onset at a younger age and lower BMI. Next, Dr. Ramachandran highlighted key results from multiple recent studies investigating the efficacy of SMS in reaching a large number of people at a low cost and influencing them to change their behavior to improve health. Most notably, a randomized clinical trial demonstrated a 36% risk reduction in the incidence of type 2 diabetes in the intervention group compared to control. The intervention involved frequent mobile phone messaging with content tailored to participant sub-groups using the trans-theoretical model (a framework for changing behavior). The intervention significantly reduced the incidence of diabetes during the 2-year period, and HDL cholesterol and diet improved as well. We are pleased to see a focus on prevention in India, where diabetes rates are climbing past 69 million, resources are limited, and simple mobile phones are ubiquitous.

Experience of How This Works In Practice

Marlis Schosser (mySugr, Vienna, Austria)

IDF young leader Ms. Marlis Schosser described diabetes technology from the perspective of a patient with type 1 diabetes. Ms. Schosser opened by emphasizing the complexity of diabetes management: “Many say diabetes is easier now because we have lots of technology, but when you get diagnosed it turns your life upside down…You have to think and react how your pancreas thinks and reacts, which is impossible.” She noted that people with diabetes only get 15 minutes with a doctor every few months, a setup that places the burden of diabetes management on the patient ~90% of the time. So then, what does it take to self-manage diabetes successfully? According to Ms. Schosser, it starts with appropriate tools, education, and motivation. With respect to the first solution, Ms. Schosser proposed that data from diabetes devices need to be more seamlessly integrated into one platform to allow patients to access and glean insights from their CGM, pump, and activity data. This has become a common refrain at diabetes meetings for the past five years, though we think the conversation should start to move past this to more substantive questions– Which data platforms are really nailing the integration? How can we better integrate them into clinical practice? How can we make the data more actionable for patients and providers?

  • Ms. Schosser also took time to advocated for online coaching tools and mobile apps that can scale diabetes education. She underscored the value of fun challenges, games, and connecting with the diabetes community, noting that, “we still have a while until a cure, so it’s up to people with diabetes to find solutions and help each other make our lives and diabetes management more fun.”

Open Forum: Public Health and Epidemiology

My “Big Data”: What Is It, How Is It Relevant to My Health, and Why Don't I Have Access to It?

Joachim Roski, PhD (Booz Allen Hamilton, Principal, Washington DC)

Dr. Joachim Roski discussed the future of big data in the context of many challenges: (i) How do we ensure data privacy and security?; (ii) How do we enable data sharing?; (iii) Who owns the data?; and (iv) How should we think about consent? Dr. Roski expressed optimism that these questions will be answered in the future though acknowledged that the field is in its early days – patients, providers, and healthcare organizations are only now beginning to ask themselves the “tough questions” and it is clear that medicine as a whole is only beginning to appreciate the promise of digital health. Dr. Roski concluded that the future is bright and that there is hope for the field as these conversations are becoming more and more common; we certainly agree and have seen the discussion around digital health come increasingly into the spotlight in 2015, particularly as diabetes devices have increasingly embraced connectivity (Dexcom G5, MiniMed Connect, Abbott’s FreeStyle LibreLink).

Applications of Social Media for Diabetes Epidemiology and Prevention Research

Joyce Lee, MD, MPH (University of Michigan, Ann Arbor, MI)

Dr. Joyce Lee provided an overview of the role of social media and the internet in promoting diabetes epidemiology and prevention research. She opened with compelling data illustrating that social media forums (YouTube, Facebook, Twitter, etc.) have now become some of the most prominent places for patients to exchange knowledge. She offered social media as the next frontier where providers can interact with patients both in terms of distributing knowledge and learning from their patients (“lurking”). On the other hand, Dr. Lee also stressed that an appreciation for the differences between social media platforms is key for those joining the community – e.g., Snapchat is more likely to be used by wealthier teens, Facebook is most popular among lower-income youth. She pointed out that each platform has a population that communicates in a very particular way – see the humorous “Social Media Doughnut” below. Dr. Lee also spoke at length about the way social media can be leveraged for research and circled around one question in particular: can social media replace traditional methods of disease surveillance? She spoke to the power of big data and predictive analytics (e.g., The Parable of Google Flu – see below), though acknowledged that the field remains far from a place where the technology can fully supplant more traditional methods of disease surveillance. Ultimately, Dr. Lee concluded that the value in social media is in using it as an ethnographic tool, one that helps us understand the patient experience and the issues with living with disease without necessarily overanalyzing/extrapolating from the results.

  • The Parable of the Google Flu: Dr. Lee spent time explaining how and why Google’s flu tracking system made headlines in 2013 after incorrectly predicting more than double the proportion of doctor visits for influenza-like illness (ILI) relative to the CDC. The latter bases its estimates on surveillance reports from clinics across the US, while Google’s flu tracker was built to analyze search terms online and to predict ILI accordingly. However, Google’s researchers made a mistake that Dr. Lee termed “big data hubris,” an implicit assumption that big data are a substitute for, rather than a supplement to, traditional data collection and analysis. In this case, the odds of finding search terms that matched the propensity of the flu but which were structurally unrelated (and did not predict the future) were quite high, resulting in an overestimate of the flu progression. As a result, Google’s flu tracker is often held up as an exemplary use of big data and the errors that can result.

Social Media Doughnut

Corporate Symposium: Non-Invasive Glucose Monitoring (NIGM): Have we reached the Holy Grail? (Sponsored by Integrity Applications)

The “Other Idea”: A Different Approach For A Truly Non-Invasive Glucose Monitoring Device - Past, Present And Future

Avner Gal (CEO, Integrity Applications, Israel)

Integrity Applications CEO Avner Gal introduced GlucoTrack, a CE-Marked and just-launched non-invasive ear lobe clip device for spot monitoring glucose in people with type 2 diabetes and prediabetes. The boldly titled corporate symposium (“Non-Invasive Glucose Monitoring (NIGM): Have we reached the Holy Grail?”) shared an unconvincing overview of the device to a small audience: an MARD of 23% vs. Hemocue fingersticks (53% in Zone A of Clarke Error Grid); an upfront cost of $2,000 and $120 for each six-month ear clip; a one-minute measurement time for each spot reading (it’s not continuous); no measurements <70 mg/dl; and the need to recalibrate the ear clip every six months with an ~20-30 minute calibration with a fingerstick. The device is said to have already launched in some places around the world (not specified), with expansion said to be expected soon. We think it has an uphill battle on many fronts (cost, accuracy, form factor, hassle), though Mr. Gal rightly noted that without early generation CGMs, the field would not be where current sensors are today. Still, the device has been in development for 12 years, and after clinical trials in >750 patients, it is hard to imagine a step function change in accuracy or form factor is coming anytime soon, particularly with just $2.1 million in cash in the bank as of 3Q15 and a market cap of $22 million on the OTC/QB exchange. The company has spoken to the FDA, and per its October announcement, plans to begin a US trial in early 2016. Integrity’s current product roadmap includes adding cloud connectivity, a type 1 indication, models for developing countries and the hospital setting, and more. We look forward to following the company and salute the team for trying to crack the extremely challenging non-invasive glucose monitoring (NIGM) – as Dr. Lutz Heinemann summarized the field in his overview talk, “NIGM has a long history of continuous ambition and failure,” but it is still worth pursuing for patients. (That said, we feel most believe FreeStyle Libre is nearly non-invasive.)  

  • Integrity’s device begs many thought provoking questions: What level of glucose monitor accuracy is good enough for type 2 diabetes and prediabetes? How should companies trade off accuracy vs. improved form factor vs. cost? When does the output from a less invasive glucose monitor cross from useful to dangerous? These questions have important implications not just for Integrity, but type 2-focused glucose monitors from Abbott, Dexcom/Google, Medtronic, Novartis/Google, and wellness CGM companies like Echo and Sano. (Abbott is arguably the leader right now on the composite profile, having achieved an outstanding form factor with FreeStyle Libre, a lower cost, and accuracy safe enough to dose insulin with factory calibration. But there is clearly a spectrum on the cost, accuracy, and form factor dimensions of any product.)
    • Not every glucose-monitoring device needs to be accurate enough for dosing insulin, but there is presumably some threshold that must be hit. What is that threshold, and how should that be weighed against a smaller or less invasive or less costly device? Does For instance, if the Novartis/Google contact lens has a MARD of 20% (our speculation), is that good enough to drive therapeutic change in type 2 diabetes and prediabetes? At what point does the device’s clinical inaccuracy outweigh any potential benefit of more frequent monitoring? Tough questions indeed, and ones that will likely be solved only with prototypes tested in clinical trials.

The "Missing Point": Importance of Frequent Monitoring of Glucose Levels by Type 2 Diabetes Patients

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

Dr. Irl Hirsch did not speak about Integrity’s device specifically; he talked broadly about glucose monitoring in type 2 diabetes. He concluded that (i) based on the totality of current evidence, SMBG results in a small reduction in A1c in non-insulin users; (ii) glucose testing and CGM for those who do take insulin seems to be underutilized – lots of hypoglycemia is missed right now with fingersticks; and (iii) A1c is not a good marker to make treatment decisions for many patients (blood glucose data is better). Dr. Hirsch did comment briefly on Integrity’s device in Q&A, noting less concern with the MARD (“it will get better”) and questioning whether GlucoTrack would have value in the hospital and long-term care settings.

  • SMBG studies in non-insulin-using type 2s do a poor job of replicating real life clinical care in the usual primary care setting, especially for the subjects randomized to more frequent SMBG. Dr. Hirsch noted that “the teaching, use, and interaction of SMBG is simply not yet part of the culture of usual primary care.” Dr. Hirsch did not provide any recommendations to counteract this; we wonder if blinded CGM could be helpful in this regard, since intermittent SMBG is extremely challenging to interpret.
    • Studies like STeP and several meta-analyses have shown small but significant effects of SMBG in non-insulin users (~0.2-0.3% A1c benefit). But studies have design and bias problems that confound results: (i) funding biases (e.g., STeP was funded by Roche; DiGEM was funded by NHS –the results were as expected based on those two founders); (ii) starting at an A1c too low to expect a benefit (e.g., 7.5% in DiGEM was too close to goal); and (iii) the intensive SMBG arm often tests too infrequently (e.g., less than once per day) to expect a benefit.
  • Many patients with type 2 are at risk for hypoglycemia. Dr. Hirsch said that 23% of all prescriptions for type 2 diabetes are for a sulfonylurea, with another ~6 million Americans using insulin in 2012 (June 2015, UBS Large Cap Pharma Monthly Handbook; CDC Report, 2014). He further estimated that ~40 million people are using inulin globally (Gal, Bernstein Research, September 2013). Assuming 5% of these 40 million people have an episode of severe hypoglycemia at some point in their life translates to 2 million people worldwide. “The number is probably much higher,” said Dr. Hirsch.
    • “The type 2 diabetes hypoglycemia data is real, and without CGM, we miss the majority of the hypoglycemia in patients who receive insulin. In one example of 52 patients receiving insulin with type 2 diabetes (A1c: 7.7%), CGM detected 64 hypoglycemia events in 42 patients, translating to 79 events per patient-year (mean duration per event: 60 minutes). The frequency caught with SMBG was only 17 events per patient-year. “We are spending so much time in hypoglycemia; too much time,” said Dr. Hirsch, particularly given concerns about cognitive functioning, cardiac arrhythmias, and inflammatory activation.
  • “A1c is a great biomarker when assessing glycemic control in a population or clinical trial. But A1c levels are problematic when comparing individuals.” Dr. Hirsch pointed to the ADAG study, which established ADA’s estimated average glucose equation by comparing A1c values to mean glucose measured via CGM. An A1c of 8.0% translated to an average blood glucose of 183 mg/dl in the study, but a tremendously wide confidence interval among patients: 147 mg/dl to 217 mg/dl. The same was true for an A1c of 7.0%: a mean of 154 mg/dl, but a range from 123 mg/dl to 185 mg/dl. “One can’t compare the A1c levels between two people,” said Dr. Hirsch. He expounded on this point by noting particular concerns in patients with aortic valvular diseases and iron deficiency.
    • “You need more data to make treatment decisions. It doesn’t make sense to make decisions based on an A1c or six tests per week,” said Dr. Hirsch. 

“Holy Grail”: History Of The Efforts To Develop A Non-Invasive Glucose Monitoring Device

Lutz Heinemann, PhD (Science & Co, Dusseldorf, Germany)

Dr. Lutz Heinemann gave an honest talk on non-invasive glucose monitoring (NIGM), summing up the field succinctly: “a long history of continuous ambition and failure” (most recently C8 MediSensors, who even raised money from the respected GE Ventures!). Though NIGM has an “image issue,” Dr. Heinemann said it warrants further investment (“we owe it to our patients”), and the concept is possible “in principle.” The challenges for scientists and companies, however, are numerous: precision of measurement, specificity, long-term stability, calibration, and real-world usability. After reviewing several failed approaches (e.g., C8, Roche, Pendra, Solianis), Dr. Heinemann concluded that non-invasive glucose monitoring is not a hot topic, and it is “tricky” to know the current status of devices in development. He noted only a small number of published clinical studies (none recently), with most being small and inconclusive. Despite the field’s negative image and years of frustration, Dr. Heinemann optimistically reminded attendees that scientists are “impressively creative” in finding new approaches – we should not lose hope. He believes trust should be re-established in this area of research through sufficient funding, transparent data evaluation, and better cooperation between academia, companies, and investors. Ultimately, any glucose monitor must be robust enough for daily life and offer precision and accuracy sufficient for clinical purposes. We appreciated Dr. Heinemann’s honest appraisal of the field, though it seems unlikely major funding will begin flowing into this area, particularly with minimally invasive products like Abbott’s FreeStyle Libre on the market and Dexcom/Verily [Google Life Sciences] and Novartis/Verily in the works.

Panel Discussion

Q: Why is this not indicated for type 1 diabetes? And does skin complexion affect the results? What about lag time?

Mr. Gal: Our technology is not impacted by skin pigmentation. We did trials with a variety of skin colors.

As for type 1, we definitely understand the need. The fluctuations in type 1 are much higher and faster than in type 2s. We can use device for type 1 diabetes, but we decided we have to go to market step by step. That was a wise decision. With all the sorrow we cannot fulfill the need for type 1 diabetes, we believe in the future we can submit the device for type 1 diabetes.

By definition we have lag time; we cannot run away from that. Lag time does impact the accuracy. In the results you saw we take into consideration lag time.

Dr. Irl Hirsch: A practical question in the clinical trials. Were patients wearing the device 24/7? Were there problems with it falling out of the ear?

Mr. Gal: The device is intended for spot measurement – not continuous. You have to clip it on the ear lobe for about one minute. Each time you want to perform a measurement, it has to be clipped on. During the clinical trials, it depended on the group. In the clinic, the research team clipped the device onto the ear lobe. In the home simulated, measurements were done by the subject.

Dr. Hirsch: I have a real interest in inpatient or long-term care facility patients. Your higher MARDs don’t concern me personally. Both in SMBG and CGM over time, it gets better. I’m not worried about that. The potential huge use for this technology is in the hospital as the MARDs get better. That is where we struggle. Not just in the hospital, but in long-term care and nursing homes. We really struggle with glucose data. Have you thought about that?

Mr. Gal: We are talking about a variety of other devices based on the same technology. One at a time. It’s hard enough to start to get into the market, penetrate, and stay stable. We have lots of ideas for our team, and we could go until 2040 and not make everything.

Q: What happens in hypoglycemia values <70 mg/dl, or values over 500 mg/dl? What does the device show?

Mr. Gal: The device recommends either a repeat measurement or using the conventional invasive device.

Dr. Heinemann: Irl, do you see any light at the end of the tunnel for a clearer view on the role of SMBG in patients with type 2 diabetes not on insulin? In Germany, this is still a hotly debated topic. Some areas get test strips; others not. My view on the literature is its difficult to interpret.

Dr. Hirsch: It is. With conventional SMBG the conclusion – which is biased – is a small but significant improvement for patients not on insulin. My biggest issue – and I am biased because I probably see more of these than PCPs – is that the A1c is not a good metric to make treatment decisions. And because of that, fingerstick testing becomes more important. Maybe what needs to be done is if you have a patient with a known reason why A1c does not give an accurate reflection of glycemia, those are patients we need to focus on glucose to make decisions. After all, all these biomarkers are just reflections of glucose. If a biomarker doesn’t work, there is nothing wrong with going back to what works. It’s glucose that’s the enemy. I showed data on cardiac valvulopathies, which very few people appreciate. That’s the reason why as an endocrinologist, if I’m listening to the heart and I hear a heart murmur, there is a good chance A1c is not reflective of glycemia. In those patients we should pay for more strips.

Dr. Heinemann: Such non-invasive devices could avoid SMBG measurements in the future.

Dr. Heinemann: When are you coming to market in the near future? Do you have a CE Mark?

Mr. Gal: The device is currently available in some territories around the world. We are expanding distribution agreements around world. Right now it is there. We users around world – not too many to be honest – in the few hundreds. We just started recently. We expect to accelerate – not dramatically – and definitely increase the devices around world.

Q: What is the ideal way to use this tool?

Mr. Gal: The major benefit is the ability to monitor more frequently. What happens now is doctors recommend patients with type 2 diabetes (non-insulin treated and insulin treated) measure once a day or twice a day. They don’t try to convince them to measure 7-8-10 times per day. All the doctors know that if they try to convince patients to monitor more frequently, they won’t do it. IDF recommends daily 4-5 times. All the physicians will agree – none of the patients will do that. “Let’s try to convince them to do it once or twice a day.” With such a device as GlucoTrack, you can measure as many times as you like. With an invasive device, the more you measure, the more you pay.

Obesity

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

Mode of Action of Liraglutide 3.0 mg in Weight Management

Lotte Bjerre Knudsen, DMSc (Novo Nordisk, Copenhagen, Denmark)

Dr. Lotte Bjerre Knudsen provided an overview of the mechanism of action of Novo Nordisk’s Saxenda (liraglutide 3.0 mg), highlighting its appetite-suppressing activity at GLP-1 receptors in the brain. She shared results from single plane illumination microscopy studies demonstrating that Saxenda interacts with distinct brain regions involved in appetite regulation. Notably, the drug binds to receptors in the hypothalamus, where it exerts its influence in the homeostatic regulation of appetite. Further, when rats were administered liraglutide, there was an increase in satiety signals (CART) and a decrease in hunger signals (NPY/AgRP) in the arcuate nucleus of the brain. In addition, Dr. Knudsen shared results from two separate studies, which showed that administering liraglutide to rats caused them to increase chow intake and decrease intake of candy and other sweet foods, indicating that liraglutide affects the reward system, suppressing appetite and enabling weight loss. This isn’t the first time Novo Nordisk has featured the neural mechanisms of liraglutide in a corporate symposium as the role of the brain in obesity is increasingly discussed – for similar discussion on this, please see our coverage from EASD and ECO.

Is Intensive Behavioral Therapy Enough in Obesity Management

David Lau, MD, PhD (University of Calgary, Canada)

Dr. David Lau provided a balanced and nuanced answer to the question he was tasked with answering: Is intensive behavioral therapy enough in obesity management? Yes, in principle, though often not in practice. Dr. Lau opened by acknowledging that patients have achieved as much as 5-10% weight loss through lifestyle interventions and that even this weight loss has been associated with many health benefits, from significant reductions in the risk for cardiovascular disease to cancer. He cited the results of LOOK AHEAD as well, describing the improvements in weight, waist circumference, fitness, and A1c as a prime example of how health behavior can improve obesity management and postpone/prevent type 2 diabetes in high-risk patients. With that in mind, he also acknowledged that the biggest challenge is not weight loss itself, but the maintenance of weight loss, a sentiment we have heard many times before. He spoke to the physiological (reductions in metabolic rate) and hormonal (increases in ghrelin, decreases in GLP-1, CCK, PYY) adaptations that favor weight regain through appetite stimulation. As a result, he noted that lifestyle interventions alone are often inadequate in sustaining desired weight loss and advocated for adjunctive pharmacotherapy in helping patients achieve weight maintenance … especially in people with diabetes who already have difficulty losing weight. Ultimately, we were big fans of Dr. Lau’s key message – “Don’t blame patients for not keeping the weight off!” – and applaud him for raising the level of conversation on this front. We’d also like to see more focus on how to motivate patients and providers.  

Focused Weight Management Strategies – Update On Clinical Practice

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

Dr. Arya Sharma’s update on clinical practice focused on drivers of obesity and barriers to management. He opened with a message we appreciated – “Telling people with obesity to eat less and exercise more is the equivalent of telling people with depression to cheer up.” Indeed! He applauded the growing awareness that obesity it not a lifestyle problem but a disease, noting that the best management is individualized to specific patients and combines several treatment modalities to maximize weight loss and sustain long-term weight maintenance. As he has noted in the past, he underscored that BMI is a very poor way to assess obesity and weight management progress since the metric entirely ignores the mental, monetary, and functional barriers/drivers of obesity. As an alternative, he introduced the audience to his Edmonton Obesity Staging System (EOSS) that he and Dr. Robert Kushner (Northwestern University Feinberg School of Medicine, Chicago, IL) developed and that has been shown to predict mortality more effectively than BMI – see below for more. We certainly see Dr. Sharma’s EOSS as an excellent step in the right direction, and continue to believe that much wider adoption of such an approach is needed. Ultimately, we continue to very much appreciate Dr. Sharma’s patient-centric approach to treating obesity (“Success is different for each individual”; “A patient’s ‘best’ weight may never be an ‘ideal’ weight”) and certainly do not think we were alone in that feeling!

  • As background, the Edmonton Obesity Staging System stratifies individuals based on comorbidities and functional status as they relate to obesity. Stage 0 individuals have no apparent risk factors for obesity, Stage 1 individuals have subclinical risk factors (e.g., impaired fasting glucose), Stage 2 individuals have obesity-related chronic disease (e.g., type 2 diabetes), Stage 3 individuals have established end-organ damage (e.g., heart failure), and Stage 4 individuals have severe disabilities from obesity-related diseases.

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

Carel Le Roux, PhD (University College Dublin, Dublin, Ireland)

Dr. Carel Le Roux presented on the challenges of personalized medicine and the potential predictors of weight loss – an area increasingly discussed in obesity. He opened by stressing that “one size does not fit all” in obesity treatment since patients with obesity are incredibly diverse, leading to heterogeneity of treatment effects. On the clinical front, Dr. Le Roux suggested personalizing approaches according to morbidity by taking into account each patient’s comorbidities such as sleep apnea or type 2 diabetes. Similarly, he highlighted the importance of clarifying patients’ expectations and framework around treatment to focus on weight as a health condition rather than an aesthetic issue – we see this as an incredibly important component of obesity treatment as it is deeply intertwined with not only metabolic health, but also with mental health. Regarding predictors, Dr. Le Roux reviewed data from Look AHEAD, which showed that participants with the most visits, greatest weekly activity, and most meal replacements tended to achieve greater weight loss. However, he stressed that early weight loss remains the best predictor of weight loss currently, as shown through analyses of the SCALE data for Novo Nordisk’s Saxenda (liraglutide 3.0 mg). Notably, Dr. Le Roux also pointed out that even non-responders experience the same levels of side effects as responders, further stressing the importance of identifying the responders and following the stopping rules of today’s obesity drugs. While these insights were not necessarily new from what we’ve heard in the past, they remind us of the lack of research surrounding how we can really personalize treatment for patients with obesity as the frontiers of the microbiome, genetics, and the brain within obesity remain young.

Panel Discussion

During a discussion on the personalization of obesity drugs, Dr. Daniel Drucker (Lunenfeld-Tanenbaum Research Institute, Toronto, Canada) stressed the need to study genetics and epigenetics. He highlighted that “we live in a world of genetics and epigenetics” which can show tremendous variation, but that we do not have the relevant data for obesity. Dr. Drucker thus encouraged conducting a “comprehensive genetic analysis” of responders and non-responders to start tease out differences in this area. In our eyes, the significant heterogeneity in response to obesity drugs is likely attributed to a wide range of factors and taking a deeper look into genetics/epigenetics is a solid foundation to further explore this variation, although we remain skeptical of how soon this work can reach obesity given the current environment and stigma around the disease. For another take on individualizing obesity drugs, please see our coverage of an observational pilot study’s results with phentermine from Obesity Week.

Symposium: Obesity – New Concepts and Treatment Approaches

Precision Medicine in Obesity: Implications for Behavioral Weight Loss Treatment

Jeanne McCaffery, PhD (Alpert School of Medicine, Providence, RI)

Dr. Jeanne McCaffery discussed the potential of precision medicine in obesity treatment, highlighting the latest genetics research and promising alternative “biomarkers.” On a high level, she stressed the huge variation in response to different interventions, noting that precision medicine can help identify which interventions are most effective for which patients. For example, this could help dissect which individuals benefit from which macronutrient diet therapies and for whom lifestyle intervention is effective. In addition, Dr. McCaffery reviewed the data from various genome-wide analyses in obesity and shared that the MTIF3 region appears to play a role in predicting weight loss but that the majority of obesity-associated loci do not seem to be strongly associated with weight loss or regain. However, she did emphasize that pathway analyses of gene expression have shown that pathways in the central nervous system appear to be most related to obesity – we have certainly heard growing commentary around the role of the brain in obesity. Looking forward, Dr. McCaffery expressed that genetic discovery methods may yield important information and that alternative “biomarkers” such as early weight loss, change in resting energy expenditure, and total caloric intake may also be promising to further investigate. In our eyes, using genetics as a tool for personalization may be a bit far off for obesity (given the disappointing results we’ve seen so far and obesity’s complex interaction with the environment), but we do hope to see greater work in these other “biomarkers.” We believe that such predictors will be extremely helpful for the obesity drug market, which currently works off a “trial and error” approach when prescribing medications – we see this as one major obstacle to bring payers onboard.

Roles of Microbiome and Gut Hormones in the Outcomes of Metabolic Surgery

Lee Kaplan, MD, PhD (Harvard Medical School, Boston, MA)

In a presentation on the mechanisms of metabolic surgery, Dr. Lee Kaplan noted surgery’s role in increasing energy expenditure. He walked attendees through data on mouse-to-mouse microbiota transfer, showing that mice with RYGB microbiota continue to experience weight loss despite increased food intake, suggesting an increase in energy expenditure. Regarding a potential mechanism, Dr. Kaplan pointed out that transplantation of RYGB microbiota increases the concentrations and alters the molecular profiles of both short chain fatty acids and bile acids, which both play a role in increasing energy expenditure. Specifically, he discussed that bile acids interact with L-cells to decrease drive for food intake but notably, he shared recent research showing that bile acids also stimulate brown adipose tissue activity to increase energy expenditure. We find this latest proposed role of brown adipose tissue within surgery particularly intriguing as this area is relatively young within obesity research – this work once again vividly illustrates how greater investigation into surgery’s mechanisms will help us further comprehend the promise of other targets for obesity treatment.

Surgery vs. Medications for Diabetes: Current Data, Future Possibilities

Philip Schauer, MD (Cleveland Clinic, Cleveland, OH)

Dr. Philip Schauer offered his signature argument in favor of greater use of bariatric surgery to treat type 2 diabetes, though he stressed that surgery should complement medical therapy, not replace it. He acknowledged the significant advances in medical therapy for type 2 diabetes in recent decades and the concurrent reductions in diabetes-related mortality. However, he also cited the enormous cost of treating diabetes, the unacceptable rates of diabetes-related comorbidities, and the burdens of polypharmacy as key limitations of medical therapy. We thought one of the most compelling statistics was the fact that adherence to therapy is under 50% among patients taking three or more drugs. We, of course, would prefer the conversation change to how patients can be better engaged – we think adherence statistics are actually probably worse than the 50% figure from what we’ve heard about “real life” stats. With this negative context at hand, Dr. Schauer reviewed the impressive data showing durable weight loss, high rates of diabetes remission, and reduced morbidity and mortality among patients with diabetes following bariatric surgery, and its advantages over medical therapy in trials like STAMPEDE. He fully acknowledged the invasiveness of these procedures and the long list of possible complications but argued that the risks should be assessed in comparison to the complications of poorly controlled diabetes. He also reviewed several studies addressing the cost of bariatric surgery, noting that all have found it to be at least cost-effective and one third have found it to be cost-saving. Given this cost-benefit profile, Dr. Schauer argued that bariatric surgery should be scaled up and incorporated more fully into diabetes treatment guidelines. He also emphasized the need to develop less invasive, less expensive procedures and ensure wider access for the appropriate patients. We agree that expanding access to surgery is a laudable goal, though we do not foresee it becoming too much more widespread as  diabetes treatment for the majority of patients.

Symposium: The Obesity Paradox – Real or Artifact?

The Benefits and Harms of Being Overweight: Some Paradoxes Illustrated by Comparing South Asian and European Origin Populations

Raj Bhopal, MD, MPH (University of Edinburgh, UK)

Dr. Raj Bhopal shared an interesting discussion around whether or not South Asians should have lower BMI cut-off points, as he presented conflicting evidence on the controversy. He first walked attendees through theories as to why South Asians are at greater risk with overweight compared to Europeans, touching on the possibility of genetic/evolutionary hypotheses, social and economic deprivation, and lifestyle factors. He stressed that adiposity seems to be the major current focus, as South Asians tend to have higher levels of adiposity at lower BMIs – potentially due to evolutionary benefits for thermoregulation, energy balance, and immunity. Dr. Bhopal noted that there is indeed good evidence in favor of lowering BMI cut-offs in this population for the purpose of reducing risk of metabolic disorders, but that there are not yet any practical or cost-effective interventions to implement this recommendation in the specified patient population. Along those lines, he pointed out that cardiovascular outcomes data on this issue is sparse and not yet convincing in favor of lowering BMI thresholds. Similarly, mortality evidence points against lower BMI cut-offs, as some data show that the BMI range of 25-30 kg/m2 may lead to the least mortality. While the obesity paradox leaves many questions unanswered, Dr. Bhopal does highlight important points that must be taken into account from a public health perspective as he noted that lowering BMI cut-offs would make for an almost unmanageably large patient population, for which we have not yet figured out how to best intervene. Thus, we feel that raising awareness on certain ethnic groups’ higher risks remains the current action to take, until the data fall closer to one side of the debate than the other. We must keep in mind that one size does not fit all and different ethnicities do need to be evaluated differently where risk is concerned.

The Obesity Paradox Explained

Jay Kaufman, PhD (McGill University, Montreal, Canada)

Dr. Jay Kaufman presented on the nuances of statistical analyses and study design to highlight that the “obesity paradox” is likely the result of a statistical artifact – specifically that of “collider stratification bias.” He explained that this bias arises whenever a condition of a variable that is affected by exposure (i.e. overweight/obesity) shares unmeasured common causes with the outcome. For example, when measuring a disease endpoint like heart failure, the results may show that for someone who already has heart failure, obesity is the least harmful risk factor compared to the others. Dr. Kaufman presented suggestions on how to eliminate this bias, noting that it is important to ensure that the start of exposure and start of follow-up for a study coincide, especially when analyzing observational studies.

Symposium: A Cure – How Do We Live While We Wait?

Our Acute and Chronic Relationship With Food

Dan Howarth (IDF, Brussels, Belgium)

Diabetes nurse consultant Mr. Dan Howarth reviewed the history of food’s role within diabetes and shared his insights on how healthcare providers and people with diabetes approach food and dietary education. According to Mr. Howarth, for both healthcare providers and people with diabetes, food is often seen as a stressful agent. Throughout the history of diabetes, food was a central focus and concern before the discovery of insulin. Specifically, Mr. Howarth shared how in the early 1900s, Dr. Frederick Allen prescribed the starvation diet as the only acceptable therapy for diabetes – an intervention that could help people with diabetes live an additional five years post-diagnosis. Fast forwarding to today, Mr. Howarth highlighted that with new insulins, people with diabetes have far fewer food restrictions, which has brought significant changes for diabetes treatment, such as the implementation of DAFNE (Dose Adjustment For Normal Eating). Notably, Mr. Howarth shared his commentary on food’s role within the clinical setting – he noted that people with diabetes do not always inform their providers of their sugar consumption due to concerns of being seen as “non-compliant” or as “bad patients”. However, he stressed that eating has a social and cultural aspect due to its influence in many traditions and celebrations, as he thus encouraged providers to be open to these scenarios. Mr. Howarth thus suggested providers to non-judgmentally ask patients what they eat rather than just asking about consumption of sugar, as he concluded that “the patient chooses the bridge he wants to cross and the one he wants to burn” and that all providers “want to be the bridge the PWD wants to cross.” We agree that these insights are valuable to share with providers as diabetes continues to very much struggle with stigma issues and forming healthy communication with providers is an important key step to addressing these challenges.

Debate: Bariatric Surgery vs. Medications in the Treatment of Type 2 Diabetes

It Is Time To Move Bariatric Surgery Into The Guidelines For Care

Philip Schauer, MD (Cleveland Clinic, Cleveland, OH)

Dr. Philip Schauer opened this lively debate by providing an overview of the breadth of scientific evidence supporting surgery as a treatment for type 2 diabetes. He drew from a variety of studies, focusing on 11 RCTs that have compared bariatric surgery to medical treatment since 2011. Ten of those studies have shown superiority of surgery over medical management at achieving remission of diabetes and glycemic improvement. He also cited additional data from the Swedish Obesity Study showing reductions in all-cause mortality, CV morbidity/mortality, and microvascular complications associated with surgery vs. medical management. Despite this degree of evidence, Dr. Schauer noted that many prominent diabetes organizations still exclude metabolic surgery from their guidelines (e.g., ADA) and he pushed for reconsideration of these guidelines …  especially in adequately controlled individuals with BMI <35 kg/m2. Indeed, we have heard growing calls for earlier intervention with surgery, as speakers including Drs. Lena Carlsson (University of Gothenburg, Sweden), Robert Eckel (University of Colorado, Aurora, CO), and Harold Lebovitz (State University of New York, Brooklyn, NY) have argued for intervention as early as in prediabetes. While surgery may not be the scalable solution we are looking for in prediabetes or patients with BMI <35 kg/m2, it is certainly encouraging to hear the support for an additional treatment option for a patient population that has very little guidance on treatment and prevention of type 2 diabetes.

Medical Therapy Is Still The Mainstay of Treatment For The Majority of Patients with Type 2 Diabetes

Ildiko Lingvay, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Ildiko Lingvay positioned bariatric surgery as “a very effective option for few” vs. medications as “the only option for many.” She did not discount the efficacy of surgical interventions (“The benefits of bariatric surgery are not to be argued”) but instead suggested that the required commitment for sustained lifestyle change is the biggest limitation for patients who are eligible for surgery. She did also acknowledge that the immediate surgical and long-term metabolic complications are important considerations that limit the pool of eligible candidates though – to our surprise – called cost a minuscule deterrent in the big scheme of things. Why? Because even in regions where bariatric surgery is well-covered by insurance (e.g., Canada), she noted that the prevalence of surgery is in <0.5% of the eligible population. Said Dr. Lingvay: “The most common response I get when I propose bariatric surgery is that, ‘I don’t want to part with my food.’” Ultimately, she noted that bariatric surgery is worth it if clinicians can identify patients who: (i) are determined and commitment to long-term lifestyle change; (ii) adherent to long-term follow up; (iii) willing to have surgery; (iv) newly diagnosed; and (v) lack preexisting psychological issues. Ultimately, we felt both speakers were closer together than they were apart and continue to feel that this discussion is moving toward a question of WHERE bariatric surgery fits within the diabetes care model than IF it fits at all. We were also especially impressed by Dr. Lingvay’s presentation – watch out for this rising star!

Response and Rebuttal

Dr. Philip Schauer: This was a very interesting talk. I wish I could have heard you discuss some of the limitations of medical therapy. I could have gone on for half an hour talking about blindness, stroke, ten-year reduction in mortality with poorly controlled diabetes. Certainly, there are significant and important long-term complications of bariatric surgery and selection is very important, but I do think we have to balance those risks with the fact that patients who have poorly controlled diabetes know exactly what kind of lifestyle they are heading toward. I think it is about getting to the best patient. I don’t think the majority of patients need surgery, but I do think that many need it. I disagree that the difference is in patients’ willingness. In my study, I showed that patients were very satisfied with surgery. I think the difference is that there are very few guidelines for bariatric surgery and that in the US, very few insurance plans cover bariatric surgery. I think we’re closer together than we are apart.

Dr. Ildiko Lingvay: I fully agree on many of the things you have said: (i) the complications of diabetes are bad; (ii) insurance companies should cover bariatric surgery; and (iii) surgery should be part of the options for patients with diabetes. This is where we stop agreeing. I think that the fact that patients are not willing to get bariatric surgery is important. The data you are citing are in patients who are willing to have the surgery. That’s a self-selected population. In my practice, I am aggressive in offering surgery and I offer it to a third or half of my patient. I probably have less than 5% who set up appointment with a bariatric surgeon and way less than 1% actually go through with surgery. So I do think that the patients are part of the problem and that by just pushing for more surgery, we are going to do more surgery but we’re not going to be selective enough.

Big Picture

Symposium: IDF Diabetes Atlas Seventh Edition

The IDF Diabetes Atlas Seventh Edition

An 8:30 am session in a small, second-floor room discussed the new IDF Diabetes Atlas, now posted online in full at www.diabetesatlas.org. The high-level session itself did not contribute major new insight or data beyond our initial coverage two weeks ago (re-pasted below), though the full 144-page Atlas goes deeper into the regional trends, cost and mortality data, and methodology. Today, we gleaned particularly valuable perspective on a few fronts: (i) how conservative the 2040 estimates might be (they assume no change in diabetes prevalence and only reflect expected population growth – in particular, the US 2040 estimate for 35 million people with diabetes is highly, highly conservative in our view); (ii) how much uncertainty comes with all these estimates (data is often old or just doesn’t exist in many cases); and (iii) how much the US disproportionately contributes to global spending on diabetes (48% of all global dollars spent on diabetes, despite having 7% of global cases!).

  • In the Atlas’ follow-up press conference, the report’s main statistician explained to us why the 2040 projections may be very, very conservative: they assume constant 2015 levels of diabetes prevalence multiplied by expected population growth. There is no other modeling involved, including for trends in obesity or people with diabetes living longer. This is concerning for the US estimate of 35 million people with diabetes by 2040, up from 29 million in 2015 – that translates to a highly conservative 240,000 newly diagnosed Americans with diabetes per year over the next 25 years, a dramatic and unrealistic slowdown from 1.4 million new annual diabetes cases in 2014 (per new CDC data posted today). While new annual diabetes cases have fallen for five straight years, the 2014 number of 1.4 million new cases is down only marginally from 1.7 million per year in 2009 – moving to 240,000 new cases per year seems hard to believe any time in the next decade.
    • The same conservatism applies to the projected 642 million people with diabetes globally by 2040. From the current level of 415 million, the 2040 projection implies 9 million new diabetes cases per year annually for the next 25 years. For comparison, from 1995 to 2015, IDF’s estimates translated to 14 million new diabetes cases per year (135 million -> 415 million). Is a 36% reduction in annual diabetes diagnoses likely over the next 25 years?
  • We were also reminded of the challenges and uncertainty in putting the Atlas together, given the available data sources. Half of all countries and territories worldwide have no recent nationwide studies on diabetes prevalence, and their estimates are based on extrapolations from other similar countries. An example of uncertainty comes from the Atlas’ mortality data (5 million deaths attributable to diabetes per year), which relies on studies that are 10+ years old to estimate relative risks. More recent data indicates improved survival with diabetes (Harding et al., Diabetes Care 2014; Green et al., Clin Epidemiology 2015). On the other hand, the 5 million deaths could be an underestimate, as it excludes those <20 years and over years, and those with prediabetes (IFG and IGT).
    • We’re glad that IDF has added confidence intervals around many of the estimates this year, though the mortality estimate does not include one. In today’s discussion of the mortality data, WHO’s Dr. Gojka Roglic said the Atlas estimates of mortality are “more realistic” than routine health stats, but there is a “high level of uncertainty” since “many assumptions” are involved and there is lack of recent large cohort studies with long-term follow-up. We have little doubt in her ultimate conclusion, however: “Diabetes causes a similar or higher number of deaths as do major priority infectious diseases.”
    • In another example, the type 1 diabetes data in the Atlas only includes children from 0-14 years, as studies typically lack data on type 1 in other age groups. The actual prevalence of type 1 diabetes – both in the US and globally – continues to remain a big mystery!
  • There was no mention of the IDF’s call to action during the 2015 G7 Summit, which asked for nations to develop and implement cost-effective policies to improve diabetes outcomes and prevent new cases. A centerpiece of this call is support for a tax on sugar-sweetened beverages as part of IDF’s 12-point Framework for Action on Sugar. This was surprising.
  • Dr. Jonathan Shaw (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) reviewed the latest atlas data on the cost of diabetes, emphasizing the vast inequities in health expenditures throughout the world. Using the assumption that healthcare expenditures for people with diabetes are on average two times higher than those without diabetes, Dr. Shaw shared that 12% of the world’s healthcare budgets are spent on diabetes (age 20-79 years) with over 80% of countries spending 5%-20% of their healthcare budgets on diabetes. He reported the total global expenditure for diabetes to be $673 billion, estimated to increase 19% by 2040 with cases of diabetes expected to increase 35% in this time period; according to Dr. Shaw, this disparity in growth is suggested to be due to the expectation that many of the countries with the largest growth in prevalence have low per capita spending.
  • Most notably, Dr. Shaw stressed the incredible imbalance of how the healthcare dollar is spent worldwide as the top countries with highest diabetes-related health expenditure do not match with the top countries with highest diabetes prevalence. Specifically, he showed that the US comfortably outspends anywhere else in the world while regions such as India and Mexico rank high on prevalence but much lower with regards to expenditure. According to Dr. Shaw, one in four people with diabetes lives in North America and Europe, although the combined region spends every two of three healthcare dollars on diabetes. In addition, the per capita health spend is 260 times greater in the US compared to the Central African Republic, significantly greater than the two regions’ differences in GDP and thus suggesting a drastic difference in prioritization of healthcare expenditures. As he pointed to differences in wealth and prevalence as contributors to this variation, Dr. Shaw concluded by emphasizing the reality that a person with diabetes has more or less money attributed to him depending on where in the world he is. Ironing out these disparities will certainly require a multidisciplinary approach and we hope that industry’s worldwide presence can direct attention to such issues and help local governments recognize the urgency of diabetes. For examples of such work, please see Novo Nordisk’s global efforts through Cities Changing Diabetes as well as the Novartis Access portfolio.

Symposium: Urbanization and Diabetes

Linking Urbanization and Diabetes: What is the Evidence?

Chaisiri Angkurawaranon, MD, PhD (Chiang Mai University, Thailand)

Dr. Chaisiri Angkurawaranon presented data from Thailand on the link between urbanization and diabetes and obesity, showing that “urbanicity” is associated with higher levels of many non-communicable disease (NCD) risk factors. He first encouraged attendees to always consider the social environment, physical environment, and provision of health and social services when thinking about the urban environment’s impact on health. With regards to urbanization’s drivers of NCDs, Dr. Angkurawaranon highlighted the underlying socioeconomic, cultural, political, and environmental determinants (i.e. globalization, urbanization, aging population) and their impacts on modifiable (i.e. unhealthy diet, physical inactivity) and intermediate risk factors (raised blood pressure, blood glucose). Reviewing data from Thailand specifically, he showed a consistent positive association between urban environments and obesity; in addition, he demonstrated evidence that living in urban environments in early life is associated with development of obesity in adulthood. Interestingly, although obesity had a consistent association, Dr. Angkurawaranon pointed out that the relationship between urban environments and diabetes varied more, as such associations can be modified by a region’s particular stage of socioeconomic development. Looking forward, Dr. Angkurawaranon called for the field to assess how we can minimize the more harmful features built in the urban environment and leverage the potential of such areas’ access to care and social support. Indeed, while urban lifestyles can bring about barriers in making healthier choices, such environments can also offer advantages in the resources and services they offer – an important component when thinking about how to solve the urban diabetes epidemic.

Designing Communities for Active Living

Avi Friedman (McGill School of Architecture, Montreal, Quebec, Canada)

This stimulating session on urban diabetes offered a refreshing change of pace – we are glad to see this subject receiving more focus. Dr. Avi Friedman provided an entertaining takedown of the absurdity of modern urban life – some of our favorite comments included “people who don’t use stairs went on to invent machines that help you climb stairs…it’s the most bizarre invention I’ve ever seen” and “cars even have fridges…now when you’re stuck in traffic you can listen to Katy Perry and eat your sushi.” He cited several examples of communities he has designed that make health a top priority, with features like streets shard between cars and pedestrians, required play spaces next to every home, and even a “3D neighborhood” with a bike path built around the perimeter of the building (so residents can bike up to the tenth floor instead of taking the elevator). He closed by challenging the audience to intervene now to cement healthier lifestyles in the next generation, who will otherwise “be our patients for years to come.”

  • The session also featured a presentation on the IDF’s Diabetes Aware Cities project, which is creating a Diabetes Prevention Score that can be used to assess cities’ performance on five categories pertinent to a healthy urban environment: access to healthy food, access to drinkable water, outdoor environment, school environment, and policy. Dr. John Nolan (Steno Diabetes Center, Gentofte, Denmark) then recapped the initial research from Novo Nordisk’s Cities Changing Diabetes program presented at its inaugural summit last month. He also celebrated the fact that initiatives like this have sparked a new conversation of diabetes over the last few years. As he put it, after 25 years in the diabetes field, only in the past year or two has he been involved in conversations with social scientists, anthropologists, city planners, architects, and experts from other non-medical fields on how to tackle the epidemic.

Symposium: Should Research Be Driven By The Global Needs Of People With Diabetes?

Should This Be A “Customer First” Approach?

Jencia Wong, PhD (University of Sydney, Australia)

Dr. Jencia Wong provided a persuasive endorsement of funding basic science research, arguing that “to truly benefit the customer, we cannot start with the customer in mind” and “it is basic research that holds the most promise for people with diabetes.” She opened with an analogy to the words of former Secretary of Defense Donald Rumsfeld – applied research builds on “known, knowns,” while basic research focuses on “unknown, unknowns.” It is the latter, things “we don’t know that we don’t know,” that lead to the biggest breakthroughs for patients. Dr. Wong argued that basic science allows investigators to follow their curiosity and acquire new knowledge without any particular application or use. She cited many important historical examples of basic science in diabetes to illustrate this point: recombinant DNA technology for producing insulin, anti-VEGF treatment for DME, laser therapy for retinopathy, and the discovery of GLP-1 via research on Gila monsters. All these projects stemmed from the curiosity of basic science researchers – not investigations that began with patients first. She concluded that underfunding basic science research will deplete the diabetes innovation pipeline and lead to a loss of a generation of scientists. Her concluding quotes were very persuasive: “People cannot foresee the future well enough to predict what’s going to develop from basic research. If we only did applied research, we would still be making better spears” (Dr. George Smoot, Berkeley National Lab) and “If at first the idea is not absurd, then there is no hope for it” (Albert Einstein).

The JDRF Experience

Aaron Kowalski, PhD (Chief Mission Officer; VP Research; New York, NY)

JDRF’s Chief Mission Officer Dr. Aaron Kowalski was fired up on the podium, declaring, “Dr. Wong, you’re wrong. Should research be driven by the global needs of patients with diabetes? Of course!!” Dr. Kowalski shared JDRF’s patient-driven approach to research, which is grounded in the organization’s founding by two type 1 moms (“Every step of the way, people with diabetes have a voice and govern the organization”). JDRF now funds a diverse portfolio of projects to tackle different patient needs over different time horizons (near-term to long-term). For instance, while a biological cure is the ultimate goal, if that will take some time, patients want therapies and technologies that make an impact now – things like CGM, artificial pancreas, and better infusion sets. In his list of JDRF’s core research funding principles, we really appreciated the first one: “Do the greatest good for the largest number of people in the shortest amount of time.” The challenge, of course, is how to adequately invest for the long-term gamechangers while pushing the short-term wins forward – JDRF’s ~$100 million in funding last year was split between artificial pancreas, complications, encapsulation, glucose control (including smart insulin), restoration, and prevention (the distribution was not specified). While patient needs drive JDRF’s research agenda, Dr. Kowalski said a holistic stakeholder approach is also key – the organization works with other funders and opinion leaders to make sure research and funding gaps are filled. In the end, he said, it’s global patient needs that should drive research, since the ultimate goal is positively impacting patient outcomes.

JDRF Core Research Funding Principles

  • Do the greatest good for the largest number of people in the shortest amount of time.
  • Capitalize on opportunities JDRF has created and/or facilitated over the last decade.
  • Fill critical gaps that help accelerate delivery to patients of new devices, drugs, and therapies that reduce the daily burden of living with type 1 diabetes.
  • Accelerate progress along the paths to cure and to prevent type 1 diabetes and ultimately create a world without type 1 diabetes.

Quotable Quotes from Q&A

Dr. Kowalski: We’ve been funding a better infusion set project. When I talk with patients about the stuff JDRF is doing, that’s one of most exciting things to them. It’s a distribution – people want to feel impact now. The same is true of anti-VEGF, which came from an innovative grant in 1989 to cycle an anti-cancer drug. People with eye disease that I know are benefitting from that. That’s impactful. When we look at funding, we bucket it into time frames – we want to have a long-term goal, but also near-term wins.

Dr. Kowalski: There’s no doubt that companies need to commercialize things. At JDRF, we try to take as agnostic a stance as possible. One of our key strategies is that companies competing against each drives innovation.

Dr. Kowalski: I work on the JDRF policy team in Washington. In the US, we are driving to outcome-based payment. That is going to be where the money is. Companies will be rewarded for having the biggest improvement in outcomes with the least cost – the highest value.

Dr. Kowalski: There’s a lack of understanding of the true costs. What is the value of a CGM? We want a study that shows a reduction in severe hypoglycemia. That’s a hard trial to do. But what if the value of CGM is more than that? Maybe it’s not just severe hypoglycemia, but days out of work, days out of school, and being more productive? Something we’ve been learning about in the US is ambulances – when one is called for a person in severe hypoglycemia, the paramedics give dextrose, and often the person comes to and refuses medical care. In that case, the paramedics can’t take you to the hospital. You avoid a bill and a few hours in the hospital. But the town or county is paying for that ambulance, and this is a hidden cost that is never added up.

Dr. Kowalski: I always distill diabetes into glucose control vs. burden of management. If you can envision better tools and treatments – transformative treatments – many problems will be eliminated. For instance, we’re in trials of glucose responsive insulin and encapsulated cells. In the next 10 years, imagine giving an injection with a prandial dose of insulin with no risk of hypoglycemia. That would be a transformative step forward. I don’t disagree that we need tremendous basic research, but the optimal state of care today is insufficient. There’s been a lot at this meeting about patient compliance. Who is at fault here? Data from the JDRF CGM trial suggests that people on pumps and CGMs testing seven to eight times per day still spend 40% of the time out of target.

Dr. Kowalski: JDRF’s Board is made up of parents of kids, a few grandparents, and a number of people with type 1. We just went through the robust process of deciding where to invest. One of the themes is people want change sooner. They want prioritization of things that change diabetes outcomes, that make life easier, and reduce the risk for having severe hypoglycemia. And they want that sooner. People are looking for impact in their lives. For my brother, the most impactful thing in his life was getting on CGM.

Dr. Wong: The Chinese say the answer to everything comes in three questions: Can it be done? Can they do it? And do I care? The “do I care” is the problem. The gestation for basic science development is somewhere in the 15-25 year range. That is the hard bit for researchers to go out and actually demonstrate benefit. Scientists need to get into the conversation, be proactive, talk about successes, and generate new ideas.

Symposium: Hemoglobin A1c – The Good, The Bad, and The Ugly

Alternative Markers of Glycemic Control

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

In front of a far far FAR-beyond capacity audience (we mean this quite literally as organizers had to turn away about ~100 attendees at the door who wanted to get in!), the highly respected Dr. Irl Hirsch discussed the ways in which alternative measures of glycemic control can complement and account of insufficiencies in A1c. His thoughts spanned from the reasons that A1c deviates from reality (particularly true for patients with other comorbidities such as anemia) to the strengths and limitations of fructosamine, glycated albumin, and 1,5 anhydroglucitol (1,5 AG). In his view, A1c remains our gold standard as a biomarker for glucose control though its limitations have provided more than enough reasons for assessing other markers. He stressed that a multi-modal approach using a combination of biomarkers may ultimately better predict long-term complications – composite outcomes are something we continue to hear more and more about – though the kicker is that Dr. Hirsch believes the BEST future biomarker is none of these ... though it is something all patients have access to: glucose! Indeed, he impressed upon the audience that glucose itself – e.g., home blood glucose monitoring and continuous glucose monitoring – is the ideal metric for making clinical decisions, suggesting that there is little utility in a biomarker when you can use the real thing. This sentiment was perhaps best summarized by Dr. Hirsch’s closing remarks: “At the end of the day, it’s glucose that’s the enemy. Glucose monitoring is going to be the best biomarker yet!” Below, we summarize a number of other major takeaways from Dr. Hirsch’s presentation along with his thoughts on beta-cell function as a novel and underappreciated marker of diabetes progression.

  • Dr. Hirsch shared that ~14-25% of patients in his practice present with glycation gaps (i.e., A1c levels that do not reflect blood glucose), stressing that the phenomenon is far more common than is widely appreciated. There are a number of reasons for the divergence – hemoglobin variants, decreased red blood cell survival, drug interference, etc. – though ultimately Dr. Hirsch stressed that A1c measurements cannot be relied on for clinical decision-making in all patients (and, we would add, certainly should not be compared between individuals!).
  • Dr. Hirsch opened his lecture by introducing the potential of fructosamine (a ketoamine that includes all glycated proteins) as an alternative biomarker to A1c. He noted that it is a cheaper and easier test to perform and, in certain situations, can resolve situations where A1c does not reflect mean glucose. Dr. Hirsch shared a personal anecdote of confronting and identifying a glycation gap, describing a 52-year-old woman who repeatedly presented with an A1c between 7.4-7.8% but whose fingerstick tests consistently ranged between 220-240 mg/dl. [For context, there is a clear discordance here as BG values of 220-240 mg/dl typically correlate with an A1c between 9.0-10%.] Dr. Hirsch’s solution? A fructosamine analysis. Dr. Hirsch stressed that clinicians have a responsibility to understand A1c and, in certain situations, depend more heavily on fructosamine and SMBG data to make treatment decisions.
    • Despite these benefits, Dr. Hirsch was quick to point out that fructosamine also has its share of problems: (i) it provides only a 21-day history of glycemia; (ii) the relationship between glycemia and fructosamine is not a straight line; (iii) fructosamine is influenced by bilirubin, uric acid, and high protein turnover (as seen in dialysis); (iv) lower levels in children and obese patients due to lower protein levels; and (v) it needs to be corrected by serum albumin, which can rarely be performed by clinical labs.
    • Of even more concern, Dr. Hirsch put forth the question that was on many clinicians’ minds: How do you translate a fructosamine reading into an A1c? As Dr. Hirsch said jokingly, “I’m not a clergy; I’m not used to converting people!” He noted that there is very little evidence for making sense of this metric, though drew from the literature to provider clinicians with “the best evidence we have.” See below.

Table: Approximate Comparison of Blood Glucose, A1c, and Fructosamine Levels

Glucose (mg/dl)               

Fructosamine (mmol)

A1c (%)

90

212.5

5.0

120

250

6.0

150

287.5

7.0

180

325

8.0

210

362.5

9.0

240

400

10.0

270

437.5

11.0

300

475

12.0

330

512.5

13.0

360

550

14.0

390

587.5

15.0

  • Dr. Hirsch also discussed the striking potential of glycated albumin (GA) as an alternative to A1c. In his view, GA has many advantages relative to fructosamine considering that there is no impact from anemia (from renal disease, pregnancy, or cirrhosis) and that there is no impact from serum albumin levels. It also better correlates to postprandial hyperglycemia than A1c, though on the other hand, he noted that albumin metabolism can impact GA levels and that the metric tends to read low with obesity (“Why is that? I’m not sure!”).
    • “That’s a surprise!” exclaimed Dr. Hirsch upon polling the audience and finding that almost no one had access to GA in their practice. He noted that the metric is gaining popularity in pockets of the US as it has been reported to be a consistent marker of glycemic variability.
  • Ultimately, Dr. Hirsch stressed that no single biomarker is sufficient for assessing glycemic control nor are any two biomarkers necessarily equivalent. He did share that both frustosamine and GA have shown a strong association with microvascular complications (similar to the association observed between complications and A1c), though only A1c has shown a correlation with cardiovascular complications. He concluded that composite biomarkers may very well better predict long-term complications than any single biomarker alone, making a few suggestions himself: A1c+ GA for diabetic retinopathy? A1c+1,5 AG for cardiovascular disease?
    • Notably, Dr. Hirsch did suggest that c-peptide levels may provide a particularly useful marker in a composite endpoint. He cited T1D Exchange data, noting that results actually elucidated a sub-population of ~25% patients who did not develop complications even after 40 years of living with diabetes and that this endogenous insulin protected patients from severe hypoglycemia. We certainly believe that there is value in investigating beta cell preservation as a marker diabetes progression though more research is certainly needed on this front.
  • We would be remiss not to mention that Dr. Hirsch also turned to 1,5 anhydroglucitol (1,5 AG) as a potential marker of short-term glycemic control … though was not so hot on its utility. For context, he noted that 1,5 AG is a metabolically inert polyol that competes with glucose for reabsorption in the kidneys. Otherwise stable levels of 1,5-AG are rapidly depleted as blood glucose levels exceed the renal threshold for glucosuria, providing a metric of how long patients are in hyperglycemia. As a result, the metric can be used in people with diabetes to identify glycemic variability or a history of high blood glucose even if current glycemic measurements (A1c or BG) have near normal values. Broadly, we hear VERY little about 1,5 AG tests (yes, they are approved by the FDA) though found it notable to hear Dr. Hirsch suggest that the metric may be useful filling the gap and offering complementary information to A1c and fructosamine tests.
    • The interesting obstacle with 1,5 AG is that the metric can only be used in patients with an A1c<8.0%. Why? Because when A1c’s rise above 8.0%, patients are in consistent glycosuria. In simple terms, there is no change from baseline, which is what informs the reading.
    • On an interesting note, Dr. Hirsch noted that 1,5 AG is actually removed from the kidneys by SGLT-4 transporters, a clinically relevant fact given the growing prominence of SGLT-2 inhibitor therapy. As a result of this mechanism, there is actually interference with the measurement of 1,5 AG in patients using SGLT-2 inhibitors that blocks the transport of 1,5 AG. As such, he encouraged the handful of those in the audience using 1,5 AG analyses to be mindful of this fact (something that we certainly weren’t aware of!).

Questions and Answers

Q: Unlike A1c, GA and frustosamine haven’t really been standardized in the same way. We don’t have a standard methodology. There are huge fluctuations between labs at different times. There’s no standardization yet.

A: I couldn’t agree with you more. The way that I look at this is that I can’t predict what’s going to happen over the next 10-15 years, but these biomarkers are still in an early stage of study like A1c was 10 years ago. I don’t think we’re going to see the same research into these metrics because we already have A1c. I’d like to think we would. But I’m not optimistic.

Symposium: Diabetes Self-Management Support

Self-Management Support in Primary Care – AADE Review on Effectiveness

Joan Bardsley, RN, CDE (MedStar Health Research Institute, Hyattsville, MD)

Ms. Joan Bardsley presented results of a systematic review of diabetes education programs, highlighting the efficacy of DSME, as she also emphasized the “real world needs” within this area. She walked attendees through the design and methodology of a review of ~23,000 adult participants in intervention and standard care groups. The results demonstrated that adults who engaged in DSME experienced a mean A1c reduction of ~0.6% - Ms. Bardsley highlighted that this outcome easily passes the FDA criteria for approving a new therapy and also has no association with adverse events. The results of this review additionally helped differentiate between different modes of delivery, as the findings suggested that DSME approaches that combine both group and individualized engagement result in the greatest A1c improvements. In addition, the findings showed that there is a greater likelihood of DSME resulting in statistically significant improvements when a team rather than a single individual is involved in the DSME’s provision. Notably, Ms. Bardsley also emphasized that the review found that DSME contact time over ten hours led to the greatest improvements, which has important policy implications as Medicare only covers up to ten hours of DSME. With these findings, however, Ms. Bardsley stressed that the reality of DSME is grim, with national data indicating that only 5%-7% of adults with type 2 diabetes engage in DSME, even when the access is there – see our coverage of this data for more.

  • Addressing this need, Ms. Bardsley then reviewed the position statement on DSME organized by the ADA, AADE, Academy of Nutrition and Dietitics, and NDEP. Specifically, this statement aims to: (i) improve the patient experience of care and education; (ii) improve the health of individuals and populations and reduce diabetes costs; (iii) provide healthcare teams with the information required to better understand educational processes and integrations into routine care; and (iv) create an algorithm that defines when, what, and how DSME should be provided for adults with type 2 diabetes. We applaud these various professional societies for taking the lead on providing much needed additional guidance on this front, but see stigma and disconnect with payers as critical barriers that will need to be overcome to better increase access and use of DSME.

Symposium: Access to Essential Medicines

What Are the Barriers to Access to Essential Medicines?

David Beran, PhD (Geneva University Hospitals, Switzerland)

Dr. David Beran argued for a shift to human insulin administered via syringe to improve access, particularly in low- and middle-income countries. He very astutely pointed out that insulin represents a rather unique case because it is an absolutely essential and very old medicine. However, he also noted that at the same time, it is a biologic that is expensive compared to other medicines (particularly generic small molecules) and represents an increasing financial burden for both health systems and individuals. Specifically, Dr. Beran suggested that the domination of the insulin market by three manufacturers (Sanofi, Lilly, and Novo Nordisk) has increased the costs of insulin by limiting generic competition and giving rise to an increase in the use of analog insulins and injection pens over human insulin and syringes. He pointed out that the 2011 update to the WHO model list of essential medicines asserted that insulin analogs provide no clinical advantages over recombinant human insulin. While this may be true in terms of A1c alone, we would strongly argue that the reduced risk of hypoglycemia with analog insulin qualifies as a major clinical advantage. In an analysis of 2009 insulin purchases in Kyrgyzstan, Dr. Beran showed that insulin products that do not meet WHO criteria (insulin analogs and pen-filled insulins) accounted for only 29% of total insulin by volume but 57% of total insulin cost. He thus suggested that switching entirely to recombinant human insulin and syringes would represent $738,936 in savings to Kyrgyzstan’s health system (which he contextualized by saying that this amount in savings equals the average US health expenditures for ~11,000 people). On an individual level, Dr. Beran calculated that a pen-filled insulin costs 2.5 times more than human insulin in a syringe and an insulin analog costs 8.5 times as much. While there’s no doubt that the upfront cost is lower for human insulin via syringe administration, we believe the long-term costs of increased hypoglycemia and increased glycemic variability potentially (to put it conservatively – but we acknowledge we don’t have the data) lower patient adherence. This can lead to increased complications, which appears to not be discussed with his rumination on the initial savings, which of course are enticing. We can see both sides of the argument and understand that the needs vary among different demographics – ultimately, we see ensuring broader access to life-saving treatments as the first step but very much hope that in tandem, we make sure that behavior and systems improvements are also emphasized.

  • Mr. Beran highlighted two core barriers to insulin access: accessibility and affordability. He also identified a host of other potential barriers to insulin access: these include a lack of data on the actual insulin needs in many countries; extremely low budget allocations for insulin; countries not using set international reference prices when purchasing insulin; a need to budget for packages of medicines (such as diabetes and hypertension drugs) or syringes when purchasing insulin; potential quality concerns; and prescriber behavior.
  • Mr. Beran also argued that the diabetes field needs to adopt parallel practices from the HIV/AIDS world. He identified three key elements that contributed to success in expanding access to HIV/AIDS medications: (i) the market was reshaped with generic competition, negotiations, and centralized procurement and financing; (ii) there was dedicated advocacy from civil society; and (iii) there was sufficient funding from a variety of government and nonprofit sources. He suggested that these three elements are currently missing within diabetes and challenged the diabetes community to change the current state of affairs to improve access to life-saving medications such as insulin.

Questions and Answers

Ms. Erin Little (Sucre Bleu, Bangalore, India): I’m sure you know that meetings are currently going on with the WHO on international cooperation for non-communicable diseases. If you look at the agenda, there is nothing on diabetes. They only have two people on the diabetes teams at the WHO. What are your thoughts on increasing representation of the diabetes community?

A: Correct me if I’m wrong, you’re the only person they have. In terms of representation, there are NGOs with official ties to the WHO. How do you have true civil society representation though? How do you include people from low- and middle-income countries and their interests? There’s no global diabetes community yet. Switzerland’s diabetes association is really good at diabetes in Switzerland, but they’re not looking at global diabetes. How do you change that? How do you go from an organization focusing on the population I serve to the wider, global world?

Symposium: Clinical Practice Guidelines – Putting Them in Perspective

The overarching theme from the ADA/EASD, IDF, NICE, and CDA talks was that guidelines implementation is very difficult. Ugh – this was pretty depressing. Many speakers praised the Knowledge to Action Cycle as a framework for thinking about guidelines implementation – unfortunately, a framework does not guarantee that the knowledge is translated into the right actions. Canada is doing some interesting work to implement its guidelines, including point-of-care decision support, summary slides and videos, quick access links, countrywide CME programs, an easily searchable online portal, and a mobile app. A clear challenge, however, remains integrating guidelines into routine clinical care. We hope EMR companies can work with professional organizations to do this, though we also wonder about clinician enthusiasm to check boxes – what is the right balance between guiding clinicians and leaving care open to clinical judgment?

NICE

Philip Home, MD (Newcastle University, Newcastle upon Tyne, UK)

In a session on clinical practice guidelines, the highly regarded Dr. Philip Home revealed that NICE’s new guidelines for type 2 diabetes and treatment algorithm were published this morning, updated for the first time since 2009. There have been updates in every recommendation section, and we’re elated to see a much bigger focus on individualization (the very first recommendation in the guidelines). Indeed, the Association of the British Pharmaceutical Industry called the guidelines “great news for patients,” praising the focus on individualized care (a move away from the 2009 guidelines, which has more of a cost focus). Dr. Home did not comment on the new guidelines specifically, but we did appreciate his comment on the rationale: “Guideline implementation is more about ensuring comprehensive quality of care than adoption of the latest advances – it’s for the 50% of diabetes care that is well below standard rather than improving the 10% at the top.” A good point indeed.

  • The 57-page document is worth a full read and includes 97 recommendations in seven sections: individualized care (2 recommendations), patient education (6), dietary advice (10), blood pressure management (14), antiplatelet therapy (2), blood glucose management (38), and managing complications (25).
  • Of the 97 recommendations, NICE lists ten as priorities for implementation: structured diabetes education; integrate dietary advice with a personalized diabetes plan; manage blood pressure to <140/80 mmHg and monitor every 1-2 months; involve adults in their A1c target (yes!); intensify therapy when A1c rises to 7.5%+; do not offer SMBG unless someone is on insulin, has hypoglycemia, is on an hypo-causing oral, or is pregnant or planning for pregnancy; and offer first-line metformin unless it is contraindicated (in which case use a DPP-4, pioglitazone, or a sulfonylurea).
  • SGLT-2 inhibitors have made it into NICE’s new one-page treatment algorithm, and can be considered in certain patients for dual or triple therapy or used in combination with insulin.
  • GLP-1 can be considered after triple therapy with orals, and only continued after six months if A1c declines 1% AND 3% body weight loss occurs.

Symposium: The Microbiome And Diabetes – Cause, Consequence And Therapeutic Target?

Summary

This session’s four speakers – Drs. Max Nieuwdorp, Patrice Cani, Remy Burcelin, and Fredrik Backhed all acknowledged the early stage of microbiome research and the field’s remaining challenges and unanswered questions. Studies are mostly preclinical at this point, and human studies are typically too small to draw meaningful conclusions from. The field has to move from association to causality, mechanism, and human interventions. We really appreciated Dr. Fredrik Backhed’s (University of Gothenburg, Sweden) list of key unanswered questions in diabetes-microbiome research: Is the gut microbiota altered before disease onset? What are the underlying mechanisms for microbial effects on host metabolism? Is the action of metformin and other medications mediated through the gut microbiota? Are the beneficial effects of bariatric surgery mediated by an altered gut microbiota? Can the microbiota be used to stratify patients to different treatments and can the microbiota be used as a therapeutic target? (“the big question”). Dr. Max Nieuwdorp (Academic Medical Center, Amsterdam, Netherlands) postulated that use of microbes in diabetes may work best for those just diagnosed or on verge of getting type 2 diabetes. He was less optimistic that microbiome interventions will do much for those already on insulin. Overall, it’s hard to know where this field will go and how quickly it will get there... will we look back in 20 years and be astounded at the central role the microbiome plays? Or will it be overhyped?

  • Two recent studies were repeatedly mentioned in this session: Tuesday’s data in Nature on metformin and the microbiome, and last month’s Cell study on personalized nutrition.
    • The Nature study was the bigger news, which analyzed 784 human gut metagenomes and found that metformin treatment itself alters the gut microbiome. The finding is significant, as it suggests having diabetes and taking a certain diabetes medication each independently affect the gut microbiome. Previous diabetes-microbiome studies did not stratify results by treatment, and results diverged as to the disease’s impact on the microbiome. The paper’s authors conclude, “The present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.” What lines of research will follow from this paper: Will certain diabetes therapies more positively or negatively alter the microbiome? Once therapy is controlled for in diabetes-microbiome studies, will consistent microbiome deficiencies emerge, paving the way for potential microbiome interventions that target insulin resistance or metabolic syndrome?
    • Cell recently published research from the prestigious Weizmann Institute of Science on the development of a machine-learning algorithm that integrates data on blood glucose, dietary habits, weight and height, physical activity, and gut microbiota to predict postprandial glycemic response (PPGR) to daily meals. The team designed the algorithm around ~137 specific physiological factors, identified through comprehensive profiling of a cohort of participants without diabetes (n=800). These participants were studied over a week, during which each individual wore a CGM (readings were blinded) and used a mobile app to record exercise, sleep patterns, stressful events, meal composition, and weight. They also completed questionnaires on their medical history and dietary habits and provided stool samples for gut microbe analysis. The results found significant variation in PPGR among participants, even in response to identical meals. For example, in response to bread, the average PPGR across 795 individuals was 44 ± 31 mg/dl – a relatively large standard deviation. Specifically, the findings demonstrated that factors including A1c, BMI, systolic blood pressure, alanine aminotransferase activity, and certain microbiome features (proteobacteria and enterobacteriaceae) were significantly associated with PPGR. The study also used a separate validation cohort, which supported the algorithm’s accuracy in predicting personalized PPGRs to complex meals, matching actual glycemic data with an impressive correlation of 0.7. In addition, the research team showed that the algorithm was effective in providing short-term personalized dietary interventions to lower post-meal glucose values. In our eyes, this algorithm illustrates the promise of using large datasets to identify trends and move personalized medicine forward. With its cost-effective, actionable recommendations of diet changes and adaptability to meals of various cultures, we also see this algorithm potentially scalable to large populations – this could be particularly valuable for people with prediabetes and may also be useful in creating meal plans for people with both type 1 and type 2 diabetes.

Symposium: Hypoglycemia Unawareness – A Long-Term Complication?

Summary

Stephanie Amiel, PhD (King’s College London, London, UK); Jane Speight, PhD (Australian Centre for Behavioural Research in Diabetes, Melbourne, Australia); Ms. Zoe Heineman (Founder of nonprofit Hypoglycemia Awareness); Dr. Fauzia Moyeen (Diabetes Wellness Centre, Lahore, Pakistan)

In a diverse symposium on hypoglycemia unawareness chaired by our very own Kelly Close, speakers underscored the psychological factors driving hypoglycemia unawareness, particularly hyperglycemia avoidance and lack of concern about hypoglycemia. The best way to regain hypoglycemia awareness? Limit exposure to hypoglycemia.

  • Dr. Speight (Australian Centre for Behavioural Research in Diabetes, Melbourne, Australia) introduced the concept of hyperglycemia avoidance, arguing that fear of long-term complications is one of the foremost factors driving recurrent hypoglycemia. Indeed, over one-third of people with type 1 diabetes worry about serious complications in the future, which ranks as the #1 concern in countries around the world. Dr. Speight presented data showing that patients with significant anxiety about developing complications have the highest risk and lowest level of concern for hypoglycemia. Further, she highlighted studies demonstrating that some people prefer being hypoglycemic and are very driven to maintain low blood glucose levels, a characteristic that was found to be predictive of severe hypoglycemic episodes and car accidents. We found this discussion on hyperglycemia avoidance fascinating; we tend to hear a lot about fear of hypoglycemia on the opposite end of the spectrum.          
  • In another illuminating presentation, the highly regarded Dr. Amiel stressed that impaired awareness is a common complication of diabetes therapy that can often be ameliorated by preventing exposure to hypoglycemia. However, in order to treat hypoglycemia unawareness, patients must be motivated to change their behavior. She noted that despite the destructive intrusion of hypoglycemia in many aspects of life (reliance on others, loss of driver’s license, loss of employment, psychological distress, etc.), only 4 in 17 people with hypoglycemia unawareness are concerned about it. She vividly illustrated this lack of concern with the story of a patient who failed to change her glycemic management habits even after crashing her car. To address such motivational barriers, her lab recently designed and tested a psychoeducational program for people with resistant hypo-unawareness (n=24) called the Dose Adjustment for Normal Eating Hypoglycemia Awareness Restoration Training (DAFNE-HART). Results from the DAFNE-HART pilot study showed that twelve months after using the program, median rates of severe hypoglycemia fell from 3 to 0 per person per year (p < 0.0001), and moderate rates fell from 14 to 0 per person per 6 weeks (p < 0.001). In addition, worry and behavior around hyperglycemia improved, and A1c did not change. This speaks to the importance of including motivational and cognitive behavioral techniques in patient training in addition to basic diabetes education. Dr. Amiel has been involved in the development of recent NICE guidelines for type 1 diabetes, and we hope that educational efforts are not only reimbursed widely, but offered widely to patients in convenient forms (e.g., online, mobile apps, etc).
  • In the same symposium, Ms. Heineman discussed the flipside of hyperglycemia avoidance – fear of hypoglycemia – from a patient perspective, emphasizing that proper preparation can mediate feelings of anxiety. She advocated for patients to train and retrain the people in their life on glucagon administration and notify people that they have diabetes. She noted that medical alert IDs and tattoos can also help in emergencies, especially for people who live alone. [Outside of this session, our team stumbled on the “medical ID” section on the Apple Health app, which displays medical information on the lock screen when someone clicks, “Emergency.” Very useful for diabetes!]
  • Dr. Fauzia Moyeen (Diabetes Wellness Centre, Lahore, Pakistan) concluded the symposium with a compassionate talk on family psychology, using videos to illustrate the crippling guilt, helplessness, and fear felt by patients with diabetes and their families. She also presented results from patient surveys indicating that social taboos and fear of restrictions cause children to hide their symptoms of low blood sugar, elevating the risk of severe hypoglycemia and hypoglycemia unawareness. She emphasized the value of mindfulness techniques, technology, and education in preventing severe hypoglycemia and relieving pressure on family members.

Open Forum: Influencing Policy Change

Successful Policy Change: The Mexican Soda Tax

Luis Encarnacion (Fundación Mídete, Mexico City, Mexico)

Mr. Luis Encarnacion provided an overview of the legislative battles he faced on the road to the implementation of Mexico’s federal soda tax, with an eye toward aiding others in achieving successful health policy implementation. Mr. Encarnacion explained that a soda tax was chosen as a policy goal for practical and political reasons. On the practical side, there are dates set aside constitutionally for the discussion of fiscal matters such as taxes and a federal tax can be implemented relatively quickly. On the political side, a soda tax is a controversial, high-profile measure that grabs the attention of the press and public, which catalyzes the public conversation surrounding the link between soda and sugar-sweetened beverages and obesity. Regarding his experiences in implementing the tax, Mr. Encarnacion identified four key characteristics that were instrumental to the tax’s success: (i) the architects of the tax had an in-depth understanding of the political and legislative context; (ii) the group built awareness of the issue in the social, political, and media agenda; (iii) the soda tax was coached as health evidence, backed by evidence from the National Institute of Public Health; and (iv) there was a strong partnership among civil society, academics, and key government actors. Mr. Encarnacion chronicled the journey of the soda tax policy proposal from being backed mainly by non-government agents to eventually garnering support at the highest levels of government from the President himself. Tentatively, the advocacy seems to have paid off – in 2014, the first year of the tax’s implementation, there was a 6% reduction in consumption of sugar-sweetened beverages and a 4% increase in water consumption. Looking in the long term, this adds up to a 1% decrease in overweight and obesity prevalence in Mexico by 2030.

  • Notably, we saw the IDF as a whole as taken a stronger stance on government initiatives to curb sugar intake. In 2015, the organization published its Framework for Action on Sugar that recommended a variety of interventions to reduce sugar intake to 5% of daily calories, with the aim of preventing new cases of type 2 diabetes. In addition to government incentives such as taxes on high-sugar foods and beverages, the framework supports clear labeling of total sugar content in foods, banning advertising of high-sugar foods and beverages to children, and making clean drinking water freely available in all schools and public space. We’re glad to see the IDF tackle policy changes that could alter the food environment to slow the diabetes and obesity epidemic and we hope the road to the Mexican soda tax can inspire other countries to put aside political biases and follow suit in the goal of improved population health.

Debate: Is Screening for Type 2 Diabetes Justified Based on Current Evidence?

No

Simon Griffin, MD (MRC Epidemiology Unit Institute of Metabolic Science, Cambridge, UK)

Dr. Simon Griffin took the podium first to present a “no” argument for the issue of whether or not widespread screening for type 2 diabetes is justified. He suggested that the rise of “overdiagnosis” and overtreatment rates could be directly attributed to screening and “disease-mongering.” His argument against screening hinged on the idea that screening is always associated with harm (physical and psychological stress from the tests, etc.) but that there is also an associated benefit – the question then comes down to whether or not the benefit outweighs the harm. Dr. Griffin especially noted the ethical dilemma of screening, suggesting that, unlike medical treatment, a patient does not ask to be screened by a doctor and when we screen, we “go out and drag them in for testing.” Dr. Griffin felt that there needed to be an absence of significant harm and demonstrated efficacy and evidence of cost-effectiveness for screening to be justified – two criteria that he felt were not necessarily met within type 2 diabetes. In addition, he argued that primary prevention should be in place and clinical management of the condition should be optimized prior to screening for the condition. In what we perceived as a somewhat provocative argument, he highlighted that unless post-diabetes diagnosis care is optimized to prevent complications, screening will not be effective or cost-effective. While it’s true that widespread screening will likely lead to a higher number of individuals diagnosed with type 2 diabetes and increase the pressure on the health system initially, early screening and diagnosis could make a huge difference at the individual level by providing patients with an opportunity to take control of their health status. In addition, in our eyes, while diabetes care has not yet completely eliminated complications, early screening and diagnosis – and earlier intervention in the progression of the disease – could nonetheless reduce incidence of complications in providing patients with the awareness and motivation needed. Of course, we also feel that reducing the stigma around type 2 diabetes and giving people the toolkit and confidence to openly ask and discuss the disease will be critical in making widespread screening truly effective.

Yes

William Herman, MD (University of Michigan, Ann Arbor, MI)

On the affirmative side, Dr. William Herman argued that type 2 diabetes meets the first six criteria to justify screening: (i) the health condition is serious; (ii) the progression of the disease is understood; (iii) the condition is detectable prior to its clinical diagnosis; (iv) the screening test itself is cheap, safe, acceptable, reliable, and valid; (v) the treatment for the condition, if detected, is safe and acceptable; and (vi) there are adequate facilities for diagnosis and treatment. However, the ultimate goal of screening is to improve outcomes by catching the disease earlier on and Dr. Herman noted that the clinical trial evidence was weaker for this point. He suggested that trials comparing screening and early treatment vs. screening and delayed treatment could address this knowledge gap, but such a trial would be ethically unsound. That said, computer simulation models have shown a substantial reduction of cardiovascular risk and all-cause mortality with primary care-based screening, early diagnosis, and treatment. Dr. Herman also noted that screening could identify individuals with prediabetes or at high-risk for developing type 2 diabetes and would allow an opportunity for interventions that could prevent type 2 diabetes altogether – as prevention and early intervention have become huge buzzwords at many meetings, we would guess that the majority of the field would agree with Dr. Herman on the need to identify high-risk patients earlier, although Dr. Griffin would suggest that there is little evidence behind this. Please see our coverage of the USPSTF’s final recommendation on screening for more.

Debate: Diabetes Prevention – Should We Bother?

Yes

Steven Kahn, MB, ChB (University of Washington, Seattle, WA)

Dr. Steven Kahn opened this debate with a passionate plea in favor of prevention. He began by contrasting the profound prevalence of prediabetes with the silent nature of the disease, sharing that six out of seven individuals with prediabetes do not even know that they have it. Even more compelling, in his view, is the economic argument – he cited recent IDF data that 12% of total health dollars in the world are spent on diabetes, noting that, “this is a disproportionate expenditure that we could be doing something about!” Coupled with the way diabetes prevalence has grown over time, he was adamant that investments into prevention and disease management are a no-brainer. After all, these are patients who are likely to become type 2 patients in a decade or less and who will present society with a significant public health concern. In light of this burden, he highlighted literature showing that lifestyle and pharmaceutical interventions can prevent the progression from prediabetes to type 2 diabetes and also help prediabetes patients revert to normoglycemia. Dr. Kahn acknowledged that interventions have produced differential effects – with lifestyle being successful in most populations tested and with medications having variable effects – though the risk-benefit tradeoff of early intervention vs. long-term complications clearly favors the former. We would agree that intervention to prevent the progression from prediabetes to diabetes represents an approach not only to reduce the impact of its deleterious outcomes but to minimize the cost of complications for the individual and society.

No

Guntram Schernthaner, MD (University of Vienna, Austria)

Dr. Guntram Schernthaner opened his side of the debate by agreeing the premise that preventing diabetes is the ultimate goal – instead, he framed his response to Dr. Kahn by suggesting that we do not yet have the right tools at the right costs to make prevention feasible in practice. He focused on two tools in particular: lifestyle intervention and pharmacotherapy. Dr. Schernthaner began by drawing from a host of literature to suggest that in, “real life,” successful prevention via lifestyle is the exception – for example, weight-loss interventions in overweight or obese adults with type 2 diabetes rarely result in weight loss >5% (which appears necessary for beneficial effects on HbA1c, lipids, and blood pressure) and long term benefits on microvascular/macrovascular complications have not been shown. On the latter, he cited LOOK AHEAD, noting that intensive lifestyle intervention did not significantly reduce CVD-related morbidity/mortality (e.g. CVD death, non-fatal MI, non-fatal stroke, hospitalized angina) after nearly 10 years of follow-up. Dr. Schernthaner then turned to pharmacotherapy, noting that we have very little evidence that drug interventions in the prediabetes state reduce the risk of adverse cardiovascular outcomes associated with type 2 diabetes. For those drugs that are associated with risk reduction – TZDs (70%) and metformin (30%) – Dr. Schernthaner pointed to the adverse effects and lack of coverage, respectively, as the biggest hurdles to utilization. Ultimately, we appreciated his realistic take – not that prevention is unwarranted but that the challenges we face in prevention are very, very steep and require practical conversation.

Meet-the-Expert: Living with Diabetes

Blood Glucose Bingo - Let’s Test: A World Diabetes Day Initiative by #dedoc

Bastian Hauck (#dedoc, Berlin, Germany)

In an engaging presentation moderated by our very own Ms. Kelly Close, Mr. Bastian Hauck shared his experience designing and deploying Blood Glucose Bingo, a World Diabetes Day 2015 awareness campaign in Germany that garnered participation from an impressive 2,000 people (647 without diabetes) and 15,000 pharmacies. The purpose of the campaign was to raise public awareness about diabetes, motivate those with diabetes to better manage their condition, and publicize the growing prevalence of undiagnosed diabetes in Germany. The campaign invited people with and without diabetes to check their blood glucose levels, upload their values to the Blood Glucose Bingo website, share a selfie (optional), and nominate friends to participate. To grow the campaign, Mr. Hauck noted that his team printed and distributed ~1 million flyers (“Two million people have diabetes and don’t know it. Test with us, and learn more about your diabetes risk”), noting that the movement simultaneously “played with fear” and inspired hope. [To be fair, we’re not quite sure whether fear is the most effective motivational tactic …] Unfortunately, World Diabetes Day 2015 coincided with the tragic terrorist attacks in Paris, and Mr. Hauck noted that Blood Glucose Bingo participation and media attention suffered as a result. Still, we were impressed to see that 15,000 people visited the website and that 2,000 participated … and even more notably, that seven previously undiagnosed were identified as having high blood sugars! “For these seven, this campaign has made a difference,” stated Mr. Hauck. We salute Mr. Hauck for this brave effort, and are eager to see the results of his next Blood Glucose Campaign, which he plans to launch globally on World Diabetes Day 2016.

  • Mr. Hauck performed a “test drive” of the campaign a week before World Diabetes Day and filmed participants’ facial expressions when they saw their blood glucose readings. The goal was to show people how it feels to measure and receive your blood glucose value and to raise awareness about the campaign. The short video is available here with English subtitles.
  • On World Diabetes Day 2012, Mr. Hauck founded #dedoc, a social media based network for people with diabetes that has enabled the German diabetes online community to grow from three blogs to over 80. On Twitter, #dedoc hosts a TweetChat every Wednesday to deliver real-life peer-to-peer support (similar to the Diabetes Social Media Advocacy TweetChat) and holds a game of Blood Glucose Bingo at the end of each chat. The website also includes an open blog, which aggregates every blog post from ~95% of all German diabetes blogs onto a single page.

Questions and Answers

Q: How did you do gain so much support from pharmacies and the media?

A: Getting the pharmacies was key, because otherwise people would not have been able to participate. It takes a lot of negotiation and it takes going to the pharmacist’s association. They weren’t coming on board until I presented it as an investment case. I told them, “If you participate and offer free tests, these people will be a future customer to you. If you don’t do this, you don’t know your business.”

Q: This is genius. I thought it was very smart to include the toll-free number for people to dial in and not to assume that people have access to the internet. Can you speak to the split: How many registered via phone, how many registered online, and how many registered in pharmacies?

A: The vast majority was online. I would estimate that ~130 called in, and those were the high-risk groups and the less affluent so it was very important to do that. Notably, each call cost $15, which is crazy but I think it was the right thing to do in order to be as inclusive as possible.

Q: We often have jobs that are not related to our passion, and commitments that take up time. How did you manage the rest of your life, and where did you find the money to commit to it and have the software developed at no cost? The barrier for us is always money.

A: I have to give credit to my wonderful girlfriend who helped take care of a lot of things. I do have a job and I run a shipyard. I knew it wasn’t going to work if I tried to do this myself, so I hired someone to take that part of my job. I took personal responsibility and thought it would be possible to get the money back but I wasn’t sure it was going to work. As for programming the software, I just reached out to the community and asked, “Who of you type 1s out there knows how to set up a database and a website and can help me study when blood glucose levels are high?” That worked really well. At the same time, working with volunteers like that is hard. About a week before diabetes day, half of my team collapsed because they couldn’t handle the pressure. We finished programming the app at midnight the night before World Diabetes Day.

Q: I think there are people in the US who are willing to help out this campaign. I think if there are people who are interested in this campaign and you share the recipe, it will work. This is genius. You took a risk and you made it happen. I’m so glad I got to listen and see the recipe.

A: The lessons learned for me were: (i) I started way too late; and (ii) I did not reach out to other countries. I made a decision early on that this year that I would only do the campaign in Germany. My two rules were that everyone on the team had to be type 1, as I didn’t want to start from zero and explain what a hypoglycemic episode was. We didn’t have time. They also had to be in Berlin, because I didn’t want to waste time on Skype.

Q: Not only do we need the recipe, but we also need to know the cost of the ingredients. You got them for free, but other people need to know how many hours you spent on this so that when we plan we know how many full-time positions to plan for. I would also encourage you to think of other pilots that could happen before World Diabetes Day. There’s World Health Day, there’s Mother’s Day and Father’s Day.

A: We didn’t need a lot of money for this. We got a lot of support, meaning that I paid for the flyers but I didn’t pay for 1 million flyers to be distributed to 15,000 pharmacies in Germany. If I had to pay for all those things, it would have been too expensive. One of the reasons I got support is that I started #dedoc and people know that I’m behind it. I am connected in some parts of the diabetes ecosystem. There are people I can call and ask for help and they’ve known me for years. Had I started from zero without being connected, this would have never, ever worked. I don’t even know how much some of this would cost. It might not work the same for everyone.

Q: If you can at least point out what the inputs were, whether paid or nonpaid, I think that would give a better idea of what goes into it, so when people are motivated, they know what they are up against.

A: I can write something like a business plan.

Q: You said you had quite a few people without diabetes who were testing. Why do you think they wanted to do it?

A: For people without diabetes, you have to get them past the threshold. Screening is very popular in Germany. There is a hurdle in that you have to get them to go out and go see a pharmacist. I think pharmacies are very important for this kind of thing. Do these patients want to check their blood glucose? I think it’s a question of how you address it. If you make it sound like a fun game and you’re giving a euro to kids etc., the underlying thread is that you get to learn your diabetes risk. It is mostly about infusing hope and having fun.

Meet-the-Expert: The Psychology of Hypoglycemia: Is There More to a Hypo Than Just Low Blood Sugar?

Is There More to a Hypo Than Just Low Blood Sugar?

Jane Speight, PhD (Australian Centre for Behavioral Research in Diabetes, Melbourne, Australia)

Professor Jane Speight argued emphatically the importance of acknowledging that hypoglycemia is more than “just low blood sugar.” Reviewing data, she noted that the incidence of hypoglycemia has not changed significantly in the last 20 years and that there is no relationship between A1c and incidence of severe hypoglycemic episodes. Furthermore, she emphasized that “mild” hypoglycemia does not mean it is inconsequential or only involves mild symptoms. On the contrary, even mild hypoglycemic episodes can cause unpleasant symptoms, distress, social embarrassment, and disruption to planned activities and can cause worrying, stress, anxiety, anger, sadness, fear, and guilt. Professor Speight stressed that brushing away “mild” hypoglycemia ignores the impact on the person with diabetes and the often severe impact on quality of life. According to her, experiencing even one severe hypoglycemic episode, and fearing another one, can lead to a loss of independence and spontaneity, an inability to drive, and get in the way of fulfilling work or family commitments. She concluded with a call to action to clinicians, industry, policy makers, and regulatory bodies to better acknowledge the psychological impact of hypoglycemia and better support people with diabetes on this front – the mental health implications within diabetes certainly deserve more attention than we believe they currently do and we’re glad to see Professor Speight direct focus toward this specific issue so passionately. For similar discussion on the psychological impacts of hypoglycemia, please see our coverage of a presentation by Dr. William Polonsky (Behavioral Diabetes Institute, San Diego, CA) at AADE.

IDF Award Lecture: Living With Diabetes

The Flourishing Approach: A Way to Treat and Live With Diabetes That Goes Beyond Coping

Riva Greenberg (Huffington Post, New York, USA)

Ms. Riva Greenberg delivered a passionate presentation on her “Flourishing Approach” to treating diabetes, underscoring the need to identify positive outcomes and build upon patient strengths. According to Ms. Greenberg, she developed the “Flourishing Approach” in part from interviews with 200 people with diabetes, where she discovered that many of them were thriving – not despite their diabetes, but because of it. She argued that diabetes can make people stronger and more resilient but that such positivity is often overcome by patients focusing on “coping” with their diabetes and doctors focusing on problem areas (weight gain, unfavorable entries in blood glucose logbook, depressive symptoms, etc.). To combat this cycle of negativity, Ms. Greenberg advocated for providers to look for what’s working well and ask patients how they did it – “the secret of change is not in fighting the old, but in building the new.” Further, she emphasized the value of starting conversations with patients to hear about their experiences and identify their strengths, and to ask them questions such as “what is one positive thing that diabetes has given you?” Ms. Greenberg concluded by sharing her own experience with type 1 diabetes, which began as a devastating diagnosis and grew into what she called an opportunity to build health, resilience, and purposeful work. We salute Ms. Greenberg for sharing her experience with the “Flourishing Approach”; this is exactly the kind of outlook we need to create health and wellness for people with diabetes – we love IDF highlighting the patient perspective here in an award lecture, a point of view that is often missed by the spotlight at these meetings.

IDF Award Lecture: Clinical Science

Sweet and Low: How Hypoglycemia Research Might Address The Diabesity Pandemic

Stephanie Amiel, MD (King's College London School of Medicine, UK)

Dr. Stephanie Amiel described the role of the brain in glucose homeostasis and energy balance, providing a historical look at how our understanding of hypoglycemia unawareness has changed over time. She opened by noting that while early studies of hypoglycemia unawareness suggested that cerebral glucose uptake was a principle component, more recent neuroimaging studies have elucidated a more complex picture. Indeed, she stressed that unawareness is associated not only with changes in the hypothalamic-pituitary pathways but also differences in the reward and hedonic pathways. Dr. Amiel cited qualitative research showing that those who are asymptomatic of their hypoglycemia also tend to described negative cognitive beliefs around this phenomenon that may interfere with their ability to treat and recover awareness – e.g., stigma. With this in mind, she suggested that psychological and behavioral therapies may have a place in restoring defenses against severe hypoglycemia; we would certainly agree considering from a patient perspective the anxiety and fear that can be associated with severe hypoglycemia. Lastly, in closing her lecture, Dr. Amiel also touched on neuroimaging research that has found abnormalities in responses to food and food cues in people with type 2 diabetes, obesity and most recently non-obese insulin resistance. Early evidence evidently suggests that insulin sensitization treatments may be able – at least partially – to reverse these effects. Taken together, the results suggest that new approaches may be needed (and may be on the horizon!) that help us change eating behavior and re-establish healthier eating patterns. Ultimately, we were struck by how much the conversation around hypoglycemia awareness/unawareness continues to change and that this remains an important scientific questions as much as an important clinical question.

 

Meet-the-Expert: Diabetes Distress – A Consequence of Complexity

Distress as a Complication of Diabetes

William Polonsky, PhD (Behavioral Diabetes Institute, San Diego, CA)

Behavioral diabetes guru Dr. William Polonsky delivered an eloquent review of diabetes distress, examining how and why it occurs and simple strategies for addressing this problem. In short, how do we help patients with diabetes flourish? Dr. Polonsky opened – in his very characteristic way – by acknowledging that living with diabetes is a tough, demanding, and often frustrating job that requires nonstop effort and vigilance. It is a balancing act of avoiding hyperglycemia and hypoglycemia, while fitting diabetes care into a “normal” life. To make matters worse, he stressed that patients often receive guidance from providers that instills a fear of complications and reminds them of the harmful consequences of poor diabetes management without providing adequate psychosocial support. With this in mind, it is no wonder that patients develop distress, a fatalistic attitude and feeling of being defeated by diabetes and self-care – not because of a lack of motivation (he noted that all people desire to live a long and healthy life) but because of the society-imposed obstacles to good care. As such, Dr. Polonsky stressed the need to invert the message we give patients, moving away from “blame and shame” tactics to a new message: “Well-controlled diabetes is the leading cause of nothing!” He bolstered this point with data from the DCCT/EDIC, showing that people with diabetes who achieve excellent control have very low rates of complications (~1% severe vision loss, ~1% amputations). To achieve this kind of care, Dr. Polonsky provided a few key strategies for addressing emotional distress: (i) providing a sense of hope; (ii) helping people to see that their own actions can make a positive difference; (iii) promoting reasonable expectations; and (iii) making diabetes less overwhelming by constructing a step-by-step plan for action. From a patient perspective, we would just echo that the critical psychological factors contributing to poor glycemic control are often more mundane than is appreciated: the stress of daily life, the daily trudge of changing habits and behavior, stigma, and so many other factors. It’s clear that these problems are recognized by experts; how do spread the knowledge with the broader medical community and scale Dr. Polonsky’s wisdom?

  • Dr. Polonsky defined “diabetes distress” with the following examples of what distress sounds like in practice:
    • … diabetes is taking up too much of my mental and physical energy every day. … I am often failing with my diabetes regimen.
    • … friends or family are not supportive enough of my self-care efforts.
    • … diabetes controls my life.
    • … I will end up with serious long-term complications no matter what I do.
  • Dr. Polonsky shared data indicating that the rate of diabetes distress is far greater than is often appreciated – 39% of type 1 and 35% of type 2 patients. This distress cannot be treated with antidepressants. Rather, it requires a new intervention paradigm with a greater focus on behavioral modification.
  • Some of our favorite quotes from this talk:
    • “Diabetes isn’t as simple as it seems from the outside … there are the emotions that surround the burden of living with this tough disease. When you are diagnosed, it feels like the universe has just handed you a new job with no pay and no vacations. If you are going to manage it, it takes effort and vigilance. That’s why it’s this balancing act.”
    • “You have to show people that their own actions can make a difference. Make behavior change go from something patients HAVE to do to something patients WANT to do.”
    • “With good care, you can live a long and healthy life with diabetes. The odds are good. That’s the message we need to give. It’s a sense of hope as we talk about real data and real findings.”
    • “There is so much blame and shame about diabetes. If we look at age groups from the T1D Exchange, which group has an average below 7.0%? Hmm … let’s see. None of them! We just want people [providers, parents, caregivers] to chill out. If you’re having a tough time, rest assured that a lot of other people are too.
    • “Well-controlled and well-managed diabetes is the leading cause of nothing. It’s the dirty little secret about diabetes that we can say with real pride. I talk to a lot of HCP groups, and it’s the other side of the coin from what they are typically saying.”

Lessons Learned with Diabetes: Minimizing Stress and Maximizing Robust Life Opportunities

Paul Madden (Project Hope, Millwood, VA)

The charismatic Mr. Paul Madden consolidated the wisdom of patients with diabetes to present the solutions he has gleaned from surveys of over 1,000 individuals living successful lives with diabetes for 50-85+ years. This was one of the most patient-centric presentations we’ve heard at IDF 2015 and loved even more the individual perspective Mr. Madden brought from his 50+ years of living with the disease. Some of our favorite tips from this talk are below.

  • For caregivers: Provide ever-present love and support; provide early and consistent messages; congratulate people with diabetes for the time that they invest in balancing their disease. [Gosh, how often is that last one ignored?!]
  • For patients: Know you are valued; remember that blood sugars are not always predictable; learn from mistakes; be prepared and take action when needed; have diabetes tools always available; and most important, “NO SMOKING!”
  • Mr. Madden also espoused the benefits of low carbohydrate diets, stressing that the science behind this approach is unequivocal. He noted that insulin does not react normally with increasing levels of carbohydrate and that the swings of blood sugar on high carbohydrate diets make it very difficult to be consistent with emotions and mood. Said Mr. Madden, “It’s not perfection we aim for with a diet … but a balance.” For more on this topic, read Adam’s recent diaTribe column.

DiabetesHub Exhibition: Six Degrees Medical

Peak Program

Aaron Kowalski, PhD (JDRF, New York, NY); Michael Riddell, PhD (York University, Toronto, Canada); Remi Rabasa-Lhoret, MD, PhD (Montreal Diabetes Research Center, Canada)

Dr. Aaron Kowalski provided an overview of the type 1 diabetes Performance in Exercise and Knowledge (PEAK) program rationale, highlighting the program’s role in filling an unmet need in type 1 diabetes and exercise guidelines. The goal of the program is to provide research-based education to help clinicians convey the “state of the art” in type 1 diabetes and exercise to patients. Dr. Michael Riddell and Dr. Remi Rabasa-Lhoret discussed the PEAK curriculum, which is 80% core courses (background and rationale, physiology, nutrition, and glycemic management), and 20% electives (pump and technology, young athlete, recreational elite athlete, and sports nutrition). The core courses focus on the unique barriers to exercise for people with diabetes such as fear of hypoglycemia, glycemic variability, and insulin therapy. The speakers announced that they have now completed two pilots of the program: one in Chicago, IL (which we attended in September) and one in the UK. Dr. Kowalski noted that Novo Nordisk has provided an unrestricted grant to support PEAK, and that the finalized program is on track to roll out by the end of 2016. We’re glad to see JDRF and Novo Nordisk addressing the lack of education in type 1 diabetes and exercise, and look forward to the final curriculum next year. For more background on PEAK, please see our detailed coverage from September’s pilot program.

Additional Topics

Symposium: Viruses and Type 1 Diabetes

Emerging Findings Regarding Viruses in Type 1 Diabetes – Lessons from nPOD

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

Dr. Mark Atkinson shared some data from nPOD (the JDRF Network for the Pancreatic Organ donors with Diabetes) on the association of viruses, in particular enteroviruses, with type 1 diabetes and discussed the network’s future directions. Specifically, he discussed the work of the nPOD-Virus group, which has shown through a variety of methods that a viral infection of the pancreas and/or pancreatic beta cells appears far more frequently in people with type 1 diabetes. For decades, studies have suggested a potential association between viral infections and the development of type 1 diabetes but those efforts, near exclusively, involved investigation of blood samples in living subjects. While such efforts are important, nPOD represents the first large-scale study of viruses at the site of the disorder’s origin, the pancreas.  Overall, Dr. Atkinson noted that data up to this point from the nPOD-Virus group, while supporting the presence of viruses, remains mostly indirect and pointed to the need for continued work to identify a specific virus or group of viruses. Looking forward, he shared that the nPOD group aims to coordinate studies toward this goal though studies involving laser capture dissection of islets, proteomics, virus amplification in vitro, electron microscopy, imaging mass-spectrometry, and RNA sequencing; all to further improve on techniques currently used. We are impressed with the magnitude of research nPOD has been able to drive forward and applaud the network’s constant innovation to do bigger and better things with its samples – to learn more about nPOD and how to help contribute, please see our diaTribe article.

Symposium: Novel Risk Factors for Type 1 Diabetes

Probiotics and the Microbiome

Marian Rewers, MD, PhD (University of Colorado, Aurora, CO)

Dr. Marian Rewers provided a review of the microbiome in type 1 diabetes and the potential impact of probiotics, concluding that early administration may be associated with reduced risk of islet autoimmunity in the highest-risk individuals. He opened by discussing the interaction of the gut microbiome and immunity, noting that initial microbiome analyses reveal suggestive associations with islet autoimmunity and type 1 diabetes. Specifically, Dr. Rewers presented data from metagenomic analyses of the TEDDY study, which illustrated that microbial compositional differences in islet autoimmunity cases are driven by low-abundance bacteria and that such cases also show impaired microbiome development with continuous shifts in bacterial community structure. In addition, the results found differences in the patterns of microbial diversity and stability among the various genotypes. In the context of probiotics as a method to positively influence the microbiome, Dr. Rewers demonstrated that research has shown that early administration during the first 27 days of life may be associated with reduced islet autoimmunity risk, although this was only seen in children with the highest risk genotype (HLA-DR3/4). Ultimately, many questions remain with regard to this intervention (which remains mostly unregulated) but this work again reminds us of the importance of advancing towards personalized medicine to help identify the most effective interventions for specific individuals.

Symposium: Diabetes Dyslipidemia – New Concepts

The Genetics of Dyslipidemia and Clinical Relevance in the Treatment of Type 2 Diabetes

Robert Eckel, MD (University of Colorado, Aurora, CO)

Dr. Robert Eckel presented on the latest genetics research of dyslipidemia in type 2 diabetes, ultimately concluding that this evidence is not yet strong enough to use clinically. Reviewing the various genes involved in the condition (i.e. APOA5, GCKR, LPL, etc.), Dr. Eckel stressed that circulating levels of plasma lipoproteins and lipids are influenced by a number of common polymorphisms, with no single gene responsible for diabetes-related dyslipidemia. Specific genes highlighted included the role of Apo CIII in atherogenecity and N-acetyltransferase-2 in hypertriglyceridemia. Notably, Dr. Eckel demonstrated that a genetic risk score (developed from 23 loci associated with triglyceride, HDL-C, and LDL-C levels) was predictive of ASCVD risk in DPP participants exposed to lifestyle intervention. In addition, Dr. Eckel touched on the recent research around Apo E2 – VLDL metabolism disorders within the homozygous Apo E2 genotype have been shown to be strongly associated with accumulation of pro-atherogenic lipoproteins, leading to type 3 hyperlipoproteinemia or broad beta disease (of which 70% have type 2 diabetes). While Dr. Eckel acknowledged the added insight of these genetic analyses, he ultimately emphasized that within the context of more ambiguous findings in this area, this work has not yet reached the point of clinical application, as he encouraged clinicians to continue focusing on modifying acquired factors and lifestyle intervention. This aligns with much of what we have heard so far, as both diabetes and obesity still remain far off from using genetics as a clinical tool, likely due to the diseases’ complex polygenic basis and interactions with the environment.

Exhibit Hall

Abbott

Abbott’s characteristic yellow booth featured a no-frills product demo of Freestyle Libre and drew an enthusiastic crowd of attendees eager to learn about the device. Representatives did not provide new insight in terms of a timeline for Pro approval or Libre submission (the consumer version), but did mention that the company has been involved in informal conversations with the FDA about both products. We were even more intrigued to hear that Abbott’s new manufacturing site in the UK will be producing “way more than double” the current output to scale up for Libre’s anticipated launch in several new markets – hmm, this is new news to us though we weren’t able to suss out which markets the rep was alluding to. It is positive to hear Abbott finally pushing forward after the capacity constraints following last September’s launch – the company has been talking about capacity expansion for some time and we continue to wonder if manufacturing challenges are also responsible – how hard is it to scale a factory calibrated sensor? Once supply is unconstrained, we will be very curious to see what sales look like.

  • We would be remiss to ignore that Libre made up a VERY tiny portion of the Abbott booth relative to Glucerna (Abbott’s nutritional supplements for diabetes) and Abbott’s other Freestyle devices – we were surprised by this in light of the fact that Libre has been submitted recently. Still, we were excited to see it on display (especially considering how it is the elephant in the room at US conferences) – a sentiment that was echoed by many (non-European) booth-goers.

Amgen

Amgen had a medium-sized booth toward the back of the exhibit hall, promoting Repatha (evolocumab) in its red/white/blue color scheme. Labeled as the first-in-class PCSK9 inhibitor, Repatha was featured in stand-up posters around the booth, which highlighted the drug’s large LDL-C reduction (74% with a statin) and the Repatha Ready patient support program. The booth also seemed to emphasize the simplicity of Repatha, pointing out that it has ONE fixed dose and ONE click every two weeks – likely efforts to differentiate from Sanofi/Regeneron’s Praluent (alirocumab) in our eyes. Ultimately, the differences between the two PCSK9 inhibitors seem minor and negotiations with payers will likely be the biggest determinant of the competition – see our coverage of Amgen’s 3Q15 update as well as Express Scripts’ recent inclusion for more on this.

AstraZeneca

As at most recent conferences, AZ’s booth featured new products Forxiga (dapagliflozin), Onglyza (saxagliptin), and the new Bydureon (exenatide once weekly) pen most prominently. The messaging around Forxiga was a clear reminder that this is an ex-US conference: representatives emphasized the drug’s status as the first-to-market SGLT-2 inhibitor and the one with the most cumulative prescriptions. The promotional materials for the Bydureon pen drew a clear contrast with insulin, with the tagline “when orals aren’t enough…insulin later, Bydureon pen today,” and a picture of a patient physically pushing away the thought of insulin. This echoes the message in Lilly’s recently launched DTC campaign for Trulicity (dulaglutide), which emphasized several times that Trulicity is not insulin. While probably effective as a promotional method for GLP-1 agonists, we do fear such messages may contribute to the barriers to insulin initiation that Dr. Larry Fisher spoke about so eloquently earlier in the conference.  AZ also brought back its interactive case study station with action figures to represent patients that debuted at EASD. The non-product-specific section of the booth focused on a summary of AZ’s ongoing clinical trials and the EVOLVE for Diabetes website, an educational platform intended for non-US HCPs.

Bayer

After absences at ADA and EASD 2015, Bayer showed up at IDF 2015 with strong marketing intent – though, notably, the name “Bayer” itself was next-to-absent in the booth. [Products were label with their product name instead – e.g., “Contour,” “Eylea”). We were glad to see the company’s presence, but even gladder to see the effort that went into the impressive display – located relatively centrally in the exhibit hall, the navy blue paneling and faux-wood floors caught our attention from a ways away. Upon closer approach, we found that Bayer has pushed it marketing strategy to the next level with celebrity endorsements from Canadian stars, most notably including 2015 World Junior Hockey Champion Max Domi (who we learned was diagnosed with type 1 diabetes at age 12). Indeed, it was hard to miss the slogans that accompanied the clear accuracy-focused campaign: “Max Domi is Powered By Accuracy”; “Accuracy you can trust”; “Remarkable accuracy that helps make the remarkable possible. On the new product front, the booth did not feature any big announcements though we did learn that the Next Link 2.4 meter (that recently launched with Medtronic’s MiniMed 640G system in Australia) is slated for a Health Canada approval in “mid-2016.” As a reminder, the meter is now available for purchase in some areas of the EU, and the device’s key innovation is the remote bolus feature, a huge convenience win for patients that we think will be well received.

  • Quite notably, Bayer’s booth featured a corner devoted to Eylea (aflibercept) for the first time in our memory. Reps offered very positive commentary on the drug, which is now Bayer’s second-best selling pharmaceutical product by sales. The campaign seemed to be aimed at increasing awareness for the product, and we were impressed to see the display getting some serious traffic when we stopped by. Of course, we expect Bayer’s presence at exhibit hall to shift more toward the drug side in coming months as the device side shifts to new ownership. We’ll be interested to see how the drug/device division of real estate changes in future booths and wonder whether this served as a feeler of sorts to test the waters.
  • We wonder what will happen to the Medtronic partnership when KKR takes over. We assume that Medtronic will renew the deal with KKR directly though were not able to confirm this today.
  • Reps did not comment on the next-generation Bluetooth-connected meter that was presented at DTM 2015. We first learned of this device at ATTD 2015, where representatives suggested a launch is “one to two years away.”

BD

BD’s colorful signage caught our eye from across the exhibit hall. We were hoping the expansive booth would give us a glimpse of the company’s recently FDA-cleared first-generation insulin infusion set – but alas, it was not there. Instead, flyers in one corner of the booth invited attendees to learn more about silent occlusions online. Two other corners of the exhibit were devoted to BD’s pipeline of pen needle products – BD’s AutoShield Duo and Ultra-Fine Nano – while the final corner provided on lipohypertrophy education station, complete with a demo that allowed attendees to “touch and see how it feels.”

Insulet

The small booth was tucked away in the corner of the hall, but represented an important milestone for Insulet, as the company took over Canadian OmniPod distribution from GSK in July. Despite management’s ongoing remarks to improve the clinical data and OmniPod marketing, we did not notice a change in the materials in today’s booth. It was excellent, however, to see OmniPod data download demos to both the Glooko and Diasend platforms in the booth. The PDM connects directly to the Glooko app on Android phones and tablets (via micro/mini-USB cable), while Apple phone users can download to the Glooko web dashboard on a computer. For Diasend, the PDM can be downloaded at home on the web or in the clinic. It is great to see Insulet thinking about data and connectivity and we wonder what improvement will come once the Bluetooth-enabled next-gen PDM comes out, slated for submission in mid-2016.

J&J/Animas

Animas occupied only a sliver of J&J’s real estate, though that did not stop attendees from crowding 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. We were dreaming and hoping to see a next-gen artificial pancreas offering on demo, but that was wishful thinking ... for now!

J&J/Lifescan

Lifescan’s dazzling portion of the J&J booth boasted large TV screens showcasing the sleek Bluetooth-enabled OneTouch Verio Flex, Lifescan’s newest meter. We learned that the Flex is currently launching in Canada (as in this week!) and should come to the US in the next two months (it received FDA 510(k) clearance earlier this year). The device has been available in the EU “for some time,” though we cannot recall having seen it previously – we learned about the US clearance for the first time at EASD 2015. As a reminder, the meter sends blood glucose data wirelessly to the Reveal mobile app on an iPhone, iPad, or iPod touch where it displays 14-, 30-, and 90- day trends that can be emailed or printed for further analysis by a healthcare provider or patient. See pictures here. The exhibit also featured interactive games – similar to what we’ve seen at past J&J booths – demonstrating the intuitive ease of color association for interpreting blood glucose readings. We are pleased by the continued expansion of connected devices but would love to see the company further exploit Bluetooth technology– how cool would it be if Verio users could integrate data from other sources (pumps, activity trackers, carb-counting apps) and view them on the app?

J&J/Janssen

As another reminder of the difference between the US and ex-US markets for SGLT-2 inhibitors, the Janssen section of J&J’s display was relatively small compared to US conferences. It featured screens playing a video with information on Invokana (canagliflozin) along with pictures of a white board with messages boasting of a patient’s A1c, weight, and blood pressure reductions at their last diabetes checkup.

LabStyle

We were very happy to see that LabStyle invested in a modest booth, tucked away toward the back corner of the exhibit hall. Reps did not share any updates on the company’s all-in-one smartphone BGM system and paired app, Dario, though it was clear that there is a TON of internal enthusiasm and confidence in the product. The excitement was certainly mirrored in booth-goers as well as the exhibit was one of the busier ones we stopped by. We were impressed, too, to see new Senior Vice President and General Manager Mr. Todd Durniak present to greet attendees himself. He informed us that the US launch of Dario is on track, though shared no new details on the timeline for FDA clearance or launch. We also got our first look at the very sleek, very user-friendly Dario app that sends data to the cloud at the touch of one button. It is intriguing to see the company capitalizing on the software/data side of its platform, and Mr. Durniak spoke to LabStyle’s ability to iterate quickly as a “software” company vs. the typical “hardware”-driven BGM brands. Along these lines, management referred to the potential for population management and leveraging big data, an approach that is already being pursued to an extent in Israel. [As a reminder, LabStyle launched in Israel earlier this year and is selling to consumers directly (via an online “eShop”) and via an HMO patient management platform (in partnership with Maccabi Healthcare).]

  • More on the Dario app! We especially liked that glucose readings can be sent (via text) to additional mobile devices – a huge patient and caregiver convenience that enables remote monitoring and peace of mind. LabStyle has mentioned its marketing intent in the pediatric population in the past and positioning Dario as a way to reduce the burden of diabetes management and to enable kids to live a more normal life (e.g., attending sleepovers) certainly fits their profile. Additional tabs within the mobile app offer insight into time-in-range, average number of tests per day as well as pages for viewing results.

Lilly

Lilly’s centrally-located booth drew attendees in with promotional materials featuring baby animals for its BI-partnered biosimilar insulin glargine Basaglar. Upon entering the booth area, a representative turned our attention to a series of videos of patients discussing their first time using insulin (tagline: “My first time was really awkward”). He shared that Basaglar is being positioned primarily for patients new to insulin, not switches from Sanofi’s Lantus (insulin glargine). We do imagine there will likely be some switches as well if patients perceive the price discount (15-20% so far) as significant. Lilly has created an “Essentials Kit” with everything from instructions to a sharps container to ease first-time insulin users. When asked about potential competition from next-generation basal insulins (Sanofi’s Toujeo [U300 insulin glargine] and Novo Nordisk’s Tresiba [insulin degludec), our guide asserted that many patients don’t need the next-generation analogs to do well. The other BI-partnered products (Jardiance [empagliflozin], Synjardy [empagliflozin/metformin], Tradjenta [linagliptin], and Jentadueto [linagliptin/metformin]) received about a sixth of the total booth space. Glyxambi (empagliflozin/linagliptin) was notably absent. This could just mean the product is not yet available in Canada, but Lilly has generally offered little comment on the combination since its launch in March and it does not appear to have had a huge impact on Jardiance franchise sales in the last two quarters. Elsewhere in the booth, the Humalog U200 KiwkPen also received floor space, as did Lilly’s big picture NCD partnership.

Lilly/BI

Directly across from Lilly’s solo booth sat Lilly/BI’s smaller joint booth. The square space featured a side each devoted to Basaglar (biosimilar insulin glargine), Jardiance (empagliflozin) and Synjardy (empagliflozin/metformin), Tradjenta (linagliptin) and Jentadueto (linagliptin/metformin), and Medical Affairs. The booth’s signature wooden accents drew attendees to the Medical Affairs section, where they found a comprehensive listing of clinical trials for Tradjenta displayed on an outline of an apple tree. The promotional materials for the products on display echoed those at the Lilly solo booth and, representatives from the two booths worked in tandem to answer questions. Like the Lilly solo booth, Glyxambi was not given any floor space. The booth also included a small corner devoted to the IntroDia study of the initial conversation between patients and physicians following a diagnosis of type 2 diabetes. Visitors received a brightly-colored deck of cards with encouraging and discouraging sample dialogues for physicians.

Medtronic

Medtronic’s booth focused on the MiniMed 640G with Enhanced Enlite, though shared no new insight on the predictive low glucose suspend system. The product is not available in Canada, though we did learn that it has launched in some Middle East and South American countries, in addition to the initial launch in Europe and Australia. We’ll hopefully hear the latest timeline on an FDA submission on tomorrow earnings call; the last timeline in September called for an FDA submission by the end of 2015.

Merck

Merck took up a decent amount of real estate near the front of the exhibit hall but it remained relatively simple and kept its usual patient-centric vibe. Its perimeters called out by “welcoming all patient champions,” as it unsurprisingly focused on its Januvia (sitagliptin) franchise including Januvia, Janumet (sitagliptin/metformin), and Janumet XR (FDC of sitagliptin/extended-release metformin). Touchscreens sprinkled throughout the booth offered attendees the chance to read through Januvia’s clinical data and label while one wall featured the timeline of the DPP-4 inhibitor class (with TECOS data marked as the latest milestone). Similar to its past booths, Merck also included iPads with hypoglycemia simulators, as reps shared the importance of understanding the patient perspective and consequently of finding medications that do not increase hypoglycemia risk. Merck’s Januvia franchise has remained the dominant force within the DPP-4 inhibitor class and appears to continue to hold the DPP-4 inhibitor fort even in light of the positive EMPA-REG results for Lilly/BI’s Jardiance (empagliflozin) – for more on Januvia’s latest performance, please see our coverage of Merck’s 3Q15 update.

Novo Nordisk

Novo Nordisk’s booth took a bit of a broader approach compared to its EASD display, where new products Tresiba (insulin degludec) and Xultophy (insulin degludec/liraglutide) were the sole focus. Those products had a heavy presence here as well, but Victoza (liraglutide) was also represented, as was next-generation premix insulin Ryzodeg (insulin degludec/insulin aspart) – likely a reflection of the wider international focus of this conference. A representative in the Tresiba section focused on the product’s long duration of action and flatter profile as key selling points. A section of the display also highlighted the evolution of Novo Nordisk’s delivery devices over time – a hands-on demonstration of the new FlexTouch pen vs. the old FlexPen illustrated the clear improvement in usability. There was also a station where attendees could sign up for the conference 5k and pose for pictures like a member of Team Novo Nordisk at the finish line.  We were excited to see some of you at the race today at 6:30 am (the shirts alone were worth it, right?)!

Novo Nordisk – Saxenda

Novo Nordisk had a small additional booth behind its main stage, with a sole focus on Saxenda (liraglutide 3.0 mg) in its purple/white color scheme. Although significantly smaller than the Saxenda booth at Obesity Week, the booth held onto similar themes, labeling Saxenda as “the only GLP-1 receptor agonist for chronic weight management in people with obesity or overweight with ≥1 weight-related comorbidity.” One notable feature was a wall of video/audio recordings of patient profiles, as different individuals shared their stories of overweight and obesity – certainly a personable touch that we think helps bring us a bit closer to reducing stigma. In addition, a video on the back of the booth highlighted Saxenda’s 97% homology to native GLP-1, the drug’s delivery pen, and some patients’ need for more than diet and exercise. Also, a wall emphasized percentages of weight loss but also risk reduction of various cardiometabolic parameters – these secondary outcomes were similarly featured in the drug’s promotional images of a woman holding up a pair of old larger jeans inscribed with text including “type 2 diabetes,” “high cholesterol,” and “high blood pressure.” We would also hope that payers can pay attention to the significant improvements in these many other comorbidities to better support coverage of obesity drugs. We missed seeing Novo Nordisk’s booth focused only on obesity education at this meeting, although we were glad to see a spotlight on the patient perspective here.

Sanofi

Sanofi’s large but minimalist booth focused largely on Lantus (insulin glargine) and Toujeo (U300 insulin glargine). The messaging on Lantus revolved around “choosing the one you know” and compared it directly to insulin degludec. Lyxumia (lixisenatide) was also given a small section of the booth, where it was positioned as a “positive addition” to a diabetes regimen. We didn’t see any mention of Apidra (insulin glulisine) or Afrezza (inhaled insulin). Sanofi had shared in its recent “Meet Sanofi Management” seminar that the insulin glargine franchise (which counts non-US-approved GLP-1 agonist/basal insulin combination LixiLan [lixisenatide/insulin glargine] among it) will be a major focus moving forward.

Sanofi/Regeneron

Sanofi/Regeneron had a medium-sized booth featuring its PCSK9 inhibitor Praluent (alirocumab) with bold text stating, “now approved in EU & US.” In a turquoise color scheme, the booth emphasized the flexibility of Praluent (in contrast to Amgen’s focus on Repatha’s [evolocumab] simplicity) by stating that it is the only PCSK9 inhibitor available in two starting doses. Posters and videos displayed two patients on the different doses (75 mg and 150 mg), promoting the flexibility to “choose your LDL-lowering power” and “more power if you need it” as well as the benefit of “increasing efficacy” without more injections. In addition, the booth emphasized the high prevalence and dangers of cardiovascular risk, warning attendees that “uncontrolled LDL-C puts your patients at higher cardiovascular risk.” As a reminder, none of the PCSK9 inhibitors are approved for type 2 diabetes but the significant presence of both Amgen and Sanofi/Regeneron at the major diabetes meetings suggests confidence in a broader indication into the diabetes patient population once CVOT results come in.

Takeda

Takeda had a relatively large boot – complete with a puzzle theme – promoting Nesina (alogliptin), Kazano (alogliptin/metformin), and Oseni (alogliptin/pioglitazone). The majority of the attention seemed to be focused on Nesina: one corner of the booth featured videos on the drug’s CVOT EXAMINE and a wall labeled Nesina as a “new DPP-4 inhibitor proven to improve glycemic control” that has flexibility of dosing options for all stages of renal impairment. In addition, a second wall highlighted Kazano as a convenient single tablet combination – in our eyes, these metformin combinations have the potential to be the future of the DPP-4 inhibitor class, as evidenced by the impressive growth of Merck’s Janumet (sitagliptin/metformin). Another corner of the booth featured a “body of evidence” with rotating slides on the pathophysiology of diabetes with some generic information on TZDs and incretins – unsurprisingly, we did not see any prominent promotion of the company’s TZD Actos (pioglitazone), whose class has very much fallen out of favor. We also saw no mention of Orexigen-partnered obesity drug Contrave (naltrexone/bupropion), which was the sole focus of Takeda’s booth at Obesity Week. But ultimately, we were pretty impressed with the magnitude of the company’s booth considering Takeda’s focus away from diabetes in recent quarters’ updates – for the latest, please see our coverage of its F2Q15 (3Q15) update.

VigiPen

In a small booth on the edge of the exhibit hall, Taiwan-based VigiPen (called Vigilant at CES 2015) showed off its pipeline of reusable smart insulin pens, including versions with built-in Bluetooth (pairs with an app), USB downloading (for those without smart phones), and even a model with an integrated blood glucose meter. The pens were clearly prototype and much thicker than standard insulin pens. A rep disclosed that the company is in the R&D stage, and an insulin partner will be required to bring the smart pens to market. We first heard about the VigiPen at CES 2015, where the real focus was on “Bee” – a pen cap that attaches to a standard insulin pen and sends dosing data (via Bluetooth) to a phone. The rep told us that Bee has not done well commercially, since it requires patients to dial up two doses: one on a standard insulin pen (to inject) and a separate on the Bee pen cap (to log the dose). Interestingly, Bee won a CES 2015 Innovation Award, though it’s not hard to imagine why patients find it burdensome. We see smart pens as a needed innovation to capture insulin dose data in injection users, though the challenges lie in cost-effectiveness (can they be incorporated into disposable pens?) and adding serious clinical value (if patients have to switch to a reusable pen, it should offer some tangible benefits).

 

-- by Melissa An, Adam Brown, Jonathan Busam, Helen Gao, Varun Iyengar, Sarah Odeh, Ronaldo Pineda-Wieselberg, Emily Regier, Ava Runge, Madellena Thornton, and Kelly Close