September 12-16, 2016; Munich, Germany; Full Report – Draft

Executive Highlights

In this full report - we provide our complete coverage of the 52nd Annual Meeting of the European Association for the Study of Diabetes (EASD), held in Munich, Germany from September 12-16, 2016. The conference drew over 15,000 delegates from more than 130 countries (similar to the number of delegates who attended EASD in 2015), who attended a slate of 264 oral presentations, over 40 symposia, 24 corporate symposia, and 900 posters – this is compared to 264 oral presentations, 30 symposia, 22 corporate symposia, and 1,202 posters from last year’s meeting in Stockholm.

To help you sort through our detailed full report, we’ve organized our commentary into ten categories: 1) GLP-1 Agonists; 2) Oral Drugs; 3) Insulin Therapy; 4) Outcomes Trials; 5) Diabetes Technology; 6) Novel Therapies; 7) Obesity; 8) Award Lectures and Additional Topics; and 9) Exhibit Hall. Each section is also available as a separate document. Titles highlighted in blue are new additions that were not mentioned in our daily updates from Munich, and those highlighted in yellow represent what we felt were the most notable talks of the meeting – narrowing down this list was a difficult task, to be sure! We congratulate the organizers on a terrific 52nd annual meeting. We’re already looking forward to next year: September 11-15 in Lisbon, Portugal.

Below we outline the key themes that emerged from the conference, followed by nearly 120 pages of detailed reporting. Enjoy!

Themes

Diabetes Drugs

GLP-1 Agonist Semaglutide, Injectable and Oral

• Novo Nordisk’s next-generation, once-weekly injectable GLP-1 agonist semaglutide made a big splash at this year’s EASD meeting, headlined by the positive SUSTAIN 6 cardiovascular outcomes results. In the trial, semaglutide demonstrated a 26% risk reduction (95% CI: 0.58-0.95; p<0.001 for non-inferiority; p=0.02 for superiority) for the primary endpoint of three-point MACE (CV death, non-fatal MI, and non-fatal stroke). For comparison, LEADER showed a 13% risk reduction for Novo Nordisk’s Victoza (liraglutide) and EMPA-REG OUTCOME showed a 14% risk reduction for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), with both CVOTs relying on the same three-point MACE used in SUSTAIN 6, and IRIS showed a 24% risk reduction in fatal/non-fatal MI and stroke in insulin resistant stroke survivors (without diabetes) for Takeda’s TZD Actos (pioglitazone). Among the components of the primary outcome, semaglutide significantly reduced the risk of non-fatal stroke by 39% (HR=0.61; 95% CI: 0.38-0.99; p=0.04) – this appeared to have driven the achievement of the primary endpoint. Non-fatal MI also trended toward reduction, though the result was not significant (HR=0.74; 95% CI: 0.51-1.08; p=0.12). Notably, the Kaplan-Meier curves for cardiovascular death in the semaglutide and placebo arms were virtually superimposable (HR=0.98; 95% CI: 0.65-1.48; p=0.92). For comparison, the LEADER trial for Novo Nordisk’s other GLP-1 agonist, Victoza (liraglutide), found a highly significant 22% reduction in cardiovascular death with liraglutide (HR = 0.78; 95% CI: 0.66-0.93; p=0.007). We expect the lack of clear cardiovascular mortality benefit might be due to the small size and short duration of the trial, contributing to a very low event number (44 adjudicated CV deaths and 46 adjudicated CV deaths).
  
  • While the results are certainly impressive, the small size of the trial and the resultant fairly large confidence intervals engendered reservations from some thought leaders. Dr. Philip Home pointed out that it might be more accurate to categorize the risk reduction in the primary endpoint as 5%-42%, based on the confidence intervals, rather than 26%. We can’t overlook the shorter span and smaller number of MACE events incurred during this CVOT, of course. Follow-up on the primary endpoint continued for only two years in SUSTAIN 6, whereas LEADER followed-up for a minimum of 3.5 and a maximum of five years and EMPA-REG OUTCOME followed-up for four years. The direct impact of a shorter CVOT is fewer MACE events – 254, 1,302, and 772 in SUSTAIN 6, LEADER, and EMPA-REG OUTCOME, respectively. As a result, it wouldn’t be possible to say that the results would definitely support a cardioprotective indication, given the complexities of the regulatory system - indeed, Novo Nordisk has already shared that it intends to conduct a larger CVOT powered for superiority for semaglutide. Despite the differences in trial size, Dr. Steven Marso emphasized that SUSTAIN 6 has more in common with LEADER than not in terms of the patient population enrolled, the endpoints, etc.
  • Among the safety outcome measures collected, the most notable finding was a significantly increased in the risk for retinopathy (HR=1.76; 95% CI: 1.11-2.78; p=0.02). Retinopathy complications, defined as vitreous hemorrhage, onset of diabetes-related blindness, or need for treatment with an intravitreal agent or retinal photocoagulation, appeared at a rate of 3% in the semaglutide group (50 events) vs. 1.8% in the placebo group (29 events). Of course, these are small event numbers and, while the findings are disturbing, they are not altogether surprising. Both Dr. Tina Vilsbøll, in presenting the clinical and metabolic outcomes of SUSTAIN 6, and Dr. Home noted that several previous studies, including the DCCT/EDIC trial, have found an association between rapid glucose-lowering and worsening of retinopathy. That said, the increased risk will surely be worrisome for some, including potentially regulatory agencies. There is nothing possible to say at this stage -  there are equal chances this is “spurious correlation” or chance – or that this is a negative finding – and a trial will need to be done to ascertain this (perhaps a two-year trial – hard to say at this stage).  In the LEADER trial, treatment with liraglutide also hinted at a trend toward increased retinopathy (HR=1.15; 95% CI: 0.87-1.52; p=0.33), but those results were non-significant. A larger trial would certainly be able elucidate this potential connection.
  • Impressively, all five other trials in the phase 3 SUSTAIN program were presented at EASD 2016 as well. SUSTAIN 3 (head-to-head vs. AZ’s Bydureon [exenatide once-weekly], previously presented at ADA 2016) and SUSTAIN 4 (head-to-head vs. Sanofi’s Lantus [insulin glargine]) were presented as oral presentations, while SUSTAIN 1 (monotherapy vs. placebo), SUSTAIN 2 (head-to-head vs. Merck’s Januvia [sitagliptin], previously presented at ADA 2016), and SUSTAIN 5 (add-on to basal insulin) were presented as posters. As a whole, semaglutide demonstrated an impressive combination of A1c efficacy and weight loss, with the expected GI side effects. Together with the unexpected and highly impressive SUSTAIN 6 results, we expect the phase 3 program will make a compelling package for regulatory submission, expected in 4Q16.
• In terms of the earlier-stage diabetes pipeline, we were particularly impressed by the much-anticipated full results from the phase 2 dose-ranging and escalation trial of Novo Nordisk’s once-daily oral formulation of GLP-1 agonist semaglutide. The double-blind, randomized, parallel-group trial (n=632) consisting of an impressive nine arms: five with escalating doses of oral semaglutide (2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg), two comparator arms with placebo and injectable semaglutide (1 mg dose), and two dose escalation arms in which oral semaglutide was titrated up to 40 mg over either eight weeks or over 26 weeks. Topline results for this trial were shared over a year and a half ago, in February 2015, noting dose-dependent improvements in A1c and comparable weight loss to the once-weekly injectable semaglutide formulation at the highest dose. The full results offered much more granularity on the specific A1c and body weight reductions with each of the five oral semaglutide doses compared to placebo and injectable semaglutide. Oral semaglutide demonstrated significantly greater A1c reductions than placebo at each of the five doses studied, with a very impressive 1.9% reduction at the 40 mg dose, matching the injectable semaglutide reduction and a 1.6% difference from placebo (baseline A1c=8.1%, p<0.0001). Participants experienced a dose-dependent mean body weight reduction of up to 6.9 kg (~15 lbs) in the 40 mg dose arm (p<0.0001). For comparison, participants in the placebo arm lost an average of 1.2 kg (~2.6 lbs) and those in the injectable semaglutide arm lost an average of 6.4 kg (~14 lbs). Furthermore, a greater proportion of participants on all doses of oral semaglutide were able to achieve an A1c target <7% or body weight loss 35% compared to placebo. See the detailed discussion and commentary for more details on these results and on the adverse event data.
  
  • The robust results demonstrating the ability of an oral peptide formulation to match the efficacy of its injectable counterpart were extremely encouraging. Semaglutide is the first peptide to advance into phase 3 development as an oral medication within the diabetes field and we hope its success could potentially pave the way for oral insulin as well (though the dose titration and narrow therapeutic range pose of insulin pose additional challenges on that front – Novo Nordisk recently completed a phase 2a trial for its oral insulin and we’re eagerly looking forward to results there as well). That said, the 40 mg dose needed to match the efficacy of injectable semaglutide is much higher than the three doses that have been advanced into phase 3 (3 mg, 7 mg, and 14 mg). Despite the lower dose, the phase 2 results suggest that we might be able to expect A1c reductions between 1.5% and 1.7% and weight loss between 5 kg and 6 kg (11 lbs-13 lbs) with the highest 14 mg dose. The phase 3 PIONEER development program is underway, with all studies initiating enrollment throughout 2016 and we absolutely cannot wait to see the results in a few years.

Future and Impact of Cardiovascular Outcomes Trials

• Following an exciting year of positive cardiovascular outcomes trial (CVOT) results, much discussion centered on how they should affect drug labeling, regulatory processes, and clinical practice. We heard opinions from numerous esteemed experts on what needs to happen in order for EMPA-REG OUTCOME, LEADER, and SUSTAIN 6 data to realize its real-world implications. Dr. Juris Meier (Ruhr University of Bochum, Germany) pushed for multi-agent CVOTs and head-to-head comparisons of newer drugs with relatively older agents. Data showing the relative CV benefits of different available diabetes drugs would be tremendously valuable for high-risk patients, he argued, and would give CVOT findings more direct purpose in clinical decision-making. Dr. Meier also advocated for a greater emphasis on primary CV prevention. Participants in published CVOTs have largely been very high-risk (understandably, as this helps a trial reach the necessary number of CV events for a sufficiently small confidence interval in a shorter amount of time), but enrolling lower-risk participants will be important for the future of CVOTs, Dr. Meier explained, noting that AZ’s DECLARE (for SGLT-2 inhibitor dapagliflozin) and EXSCEL (for GLP-1 agonist exenatide) will each include a cohort of patients without prior CV history. In his view (and ours), positive results on primary CV prevention could be a major win in two ways: (i) by promoting greater utilization of these agents across a much wider spectrum of the diabetes patient population, and (ii) by providing even more compelling evidence for cardioprotection in a broader population. We see expanding CVOTs into primary prevention as a worthwhile goal, although we acknowledge the associated cost would be enormous.

EMPA-REG OUTCOME: One Year Later

• We heard much discussion on the potential mechanism of cardioprotection seen in EMPA-REG OUTCOME, one-year after the groundbreaking CVOT was presented at EASD 2015. Dr. Silvio Inzucchi (Yale University, New Haven, CT) – who also presented the cardiovascular outcomes from the study at last year’s meeting – admitted that the initial thinking on why empagliflozin might offer CV benefit was off-base. “With a great deal of modesty, we had it all wrong.” The early divergence of the Kaplan-Meier curves suggests that the SGLT-2 inhibitor works not by an overarching atherosclerotic effect (which is more likely for GLP-1 agonist liraglutide based on LEADER data), but rather by some other mechanism. Dr. Bernard Zinman (University of Toronto, Canada) later presented a univariate mediation analysis of EMPA-REG OUTCOME (first presented at ADA 2016), which attributed 52% of empagliflozin’s cardioprotection to volume contraction, as reflected by an increase in hematocrit. The same analysis attributed 25% to decreased uric acid concentration and only 3% to between-group A1c differences – this last point underscores that the CV benefit is independent of glycemic effects. Dr. Zinman shared that a multivariate analysis, which will prove more accurate in illuminating mechanism, is underway – we’re glad to see this hypothesis-generating work underway, though we recognize it may be quite a while before we have a consensus mechanism for the cardioprotective benefit, particularly across a broad group of patients.
• On the other hand, many speakers wondered aloud: how crucial is it that we understand mechanism? Several speakers felt that while it’s interesting and important to investigate the mechanism, it’s not so crucial that we must wait for a definitive answer before affecting clinical practice or adding positive CV results to drug labels for Lilly/BI’s Jardiance (empagliflozin) or Novo Nordisk’s Victoza (liraglutide). Dr. Inzucchi urged the committee charged with authoring the next iteration of the ADA/EASD diabetes treatment guidelines to consider EMPA-REG OUTCOME and other recent CVOTs, including LEADER, SUSTAIN 6, and even IRIS (for the TZD pioglitazone), despite lingering mechanism questions. Having data from EMPA-REG OUTCOME and LEADER readily available on the label for these drugs would be enormously helpful for patients and HCPs even among narrow patient groups, and we agree wholeheartedly with what these renowned thought leaders had to say:
  
  • “A stone falls today the same way that it fell 200 years ago, but our theory of gravity has changed dramatically. You don’t need to know how a drug works to benefit from it.” – Dr. Hertzel Gerstein
  • “One excuse at the Jardiance Advisory Committee was ‘we’re not quite sure about the mechanism’ – who cares?! While I applaud conservatism, it’s time to take action.” – Dr. Neil Poulter
  • “At a certain point it’s okay to be pragmatic and say even if we don’t know exactly how we’re saving lives, let’s save lives.” – Dr. Juris Meier

Renal Outcomes in CVOTs

• We noticed growing interest in renal complications of diabetes at this year’s EASD, as highlighted by encouraging renal outcomes results from the SUSTAIN-6 trial and  a new sub-analysis of the LEADER trial. In SUSTAIN-6, renal complications appeared at a rate of 3.6% in the semaglutide group (59 events) vs. 6.0% in the placebo group (99 events), an impressive 36% risk reduction. The renal benefit was driven primarily by a difference in the diagnosis of persistent macroalbuminuria, which occurred at a rate of 2.5% in the semaglutide group, versus 4.9% with placebo. This parallels the 22% risk reduction in renal complications reported in the LEADER trial (HR=0.88; 95% CI: 0.67-0.92, p=0.003), which were driven by a 26% reduction in the onset of persistent macroalbuminuria (HR=0.74, 95% CI: 0.60-0.91) and a 19% reduction in urinary albumin-creatinine ratio, a measure of microalbuminuria (HR=0.31, 95% CI: 0.76-0.86). Two new findings from the ongoing subgroup analysis of the LEADER trial’s renal data further revealed that: (1) Among participants with kidney disease (eGFR <60 ml/min/1.73 m2) there was a 22% reduction in time to first renal event (HR: 0.78; 95% CI: 0.56-1.09); (2) Among participants with severe kidney disease (30-60 ml/min/1.73 m2) or end-stage renal disease there was a 27% reduction in time to next additional composite renal outcome (HR: 0.73; 95% CI: 0.50-1.07). These two findings provide the intriguing suggestion that liraglutide’s renal benefits may be particularly applicable to patients already experiencing renal disease. 
• Renal complications are among the costliest of diabetes complications, so it is very encouraging to see evidence of renal-protective effects in not one but two members of the GLP-1 agonist class. As of now it remains unclear whether these renal benefits are due to improvements in glucose control and blood pressure or are instead the product of a direct effect of semaglutide on the kidney. We will be awaiting further dissection of these renal findings, and perhaps even a dedicated chronic kidney disease trial for liraglutide and semaglutide. We were also impressed by the renal outcomes from EMPA-REG OUTCOME for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), first presented at ADA 2016. We’re hopeful that improvements in our understanding of the renal impact of diabetes drugs can direct patients with diabetic nephropathy to treatment options most likely to help address this area of high unmet need. That said, as Dr. Meier said above, we do not necessarily need to understand the mechanism in order for it to be helpful. (We do continue to be concerned that the right education and training happen in terms of the DKA safety issues.)

Co-administration Combinations

• Several talks at EASD discussed the use of multiple diabetes therapies in combination, with a particular spotlight on dual therapy with GLP-1 agonists and SGLT-2 inhibitors – assessed for the first time in the DURATION-8 trial. Results from the DURATION-8 trial showed improved glycemic control and cardiovascular risk factors with dual therapy consisting of AZ’s once-weekly GLP-1 agonist Bydureon (exenatide) and AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) vs. either drug as monotherapy. After 28 weeks, patients (n=695) in all three arms of the study – exenatide and dapagliflozin, exenatide alone, and dapagliflozin alone – experienced impressive reductions in A1c: -2.0% (95% CI: -2.1 to -1.8), –1.6% (-1.8 to -1.4), and -1.4% (-1.6 to -1.2) respectively (baseline A1c=9.3%). However, the exenatide/dapagliflozin dual therapy reduced baseline A1c to a significantly greater extent than either monotherapy: a -0.4% improvement versus exenatide (95% CI: -0.6 to -0.1; p=0.004) and a -0.6% improvement versus dapagliflozin (95% CI: -0.8 to -0.3; p<0.001). Furthermore, exenatide/dapagliflozin dual therapy demonstrated superiority to either monotherapies for all secondary endpoints, including fasting plasma glucose, postprandial glucose, systolic blood pressure, and weight loss.
• Despite the promise of combination therapy, controversy surrounds the issue of whether multiple drug regimens should be implemented simultaneously or sequentially. This issue was at the forefront of a staged debate featuring Dr. Julio Rosenstock (UT Southwestern, Dallas, TX) and Dr. Neil Skolnik (Temple University, Philadelphia, PA). Dr. Rosenstock argued that an aggressive, simultaneous approach to beginning a combination therapy regimen will produce better diabetes outcomes, characterizing the current AACE/ACE and ADA/EASD diabetes treatment guidelines – both of which follow the broad pattern of metformin as first-line therapy, followed by the gradual addition of other agents – as unhelpfully promoting a “treat-to-fail” paradigm whereby therapy is intensified only after patients begin failing to meet their treatment goals.  By contrast, Dr. Skolnik reminded the audience that no clinical trial to date has been designed to directly compare the efficacy of a simultaneous versus sequential approach to diabetes combination therapy. In his view, though the idea of combatting the progression of diabetes with an aggressive combination of complementary drugs is intuitively appealing, there simply is no empirical data to support the superiority of simultaneous versus sequential therapy. Although we are skeptical of the effectiveness of delaying the initiation of a more potent and aggressive treatment regimen, especially given the existing long delays in diabetes treatment escalation, Dr. Skolnik brings up a valuable point that we must be careful not to let our clinical decision-making extend past the available evidence.
• A morning symposium also highlighted a critical unsolved dichotomy in type 2 diabetes: strong enthusiasm for combination therapy (Dr. Stefano Del Prato), but poor tools to actually guide clinician decision making and profile patients (Dr. John Wilding). Can we truly individualize therapy right now? Dr. Del Prato gave many compelling arguments in favor of early combination therapy: pathogenetic complexity of type 2, complementary treatment modes of action, balances efficacy and side effects, potentially more sustained efficacy (to reduce the risk of long-term complications), and better therapy individualization. But then Dr. Wilding followed with a reality check – it is extremely difficult for clinicians to know what drug to choose for a particular patient at a given point in time. The guidelines don’t give enough tools to make precision estimates, do not consider recent outcome trials (they aren’t updated frequently enough), and don’t account for variability of response to treatment. As just one example, Dr. Wilding pointed out the remarkable spectrum of individual patient responses in a dapagliflozin trial: weight change ranged from -15 kg to +10 kg, while A1c changes ranged from -2% to +4%! Dr. Wilding also showed a slide with 21 different factors to consider when choosing a drug (see below), an overwhelming task even for the best clinicians. Still, both speakers seemed to lean towards greater use of SGLT-2s and GLP-1s, given the cardioprotective results (EMPA-REG, LEADER) and weight loss without hypoglycemia. We appreciated Dr. Wilding’s insightful concluding series of questions, (see below) particularly his suggestion that we need more n=1 trials in diabetes – what is best for me? We think greater use of CGM in type 2 diabetes would help a lot here, particularly something as low-hassle as FreeStyle Libre Pro, which seems ideally designed as a companion diagnostic for prescribing type 2 diabetes drugs. Dr. Wilding noted that prospectively testing every combination and sequence of drugs would not be practical, but pharmacogenomics, other biomarkers (C-peptide), and big data may help HCPs make better treatment choices in the future. We hope digital tools from tech-pharma partnerships (IBM Watson/Novo Nordisk, Sanofi/Verily) can make serious progress on this front.

Fixed-Dose and Fixed-Ratio Combinations

• Interest in fixed-ratio and fixed-dose combinations ran high at this year’s EASD, as in previous years. We heard several oral presentations focused on GLP-1 agonist/basal insulin or SGLT-2 inhibitor/DPP-4 inhibitor products for type 2 diabetes, with speakers consistently emphasizing improvements in composite endpoints (A1c reduction with weight loss and no hypoglycemia, for example) as an advantage of combination therapy, driving home the point that a fixed-dose of two agents can often do more than one agent alone. As Dr. Timothy Bailey (UCSD, San Diego, CA) articulated in a presentation on the LIRA-SWITCH trial, composite endpoints are “most meaningful to patients.” Real-world patients want – and deserve – a drug that goes beyond A1c-lowering in its efficacy; patients care about weight loss, blood pressure, avoiding hypoglycemia, and quality of life. Dr. Vanita Aroda (Medstar Health Research Institute, Washington, DC) also highlighted composite endpoints in her discussion of a LixiLan-L post-hoc analysis, positioning Sanofi’s iGlarLixi (lixisenatide/insulin glargine) as a GLP-1 agonist/basal insulin product that can get type 2 diabetes patients to A1c goal without causing weight gain or hypoglycemia. In a presentation of the full results from Merck’s VERTIS SITA2 trial, Dr. Brett Lauring (Merck, Kenilworth, NJ) showed how SGLT-2 inhibitor ertugliflozin added-on to DPP-4 inhibitor Januvia (sitagliptin) and metformin yields significant improvements in glycemic control (the primary endpoint) but also significant and clinically meaningful improvements on secondary endpoints such as weight loss, fasting plasma glucose, and systolic blood pressure. We were very happy to see this recognition of composite and secondary outcomes beyond A1c, as we continue to push for drug developers, healthcare providers, clinical trialists, and regulators to consider metrics that matter most to patients in their daily lives. (This was the takeaway from a recent FDA workshop on outcomes beyond A1c, and notably, we also heard much conversation on the limitations of A1c at ADA 2016.)
• New data from the VERTIS program for Merck/Pfizer’s SGLT-2 inhibitor ertugliflozin renewed interest in SGLT-2 inhibitor/DPP-4 inhibitor fixed-dose combinations. Dr. Brett Lauring (Merck, Kenilworth, NJ) presented full results from VERTIS SITA2, demonstrating that treatment with ertugliflozin in patients on a background of sitagliptin (Merck’s Januvia) and metformin led to significantly greater A1c reductions (0.8% with a 5 mg dose and 0.9% with a 15 mg dose) vs. placebo (p<0.001). In addition, 32% of patients on 5 mg ertugliflozin reached an A1c target <7% in 26 weeks, compared to an even higher 40% of the 15 mg group and only 17% of the placebo group (p<0.001 for both doses based on adjusted odds ratio). Importantly, ertugliflozin add-on therapy also caused significantly greater weight loss, reductions in fasting plasma glucose, and reductions in systolic blood pressure vs. placebo. Results from the VERTIS FACTORIAL study were presented on a poster: In patients on metformin, a 15 mg dose of ertugliflozin alongside a 100 mg dose of sitagliptin caused a mean 1.5% A1c reduction at 26 weeks vs. 1.1% for 100 mg sitagliptin alone and 1.1% for 15 mg ertugliflozin alone (p<0.001 for both comparisons). Fasting blood glucose, proportion of patients reaching target A1c, and body weight all trended in the same direction and achieved statistical significance as well, supporting the efficacy of an ertugliflozin/sitagliptin fixed-dose combination. Indeed, a Merck press release issued when Dr. Lauring’s presentation began announced that the company will submit fixed-dose ertugliflozin/sitagliptin and ertugliflozin/metformin to the FDA. We’d certainly be excited about another SGLT-2 inhibitor/DPP-4 inhibitor fixed-dose combination on the market, as data continues to underscore the therapeutic potency of this particular combo. As of now, the only such fixed-dose combination available in the US is Lilly/BI’s Glyxambi (empagliflozin/linagliptin), while AZ’s Qtern (dapagliflozin/saxagliptin) is approved in Europe. That said, we haven’t seen widespread adoption of these particular combinations as of yet, largely due to cost and access concerns – we hope that positive composite endpoint data from these trials may help convince payers of the value of these combinations.
• GLP-1 agonist/basal insulin products were a major focus within the realm of fixed-ratio combinations, with new post-hoc analyses of LixiLan-O and LixiLan-L. Dr. Boris Kovatchev (University of Virginia, Charlottesville, VA) presented on LixiLan-O, “deconstructing” the A1c-lowering effect of Sanofi’s iGlarLixi (lixisenatide/insulin glargine) into the impact of each individual component on fasting and postprandial glucose, separately. Insulin glargine lowered average glucose (mean of seven-point SMBG measures) by 45 mg/dl (p<0.0001) and lixisenatide lowered average glucose by 34 mg/dl (p<0.0001) over 30 weeks. When put together as iGlarLixi, the combination caused a more substantial 61 mg/dl drop in average glucose (p<0.0001). Glucose variability (measured by the High Blood Glucose Index) declined by a mean of 6.3 from a baseline of 9.8 if treated with insulin glargine alone, by 5.3 from a baseline of 10.4 if treated with lixisenatide alone, and by 8.3 from a baseline of 10.3 if given iGlarLixi. Then, using vector analyses, Dr. Kovatchev suggested that the postprandial effect of lixisenatide might have a greater impact on iGlarLixi’s reduction of glycemic variability than on its reduction of overall plasma glucose. While this information is certainly helpful to theorists and academic researchers, we think “time in zone” data would be more understandable for patients and some HCPs. Dr. Vanita Aroda (Medstar Health Research Institute, Washington, DC) presented on LixiLan-L, sharing a post-hoc analysis to show that participants treated with iGlarLixi were 30% more likely to reach A1c <7% with no weight gain and 11% more likely to reach A1c <7% with no weight gain or documented hypoglycemia (p<0.0001 for both comparisons vs. insulin glargine alone). The issue arose that while LixiLan-L touts the result of no increased hypoglycemia risk with iGlarLixi, we might expect a reduced risk of hypoglycemia, because a basal insulin/GLP-1 agonist combination should have an insulin sparing effect. Dr. Aroda noted that disappointingly, no such insulin sparing was observed in LixiLan-L.
  
  • Notably, GLP-1 agonist/basal insulin combinations were also a recurring theme at last year’s EASD meeting in Stockholm. We noted the buzz surrounding these products, which as a class, are perhaps the most highly-anticipated fixed-ratio or fixed-dose combinations for type 2 diabetes care. We’re eager to see these combination therapies (which have been “on the horizon” for some time now) in real-world clinical practice, although we have to wait a little while longer still in the US – the FDA recently delayed approval for Sanofi’s iGlarLixi (insulin glargine/lixisenatide) and for Novo Nordisk’s IDegLira (insulin degludec/liraglutide) by three months each. We are concerned about payers missing the “forest for the trees” in not necessarily understanding well who should receive these compounds.

Diabetes Technology

Major Journal Publications: JAMA (670G), Lancet (Libre), Lancet Diabetes & endocrinology (CGM & Severe Hypo)

• EASD is a small meeting for diabetes tech, but we were glad to see three notable journal publications released in tandem with the conference: (i) Medtronic’s MiniMed 670G US pivotal trial was published as a two-page Research Letter in JAMA (an oral at this EASD and originally a late-breaking ADA poster); (ii) Abbott’s FreeStyle Libre IMPACT study was published in the prominent UK medical journal The Lancet (also presented in poster form at ADA); and (iii) Lancet Diabetes and Endocrinology published a robust randomized crossover study showing CGM reduces severe hypoglycemia in type 1s with impaired awareness (also an oral at this EASD). (As an honorable mention, about a month before the meeting began, Diabetes Technology and Therapeutics published the 52-week COMISAIR study showing that CGM confers significant benefits in MDIs.) We’re glad to see the field of diabetes technology maturing to longer studies, broader populations, and publications in high-profile journals.
  
  • We previously covered most of the MiniMed 670G pivotal data from the ADA late-breaking poster, but the JAMA Letter included a few additional metrics: mean and median glucose in the trial (~150 mg/dl); time spent >300 mg/dl (a strong 26% decline), nocturnal time-in-range data (excellent), within-day coefficient of variation, and median values for all CGM metrics. We assume this could not be an “original article” as a single arm, non-randomized study, which Medtronic obviously choose for speed and getting to market quickly – we’re glad to see that was prioritized over a perfect pre-market RCT that gets published in long-form in a major journal, but takes longer to complete. To us, the big takeaway is that the 670G is safe and effective (even in a motivated patient population), and it will be a good first-generation starting point to learn and improve upon. The device was approved in the US on September 28 after a remarkably ~3-month priority review; launch is expected in Spring 2017 in the US. International approval is expected in Summer 2017.
  • Abbott’s IMPACT study of FreeStyle Libre in type 1s (a poster at ADA) was published in the prominent UK medical journal The Lancet, alongside a balanced (but mostly positive) accompanying Comment from Cambridge’s Dr. Roman Hovorka and colleagues. This publication represents a major victory for the company and the field and hopefully a positive for broad EU reimbursement. Getting the dramatic 38% hypoglycemia reduction (~74 minutes fewer per day) published in such a prestigious journal helps build the evidence base and cost-effectiveness proposition around this device, corroborates the REPLACE outcomes study in type 2 (presented at ATTD), and certainly reduces the noise factor around “no alarms.”
  • In a major outcomes victory for CGM, a randomized crossover trial in type 1s with impaired hypo awareness (published in the Lancet Diabetes and Endocrinology) demonstrated a significant 53% fewer severe hypoglycemia events with CGM vs. SMBG (14 events vs. 34 events; p=0.03). The very well conducted trial (out of the VU university hospital and Academic Medical Center, both in Amsterdam) randomly assigned 52 patients to either (i) 16 weeks of CGM followed by SMBG (n=26); or (ii) 16 weeks of SMBG followed by CGM (n=26). The study used the Medtronic Enlite CGM running on the Veo pump, but used only as a receiver (no low glucose suspend turned on). Severe hypoglycemia (requiring third-party assistance) was actually a secondary endpoint, but boy was it powerful to see the major change in this high-risk population in a fairly small study – that the SMBG phase included 34 severe hypoglycemia events in 52 patients over just 16 weeks was striking. Notably, the proportion of patients with >1 severe hypoglycemia event was 10 (CGM) vs. 18 (SMBG), translating to a compelling 0.48 odds ratio (borderline significant at p=0.06). As expected, time-in-range (70-180 mg/dl), significantly improved during the CGM phase (65% with CGM vs. 55% with SMBG; p<0.0001), translating to over two extra hours in range per day with CGM. This included a whopping 40% reduction in time spent <70 mg/dl (7% vs. 11%; p<0.0001) and 15% less time spent >180 mg/dl (28% vs. 33%; p<0.0001). A1c was not significantly different (-0.1%), meaning glycemic control was not ceded for the hypoglycemia benefits – yes! This trial further builds the case for CGM’s cost-effectiveness (even with an older CGM sensor), and we especially hope it helps convince payers that this technology saves money in the short-term and long-term.

Digital Health and Diabetes Data – the Era of Partnerships?

• In major news during EASD, Diasend and Glooko merged into one joint company under the Glooko name and will create a unified data management platform in the next year. The company will be led by current Glooko CEO Rick Altinger, while Diasend CEO Anders Sonesson will manage Global Operations. Combined, the two companies cover 95% of devices and are currently deployed at 4,000+ health systems in 23 countries and 15 languages – wow! We spoke to reps from both sides at the Glooko booth, who were eager to share details on the merger aimed at creating the “World’s Premier Diabetes Management Platform.” We see tremendous synergy in the combined company – Diasend brings existing integration with 140+ devices, a sizable global footprint (23 countries), and reimbursement expertise in a wide variety of markets, while Glooko brings strong user interface, great data analytics and reporting, population tracking, and pipeline of insulin dose titration algorithms. We see this as excellent news for the field, given the upside from a go-to global diabetes data repository that works with every device, enables easy zero-hassle upload (in clinic, at home, in real-time), and gives patients and providers quick, actionable analysis. We believe both companies – and diabetes data in general – will move faster by combining efforts. See our detailed thoughts on the merger and an interview with the Glooko and Diasend teams.
• A new integration agreement between Abbott and mySugr will allow Libre users to automatically and passively upload data to their mySugr accounts via the LibreLink Android app. We’re glad to see Abbott now enabling a broader data ecosystem around Libre, as the company has arguably made fewer moves than Medtronic and Dexcom on this front. This news is also a win for the widely loved mySugr app, which has nearly 800,000 users globally (!) and a partnership with Roche’s Accu-Chek Connect BGM. The Abbott team also told us about a new partnership with Social Diabetes, a popular Android app in the EU that enables users to log their food and insulin and get dosing recommendations from the app. We have not ever heard of this app, but it has a notable 50,000+ downloads on Android and very positive reviews. With the hot-off-the-press FDA approval of Libre Pro two weeks ago and the 3Q16 submission of the consumer version (approval expected as early as 1Q17, per the 2Q16 financial update, which occurred before submission), these data integration agreements could be relevant for American customers very soon.

The CGM vs. FGM Debate – When Should Each Be Used?

• A small, head-to-head, investigator-initiated trial compared the hypoglycemia impact of Dexcom’s G5 (n=15) vs. Abbott’s FreeStyle Libre (n=17) in type 1s with very impaired hypoglycemia awareness. Dexcom’s G5 bested Libre on hypoglycemia, showing a significant reduction in time spent <60 mg/dl (3.3 mmol/l): from 6.1% at baseline to 3.3% in the last four weeks of the study (p=0.02). By contrast, the FreeStyle Libre group saw no significant change in hypoglycemia (from 7.4% to 8.2%; p=0.5), for a between-group difference of 3.6% (p=0.03). This translated to a clinically significant 52 minutes per day less time in hypoglycemia (<60 mg/dl) with G5 vs. Libre in a very high-risk group, and all other hypoglycemia thresholds were also in favor of G5 and statistically significant. Notably, there were no significant between-group differences in time-in-range or time in hyperglycemia – both groups saw strong and nearly equal improvements, which was a positive for Abbott in our view (despite alarms, time in range was the same as with Dexcom). Dr. Nick Oliver emphasized that the alarms really drove the greater hypoglycemia improvement in the G5 group, a key device feature for patients with a high degree of impaired hypoglycemia awareness. He characterized the FreeStyle Libre as “reflective” and the G5 as “reactive,” and noted that hypoglycemia measurement (frequency, severity) and awareness should be considered before commencing CGM – presumably to stratify patients to see if they need alarms. The study is not yet complete and will report more data in early 2017.
  
  • The temptation is to say “G5 > Libre,” but this misses the more interesting point: when should one glucose sensing technology be used vs. another? All else equal (cost, size on the body, hassle, patient preference), high-risk patients with significant hypoglycemia unawareness SHOULD have the benefit of CGM alarms. Of course, access and patient preferences are rarely equal between two options, which is why both of these technologies exist in the first place – offering a broader spectrum of device form factors, cost, and features to target different patient populations. This is not an “either-or” but a “both-and” – how can we bring glucose sensing to the masses in the most cost-effective way? CGM has not been accessible to nearly enough people to date, which is what motivated Abbott to rethink the design with FreeStyle Libre. We’re glad to see Dexcom/Verily doing the same and we hope both companies can expand the market significantly beyond those studied in this trial (who will most certainly benefit from traditional CGM, and for whom reimbursement should be a no-brainer).

Obesity

• We saw very little new clinical data on obesity management, with the exception of a phase 3 trial of canagliflozin/phentermine coadministration and a study investigating the appetite-inhibiting hormones PYY and GLP-1 post-gastric bypass surgery. Dr. Priscilla Hollander (Baylor College of Medicine, Houston, TX) presented on the first, sharing data from a 26-week trial of overweight or obese individuals without type 2 diabetes. Canagliflozin (J&J’s Invokana) and phentermine together produced 7.5% weight loss vs. 0.6% weight loss in the placebo arm (p<0.001), and while coadministration also caused greater weight loss than either drug alone, these comparisons were not statistically significant. Dr. Hollander argued that the synergistic effects of these two agents are clinically meaningful for chronic weight management, and advocated for further research into a canagliflozin/phentermine combination based on these promising results. Dr. Maria Svane (University of Gothenburg, Sweden) discussed the critical role of PYY and GLP-1, which act in concert after a patient’s bariatric surgery to suppress appetite and help sustain weight loss. Her small study (n=12 patients post-RYGB) found that food intake increased when GLP-1 and PYY were both inhibited with Exendin 9-39 and sitagliptin, respectively. Dr. Svane thus concluded that the synergistic effects of GLP-1 and PYY might explain successful maintenance of weight loss following a gastric bypass procedure. She expressed enthusiasm for these hormones as new targets for obesity pharmacotherapies. Notably, Novo Nordisk’s Chief Scientific Officer Dr. Mads Thomsen also brought up this PYY research during a company press conference at this year’s EASD. He shared excitement over PYY as a molecule to investigate further in developing better obesity drugs, which are much-needed. We’re particularly intrigued by Novo Nordisk’s phase 1 PYY candidate, which is being investigated both alone and in combination with its once-weekly GLP-1 agonist semaglutide. Still, we can’t ignore the persistent patient/provider reluctance to turn to pharmacotherapies for weight loss – as many have quoted, “drugs don’t work in patients who don’t take them.” Within the exhibit hall or among the industry-sponsored symposia, Novo Nordisk was the only company present with an obesity drug in its portfolio, and there was little mention of Saxenda (liraglutide 3.0 mg) at the company’s exhibit hall booth (at least, relative to the square footage dedicated to Tresiba, Xultophy, and Victoza). We might’ve hoped for more insight on obesity management as a type 2 diabetes prevention tactic, especially as prediabetes prevalence skyrockets.

GLP-1 Agonists

Symposium: SUSTAIN 6

Study Design and Baseline Characteristics

Lawrence Leiter, MD (St. Michael’s Hospital, Toronto, Canada)

Dr. Lawrence Leiter provided an overview of the trial design and baseline population characteristics in the SUSTAIN 6 cardiovascular outcomes trial (CVOT). SUSTAIN 6 was a double-blind, randomized, placebo-controlled, time- and event-driven trial: 3,297 individuals with type 2 diabetes from 230 sites across 20 countries were enrolled so long as they were (i) ≥ 50 years old with evidence of CVD (83% of subjects) or ≥ 60 years old with subclinical evidence of CVD (17% of subjects); (ii) diabetes drug-naïve, or on 0-2 oral diabetes agents with or without basal or premix insulin; and (iii) had an A1c ≥ 7.0%. Clinicians were repeatedly encouraged to treat according to local standard of care guidelines to achieve optimal glycemic control. Participants were randomized in a 1:1:1:1 fashion to 1.0 mg semaglutide, 0.5 mg semaglutide, or volume-matched placebos and were observed for 109 weeks (104-week treatment period followed by a 5-week follow-up period). The trial required at least 122 primary events (cardiovascular death, non-fatal MI, and non-fatal stroke) to achieve appropriate statistical power, though the trial yielded more than double that minimum number of events. Key secondary outcomes included time to first occurrence of an expanded composite CV outcome (CV death, non-fatal MI, non-fatal stroke, revascularization, unstable angina requiring hospitalization, and hospitalization for heart failure). All-cause death and each individual component in the expanded composite CV outcome were pre-specified secondary outcomes as well. The outcomes addressing secondary safety and efficacy objectives included glycemic control, body weight, patient-reported outcomes, microvascular outcomes (retinopathy and nephropathy), and adverse events (including hypoglycemia). Dr. Leiter noted that the study was extremely well-executed, given that 98.0% of patients completed the trial (those in the semaglutide group were slightly more likely to drop out, most commonly due to the documented GI consequences of GLP-1 therapy), and the vital status of 99.6% was known at trial’s end.

• Baseline characteristics were well-balanced between the semaglutide-treated arms and placebo. The study population had a mean age of 65 years, body weight of 92 kg (~202 lbs), 14-year diabetes duration, and 8.7% baseline A1c. Notably, a high proportion of patients had hypertension (~93%) and ischemic heart disease (~61%) at baseline, and many were taking CV medications – ~94% were on anti-hypertensive agents, ~73% on statins, and ~76% on anti-thrombotics. In addition, ~58% of the subjects were on some sort of insulin therapy, and ~84% were taking non-insulin glucose-lowering medications, the most prevalent being metformin (~73%) and sulfonylureas (~43%).

Cardiovascular Outcomes

Steven Marso, MD (UT Southwestern, Dallas, TX)

Cardiologist Dr. Steven Marso presented the headlining cardiovascular outcomes from SUSTAIN 6. Novo Nordisk’s next-generation once-weekly GLP-1 agonist semaglutide demonstrated a 26% (!) risk reduction for the primary endpoint of three-point MACE (CV death, non-fatal MI, and non-fatal stroke), eliciting a loud round of applause and joyful murmuring from the audience. This primary outcome occurred in 7% of semaglutide patients (n=1,648) titrated to a dose of either 0.5 mg or 1.0 mg of the agent vs. 9% of the placebo group (n=1,649) over 104 weeks, producing a hazard ratio of 0.74 (95% CI: 0.58-0.95; p<0.001 for non-inferiority; p=0.02 for superiority). Dr. Marso emphasized that the point estimates for the primary outcomes continued to favor placebo across subgroup analyses for sex, baseline age, baseline BMI, baseline A1c, baseline duration of diabetes, and region, with hazard ratios ranging from 0.58 to 0.84. The p-value for interaction among subgroups within each category was non-significant, suggesting that the results are consistent across all subgroups. Similarly, the point estimates for subgroup analyses of race, ethnicity, baseline heart failure status, history of MI/stroke, cardiovascular disease status, insulin treatment at baseline, and eGFR at baseline (<60 ml/min/1.73m² and <30 ml/min/1.73m²) were all to the left of or right at unity and the p-values for interaction for all were non-significant.

• The 26% risk reduction for the composite primary endpoint is remarkable! For comparison, LEADER showed a 13%  risk reduction for Novo Nordisk’s Victoza (liraglutide) and EMPA-REG OUTCOME showed a 14% risk reduction for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), with both CVOTs relying on the same three-point MACE used in SUSTAIN 6. That said, in a conversation with us, Dr. Philip Home (Newcastle University, UK) suggested that reporting the relative risk reduction as being in the range of 5%-42% would be more accurate, given the large confidence intervals. Within this context, the SUSTAIN 6 results are consistent with the LEADER results. We also can’t overlook the shorter span and smaller number of MACE events incurred during this CVOT. Follow-up on the primary endpoint continued for only two years in SUSTAIN 6, whereas LEADER followed-up for a minimum of 3.5 and a maximum of five years and EMPA-REG OUTCOME followed-up for four years. The direct impact of a shorter CVOT is fewer MACE events – 254, 1,302, and 772 in SUSTAIN 6, LEADER, and EMPA-REG OUTCOME, respectively. As a result, it wouldn’t be possible to say that the results would definitely support a cardioprotective indication, given the complexities of the regulatory system - indeed, Novo Nordisk has already shared that it intends to conduct a larger CVOT powered for superiority for semaglutide. Despite the differences in trial size, Dr. Marso emphasized to us that SUSTAIN 6 has more in common with LEADER than not in terms of the patient population enrolled, the endpoints, etc.
• Individual components of primary outcome: Among the components of the primary outcome, semaglutide significantly reduced the risk of non-fatal stroke by 39% (HR=0.61; 95% CI: 0.38-0.99; p=0.04). Non-fatal MI also trended toward reduction, though the result was not significant (HR=0.74; 95% CI: 0.51-1.08; p=0.12). Notably, the Kaplan-Meier curves for cardiovascular death in the semaglutide and placebo arms were virtually superimposable (HR=0.98; 95% CI: 0.65-1.48; p=0.92). For comparison, the LEADER trial for Novo Nordisk’s other GLP-1 agonist, Victoza (liraglutide), found a highly significant 22% reduction in cardiovascular death with liraglutide (HR = 0.78; 95% CI: 0.66-0.93; p=0.007). We expect the lack of clear cardiovascular mortality benefit might be due to the small size and short duration of the trial, contributing to a very low event number (44 adjudicated CV deaths and 46 adjudicated CV deaths).
• Key secondary endpoints: Semaglutide demonstrated a significant 26% risk reduction for the expanded composite outcome (cardiovascular death, non-fatal MI, non-fatal stroke, revascularization, and hospitalization for unstable angina or heart failure) (HR=0.74; 95% CI: 0.62-0.89; p=0.002). The composite endpoint of non-fatal MI, non-fatal stroke, and all-cause mortality (replacing cardiovascular mortality) was reduced by 23% (HR=0.77; 95% CI: 0.61-0.97; p=0.03). Like the cardiovascular mortality results, the Kaplan-Meier curves for all-cause mortality were largely superimposable with 62 deaths in the semaglutide group and 60 deaths in the placebo group (HR=1.05; 95% CI: 0.74-1.50; p=0.79).
• Revascularization: Revascularization, including both coronary and peripheral revascularization, was also significantly reduced by 35% with semaglutide treatment (HR=0.65; 95% CI: 0.50-0.86; p=0.003). This event occurred in 83 participants in the semaglutide group and 126 participants in the placebo group, driving event rates of 5% and 8%, respectively. All other individual components were not significantly different from placebo.
• Hospitalization for unstable angina and for heart failure: Neither hospitalization for unstable angina nor for heart failure with semaglutide treatment achieved a significant difference from placebo. The hazard ratio point estimate for unstable angina requiring hospitalization was 0.82 (95% CI: 0.47-1.44; p=0.49), with 22 events in the semaglutide arm and 27 events in the placebo arm. The hazard ratio for hospitalization for heart failure slightly favored placebo, but the wide confidence intervals suggest no significant relationship between semaglutide treatment and increased risk of hospitalization for heart failure (HR=1.11; 95% CI: 0.77-1.61; p=0.57).
• As expected, semaglutide treatment produced modest increases in heart rate and decreases in systolic blood pressure. Pulse increased 2.1 beats/min and 2.4 beats/min in the 0.5 mg and 1.0 mg dose groups, respectively. Systolic blood pressure decreased 1.27 mmHg with semaglutide 0.5 mg and 2.59 mmHg with semaglutide 1.0 mg.

Clinical and Metabolic Outcomes

Tina Vilsbøll, MD (University of Copenhagen, Copenhagen, Denmark)

Dr. Tina Vilsbøll presented the key clinical and metabolic outcomes from the SUSTAIN 6 trial, overviewing semaglutide’s efficacy outcomes (in terms of A1c and weight reductions) and microvascular outcomes (encompassing renal and opthalamic complications). At the pre-specified time point of two years post-randomization, mean A1c in the semaglutide vs. placebo groups was 0.66% lower for the 0.5 mg dose and 1.05% lower for the 1.0 mg dose, both of which were statistically significant (baseline A1c=8.7%; p<0.0001). Similarly, mean body weight (baseline = 92 kg) in the semaglutide vs. placebo groups was 2.87 kg (~6.3 lbs) lower for the 0.5 mg dose and 4.35 kg (~10 lbs) lower for the 1.0 mg dose (baseline=92 kg [~203 lbs); p<0.0001 for both). The microvascular outcome measures collected were a double-edged sword, showing an encouraging decreased risk of nephropathy (HR= 0.64; 95% CI: 0.46-0.88; p=0.005) and a concerning increase in the risk for retinopathy (HR=1.76; 95% CI: 1.11-2.78; p=0.02).

• Retinopathy complications appeared at a rate of 3% in the semaglutide group (50 events) vs. 1.8% in the placebo group (29 events), a 1.2% absolute risk increase and a 76% relative risk increase. Of course, these are very small event numbers but the increased risk of retinopathy complications (which were defined in this study as vitreous hemorrhage, onset of diabetes-related blindness, or need for treatment with an intravitreal agent or retinal photocoagulation) will surely be worrisome for some, including potentially regulatory agencies. That said, Dr. Visbøll emphasized that all of the patients that experienced worsening retinopathy had pre-existing retinopathy at baseline. Among the five semaglutide-treated patients with onset of diabetes-related blindness during the trial, all had proliferative retinopathy at baseline according to Dr. Visbøll. There is nothing possible to say at this stage – there are equal chances this is “spurious correlation” or chance – or that this is a negative finding – and a trial will need to be done to ascertain this (perhaps a two-year trial – hard to say at this stage). 50 vs. 29 events are simply too small numbers to confidently assess, especially given the multiple endpoints at play in this trial. A larger trial would certainly be able elucidate this potential connection. It is concerning that in the LEADER trial, treatment with liraglutide also hinted at a trend toward increased retinopathy (HR=1.15; 95% CI: 0.87-1.52; p=0.33), although those results were non-significant.
  
  • Certainly these findings are disturbing on the face of it, but they do not come completely unexpectedly. Dr. Visbøll mentioned that rapid glucose lowering is associated with worsening of retinopathy, as reported in the DCCT/EDIC study – although the applicability of this finding to the SUSTAIN 6 results is not yet clear, it’s important to think about this particularly related to the very small numbers shown. In a conversation with us, Dr. Philip Home (Newcastle University, Newcastle, UK) echoed this sentiment, also noting a similar finding in the Kroc study in the 1980s. He explained that the mechanism is believed to be reduction of blood flow in a damaged vasculature previously protected by the high blood flow (through vascular dilatation) of hyperglycemia, which is consistent with the large improvement in A1c also seen after intensive glucose lowering. It will be great to hear opinions on various approaches, keeping in mind what will keep things easy for patients and HCPs – we would not want to see complicated regimens that would threaten adherence. We wondered if possibly a slower dose titration or if more gradual treatment intensification (perhaps to a DPP-4 inhibitor or an SGLT-2 inhibitor, or even a less potent GLP-1 agonist before initiating semaglutide) could help ameliorate some of this risk among patients with pre-existing retinopathy but this is pure speculation and we will look forward to amassing expert views.
• Renal complications appeared at a rate of 3.6% in the semaglutide group (59 events) vs. 6.0% in the placebo group (99 events), an impressive 36% risk reduction. The renal benefit was driven primarily by a difference in the diagnosis of persistent macroalbuminuria, which occurred at a rate of 2.5% in the semaglutide group, versus 4.9% with placebo. This parallels the nature of the renal benefits reported in the LEADER trial (HR=0.88; 95% CI: 0.67-0.92, p=0.003), which were also driven by reductions in macroalbuminuria. Renal complications (which were defined in this study as new onset of persistent macroalbuminuria, persistent doubling of serum creatinine, need for continuous renal replacement therapy, or death due to renal disease) are among the costliest of diabetes complications, so it is very encouraging to see evidence of renal protective effects in a second member of the GLP-1 agonist class. As of now it remains unclear whether these renal benefits are due to improvements in glucose control and blood pressure or are instead the product of a direct effect of semaglutide on the kidney. We will be awaiting further dissection of these renal findings, and perhaps even a dedicated chronic kidney disease trial for semaglutide (which has been suggested for liraglutide). If Novo Nordisk does undertake a dedicated chronic kidney disease trial, we expect it would be for semaglutide as management has stated that it will focus more of its resources on semaglutide, which it views as the more efficacious and potent GLP-1 agonist molecule – it’s also, presumably, easier to prescribe for HCPs and use for patients. We’re curious if it would be possible to conduct a single combined outcomes trial that both rigorously assesses the cardiovascular benefit (as Novo Nordisk is already planning on initiating) and the potential renal benefit. Of course, this trial would be massive and likely very costly, though we expect less costly than conducting two separate outcomes trials. Compared to the overall costs of kidney disease, it is very very low.
  
  • Dr. Home noted that these nephropathy findings are encouraging, but do not directly address renal function. This would require assessment of eGFR, which we hope will appear in later analyses of the SUSTAIN 6 data.
• Semaglutide demonstrated significant improvements in a variety of additional efficacy outcomes related to A1c and weight reduction, which were sustained over the 2 year treatment period. Semaglutide was efficacious in reaching A1c goals: 39% and 49% of participants in the semaglutide 0.5 mg and 1.0 mg arms respectively achieved an A1c <7% vs. 16% and 15% with equivalent doses of placebo (p<0.0001 for both); 23% and 34% of participants on semaglutide 0.5 mg and 1.0 mg respectively achieved an A1c <6.5% vs. 7% and 8% with equivalent doses of placebo (p<0.0001 for both). Furthermore, after 104 weeks, a higher proportion of semaglutide-treated patients were able to achieve 5% and 10% weight loss. 36% (versus 18%) of patients in the low dose arms and 47% (versus 19%) of patients in the high dose arms achieved 5% weight loss. 13% (versus 6%) of patients in the low dose arms and 20% (versus 7%) of patients the high dose arms achieved 10% weight loss. Dr. Vilsbøll highlighted this latter finding as particularly notable; indeed, it is quite impressive that 1.0 mg semaglutide produces such substantial weight loss in as many as 1 in 5 patients.
• Additionally, semaglutide demonstrated significant improvements on a range of patient-reported outcomes (PROs), as assessed by the SF-36v2 survey. Encouragingly, the 1.0 mg semaglutide demonstrated statistically significant improvements on ALL (!) patient-reported outcomes assessed, including physical functioning, bodily pain, general health, vitality, social functioning, and mental health (The 0.5 mg semaglutide dose produced positive trends in these PROs, but only general health reached statistical significance). We applaud the trial designers for including PROs in this analysis. To our knowledge (and we need to check this!) this is the first time such outcomes have been assessed in a CVOT, and we hope this more holistic and patient-centered approach becomes the standard going forward.
• Patients in the semaglutide and placebo groups alike experienced similar low rates of hypoglycemia.  Severe or blood-glucose confirmed hypoglycemia occurred at a rate of 23.1% (191 events) and 21.7% (178 events) in the 0.5 mg and 1.0 mg semaglutide groups, respectively, and 21.5% (177 events) and 21.0% (173 events) in the corresponding placebo groups. Severe hypoglycemia occurred at a rate of 1.7% (14 events) and 1.3% (11 events) in the 0.5 mg and 1.0 mg semaglutide groups, respectively, and 1.5% (12 events) and 2.1% (17 events) in the corresponding placebo groups.

Safety Outcomes

Stephen Bain, MD (Swansea University, UK)

Dr. Stephen Bain stepped up next to discuss additional safety outcomes of interest. Treatment discontinuation due to an adverse event was higher among semaglutide patients (214 cases amounting to 12% of the 0.5 mg group and 15% of the 1.0 mg group) vs. placebo (110 cases amounting to 6% of the 0.5 mg group and 8% of the 1.0 mg group), although the total numbers of adverse events and serious adverse events were greater for placebo vs. semaglutide. Adverse events occurred in 90% of patients on 0.5 mg semaglutide vs. 91% of their placebo counterparts, and in 89% of patients on 1.0 mg semaglutide vs. 89% of their placebo counterparts. Serious adverse events (including death, life-threatening episodes, and hospitalizations) occurred in 35% of patients on 0.5 mg semaglutide vs. 40% of their placebo counterparts, and in 34% of patients on 1.0 mg semaglutide vs. 36% of their placebo counterparts. Researchers focused on many adverse events in SUSTAIN 6 that have been raised as points of consideration for GLP-1 agonists and other incretin-based therapies, such as GI side-effects, pancreatitis, and neoplasms, particularly in the pancreas.

• Nausea was the no. 1 factor leading to discontinuation of treatment, accounting for nearly 5% of premature cessation in the 1.0 mg semaglutide arm. There were 233 nausea events reported in the 0.5 mg semaglutide group (75% mild, 21% moderate, 5% severe) vs. 79 in the 0.5 mg placebo group (72% mild, 27% moderate, 1% severe), and 285 nausea events in the 1.0 mg semaglutide group (66% mild, 28% moderate, 5% severe) vs. 95 in the 1.0 mg placebo group (82% mild, 18% moderate, 0% severe).
• Diarrhea occurred 279 times in the 0.5 semaglutide group vs. 161 times in placebo, and 251 times in the 1.0 mg semaglutide group vs. 113 times in placebo. As was the case for nausea, a majority of these events were mild.
• There were 128 vomiting events among patients on 0.5 mg semaglutide vs. 53 in the corresponding placebo group; there were 173 vomiting events among patients on 1.0 mg semaglutide vs. 43 in the corresponding placebo group. Once again, as was seen in the data on nausea and diarrhea, a majority of these cases were mild.
• Acute pancreatitis occurred in 0.7% of patients on 0.5 mg semaglutide vs. 0.4% of their placebo counterparts, and in 0.4% of patients on 1.0 mg semaglutide vs. 1.1% of their placebo counterparts. In total, there were nine semaglutide-treated patients and 12 placebo patients who experienced acute pancreatitis. There were no instances of severe pancreatitis observed during the trial.
• Adverse events related to the gallbladder were reported in 4%, 3%, 5%, and 3% of the 0.5 mg semaglutide, 1.0 mg semaglutide, 0.5 mg placebo, and 1.0 mg placebo arms, respectively. Gallbladder adverse events included cholelithiasis and cholecystitis acute.
• The frequency of malignant neoplasms was similar across treatment arms, and the hazard ratio for pancreatic cancer was 0.25 in favor of semaglutide (though this ratio was not statistically significant). In total, pancreatic cancer affected one individual in the semaglutide group and four individuals in the placebo group during the study period. The hazard ratio for total neoplasms, encompassing those that were benign, was 1.12 in favor of placebo; however, this value was once again not statistically significant.

Discussant

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

Dr. Lars Rydén endeavored to contextualize the SUSTAIN 6 results, providing a historical perspective on the path to modern CVOTs and a comparison to other neutral and positive CVOTs for diabetes drugs that have reported in the last few years. Dr. Rydén congratulated the trial lead investigators for a “carefully planned, well performed, objectively reported” trial and underscored that he would not be nitpicking the details of the trial design or interpretation. Instead, he emphasized that both the 26% relative risk reduction and the 2.3% absolute risk (from 8.9% to 6.6%) in the primary endpoint with semaglutide treatment is substantial and clinically meaningful. He pointed out that cardiologists are often pleased if new platelet therapies are able to demonstrate a much smaller absolute risk reduction.

• Regarding the mechanism of action, Dr. Rydén emphasized that the results appear to be driven by a positive impact of semaglutide on non-fatal stroke and non-fatal MI. Considered along with the benefit on risk reduction for revascularization and the slow onset of benefit, Dr. Rydén suggested that semaglutide’s cardioprotective effect could be mediated through a delay in progression or even regression of atherosclerosis. Dr. Rydén also suggested that duration of action may account for the heterogeneity seen in the large 26% risk reduction observed in SUSTAIN 6 compared to the smaller – but still positive – 13% risk reduction of liraglutide in LEADER and to the neutral ELIXA results for lixisenatide (Sanofi’s Lyxumia/Adlyxin). Lixisenatide is a short-acting GLP-1 agonist, while liraglutide is a longer-acting GLP-1 agonist and semaglutide (as a once-weekly injection) is longer-acting still. He hypothesized that the bioavailability of the GLP-1 agonist must last at least through an entire day to demonstrate a cardioprotective benefit.
• In a comparison to the LEADER and EMPA-REG OUTCOME trials, Dr. Rydén highlighted that both the relative and absolute risk reduction was greater in SUSTAIN 6. Semaglutide’s relative risk reduction of 26% and absolute risk reduction of 2.3% compares to liraglutide’s relative risk reduction of 13% and absolute risk reduction of 1.9% and empagliflozin’s relative risk reduction of 14% and absolute risk reduction of 1.6%. Dr. Rydén also pointed out that the A1c reduction in SUSTAIN 6 was greater than in the LEADER and EMPA-REG OUTCOME trials: a placebo-adjusted difference of 0.8%, compared to 0.4% and 0.2%. As expected for a pre-approval safety trial, the follow-up duration in SUSTAIN 6 was shorter at 2.1 years compared to 3.8 years for LEADER and 3.1 years for EMPA-REG OUTCOME.
• Regarding the retinopathy data, Dr. Rydén largely deferred to future clinical or registry-based trials. He pointed out that the LEADER trial had also observed a 15% increase in retinopathy, though it was not statistically significant, but ultimately suggested that time will tell how much of a concern this finding is. We were a little disappointed that Dr. Rydén did not dig into the retinopathy outcomes more – though of course he was already fitting a lot into the mere 10 minutes he was allotted already! – and we expect we’ll hear much discussion of this finding in the coming months.
• Dr. Rydén concluded with three main areas of impact for the SUSTAIN 6 results in his view: (i) raising interest in mechanistic studies delineating mechanisms and refining treatment; (ii) catalyzing the initiation of new clinical trials investigating the combination of a GLP-1 agonist and an SGLT-2 inhibitor; and (iii) creating an immediate therapeutic option for a sizeable and vulnerable patient population.

Close Concerns Questions

Q: Is the remarkable 26% risk reduction for three-point MACE a product of smaller sample size of events? How much of this risk reduction should be attributed to the smaller number of MACE events?

Q: Will empirical support for semaglutide’s CV benefits make an even stronger case for the CV benefits of Victoza (liraglutide)? Will this influence the FDA’s decision to revise the Victoza label?

Q: What is the prospective timeline for a larger CVOT of semaglutide that includes a higher number of MACE events on par with LEADER or EMPA-REG OUTCOME?

Q: Does the physiological action of semaglutide directly increase retinopathy risk?

Q: How will follow-up research unpack the association between semaglutide and eye complications?

Q: Do the significant weight loss results foreshadow semaglutide’s potential as an obesity drug, paralleling Saxenda (high dose liraglutide)?

Q: Does SUSTAIN 6, in conjunction with LEADER, offer support for a cardioprotective class effect of GLP-1 agonists?

Q: Is there an aspect of the once-weekly formulation (perhaps improved adherence) that causes more powerful CV effects vs. the once-daily formulation?

Q: Given the more dramatic 24% risk reduction on three-point MACE vs. Victoza’s 13% risk reduction, does semaglutide have more potential as a cardioprotective agent in a lower-risk patient population vs. liraglutide?

Symposium: Combination Treatment with SGLT-2 Inhibitors/GLP-1 Receptor Agonists

DURATION-8 Study: dapagliflozin and Exenatide QW Combinaton

Cristian Guja, MD (University of Medicine and Pharmacy, National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania)

Dr. Cristian Guja (University of Medicine and Pharmacy, Bucharest, Romania) presented the results of the DURATION-8 trial demonstrating improvement of glycemic control and of some cardiovascular risk factors with dual therapy consisting of AZ’s once-weekly GLP-1 agonist Bydureon (exenatide) and AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) vs. either drug as monotherapy. After 28 weeks, patients (n=695) in all three arms of the study – exenatide and dapagliflozin, exenatide alone, and dapagliflozin alone – experienced impressive reductions in A1c: -2.0% (95% CI: -2.1 to -1.8), –1.6% (-1.8 to -1.4), and -1.4% (-1.6 to -1.2) respectively, from a baseline A1c of 9.3%. Interestingly, Dr. Guja noted that the trial enrolled participants with a baseline A1c of 8%-12% to minimize the risk of potential hypoglycemia if the trial enrolled participants with a lower A1c. The A1c reduction of 1.4% in the standalone dapagliflozin arm is certainly very robust for an SGLT-2 inhibitor, which is undoubtedly at least partly attributable to the high baseline A1c. That said, the exenatide/dapagliflozin dual therapy reduced still produced a significantly greater A1c reduction than either monotherapy: a -0.4% improvement versus exenatide (95% CI: -0.6 to -0.1; p=0.004) and a -0.6% improvement versus dapagliflozin (95% CI: -0.8 to -0.3; p<0.001). Given the potential for additive CV risk reduction stemming from both classes (this still has to be proven, of course), the positives in taking the two compounds together may be even larger. Although no labels have yet been updated in the US concerning cardiovascular or renal risk reduction, we imagine this is a “when” not “if” and the number of trials to happen in combinations in the coming years should provide great learning and excitement for now to improve public health. The full results from the trial were simultaneously published in The Lancet Diabetes and Endocrinology.

• In a conversation with AZ’s VP of Global Medicines Development, Dr. Elisabeth Bjork, we learned more about the additive effects of Bydureon and Farxiga on A1c. Namely, Dr. Bjork articulated how diabetes drugs are mostly baseline-dependent – as one product in this combination improves a patient’s glycemic control, the second will have a marginally smaller impact on A1c, although the essential takeaway is that exenatide and dapagliflozin in combination achieved superior A1c reductions vs. either agent alone. Dr. Bjork also remarked that there is interesting potential for the additive cardioprotective effects of Bydureon and Farxiga, especially since the dominant thought is that SGLT-2 inhibitors and GLP-1 agonists operate through distinct mechanisms of action when it comes to cardioprotection. There’s no CVOT in the works for this combination per se, although EXCEL (for exenatide) and DECLARE (for dapagliflozin) are ongoing and will reveal any impact of these drugs on MACE events and CV mortality. Finally, Dr. Bjork explained that the baseline A1c of 9.3% was an important piece of this study because these are the patients who might benefit most from a combination therapy when uncontrolled on metformin alone.
• Exenatide/dapagliflozin dual therapy demonstrated superiority to either monotherapies for all secondary endpoints. Dual therapy produced significantly greater reductions in fasting plasma glucose (FPG) than exenatide or dapagliflozin monotherapy (-3.61 mmol/l [65 mg/dl] vs. -2 mmol/l [36 mg/dl] and -2.7 mmol/l [49 mg/dl]; p<0.001). The same was true for reductions in postprandial glucose (PPG) (-4.83 mmol/l [87 mg/dl] vs. -3.31 mmol/l [87 mg/dl] and -3.41 mmol/l [61 mg/dl]; p<0.0001) and reductions in systolic blood pressure (-4.2 mmHg vs. -1.3 mmHg and -1.8 mmHg; p<0.007).
• Furthermore, dual therapy with exenatide and dapagliflozin produced greater weight loss (-3.41 kg [~7.5 lbs] vs. -1.54 kg [~3.4 lbs] and -2.19 kg [~4.8]; p<0.001) and a greater proportion of patients with weight loss of 5% or more (33% vs. 14% and 20%; p<0.001). Dr. Guja noted that the weight loss effects of the co-administration appear to be additive. Notably, participants with a baseline A1c between 8% and 9% appeared to experience a greater, more additive weight loss benefit from the co-administration of the two products. In this subgroup, participants treated with both dapagliflozin and exenatide experienced a mean 4.5 kg (~10 lbs) weight reduction, compared to 1.9 kg (~4.2 lbs) in the standalone exenatide group and 2.2 kg (~4.9 lbs) in the standalone dapagliflozin group (p<0.001 for the combination compared to both exenatide and dapagliflozin). In comparison, participants with a baseline A1c³9% treated with both dapagliflozin and exenatide experienced a mean weight loss of 2.6 kg (~5.7 lbs), compared to 1.2 kg (~2.6 lbs) in the standalone exenatide group and 2 kg (~4.4 lbs) in the standalone dapagliflozin group (p<0.01 vs. exenatide, non-significant vs. dapagliflozin). Based on these promising results, we’d be especially eager to see a trial of co-administration of the two products in patients with lower A1cs down to 7.5%.
• Adverse events occurred with approximately equal frequency in each group: exenatide plus dapagliflozin (57%), exenatide alone (54%), and dapagliflozin alone (52%). Respectively, serious adverse events occurred evenly across all groups (4% vs. 3% and 4%), as did adverse events leading to discontinuation (4% vs. 5% and 2%). The most commonly-occurring adverse events were: (i) diarrhea (4% vs. 6% and 3%); (ii) injection-site nodules (8% vs. 6% and 5%); (iii) nausea (5% vs. 7% and 3%); and (iv) urinary tract infections (4% vs. 5% and 6%). No major, minor, or severe hypoglycemia events occurred throughout the trial. There was only one case of diabetic ketoacidosis in the trial that occurred in the standalone exenatide arm. There was one case of pancreatitis in the standalone exenatide arm and one case in the combination treatment group. As expected, the rate of genital mycotic infections in the co-administration and standalone dapagliflozin arms were higher than in the exenatide arm (4%, 6%, and 2%, respectively). Overall, this adverse event profile seems very positive.

Pathophysiological Basis of SGLT-2 Inhibitor/GLP-1 Agonist Combination

Ele Ferrannini, MD (University of Pisa, Italy)

In a discussion immediately preceding the discussion of the DURATION-8 results, the highly renowned Dr. Ele Ferrannini (University of Pisa, Italy) argued that co-administration of GLP-1 agonists and SGLT-2 inhibitors is both rational and likely to work. He emphasized the distinct mechanisms of action of the two drugs (pointing out SGLT-2 inhibitors’ non-insulin-dependent glucose lowering) and the impressive benefits both classes appear to offer in terms of weight loss and potential cardioprotection. Notably, pointing out that it would be impossible for us to empirically evaluate every single possible combination of diabetes drugs with rigorous randomized controlled clinical trials, Dr. Ferrannini advocated for a “rational” approach to determining which drugs should be used together in combination therapy – SGLT-2 inhibitors and GLP-1 agonists certainly seem to fit the bill and there’s already been some very cogent discussion by Professor Philip Home on how it may be possible to profile cohorts of patients by their profile (complications etc).

Symposium: Liraglutide Effect and Action in Diabetes

Evaluation of Cardiovascular Outcome Results – A Long-Term Evaluation (LEADER)

Rury Holman, MD (University of Oxford, UK); John Buse, MD (University of North Carolina, Chapel Hill, NC); Steven Marso, MD (UT Southwestern, Dallas, TX); Michael Nauck, MD (Diabeteszentrum Bad Lauterberg, Germany); Johannes Mann, MD (Friedrich Alexander University of Erlagen, Germany)

In a symposium largely recapping LEADER cardiovascular outcomes trial data for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide), we saw several new sub-analyses of the cardiovascular, renal, and pancreatic data. The double-blind, randomized, placebo-controlled, time- and event-driven LEADER trial (n=9,340) results were originally presented ADA 2016, demonstrating a 13% relative risk reduction for the primary outcome of three-point MACE (cardiovascular death, non-fatal MI, and non-fatal stroke) and a 16% improvement in microvascular outcomes (driven entirely by a 22% improvement in renal outcomes), among a barrage of other secondary endpoints. See our detailed coverage of the ADA 2016 LEADER results presentation for more.

• Dr. Johannes Mann (Friedrich Alexander University of Erlagen, Germany) presented an expanded analysis of the microvascular outcomes from the LEADER trial.  The microvascular benefit – or, perhaps more accurately, the renal benefit – was driven primarily by a 26% reduction in the onset of persistent macroalbuminuria with liraglutide (HR=0.74, 95% CI: 0.60-0.91) and a 19% reduction in urinary albumin-creatinine ratio, a measure of microalbuminuria (HR=0.31, 95% CI: 0.76-0.86). Dr. Mann also revealed two new findings from the ongoing subgroup analysis of the LEADER trial’s renal data: (1) Among participants with kidney disease (eGFR <60 ml/min/1.73 m2) there was a 22% reduction in time to first renal event (HR: 0.78; 95% CI: 0.56-1.09); (2) Among participants with severe kidney disease (30-60 ml/min/1.73 m2) or end-stage renal disease there was a 27% reduction in time to next additional composite renal outcome (HR: 0.73; 95% CI: 0.50-1.07). The trial investigators had previously shared that the hazard ratio point estimate for participants was 0.94 (95% CI: 0.83-1.07). The full subgroup analysis is expected in two months at the upcoming American Society of Nephrology meeting, but these two findings provide the intriguing suggestion that liraglutide’s renal benefits may be particularly applicable to patients already experiencing renal disease.  The implications of this strong renal benefit are substantial, and may even prompt consideration of a dedicated chronic kidney disease trial for liraglutide. We are curious whether this effect of liraglutide is a consequence of improvements in renal risk factors like glucose and blood pressure, or whether it is a direct effect (GLP-1 is known to mediate the muscles around renal glomeruli, the functional filtering units of the kidney). These results should surely result in much more robust discussion on this front.
• Highly regarded cardiovascular expert Dr. Steven Marso shared additional analyses of the heart failure data from LEADER. The combined endpoint of hospitalization for heart failure and all-cause death was reduced by 13% in the overall trial (95% CI: 0.77-0.97). Recognizing that heart failure is of particular interest to many given the conditions significant in EMPA-REG OUTCOME and DPP-4 inhibitor CVOTs thus far, Dr. Marso also shared two subgroup analyses examining cardiovascular outcomes in patients with and without heart failure at baseline. The hazard ratio for the primary three-point MACE endpoint among patients without heart failure at baseline was 0.85 (95% CI: 0.76-0.96) while the hazard ratio among patients with heart failure at baseline was 0.94 (95% CI: 0.72-1.21). While the risk reduction was not significant among patients with heart failure, the point estimate trended in the right direction and the p-value for interaction between the two subgroups was non-significant at 0.53. Among participants without heart failure at baseline, the hazard ratio for hospitalization for heart failure throughout the trial was 0.82 (95% CI: 0.65-1.04). Among participants with heart failure at baseline, the hazard ratio was 0.95 (95% CI: 0.71-1.28) – like the MACE results, the point estimate here trended in the right direction and the p-value for interaction between the two groups was non-significant at 0.45.
• A more detailed sub-analysis of the LEADER trial presented by Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Germany) supported the initial finding that liraglutide does not increase the incidence of pancreatitis, though a wide confidence interval prevents us from ruling out the possibility entirely. Nineteen events of acute pancreatitis occurred in 18 patients on liraglutide, compared to 33 events in 25 patients on placebo. Dr. Nauck shared a graph depicting time to acute pancreatitis in the Victoza-treated vs. placebo groups and reported a hazard ratio of 0.78 over in favor of liraglutide. However, due to the confidence interval for the hazard ratio ranging from 0.42-1.44, Dr. Nauck stated that “we cannot rule out the possibility that liraglutide could have a minute enhancement of risk for pancreatitis.” Based on this sub-analysis, the worst case scenario would be a 44% greater risk of acute pancreatitis associated with liraglutide (or a best case scenario of a 58% risk reduction in pancreatitis). There were very low rates of neoplasms in LEADER, Dr. Nauck continued, which poses a challenge in precise determination of pancreatic cancer risk. The rate of pancreatic cancer was 0.3% in the liraglutide group and 0.1% in the placebo group, representing a hazard ratio of 2.59, though Dr. Nauck reiterated the high amount of uncertainty linked to this value. Overall, the results are reassuring and further support the general consensus that the benefits of GLP-1 agonist treatment outweigh the small possible risks of pancreatitis.

Oral Presentations: GLP-1 Receptor Agonists: The Longer, the Better?

Dose-Dependent Glucose Lowering and Body Weight Reductions with the Novel Oral Formulation of Semaglutide in Patients with Early Type 2 Diabetes

Melanie Davies, MD (University of Leicester, UK)

Dr. Melanie Davies (University of Leicester, UK) presented much-anticipated full results from the phase 2 dose-ranging and escalation trial of Novo Nordisk’s once-daily oral formulation of GLP-1 agonist semaglutide. The double-blind, randomized, parallel-group trial (n=632) consisting of an impressive nine arms: five with escalating doses of oral semaglutide (2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg), two comparator arms with placebo and injectable semaglutide (1 mg dose), and two dose escalation arms in which oral semaglutide was titrated up to 40 mg over either eight weeks or over 26 weeks. Topline results for this trial were shared over a year and a half ago, in February 2015, noting dose-dependent improvements in A1c and comparable weight loss to the once-weekly injectable semaglutide formulation at the highest dose. The full results offered much more granularity on the specific A1c and body weight reductions with each of the five oral semaglutide doses compared to placebo and injectable semaglutide. Oral semaglutide demonstrated significantly greater A1c reductions than placebo at each of the five doses studied: 0.7% with the 2.5 mg dose (baseline A1c=8%, p=0.0069), 1.2% with the 5 mg dose (baseline A1c=7.8%, p<0.0001), 1.5% with the 10 mg dose (baseline A1c=7.8%, p<0.0001), 1.7% with the 20 mg dose (baseline A1c=7.9%, p<0.0001), and 1.9% with the 40 mg dose (baseline A1c=8.1%, p<0.0001). For comparison, the placebo arm experienced an A1c reduction of 0.3% (baseline A1c=8%) and the injectable semaglutide arm experienced an A1c reduction of 1.9% (baseline A1c 7.8%, p<0.0001 vs. placebo).

• Oral semaglutide demonstrated dose-dependent, significantly greater reductions in fasting plasma glucose (FPG) compared to placebo: 1 mmol/l (18 mg/dl) with the 2.5 mg dose (p=0.0078), 1.5 mmol/l (27 mg/dl) with the 5 mg dose (p<0.0001), 2.3 mmol/l (41 mg/dl) with both the 10 mg and 20 mg doses (p<0.0001 for both), and 2.8 mmol/l (50 mg/dl) with the 40 mg dose (p<0.0001), compared to 0.1 mmol/l (1.8 mg/dl) with placebo. That said, the FPG reduction at the highest 40 mg oral dose didn’t quite match the 3.1 mmol/l (56 mg/dl) observed with injectable semaglutide (p<0.0001 vs. placebo).
• Oral semaglutide produced dose-dependent reductions in body weight. Participants experienced a mean body weight reduction of 2.1 kg (~4.6 lbs) in the 2.5 mg dose arm (non-significant vs. placebo), 2.7 kg (~6 lbs) in the 5 mg dose arm (just barely non-signifcant at p=0.0577), 4.8 kg (~11 lbs) in the 10 mg dose arm (p<0.0001), 6.1 kg (~13 lbs) in the 20 mg dose arm (p<0.0001), and 6.9 kg (~15 lbs) in the 40 mg dose arm (p<0.0001). For comparison, participants in the placebo arm lost an average of 1.2 kg (~2.6 lbs) and those in the injectable semaglutide arm lost an average of 6.4 kg (~14 lbs). We were impressed to see that, at the highest dose, the oral formulation of semaglutide was able to match that of the injectable version. Injectable semaglutide is currently in phase 2 for obesity and we’re curious if an obesity indication for oral semaglutide could eventually be possible, though of course it could be cost-prohibitive given that 40 mg once-daily is 280x the dose of 1 mg once-weekly (pricing could also change – it would not necessarily need to be linear).
• A greater proportion of participants on all doses of oral semaglutide were able to achieve an A1c target <7% or body weight loss >5% compared to placebo. 44% of participants treated with 2.5 mg oral semaglutide were able to achieve an A1c<7% (p=0.0142 vs. placebo), as did 81% of participants treated with 5 mg, 84% of participants treated with 10 mg, 86% of participants treated with 20 mg, and 90% of participants treated with 40 mg (p<0.0001 for 5, 10, 20, and 40 mg vs. placebo). For comparison, 28% of participants in the placebo arm and 93% of participants in the injectable semaglutide achieved this goal. In terms of weight loss, a significantly greater proportion of participants in the 10 mg, 20 mg, and 40 mg dose arms were able to achieve body weight reductions ³5% compared to placebo (56% of participants, 64%, and 71%, respectively, p<0.0001). 21% of participants in the 2.5 mg and 5 mg groups achieved this goal, a non-significant difference statistically from the 13% in the placebo group that did so. For comparison, 66% of participants in the injectable semaglutide group were able to achieve this goal.
• Adverse event rates were dose dependent and ranged from 67%-81%. For comparison, adverse event rate in the placebo arm was 68% and in the injectable semaglutide arm was 81%. Notably, however, serious adverse event rate was much lower for every dose of oral semaglutide compared to placebo (1.4%-3% in the oral semaglutide groups vs. 7% in the placebo group). Fast dose escalation of oral semaglutide appeared to be associated with a higher rate of both overall and serious adverse events (86% and 7%, respectively). Treatment discontinuations were higher in all oral semaglutide groups compared to placebo, ranging from 6% to 27% compared to 1.4% with placebo. The treatment discontinuation rate of injectable semaglutide was 15%. As expected, GI side effects were the most common adverse events, with nausea rates of 33%-34% in the 10, 20, and 40 mg dose groups (compared to 13%-14% in the 2.5 and 5 mg dose groups, 1.4% in the placebo group, and 32% in the injectable semaglutide group). Vomiting occurred in 16%-22% of participants in the 10, 20, and 40 mg oral semaglutide groups, compared to 6% in the 2.5 and 5 mg groups, 4% in the placebo group, and 9% in the injectable semaglutide group. We’re curious if the higher rate of vomiting in the oral semaglutide groups may be due to a specific aspect of the mechanism of oral delivery. Diarrhea rates varied across the oral semaglutide dose groups with no clear dose relationship, ranging from 7% in the 2.5 mg group to 14% in the 40 mg group to a high of 23% in the 10 mg group. Diarrhea rates in the placebo group were 10% and 15% in the injectable semaglutide group. Reductions in systolic blood pressure across all doses of oral semaglutide and heart rate increases with the 10 mg and higher doses were comparable to that observed with injectable semaglutide.
• In terms of safety: overall hypoglycemia rate was low, with only two cases of severe hypoglycemia reported in the trial – one in the injectable semaglutide arm and one in the fast dose escalation oral semaglutide arm. Three patients in the trial experienced pancreatitis, two taking oral semaglutide and one taking injectable semaglutide. Three neoplasms were reported as well, two in oral semaglutide-treated arms (one malignant and one benign) and on in the injectable semaglutide arm. Notably, two cardiovascular events occurred in the 71-participant placebo arm while three cardiovascular events occurred in the combined oral semaglutide arms (totaling 491 patients). While it’s obviously impossible to draw any conclusions from such low numbers, taken together with the positive SUSTAIN 6 cardiovascular outcome results for injectable semaglutide, it certainly suggests optimism for a cardiovascular benefit for the oral formulation as well – we look forward to PIONEER 6 shedding more light on this and other important complication questions in the coming years.

Oral semaglutide phase 2 efficacy results summary

	A1c reduction (p-value vs. placebo)	Fasting plasma glucose (FPG) reduction (p-value vs. placebo)	Body weight reduction	Proportion achieving A1c <7% (p-value vs. placebo)	Proportion achieving body weight reduction ³5%
2.5 mg oral semaglutide	0.7% (p=0.0069)	18 mg/dl (p=0.0078)	2.1 kg (~4.6 lbs)	44% (p=0.0142)	21% (p=0.1226)
5 mg oral semaglutide	1.2% (p<0.0001)	27 mg/dl (p<0.0001)	2.7 kg (~6 lbs) (p=0.0577)	81% (p<0.0001)	21% (p=0.1875)
10 mg oral semaglutide	1. 5% (p<0.0001)	41 mg/dl (p<0.0001)	4.8 kg (~11 lbs) (p<0.0001)	84% (p<0.0001)	56% (p<0.0001)
20 mg oral semaglutide	1.7% (p<0.0001)	41 mg/dl (p<0.0001)	6.1 kg (~13 lbs) (p<0.0001)	86% (p<0.0001)	64% (p<0.0001)
40 mg oral semaglutide	1.9% (p<0.0001)	50 mg/dl (p<0.0001)	6.9 kg (~15 lbs) (p<0.0001)	90% (p<0.0001)	71% (p<0.0001)
1 mg injectable semaglutide	1.9% (p<0.0001)	56 mg/dl (p<0.0001)	6.4 kg (~14 lbs) (p<0.0001)	93% (p<0.0001)	66% (p<0.0001)
placebo	0.3%	1.8 mg/dl	1.2 kg (~2.6 lbs)	28%	13%

EFFICACY AND SAFETY OF ONCE-WEEKLY SEMAGLUTIDE VS. ONCE-DAILY INSULIN GLARGINE IN INSULIN-NAÏVE SUBJECTS WITH TYPE 2 DIABETES (SUSTAIN 4)

Hans DeVries, MD (University of Amsterdam, the Netherlands)

Dr. Hans DeVries (University of Amsterdam, Amsterdam, the Netherlands) presented full results from  the SUSTAIN 4 trial, demonstrating the superiority of Novo Nordisk’s once-weekly GLP-1 agonist semaglutide versus once-daily insulin glargine (Sanofi’s Lantus) at improving glycemic control in participants with type 2 diabetes. We first saw topline data from this study at Novo Nordisk’s Capital Markets Day and in a poster at AACE 2016. In this open-label, active-controlled, parallel-group, trial (n=1089), insulin-naïve patients with type 2 diabetes were randomized to one of two doses of semaglutide (0.5 mg and 1.0 mg) once weekly or insulin glargine once-daily for 30 weeks. Primary endpoint results showed impressive A1c reductions of 1.2 % and 1.6% with the two respective doses of semaglutide, representing A1c reductions of 0.38% and 0.81% greater than the 0.8% A1c reduction observed in the insulin glargine active comparator group (baseline A1c=8.2%; p<0.0001). Likewise, semaglutide 0.5 mg and 1.0 mg was efficacious in reaching A1c goals. 58% and 73% of participants respectively achieved an A1c <7% with semaglutide vs. 38% with insulin glargine (p<0.0001). Moreover, 37% and 54% of participants on semaglutide respectively achieved an A1c <6.5% vs. 18% with insulin glargine (p<0.0001).

• Semaglutide was superior to insulin glargine at reducing body weight. Participants experienced weight loss of 3.5 kg (~7.7 lbs) and 5.2 kg (~11.5 lbs) with the two respective semaglutide doses vs. 1.2 kg (~2.6 lbs) weight gain with insulin glargine (p<0.0001 for both). Additionally, 37% and 51% of participants given semaglutide 0.5 mg and 1.0 mg achieved ³5% weight loss, compared to 5% with insulin glargine (p<0.0001 for both).8% of patients in the semaglutide 0.5 mg dose group (p=0.0002) and 16% of patients in the 1.0 mg dose group (p<0.0001) achieved ³10% weight loss, compared to 2% with placebo.
• Semaglutide showed significant reductions in the proportion of participants who experienced severe or blood glucose-confirmed symptomatic hypoglycemia. Of the participants in the semaglutide 0.5 mg and 1.0 mg groups, 4.4% and 5.6% experienced hypoglycemia, vs. 10.6% in the insulin glargine group (p<0.0001). This distinction was particularly stark among the subset of participants taking a sulfonylurea: 8.1% and 8.6% hypoglycemia rates with semaglutide vs. 18.1% with placebo. Among participants not on a sulfonylurea, hypoglycemia rates were lower and did not differ between the treatment groups (0.6% and 2.3% vs. 2.3%).
• Adverse events were similar between the semaglutide and insulin glargine arms (70% and 73% vs. 65%), but the semaglutide 0.5 mg and 1.0 mg groups had a higher number of serious AEs (6% and 5% vs. 5%), severe AEs (7% and 6% vs. 3%), and AEs leading to discontinuation (6% and 8% vs. 1%). As is to be expected for the GLP-1 agonist class, gastrointestinal-related adverse events were the most commonly reported: compared to participants in the insulin glargine arm, participants in the two semaglutide arms experienced more nausea (21% and 22% vs. 4%), diarrhea (16% and 19% vs. 4%), vomiting (7% and 10% vs. 3%), and dyspepsia (3% and 7% vs. 1%). Other adverse events included decreased appetite (7% and 6% vs. 0%), increased lipase (10% and 8% vs. 4%, nasopharyngitis (12% and 8% vs. 12), and headache (5% and 6% vs. 6%).
  
  • Additional safety data included six fatalities (4 in the semaglutide arms, 2 in the insulin glargine arm), five malignant neoplasms (4 in the semaglutide arms, 1 in the insulin glargine arm), two incidences of pancreatitis (both in the 0.5 mg semaglutide arm), and three instances of cholelithiasis (both in the semaglutide arms).
• Dr. DeVries (and one very astute questioner from the audience!) commented that the SUSTAIN 4 trial’s main limitation was less-than-aggressive titration of insulin glargine in the active-control arm. Daily glargine doses began at a rather low 10 units/day and were gradually titrated up to a mean dose of 29.2 units/day by the end of the 30 week trial. Dr. DeVries acknowledged that more aggressive titration may have resulted in less of an A1c difference between the semaglutide and insulin glargine groups, but also noted that such a situation would have produced a greater difference in weight loss between the two treatments. Furthermore, he noted that the 29.2 units/day dose of insulin glargine is “rather typical” for clinical trials and may reflect real life insulin titration more accurately.

uncontrolled type 2 diabetes patients on metformin monotherapy: results of the FREEDOM-2 study

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

Dr. Julio Rosenstock reviewed the results of the FREEDOM-2 study investigating Intarcia’s implantable exenatide mini-pump ITCA 650 (60 mcg/day) vs. Merck’s Januvia (sitagliptin) in patients with type 2 diabetes on metformin (n=535). Dr. Rosenstock previously presented these results at ADA 2016. The trial demonstrated significantly greater A1c reductions (1.5% vs. 0.8%) and weight loss (4 kg vs. 1.3 kg) with ITCA 650 vs. Januvia after 52 weeks (p<0.001 for both; baseline A1c = 8.5% in the ITCA 650 group and 8.7% in the Januvia group). ITCA 650 was also superior in terms of the percentage of patients achieving a secondary composite efficacy endpoint (>0.5% A1c reduction and ≥2 kg weight loss) and the percentage of patients achieving an A1c <7%. See our coverage of the results presentation at ADA 2016 for more – we were particularly impressed by the durability of the A1c and weight reductions. As a reminder, ITCA 650 is the first implantable GLP-1 agonist delivery therapy under development, and involves a small matchstick sized device placed subdermally for 6-12 month intervals in a simple outpatient procedure. Although not touched upon in Dr. Rosenstock’s presentation, earlier this year Intarcia also announced positive topline results from the FREEDOM-CVO pre-approval cardiovascular outcomes trial (n=~4,000) demonstrating non-inferiority for the primary endpoint of four-point MACE (cardiovascular death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina) with ITCA 650 vs. placebo. Given this growing body of impressive clinical trial data and the potential adherence advantage of ITCA 650 over existing injectable GLP-1 agonist options, the product certainly has significant disruptive potential. That said, we really think it’s just going to expand the market if all goes well – we think the entire GLP-1 market has major potential to expand, particularly with the advent of using more real-time “intermittent” professional CGM. According to Intarcia, preliminary plans are ongoing for a larger CVOT for ITCA 650 designed to demonstrate superiority in cardiovascular outcomes and an NDA submission for ITCA 650 is expected in 4Q16.

Questions and Answers

Q: Are there any data on patient reported outcomes, quality of life, and how patients perceive this compared to other treatments?

A: I think there is data on that, but I haven’t seen it yet. [This would be interesting to see – essentially the questioner was asking for a patient preference study.]

Q: Do you have data to show glucose variability over weeks and days?

A: Great suggestion. I want to use CGM in future studies like this.  **** note – please pull this to the top and put it in the intro – this is a big deal ….

Q: Is there any contraindication in patients taking anti-coagulants or anti-aggregants?

A: There was no sign of extra bruising in these patients. ITCA-650 requires only a very tiny incision. It’s no big deal. You can see the device in the exhibit hall!

Oral Presentations: GLP-1 Receptor Agonists: Combinations, Type 1 Diabetes, and Long-term Use

Efficacy and Safety of liraglutide Added to Insulin Treatment in Type 1 Diabetes, the ADJUNCT ONE Treat-to-Target Randomized Trial

Bernard Zinman, MD (University of Toronto, Canada)

Dr. Bernard Zinman (Mount Sinai Hospital, Toronto, Canada) presented long-awaited full results from the ADJUNCT ONE trial of Novo Nordisk’s Victoza (liraglutide) in type 1 diabetes, demonstrating modest reductions in A1c, body weight, and insulin dose and less-welcome increases in adverse events. The randomized, double-blind, placebo-controlled compared the efficacy and safety of three doses of liraglutide – 0.6 mg, 1.2 mg, and 1.8 mg – to placebo in patients with type 1 diabetes (n=1,398) over 52 weeks of treatment. The trial found a modest, dose-dependent effect for liraglutide on A1c: mean placebo-adjusted reductions were 0.2% with the 1.8 mg dose (baseline A1c=8.14, p<0.05), 0.15% with the 1.2 mg dose (baseline A1c=8.16 mg, p<0.05), and 0.09% with the 0.6 mg dose (baseline A1c 8.16%, non-significant compared to placebo). Dr. Zinman emphasized that the placebo group in the trial also experienced a significant improvement in A1c (of course! It’s a randomized controlled trial!) and the additional liraglutide-associated reductions should be considered in this context. All three doses of liraglutide also produced statistically significant body weight reductions: -4.9 kg (~11 lbs) with the 1.8 mg dose (p<0.05), -3.55 kg (~8 lbs) with the 1.2 mg dose (p<0.05), and -2.19 kg (~5 lbs) with the 0.6 mg dose (p<0.05). Furthermore, treatment with the two higher doses of liraglutide led to modest but statistically significant reductions in insulin dose of about 0.08 units and 0.05 units per unit of insulin compared to the placebo group, respectively (p<0.05 for both). A greater proportion of patients on the two higher doses achieved a composite outcome of an A1c <7% and no severe hypoglycemia compared to placebo as well: 18% of participants were able to achieve this goal in the 1.8 mg dose group (p=0.0024) and 20% of participants were able to in the 1.2 mg dose group (p=0.0003). For comparison, less than 10% of participants in the placebo group were able to achieve this composite goal.

• The adverse event profile of liraglutide in ADJUNCT ONE raised several potential safety concerns. As expected, nausea was the most common adverse event, the association was dose-dependent, and the nausea rates subsided over time. More worrisome was the 31% increase in symptomatic hypoglycemia in the 1.8 mg group (p=0.0081) and the 27% in the 1.2 mg group (p=0.0219) – symptomatic hypoglycemia was numerically increased in the 0.6 mg group but was not statistically significant. This translated to 16.5 hypoglycemic events per patient year of exposure for the 1.8 mg dose and 16.1 events per patient year of exposure for the 1.2 mg dose. On the other hand, adjudicated confirmed severe hypoglycemia trended lower in the liraglutide-treated groups (hazard ratios of 0.85, 0.61, and 0.64 in the 1.8 mg, 1.2 mg, and 0.6 mg groups, respectively), though the confidence intervals were very wide and none of the differences were statistically significant due to low event rates. Our guess is that the insulin reduction just wasn’t quite enough as the GLP-1 ramped up and we think this could’ve been managed over time. We would’ve been very interested to see the “time in zone” profile had patients worn CGM – we think the trial was done before the best CGM tools were available. Of bigger concern was the more than three-fold, statistically significant increase in hyperglycemia with ketosis with the highest 1.8 mg dose of liraglutide (HR=2.22; 95% CI: 1.13-4.34; p=0.0205). Hyperglycemia with ketosis was also increased in the 1.2 mg and 0.6 mg groups, though the results were not statistically significant. Notably, there were eight episodes of full-blown diabetic ketoacidosis (DKA) in ADJUNCT ONE, all of which occurred in the liraglutide-treated groups (three episodes in the 1.8 mg group, one episode in the 1.2 mg group, and four episodes in the 0.6 mg group). Dr. Zinman noted that all the cases of DKA occurred in patients with no detectable C-peptide levels and suggested in Q&A that liraglutide has differential effects in patients with type 1 diabetes with and without C-peptide, though he acknowledged that the number of patients with C-peptide was too low to conduct a rigorous analysis of this. Overall, however, Dr. Zinman concluded that the safety signals combined with the modest efficacy demonstrated by liraglutide in this trial limits its value and utility in patients with type 1 diabetes – we agree with this although we think the way that outcomes could be done today are different from back then and we do think GLP-1 is still of interest to type 1 patients – but difficult to know how to personalize for which patients and safety issues are definitely greater than we had realized (though some would still want to figure out how to use GLP-1 because the risk/benefit in their view would be worth it). Based on these results, Novo Nordisk announced its decision not to pursue a type 1 diabetes indication for Victoza over a year ago (concurrent with the release of the topline data). At the time, little detail on the adverse event profile was provided. While the increase in hypoglycemia and hyperglycemic ketosis, as well as the decision not to pursue an expanded indication, are very disappointing, we’re intrigued by the possibility of a subset of patients with type 1 diabetes responding better to treatment. We hope that future studies can perhaps dig further into the efficacy and safety of liraglutide among patients with type 1 diabetes and some degree of remaining C-peptide, though we recognize that Novo Nordisk has many other ongoing projects in diabetes on which it is focused.

Switching from Sitagliptin to Liraglutide in Subjects with Type 2 Diabetes: Analysis of Composite Endpoints from the LIRA-SWITCH Randomized Trial

Timothy Bailey, MD (AMCR Institute, Escondido, CA)

Dr. Timothy Bailey presented results from the LIRA-SWITCH trial, which we first got a glimpse of at ENDO 2016. The trial’s findings showed that at 26 weeks, adults with type 2 diabetes who switched from Merck’s DPP-4 inhibitor Januvia (sitagliptin, n=407) to Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) achieved greater A1c reductions compared to those who continued Januvia treatment (n=204) (-1.1% vs. -0.5%; baseline A1c of 8.2%-83%). In addition, the Victoza arm experienced greater body weight reductions compared to the Januvia arm (-3.3 kg vs. -1.6 kg) (baseline weight of 89 kg-91 kg). Dr. Bailey particularly highlighted Victoza’s superiority in a number of composite endpoints, including the proportion of patients in each treatment group who reached an A1c <7% with no weight gain and no confirmed hypoglycemia at 26 weeks. Of all participants switched to liraglutide therapy, 48% achieved this composite endpoint, compared to only 24% of the sitagliptin group. This corresponds to an odds ratio of 3.4 (p<0.0001). Additionally, 53% of Victoza-treated participants experienced an A1c reduction of >1% with no weight gain vs. 29% of Januvia-treated participants (OR=2.85, p<0.0001), 48% of Victoza-treated participants reached A1c <7% with no weight gain vs. 24% of Januvia-treated participants (OR=3.34, p<0.0001), and 45% of Victoza-treated participants reached A1c <7% with no weight gain and systolic blood pressure <140 mmHG vs. 19% of Januvia-treated participants (OR=3.88, p<0.0001). Dr. Bailey underscored that each of these composite endpoints, and especially the outcome on A1c <7% alongside no weight gain or hypoglycemia, is valuable – these are the endpoints that are “most meaningful to patients,” he argued. We definitely agree. There are so many outcomes that matter to patients beyond A1c-lowering (as hammered home at the August FDA workshop on outcomes beyond A1c), and we were happy to see this focus on hypoglycemia, body weight, and blood pressure in a LIRA-SWITCH post-hoc analysis.

Questions and Answers

Q: It seems that when you choose patients for these trials, the mean A1c is always <9%. Can you comment on that?

A: Qualifications for this trial were relatively narrow – an A1c between 7.5-9.5% - so the average baseline A1c we saw was expected. There were a few people in the study with A1c >9%, but not many. I think that’s fine, because our target group should be baseline a little below 9% A1c. In most countries, we see clinical inertia, where therapies are not switched until A1c is quite high. Historically, we’ve endorsed one target to reach, and a separate target A1c where providers actually do things differently. I believe the target to take action should be much closer to the target A1c. If you’re not reaching goals, switch therapies. The optimal thing is to test therapies in patients who are failing above goals of 7% or 8%.

Q: Since you only reached glycemic targets in half of patients, isn’t that a hint that you should start earlier and switch treatments at an even lower A1c?

A: Indeed, this is a common theme. It’s why so many patients have an A1c >9%, because of providers’ inertia to take action until A1c is already quite high.

Q: Since only half of patients reached targets, even in the liraglutide group, what’s your view on leaving sitagliptin and adding in liraglutide or another GLP-1 agonist?

A: That’s been proposed, but the data doesn’t suggest an additional benefit that would justify the additional cost. Where I live, the cost of sitagliptin is ~$6/day. Even if there was a marginal clinical benefit, this wouldn’t be economically cost-effective.

Q: Do you have any data on double diabetes, the coincidence of having both type 1 and type 2 diabetes?

A: Yes, it’s possible to develop both. These patients would presumably be on a background of insulin therapy. I don’t have data on double diabetes, per se.

Q: Can you talk a little bit about the safety profile of these two drugs?

A: So far, we haven’t seen a greater incidence of pancreatitis predicted by switching from sitagliptin to liraglutide. That said, in patients with a history of pancreatitis, you wouldn’t want to use either of these agents.

The Differential and Combined Action of Insulin Glargine and Lixisenatide on the Fasting and Post-Prandial Components of Glucose Control

Boris Kovatchev, MD (University of Virginia, Charlottesville, VA)

Dr. Boris Kovatchev presented a new post-hoc analysis of the phase 3 LixiLan-O trial of Sanofi’s iGlarLixi (insulin glargine/lixisenatide), which found distinct and differential effects of each component agent on fasting and postprandial glucose. Initial results from LixiLan-O demonstrated that iGlarLixi produces greater A1c reductions than insulin glargine (Sanofi’s Lantus) or lixisenatide (Sanofi’s Lyxumia) alone. Dr. Kovatchev positioned this post-hoc as a “deconstruction” of the A1c lowering effect, as the analysis elucidated the specific impact of each drug on fasting and postprandial glucose. Insulin glargine lowered average glucose (mean of seven-point SMBG measures) from 10.2 mmol/l (184 mg/dl) at baseline to 7.7 mmol/l (138 mg/dl) at 30 weeks (a 2.5 mmol/l [45 mg/dl] drop, p<0.0001) and lixisenatide lowered average glucose from 10.4 mmol/l (187 mg/dl) at baseline to 8.5 mmol/l (153 mg/dl) at 30 weeks (a 1.9 mmol/l [34 mg/dl] drop, p<0.0001). When put together as iGlarLixi, the combination lowered average glucose from 10.4 mmol/l (187 mg/dl) to 7.0 mmol/l (126 mg/dl), marking a more substantial 3.4 mmol/l (61 mg/dl, p<0.0001) decline. Dr. Kovatchev noted that this glucose effect is not completely additive, and explained how this indicates some overlap in the type of hyperglycemia (fasting or postprandial) targeted by each component, glargine and lixisenatide. Similarly, the effects of insulin glargine and lixisenatide on glucose variability and glycemic exposure are not completely additive. Patients’ glucose variability, as measured by the High Blood Glucose Index (HBGI), declined by a mean of 6.3 from a baseline of 9.8 if treated with insulin glargine alone, by 5.3 from a baseline of 10.4 if treated with lixisenatide alone, and by 8.3 from a baseline of 10.3 if given iGlarLixi. Glycemic exposure, as measured by area under the curve, fell ~34 mmol-hr/l from a baseline of 144 mmol-hr/l in the glargine group, fell ~27 mmol-hr/l from a baseline of 147 mmol-hr/l in the lixisenatide group, and fell ~48 mmol-hr/l from a baseline of 146 mmol-hr/l in the iGlarLixi group. Using vector analyses of the contributions of insulin glargine and lixisenatide to iGlarLixi’s effect, Dr. Kovatchev suggested that the postprandial effect of lixisenatide might have a greater impact on iGlarLixi’s reduction of glycemic variability than on its reduction of overall plasma glucose. While this information is certainly helpful to theorists and academic researchers, we think “time in zone” data would be more understandable for patients and some HCPs.

Questions and Answers

Q: What was the dose of glargine for the combination therapy group vs. the insulin glargine only group?

A: As I recall, it was lower in the combination group, but I can’t give you the exact numbers.

Q: On mechanism of action: Do you presume these effects are observed because of the gastric emptying effect of lixisenatide?

A: Yes, that was the original thought.

Q: When you’re talking about postprandial glucose, are you addressing all meals or just breakfast?

A: Average across all meals.

Q: The effect of insulin glargine on postprandial glucose was more than the effect of lixisenatide on postprandial glucose, despite the notion that insulin glargine is working mostly on the fasting glucose axis. Can you explain that, please?

A: Yes, you’re right. That’s because insulin glargine is still bringing the entire glucose curve down.

Efficacy and SAfety of LixiLan, a Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Not Adequately Controlled on Basal Insulin: LixiLan-L Trial

Vanita Aroda, MD (Medstar Health Research Institute, Washington, DC)

Dr. Vanita Aroda reviewed major findings from the LixiLan-L trial comparing Sanofi’s combination drug iGlarLixi (insulin glargine/lixisenatide) to Lantus (insulin glargine) alone. These data were also presented at ADA 2016, and Dr. Aroda shared that the results had just been accepted for publication. The critical takeaway, she articulated, is that treatment with iGlarLixi lowered A1c to 6.9% vs. 7.5% with Lantus from a baseline A1c of 8.1% in both groups. She also discussed composite endpoints – a theme of this session, as speakers highlighted GLP-1 agonist combinations for their multifaceted effects on various aspects of diabetes. Participants treated with the combination product were 30% more likely to reach A1c <7% with no weight gain at week 30 (p<0.0001), 13% more likely to reach A1c <7% with no documented hypoglycemia at week 30 (no p-value calculated), and 11% more likely to reach A1c <7% with no weight gain or documented hypoglycemia at week 30 (p<0.0001). During Q&A, the issue arose that while LixiLan-L touts the result of no increased hypoglycemia risk with iGlarLixi, we might actually expect a reduced risk of hypoglycemia, because a basal insulin/GLP-1 agonist combination should have an insulin sparing effect. Dr. Aroda noted that disappointingly, no such insulin sparing was observed in the trial.

Questions and Answers

Q: You said you were happy about no extra hypoglycemia, probably referring to the fact that with the fixed-dose combination you achieved better A1c, and lower glucose translates to greater hypoglycemia risk. But on the other hand, if in one group the reduction of glucose rests on insulin only and in the other group there’s some component contributed by a GLP-1 agonist (which alone should not cause hypoglycemia), shouldn’t there be hope of reducing hypoglycemia? And that’s not what we see in these data.

A: To clarify, I didn’t say I was happy. You’re right, it doesn’t appear that iGlarLixi has an insulin sparing effect.

Q: Did you measure heart rate in the two groups? Is there a way to split this combo into two injections/day?

A: There was maybe a 1 beat/minute difference between the iGlarLixi and Lantus treatment groups, but nothing notable. We did look at the percentage of patients with heart rate >120 beats/minute, and there were none. Sponsors have chosen to pursue once-daily dosing based on earlier studies which didn’t demonstrate pronounced benefits of twice-daily injections of this class of product, but this investigation hasn’t been done with iGlarLixi, specifically.

Q: What was the difference for patients using sulfonylureas vs. not?

A: Sulfonylureas were discontinued during run-in.

Q: Why are patients, on average, needing the same insulin dose, in both groups?

A: That’s an astute observation, and it points to lixisenatide not having an insulin sparing effect.

Q: Let’s think about an international population. In some places, culture emphasizes big dinners. In other places, it’s the norm to eat a big breakfast. Did you see cross-cultural differences?

A: Great point. This isn’t something we analyzed.

Factors Associated with three Years of Response to A1c Goal with Exenatide QW or Insulin Glargine: Retrospective Analysis of DURATION-3

Michael Trautmann, MD (Diabetes Research, Hamburg, Germany)

Germany’s Dr. Michael Trautmann presented a new retrospective analysis of DURATION-3, a head-to-head study comparing AZ’s Bydureon (exenatide once-weekly) with Sanofi’s Lantus (insulin glargine). He outlined one goal of this post-hoc analysis was to pinpoint specific factors that predict a patient’s long-term success on the once-weekly GLP-1 agonist, although there were few differences at baseline between sustained responders (individuals who achieved an A1c <7% at 26 weeks and maintained an A1c <7% for 80% of the next 11 visits, including at least one of two visits in the last six months) and non-sustained responders (individuals who achieved an A1c <7% at 26 weeks but did not maintain this for 80% of the remaining 11 visits). Of 233 participants randomized to exenatide therapy, 53 (or ~23%) were sustained responders, vs. 31 (~14%) of 233 participants randomized to insulin glargine alone. Comparing baseline characteristics of 84 sustained responders vs. 91 non-sustained responders, this post-hoc analysis found no significant differences in starting A1c (7.8% for the sustained responders vs. 8.1% for the non-sustained responders), fasting plasma glucose (8.9 mmol/l vs. 9.6 mmol/l, respectively), or postprandial glucose (11.1 mmol/l for both arms). It certainly would be helpful to be able to predict response to relatively expensive GLP-1 agonists prior to starting therapy, but the benefits of these agents are such that it is probably worthwhile for a wide range of patients to at least try them. Indeed, Dr. Trautmann emphasized that long-term, over seven years (in fact, this is the longest spanning clinical study of a GLP-1 agonist), treatment with once-weekly exenatide increases a patient’s chances of sustained improvements in A1c and body weight vs. treatment with insulin glargine alone.

DURATION-1 Extension in Patients with Type 2 Diabetes: Efficacy and Tolerability of Exenatide Once-Weekly over 7 Years

Athena Phillis-Tsimikas, MD (Scripps Diabetes Institute, La Jolla, CA)

Dr. Athena Phillis-Tsimikas discussed a seven-year follow-up to the DURATION-1 study of AZ’s Bydureon (exenatide once-weekly) comparing completers vs. non-completers. She emphasized that a once-weekly, 2 mg injection of the GLP-1 agonist, alongside regular screening visits, was a rather intensive regimen to continue for seven years, which is why there were only 122 completers out of the 293 participants from the initial 30-week assessment. Seven-year completers of DURATION-1 experienced a mean 2.2% A1c reduction in the first year of treatment (p<0.05), and although A1c bounced back slightly, the average reduction from baseline at seven years was still significant at 1.5% (p<0.05). Among completers who had no new concomitant drugs added to their diabetes care (which most often was insulin), the results were even more impressive, with a mean 2.4% A1c reduction at one year (p<0.05) and a sustained 1.8% reduction at seven years (p<0.05). We expect this is a function of poorer response to Bydureon and long-term glucose control precipitating the intensification of therapy, rather than therapy intensification causing poorer glucose control. Similar sustained but attenuated trends were observed for fasting plasma glucose, though there did not appear to be a substantial difference among those with and without concomitant medications: Average lowering of fasting plasma glucose at one year was 2.7 mmol/l and 2.8 mmol/l for completers with and without new concomitant medications, respectively, and was 1.3 mmol/l for both groups at seven years (p<0.05 for all interactions). Weight loss was 4.7 kg on average for completers at one year and 3.9 kg at seven years (p<0.05 for both interactions). Meanwhile, completers with no new concomitant drugs saw a mean 5.7 kg weight loss at one year, which actually increased to a mean 6.5 kg weight loss at seven years (p<0.05 for both interactions) – this is an exciting piece of data for type 2 diabetes care, as it reflects a possible sustained weight loss benefit of exenatide, which we have always assumed existed but did not have proof. Dr. Phillis-Tsimikas also reported that cholesterol and triglyceride levels declined significantly for completers over seven years, but notably, statin use increased during this study period as well, which makes it difficult to interpret the lipid effects of exenatide. In concluding her presentation, Dr. Phillis-Tsimikas listed a few limitations of this DURATION-1 follow-up – namely, that 59% (n=173) participants withdrew and that due to the intensity of the regimen, completers may have been more dedicated, motivated patients to begin with.

Questions and Answers

Q: Did beta cell function improve throughout the study? Will you continue to investigate effects on beta cell function after discontinuation of exenatide, to probe for durability?

A: I don’t think that’s planned, but you’re absolutely right – it would be very interesting.

Posters

Efficacy and Safety of Semaglutide Once-Weekly vs. Placebo as Add-On to Basal Insulin Alone or in Combination with Metformin in Subjects with Type 2 Diabetes (SUSTAIN 5)

H Rodbard, I Lingvay, J Reed, R De La Rosa, L Rose, D Sugimoto, E Araki, P-L Chu, N Wijayasingh, P Norwood

A Novo Nordisk poster unveiled the full results of the SUSTAIN 5 trial, which demonstrated superior glycemic control and weight loss for next-generation once-weekly GLP-1 agonist semaglutide versus placebo in patients with type 2 diabetes on basal insulin. As was previously reported in the topline results, adults with type 2 diabetes inadequately managed with basal insulin alone or in combination with metformin (n=397) achieved superior A1c reductions of 1.4% and 1.8% after 30 weeks of add-on treatment with 0.5 mg and 1.0 mg of semaglutide, respectively, compared to a 0.1% reduction with placebo (mean baseline A1c=8.4%, p<0.0001). Semaglutide also demonstrated superior weight loss (3.7 kg-6.4 kg vs. 1.4 kg; baseline = 92 kg), and insulin dose reductions (10%-15% vs. 3%). The full results shared impressive data on the proportion of semaglutide-treated patients that were able to achieve an A1c target <7%, an A1c target <6.5%, a weight loss of 5% or more, a weight loss of 10% or more, and a composite endpoint of A1c<7% without hypoglycemia or weight gain. We also got a glimpse at semaglutide’s impact on fasting plasma glucose (FPG), mean 7-point self-monitored plasma glucose (SMPG), insulin dose, and blood pressure and saw more granularity on the adverse event data. See below for a deep dive into these long-awaited results.

• From the full results, we further learned that higher proportions of semaglutide-treated participants achieved their A1c targets and weight loss goals. For participants receiving 0.5 mg and 1.0 mg semaglutide, 61% and 79% achieved an A1c <7%, compared to 11% with placebo (p<0.0001). 41% and 61% of subjects respectively achieved an A1c <6.5%, compared to 5% with placebo (p<0.0001). Additionally, 42% and 66% of subjects given 0.5 mg and 1.0 mg semaglutide achieved 5% weight loss, compared to 11% with placebo (p<0.0001 for both). Furthermore, a higher proportion of participants taking semaglutide achieved 10% weight loss or greater (9% with the 0.5 mg dose [p=0.04] and 26% of patients with the 1.0 mg dose [p<0.0001], compared to 3% with placebo).  Finally, the full results revealed that a significantly higher proportion of subjects achieved the triple goal of A1c <7% without severe or BG-confirmed symptomatic hypoglycemia and without weight gain: 54% and 67% respectively with 0.5 mg and 1.0 mg semaglutide, versus 7% with placebo.
• New efficacy data also elaborated upon the secondary outcomes of mean fasting plasma glucose (FPG), mean 7-point self-monitored plasma glucose (SMPG), and blood pressure. From a baseline of 8.6 mmol/l (154 mg/dl), mean FPG decreased by 1.6 mmol/l (29 mg/dl) and 2.4 mmol/l (43 mg/dl) in the semaglutide 0.5 mg and 1.0 mg groups, respectively, significant reductions as compared to the 0.5 mmol/l (9 mg/dl) FPG reduction seen in the placebo group (p=0.0002 and p=0.0001, respectively). Furthermore, mean 7-point SMPG decreased by 2.5 mmol/l (45 mg/dl) and 3.0 mmol/l (54 mg/dl) in the semaglutide treatment groups, respectively, significantly more than the 0.8 mmol/l (14 mg/dl) reduction observed in the placebo group (p=0.0001 for both). Postprandial increments for mean 7-point SMPG also decreased significantly more in the 0.5 mg and 1.0 mg semaglutide groups (-0.8 mmol/l [14 mg/dl] and -1.2 mmol/l [22 mg/dl], respectively), versus a 0.2 mmol/l [4 mg/dl] reduction in the placebo group (p=0.003 and p<0.0001, respectively). The larger 1.0 mg semaglutide dose was significantly more effective at reducing systolic blood pressure than placebo (-6.29 mmHg; p=0.0007). The 0.5 mg semaglutide dose also reduced systolic blood pressure, but the reduction was not significantly different from that seen with placebo.
• Over the 30-week trial, insulin dose decreased in all treatment doses. Overall, subjects on semaglutide 0.5 mg and 1.0 mg decreased their insulin dose by 10% and 15%, versus 4% in the placebo group (p=0.0046 and p<0.0001, respectively, compared with placebo). Among patients with A1c >8.0% at screening, the semaglutide 0.5 mg and 1.0 mg groups reduced their insulin dose by 6% and 10%, versus 2% with placebo. Patients with A1c <8.0% at screening mandatorily reduced their insulin dose by 20% at the beginning of the trial to minimize hypoglycemia risk. By the end of the trial they had reduced their insulin dose from baseline by 18% and 24% with semaglutide 0.5 mg and 1.0 mg, versus 7% with placebo.
• New safety data revealed that subjects given semaglutide 0.5 mg, 1.0 mg, and placebo experienced adverse events (AEs) in the proportions of 69%, 64%, and 58%, respectively. 6.1%, 9.2%, and 6.8% of subjects respectively reported serious AEs across multiple organ classes, and 4.5%, 6.1%, and 0.8% permanently discontinued treatment due to AEs. Treatment with 0.5 mg and 1.0 mg semaglutide increased pulse rate by 1 and 4 beats per minute, respectively; by contrast, placebo decreased pulse rate by 1 beat per minute. No event adjudication committee (EAC)-confirmed pancreatitis events or fatal events were reported, but there were four instances of gallbladder disease and one instance of EAC-confirmed malignant neoplasm among the semaglutide-treated groups.
  
  • As expected, the most frequent AEs in semaglutide-treated subjects were gastrointestinal, and mild to moderate in nature. 11.4% and 16.8% of subjects treated with 0.5 mg and 1.0 mg semaglutide reported nausea, as compared to 4.5% of subjects on placebo.
  • Severe or BG-confirmed symptomatic hypoglycemia occurred in 8.3%, 10.7%, and 5.3% of subjects treated with semaglutide 0.5, 1.0 mg and placebo. The proportions of subjects experiencing hypoglycemia were comparable between the semaglutide and placebo groups among patients with A1c >8.0% at screening, but among patients with A1c <8.0%, hypoglycemia occurred in a higher proportion of the semaglutide-treated groups. We think that is manageable – this is expected given people had to reduce insulin and that’s always a bit tricky (in the “real world” of course more people would go on this drug before going on to insulin).
• Semaglutide is poised to become Novo Nordisk’s star GLP-1 agonist once the patent for the hugely-successful Victoza (liraglutide) expires. This new evidence demonstrating the safety and efficacy of semaglutide in combination with basal insulin therapy indicates that the drug has a promising future in store, and enhances our anticipation for Friday’s announcement of the SUSTAIN 6 trial results, assessing cardiovascular outcomes for semaglutide. 

Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Type 1 Diabetes, The ADJUNCT TWO Randomized Trial

IB Hirsch, B Ahrén, T Pieber, C Mathieu, F Gomez-Peralta, T Hansen, A Philotheou, E Christiansen, TJ Jensen, S Birch, and J Buse

The ADJUNCT TWO trial investigated the therapeutic efficacy of liraglutide (Novo Nordisk’s Victoza) in patients with type 1 diabetes (n=835) as an adjunct to insulin treatment over 26 weeks, randomizing patients to either 0.6 mg, 1.2 mg, 1.8 mg, or placebo. Each dose of the GLP-1 agonist led to statistically significant A1c and body weight reductions vs. placebo. A1c-lowering was 0.24%, 0.23%, and 0.35% greater with the 0.6 mg, 1.2 mg, and 1.8 mg doses, respectively (baseline A1c=~8%; p<0.05). Estimated treatment difference in weight loss amounted to 2.2 kg, 3.7 kg, and 4.8 kg for the 0.6 mg, 1.2 mg, and 1.8 mg doses of liraglutide, respectively vs. placebo (p<0.05). Insulin requirements also decreased significantly for participants on liraglutide, with participants on 0.6 mg, 1.2 mg, and 1.8 mg liraglutide taking 0.05, 0.07, and 0.1 units less insulin per unit of insulin in the placebo group (p<0.05). At 26 weeks, 15% of patients treated with 1.8 mg liraglutide achieved an A1c reduction >1%, compared to 11% of patients on 1.2 or 0.6 mg of the agent and only 4% of patients receiving placebo injections. While the authors conclude that liraglutide added to insulin could be an effective glucose- and weight-lowering therapy for type 1 diabetes patients, they note that concerns over hypoglycemia may limit clinical use. Symptomatic hypoglycemia occurred most frequently in the 1.2 mg liraglutide arm of the study, affecting 175 or 84% of patients vs. 160 or 78% of patients on 1.8 mg liraglutide, 166 or 79% of patients on 0.6 mg liraglutide, and 162 or 78% of patients on placebo. In the 1.2 mg group, this represented a 31% increase in hypoglycemia over the placebo group. Additionally, liraglutide treatment increase the rate of hyperglycemic episodes with ketosis: liraglutide 1.8 mg was associated with a nearly four-fold increase in these events (HR=3.96, 95% CI=1.49-10.55, liraglutide n=42, placebo n=10). The most common adverse event in the trial was, as expected for a GLP-1 agonist, dose-dependent nausea and vomiting.

• These results mirror that of the similarly-designed but larger ADJUNCT ONE trial (n=1,398 patients with type 1 diabetes followed for one year), which were presented at this meeting by Dr. Bernie Zinman. The modest improvements in glycemic control and weight coupled with concerning safety signals in ketosis and hypoglycemia led Novo Nordisk to decline to pursue a type 1 diabetes indication for Victoza over a year ago. While Novo Nordisk certainly has many other projects within diabetes and obesity to which to turn its attention, we do still think GLP-1 agonists remain of interest for type 1 diabetes and we hope future studies can perhaps identify sub-populations of responders where the metabolic benefits may be enhanced and the safety concerns minimized – for instance, Dr. Zinman suggested in the ADJUNCT ONE presentation that patients with detectable levels of C-peptide may fare better and we wonder if the use of GLP-1 agonists in this population may potentially have a beta cell-protective effect. We would also love to see data on the impact of liraglutide or other GLP-1 agonists on time-in-range, as measured by CGM, and on patient-reported outcomes.

Safety and Efficacy of IDegLira Titrated Once Weekly Versus Twice Weekly in Patients with T2D Uncontrolled on Oral Antidiabetic Drugs: DUAL VI Study

SB Harris, G Kocsis, R Prager, T Ridge, K Chandarana, N Halladin, and S Jabbour

In this 32-week, open-label, non-inferiority trial, insulin-naïve patients (n=420) uncontrolled on metformin alone or on metformin/TZD (pioglitazone) therapy were randomized to once- or twice-weekly titration of Novo Nordisk’s IDegLira (insulin degludec/liraglutide, branded Xultophy). Among the 210 patients on once-weekly titration, the average A1c drop was 2.1%, from a baseline of 8.2% to 6.1%. The mean A1c reduction for the twice-weekly titration IDegLira group (n=210) was also 2.1%, from a baseline of 8.1% to 6%, and the estimated treatment difference between the two dosing regimens was 0.12% (p=0.012 for non-inferiority). Similar proportions of each treatment group achieved target A1c: (i) ~90% of both dosing arms reached A1c <7%; (ii) 86% of once-weekly patients experienced A1c <7% with no hypoglycemia vs. 84% of twice-weekly patients; (iii) 84% of once-weekly patients reached A1c <6.5% vs. 85% of twice-weekly patients; and (iv) 79% of both groups experienced A1c <6.5% with no hypoglycemia. Fasting plasma glucose decreased by 4.3 mmol/l (77 mg/dl) with once-weekly IDegLira (from a baseline of 10.1 mmol/l) and by 4.6 mmol/l with twice-weekly IDegLira (from the same baseline of 10.1 mmol/l [182 mg/dl]), marking a 0.2 mmol/l (3.5 mg/dl) estimated treatment difference (p=0.2 for non-inferiority). The once-weekly titration group experienced 1 kg (2.2 lb) weight loss on average, compared to 2 kg (4.4 lb) mean weight loss for the twice-weekly group – a statistically significant treatment difference (p=0.014). While the holistic safety profile was similar for both doses of IDegLira (253 adverse events in the once-weekly arm vs. 307 in the twice-weekly arm, affecting 49% and 51% of patients, respectively), hypoglycemia rates were noticeably higher for patients in whom the dose was titrated twice a week. Severe, symptomatic hypoglycemia occurred in 6% and 16% of the once- and twice-weekly titration groups, respectively, and in 1% and 7% of both groups respectively overnight. Overall, the results support the efficacy and safety of the simpler once-weekly titration strategy, which could help reduce the patient and provider burden associated with IDegLira initiation.

Patient-Reported Outcomes with Once Weekly Dulaglutide Versus Placebo, Both in Combination with Once Daily Insulin Glargine (+/- Metformin) in Type 2 Diabetes (AWARD-9)

M Yu, K Van Brunt, Z Milicevic, O Varnado, K Boye

AWARD-9 was a 28-week, phase 3b, randomized study in patients with type 2 diabetes treated with or without metformin (≥1500 mg/day), who received weekly titrated basal insulin glargine with either 1.5 mg of dulaglutide (Lilly’s Trulicity) or placebo. Dulaglutide (n=150) resulted in significantly greater reductions in A1c – 1.4% drop from an average baseline of 8.4% – and fasting plasma glucose ­– 2.5 mmol/l (45 mg/dl) decline from a baseline of 8.7 mmol/l (157 mg/dl) – vs. placebo (p<0.001). For comparison, the placebo group (n=150) saw an average A1c decline of 0.7% from baseline 8.3% and an average fasting plasma glucose decline of 1.6 mmol/l (29 mg/dl) from baseline 8.7 mmol/l (157 mg/dl). A larger proportion of dulaglutide-treated patients (67%) reached a target A1c <7% compared to placebo (33%, p<0.001). There was a greater observed increase in insulin glargine dose with placebo at 26u vs. dulaglutide at 13u (p<0.001), though the rate of hypoglycemia was similar in both groups (82% and 76% for dulaglutide and placebo arms, respectively). In addition, body weight decreased in the dulaglutide arm by a mean 1.9 kg (4.2 lbs) but increased in the placebo arm by 0.5 kg (1.1 lbs), both from a 93 kg (205 lbs) baseline (p<0.001). Nausea and diarrhea were common side-effects of dulaglutide, occurring with 12% and 11% frequency, respectively. These GI side-effects were less common for placebo-treated participants, at 1% and 4%, respectively. Importantly, investigators also looked at patient reported outcomes (PRO) in AWARD-9. PROs were administered at baseline and then again after 28 weeks of treatment, revealing significant improvements on weight-related quality of life metrics. Specifically, score on the “Impact of Weight on Self-Perceptions” test improved by a greater margin in dulaglutide-treated patients vs. placebo-treated patients – total transformed score at 28 weeks was 6.14 for the dulaglutide group (p<0.05 vs. baseline) vs. 0.07 for the placebo group (p<0.05). We greatly appreciated the inclusion of patient-reported outcomes data and hope to see greater standardization among trials and within the regulatory process on how these are measured.

Efficacy and Safety of Once-Weekly Semaglutide Monotherapy Versus Placebo in Subjects with Type 2 Diabetes (sustain 1)

C Sorli, S-I Harashima, G Tsoukas, J Unger, J Derving Karsbøl, T Hansen, and S Bain

SUSTAIN 6 may have been a looming highlight of EASD 2016, but other notable data from the SUSTAIN program for Novo Nordisk’s GLP-1 agonist semaglutide was also presented in Munich, including this poster on SUSTAIN 1. The 30-week, phase 3a trial randomized 388 adults with type 2 diabetes to semaglutide 0.5 mg (n=129), semaglutide 1.0 mg (n=130), or placebo (n=129). A1c decreased by 1.5% and 1.6% with semaglutide 0.5 mg and 1.0 mg, respectively, and declined by <0.1% with placebo (baseline A1c=8%, p<0.0001 for both comparisons). Moreover, 66% and 65% of participants treated with semaglutide 0.5 mg and 1.0 mg, respectively, achieved target A1c <7% without severe or blood glucose-confirmed symptomatic hypoglycemia or weight gain, whereas only 19% of the placebo group achieved this composite endpoint. Improvement on seven-point self-monitored plasma glucose (SMPG) was found to be significant for 1.0 mg semaglutide vs. placebo – there was a 1.1 mmol/l (20 mg/dl) decrease in seven-point SMPG with 1.0 mg of the active agent vs. a 0.3 mmol/l (5.4 mg/dl) decrease with placebo (p=0.0014). Seven-point SMPG decreased by a mean 0.8 mmol/l (14 mg/dl) among patients on 0.5 mg semaglutide, but this treatment difference vs. placebo did not reach statistical significance. Mean body weight decreased by 4 kg (8.8 lbs) and 5 kg (11 lbs) with semaglutide 0.5 mg and 1.0 mg, respectively, and by 1 kg (2.2 lbs) with placebo (p<0.0001 for both comparisons). Adverse event rates were comparable across groups and were reported in 64%, 56%, and 54% of participants on semaglutide 0.5 mg, semaglutide 1.0 mg, and placebo, respectively. As expected, the most frequent side-effects were GI-related (including nausea and diarrhea); there were no fatal adverse events reported throughout the trial period. In total, 47 participants discontinued treatment prematurely and were fairly well-balanced among the three groups – 17 from the 0.5 mg semaglutide arm, 16 from the 1.0 mg semaglutide arm, and 14 from the placebo arm.

Oral Agents

Oral Presentations: SGLT-2 Inhibitor Trials

Efficacy and Safety of Ertugliflozin in Subjects with Type 2 Diabetes Mellitus Inadequately Controlled on the Dual Combination of Metformin and Sitagliptin: The VERTIS SITA2 Trial

Brett Lauring (Merck, Kenilworth, NJ)

Dr. Brett Lauring presented findings from the phase 3 VERTIS SITA2 trial demonstrating significant A1c reductions for Merck’s SGLT-2 inhibitor candidate ertugliflozin as an add-on to DPP-4 inhibitor Januvia (sitagliptin) and metformin in patients with type 2 diabetes (n=463). A 5 mg dose of ertugliflozin lowered A1c by a mean 0.8% after 26 weeks, while a 15 mg dose lowered A1c by 0.9% (baseline A1c=8%, p=0.001 for both vs. placebo). For comparison, the placebo group experienced a substantially smaller 0.1% A1c reduction. The between-group difference in glucose-lowering was apparent at six weeks and increased through the end of the 26-week study period. Among patients treated with 5 mg ertugliflozin, 32% achieved A1c <7% vs. 17% in the placebo group (p<0.001 for both doses based on adjusted odds ratio). An even higher 40% of patients in the 15 mg ertugliflozin group achieved this A1c target (p<0.001). Ertugliflozin treatment added to sitagliptin and metformin also demonstrated a significant improvement on a number of secondary endpoints, namely (i) weight loss; (ii) reductions in fasting plasma glucose; and (iii) reductions in systolic blood pressure. Weight loss amounted to an average of 3.3 kg (~7.3 lbs) in the 5 mg arm (p<0.001) and 3 kg (~6.6 lbs) in the 15 mg arm (p<0.001), compared to 1.3 kg (~2.9 lbs) in the placebo arm. Fasting plasma glucose was 25 mg/dl lower after 26 weeks in the 5 mg ertugliflozin group and 31 mg/dl lower in the 15 mg group compared to placebo (p<0.001 for both). There was a 4 mmHg drop in systolic blood pressure, on average, for patients given a 5 mg dose of ertugliflozin vs. a 1 mmHg drop for patients on placebo (p=0.019). Patient taking the 15 mg dose experienced a mean 5 mmHg decline in systolic blood pressure (p=0.002).

• Dr. Lauring noted that the higher dose trended better on most primary and secondary outcome measures. The exception was weight loss, which was similar for both doses.
• Ertugliflozin was well-tolerated, showing no increased risk of urinary tract infections (4, 7, and 3 subjects in the 5 mg, 15 mg, and placebo groups, respectively), symptomatic hypoglycemia (6, 1, and 4 subjects in the 5 mg, 15 mg, and placebo groups, respectively), or hypovolemia (1, 0, and 1 subjects in the 5 mg, 15 mg, and placebo groups, respectively). As expected, the incidence of genital mycotic infections was higher in both males and females and the differences from placebo were statistically significantly different (p<0.05) for the 5 mg dose for males and the 15 mg dose for females (6, 9, and 1 subjects in 5 mg, 15 mg and placebo for females and 4, 3, and 0   subjects in 5 mg, 15 mg and placebo for males). All four of these adverse events types were pre-specified for further analysis in VERTIS SITA2, according to Dr. Lauring, because of concerns related to SGLT-2 inhibitor agents more generally.
• According to an announcement released as soon as Dr. Lauring’s presentation began, Merck and partner Pfizer will submit NDAs for standalone ertugliflozin, ertugliflozin/sitagliptin and ertugliflozin/metformin by the end of 2016. Further regulatory submissions in international markets are expected in 2017.
• In an interview with Dr. Sam Engel (Merck, Kenilworth, NJ), Associate VP of clinical research in diabetes and endocrinology, we learned that Merck views ertugliflozin as part of a larger strategy of developing diabetes therapies that patients can use at any point during the course of their care. In other words, the people who could benefit from ertugliflozin and its combinations would span a wide spectrum encompassing patients regardless of diabetes duration, whether newly-diagnosed as a first-line therapy or already a few decades into diabetes management in need of therapy intensification. On a similar theme, Dr. Lauring argued during Q&A following his presentation that bringing a fourth SGLT-2 inhibitor to market would benefit patients by expanding choice. Ertugliflozin would join Lilly/BI’s Jardiance (empagliflozin), Janssen’s Invokana (canagliflozin), and AZ’s Farxiga (dapagliflozin).
• Dr. Lauring shared enthusiasm for the therapeutic potential of a SGLT-2 inhibitor/DPP-4 inhibitor combination product. Right now, the only such fixed-dose combination available in the US is Lilly/BI’s Glyxambi (empagliflozin/linagliptin), while AZ’s Qtern (dapagliflozin/saxagliptin) was recently approved in Europe. We expect the very neutral CV safety results for the sitagliptin component of the ertugliflozin/sitagliptin combination will be reassuring for many providers, though we expect much of the buzz for SGLT-2 inhibitors will continue to center around the empagliflozin franchise, at least until further CVOTs are able to confirm a cardiovascular class effect.

Questions and Answers

Q: We already have three SGLT-2 inhibitors, so was there a reason why you embarked on producing a fourth? Do we expect anything better here?

A: With more agents on the market, there are always better choices for patients. As in other drug classes, differentiation among agents emerges over time. We’re running a large CVOT program within this program, so we’ll have to wait and see. With our emerging profile for ertugliflozin, we’re very happy with what seems like a comparable efficacy profile. Plus, development of a fixed-dose combination with sitagliptin might be an attractive option for many patients.

Q: I see there was a small drop in eGFR noted, which is fairly typical. Were there any patients who reached criteria for acute kidney injury?

A: Using laboratory tests, we found one subject with a substantial drop in eGFR, and I think that was in the placebo arm. No, we didn’t see any adverse kidney injuries resulting in hospitalization, or anything like that.

Q: Did any patients develop DKA?

A: We did not observe any acute cases of ketoacidosis in this trial, but I’ll remind you that it was a six-month study with ~500 patients. For ethical purposes, we did provide rescue therapy. Over the course of 26 weeks, ~16% of participants in the placebo arm received rescue therapy, and this percentage was much lower in the treatment arms.

Q: Looking more closely at the genital infection rates – here, the rates seem relatively low (~10%) compared to the VERTIS MONO trial (~20%). Do we have evidence to suggest that a SGLT-2/DPP-4 combo may be less aversive in this regard than an SGLT-2 inhibitor alone?

A: Yes, there was a higher incidence of genital mycotic infections in VERTIS MONO (which, for anyone who is curious, is abstract 727 at this meeting). The patient populations of these two studies were very similar, and we used the same definition. So we think it was just normal variation. In VERTIS MONO, we saw greater rates in both groups – treatment and placebo. My personal opinion is that this is just random variability from trial to trial.

Oral Presentations: SGLT-2 Inhibitors: Metabolic Effects

canagliflozin Slows Progression of Renal Function Decline Independent of Glycemic Effects

Hiddo Heerspink, MD (University Medical Center Groningen, the Netherlands)

Dr. Hiddo Heerspink (University Medical Center Groningen, Groningen, the Netherlands) presented a compelling new post-hoc analysis of CANTATA-SU to support a glucose-independent, renal-protective benefit for the SGLT-2 inhibitor canagliflozin (Janssen’s Invokana). The analysis was published recently in the Journal of the American Society of Nephrology. CANTATA-SU was a phase 3, double-blind, head-to-head study of canagliflozin (100 or 300 mg/day) vs. sulfonylurea glimepiride (titrated to 6-8 mg/day) over 24 months in patients with type 2 diabetes (n=1,450) on metformin monotherapy. In the post-hoc analysis, eGFR declines throughout the trial were smaller with both doses of canagliflozin compared to glimepiride (declining 0.5 ml/min in the canagliflozin 100 mg group [p=0.01] and 0.9 ml/min in the canagliflozin 300 mg group [p=0.01], compared to a 3.3 ml/min reduction in the glimepiride group. The results suggest that canagliflozin, compared with glimepiride, slows the progression of renal disease in type 2 diabetes patients over two years. Canagliflozin furthermore produced reductions in urinary albumin:creatinine ratio (UACR) compared to glimepiride (5.7% reduction with the 100 mg dose and 11.2% reduction with the 300 mg dose, p=0.01). This was especially pronounced in the subgroup of patients with baseline UACR above 30 mg/g, who experienced a 31.7% (p=0.01) decline in this ratio with canagliflozin 100 mg and a 49.3% (p=0.01) decline in this ratio on the 300 mg canagliflozin dose compared to glimepiride treatment. Further post-hoc analysis revealed that the treatment effect of canagliflozin on albuminuria persisted even after statistically controlling for the differences in A1c reduction, systolic blood pressure, body weight, or the combined changes in all three of these factors between the canagliflozin and glimepiride arms. This suggests that canagliflozin’s effect on albuminuria occurs independently of its glycemic effects – wow! We’re intrigued by the suggestion of renal-protection for canagliflozin demonstrated by these analyses and our curiosity is piqued regarding the mechanism by which SGLT-2 inhibitors achieve this renal-protective effect. Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) recently demonstrated impressive renal-protective benefits in EMPA-REG OUTCOME and we’re certainly looking forward to more renal outcomes data from other products in the class – as well as for GLP-1 compounds. Diabetic nephropathy is an extremely costly complication of diabetes, both in human and economic terms, and the availability of glucose-lowering drugs with additional renal-protective benefits is a major win for patients. We look forward to hearing more on renal impact of diabetes drugs in the coming days at EASD.

• An astute comment during the ensuing Q&A session pointed out that this study lacks a sufficient control group. Thus it is impossible to tell whether the renal benefits of canagliflozin over glimiperide are due to canagliflozin being beneficial or glimiperide being harmful. To resolve this issue, we would love to see similarly-designed trials in the future that includes a third, placebo-controlled arm. Also, just in general, we’d love to see SFUs used in more outcomes trials. Though it may make more patients not want to participate in the trials, we think that more data is needed to show the negativity of SFUs – so many patients are forced to be on SFUs still and there is not enough data for patient advocates to try to push back for these patients. For some group of course, lower-dose SFUs may be fine, but we think the combination of weight gain and hypoglycemia and fracture risk and beta cell burnout is quite negative for most.
• The CREDENCE trial is underway to assess the effects of canagliflozin (100 mg/day) on renal endpoints in patients with diabetic kidney disease. With nearly 4,000 subjects enrolled, Dr. Heerspink explained that the CREDENCE trial will be powered to definitively show whether canagliflozin has renal-protective effects. According to ClinicalTrials.gov, this trial is estimated to complete in January 2020.

Effect of Empagliflozin (EMPA) on Bone Fractures and DKA in Patients with Type 2 Diabetes

Stefan Kaspers, MD (Boehringer Ingelheim, Germany)

In a completely packed, at-capacity session, Dr. Stefan Kaspers presented results from two meta-analyses examining the impact of treatment with Lilly/BI’s Jardiance (empagliflozin) on diabetic ketoacidosis (DKA) and bone fracture rates across the body of clinical trial data available. The results were very reassuring overall, demonstrating no clear association between empagliflozin and increased DKA or bone fracture event rates in a clinical trial setting. The completely packed, large presentation room and the audience’s rapt attention is a testament to both the interest in the SGLT-2 inhibitor class and the concerns many providers have about the relationship between SGLT-2 inhibitors and these two adverse events. We expect these reassuring results, coupled with the compelling EMPA-REG OUTCOME data demonstrating potential cardioprotective and renal-protective benefits for empagliflozin, might lead to some providers and patients preferring empagliflozin over other SGLT-2 inhibitors in the class (though, of course, many prescribing decisions today are too often dictated by reimbursement and access as well).

• The DKA meta-analysis found DKA event rates were very low and balanced between empagliflozin-treated and comparator groups, though increased urinary ketones was more common among participants treated with empagliflozin. The analysis was conducted with data from 18 randomized phase 1-3 clinical trials for empagliflozin (including the EMPA-REG OUTCOME cardiovascular outcomes trial) and from six extension studies. The analysis was based on investigator-reported outcomes and included a total of 15,677 patients. In total, the analysis included over 19,000 patient-years of exposure to empagliflozin. The DKA meta-analysis found only 12 cases of DKA in all of the clinical trials combined: 5 events among participants treated with the 10 mg dose of empagliflozin, 2 events among those treated with 25 mg of empagliflozin, and 5 events among those in the comparator groups. The event rate of each of these groups per 100 patient-years was 0.06, 0.02, and 0.05, respectively. 10 of these DKA events were classified as serious, 5 in those treated with 10 mg empagliflozin, 1 in those treated with 25 mg empagliflozin, and 4 in those treated by comparators (events rates were 0.06, 0.01, and 0.04 per 100 patient-years, respectively). Of the seven participants who experienced a DKA event while on empagliflozin, only two discontinued the study drug (none of the five participants who experienced a DKA events on placebo discontinued). The meta-analysis also showed that, based on regular urinary ketone tests from these trials, the vast majority of patients either never experienced a positive ketone test (76% of patients in empagliflozin-treated arms and 82% in comparator arms) or never experienced higher than trace levels of ketones (14%-15% of those in the empagliflozin-treated arms and 14% in the comparator arms. That said, a greater proportion of participants treated with empagliflozin experienced elevated urinary ketones across the studies than those in comparator arms (10% in the empagliflozin-treated arms compared to 4% in the comparator arms).
• The bone fracture meta-analysis found that the proportion of patients experiencing bone fractures was comparable between empagliflozin-treated groups and comparators overall and in all age, gender, and eGFR subgroups. The bone fracture meta-analysis was conducted with data from 15 placebo-controlled phase 1-3 clinical trials and four extension studies – one trial, the EMPA-REG H2H-SU head-to-head study of empagliflozin vs. sulfonylurea glimepiride, was discussed separately. The main meta-analysis was based on investigator-reported outcomes and included a total of 12,620 patients. The overall bone fracture event rate per 100 patient-years was 1.55, 1.36, and 1.69 with empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively (absolute event rates were 2.8%, 2.5%, and 2.9%, respectively). The event rate per 100 patient-years and the absolute rate were similarly comparable across empagliflozin and placebo groups for serious bone fractures (0.38 [0.7%] with empagliflozin 10 mg, 0.47 [0.9%] with empagliflozin 25 mg, and 0.59 [1%] with placebo). For bone fractures leading to discontinuation, the rate per 100 patient-years and absolute rate remained comparable and were even lower across the board (0.08 [0.1%] with empagliflozin 10 mg, 0.10 [0.2%] with empagliflozin 25 mg, and 0.23 [0.4%] with placebo). Bone fractures were similarly comparable regardless of type (upper limb, lower limb, thoracic cage, spinal, skull and facial, pelvic, or other). The subgroup analyses found that bone fractures were more frequent in both empagliflozin and placebo arms among females, increasingly older patients, and those with decreasing renal function. Dr. Kaspers emphasized that within these subgroups of increased risk, bone fracture rates among empagliflozin-treated participants were comparable to rates among the placebo groups. Dr. Kaspers also pointed out that there were no changes in calcium or phosphate levels with empagliflozin or placebo and no notable differences in changes in other bone markers between empagliflozin and placebo groups. Analysis of bone fracture rates in EMPA-REG H2H-SU found similar results regarding the comparability of bone fracture rates between the empagliflozin and glimepiride groups. Furthermore, EMPA-REG H2H-SU included measures of bone mineral density from femoral neck and lumbar spine DXA scans after 52, 104, 156, and 208 weeks of treatment. The results demonstrated that bone mineral density remained stable throughout the four years of empagliflozin treatment and were comparable between those treated with empagliflozin and those treated with glimepiride. We’re certainly glad that the potential relationship between SGLT-2 inhibitors and bone fracture risk does not appear to be a class effect – where it has been seen to date may have been spurious correlation and we look forward to more data all around. As a reminder, the FDA strengthened the label warning on bone fracture risk with J&J’s Invokana (canagliflozin) last year.

Metabolic Mechanisms of Increased Plasma Ketones with Dapagliflozin

Carolina Solis-Herrera, MD (Texas Tech University Health Sciences Center, San Antonio, TX)

Dr. Carolina Solis-Herrera delivered a fascinating presentation on the molecular mechanisms underlying the action of the SGLT-2 inhibitor dapagliflozin. In a randomized, double-blind, placebo controlled trial, participants were randomized to 10 mg/day dapagliflozin or matching placebo. At baseline and at the culmination of the 14-day treatment period, participants underwent a euglycemic clamp procedure and indirect calorimetry tests. Fourteen days of treatment with dapagliflozin caused: (i) a shift from glucose oxidation to lipid oxidation; and (ii) an increase in the plasma glucagon to insulin ratio, increasing hepatic glucose production, and (iii) an increase in urinary glucose excretion thereby decreasing plasma glucose. Dr. Solis-Herrera contextualized these findings, explaining that a shift from glucose to fat oxidation increases the product of fatty acid oxidation, acetyl CoA, which either can enter the TCA cycle or be converted to ketones, the latter being favored by the SGLT2 inhibitor induced stimulation of glucagon secretion. Moreover, the increased glucagon insulin ratio will downregulate the enzyme Acetyl CoA Carboxylase resulting in a decreased conversion from acetyl CoA to malonyl CoA. Malonyl coA is the downregulator of CTP1 (carnitine palmitoyltransferase), the enzyme that allows acetylCoA to enter the mitochondria and start beta oxidation. When malonyl CoA is low, the activity of CPT1 increases and this will increase beta oxidation and ketogenesis. The downstream consequence of these SGLT-2 inhibitor-mediated changes is increased ketogenesis – a process that, paradoxically, is harmful for precipitating DKA, but potentially beneficial in cardiovascular terms. Ketogenesis seems to increase cardiac efficiency and reduces oxygen consumption and oxidative stress; Dr. Solis-Herrera argued that these effects are potentially the driving force underlying the cardiovascular benefits seen with a different SGLT-2 inhibitor, empagliflozin, in the EMPA-REG OUTCOME trial. This is largely the thrust of Dr. Ele Ferrannini’s “thrifty substrate” hypothesis regarding the mechanism of empagliflozin’s cardioprotective benefit, which was presented at ADA 2016 and published in Diabetes Care. While this hypothesis is clearly very speculative at this point, the replication of this potential mechanism and pathway with dapagliflozin lends tentative support to the notion that the cardioprotection might be a class effect. Dr. Solis-Herrera’s overarching message was the importance of appreciating the complexity of dapagliflozin’s ketogenesis-promoting mechanism; future work with SGLT-2 inhibitors should carefully weigh the costs and benefits of ketogenesis-associated cardioprotection and DKA. 

Questions and Answers:

Q: You said that SGLT-2 inhibitors may improve beta cell function. Is this via the ketogenesis mechanism, or does dapagliflozin have an independent beneficial effect on the beta cell?

A: We do not know if it is a direct effect on the beta cell.

Q: There might be differences in the propensity to develop DKA between the different SGLT-2 inhibitors. Do you think this may have to do with the different effects on lipid and glucose oxidation?

A: We believe our findings regarding lipid and glucose metabolism represent a class effect. Different does with different drugs may produce a more marked effect, but it is nevertheless a something that we expect to see in all SGLT-2 inhibitors.

Q: Do you have any information as to the onset of these metabolic shifts, and whether they continue at the same level? Is there change or accommodation over time to different substrate availability?

A: We have noticed that there is an acute effect immediately upon drug exposure and it persists for the first 48 hours.

Q: We have learned that DKA incidence is low in well-controlled studies. It seems probable that many patients are getting SGLT-2 inhibitors who shouldn’t be.

A: I think we need to learn more about these drugs to assess this. It is hard to say if they will be approved for type 1 diabetes.

Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function

David Sjöström, MD, PhD (AstraZeneca, Göteborg, Sweden)

Dr. David Sjöström (AstraZeneca, Gothenburg, Sweden) presented the results of a meta-analysis examining  whether the effects of dapagliflozin vary in patients with varying eGFR levels, given a 2014 study suggesting that dapagliflozin’s A1c lowering efficacy is attenuated in patients with low eGFR (≥30-59 ml/min/1.73 m2). The pooled analysis, which included 11 phase 3 trials (n=4404), found that treatment with dapagliflozin 10 mg for 24 weeks consistently reduced body weight, systolic blood pressure, pulse pressure, and urine albumin to creatinine ratio (UACR) – regardless of baseline eGFR. According to Dr. Sjöström, the presence of these eGFR-independent effects offers the fascinating suggestion that dapagliflozin’s mechanisms of action is mediated in part by processes independent of urinary excretion of glucose. He hypothesized that one such mechanism may be reduction of sodium reabsorption in the proximal tubule of the nephron, since this process commonly occurs due to dampened action of the NHE3, a protein co-localized with the SGLT-2 protein and thus likely impinged upon by SGLT-2 inhibiting agents like dapagliflozin.

Symposium: Combination Treatment with SGLT-2 Inhibitors/GLP-1 Receptor Agonists

DURATION-8 Study: dapagliflozin and Exenatide QW Combinaton

Cristian Guja, MD (University of Medicine and Pharmacy, National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania)

Dr. Cristian Guja (University of Medicine and Pharmacy, Bucharest, Romania) presented the results of the DURATION-8 trial demonstrating improvement of glycemic control and of some cardiovascular risk factors with dual therapy consisting of AZ’s once-weekly GLP-1 agonist Bydureon (exenatide) and AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) vs. either drug as monotherapy. After 28 weeks, patients (n=695) in all three arms of the study – exenatide and dapagliflozin, exenatide alone, and dapagliflozin alone – experienced impressive reductions in A1c: -2.0% (95% CI: -2.1 to -1.8), –1.6% (-1.8 to -1.4), and -1.4% (-1.6 to -1.2) respectively, from a baseline A1c of 9.3%. Interestingly, Dr. Guja noted that the trial enrolled participants with a baseline A1c of 8%-12% to minimize the risk of potential hypoglycemia if the trial enrolled participants with a lower A1c. The A1c reduction of 1.4% in the standalone dapagliflozin arm is certainly very robust for an SGLT-2 inhibitor, which is undoubtedly at least partly attributable to the high baseline A1c. That said, the exenatide/dapagliflozin dual therapy reduced still produced a significantly greater A1c reduction than either monotherapy: a -0.4% improvement versus exenatide (95% CI: -0.6 to -0.1; p=0.004) and a -0.6% improvement versus dapagliflozin (95% CI: -0.8 to -0.3; p<0.001). Given the potential for additive CV risk reduction stemming from both classes (this still has to be proven, of course), the positives in taking the two compounds together may be even larger. Although no labels have yet been updated in the US concerning cardiovascular or renal risk reduction, we imagine this is a “when” not “if” and the number of trials to happen in combinations in the coming years should provide great learning and excitement for now to improve public health. The full results from the trial were simultaneously published in The Lancet Diabetes and Endocrinology.

• In a conversation with AZ’s VP of Global Medicines Development, Dr. Elisabeth Bjork, we learned more about the additive effects of Bydureon and Farxiga on A1c. Namely, Dr. Bjork articulated how diabetes drugs are mostly baseline-dependent – as one product in this combination improves a patient’s glycemic control, the second will have a marginally smaller impact on A1c, although the essential takeaway is that exenatide and dapagliflozin in combination achieved superior A1c reductions vs. either agent alone. Dr. Bjork also remarked that there is interesting potential for the additive cardioprotective effects of Bydureon and Farxiga, especially since the dominant thought is that SGLT-2 inhibitors and GLP-1 agonists operate through distinct mechanisms of action when it comes to cardioprotection. There’s no CVOT in the works for this combination per se, although EXCEL (for exenatide) and DECLARE (for dapagliflozin) are ongoing and will reveal any impact of these drugs on MACE events and CV mortality. Finally, Dr. Bjork explained that the baseline A1c of 9.3% was an important piece of this study because these are the patients who might benefit most from a combination therapy when uncontrolled on metformin alone.
• Exenatide/dapagliflozin dual therapy demonstrated superiority to either monotherapies for all secondary endpoints. Dual therapy produced significantly greater reductions in fasting plasma glucose (FPG) than exenatide or dapagliflozin monotherapy (-3.61 mmol/l [65 mg/dl] vs. -2 mmol/l [36 mg/dl] and -2.7 mmol/l [49 mg/dl]; p<0.001). The same was true for reductions in postprandial glucose (PPG) (-4.83 mmol/l [87 mg/dl] vs. -3.31 mmol/l [87 mg/dl] and -3.41 mmol/l [61 mg/dl]; p<0.0001) and reductions in systolic blood pressure (-4.2 mmHg vs. -1.3 mmHg and -1.8 mmHg; p<0.007).
• Furthermore, dual therapy with exenatide and dapagliflozin produced greater weight loss (-3.41 kg [~7.5 lbs] vs. -1.54 kg [~3.4 lbs] and -2.19 kg [~4.8]; p<0.001) and a greater proportion of patients with weight loss of 5% or more (33% vs. 14% and 20%; p<0.001). Dr. Guja noted that the weight loss effects of the co-administration appear to be additive. Notably, participants with a baseline A1c between 8% and 9% appeared to experience a greater, more additive weight loss benefit from the co-administration of the two products. In this subgroup, participants treated with both dapagliflozin and exenatide experienced a mean 4.5 kg (~10 lbs) weight reduction, compared to 1.9 kg (~4.2 lbs) in the standalone exenatide group and 2.2 kg (~4.9 lbs) in the standalone dapagliflozin group (p<0.001 for the combination compared to both exenatide and dapagliflozin). In comparison, participants with a baseline A1c³9% treated with both dapagliflozin and exenatide experienced a mean weight loss of 2.6 kg (~5.7 lbs), compared to 1.2 kg (~2.6 lbs) in the standalone exenatide group and 2 kg (~4.4 lbs) in the standalone dapagliflozin group (p<0.01 vs. exenatide, non-significant vs. dapagliflozin). Based on these promising results, we’d be especially eager to see a trial of co-administration of the two products in patients with lower A1cs down to 7.5%.
• Adverse events occurred with approximately equal frequency in each group: exenatide plus dapagliflozin (57%), exenatide alone (54%), and dapagliflozin alone (52%). Respectively, serious adverse events occurred evenly across all groups (4% vs. 3% and 4%), as did adverse events leading to discontinuation (4% vs. 5% and 2%). The most commonly-occurring adverse events were: (i) diarrhea (4% vs. 6% and 3%); (ii) injection-site nodules (8% vs. 6% and 5%); (iii) nausea (5% vs. 7% and 3%); and (iv) urinary tract infections (4% vs. 5% and 6%). No major, minor, or severe hypoglycemia events occurred throughout the trial. There was only one case of diabetic ketoacidosis in the trial that occurred in the standalone exenatide arm. There was one case of pancreatitis in the standalone exenatide arm and one case in the combination treatment group. As expected, the rate of genital mycotic infections in the co-administration and standalone dapagliflozin arms were higher than in the exenatide arm (4%, 6%, and 2%, respectively). Overall, this adverse event profile seems very positive.

Pathophysiological Basis of SGLT-2 Inhibitor/GLP-1 Agonist Combination

Ele Ferrannini, MD (University of Pisa, Italy)

In a discussion immediately preceding the discussion of the DURATION-8 results, the highly renowned Dr. Ele Ferrannini (University of Pisa, Italy) argued that co-administration of GLP-1 agonists and SGLT-2 inhibitors is both rational and likely to work. He emphasized the distinct mechanisms of action of the two drugs (pointing out SGLT-2 inhibitors’ non-insulin-dependent glucose lowering) and the impressive benefits both classes appear to offer in terms of weight loss and potential cardioprotection. Notably, pointing out that it would be impossible for us to empirically evaluate every single possible combination of diabetes drugs with rigorous randomized controlled clinical trials, Dr. Ferrannini advocated for a “rational” approach to determining which drugs should be used together in combination therapy – SGLT-2 inhibitors and GLP-1 agonists certainly seem to fit the bill and there’s already been some very cogent discussion by Professor Philip Home on how it may be possible to profile cohorts of patients by their profile (complications etc).

Symposium: EMPA-REG OUTCOME: One Year Later

Introduction and Context

Bernard Zinman, MD (University of Toronto, Canada)

Dr. Bernard Zinman (University of Toronto, Canada) set the tone for this session, a one-year later update on EMPA-REG OUTCOME, by focusing attention on mechanism. Whenever the field sees a robust clinical finding, he explained, we’re understandably eager to know the underlying biology. Dr. Zinman reviewed data from a univariate mediation analysis of EMPA-REG OUTCOME which attributed 52% of the cardioprotection finding to volume contraction, as reflected by an increase in hematocrit. The analysis attributed 25% to decreased uric acid concentration and only 3% to between-group A1c differences – this last point underscores that the CV benefit of Lilly/BI’s Jardiance (empagliflozin) is independent of glycemic effects. That said, Dr. Zinman mentioned a few caveats: (i) this univariate analysis was post-hoc and should only be considered hypothesis-generating; (ii) variables that weren’t factored into the analysis, such as ketone bodies, might play a mediating role between empagliflozin and reduced CV death; and (iii) a multivariate model of combined mechanisms would be more accurate, though this analysis is also much more complicated. He remarked that a multivariate analysis is underway.

Macrovascular and Heart Failure Outcomes: An Update

David Fitchett, MD (University of Toronto, Canada)

Dr. David Fitchett (University of Toronto, Canada) discussed an interesting post-hoc analysis to EMPA-REG OUTCOME, zooming in on heart failure burden. He also presented these post-hoc results at this year’s European Society of Cardiology Congress in Rome. The recent analysis showed that empagliflozin reduces the risk of a variety of heart failure measures by a substantial margin: (i) the risk of investigator-reported heart failure declined by 30% with empagliflozin  treatment; (ii) the risk of a composite endpoint of hospitalization for heart failure or investigator-reported heart failure also declined by 30%; (iii) the introduction of loop diuretics was delayed by 38%; and (iv) the risk of a composite endpoint of hospitalization for heart failure and introduction of loop diuretics declined by 37%. Dr. Fitchett emphasized that these risk reductions are clinically meaningful. He also underscored that the decrease in CV death with empagliflozin vs. placebo was similar in patients with and without heart failure at baseline or during the trial. For more on this data, see our coverage from ESC 2016.

Microvascular and Renal Outcomes

Christoph Wanner, MD (University of Würzburg, Germany)

Dr. Christoph Wanner (University of Würzburg, Germany) outlined findings on the positive renal effects of empagliflozin treatment regardless of baseline kidney function. He described how patients with healthy kidneys, microalbuminuria, or macroalbuminuria all experience clinically significant changes in urinary albumin creatinine ratio (UACR) over the course of 192 weeks on empagliflozin. Among patients who at baseline showed normoalbuminuria, there was a mean 7% decline in UACR at 12 weeks (p<0.05 vs. placebo) and a mean 21% decline at 192 weeks (p<0.01 vs. placebo). For patients with baseline microalbuminuria, these values were 25% (p<0.001) and 40% (p<0.001), respectively, while patients with baseline macroalbuminuria experienced an average 32% drop (p<0.001) and 38% drop (p<0.05) in UACR at 12 and 192 weeks, respectively. Though UACR is not yet accepted as an outcome parameter, Dr. Wanner emphasized that it is connected to renal outcomes and thus should hold weight in evaluations of empagliflozin’s renal benefits. Continuing on, he shared incidence rate ratios for adverse events, breaking down the study population into baseline eGFR <60 ml/min/1.73m² and >60 ml/min/1.73m². In patients with lower eGFR, signaling a higher risk for kidney complications or disease, the hazard ratios for adverse events, serious adverse events, and severe adverse events all favored empagliflozin vs. placebo. In fact, the only hazard ratios near unity were urinary tract infections (UTI) and complicated UTIs. Genital infections were markedly more common in the empagliflozin group. These trends were similar among patients with higher baseline eGFR. The important takeaway from this additional data, according to Dr. Wanner, is that there were pronounced benefits to empagliflozin among the patients at risk for kidney complications in EMPA-REG OUTCOME. Treatment with the SGLT-2 inhibitor slowed the progression of kidney disease and reduced clinically relevant renal events. Dr. Wanner ended his presentation with a brief explanation of the glomerular hypertension hypothesis for mechanism of renal protection, which he also discussed in relation to empagliflozin at ADA 2016. The expanded renal results presented at EASD were certainly encouraging and reassuring – we would love to see Lilly/BI tackle a dedicated renal outcomes trial for empagliflozin and potentially pursue a diabetic nephropathy indication given the high unmet need in this area. We’d also like to better understand regulatory requirements on this front – previously they have been quite challenging.

Implications for the Management of Patients with Type 2 Diabetes and High CV Risk

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

How important is the explanation of mechanism? Dr. Hertzel Gerstein (McMaster University, Ontario, Canada) suggested that understanding mechanism of cardioprotection for empagliflozin (Lilly/BI’s Jardiance) shouldn’t be a prerequisite for using this knowledge of the drug’s CV benefits in clinical practice. While he acknowledged that we need to support research to find out more about mechanism, he argued that this lingering uncertainty shouldn’t stop us from applying this evidence toward optimal diabetes care for patients with type 2 diabetes and high CV risk. “Empagliflozin reduces some extremely serious health outcomes,” he put simply, and even though “we’re not sure why, that shouldn’t stop us from offering these benefits to patients.” We so appreciated this commentary as we’d love to see improved prognosis for patients, especially those at high risk for CV morbidity and mortality who stand to benefit most from empagliflozin therapy. It seems like such a shame to be sitting on compelling evidence for cardioprotection without harnessing the latest clinical data to provide better patient care. Dr. Gerstein summed it up perfectly: “A stone falls today the same way that it fell 200 years ago, but our theory of gravity has changed dramatically. You don’t need to know how a drug works to benefit from it.”

EASD/ADA Symposium: Changing Paradigms: The Role of SGLT-2 Inhibitors

SGLT-2 Inhibition and Cardiovascular Outcomes

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

Dr. Silvio Inzucchi (Yale University, New Haven, CT) presented cardiovascular results from EMPA-REG OUTCOME at last year’s EASD in Stockholm, Sweden – he returned this year with a focus on mechanism, and started off by admitting “with a great deal of modesty, we had it all wrong.” Dr. Inzucchi explained how the initial thinking on Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) was that the agent would confer CV benefits through an overarching atherosclerotic effect. The early divergence of the Kaplan Meier curves in EMPA-REG OUTCOME suggests otherwise. Results from blood pressure and statins trials demonstrate that an atherosclerotic mechanism shows up as divergence much later, around 12-18 months, which is also what was seen in the LEADER trial for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). Despite lingering questions surrounding mechanism of cardioprotection, Dr. Inzucchi called upon the ADA and EASD to consider powerful CVOT data in drafting the next position statement for the diabetes field. He urged the committee charged with authoring the next ADA-EASD treatment guidelines to look closely at EMPA-REG OUTCOME and other recent CVOTs, including LEADER, SUSTAIN 6 (for GLP-1 agonist semaglutide), and even IRIS (for the TZD pioglitazone, perhaps at low doses), because in his view, these CV benefits should be making their mark and improving real-world diabetes care.

Questions and Answers

Q: Can you pick up on heart failure data from DPP-4 inhibitor CVOTs, SAVOR and EXAMINE? The FDA has listed a warning, but on this side of the Atlantic, our European agency has posted a statement saying that the changes seen in heart failure are too small and should not alter practice. What are your thoughts on this?

A: The effect with alogliptin was not statistically significant. I still don’t completely understand why the FDA compelled that label to change. There’s no reason to believe a DPP-4 inhibitor could increase heart failure hospitalization rates, but the data is the data. Could it be a chance finding? Perhaps. We’re still obligated to follow drug labels in the US.

SGLT-2 Inhibitors and Renal Outcomes

David Cherney, MD (University of Toronto, Canada)

Dr. David Cherney (University of Toronto, Canada) picked up on the topic of SGLT-2 inhibition and continued the conversation on mechanism, but shifted focus from the heart to the kidneys. Post-hoc analysis of a composite renal endpoint in EMPA-REG OUTCOME found an impressive hazard ratio of 0.54 in favor of empagliflozin (Lilly/BI’s Jardiance), representing a 46% risk reduction with the SGLT-2 inhibitor therapy (p<0.001). More specifically, Dr. Cherney mentioned that the drug was associated with fewer cases of acute kidney injury and acute renal failure. What were the mechanisms responsible for improved renal outcomes? The short answer, as Dr. Cherney put it, is “we don’t know yet.” Still, he discussed in great detail what is known about the impact of SGLT-2 inhibitors – including empagliflozin, dapagliflozin (AZ’s Farxiga), and canagliflozin (J&J’s Invokana) – on kidney function, summarizing the leading hypotheses related to hyperfiltration and how agents in this class consistently reduce hyperfiltration, now evidenced through both animal and human data. He pointed out an interesting observation that 80% of patients enrolled in EMPA-REG OUTCOME were on a background of RAAS blockers. RAAS inhibition tends to dilate the kidney’s efferent arteriole, while SGLT-2 inhibition constricts the afferent arteriole. Therefore, one interesting theory for the renal protection seen in the CVOT is an additive effect of empagliflozin plus RAAS blockade, which may have more effectively lowered intraglomerular pressure to provide long-term kidney benefits. Another intriguing explanation is that empagliflozin delayed time to introduction of loop diuretics for participants (hazard ratio 0.62, p<0.001). Dr. Cherney also presented a combined renal-cardio hypothesis for the kidney and heart benefits seen in EMPA-REG OUTCOME. While cardioprotection has been getting more overt attention from the field of late, he suggested that renal preservation with SGLT-2 inhibitor therapy could be the gateway to lowering CV morbidity and mortality. Dr. Cherney outlined four potential pathways for this renal-cardio hypothesis: Lowering intraglomerular hypertension and albuminuria could (i) decrease blood pressure, arterial stiffness, cardiac afterload, and left ventricular remodeling, the last of which is cardioprotective; (ii) reduce renal systemic inflammation which decreases left ventricular remodeling; (iii) preserve sodium/water homeostasis which enhances maintenance of euvolemia, which is cardioprotective; and/or (iv) decrease cardiac preload, myocardial wall tension, and arrhythmogenesis, which is directly cardioprotective.

• Dr. Cherney picked up on Dr. Inzucchi’s call-to-action for guidelines committees as well. “In Canada, we do have exactly what’s suggested – in patients with high CV risk, SGLT-2 inhibitors are now indicated in guidelines as the next therapy of choice.” He endorsed this designation of SGLT-2 inhibitors as second-line therapy.

Insulin Therapy

Oral Presentations: Hypoglycemia: The Low Down

SWITCH 1: Reduced Risk of Hypoglycemia with Insulin Degludec vs. Insulin Glargine U100 in Patients with Type 1 Diabetes

Wendy Lane, MD (Mountain Diabetes and Endocrine Center, Asheville, NC)

Dr. Wendy Lane (Mountain Diabetes and Endocrine Center, Asheville, NC) presented data from the SWITCH 1 trial demonstrating a reduced risk of hypoglycemia with Novo Nordisk’s next-generation basal insulin Tresiba (insulin degludec) compared to Sanofi’s Lantus (insulin glargine) in patients with type 1 diabetes. Much of this data was previously shared in a late-breaking poster at ADA 2016. As previously shared, SWITCH 1 found a 11% reduction in severe or blood-glucose confirmed symptomatic hypoglycemia (p<0.0001), a 36% reduction in severe or blood glucose-confirmed nocturnal symptomatic hypoglycemia (p<0.0001), and a 35% reduction in severe hypoglycemia (p<0.05) in the maintenance period with Tresiba vs. Lantus in patients (n=501) with type 1 diabetes. This oral presentation at EASD 2016 shared impressive new number needed to treat (NNT) figures. In SWITCH 1, one patient with type 1 diabetes would only need to be treated for four months to prevent one incident of symptomatic confirmed hypoglycemia. One patient would need to be treated for one year to prevent a nocturnal symptomatic confirmed hypoglycemia event and 3 patients would need to be treated for one year to prevent a severe hypoglycemia event. This very low number needed to treat certainly makes a strong case for the non-glycemic benefits of next-generation basal insulin Tresiba. Novo Nordisk plans to submit the SWITCH 1 (and 2) data to the FDA by the end of the month – we hope an expanded indication can help make the case to payers on the value of this product. In light of the greater attention to “outcomes beyond A1c” made at the FDA in late summer, we hope that patient engagement with “time in zone” will enable hypoglycemia data to be used on labels.

SWITCH 2: Reduced Risk of Hypoglycemia with Insulin Degludec vs. Insulin Glargine U100 in a Type 2 Diabetes Population on Basal Insulin

Carol Wysham, MD (University of Washington, Spokane, WA)

Dr. Carol Wysham (University of Washington, Spokane, WA) presented the SWITCH 2 trial demonstrating a reduced risk of hypoglycemia with Novo Nordisk’s next-generation basal insulin Tresiba (insulin degludec) compared to Sanofi’s Lantus (insulin glargine) in patients with type 2 diabetes. Like SWITCH 1, much of this data was previously shared in a late-breaking poster at ADA 2016. As previously shared, in patients with type 2 diabetes (n=721) Tresiba treatment produced a 30% reduction in severe or blood-glucose confirmed symptomatic hypoglycemia (p<0.0001) and a 42% reduction in severe or blood glucose-confirmed nocturnal symptomatic hypoglycemia (p<0.0001) in the maintenance period compared to Lantus (rates of severe hypoglycemia were low in both groups and numerically but not significantly lower with Tresiba). Dr. Wysham’s presentation shared new number needed to treat (NNT) figures. In SWITCH 2, one patient would need to be treated for one year to prevent one incident of overall symptomatic confirmed hypoglycemia and three patients would need to be treated for one year to prevent one incident of nocturnal symptomatic confirmed hypoglycemia. While the severe hypoglycemia difference was non-significant in the maintenance period due to low events, analysis of the full treatment period revealed a statistically significant 51% reduction in severe hypoglycemia (p<0.05) for Tresiba, with an associated NNT of 21. Very low numbers needed to treat across both trials certainly make a strong case for the non-glycemic benefits of next-generation basal insulin Tresiba. Novo Nordisk plans to submit the SWITCH 1 and 2 data to the FDA by the end of the month – we hope an expanded indication can help make the case to payers on the value of this product. In light of the greater attention to “outcomes beyond A1c” made at the FDA in late summer, we hope that patient engagement with “time in zone” will enable hypoglycemia data to be used on labels.

• Very notably, Dr. Wysham shared TRIM-H patient-reported outcomes data from SWITCH 2, demonstrating improvements in daily function, diabetes management, emotional well-being, sleep disruption, work productivity, and TRIM-H total score with Tresiba. This seems like a very positive instrument and as the field moves toward greater standardization, we hope this tool is examined closely. Both Tresiba-treated and Lantus-treated patients reported improvements in all of these outcomes in the first phase of the trial, though patients on Tresiba reported greater improvements than those on Lantus. Notably, however, those who switched from Lantus to Tresiba in the second, crossover phase of the study continued to report improvements in every outcome. On the other hand, patients who switched from Tresiba to Lantus in the second phase of the trial reported declines in daily function, diabetes management, emotional well-being, sleep disruption, and TRIM-H total score (and no change in work productivity).

Corporate Symposium: Improving Care: Individualized Treatment Across the Diabetes Spectrum (Sponsored by Novo Nordisk)

Hypoglycemia in Patients with Type 1 Diabetes Treated with Insulin Degludec Compared to Insulin Glargine U100: The Double-Blinded SWITCH 1 Trial

Wendy Lane, MD (Mountain Diabetes and Endocrine Center, Asheville, NC); Simon Heller, MD (University of Sheffield, UK)

A Novo Nordisk-sponsored symposium provided an enthusiastic and comprehensive overview of the company’s next-generation basal insulin profile, highlighting the benefits of Tresiba (insulin degludec) beyond glycemic control, as evidenced by the recent SWITCH 1 trial. In this double-blind trial, first presented in poster form at ADA 2016, 501 patients with type 1 diabetes were randomized to receive once-daily doses of either Novo Nordisk’s Tresiba (insulin degludec) or Sanofi’s Lantus (insulin glargine) for 32 weeks, followed by a crossover to the other drug for another 32 weeks. Tresiba produced impressive reductions in hypoglycemia over Lantus: an 11% reduction in blood glucose-confirmed symptomatic hypoglycemia, a 36% reduction in nocturnal hypoglycemia, and a 35% reduction in severe hypoglycemia. Furthermore, Tresiba achieved this in the context of non-inferiority to Lantus in terms of A1c reduction. Hypoglycemia is one of the principal concerns surrounding insulin therapy, and an unending source of worry for patients, families, and physicians alike. We applaud the arrival of an insulin with reduced hypoglycemia risk, and hope Tresiba sets the stage for an era of insulins with benefits beyond glycemic control.

Corporate Symposium: Overcoming Insulin Treatment Challenges: What We Can Learn from Clinical and Real World Evidences (Sponsored by Lilly)

Insulin Treatment Regimens in Type 2 Diabetes: How Does Real World Evidence Support RCT Findings?

Denis Raccah, MD (Assistance Publique des Hôpitaux de Marseille, France)

Dr. Denis Raccah overviewed literature surrounding insulin intensification strategies in patients with type 2 diabetes. He stressed that basal insulin, when properly titrated, is sufficient to control fasting blood glucose and A1c in ~45% of patients. However, the remaining ~55%, even with well-titrated basal insulin and satisfactory fasting blood glucose, will eventually require therapy intensification. At this point, the patient can be moved straight to full basal-bolus therapy, pre-mixed insulins, basal-plus/mixed plus, or combination therapy with GLP-1 agonists (though this last aspect was beyond the scope of the talk). The immediate transition to basal-bolus or pre-mixed therapies, Dr. Raccah noted, is efficient at lowering A1c to target, but also raises concerns of hypoglycemia and weight gain. He advocated instead for the gradual inclusion of rapid-acting prandial injections to bring A1c into an acceptable range. The basal-plus strategy involves basal therapy supplemented by one rapid-acting injection at the main meal, and more if/when necessary. In both OSIRIS and FullSTEP, two trials comparing basal-plus with full basal-bolus therapy in type 2 patients requiring therapy intensification, there was no different in treatment efficacy (no significant difference in A1c at the end of the trial), but there was less weight gain, fewer hypoglycemia episodes, and higher patient satisfaction with basal-plus. Moreover, the majority of patients did not require three injections of prandial insulin, suggesting that full basal-bolus therapy is an overtreatment, which is costly both financially and in terms of side-effects. Mix-plus (supplementing pre-mixed insulin with prandial doses as needed) has a very similar therapeutic effect to that of basal-plus in clinical trials, with no difference in side-effects

• Data from Dr. Steve Edelman’s (TCOYD, San Diego, CA) AUTONOMY study suggests that patients in RCTs can self-titrate insulin to improve glycemic control and reach target A1c when properly educated and supported. In the study, patients were randomized to self-titrate Humalog (insulin lispro) either once-daily or once every three days. By the end of the 24-week trial period, both groups were quite successful, with between 40%-50% of subjects dropping their A1c from a mean of ~8.3% to below 7%. This goes to show that patients are capable of managing their diabetes when provided with proper support and education.

Expert Perspectives: Learnings and Options to Overcome Insulin Treatment Challenges

Frank Snoek, PhD (VU University Medical Center, Amsterdam, Netherlands); Melanie Davies, MD (University of Leicester, UK); Peter Lin, MD (Canadian Heart Research Center, Ontario, Canada); Seoyoung Kim, MD (Brigham and Women’s Hospital, Boston, MA)

Dr. Seoyoung Kim (Brigham and Women’s Hospital, Boston, MA) chaired this panel discussion on patient psychology and insulin therapy. Dr. Frank Snoek (VU Medical Center, Amsterdam, Netherlands) hit the nail on the head when he pointed out that patients prescribed a new therapy inevitably wonder: (i) do I need this?; and (ii) what’s in it for me? Dr. Snoek noted that it is the job of the patient’s care network to adequately answer these questions (particularly in type 2 diabetes, where symptoms don’t necessarily reflect state of the disease). In exploring the best way to address these two questions, Drs. Snoek, Peter Lin (Canadian Heart Research Center, Ontario, Canada), and Melanie Davies (University of Leicester, UK) adopted three different, but equally valid, perspectives. Dr. Snoek preached embracing the patient perspective – understand their personal risk-benefit calculation and communicate until they’re ready to make the decision to begin insulin therapy. Dr. Lin was a staunch advocate for teaching the patient the biology of insulin therapy and diabetes. In his view, providers can create a perceived need for insulin by telling patients that exogenous insulin is crucial because it supplements the struggling pancreas – “we need to view it as insulin replacement. No one has a problem with thyroid hormone replacement.” Dr. Davies pushed for greater utilization of peer support as well as guidance from educators and loved ones. See the transcript below for more from all three experts.

• Below is an audience-generated word cloud with terms relating to insulin therapy. We thought this was pretty neat! Aside from a few typos (we know as well as you do it’s hard to type on those tiny iPhone keyboards!), the word cloud came out with many of the classic buzzwords: patient, cost, support, weight, lifestyle, etc. Interestingly, “lack” also appeared in large type on the screen, reflecting either the fact that many people who need insulin don’t have access or the high prevalence of clinical inertia.

Questions and Answers

Dr. Kim: Is there anything you would like to start off by saying?

Dr. Snoek: It’s important that we understand that initiating any medication raises two patient questions: (i) Do I need it? and (ii) What’s in it for me? This is not specific to insulin, but insulin is a good example of where we healthcare providers should show interest. Understanding what the patient understands is my mantra for the day. Not only the knowledge, but the concerns and the perceived need as well. Many type 2 diabetes patients are not aware of the need – A1c may be high, but that is abstract. There is a big disconnect between symptoms and the disease state. One of the issues we haven’t talked about is that insulin is not only associated with the perception of more severe illness, but it also has an impact on relationships, job opportunities, etc. We need to start by appreciating the patient’s perspectives before we try to convince them they need to go on insulin. As professionals, we’re happy to see A1c go down because we know the correlation with microvascular complications, but that’s not the same for the patient.

Dr. Lin: After 9 years on the market, 1.5 billion people have an iPhone. The industry has created huge perceived need for the iPhone, which we don’t really need. We haven’t done that in the diabetes industry. Patients can’t tell us why sugar kills. The other thing is that, for A1c, the red blood cell only lasts for ~12o days, so that’s the maximum damage we can assess. The back of the eye doesn’t regenerate, so that tells you a lifetime of damage. And that explains the legacy effect – if you treat people well at the beginning, you’ll see better outcomes. The way we talk about insulin is that it’s like another drug. It’s actually what your body needs. Maybe we should talk about the pancreas not making enough, so we need to give it some help. Maybe we can give you one shot to give it some support. If I take away the basal part and let the pancreas deal with the spikes, that might help. At some point, the pancreas won’t be able to handle the spikes, at which point we’ll give you help there too. We need to explain insulin as helping the pancreas do work, maybe that’ll be a useful way of explaining it to patients.

Dr. Davies: Can I challenge that? Far too many patients come along after having been threatened by insulin. There’s a lot we need to get out there about insulin being your friend.

Dr. Lin: We need to view it as insulin replacement. No one has a problem with thyroid hormone replacement.

Dr. Davies: But it’s the titration issue. We heard from Dr. Denis about “too little too late.” We so often hear, “patients can’t self-manage and they can’t self-titrate” – we underestimate them. If you have someone who’s going to take 50 or 60 units of basal, it’ll take a while to get them up using your paradigm. In titration paradigms, we need to give them an idea of where they’re going to end up or they feel like a failure.

Dr. Lin: It may take two weeks to get them up, but they’ll get there. Previously, when providers were calculating doses, it sounded like magic to patients. Now, we say start low so side effects are low, and work your way up. It takes longer, but they get there.

Q: How could healthcare providers engage with patient to improve adherence?

Dr. Snoek: There is a lot of room for improvement. We too often prescribe assuming the patient understands and accepts. Many times, they leave the room not sure if they will accept. We need to invest more in talk about medication and what it takes for the patient to succeed. Although we all advocate early initiation, pushing it back one week to let the patient think will not make a difference – that may be better. Clinical trial results are so good because they’re proof-of-concept – the difference is the support part that we’re not utilizing. That doesn’t mean 24/7 attention – it’s about being attentive, responsive, allowing patients to ask questions. It’s called shared decision making. It sounds easy, but it’s not easy to get patients involved. I think we need to invest in decision making because that would translate to better adherence. It’s a decision the patient made and is allowed to ask questions. The second part is that we need to be there for the follow-up. In an old study, patients stopped self-monitoring because no one looked at their numbers. Providers should be more a coach than a prescriber.

Dr. Lin: If we’re trying to titrate insulin, we asked patients to keep exercise and diet relatively the same. Once that’s set, we can adjust exercise, and then diet – sequentially like that. We found that this empowers patients. In terms of rotation, we showed them pictures, which is no work. Then we tell them to rotate so they won’t develop lumps, because if you inject into lumps, absorption will be different. I find this empowerment is very useful. It’s knowledge that helps them self-manage, which makes the provider’s life easier.

Dr. Snoek: Overall, initiating insulin actually increases quality of life. Needle and self-injecting is actually doable for people; hypoglycemia doesn’t present such a problem. I would advocate that when prescribing, come with the evidence. Convince them it’s doable. From what I’ve heard, many clinicians try to convince patients, and once they get over the hurdle, the patients are very satisfied. There is evidence to show it’s not that bad. It’s about framing it in a positive way.

Dr. Davies: We all face the hurdles of time and resources. We’ve shown that adherence is better when we have people initiate in groups – they learn from and support each other. Also, the use of educators is encouraged. They are an underutilized resource. They have skills in terms of communicating and bringing groups together. We don’t have a problem with choice of therapies, it’s about translating that efficacy into the clinic. We need to be almost marketing as if we were selling people a vacuum cleaner, and we don’t do that well. And there’s no good in giving threats if you don’t follow up with “this is how it could help you.” Sometimes people do need to know what the consequences of type 2 diabetes are.

Dr. Lin: The purpose of insulin isn’t really to lower sugar, it’s to give your body fuel for energy. Patients stop. I don’t think they’d unplug their generators if they knew what it was actually there for.

Dr. Snoek: Its honest to provide that information early rather than late. The earlier you talk about diabetes as a progressive disease with an eventual loss of beta cell function leading to insulin requirements, the better. I would be in favor of including it from the start rather than later.

Dr. Davies: We talk about insulin as life-saving therapy, and the whole concept of self-management, if we get it right at the beginning. Every patient needs support so they know what their condition is. We can make a big difference if we do a really good job at the point of diagnosis.

Q: What has not been touched on is the involvement of family members, which is extremely important, as we see in the DAWN study. Especially when bringing in rather complicated therapy.

Dr. Davies: And it’s also peer support – patient forums, social media – that really makes a difference. Thanks.

Dr. Lin: That’s very important, but we never think about it. We need to move away from “complex therapy.” I think that’d be helpful as we teach patients and families. Tell them it is manageable.

Dr. Kim: Some audience members alluded to difficulty with time in practice, which is a major hurdle. How do you improve effectiveness of communication in a short time?

Dr. Davies: It’s the way you frame questions. Also group sessions outside of clinic and using educators is a better overall use of the team’s time.

Dr. Lin: In solo practice, it’s getting everyone to understand each concept. That’s how you reduce burden with a short intervention.

Pre-Conference Sessions

The Role of New Insulins in Diabetes Treatment

Nebojsa Lalic, MD (University of Belgrade, Serbia); Asimina Mitrakou, MD (National and Kapodistrian University of Athens, Greece)

In a joint session, Drs. Nebojsa Lalic (University of Belgrade, Serbia) and Asimina Mitrakou (National and Kapodistrian University of Athens, Greece) emphasized the many non-glycemic benefits offered by Tresiba and Sanofi’s fellow next-generation basal insulin Toujeo (U300 insulin glargine). In particular, Dr. Lalic highlighted the improvements in hypoglycemia with both products while Dr. Mitrakou emphasized their benefits on body weight and overall patient quality of life (as measured by patient-reported questionnaires). In the ensuing Q&A discussion, both speakers readily agreed that there was “no doubt” that analog insulins – both “old” and “new” – are vast improvements over human insulin. We certainly appreciated the focus on the substantial benefits of these new insulins beyond A1c reduction and the illustration of the added value of these products, despite their non-inferior status with “old” basal insulin Lantus (insulin glargine) in terms of A1c. Unfortunately, despite this consensus, the discussion also revealed the challenges to insulin access in developing countries: Dr. Lalic shared that, in Serbia, patients must first initiate human insulin and generally only switch to insulin analogs if the patient is experiencing poor outcomes with the human insulin. As an audience member from the UK put it, this sort of strategy could be considered unethical to the extent that patients with good glucose management are in a sense “punished” by denying them access to the latest treatments. We certainly hope that governments and other payers will begin considering patient-centric outcomes beyond A1c in their reimbursement decisions.

Posters

Clinical Perspectives from the BEGIN and EDITION Programmes: Trial-Level Meta-Analyses Outcomes with Either Degludec or Glargine 300 u/ml vs Glargine 100 u/ml in Type 2 Diabetes Mellitus

R Roussel, R Ritzel, S Chevalier, B Balkau, J Rosenstock

This meta-analysis looked at the wealth of data from the BEGIN and EDITION phase 3 clinical trial programs. In sum, the analysis included evidence from 6,123 adults with type 2 diabetes randomized to either insulin degludec (Novo Nordisk’s Tresiba) vs. insulin glargine U100 (Sanofi’s Lantus) or insulin glargine U300 (Sanofi’s Toujeo) vs. insulin glargine U100, in the BEGIN and EDITION programs, respectively.

• In terms of A1c reduction across all BEGIN studies, this poster reported an estimated treatment difference of 0.09% in favor of Lantus (95% CI: 0.01%-0.18%, p=0.024), despite insulin degludec showing enhanced ability to lower fasting plasma glucose (estimated treatment difference of 0.35 mmol/l [6.3 mg/dl] in favor of Tresiba, p<0.001). Average 24-hour self-monitored plasma glucose (SMPG) also saw more significant lowering with insulin glargine vs. insulin degludec in the BEGIN program, with an estimated treatment difference of 0.19 mmol/l (3.4 mg/dl, p=0.032). Risk of symptomatic hypoglycemia was comparable for the two basal insulins throughout the day – the meta-analysis found a relative risk of 1.02 ever-so-slightly in favor of insulin degludec, though this was not statistically significant. However, nocturnal hypoglycemia risk was greater for patients on basal insulin glargine, with a relative risk of 0.87 for nocturnal events in favor of insulin degludec (p=0.007).
• Focusing on the EDITION program specifically, this poster highlighted that A1c, fasting plasma glucose, and average 24-hour SMPG were all lowered by similar margins with Lantus and Toujeo, meaning none of these treatment differences reached statistical significance. Change in pre-breakfast SMPG was significantly better for patients on Lantus vs. Toujeo, with an estimate treatment difference of 0.23 mmol/l (4.1 mg/dl) in favor of Lantus (p<0.001). On the other than, risk of symptomatic hypoglycemia was consistently lower with Toujeo vs. Lantus across EDITION studies both during the day – hazard ratio of 0.81 in favor of Toujeo (p=0.007) – and at night – relative risk of 0.75 again in favor of Toujeo (p=0.007).
• Coinciding with EASD, Sanofi announced topline results from a PK/PD study of Toujeo (U300 insulin glargine) vs. Tresiba (insulin degludec) in people with type 1 diabetes (n=48). The study – which dosed all participants with both insulin glargine and insulin degludec during two separate periods of data collection – found a more even distribution of insulin exposure and activity with Toujeo vs. Tresiba and reported that 67% of participants achieved lower within-day variability of metabolic activity with Toujeo vs. Tresiba. Further comparative data from ongoing head-to-head trials is expected.
• In an interview with our team, Sanofi’s new Head of Diabetes Mr. Stefan Oelrich expressed great optimism for Toujeo. Mr. Olerich presented one potential advantage of Toujeo over Tresiba – because the insulin degludec molecule has a longer arch of action, a remainder of the previous Tresiba injection is often still present when a patient administers his/her next day’s Tresiba injection. He conveyed great interest in how Toujeo’s “cleaner” profile might lead to positive results for Sanofi’s basal insulin in ongoing head-to-head clinical trials. “We feel extremely strong about our product,” Mr. Olerich stated, referring both to trial data and to feedback from HCPs and patients. On the other hand, Tresiba’s long profile of action did win the product a flexible dosing claim on its label, which we’ve heard several diabetes experts praise recently.

Safety and Efficacy of IDegLira Titrated Once Weekly Versus Twice Weekly in Patients with T2D Uncontrolled on Oral Antidiabetic Drugs: DUAL VI Study

SB Harris, G Kocsis, R Prager, T Ridge, K Chandarana, N Halladin, and S Jabbour

In this 32-week, open-label, non-inferiority trial, insulin-naïve patients (n=420) uncontrolled on metformin alone or on metformin/TZD (pioglitazone) therapy were randomized to once- or twice-weekly titration of Novo Nordisk’s IDegLira (insulin degludec/liraglutide, branded Xultophy). Among the 210 patients on once-weekly titration, the average A1c drop was 2.1%, from a baseline of 8.2% to 6.1%. The mean A1c reduction for the twice-weekly titration IDegLira group (n=210) was also 2.1%, from a baseline of 8.1% to 6%, and the estimated treatment difference between the two dosing regimens was 0.12% (p=0.012 for non-inferiority). Similar proportions of each treatment group achieved target A1c: (i) ~90% of both dosing arms reached A1c <7%; (ii) 86% of once-weekly patients experienced A1c <7% with no hypoglycemia vs. 84% of twice-weekly patients; (iii) 84% of once-weekly patients reached A1c <6.5% vs. 85% of twice-weekly patients; and (iv) 79% of both groups experienced A1c <6.5% with no hypoglycemia. Fasting plasma glucose decreased by 4.3 mmol/l (77 mg/dl) with once-weekly IDegLira (from a baseline of 10.1 mmol/l) and by 4.6 mmol/l with twice-weekly IDegLira (from the same baseline of 10.1 mmol/l [182 mg/dl]), marking a 0.2 mmol/l (3.5 mg/dl) estimated treatment difference (p=0.2 for non-inferiority). The once-weekly titration group experienced 1 kg (2.2 lb) weight loss on average, compared to 2 kg (4.4 lb) mean weight loss for the twice-weekly group – a statistically significant treatment difference (p=0.014). While the holistic safety profile was similar for both doses of IDegLira (253 adverse events in the once-weekly arm vs. 307 in the twice-weekly arm, affecting 49% and 51% of patients, respectively), hypoglycemia rates were noticeably higher for patients in whom the dose was titrated twice a week. Severe, symptomatic hypoglycemia occurred in 6% and 16% of the once- and twice-weekly titration groups, respectively, and in 1% and 7% of both groups respectively overnight. Overall, the results support the efficacy and safety of the simpler once-weekly titration strategy, which could help reduce the patient and provider burden associated with IDegLira initiation.

Outcomes Trials

Symposium: SUSTAIN 6

Study Design and Baseline Characteristics

Lawrence Leiter, MD (St. Michael’s Hospital, Toronto, Canada)

Dr. Lawrence Leiter provided an overview of the trial design and baseline population characteristics in the SUSTAIN 6 cardiovascular outcomes trial (CVOT). SUSTAIN 6 was a double-blind, randomized, placebo-controlled, time- and event-driven trial: 3,297 individuals with type 2 diabetes from 230 sites across 20 countries were enrolled so long as they were (i) ≥ 50 years old with evidence of CVD (83% of subjects) or ≥ 60 years old with subclinical evidence of CVD (17% of subjects); (ii) diabetes drug-naïve, or on 0-2 oral diabetes agents with or without basal or premix insulin; and (iii) had an A1c ≥ 7.0%. Clinicians were repeatedly encouraged to treat according to local standard of care guidelines to achieve optimal glycemic control. Participants were randomized in a 1:1:1:1 fashion to 1.0 mg semaglutide, 0.5 mg semaglutide, or volume-matched placebos and were observed for 109 weeks (104-week treatment period followed by a 5-week follow-up period). The trial required at least 122 primary events (cardiovascular death, non-fatal MI, and non-fatal stroke) to achieve appropriate statistical power, though the trial yielded more than double that minimum number of events. Key secondary outcomes included time to first occurrence of an expanded composite CV outcome (CV death, non-fatal MI, non-fatal stroke, revascularization, unstable angina requiring hospitalization, and hospitalization for heart failure). All-cause death and each individual component in the expanded composite CV outcome were pre-specified secondary outcomes as well. The outcomes addressing secondary safety and efficacy objectives included glycemic control, body weight, patient-reported outcomes, microvascular outcomes (retinopathy and nephropathy), and adverse events (including hypoglycemia). Dr. Leiter noted that the study was extremely well-executed, given that 98.0% of patients completed the trial (those in the semaglutide group were slightly more likely to drop out, most commonly due to the documented GI consequences of GLP-1 therapy), and the vital status of 99.6% was known at trial’s end.

• Baseline characteristics were well-balanced between the semaglutide-treated arms and placebo. The study population had a mean age of 65 years, body weight of 92 kg (~202 lbs), 14-year diabetes duration, and 8.7% baseline A1c. Notably, a high proportion of patients had hypertension (~93%) and ischemic heart disease (~61%) at baseline, and many were taking CV medications – ~94% were on anti-hypertensive agents, ~73% on statins, and ~76% on anti-thrombotics. In addition, ~58% of the subjects were on some sort of insulin therapy, and ~84% were taking non-insulin glucose-lowering medications, the most prevalent being metformin (~73%) and sulfonylureas (~43%).

Cardiovascular Outcomes

Steven Marso, MD (UT Southwestern, Dallas, TX)

Cardiologist Dr. Steven Marso presented the headlining cardiovascular outcomes from SUSTAIN 6. Novo Nordisk’s next-generation once-weekly GLP-1 agonist semaglutide demonstrated a 26% (!) risk reduction for the primary endpoint of three-point MACE (CV death, non-fatal MI, and non-fatal stroke), eliciting a loud round of applause and joyful murmuring from the audience. This primary outcome occurred in 7% of semaglutide patients (n=1,648) titrated to a dose of either 0.5 mg or 1.0 mg of the agent vs. 9% of the placebo group (n=1,649) over 104 weeks, producing a hazard ratio of 0.74 (95% CI: 0.58-0.95; p<0.001 for non-inferiority; p=0.02 for superiority). Dr. Marso emphasized that the point estimates for the primary outcomes continued to favor placebo across subgroup analyses for sex, baseline age, baseline BMI, baseline A1c, baseline duration of diabetes, and region, with hazard ratios ranging from 0.58 to 0.84. The p-value for interaction among subgroups within each category was non-significant, suggesting that the results are consistent across all subgroups. Similarly, the point estimates for subgroup analyses of race, ethnicity, baseline heart failure status, history of MI/stroke, cardiovascular disease status, insulin treatment at baseline, and eGFR at baseline (<60 ml/min/1.73m² and <30 ml/min/1.73m²) were all to the left of or right at unity and the p-values for interaction for all were non-significant.

• The 26% risk reduction for the composite primary endpoint is remarkable! For comparison, LEADER showed a 13%  risk reduction for Novo Nordisk’s Victoza (liraglutide) and EMPA-REG OUTCOME showed a 14% risk reduction for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), with both CVOTs relying on the same three-point MACE used in SUSTAIN 6. That said, in a conversation with us, Dr. Philip Home (Newcastle University, UK) suggested that reporting the relative risk reduction as being in the range of 5%-42% would be more accurate, given the large confidence intervals. Within this context, the SUSTAIN 6 results are consistent with the LEADER results. We also can’t overlook the shorter span and smaller number of MACE events incurred during this CVOT. Follow-up on the primary endpoint continued for only two years in SUSTAIN 6, whereas LEADER followed-up for a minimum of 3.5 and a maximum of five years and EMPA-REG OUTCOME followed-up for four years. The direct impact of a shorter CVOT is fewer MACE events – 254, 1,302, and 772 in SUSTAIN 6, LEADER, and EMPA-REG OUTCOME, respectively. As a result, it wouldn’t be possible to say that the results would definitely support a cardioprotective indication, given the complexities of the regulatory system - indeed, Novo Nordisk has already shared that it intends to conduct a larger CVOT powered for superiority for semaglutide. Despite the differences in trial size, Dr. Marso emphasized to us that SUSTAIN 6 has more in common with LEADER than not in terms of the patient population enrolled, the endpoints, etc.
• Individual components of primary outcome: Among the components of the primary outcome, semaglutide significantly reduced the risk of non-fatal stroke by 39% (HR=0.61; 95% CI: 0.38-0.99; p=0.04). Non-fatal MI also trended toward reduction, though the result was not significant (HR=0.74; 95% CI: 0.51-1.08; p=0.12). Notably, the Kaplan-Meier curves for cardiovascular death in the semaglutide and placebo arms were virtually superimposable (HR=0.98; 95% CI: 0.65-1.48; p=0.92). For comparison, the LEADER trial for Novo Nordisk’s other GLP-1 agonist, Victoza (liraglutide), found a highly significant 22% reduction in cardiovascular death with liraglutide (HR = 0.78; 95% CI: 0.66-0.93; p=0.007). We expect the lack of clear cardiovascular mortality benefit might be due to the small size and short duration of the trial, contributing to a very low event number (44 adjudicated CV deaths and 46 adjudicated CV deaths).
• Key secondary endpoints: Semaglutide demonstrated a significant 26% risk reduction for the expanded composite outcome (cardiovascular death, non-fatal MI, non-fatal stroke, revascularization, and hospitalization for unstable angina or heart failure) (HR=0.74; 95% CI: 0.62-0.89; p=0.002). The composite endpoint of non-fatal MI, non-fatal stroke, and all-cause mortality (replacing cardiovascular mortality) was reduced by 23% (HR=0.77; 95% CI: 0.61-0.97; p=0.03). Like the cardiovascular mortality results, the Kaplan-Meier curves for all-cause mortality were largely superimposable with 62 deaths in the semaglutide group and 60 deaths in the placebo group (HR=1.05; 95% CI: 0.74-1.50; p=0.79).
• Revascularization: Revascularization, including both coronary and peripheral revascularization, was also significantly reduced by 35% with semaglutide treatment (HR=0.65; 95% CI: 0.50-0.86; p=0.003). This event occurred in 83 participants in the semaglutide group and 126 participants in the placebo group, driving event rates of 5% and 8%, respectively. All other individual components were not significantly different from placebo.
• Hospitalization for unstable angina and for heart failure: Neither hospitalization for unstable angina nor for heart failure with semaglutide treatment achieved a significant difference from placebo. The hazard ratio point estimate for unstable angina requiring hospitalization was 0.82 (95% CI: 0.47-1.44; p=0.49), with 22 events in the semaglutide arm and 27 events in the placebo arm. The hazard ratio for hospitalization for heart failure slightly favored placebo, but the wide confidence intervals suggest no significant relationship between semaglutide treatment and increased risk of hospitalization for heart failure (HR=1.11; 95% CI: 0.77-1.61; p=0.57).
• As expected, semaglutide treatment produced modest increases in heart rate and decreases in systolic blood pressure. Pulse increased 2.1 beats/min and 2.4 beats/min in the 0.5 mg and 1.0 mg dose groups, respectively. Systolic blood pressure decreased 1.27 mmHg with semaglutide 0.5 mg and 2.59 mmHg with semaglutide 1.0 mg.

Clinical and Metabolic Outcomes

Tina Vilsbøll, MD (University of Copenhagen, Copenhagen, Denmark)

Dr. Tina Vilsbøll presented the key clinical and metabolic outcomes from the SUSTAIN 6 trial, overviewing semaglutide’s efficacy outcomes (in terms of A1c and weight reductions) and microvascular outcomes (encompassing renal and opthalamic complications). At the pre-specified time point of two years post-randomization, mean A1c in the semaglutide vs. placebo groups was 0.66% lower for the 0.5 mg dose and 1.05% lower for the 1.0 mg dose, both of which were statistically significant (baseline A1c=8.7%; p<0.0001). Similarly, mean body weight (baseline = 92 kg) in the semaglutide vs. placebo groups was 2.87 kg (~6.3 lbs) lower for the 0.5 mg dose and 4.35 kg (~10 lbs) lower for the 1.0 mg dose (baseline=92 kg [~203 lbs); p<0.0001 for both). The microvascular outcome measures collected were a double-edged sword, showing an encouraging decreased risk of nephropathy (HR= 0.64; 95% CI: 0.46-0.88; p=0.005) and a concerning increase in the risk for retinopathy (HR=1.76; 95% CI: 1.11-2.78; p=0.02).

• Retinopathy complications appeared at a rate of 3% in the semaglutide group (50 events) vs. 1.8% in the placebo group (29 events), a 1.2% absolute risk increase and a 76% relative risk increase. Of course, these are very small event numbers but the increased risk of retinopathy complications (which were defined in this study as vitreous hemorrhage, onset of diabetes-related blindness, or need for treatment with an intravitreal agent or retinal photocoagulation) will surely be worrisome for some, including potentially regulatory agencies. That said, Dr. Visbøll emphasized that all of the patients that experienced worsening retinopathy had pre-existing retinopathy at baseline. Among the five semaglutide-treated patients with onset of diabetes-related blindness during the trial, all had proliferative retinopathy at baseline according to Dr. Visbøll. There is nothing possible to say at this stage – there are equal chances this is “spurious correlation” or chance – or that this is a negative finding – and a trial will need to be done to ascertain this (perhaps a two-year trial – hard to say at this stage). 50 vs. 29 events are simply too small numbers to confidently assess, especially given the multiple endpoints at play in this trial. A larger trial would certainly be able elucidate this potential connection. It is concerning that in the LEADER trial, treatment with liraglutide also hinted at a trend toward increased retinopathy (HR=1.15; 95% CI: 0.87-1.52; p=0.33), although those results were non-significant.
  
  • Certainly these findings are disturbing on the face of it, but they do not come completely unexpectedly. Dr. Visbøll mentioned that rapid glucose lowering is associated with worsening of retinopathy, as reported in the DCCT/EDIC study – although the applicability of this finding to the SUSTAIN 6 results is not yet clear, it’s important to think about this particularly related to the very small numbers shown. In a conversation with us, Dr. Philip Home (Newcastle University, Newcastle, UK) echoed this sentiment, also noting a similar finding in the Kroc study in the 1980s. He explained that the mechanism is believed to be reduction of blood flow in a damaged vasculature previously protected by the high blood flow (through vascular dilatation) of hyperglycemia, which is consistent with the large improvement in A1c also seen after intensive glucose lowering. It will be great to hear opinions on various approaches, keeping in mind what will keep things easy for patients and HCPs – we would not want to see complicated regimens that would threaten adherence. We wondered if possibly a slower dose titration or if more gradual treatment intensification (perhaps to a DPP-4 inhibitor or an SGLT-2 inhibitor, or even a less potent GLP-1 agonist before initiating semaglutide) could help ameliorate some of this risk among patients with pre-existing retinopathy but this is pure speculation and we will look forward to amassing expert views.
• Renal complications appeared at a rate of 3.6% in the semaglutide group (59 events) vs. 6.0% in the placebo group (99 events), an impressive 36% risk reduction. The renal benefit was driven primarily by a difference in the diagnosis of persistent macroalbuminuria, which occurred at a rate of 2.5% in the semaglutide group, versus 4.9% with placebo. This parallels the nature of the renal benefits reported in the LEADER trial (HR=0.88; 95% CI: 0.67-0.92, p=0.003), which were also driven by reductions in macroalbuminuria. Renal complications (which were defined in this study as new onset of persistent macroalbuminuria, persistent doubling of serum creatinine, need for continuous renal replacement therapy, or death due to renal disease) are among the costliest of diabetes complications, so it is very encouraging to see evidence of renal protective effects in a second member of the GLP-1 agonist class. As of now it remains unclear whether these renal benefits are due to improvements in glucose control and blood pressure or are instead the product of a direct effect of semaglutide on the kidney. We will be awaiting further dissection of these renal findings, and perhaps even a dedicated chronic kidney disease trial for semaglutide (which has been suggested for liraglutide). If Novo Nordisk does undertake a dedicated chronic kidney disease trial, we expect it would be for semaglutide as management has stated that it will focus more of its resources on semaglutide, which it views as the more efficacious and potent GLP-1 agonist molecule – it’s also, presumably, easier to prescribe for HCPs and use for patients. We’re curious if it would be possible to conduct a single combined outcomes trial that both rigorously assesses the cardiovascular benefit (as Novo Nordisk is already planning on initiating) and the potential renal benefit. Of course, this trial would be massive and likely very costly, though we expect less costly than conducting two separate outcomes trials. Compared to the overall costs of kidney disease, it is very very low.
  
  • Dr. Home noted that these nephropathy findings are encouraging, but do not directly address renal function. This would require assessment of eGFR, which we hope will appear in later analyses of the SUSTAIN 6 data.
• Semaglutide demonstrated significant improvements in a variety of additional efficacy outcomes related to A1c and weight reduction, which were sustained over the 2 year treatment period. Semaglutide was efficacious in reaching A1c goals: 39% and 49% of participants in the semaglutide 0.5 mg and 1.0 mg arms respectively achieved an A1c <7% vs. 16% and 15% with equivalent doses of placebo (p<0.0001 for both); 23% and 34% of participants on semaglutide 0.5 mg and 1.0 mg respectively achieved an A1c <6.5% vs. 7% and 8% with equivalent doses of placebo (p<0.0001 for both). Furthermore, after 104 weeks, a higher proportion of semaglutide-treated patients were able to achieve 5% and 10% weight loss. 36% (versus 18%) of patients in the low dose arms and 47% (versus 19%) of patients in the high dose arms achieved 5% weight loss. 13% (versus 6%) of patients in the low dose arms and 20% (versus 7%) of patients the high dose arms achieved 10% weight loss. Dr. Vilsbøll highlighted this latter finding as particularly notable; indeed, it is quite impressive that 1.0 mg semaglutide produces such substantial weight loss in as many as 1 in 5 patients.
• Additionally, semaglutide demonstrated significant improvements on a range of patient-reported outcomes (PROs), as assessed by the SF-36v2 survey. Encouragingly, the 1.0 mg semaglutide demonstrated statistically significant improvements on ALL (!) patient-reported outcomes assessed, including physical functioning, bodily pain, general health, vitality, social functioning, and mental health (The 0.5 mg semaglutide dose produced positive trends in these PROs, but only general health reached statistical significance). We applaud the trial designers for including PROs in this analysis. To our knowledge (and we need to check this!) this is the first time such outcomes have been assessed in a CVOT, and we hope this more holistic and patient-centered approach becomes the standard going forward.
• Patients in the semaglutide and placebo groups alike experienced similar low rates of hypoglycemia.  Severe or blood-glucose confirmed hypoglycemia occurred at a rate of 23.1% (191 events) and 21.7% (178 events) in the 0.5 mg and 1.0 mg semaglutide groups, respectively, and 21.5% (177 events) and 21.0% (173 events) in the corresponding placebo groups. Severe hypoglycemia occurred at a rate of 1.7% (14 events) and 1.3% (11 events) in the 0.5 mg and 1.0 mg semaglutide groups, respectively, and 1.5% (12 events) and 2.1% (17 events) in the corresponding placebo groups.

Safety Outcomes

Stephen Bain, MD (Swansea University, UK)

Dr. Stephen Bain stepped up next to discuss additional safety outcomes of interest. Treatment discontinuation due to an adverse event was higher among semaglutide patients (214 cases amounting to 12% of the 0.5 mg group and 15% of the 1.0 mg group) vs. placebo (110 cases amounting to 6% of the 0.5 mg group and 8% of the 1.0 mg group), although the total numbers of adverse events and serious adverse events were greater for placebo vs. semaglutide. Adverse events occurred in 90% of patients on 0.5 mg semaglutide vs. 91% of their placebo counterparts, and in 89% of patients on 1.0 mg semaglutide vs. 89% of their placebo counterparts. Serious adverse events (including death, life-threatening episodes, and hospitalizations) occurred in 35% of patients on 0.5 mg semaglutide vs. 40% of their placebo counterparts, and in 34% of patients on 1.0 mg semaglutide vs. 36% of their placebo counterparts. Researchers focused on many adverse events in SUSTAIN 6 that have been raised as points of consideration for GLP-1 agonists and other incretin-based therapies, such as GI side-effects, pancreatitis, and neoplasms, particularly in the pancreas.

• Nausea was the no. 1 factor leading to discontinuation of treatment, accounting for nearly 5% of premature cessation in the 1.0 mg semaglutide arm. There were 233 nausea events reported in the 0.5 mg semaglutide group (75% mild, 21% moderate, 5% severe) vs. 79 in the 0.5 mg placebo group (72% mild, 27% moderate, 1% severe), and 285 nausea events in the 1.0 mg semaglutide group (66% mild, 28% moderate, 5% severe) vs. 95 in the 1.0 mg placebo group (82% mild, 18% moderate, 0% severe).
• Diarrhea occurred 279 times in the 0.5 semaglutide group vs. 161 times in placebo, and 251 times in the 1.0 mg semaglutide group vs. 113 times in placebo. As was the case for nausea, a majority of these events were mild.
• There were 128 vomiting events among patients on 0.5 mg semaglutide vs. 53 in the corresponding placebo group; there were 173 vomiting events among patients on 1.0 mg semaglutide vs. 43 in the corresponding placebo group. Once again, as was seen in the data on nausea and diarrhea, a majority of these cases were mild.
• Acute pancreatitis occurred in 0.7% of patients on 0.5 mg semaglutide vs. 0.4% of their placebo counterparts, and in 0.4% of patients on 1.0 mg semaglutide vs. 1.1% of their placebo counterparts. In total, there were nine semaglutide-treated patients and 12 placebo patients who experienced acute pancreatitis. There were no instances of severe pancreatitis observed during the trial.
• Adverse events related to the gallbladder were reported in 4%, 3%, 5%, and 3% of the 0.5 mg semaglutide, 1.0 mg semaglutide, 0.5 mg placebo, and 1.0 mg placebo arms, respectively. Gallbladder adverse events included cholelithiasis and cholecystitis acute.
• The frequency of malignant neoplasms was similar across treatment arms, and the hazard ratio for pancreatic cancer was 0.25 in favor of semaglutide (though this ratio was not statistically significant). In total, pancreatic cancer affected one individual in the semaglutide group and four individuals in the placebo group during the study period. The hazard ratio for total neoplasms, encompassing those that were benign, was 1.12 in favor of placebo; however, this value was once again not statistically significant.

Discussant

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

Dr. Lars Rydén endeavored to contextualize the SUSTAIN 6 results, providing a historical perspective on the path to modern CVOTs and a comparison to other neutral and positive CVOTs for diabetes drugs that have reported in the last few years. Dr. Rydén congratulated the trial lead investigators for a “carefully planned, well performed, objectively reported” trial and underscored that he would not be nitpicking the details of the trial design or interpretation. Instead, he emphasized that both the 26% relative risk reduction and the 2.3% absolute risk (from 8.9% to 6.6%) in the primary endpoint with semaglutide treatment is substantial and clinically meaningful. He pointed out that cardiologists are often pleased if new platelet therapies are able to demonstrate a much smaller absolute risk reduction.

• Regarding the mechanism of action, Dr. Rydén emphasized that the results appear to be driven by a positive impact of semaglutide on non-fatal stroke and non-fatal MI. Considered along with the benefit on risk reduction for revascularization and the slow onset of benefit, Dr. Rydén suggested that semaglutide’s cardioprotective effect could be mediated through a delay in progression or even regression of atherosclerosis. Dr. Rydén also suggested that duration of action may account for the heterogeneity seen in the large 26% risk reduction observed in SUSTAIN 6 compared to the smaller – but still positive – 13% risk reduction of liraglutide in LEADER and to the neutral ELIXA results for lixisenatide (Sanofi’s Lyxumia/Adlyxin). Lixisenatide is a short-acting GLP-1 agonist, while liraglutide is a longer-acting GLP-1 agonist and semaglutide (as a once-weekly injection) is longer-acting still. He hypothesized that the bioavailability of the GLP-1 agonist must last at least through an entire day to demonstrate a cardioprotective benefit.
• In a comparison to the LEADER and EMPA-REG OUTCOME trials, Dr. Rydén highlighted that both the relative and absolute risk reduction was greater in SUSTAIN 6. Semaglutide’s relative risk reduction of 26% and absolute risk reduction of 2.3% compares to liraglutide’s relative risk reduction of 13% and absolute risk reduction of 1.9% and empagliflozin’s relative risk reduction of 14% and absolute risk reduction of 1.6%. Dr. Rydén also pointed out that the A1c reduction in SUSTAIN 6 was greater than in the LEADER and EMPA-REG OUTCOME trials: a placebo-adjusted difference of 0.8%, compared to 0.4% and 0.2%. As expected for a pre-approval safety trial, the follow-up duration in SUSTAIN 6 was shorter at 2.1 years compared to 3.8 years for LEADER and 3.1 years for EMPA-REG OUTCOME.
• Regarding the retinopathy data, Dr. Rydén largely deferred to future clinical or registry-based trials. He pointed out that the LEADER trial had also observed a 15% increase in retinopathy, though it was not statistically significant, but ultimately suggested that time will tell how much of a concern this finding is. We were a little disappointed that Dr. Rydén did not dig into the retinopathy outcomes more – though of course he was already fitting a lot into the mere 10 minutes he was allotted already! – and we expect we’ll hear much discussion of this finding in the coming months.
• Dr. Rydén concluded with three main areas of impact for the SUSTAIN 6 results in his view: (i) raising interest in mechanistic studies delineating mechanisms and refining treatment; (ii) catalyzing the initiation of new clinical trials investigating the combination of a GLP-1 agonist and an SGLT-2 inhibitor; and (iii) creating an immediate therapeutic option for a sizeable and vulnerable patient population.

Close Concerns Questions

Q: Is the remarkable 26% risk reduction for three-point MACE a product of smaller sample size of events? How much of this risk reduction should be attributed to the smaller number of MACE events?

Q: Will empirical support for semaglutide’s CV benefits make an even stronger case for the CV benefits of Victoza (liraglutide)? Will this influence the FDA’s decision to revise the Victoza label?

Q: What is the prospective timeline for a larger CVOT of semaglutide that includes a higher number of MACE events on par with LEADER or EMPA-REG OUTCOME?

Q: Does the physiological action of semaglutide directly increase retinopathy risk?

Q: How will follow-up research unpack the association between semaglutide and eye complications?

Q: Do the significant weight loss results foreshadow semaglutide’s potential as an obesity drug, paralleling Saxenda (high dose liraglutide)?

Q: Does SUSTAIN 6, in conjunction with LEADER, offer support for a cardioprotective class effect of GLP-1 agonists?

Q: Is there an aspect of the once-weekly formulation (perhaps improved adherence) that causes more powerful CV effects vs. the once-daily formulation?

Q: Given the more dramatic 24% risk reduction on three-point MACE vs. Victoza’s 13% risk reduction, does semaglutide have more potential as a cardioprotective agent in a lower-risk patient population vs. liraglutide?

Symposium: EMPA-REG OUTCOME: One Year Later

Introduction and Context

Bernard Zinman, MD (University of Toronto, Canada)

Dr. Bernard Zinman (University of Toronto, Canada) set the tone for this session, a one-year later update on EMPA-REG OUTCOME, by focusing attention on mechanism. Whenever the field sees a robust clinical finding, he explained, we’re understandably eager to know the underlying biology. Dr. Zinman reviewed data from a univariate mediation analysis of EMPA-REG OUTCOME which attributed 52% of the cardioprotection finding to volume contraction, as reflected by an increase in hematocrit. The analysis attributed 25% to decreased uric acid concentration and only 3% to between-group A1c differences – this last point underscores that the CV benefit of Lilly/BI’s Jardiance (empagliflozin) is independent of glycemic effects. That said, Dr. Zinman mentioned a few caveats: (i) this univariate analysis was post-hoc and should only be considered hypothesis-generating; (ii) variables that weren’t factored into the analysis, such as ketone bodies, might play a mediating role between empagliflozin and reduced CV death; and (iii) a multivariate model of combined mechanisms would be more accurate, though this analysis is also much more complicated. He remarked that a multivariate analysis is underway.

Macrovascular and Heart Failure Outcomes: An Update

David Fitchett, MD (University of Toronto, Canada)

Dr. David Fitchett (University of Toronto, Canada) discussed an interesting post-hoc analysis to EMPA-REG OUTCOME, zooming in on heart failure burden. He also presented these post-hoc results at this year’s European Society of Cardiology Congress in Rome. The recent analysis showed that empagliflozin reduces the risk of a variety of heart failure measures by a substantial margin: (i) the risk of investigator-reported heart failure declined by 30% with empagliflozin  treatment; (ii) the risk of a composite endpoint of hospitalization for heart failure or investigator-reported heart failure also declined by 30%; (iii) the introduction of loop diuretics was delayed by 38%; and (iv) the risk of a composite endpoint of hospitalization for heart failure and introduction of loop diuretics declined by 37%. Dr. Fitchett emphasized that these risk reductions are clinically meaningful. He also underscored that the decrease in CV death with empagliflozin vs. placebo was similar in patients with and without heart failure at baseline or during the trial. For more on this data, see our coverage from ESC 2016.

Microvascular and Renal Outcomes

Christoph Wanner, MD (University of Würzburg, Germany)

Dr. Christoph Wanner (University of Würzburg, Germany) outlined findings on the positive renal effects of empagliflozin treatment regardless of baseline kidney function. He described how patients with healthy kidneys, microalbuminuria, or macroalbuminuria all experience clinically significant changes in urinary albumin creatinine ratio (UACR) over the course of 192 weeks on empagliflozin. Among patients who at baseline showed normoalbuminuria, there was a mean 7% decline in UACR at 12 weeks (p<0.05 vs. placebo) and a mean 21% decline at 192 weeks (p<0.01 vs. placebo). For patients with baseline microalbuminuria, these values were 25% (p<0.001) and 40% (p<0.001), respectively, while patients with baseline macroalbuminuria experienced an average 32% drop (p<0.001) and 38% drop (p<0.05) in UACR at 12 and 192 weeks, respectively. Though UACR is not yet accepted as an outcome parameter, Dr. Wanner emphasized that it is connected to renal outcomes and thus should hold weight in evaluations of empagliflozin’s renal benefits. Continuing on, he shared incidence rate ratios for adverse events, breaking down the study population into baseline eGFR <60 ml/min/1.73m² and >60 ml/min/1.73m². In patients with lower eGFR, signaling a higher risk for kidney complications or disease, the hazard ratios for adverse events, serious adverse events, and severe adverse events all favored empagliflozin vs. placebo. In fact, the only hazard ratios near unity were urinary tract infections (UTI) and complicated UTIs. Genital infections were markedly more common in the empagliflozin group. These trends were similar among patients with higher baseline eGFR. The important takeaway from this additional data, according to Dr. Wanner, is that there were pronounced benefits to empagliflozin among the patients at risk for kidney complications in EMPA-REG OUTCOME. Treatment with the SGLT-2 inhibitor slowed the progression of kidney disease and reduced clinically relevant renal events. Dr. Wanner ended his presentation with a brief explanation of the glomerular hypertension hypothesis for mechanism of renal protection, which he also discussed in relation to empagliflozin at ADA 2016. The expanded renal results presented at EASD were certainly encouraging and reassuring – we would love to see Lilly/BI tackle a dedicated renal outcomes trial for empagliflozin and potentially pursue a diabetic nephropathy indication given the high unmet need in this area. We’d also like to better understand regulatory requirements on this front – previously they have been quite challenging.

Implications for the Management of Patients with Type 2 Diabetes and High CV Risk

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

How important is the explanation of mechanism? Dr. Hertzel Gerstein (McMaster University, Ontario, Canada) suggested that understanding mechanism of cardioprotection for empagliflozin (Lilly/BI’s Jardiance) shouldn’t be a prerequisite for using this knowledge of the drug’s CV benefits in clinical practice. While he acknowledged that we need to support research to find out more about mechanism, he argued that this lingering uncertainty shouldn’t stop us from applying this evidence toward optimal diabetes care for patients with type 2 diabetes and high CV risk. “Empagliflozin reduces some extremely serious health outcomes,” he put simply, and even though “we’re not sure why, that shouldn’t stop us from offering these benefits to patients.” We so appreciated this commentary as we’d love to see improved prognosis for patients, especially those at high risk for CV morbidity and mortality who stand to benefit most from empagliflozin therapy. It seems like such a shame to be sitting on compelling evidence for cardioprotection without harnessing the latest clinical data to provide better patient care. Dr. Gerstein summed it up perfectly: “A stone falls today the same way that it fell 200 years ago, but our theory of gravity has changed dramatically. You don’t need to know how a drug works to benefit from it.”

Symposium: Liraglutide Effect and Action in Diabetes

Evaluation of Cardiovascular Outcome Results – A Long-Term Evaluation (LEADER)

Rury Holman, MD (University of Oxford, UK); John Buse, MD (University of North Carolina, Chapel Hill, NC); Steven Marso, MD (UT Southwestern, Dallas, TX); Michael Nauck, MD (Diabeteszentrum Bad Lauterberg, Germany); Johannes Mann, MD (Friedrich Alexander University of Erlagen, Germany)

In a symposium largely recapping LEADER cardiovascular outcomes trial data for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide), we saw several new sub-analyses of the cardiovascular, renal, and pancreatic data. The double-blind, randomized, placebo-controlled, time- and event-driven LEADER trial (n=9,340) results were originally presented ADA 2016, demonstrating a 13% relative risk reduction for the primary outcome of three-point MACE (cardiovascular death, non-fatal MI, and non-fatal stroke) and a 16% improvement in microvascular outcomes (driven entirely by a 22% improvement in renal outcomes), among a barrage of other secondary endpoints. See our detailed coverage of the ADA 2016 LEADER results presentation for more.

• Dr. Johannes Mann (Friedrich Alexander University of Erlagen, Germany) presented an expanded analysis of the microvascular outcomes from the LEADER trial.  The microvascular benefit – or, perhaps more accurately, the renal benefit – was driven primarily by a 26% reduction in the onset of persistent macroalbuminuria with liraglutide (HR=0.74, 95% CI: 0.60-0.91) and a 19% reduction in urinary albumin-creatinine ratio, a measure of microalbuminuria (HR=0.31, 95% CI: 0.76-0.86). Dr. Mann also revealed two new findings from the ongoing subgroup analysis of the LEADER trial’s renal data: (1) Among participants with kidney disease (eGFR <60 ml/min/1.73 m2) there was a 22% reduction in time to first renal event (HR: 0.78; 95% CI: 0.56-1.09); (2) Among participants with severe kidney disease (30-60 ml/min/1.73 m2) or end-stage renal disease there was a 27% reduction in time to next additional composite renal outcome (HR: 0.73; 95% CI: 0.50-1.07). The trial investigators had previously shared that the hazard ratio point estimate for participants was 0.94 (95% CI: 0.83-1.07). The full subgroup analysis is expected in two months at the upcoming American Society of Nephrology meeting, but these two findings provide the intriguing suggestion that liraglutide’s renal benefits may be particularly applicable to patients already experiencing renal disease.  The implications of this strong renal benefit are substantial, and may even prompt consideration of a dedicated chronic kidney disease trial for liraglutide. We are curious whether this effect of liraglutide is a consequence of improvements in renal risk factors like glucose and blood pressure, or whether it is a direct effect (GLP-1 is known to mediate the muscles around renal glomeruli, the functional filtering units of the kidney). These results should surely result in much more robust discussion on this front.
• Highly regarded cardiovascular expert Dr. Steven Marso shared additional analyses of the heart failure data from LEADER. The combined endpoint of hospitalization for heart failure and all-cause death was reduced by 13% in the overall trial (95% CI: 0.77-0.97). Recognizing that heart failure is of particular interest to many given the conditions significant in EMPA-REG OUTCOME and DPP-4 inhibitor CVOTs thus far, Dr. Marso also shared two subgroup analyses examining cardiovascular outcomes in patients with and without heart failure at baseline. The hazard ratio for the primary three-point MACE endpoint among patients without heart failure at baseline was 0.85 (95% CI: 0.76-0.96) while the hazard ratio among patients with heart failure at baseline was 0.94 (95% CI: 0.72-1.21). While the risk reduction was not significant among patients with heart failure, the point estimate trended in the right direction and the p-value for interaction between the two subgroups was non-significant at 0.53. Among participants without heart failure at baseline, the hazard ratio for hospitalization for heart failure throughout the trial was 0.82 (95% CI: 0.65-1.04). Among participants with heart failure at baseline, the hazard ratio was 0.95 (95% CI: 0.71-1.28) – like the MACE results, the point estimate here trended in the right direction and the p-value for interaction between the two groups was non-significant at 0.45.
• A more detailed sub-analysis of the LEADER trial presented by Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Germany) supported the initial finding that liraglutide does not increase the incidence of pancreatitis, though a wide confidence interval prevents us from ruling out the possibility entirely. Nineteen events of acute pancreatitis occurred in 18 patients on liraglutide, compared to 33 events in 25 patients on placebo. Dr. Nauck shared a graph depicting time to acute pancreatitis in the Victoza-treated vs. placebo groups and reported a hazard ratio of 0.78 over in favor of liraglutide. However, due to the confidence interval for the hazard ratio ranging from 0.42-1.44, Dr. Nauck stated that “we cannot rule out the possibility that liraglutide could have a minute enhancement of risk for pancreatitis.” Based on this sub-analysis, the worst case scenario would be a 44% greater risk of acute pancreatitis associated with liraglutide (or a best case scenario of a 58% risk reduction in pancreatitis). There were very low rates of neoplasms in LEADER, Dr. Nauck continued, which poses a challenge in precise determination of pancreatic cancer risk. The rate of pancreatic cancer was 0.3% in the liraglutide group and 0.1% in the placebo group, representing a hazard ratio of 2.59, though Dr. Nauck reiterated the high amount of uncertainty linked to this value. Overall, the results are reassuring and further support the general consensus that the benefits of GLP-1 agonist treatment outweigh the small possible risks of pancreatitis.

EASD/ADA Symposium: Changing Paradigms: The Role of SGLT-2 Inhibitors

SGLT-2 Inhibition and Cardiovascular Outcomes

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

Dr. Silvio Inzucchi (Yale University, New Haven, CT) presented cardiovascular results from EMPA-REG OUTCOME at last year’s EASD in Stockholm, Sweden – he returned this year with a focus on mechanism, and started off by admitting “with a great deal of modesty, we had it all wrong.” Dr. Inzucchi explained how the initial thinking on Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) was that the agent would confer CV benefits through an overarching atherosclerotic effect. The early divergence of the Kaplan Meier curves in EMPA-REG OUTCOME suggests otherwise. Results from blood pressure and statins trials demonstrate that an atherosclerotic mechanism shows up as divergence much later, around 12-18 months, which is also what was seen in the LEADER trial for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). Despite lingering questions surrounding mechanism of cardioprotection, Dr. Inzucchi called upon the ADA and EASD to consider powerful CVOT data in drafting the next position statement for the diabetes field. He urged the committee charged with authoring the next ADA-EASD treatment guidelines to look closely at EMPA-REG OUTCOME and other recent CVOTs, including LEADER, SUSTAIN 6 (for GLP-1 agonist semaglutide), and even IRIS (for the TZD pioglitazone, perhaps at low doses), because in his view, these CV benefits should be making their mark and improving real-world diabetes care.

Questions and Answers

Q: Can you pick up on heart failure data from DPP-4 inhibitor CVOTs, SAVOR and EXAMINE? The FDA has listed a warning, but on this side of the Atlantic, our European agency has posted a statement saying that the changes seen in heart failure are too small and should not alter practice. What are your thoughts on this?

A: The effect with alogliptin was not statistically significant. I still don’t completely understand why the FDA compelled that label to change. There’s no reason to believe a DPP-4 inhibitor could increase heart failure hospitalization rates, but the data is the data. Could it be a chance finding? Perhaps. We’re still obligated to follow drug labels in the US.

SGLT-2 Inhibitors and Renal Outcomes

David Cherney, MD (University of Toronto, Canada)

Dr. David Cherney (University of Toronto, Canada) picked up on the topic of SGLT-2 inhibition and continued the conversation on mechanism, but shifted focus from the heart to the kidneys. Post-hoc analysis of a composite renal endpoint in EMPA-REG OUTCOME found an impressive hazard ratio of 0.54 in favor of empagliflozin (Lilly/BI’s Jardiance), representing a 46% risk reduction with the SGLT-2 inhibitor therapy (p<0.001). More specifically, Dr. Cherney mentioned that the drug was associated with fewer cases of acute kidney injury and acute renal failure. What were the mechanisms responsible for improved renal outcomes? The short answer, as Dr. Cherney put it, is “we don’t know yet.” Still, he discussed in great detail what is known about the impact of SGLT-2 inhibitors – including empagliflozin, dapagliflozin (AZ’s Farxiga), and canagliflozin (J&J’s Invokana) – on kidney function, summarizing the leading hypotheses related to hyperfiltration and how agents in this class consistently reduce hyperfiltration, now evidenced through both animal and human data. He pointed out an interesting observation that 80% of patients enrolled in EMPA-REG OUTCOME were on a background of RAAS blockers. RAAS inhibition tends to dilate the kidney’s efferent arteriole, while SGLT-2 inhibition constricts the afferent arteriole. Therefore, one interesting theory for the renal protection seen in the CVOT is an additive effect of empagliflozin plus RAAS blockade, which may have more effectively lowered intraglomerular pressure to provide long-term kidney benefits. Another intriguing explanation is that empagliflozin delayed time to introduction of loop diuretics for participants (hazard ratio 0.62, p<0.001). Dr. Cherney also presented a combined renal-cardio hypothesis for the kidney and heart benefits seen in EMPA-REG OUTCOME. While cardioprotection has been getting more overt attention from the field of late, he suggested that renal preservation with SGLT-2 inhibitor therapy could be the gateway to lowering CV morbidity and mortality. Dr. Cherney outlined four potential pathways for this renal-cardio hypothesis: Lowering intraglomerular hypertension and albuminuria could (i) decrease blood pressure, arterial stiffness, cardiac afterload, and left ventricular remodeling, the last of which is cardioprotective; (ii) reduce renal systemic inflammation which decreases left ventricular remodeling; (iii) preserve sodium/water homeostasis which enhances maintenance of euvolemia, which is cardioprotective; and/or (iv) decrease cardiac preload, myocardial wall tension, and arrhythmogenesis, which is directly cardioprotective.

• Dr. Cherney picked up on Dr. Inzucchi’s call-to-action for guidelines committees as well. “In Canada, we do have exactly what’s suggested – in patients with high CV risk, SGLT-2 inhibitors are now indicated in guidelines as the next therapy of choice.” He endorsed this designation of SGLT-2 inhibitors as second-line therapy.

Symposium: Diabetes Prevention

What Has the ADDITION Trial Added?

Annelli Sandbaek, MD (University of Aarhus, Denmark); Simon Griffin, MD (University of Cambridge, UK); William Herman, MD (University of Michigan, Ann Arbor, MI)

Drs. Simon Griffin (University of Cambridge, UK) and Annelli Sandbaek (University of Aarhus, Denmark) presented five- and 10-year results from the ADDITION trial demonstrating a 12% reduction in risk of a composite cardiovascular endpoint and a 9% reduction in risk of all-cause mortality associated with small but statistically significant improvements in diabetes care of people with screen-detected diabetes in primary care. The trial examined the effect of early and intensive primary care-based diabetes treatment (vs. routine care) on time to first cardiovascular outcome over the course of a decade among people with type 2 diabetes detected by screening. The trial randomized clinics to provide either screening and routine care according to national standards or screening and intensive treatment (with target A1c£7% and a recommendation to initiate treatment at a threshold of 6.5%, intensive blood pressure and lipid targets, widespread aspirin use, and lifestyle modifications including diet, physical activity, and smoking cessation). The intensive care regimen also involved diabetes education classes, peer group meetings, and feedback about the course of each individual’s diabetes management. In total, 3,057 patients were included in the trial and the results were based on an impressive 96.9% follow-up rate at 10 years. After five years, intensive treatment non-significantly improved the primary CVD composite (cardiovascular mortality, non-fata MI, non-fatal stroke, non-fatal revascularization, and non-traumatic amputation) endpoint by 17% (HR: 0.83, 95% CI: 0.65-1.05; p=0.12), and reduced relative risk of all-cause mortality by 9% (HR: 0.91; 95% CI: 0.69-1.21). Additional intermediate outcomes include: (i) reduction of systolic blood pressure by 2.86 mmHg from a baseline of 151 mmHg; (ii) reduction of baseline A1c by 0.08% from a baseline of 7%; (iii) reduction of BMI by 0.02 kg/m2 from a baseline of 31.6 kg/m2; and (iv) a 2.02-fold smaller risk of cardiovascular disease (95% CI: 3.12-0.92). In terms of secondary endpoints, intensive treatment caused a downward, but non-significant, trend in the microvascular complications of diabetes, producing a 16% reduction in retinopathy (HR: 0.84, 95% CI: 0.64-1.10) and a 13% reduction in nephropathy, as measured by albuminuria (HR:0.87, 95% CI: 0.72-1.07). Furthermore, patient reported outcomes on the EQ-5D and EQ-VAS scales were also higher in the intensive treatment group, though the difference did not reach significance. Though the intensive intervention largely did not produce a statistically significant improvement in most of the outcomes measured, the consistent trend toward positive outcomes suggests that there may be some benefit to intensive treatment early in the course of disease.

• This trend toward decreased risk of cardiovascular disease and all-cause mortality persisted ten years following the initiation of the intensive primary-care diabetes treatment regimen. Intensive treatment improved the primary CVD composite endpoint by 12% (HR: 0.88; 95% CI: 0.73-1.06; p=0.17) and non-significantly reduced all-cause mortality by 9% (HR: 0.91; 95% Ci: 0.76-1.08). As was true in the five-year analysis, these trends in CVD risk and all-cause mortality were accompanied by modest but statistically significant improvements in systolic blood pressure, A1c, and total cholesterol; after ten years of treatment, 46%, 63%, and 85% of patients in the intensive treatment group respectively achieved target levels of these outcomes. Dr. Griffin shared that these data are quite new and more analyses (likely regarding overall cardiovascular burden and microvascular complications) are forthcoming.
  
  • Interestingly, the early intensive treatment intervention appeared to have a stronger effect on older individuals (i.e. age >60 years), producing a 24% relative risk reduction (HR: 0.76, 0.60-0.96, p=0.07).
• Dr. William Herman (University of Michigan, Ann Arbor) discussed the cost-effectiveness of early intensive diabetes treatment as demonstrated by ADDITION. One of the study’s most pressing follow-up questions is “given the high baseline cardiovascular risk and the beneficial effects of early diabetes treatment, should diabetes screening and primary care treatment regimens become a part of standard policy?” In short, the answer is “yes.” The ADDITION study provided compelling evidence of the ability of early intervention with a dedicated primary care diabetes treatment regimen to meaningfully improve patient outcomes. Using statistical models based on the raw ADDITION study data, Dr. Herman determined what the 10-year incidence of the composite CV outcome would be with and without screening and early diabetes treatment. When compared to no screening and a 3 or 6 year delay in the initiation of diabetes treatment, screening and early intervention produced a dramatic 30%-40% relative risk reduction for the composite CV outcome at 10 years, clear evidence of the major health benefits that accrue as a result of early diagnosis and treatment of diabetes.
  
  • In addition to having a positive effect on outcomes, screening and early intervention are affordable. Dr. Herman stated that with new guidelines for the diagnosis of diabetes, A1c can be used as both a screening and diagnostic test. The cost of an A1c test is small even considering the number needed to screen in order to detect one individual requiring treatment, and the total cost of medications for risk factor management for patients with newly diagnosed diabetes are small compared to the total costs of diabetes.
• This presentation of the ADDITION study’s full five-year and ten-year results marks the first time these data have been summarized together in entirety. Previously the results of this massive study had been spread among a series of presentations and publications (including Griffin et al., 2011, Donk et al., 2013, Black et al., 2014, and Sandbæk et al., 2014).

Corporate Symposium: Type 2 Diabetes: Beyond the Beta Cell (Sponsored by AZ)

Can We Reduce the Incidence of Macrovascular Complications?

Neil Poulter, MD (Hammersmith Hospital and Imperial College, London, UK)

Dr. Neil Poulter spoke first in trio of presentations on diabetes-related macrovascular complications, specifically the cardiovascular consequences of the disease. He advocated strongly for aggressive treatment for patients with type 2 diabetes, with lower A1c targets, lower systolic blood pressure goals, and statin therapy. “It’s a no brainer – if a patient has type 2 diabetes, they should be on a statin.” To support this view, Dr. Poulter highlighted data on how lipid-lowering reduces the risk of stroke for type 2 diabetes patients by ~48%. “We can certainly reduce macrovascular events via lipid-lowering,” he articulated, so “you have to find a very good excuse not to give a type 2 diabetes patient a statin, in my opinion.” He expressed doubts about the ADA’s decision to increase the recommended A1c target for macrovascular risk reduction to <7% – “I suspect that will go back down again with time, and I think it should.” Dr. Poulter also touched upon systolic blood pressure as a way to prevent macrovascular complications. In response to results from the ACCORD trial, which showed no significant benefits of tighter blood pressure control of <120 mmHg vs. <140 mmHg, many guidelines committees raised the recommended systolic blood pressure for type 2 diabetes patients to 140 mmHg. Again, Dr. Poulter stood in favor of more aggressive treatment: “Previously the recommendation was at 130 mmHG, and I think that’s where it should have stayed.” He added that since ACCORD, more recent studies have found highly significant benefits of lower systolic blood pressure on macrovascular risk reduction. We appreciated Dr. Poulter’s willingness to share his opinions candidly, and we found his commentary to be quite compelling. We are proponents of tighter A1c control when possible, given the long-term health benefits to patients and the ability for CGM and insulin-independent therapies to keep hypoglycemia risk in check. By similar thinking, we hope guidelines committees and HCPs encourage patients toward lower lipid levels and systolic blood pressure when safe, especially when patients are willing to do so.

Cardiovascular Outcomes Trials: Current Status

Bernard Zinman, MD (University of Toronto, Canada)

Dr. Bernard Zinman (University of Toronto, Canada) told the story of cardiovascular outcomes trials to date, starting with 2008 FDA guidance aimed at ensuring CV safety, covering the major trials for DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 agonists, and highlighting the positive results reported in EMPA-REG OUTCOME (for Lilly/BI’s SGLT-2 inhibitor Jardiance [empagliflozin]) and LEADER (for Novo Nordisk’s GLP-1 agonist Victoza [liraglutide]). On the current state of diabetes drugs, Dr. Zinman stated optimistically “we’re in a new era of hypoglycemia therapies with a positive impact on CV outcomes.” He described his ideal drug as an agent that doesn’t cause hypoglycemia, doesn’t cause weight gain, and confers “added value” in the form of beta cell preservation or reduced CV events – we’re nearing this ambition with SGLT-2 inhibitors and GLP-1 agonists, and hopefully upcoming CVOT data will show cardioprotection from even more products. Dr. Zinman was also optimistic about results from CVOTs and other large-scale clinical trials impacting real-world clinical practice. SGLT-2 inhibitors and GLP-1 agonists have been elevated in the AACE 2016 algorithm, he explained, and the dominant message in the field right now supports earlier use of agents in both drug classes. “We’ve always said we should practice evidence-based medicine, and now studies will help us make informed decisions on optimal management of patients with type 2 diabetes.”

Cardiovascular Outcomes Trials: Implications for Clinical Practice

Juris Meier, MD (Ruhr University of Bochum, Germany)

Anchoring this trio of talks on cardiovascular outcomes, Dr. Juris Meier (Ruhr University of Bochum, Germany) advocated for a number of changes to CVOT study design in order to optimize the impact of these trials on diabetes care. He suggested (i) eliminating the glycemic equipoise design; (ii) investigating the CV effects of both established and newer therapies; and (iii) expanding the focus to include primary prevention. We found Dr. Meier’s proposed change to the glycemic equipoise design of CVOTs to be his most controversial suggestion. He argued that this trial design, in which participants in the placebo arm receive higher insulin doses or other treatment intensification to narrow the A1c gap between agent and placebo groups, makes it difficult to discern the true CV effects of the agent in question, as its glycemic effect likely contributes to its CV benefit somewhat. This opinion stands in contrast to the more common support we’ve heard for the glycemic equipoise design, although we believe there are so many issues around CVOT trials in general that it would be great to have an expert session hosted by FDA (as raised in the August 2014 meeting “FDA Public Hearing on the Confidentiality of Interim Results in Cardiovascular Outcome Safety Trials”). Dr. Meier also advocated for multi-agent CVOTs, pointing out that most CVOTs published thus far compare a relatively new diabetes drug vs. placebo and suggested that head-to-head comparisons of the potential CV benefits of new drugs and relatively older agents would be helpful. Data showing the relative CV benefits of different drugs could be tremendously valuable for high-risk patients – this is certainly something we’d like to see in the coming years as CVOTs gain even more traction, though of course the costs of such a trial would be enormous and it’s unclear which stakeholders might have the incentives and means to fund the endeavor. Dr. Meier also emphasized that published CVOTs have largely investigated secondary prevention, enrolling participants with type 2 diabetes and a history of CV disease. That said, he noted that AZ’s DECLARE (for SGLT-2 inhibitor dapagliflozin) and EXSCEL (for GLP-1 agonist exenatide) will each include a cohort of participants without prior CV history. In his view (and ours), these results on primary CV prevention will be very interesting, and positive results could be a major win in two ways: (i) by promoting greater utilization of these agents across a much wider spectrum of the diabetes patient population; and (ii) by providing even more compelling evidence for cardioprotection in a broader population. We’d be thrilled to see cardioprotective medications that address primary and secondary prevention alike, though we acknowledge the massive time and monetary investment behind CVOTs which presents an obstacle to research in lower-risk populations. Ultimately, we were intrigued by Dr. Meier’s perspective on how to make CVOTs more influential in clinical practice – definitely a worthwhile goal and an important topic for discourse.

Panel Discussion

Neil Poulter, MD (Hammersmith Hospital and Imperial College, London, UK); Bernard Zinman, MD (University of Toronto, Canada); Juris Meier, MD (Ruhr University of Bochum, Germany)

Q: What’s the single trial that has had the biggest impact for you and your patients?

Dr. Zinman: For type 1 diabetes, it would be the DCCT, obviously. For type 2 diabetes patients, EMPA-REG OUTCOME provided a lot of good data (although I am a little biased). It was the first clear evidence we’ve seen that a diabetes therapy can have added value, reducing CV events. CV death is a big issue, as is heart failure in type 2 diabetes.

Dr. Poulter: EMPA-REG OUTCOME.

Dr. Meier: I think the UKPDS was very important, and the follow-up to that was very interesting because it showed a mortality benefit from tighter glycemic control.

Dr. Poulter: Can I say, the FDA voting of 12-11 was extraordinary for Jardiance, when you have such a fantastic benefit. Excuses were “we’re not quite sure about mechanism” – who cares?! – and “maybe it’s chance” – very, very unlikely. While I applaud conservatism, I’m with the Canadian guidelines, and I think it’s time to take action.

Dr. Zinman: Health Canada is usually behind, but we already have an approved indication on the label for empagliflozin for the prevention of cardiovascular death.

Dr. Meier: It’s extremely difficult to understand these trials because of the multiplicity of effects. At a certain point it’s okay to be pragmatic and say even if we don’t know exactly how we’re saving lives, let’s save lives.

Dr. Zinman: To interfere with atherosclerosis by glucose lowering, an agent has to be introduced early. A glucose lowering strategy initiated late in diabetes doesn’t do much for atherosclerosis. SGLT-2 inhibitors, I think, are very good diabetes drugs even independent of their CV benefit, and they could be used early on just like any other oral agent. They lead to weight loss, they lower blood pressure, they’re good for glucose control. Will they be helpful in prediabetes? Perhaps, by reducing hyperglycemia and also helping to preserve beta cell function.

Q: Can you talk about the mechanism of cardioprotection seen in EMPA-REG OUTCOME, and also in LEADER?

Dr. Zinman: Several things might be going on. With empagliflozin, there was probably a volume effect. An increase in hematocrit is a measure of volume reduction, and we think that clearly plays an important role. Notably, the differences in CV death with empagliflozin vs. placebo spread very early, which is different from LEADER, where you see it takes more time and is likely an atherosclerotic effect. There’s been a metabolic effect postulated for EMPA-REG OUTCOME related to ketones as an energy source. We’re looking. It will be unraveled.

Dr. Meier: I can speculate, as all of us can. Empagliflozin’s cardioprotection probably has something to with a combined effect on various risk factors, including glucose, weight loss, lipids, and blood pressure. There’s also a hypothesis in the mix that GLP-1 agonists may exert CV benefits independent of glucose-lowering. We have plenty of evidence for this in rodents, and with the unexpectedly positive results from LEADER, I wouldn’t be surprised to find out about liraglutide’s independent, direct cardioprotective effects.

Oral Presentations: SGLT-2 Inhibitors: Metabolic Effects

canagliflozin Slows Progression of Renal Function Decline Independent of Glycemic Effects

Hiddo Heerspink, MD (University Medical Center Groningen, the Netherlands)

Dr. Hiddo Heerspink (University Medical Center Groningen, Groningen, the Netherlands) presented a compelling new post-hoc analysis of CANTATA-SU to support a glucose-independent, renal-protective benefit for the SGLT-2 inhibitor canagliflozin (Janssen’s Invokana). The analysis was published recently in the Journal of the American Society of Nephrology. CANTATA-SU was a phase 3, double-blind, head-to-head study of canagliflozin (100 or 300 mg/day) vs. sulfonylurea glimepiride (titrated to 6-8 mg/day) over 24 months in patients with type 2 diabetes (n=1,450) on metformin monotherapy. In the post-hoc analysis, eGFR declines throughout the trial were smaller with both doses of canagliflozin compared to glimepiride (declining 0.5 ml/min in the canagliflozin 100 mg group [p=0.01] and 0.9 ml/min in the canagliflozin 300 mg group [p=0.01], compared to a 3.3 ml/min reduction in the glimepiride group. The results suggest that canagliflozin, compared with glimepiride, slows the progression of renal disease in type 2 diabetes patients over two years. Canagliflozin furthermore produced reductions in urinary albumin:creatinine ratio (UACR) compared to glimepiride (5.7% reduction with the 100 mg dose and 11.2% reduction with the 300 mg dose, p=0.01). This was especially pronounced in the subgroup of patients with baseline UACR above 30 mg/g, who experienced a 31.7% (p=0.01) decline in this ratio with canagliflozin 100 mg and a 49.3% (p=0.01) decline in this ratio on the 300 mg canagliflozin dose compared to glimepiride treatment. Further post-hoc analysis revealed that the treatment effect of canagliflozin on albuminuria persisted even after statistically controlling for the differences in A1c reduction, systolic blood pressure, body weight, or the combined changes in all three of these factors between the canagliflozin and glimepiride arms. This suggests that canagliflozin’s effect on albuminuria occurs independently of its glycemic effects – wow! We’re intrigued by the suggestion of renal-protection for canagliflozin demonstrated by these analyses and our curiosity is piqued regarding the mechanism by which SGLT-2 inhibitors achieve this renal-protective effect. Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) recently demonstrated impressive renal-protective benefits in EMPA-REG OUTCOME and we’re certainly looking forward to more renal outcomes data from other products in the class – as well as for GLP-1 compounds. Diabetic nephropathy is an extremely costly complication of diabetes, both in human and economic terms, and the availability of glucose-lowering drugs with additional renal-protective benefits is a major win for patients. We look forward to hearing more on renal impact of diabetes drugs in the coming days at EASD.

• An astute comment during the ensuing Q&A session pointed out that this study lacks a sufficient control group. Thus it is impossible to tell whether the renal benefits of canagliflozin over glimiperide are due to canagliflozin being beneficial or glimiperide being harmful. To resolve this issue, we would love to see similarly-designed trials in the future that includes a third, placebo-controlled arm. Also, just in general, we’d love to see SFUs used in more outcomes trials. Though it may make more patients not want to participate in the trials, we think that more data is needed to show the negativity of SFUs – so many patients are forced to be on SFUs still and there is not enough data for patient advocates to try to push back for these patients. For some group of course, lower-dose SFUs may be fine, but we think the combination of weight gain and hypoglycemia and fracture risk and beta cell burnout is quite negative for most.
• The CREDENCE trial is underway to assess the effects of canagliflozin (100 mg/day) on renal endpoints in patients with diabetic kidney disease. With nearly 4,000 subjects enrolled, Dr. Heerspink explained that the CREDENCE trial will be powered to definitively show whether canagliflozin has renal-protective effects. According to ClinicalTrials.gov, this trial is estimated to complete in January 2020.

Diabetes Technology

Oral Presentations: Devices and Desires

Hybrid closed-loop (HCL) pivotal trial in type 1 diabetes

Richard Bergenstal, MD (International Diabetes Center at Park Nicollet, Minneapolis, MN)

JAMA published Medtronic’s MiniMed 670G US pivotal trial as a two-page Research Letter, concurrently presented as an oral presentation by Dr. Richard Bergenstal this afternoon. We saw the data in a late-breaking ADA poster in June, but it was excellent to see the visibility in JAMA (even as a “research letter”), and we were glad to see several metrics we did not see in the ADA poster: mean and median glucose in the trial (~150 mg/dl); time spent >300 mg/dl (a strong 26% decline), nocturnal time-in-range data (excellent), within-day coefficient of variation, and median values for all CGM metrics. The data is otherwise identical to what we saw at ADA and reinforces the topline takeaways: (i) a strong safety profile; (ii) a solid 0.5% reduction in A1c from a low baseline (7.4%); (iii) excellent hypoglycemia avoidance (time <70 mg/dl declined 44%; (iv) outstanding efficacy overnight (75% time in 70-180); and (v) much-improved accuracy for Enlite 3 (MARD: 10.3%). A group of serious luminaries in the field authored the JAMA letter – Drs. Rich Bergenstal, Satish Garg, Stu Weinzimer, Bruce Buckingham, Bruce Bode, Bill Tamborlane, and Fran Kaufman. We assume this could not be an “original article” as a single arm, non-randomized study, which Medtronic obviously choose for speed and getting to market quickly – we’re glad to see that was prioritized over a perfect pre-market RCT that gets published in long-form in a major journal, but takes longer to complete. As would be expected, the JAMA Research Letter places less focus on efficacy: “Safety” is the first word in the piece’s title, “Table 1” shows device related adverse events (“Table 2” shows the study outcomes), and no p-values are shown comparing the two-week baseline to the intervention period. We hope readers can infer the efficacy from the Research Letter’s table, though it will be interesting to see if closed loop shows better “real-world” efficacy than in trials. Managing expectations will of course be critical as this comes to market, something we heard over and over again at ADA. The 670G was submitted to FDA in June, and as of the 2Q16 call earlier this month, was “on track” for approval by April 2017. 

• To us, the big takeaway is that the 670G is safe and effective (even in a motivated patient population), and it will be a good first-generation starting point to learn and improve upon. Patients in the pivotal clearly loved the system (80% chose to continue using it), a sign that these first-gen products will appeal to current pumpers. Though we’ve heard the 670G requires a fair amount of setup and the user interface needs improvement, it should reduce burden from what many are currently doing every day, and it certainly gives amazing peace of mind overnight and a great morning glucose to start the day.

Real-time continuous glucose monitoring improves time spent in euglycaemia and prevents severe hypoglycaemia in type 1 diabetes mellitus patients with impaired awareness of hypoglycaemia

Koen van Beers, MD (VU University Medical Center, Amsterdam, Netherlands)

In a huge outcomes victory for CGM, a randomized crossover trial in type 1s with impaired hypo awareness demonstrated a significant 53% fewer severe hypoglycemia events with CGM vs. SMBG (14 events vs. 34 events; p=0.03). The study was concurrently published in the Lancet Diabetes and Endocrinology. The very well conducted trial (out of Dr. Hans DeVries’ group at Academic Medical Center) randomly assigned 52 patients to either (i) 16 weeks of CGM followed by SMBG (n=26); or (ii) 16 weeks of SMBG followed by CGM (n=26). A 12-week washout came in between the periods, and the study enrolled type 1 adults with impaired hypoglycemia awareness, a baseline A1c of 7.5%, a mean age of 49 years, 31 years of diabetes duration, and 56% MDI users. The CGM study phase used the Medtronic Enlite CGM running on the Veo pump, but used only as a receiver (no low glucose suspend turned on). A blinded iPro2 device collected CGM data during the SMBG phase. The primary endpoint, time-in-range (70-180 mg/dl), significantly improved during the CGM phase: 65% with CGM vs. 55% with SMBG (p<0.0001), translating to 2.3 extra hours in range per day with CGM. This included a 40% reduction in time spent <70 mg/dl with CGM (6.8% vs. 11.4%; p<0.0001) and 15% less time spent >180 mg/dl (28.2% vs. 33.2%; p<0.0001). Severe hypoglycemia (requiring third-party assistance) was actually a secondary endpoint, but it was still powerful to see the huge change in this high-risk population – that the SMBG phase included 34 severe hypoglycemia events in 52 patients over 16 weeks was striking. Notably, the proportion of patients with >1 severe hypoglycemia event was 10 (CGM) vs. 18 (SMBG), translating to a compelling 0.48 odds ratio (borderline significant at p=0.06). A1c was not significantly different (-0.1%), meaning glycemic control was not ceded for the hypoglycemia benefits – yes! CGM surprisingly did not significantly improve awareness of hypoglycemia (as measured by Gold Score) after 16 weeks, though perhaps a longer trial would be needed. Interestingly, Lilly and Sanofi funded the trial. We think the results would be even better with a more recent device.

• This trial further builds the case for CGM’s cost-effectiveness (even with an older CGM sensor), and we especially hope it helps with European reimbursement. The publication neatly summarized the study implications: “In earlier trials, CGM did not live up to the expectations of the diabetes community regarding its ability to reduce severe hypoglycemia. However, our findings here support the benefit of CGM, both with and without combining it with continuous subcutaneous insulin infusion, for improving glycemic control and diminishing severe hypoglycemia in adult patients with type 1 diabetes and impaired awareness of hypoglycemia, who are at highest risk of severe hypoglycemia.”
• There was no carryover effect, meaning the time-in-range improvement from CGM came solely from wearing it and using the data real-time (not a learning effect that persisted). See below for the time-in-range outcome for the CGM-SMBG sequence (red line) and SMBG-CGM sequence (blue line). CGM immediately benefited time-in-range, and as soon as it stopped, patients returned to their baseline. There was also no interaction between insulin treatment modality (MDI vs. pump), confirming Dexcom’s recent studies (DIaMonD study, COMISAIR) showing the benefits of CGM in MDI users.

Corporate Symposium: Dexcom Continuous Glucose Monitoring: Leading the Way as the Standard of Care, Clinical Outcomes and Market Access

Impact On Hypoglycemia Awareness Of Real-Time CGM And Intermittent Continuous Glucose Data (I HART CGM)

Nick Oliver, MD (Imperial College, London, UK)

Dr. Nick Oliver presented preliminary data from a fascinating investigator-initiated head-to-head study comparing the hypoglycemia impact of Dexcom’s G5 (n=15) vs. Abbott’s FreeStyle Libre (n=17) in type 1s with very impaired hypoglycemia awareness (one severe event in the past 12 months or a Gold Score >4). Following a two-week baseline run-in with blinded Dexcom G4, CGM-naïve patients on MDI (baseline A1c: 7.5%) were randomized to use either G5 or FreeStyle Libre for eight weeks. Dexcom’s G5 won handily on the primary hypoglycemia endpoint, showing a significant reduction in time spent <60 mg/dl (3.3 mmol): from 6.1% at baseline to 3.3% in the last four weeks of the study (p=0.02). By contrast, the FreeStyle Libre group saw no significant change in hypoglycemia (from 7.4% to 8.2%; p=0.5), for a between-group difference of 3.6% (p=0.03). This translated to a clinically significant 52 minutes per day less time in hypoglycemia (<60 mg/dl) with G5 in a very high-risk group. All other hypoglycemia thresholds were also in favor of G5 (<70, <63, <50 mg/dl) and statistically significant. Notably, there were no significant between-group differences in time-in-range or time in hyperglycemia – both groups saw strong and nearly equal improvements. Dr. Oliver emphasized that the alarms really drove the greater hypoglycemia improvement in the G5 group, a key device feature for patients with a high degree of impaired hypoglycemia awareness. He called FreeStyle Libre “reflective” and G5 “reactive,” and noted that hypoglycemia measurement (frequency, severity) and awareness should be considered before commencing CGM – presumably to stratify patients to see if they need alarms. The study is not yet complete and will report more data in early 2017. Dr. Oliver emphasized that these are preliminary results and will hopefully be published at some point in the future.

• Though these were preliminary results from a small trial, we were glad to see a very strong study design (randomized, parallel group, strong parity, latest devices), an investigator initiated study, a test of these two great technologies head-to-head, and an important study in a high-risk patient group. These comparative effectiveness studies must happen to give providers, payers, and patients better data – who is most likely to benefit from a particular technology?
• The temptation is to say “G5 > Libre,” but this misses the more interesting point: when should one glucose sensing technology be used vs. another? High-risk patients with significant hypoglycemia unawareness SHOULD have the benefit of CGM alarms – this small study provides clear data on that front, assuming equal access and patient preferences. Of course, access and patient preferences are rarely equal between two options, which is why both of these technologies exist in the first place – offering a broader spectrum of device form factors, cost, and features to target different patient populations. This is not an “either-or” but a “both-and” – how can we bring glucose sensing to the masses in the most cost-effective way? CGM has not been accessible to nearly enough people to date, which is what motivated Abbott to rethink the design with FreeStyle Libre. We’re glad to see Dexcom/Verily doing the same and we hope both companies can expand the market significantly beyond those studied in this trial (who will most certainly benefit from traditional CGM, and for whom reimbursement should be a no-brainer).
• As might be expected, the sensor failure rate was higher in the FreeStyle Libre arm (7/60 sensors, 11.7%) vs. the G5 arm (1/120 sensors, 0.8%) – each group had only one sensor with unacceptable accuracy, though the Libre group had six out of the 60 sensors fall out before the 14-day life. We have heard some complaints about this aspect of FreeStyle Libre – particularly for very active patients – and we wonder if Abbott will work on improving the adhesive or providing patients with over-tape.

 HYPOGLYCEMIA RESULTS

• Dexcom’s G5 won handily on the primary hypoglycemia endpoint, showing a significant reduction in time spent <60 mg/dl (3.3 mmol): from 6.1% at baseline to 3.3% in the last four weeks of the study (p=0.02). By contrast, the FreeStyle Libre group saw no significant change in hypoglycemia (from 7.4% to 8.2%; p=0.5), for a between-group difference of 3.6% (p=0.03). This translated to a clinically significant 52 minutes per day less time in hypoglycemia (<60 mg/dl) with G5 in a very high-risk group.
• The results were highly consistent for time <50 mg/dl and <70 mg/dl, suggesting across-the-board reduction in hypoglycemia with G5.
  
  • Time <50 mg/dl was 3.7% with G5 at baseline, which was more than halved in the last four weeks of the study to 1.4% (p=0.02). Libre users saw no significant change in time <50 mg/dl (4.6% to 5.2%; p=0.49), translating to a between group difference of 2.9% in favor of G5 (p=0.02), or 42 minutes fewer per day under 50 mg/dl.
  • Time <70 mg/dl was 10.1% in the G5 group at baseline, which improved to 7.1% in the last four weeks of the study (p=0.04). By contrast, the FreeStyle Libre group saw no significant change in time <70 mg/dl (from 11.1% to 12.9%; p=0.33), for a between-group difference of 4.9% in favor of G5 (p=0.04), or 71 minutes per day fewer under 70 mg/dl with G5.

TIME-IN-RANGE RESULTS

• Both G5 and FreeStyle Libre improved time-in-range from baseline, but there were no significant differences between the groups.
  
  • Time in 70-180 mg/dl improved a whopping +9.6%-point with G5 (57.2% to 66.8%; p=0.03) and +6.6%-points with Libre (52.2% to 58.8%; p=0.004) from baseline to the last four weeks of the study. This equated to over two more hours per day in range with G5 and 90 minutes more per day in range with Libre. There was no statistical difference between the groups (p=0.5).
  • Time in 70-140 mg/dl was 39.8% with G5 at baseline and improved to 45.4% in the final four weeks of the study (+5.6%; p=0.23). Libre users saw a similar +4.6%-point boost in time in range (35.1% to 39.8%; p=0.06). Put simply, both groups saw roughly one more hour per day in range by the end of the study, and no statistically significant difference between the groups (p=0.86).

HYPERGLYCEMIA RESULTS

• Both G5 and FreeStyle Libre improved hyperglycemia from baseline, but there were no significant differences between the groups.
  
  • Time >180 mg/dl improved a solid -6.5%-point with G5 (32.6% to 26.1%; p=0.11) and -8.4%-points with Libre (36.7% to 28.3%; p=0.01) from baseline to the last four weeks of the study. This equated to 90 minutes less per day in hyperglycemia with G5 and two hours less per day in hyperglycemia with Libre. There was no statistical difference between the groups (p=0.69).
  • Time >270 mg/dl was cut in both study groups: from 10.8% to 5.5% in the G5 group (-5.3%; p=0.007) and 10.7% to 6.1% in the Libre group (-4.6%; p=0.018). This translates to an hour less per day in each group spent at dangerously high blood glucose levels over 270 mg/dl. There was no statistical difference between the groups (p=0.77).

STUDY DESIGN DETAILS

• At baseline, patients had a mean A1c of 7.5%, a mean age of ~50 years, a mean duration of diabetes of ~29 years, and a mean Gold Score of ~4.8. There were no significant differences between the groups. The study enrolled patients that experienced severe hypoglycemia in the last 12 months requiring third party assistance, or those with a gold score of >4. Patients had to have been on MDI for >6 months and type 1 diabetes for greater than three years.
• Notably, the study hypothesized that FreeStyle Libre Libre would have an equivalent impact on hypoglycemia as the Dexcom G5 CGM. The primary outcome was the difference in % time spent <60 mg/dl from baseline to the end of the eight week study. Glucose data from baseline came from a two week run-in period measured via blinded Dexcom G4. Patients were then randomized to use FreeStyle Libre or Dexcom G5 for eight weeks. Glucose outcomes were calculated from the last 30 days of each treatment period. Analysis was intention to treat. A telephone visit occurred at week 2 and a clinic visit occurred at week 4.
• The data today reported results from 32 out of a planned 45 CGM naïve, MDI-using adults (18+ years) with type 1 diabetes. Patients also had the opportunity to continue on Dexcom G5 for 8 weeks following the main study period, though that data was not presented today. A total of 34 patients have been randomized to date, and two are currently ongoing (one in each group), leaving 32 presented today.

Questions and Answers

Dr. Pratik, Choudhary (London, UK): This is a really important debate. In the Dexcom group, did you have predictive alarms set up to avoid hypos? And the algorithms in Dexcom and Libre are very different. Is there a problem in interpreting the hypoglycemia data?

A: We call this hypoglycemia, but it’s not. It’s interstitial fluid measurement, either calibrated in the factory or fingersticks to the blood value. It’s not true hypoglycemia. These are different algorithms. It may be if we had YSI, we would see different results. But these are the devices we have, these are how they work in real time, and these are the outcomes we measure and things we are empowering and asking patients to respond and react to. For the technical aspects, there may be differences we are not pulling out, but this is the real life hypoglycemia point of view, and it’s important.

For predictive alarms, apart from setting it at 3.9 mmol/l (70 mg/dl), we let participants do what they wanted with receiver.

Q: I assume you don’t have A1c for an eight-week study, but do you have mean sugar?

A: I’m not sure it adds a great deal. This is a high risk group of people with severe hypoglycemia. In my clinical practice, if they had an A1c that went up, I wouldn’t be too bothered – that’s an acceptable outcome to reduce the risk of severe hypoglycemia. In both groups A1c fell, and fell significantly, but there were no between group differences.

Q: What about nighttime?

A: I’ll tell you in January. We will look at nocturnal and 24-hour data.

Q: Did you have any questionnaires on fear of hypoglycemia and fear of hypoglycemia at night?

A: No, we don’t have a night-specific one.

Q: Which system is more closely to real blood glucose?

A: Within this study, I don’t know. This is not an accuracy study. Both technologies in the UK are licensed for non-adjunctive use. FreeStyle Libre has no fingersticks. We are unable to make any accuracy comparison. There are other data, not in a hypoglycemia impaired population, that compare accuracy. With G5, it’s about 9%-10% absolute difference from blood glucose.

CGM Reimbursement Update and Cost Effectiveness in 2016

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

Dr. Claudia Graham gave a persuasive and highly encouraging update on CGM reimbursement, arguing that CGMs are highly cost effective (evidence: Germany’s positive reimbursement decision), should absolutely come before pumps (“If you have only $5,000 to spend per year, where would you spend that money?”), and now have some reimbursement (albeit limited) in 11 EU countries (see slide below). She shared a fascinating cost-effectiveness analysis used as an example in Germany, which gave Dexcom CGM a compelling incremental cost-effectiveness ratio (ICER) of 12,533 euros/QALY, far below NICE’s threshold of 20,000-30,000 euros/QALY, and even better than atorvastatin’s 40,069 euros/QALY. This assumed 2.3 fingersticks per day (calibration plus some extra), no receiver cost, and a 50% reduction in severe hypoglycemia events – the latter is of course not a proven fact with CGM, but is “very doable” in Dr. Graham’s view. She highlighted the DiaMonD study results from ADA 2016 and noted the study has been submitted for publication and will hopefully be out soon. In her slide on US reimbursement, Dr. Graham encouragingly said that 25% of US payers have CGM coverage policies for type 2s on insulin, more than we would have guessed. Overall, her talk echoed the one she gave at EASD 2015, strongly urging CGM first, given the high cost of pumps. In the UK, Dexcom CGM costs 3,465 pounds per year (direct pricing from Dexcom), less than half of the 7,196 pounds per year for sensor-augmented pump therapy as listed in the NICE sensor augmented pump assessment in 2015 (slide below). “Let’s give CGM that first start,” she said. Dexcom is focused on driving cost-effectiveness in three areas: (i) appropriate patient selection (e.g., hypoglycemia prone, high A1c patients, pediatrics); (ii) lower-cost technology (e.g., remove cost of receiver, reduce transmitter costs, reduce/eliminate fingersticks); and (iii) simplifying healthcare instructions (e.g., online training).

• “Why has it taken so long for CGM to gain access in Europe?” Dr. Graham highlighted the lengthy assessment processes (70 months on average in Germany, five years in the UK) and individual country-by-country systems. “It takes a long time in Europe to convince the authorities, to have the right data, and to have support of the experts and position statements. But it’s still taken too long for CGM. I’m disappointed about that.” She noted three particular challenges:
  
  • Misperceptions that CGM had to be used with a pump, or follow a pump, or be a last resort. Pumps came to market first, and have been linked to the artificial pancreas quest for a long time. There has also been a belief that MDIs are not “tech savvy” (“it’s too much for my patients”) – DIaMonD and COMISAIR (see below) disprove that. “We lost sight that CGM and pumps can be used alone. Most of Dexcom patients are trained online in how to use the device in under an hour, and they get it. It’s surprisingly intuitive on how to use this.”
  • Rapid product iterations make it difficult to assess effectiveness. Outdated publications are used in meta-analyses for health technology assessment, and these include much older technologies that are less effective.
  • Outcome publications and models have primarily been done on sensor-augmented pumps. These are “confusing and costly,” she noted.

CGM and Multiple Daily Injection Patients: A1c Outcomes and Clinical Benefit Demonstrated by the COMISAIR Study

Martin Prazny, MD (Charles University, Prague, Czech Republic)

Dr. Prazny covered the newly published 52-week (!) COMISAIR trial (n=65; Soupal et al., DT&T 2016), offering a highly positive takeaway for Dexcom: adding CGM to MDI drove a similar A1c reduction as adding CGM and a pump (-1.2%; baseline: 8.3%). Further, adding a pump alone (no CGM) only drove a 0.5% reduction in A1c (baseline: 8.4%). Though the study was very small (n=18 on MDI + SMBG, n=12 on MDI+CGM, n=20 on pump + SMBG, and n=15 on pump + CGM), it was great to see the long length and four-group design. We first heard about this study in the AADE 2016 exhibit hall, and the results confirm the preliminary findings from the DIaMonD study (presented at ADA) – CGM offers significant benefits to MDIs.

Corporate Symposium: Redefining Diabetes Management with Metrics Beyond HbA1c (Sponsored by Abbott)

Data from Abbott’s IMPACT study (presented in poster form at ADA) was published in the prominent UK medical journal The Lancet today, alongside a very balanced (but mostly positive) accompanying Comment from Cambridge’s Dr. Roman Hovorka and colleagues. This publication was mentioned only briefly in today’s symposium, and represents a major victory for the company and hopefully a positive for eventual reimbursement. There were not major new details in the paper vs. the ADA poster, but getting the dramatic 38% hypoglycemia reduction (~74 minutes fewer per day) published in such a prestigious journal helps build the evidence base and reduces the noise factor around “no alarms.” We also learned today that a new integration agreement between Abbott and mySugr will allow Libre users to automatically and passively upload data to their mySugr accounts via the LibreLink Android app. This is outstanding news for Abbott to begin leveraging data from Libre in the widely loved mySugr app, which also has a partnership with Roche’s Accu-Chek Connect BGM. The Abbott team also told us about a new partnership with Social Diabetes, a popular Android app in the EU that enables users to log their food and insulin and get dosing recommendations from the app. We have not ever heard of this app, but it has a notable 50,000+ downloads on Android and very positive reviews. Abbott’s actual symposium did not share new data or pipeline updates, but the session – “FLASH GLUCOSE MONITORING: Redefining Diabetes Management with Metrics beyond HbA1c” – featured an established slate of experts (Drs. Irl Hirsch, Thomas Danne) who spoke about recent clinical trials of the Libre and reasons why A1c is a flawed, or at least, incomplete outcome metric.

• The Lancet publication is largely comprised of the information we covered at ADA (Poster 868-P). The accompanying commentary from Dr. Hovorka et al. is balanced but mostly positive, noting that the Libre’s lack of alarms “has surprisingly little effect on user acceptability” and that the device could alleviate many of the barriers to wider adoption of CGM, such as the need for calibrations, alarm fatigue, frequent sensor changes, and cost. However, they do caution that “studies in a more generalizable clinical population, in which aspects of behavior modification induced by use of this technology can be ascertained, are needed to provide further guidance to healthcare providers and funders, as well as comparisons with emerging automated insulin-delivery systems.” 
  
  • The Commentary notes that the convenience of FGM trumps that of SMBG (after 90 days, Libre users scanned an average of 15 times/day, compared with the 6 fingersticks/day of the SMBG group), which fosters rapid behavioral adaptation. The downside is that this requires “unrelenting round-the-clock attention to diabetes self-care,” which many patients may not commit to. The study did not include details on how the patients altered their management in response to the additional data (and Dr. Bolinder indicated during Q&A that it is unknown at this point). As a reminder, the study population was intentionally composed of well-controlled patients with lots of hypoglycemia at baseline (mean A1c=6.7%), though the commentary wonders how well the improvements would translate to other groups who may have different interactions with the technology. This is the classic commentary about any study, and overall, we think Abbott should be highly commended for running IMPACT in type 1s and REPLACE in poorly controlled type 2s.
• Abbott’s integration with mySugr is a win for both companies and particularly for Libre users, who can now view glucose levels alongside the rest of their food and medication data in the motivating mySugr app. In June, Abbott struck a similar data integration agreement with Diasend’s mobile app. It is excellent to see Abbott making it easier for patients to view and extract insights from their data, especially in a mobile app. Abbott has lagged behind Medtronic and Dexcom on the data front and we’re glad to see it now making moves to maximize the value of its sensor.
• Highlights from the symposium included: Dr. Thomas Danne (Auf der Bult Hospital for Children and Adolescents, Hannover, Germany) on FGM in the pediatric population, Dr. Jan Bolinder (Karolinsak University Hospital Huddinge, Stockholm, Sweden) on IMPACT results, and Dr. Irl Hirsch (University of Washington Medical School, Seattle, WA) on the limitations of A1c.
  
  • Dr. Danne championed the use of FGM in pediatric populations. Children are notorious for their unpredictable lifestyles, which give rise to higher glycemic variability and risk of hypoglycemia. Due to the legacy effect (or “metabolic memory”), it is crucial that both elements of poor glucose control are minimized as soon and as much as possible. Dr. Danne asserted that FGM can lead to better control and higher quality of life of the child and family – reducing painful fingersticks, allowing parents to check a child’s glucose at night without disturbing him/her, etc. Libre is currently approved for children as young as four years in Europe; we saw the accuracy data in an oral at ATTD 2016).
  • Dr. Bolinder’s talk focused on the IMPACT trial (presented in poster form at ADA), which found that, relative to SMBG, well-controlled (baseline A1c: 6.7%) type 1 patients using FreeStyle Libre spent ~74 minutes fewer per day <70 mg/dl (a 38% reduction; p<0.001). There was not a significant difference in A1c between the groups by study end, though both saw a non-significant 0.15% increase from baseline to six months (6.7% to 6.9%). The quality of the A1c was unquestionably better in the Libre group. In addition, quality of life metrics were almost entirely in favor of Libre. See our detailed coverage here and the Lancet publication here.
  • Dr. Irl Hirsch on how we manage type 2 diabetes: “Wrong!” Dr. Hirsch walked attendees through a litany of primary literature to prove his point: A1c does not reliably correlate with an average glucose level on an individual basis, ESAs (erythropoietin stimulating agents) cause a decrease in A1c, iron causes an increase in A1c, aortic disease causes reduced red blood cell survival and subsequent decrease in A1c, the list goes on. Yet the standard of care is to escalate or deescalate a type 2 patients’ therapy based on an A1c, which may or may not accurately reflect the patient’s glycemia, measured every 3-4 months. As only Dr. Hirsch could put it, “It is ok to be glucocentric while treating glucose.” Well said!

Selected Questions and Answers

Q: What do patients do on Libre to improve metabolic control and achieve benefits?

Dr. Bolinder: We don’t know exactly. My personal guess is that they make proactive decisions rather than retrospective analyses. It’s not the one and only value that you measure that’s important, it’s the trend. If you look at where your glucose is heading within the next hour or two, you can make proactive changes. I think this because of the SWITCH study, where patients used a sensor for a period and were switched over to SMBG again. All improvements from using the sensor were damaged when they switched back SMBG.

Q: Do patients/parents need education to use FGM properly because of all  of the data generated?

Dr. Danne: Yes, I think that’s imperative. The first prescription should be made by a diabetes team experienced with the system, one that understands the trends and arrows. It’s not a BGM, but it measures interstitial glucose.

Q: How are reductions in nocturnal hypoglycemia explained without alarms?

Dr. Ramzi Ajjan (Leeds University, UK): Because we review the patterns of glucose. That way we can find hypoglycemias and adjust accordingly. You don’t necessarily need the alarm.

Dr. Bolinder: I’m not an entirely AGP fan, because I think it’s the proactive manner that you make the changes. The highest frequency of scanning [in IMPACT] occurred in the evening before going to bed, then patients can make the adjustments to minimize risk of hypoglycemia during the night. In addition, please remember that these patients also monitored on average 1-2 times every night. That is something that we perhaps had not been aware of. Night contains things that we are not quite aware of that the patients do.

Q: Why was IMPACT restricted to type 1 diabetes with A1c higher than 7.5%?

Dr. Bolinder: Please remember that the aim of the study was to evaluate effectiveness in preventing hypoglycemia. So we selected patients in which you’d expect increased risk of hypoglycemia. We clearly stated that future studies are needed to evaluate the device in other patient groups. The first that comes to mind is patients that don’t achieve targets.

Improving Diabetes Management with Advances in Health Technology (Sponsored by Roche)

Characteristics of the new Accu-Chek Insight CGM system

Günther Schmelzeisen-Redeker (Roche, Mannheim, Germany)

Roche’s Günther Schmelzeisen-Redeker presented the most details ever on its Accu-Chek Insight CGM, which is currently in CE Mark approval trials and on track to launch by the end of the year – we learned today that the initial launch will be limited to “specialized diabetes centers” in the Netherlands, Norway, Denmark, and Sweden. Preliminary pivotal data in 36 patients wearing two sensors each (abdomen) suggests an overall mean ARD of 10.5% over seven days with two fingerstick calibrations per day (n=6,403 paired fingerstick BGM-CGM points). The accuracy was similar across the different glucose ranges (see below), though we’d note very few (3.7%) points in the <70 mg/dl range. Consistent with other CGMs, accuracy was slightly worse on day one (13%) and improved by day seven (9%). The Insight’s accuracy was similar during induced glycemic excursions (10.9%), and a section of the talk highlighted the short five-minute CGM-blood glucose time delay – we assume that is equal to or within a few minutes of other systems and are not sure if it is a clinically meaningful advantage. The sensor has a two-hour warm-up time and seven-day wear.

We also saw the first pictures of the commercial system today (see below), which has a round adhesive, a fairly large on-body transmitter (roughly two thumb drives in size; see second picture for a sense of thickness), and a slightly intimidating syringe-like insertion device. The Bluetooth-enabled transmitter sends data directly to an Android smartphone app, and it appeared that no receiver will be included – this is great to see at launch and key for competition. The app has the standard Roche utilitarian design – nothing flashy and roughly similar-looking to the Accu-Chek Connect BGM app.

• How does the Insight CGM stack up against the competition? This accuracy – if observed in real life –puts Roche right in the ballpark of competitor systems: Abbott’s FreeStyle Libre (11.8% factory cal), Dexcom’s G5 (9.0%, two cals per day), Medtronic’s Enlite 3 (10.5%, two cals per day), and Senseonics’ Eversense (8.8%-11.6%, two cals per day). Of course, it is always difficult to understand how systems compare based on individual trials. Competitively speaking, just as important for the Insight CGM are the cost, insertion process, calibration hassle, and on-body form factor, which appear to lag behind competitors based on what we saw today. It’s excellent to see Bluetooth compatibility and Android at launch.
  
  • Still, we’re glad to see a major player like Roche investing significantly CGM, which should help build the highly underpenetrated EU market. Given the number of patients in need, we believe many companies can be successful and help make CGM standard of care. Of course, Roche also has diversified its portfolio with the Senseonics distribution partnership, giving it two different CGM products to market.

Glucose Range	Mean ARD*	Paired CGM-BGM Points
Overall (40-400 mg/dl)	10.5%	N=6,403
<70 mg/dl	9.4 mg/dl	N=241
70-180 mg/dl	10.5%	N=4,350
>180 mg/dl	10.7%	N=1,812

*SMBG >80 mg/dl – relative differences; SMBG <80 mg/dl – absolute differences

• Study design details: CGM accuracy was compared to BGM (presumably Roche’s own). The study is ongoing, but data presented today was from 36 patients (n=27 type 1s, n=9 type 2s) wearing two CGM systems simultaneously for seven days. On two of the days patients had induced glucose variations, which were not further detailed (e.g., were they on days 4 and 7?). The frequency of SMBG measurement was one per hour during the daytime, and increased to one every 15 minutes during the induced excursions
  
  • Study Design Limitations: The study (i) is smaller compared to competitor studies (e.g., Enlite 3’s pivotal had a remarkable 23,709 total paired CGM-YSI points); (ii) had very few points (3.7%) in hypoglycemia (e.g., Dexcom’s G4 and Software 505 pivotal had 14%-15% of points <80 mg/dl); (iii) included 9 of the 36 patients as type 2s (we’re not sure if they were all on insulin); and (iv) only include two in-clinic days (relative to the typical three in competitor studies of seven-day CGMs). We note the trial did not use YSI, which is a limitation in one sense (doesn’t show the true accuracy of the system), but a strength in another (accuracy vs. BGM is more real-world from a patient perspective).

Questions and Answers

Dr. Boris Kovatchev (UVA, Charlottesville, VA): Do you have data on the frequency of large sensor deviations beyond 20%?

A: I don’t have it with me. We’re in the middle of data evaluation.

Dr. Kovatchev: That would be good to add.

Q: What about newer sensors with no need for calibration?

A: We need calibration – two per day over seven days. We need this for our performance data.

Non Commercial Symposium: New Technologies and Therapies in Diabetes Improving Patient Quality of Life (Sponsored by IDF Europe)

Monitoring Technologies and Apps

Mr. Jaivir Pall (National Health Services, London, UK)

NHS’s Mr. Jaivir Pall shared his takeaways from interviewing people with diabetes about current technology and their biggest needs. He said patients predominantly value three things in devices and apps: (i) support networks; (ii) convenience; and (iii) data access. Moving forward, he said, patients should be more involved in the development of the tools that are designed for them – nothing new there, but we hope to see this implemented far more rigorously and far earlier in the diabetes device design process. Mr. Pall said that only 1.2% of people with diabetes use apps, meaning there is a disconnect between what’s available and what’s desired – we’d note that data is from a 2014 report (Research2Guidance) and has likely improved since that time (e.g., connected CGM, connected BGM, etc.). Still, the point is well taken that apps are not nearly useful enough for a broad population of people with diabetes (not just those interested in data or already doing pretty well). Much of Mr. Pall’s talk shared patients’ most common sentiments about apps and devices, which we found valuable for guiding future developments in the field:

• “I want to connect to people/I want a support network.” Mr. Pall suggested that clinicians can facilitate the formation of such networks, a lot of times, by stepping back and allowing patients to solve problems. His number one advice to the clinician in this case is to “be brave.” Patients frequently mentioned that they would like Facebook and Twitter to help with network building.
  
  • We do wonder what percentage of people with diabetes globally are involved in the diabetes online community – Is it 15 million patients globally? 50 million? We have no idea, but it would be an interesting analysis to see how penetrated the diabetes online community is.
• “Don’t give me something that tries to meet every requirement.” Many patients become frustrated when they have to set up new accounts on new platforms despite already having software that supports the same function. Developers should strive to integrate their function with an existing one, if possible. Mr. Pall gave the example of Skype: if an app offers video chatting, funnel it through Skype so that the user doesn’t have to sign up for an additional account on a new platform. We do agree with the account overload problem but aren’t sure this is going to improve – most legitimate apps require creating an account to store data in the cloud and presumably to secure it.
• “Give me the ability to share my diabetes metrics with whomever I want, but make it easy.” Patients want access to free and actionable information. Mr. Pall described a Facebook group that is just open to patients and automatically populated with data from their Diasend accounts. He claimed that such group-monitoring and management removes stigma, helping people feel comfortable in the community. In fact, in a recent study, he said that patients opting to share their data saw a drop in A1c relative to non-sharers. Mr. Pall couldn’t comment on the size of the effect because it is not yet published. This is not surprising to us – human accountability works wonders for behavior change. The challenge is probably getting the majority of people with diabetes to do this, particularly those who feel guilty about not doing well.

Questions and Answers

Q: It’s excellent to see how patients can, and want to, self-manage. Do you have experience in how healthcare providers think of the sharing of data and networks?

Mr. Pall: Depends on the particular network. At my clinic, providers are very interested in data. They want it all, qualitative and quantitative. It comes down to the person that’s treating you – do they value it? What do they do with it after? I won’t send my information if it’s not being used. Many patients are disengaged because they send the data to providers and it’s not used. There is no parity and the power is all with the clinician. In my mind, the best clinicians respond to all data, whether it’s useful or not. It’s as simple as saying “I saw your results, are you ok? It looks like you go low at such and such time every day. Have you tried this?” It’s a balance of not overworking and burning out, but also having valuable communication with patients. We’re getting into a study where patients are opting to share CGM data with us, and we’re seeing a drop in A1c, improved patient satisfaction, and improved ability to concentrate at work relative to an SMBG cohort. These outcomes are beneficial at the local level and could lead to reimbursement.

Q: The patients you’re talking about are mainly younger, it seems. What age are they? Do you see the way you are collaborating with them as a way to collaborate with older groups as well?

Mr. Pall: On Facebook, they are all of our patients, both young and old. When trying to design a service, we have to get a full spectrum of opinions. On type 2 diabetes, we have a relationship with Diabetes UK which allows us to tap into type 2 diabetes patients across the country. Whenever we devise a project, we go there first to make sure we’re addressing the correct problems. Interestingly, functionality requests across different conditions were often the same – MS patients wanted connectivity as well. Even older patients are asking to interact via Facebook, which surprised me.

Q: How many people are engaging in your forums?

Mr. Pall: Depends on the project. We have 900 on Facebook. Engaged in that population? 10% post daily, 50% would say they interact on those forums. When you look at diabetes overall, only about 1.2% of patients use apps, and that number is expected to climb to 7.8% by 2018 (Editor’s Note: this is a 2014 report from Research2Guidance). Are we designing for the wrong market? We need to leverage what’s already there, not develop new apps. [Editor’s Note: We would debate this point – if what is out there is not being used, it could also be that the apps are not useful enough.]

Q: How easy is it for clients to get in touch with providers through Facebook or Skype? Is it just available at certain hours? Or 24 hours?

Mr. Pall: None of our services are 24 hours. I answer questions whenever I can. In terms of Skype, we’re exploring the way we use it. A lot of UK talk is about sharing information over an unsecured platform, but the risk is fine for me. Patients actually don’t want 24-hour service with Skype. What they really want is to be able to schedule a set time to talk.

Q: It’s interesting that you saw a drop in A1c from those who shared data – can you quantify that drop?

Mr. Pall: The drop is not published so I can’t talk too much. We just asked patients if they wanted to share sensor readouts – no goal for reimbursement, just looking for trends and algorithms across patients.

Q: Who is taking responsibility at the end of the day? What if, through advice coming from networks, through Skype, a patient dies?

Mr. Pall: At a personal level, I’d say I’m responsible. On a systematic level – that is a very good question. A quick anecdote: A woman has been giving advice on Twitter and she is now becoming a certified nurse – does she lose her indemnity? The alternative to this sort of networking is that people don’t get access to the information, so they are actually receiving more harm through inaction. We define inaction as an action. We do give them permission to go to social media, and empower them to validate the information themselves.

Comment: What if the clinician can see hypoglycemia if he’s on duty. Is he obligated to intervene?

Mr. Pall: In the UK, if a doctor drives by a car accident and doesn’t stop, he can be brought before the medical council. So yes, I’d imagine it’d be the same in this case. But I don’t think regulatory should be a barrier to going out and trying all of this.

Novel Therapies

Oral Presentations: GLP-1 Receptor Agonists: The Longer, the Better?

Dose-Dependent Glucose Lowering and Body Weight Reductions with the Novel Oral Formulation of Semaglutide in Patients with Early Type 2 Diabetes

Melanie Davies, MD (University of Leicester, UK)

Dr. Melanie Davies (University of Leicester, UK) presented much-anticipated full results from the phase 2 dose-ranging and escalation trial of Novo Nordisk’s once-daily oral formulation of GLP-1 agonist semaglutide. The double-blind, randomized, parallel-group trial (n=632) consisting of an impressive nine arms: five with escalating doses of oral semaglutide (2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg), two comparator arms with placebo and injectable semaglutide (1 mg dose), and two dose escalation arms in which oral semaglutide was titrated up to 40 mg over either eight weeks or over 26 weeks. Topline results for this trial were shared over a year and a half ago, in February 2015, noting dose-dependent improvements in A1c and comparable weight loss to the once-weekly injectable semaglutide formulation at the highest dose. The full results offered much more granularity on the specific A1c and body weight reductions with each of the five oral semaglutide doses compared to placebo and injectable semaglutide. Oral semaglutide demonstrated significantly greater A1c reductions than placebo at each of the five doses studied: 0.7% with the 2.5 mg dose (baseline A1c=8%, p=0.0069), 1.2% with the 5 mg dose (baseline A1c=7.8%, p<0.0001), 1.5% with the 10 mg dose (baseline A1c=7.8%, p<0.0001), 1.7% with the 20 mg dose (baseline A1c=7.9%, p<0.0001), and 1.9% with the 40 mg dose (baseline A1c=8.1%, p<0.0001). For comparison, the placebo arm experienced an A1c reduction of 0.3% (baseline A1c=8%) and the injectable semaglutide arm experienced an A1c reduction of 1.9% (baseline A1c 7.8%, p<0.0001 vs. placebo).

• Oral semaglutide demonstrated dose-dependent, significantly greater reductions in fasting plasma glucose (FPG) compared to placebo: 1 mmol/l (18 mg/dl) with the 2.5 mg dose (p=0.0078), 1.5 mmol/l (27 mg/dl) with the 5 mg dose (p<0.0001), 2.3 mmol/l (41 mg/dl) with both the 10 mg and 20 mg doses (p<0.0001 for both), and 2.8 mmol/l (50 mg/dl) with the 40 mg dose (p<0.0001), compared to 0.1 mmol/l (1.8 mg/dl) with placebo. That said, the FPG reduction at the highest 40 mg oral dose didn’t quite match the 3.1 mmol/l (56 mg/dl) observed with injectable semaglutide (p<0.0001 vs. placebo).
• Oral semaglutide produced dose-dependent reductions in body weight. Participants experienced a mean body weight reduction of 2.1 kg (~4.6 lbs) in the 2.5 mg dose arm (non-significant vs. placebo), 2.7 kg (~6 lbs) in the 5 mg dose arm (just barely non-signifcant at p=0.0577), 4.8 kg (~11 lbs) in the 10 mg dose arm (p<0.0001), 6.1 kg (~13 lbs) in the 20 mg dose arm (p<0.0001), and 6.9 kg (~15 lbs) in the 40 mg dose arm (p<0.0001). For comparison, participants in the placebo arm lost an average of 1.2 kg (~2.6 lbs) and those in the injectable semaglutide arm lost an average of 6.4 kg (~14 lbs). We were impressed to see that, at the highest dose, the oral formulation of semaglutide was able to match that of the injectable version. Injectable semaglutide is currently in phase 2 for obesity and we’re curious if an obesity indication for oral semaglutide could eventually be possible, though of course it could be cost-prohibitive given that 40 mg once-daily is 280x the dose of 1 mg once-weekly (pricing could also change – it would not necessarily need to be linear).
• A greater proportion of participants on all doses of oral semaglutide were able to achieve an A1c target <7% or body weight loss >5% compared to placebo. 44% of participants treated with 2.5 mg oral semaglutide were able to achieve an A1c<7% (p=0.0142 vs. placebo), as did 81% of participants treated with 5 mg, 84% of participants treated with 10 mg, 86% of participants treated with 20 mg, and 90% of participants treated with 40 mg (p<0.0001 for 5, 10, 20, and 40 mg vs. placebo). For comparison, 28% of participants in the placebo arm and 93% of participants in the injectable semaglutide achieved this goal. In terms of weight loss, a significantly greater proportion of participants in the 10 mg, 20 mg, and 40 mg dose arms were able to achieve body weight reductions ³5% compared to placebo (56% of participants, 64%, and 71%, respectively, p<0.0001). 21% of participants in the 2.5 mg and 5 mg groups achieved this goal, a non-significant difference statistically from the 13% in the placebo group that did so. For comparison, 66% of participants in the injectable semaglutide group were able to achieve this goal.
• Adverse event rates were dose dependent and ranged from 67%-81%. For comparison, adverse event rate in the placebo arm was 68% and in the injectable semaglutide arm was 81%. Notably, however, serious adverse event rate was much lower for every dose of oral semaglutide compared to placebo (1.4%-3% in the oral semaglutide groups vs. 7% in the placebo group). Fast dose escalation of oral semaglutide appeared to be associated with a higher rate of both overall and serious adverse events (86% and 7%, respectively). Treatment discontinuations were higher in all oral semaglutide groups compared to placebo, ranging from 6% to 27% compared to 1.4% with placebo. The treatment discontinuation rate of injectable semaglutide was 15%. As expected, GI side effects were the most common adverse events, with nausea rates of 33%-34% in the 10, 20, and 40 mg dose groups (compared to 13%-14% in the 2.5 and 5 mg dose groups, 1.4% in the placebo group, and 32% in the injectable semaglutide group). Vomiting occurred in 16%-22% of participants in the 10, 20, and 40 mg oral semaglutide groups, compared to 6% in the 2.5 and 5 mg groups, 4% in the placebo group, and 9% in the injectable semaglutide group. We’re curious if the higher rate of vomiting in the oral semaglutide groups may be due to a specific aspect of the mechanism of oral delivery. Diarrhea rates varied across the oral semaglutide dose groups with no clear dose relationship, ranging from 7% in the 2.5 mg group to 14% in the 40 mg group to a high of 23% in the 10 mg group. Diarrhea rates in the placebo group were 10% and 15% in the injectable semaglutide group. Reductions in systolic blood pressure across all doses of oral semaglutide and heart rate increases with the 10 mg and higher doses were comparable to that observed with injectable semaglutide.
• In terms of safety: overall hypoglycemia rate was low, with only two cases of severe hypoglycemia reported in the trial – one in the injectable semaglutide arm and one in the fast dose escalation oral semaglutide arm. Three patients in the trial experienced pancreatitis, two taking oral semaglutide and one taking injectable semaglutide. Three neoplasms were reported as well, two in oral semaglutide-treated arms (one malignant and one benign) and on in the injectable semaglutide arm. Notably, two cardiovascular events occurred in the 71-participant placebo arm while three cardiovascular events occurred in the combined oral semaglutide arms (totaling 491 patients). While it’s obviously impossible to draw any conclusions from such low numbers, taken together with the positive SUSTAIN 6 cardiovascular outcome results for injectable semaglutide, it certainly suggests optimism for a cardiovascular benefit for the oral formulation as well – we look forward to PIONEER 6 shedding more light on this and other important complication questions in the coming years.

Oral semaglutide phase 2 efficacy results summary

	A1c reduction (p-value vs. placebo)	Fasting plasma glucose (FPG) reduction (p-value vs. placebo)	Body weight reduction	Proportion achieving A1c <7% (p-value vs. placebo)	Proportion achieving body weight reduction ³5%
2.5 mg oral semaglutide	0.7% (p=0.0069)	18 mg/dl (p=0.0078)	2.1 kg (~4.6 lbs)	44% (p=0.0142)	21% (p=0.1226)
5 mg oral semaglutide	1.2% (p<0.0001)	27 mg/dl (p<0.0001)	2.7 kg (~6 lbs) (p=0.0577)	81% (p<0.0001)	21% (p=0.1875)
10 mg oral semaglutide	1. 5% (p<0.0001)	41 mg/dl (p<0.0001)	4.8 kg (~11 lbs) (p<0.0001)	84% (p<0.0001)	56% (p<0.0001)
20 mg oral semaglutide	1.7% (p<0.0001)	41 mg/dl (p<0.0001)	6.1 kg (~13 lbs) (p<0.0001)	86% (p<0.0001)	64% (p<0.0001)
40 mg oral semaglutide	1.9% (p<0.0001)	50 mg/dl (p<0.0001)	6.9 kg (~15 lbs) (p<0.0001)	90% (p<0.0001)	71% (p<0.0001)
1 mg injectable semaglutide	1.9% (p<0.0001)	56 mg/dl (p<0.0001)	6.4 kg (~14 lbs) (p<0.0001)	93% (p<0.0001)	66% (p<0.0001)
placebo	0.3%	1.8 mg/dl	1.2 kg (~2.6 lbs)	28%	13%

Corporate Symposium: Facing New Horizons: Optimism & Opportunities in Diabetes Management (Sponsored by Sanofi)

The Next Treatment Options for the Journey Ahead

Clifford Bailey, MD (Aston University, Birmingham, UK)

The always-insightful Dr. Clifford Bailey (Aston University, Birmingham, UK) provided an overview of the positives and potential drawbacks of a wide range of upcoming diabetes treatments under investigation, offering a glimpse at what might be the next frontier of diabetes therapy. Dr. Bailey categorized the investigational treatments into six broad mechanisms of action: (i) support pancreatic beta cells; (ii) curb alpha cells; (iii) enhance incretin effects; (iv) counter insulin resistance; (v) induce glucosuria; and (vi) insulins.

• Support pancreatic beta cells: Dr. Bailey noted that there’s a litany of different candidate classes targeting beta cell function in some way, including glucokinase activators (GKA), imeglimin, GPR40, GPR119, GIP, and PDE inhibitors. He emphasized that it’s extremely difficult to determine at this point which of these strategies will prove successful and underscored that, ultimately, all of these therapies depend on some degree of beta cell function. Given the progressive beta cell decline associated with type 2 diabetes and the current lack of beta cell restoration options, Dr. Bailey suggested that other, non-beta cell strategies of treatment may be more promising in the long term.
• Curb alpha cells: Dr. Bailey did not express a ton of confidence in this strategy for diabetes treatment. He acknowledged that clinical data for Lilly’s discontinued glucagon receptor antagonist LY2409021 demonstrated impressive rapid A1c reductions, but cautioned that if a patient stopped taking the glucagon receptor antagonist, he would quickly experience a rebound in hyperglycemia.
• Enhance incretin effects: Dr. Bailey was very positive about several intriguing therapies in the pipeline that harness the incretin effect. In terms of innovations in delivery, he highlighted Novo Nordisk’s oral formulation of GLP-1 agonist semaglutide and Intarcia’s implantable GLP-1 agonist ITCA 650 (exenatide mini-pump). Looking beyond GLP-1 agonists, Dr. Bailey expressed optimism for GLP-1/glucagon dual agonists, GLP-1/GIP/glucagon triple agonists, and fixed-ratio combinations of GLP-1 agonists and basal insulins.
• Counter insulin resistance: Dr. Bailey particularly highlighted the potential of adiponectin receptor agonism to improve insulin sensitivity and was especially impressed by the preclinical results of small molecule adiponectin receptor agonist AdipoRon.
• Induce glucosuria: After briefly touching on the three currently-available SGLT-2 inhibitors (Lilly/BI’s Jardiance [empagliflozin], J&J’s Invokana [canagliflozin], and AZ’s Farxiga [dapagliflozin]), Dr. Bailey expressed optimism for the potential of SGLT-1 inhibition with Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin. He suggested that the dual inhibitor will be able to offer greater A1c reduction than single SGLT-2 inhibitors through the effect of the SGLT-1 inhibition in the GI tract.
• Insulins: “We gotta get smart.” Dr. Bailey emphasized that glucose-responsive insulin is the next frontier for this class. He outlined two main methods through which to achieve this goal: (i) encasing the insulin in a microencapsulation device or in nanoparticles that break apart and release increasing doses of insulin in response to higher levels of glucose and (ii) attaching an oligosaccharide to insulin so that it will be bound by lectin and inactive until higher concentrations of glucose compete for the lectin binding sites and release the insulin. This was recently discussed at a JDRF forum on smart insulin. 

Corporate Symposium: Type 2 Diabetes: Beyond the Beta Cell (Sponsored by AZ)

Hormonal Dysregulation: What is the Impact on Glycemic Control and the Broader Pathophysiology?

Daniel Drucker, MD (Mount Sinai Hospital, Toronto, Canada)

The always-eloquent Dr. Daniel Drucker (Mount Sinai Hospital, Toronto, Canada) called attention to the role of glucagon and the alpha cell (often overshadowed by the beta cell) in diabetes and expressed enthusiasm for combination and bihormonal therapies around the corner. According to Dr. Drucker, tackling the alpha cell may be just as important as preserving the beta cell in successful approaches to diabetes. He pointed out that alpha cell function is disrupted fairly early on in the progression of this disease, which leads to irregular endogenous glucagon secretion. The precise cause of these alpha cell effects is unknown, but Dr. Drucker explained that the causative factor is likely insulin-independent because research in type 1 diabetes shows that a patient’s abnormal glucagon profile is unimproved even after insulin treatment lowers A1c. Thus, skewed glucagon levels may have an impact on diabetes independent of insulin sensitivity and blood glucose. While diabetes drugs don’t receive much attention for their alpha cell/glucagon effects, Dr. Drucker outlined how GLP-1 agonists (including long-acting, once-weekly exenatide [AZ’s Bydureon]), DPP-4 inhibitors (such as vildagliptin [Novartis’ Galvus]), and amylin analogs are actually quite effective in reducing, and then sustaining low levels of glucagon and in decreasing hepatic glucose production. He described amylin analogs as a “very potent inhibitor of glucagon” which unfortunately haven’t seen much success in global or US markets, perhaps because the product requires multiple daily injections. Notably, SGLT-2 inhibitors increase glucagon levels and hepatic glucose production, but Dr. Drucker qualified that this issue can be easily managed by prescribing a DPP-4 inhibitor alongside an SGLT-2 inhibitor. Fixed-dose combinations of SGLT-2 inhibitors and DPP-4 inhibitors are mechanistically and clinically intriguing, though Lilly/BI’s Glyxambi (empagliflozin/linagliptin) has not appeared to gain significant traction in the US thus far – we believe that could well be due to payers, not to appetite for combo therapy. AZ’s Qtern (saxagliptin/dapagliflozin) was recently approved in the EU and we’re curious if the combination of the two classes will prove more popular in Europe (though we expect reimbursement will be a major challenge in many countries). We felt that Dr. Drucker’s talk provided another strong argument for combination therapies – they can offer multifactorial biological effects and holistic care that matches the complicated molecular machinery underlying diabetes, not to mention greater convenience for patients. Furthermore, Dr. Drucker remarked that while pump devices have mostly relied on insulin so far, the future is bright for bihormonal pump therapy. He concluded with an optimistic statement: “We’re on the cusp of treating diabetes with bihormonal agents.”

Treating Today, Managing for the Future

Marcus Schindler, MD (AstraZeneca, Stockholm, Sweden)

AZ’s head of Cardiovascular and Metabolic Disease Development Dr. Marcus Schindler offered an exciting glimpse into AZ’s areas of focus in terms of promising early-stage diabetes therapies. Echoing executives from other pharmaceutical companies, Dr. Schindler emphasized the need for differentiation for new diabetes candidate therapies – new therapies must provide added value for patients, payers, and society or else payers are unlikely to reimburse them. With this framework in mind, Dr. Schindler highlighted five particularly promising avenues that AZ has invested in: (i) beta cell regeneration; (ii) thermogenesis; (iii) mimic bariatric surgery; (iv) heart failure; and (v) precision medicine. See below for details on AZ’s efforts in each of these areas. We appreciated this look at the future of diabetes therapy from AZ’s perspective and share the excitement over the potential of many of these strategies.

• Beta cell regeneration: Dr. Schindler underscored AZ’s interest in developing a deeper understanding of the beta cell, facilitated by its partnership with Harvard Medical School’s Dr. Doug Melton to produce an unlimited supply of human beta cells for study (and, eventually, for use therapeutically). In Q&A, Dr. Schindler asserted that understanding beta cell biology will be key to decoding type 2 diabetes pathophysiology and to the future of diabetes therapy.
• Thermogenesis: Dr. Schindler expressed optimism on the potential of transforming normal human white adipose tissue into metabolically-active “beige” tissue by inducing upregulation of UCP1. He shared that AZ has identified a small molecule compound that is able to dramatically increase UCP1 in human adipose tissue in vitro and suggested that, as a therapy, this compound could perhaps induce both potent insulin sensitization and weight loss. This is the first that we’ve heard of this candidate and, while it’s clearly very early-stage, we’re intrigued by AZ’s investment in this area and look forward to its fruits.
• Mimic bariatric surgery: Regarding the use of gut hormones to pharmacologically replicate the metabolic effects of bariatric surgery, Dr. Schindler especially highlighted AZ/MedImmune’s phase 1 GLP-1 agonist/glucagon dual agonist MEDI0382. New preclinical data for MEDI0382 will be presented at EASD on Wednesday, September 14 and promising phase 1 results were presented at ADA 2016 this past June. In Q&A, Dr. Schindler suggested that, in the near-term, the most-talked about novel diabetes drug class in the pipeline will be the GLP-1 agonist/glucagon dual agonists. The flurry of industry investment, as illustrated by ourcompetitive landscape, would certainly support Dr. Schindler’s point. Dr. Schindler also noted that there is some interest in FGF21 to pharmacologically achieve the metabolic effects of bariatric surgery, though he felt that the data on the impact of FGF21 on glucose thus far was less compelling than the data on its impact on lipids.
• Heart failure: Dr. Schindler noted that there is significant interest in the use of SGLT-2 inhibitors in heart failure. He further emphasized that the Cardiovascular and Metabolic Disease unit at AZ is focused on multiple, interlinked co-morbidities of diabetes, including heart failure, NASH, and chronic kidney disease. We think it’s very smart of AZ to look at diabetes and its co-morbidities as a cohort – drugs like SGLT-2 inhibitors certainly hint at the potential for pharmacotherapies to address multiple conditions and indications.
• Precision medicine: Dr. Schindler discussed the potential of precision medicine to develop very targeted therapies. In particular, he highlighted the company’s phase 1 anti-microRNA AZD4076, which targets upregulated miR-103/107 in patients with NASH. Thus, it will hopefully eventually be possible to target this therapy to patients with higher levels of miR-103/107. Dr. Schindler also shared that this compound is an insulin sensitizer as well and could be a treatment for both diabetes and obesity and confirmed that this candidate will be injectable. Overall, Dr. Schindler was very optimistic on the prospects of the microRNA field, calling it the “next wave of innovation.” We’ve heard little about concrete precision medicine-based therapies for diabetes and we’re glad to see the promise of harnessing individual characteristics for target treatment coming into fruition and materializing into actual therapeutic candidates.

Obesity

Oral Presentations: Pills or Surgery for Weight Loss?

Coadministration of canagliflozin and Phentermine for Weight Management in Overweight and Obese Adults

Priscilla Hollander, MD (Baylor College of Medicine, Houston, TX)

Dr. Priscilla Hollander presented phase 2 findings that the co-administration of canagliflozin (J&J’s Invokana) and phentermine produced significant weight loss vs. placebo in a 26-week trial enrolling overweight and obese participants without type 2 diabetes, but did not achieve statistically greater weight loss vs. either drug alone. We first saw these results in a poster at ADA 2016. After 26 weeks of treatment, participants randomized to canagliflozin/phentermine coadministration (n=61) experienced 7.5% weight loss on average from a baseline of ~222 lbs (101 kg) vs. 0.6% mean weight loss in the placebo arm (n=57) from a baseline of ~229 lbs (104 kg), p<0.001. Participants receiving 300 mg canagliflozin only (n=53) saw 1.9% weight loss from a baseline of ~227 lbs (103 kg), while those receiving 15 mg phentermine only (n=60) saw 4.1% weight loss from a baseline of ~227 lbs (103 kg). Comparing the canagliflozin/phentermine group with the canagliflozin only and phentermine only groups, there was no statistically significant weight loss benefit to the combination therapy. Dr. Hollander noted that the independent weight loss effects of canagliflozin and phentermine weren’t completely additive in the study, in that average weight loss from coadministration is less than the sum of average weight loss from canagliflozin treatment and phentermine treatment separately. That said, she didn’t rule out the possibility that more substantial weight loss from co-administration could be clinically meaningful – she argued that the two drugs are still working synergistically, and pointed out that individuals taking both agents at once may be compensating for the SGLT-2 inhibitor’s physiological effects by increasing their daily caloric intake. Dr. Hollander concluded that further research into a canagliflozin/phentermine combination will reveal its true potency for chronic weight management.

• Canagliflozin/phentermine coadministration was well-tolerated. Dr. Hollander summarized safety data from the 26-week trial, showing only one serious adverse event (occurring in the combination treatment group), no deaths, and no significant difference in adverse event rates between treatment arms. There were 47 adverse events (57%) in the placebo group, 50 (60%) in the canagliflozin group, 46 (54%) in the phentermine group, and 55 (66%) in the canagliflozin/phentermine group. In total, 22 adverse events led to treatment discontinuation: 5 (6%) in the placebo arm; 9 (11%) in the canagliflozin arm; 5 (6%) in the phentermine arm; and 3 (4%) in the coadministration arm. There were also 69 adverse events that investigators attributed directly to the study drug: 8 (10%) in the placebo group; 21 (25%) in the canagliflozin group; 15 (18%) in the phentermine group; and 25 (30%) in the coadministration group. The most common adverse events were related to osmotic diuresis or were genital mycotic infections occurring in females.

Questions and Answers

Q: Given the current discussion on DKA in response to SGLT-2 inhibitors, I assume that with a combination of canagliflozin/phentermine alongside reduced food intake, the issue came up. Did you see differences in ketone levels between treatment arms?

A: There did not appear to be differences in ketones between treatment groups. But I should emphasize, again, that these were not diabetes patients.

Q: Did you do any analysis that factored in weight loss during the run-in period?

A: Yes, that analysis has been done, but I don’t yet have access to it.

Q: The majority of participants were female, and many would have been around the age of menopause. Do you think menopause symptoms affected any side-effects of patients on phentermine?

A: No, this doesn’t appear to have been the case. Phentermine isn’t used that often in Europe, but the most common side-effects are tachycardia, along with possible increases in blood pressure and insomnia. If we’re thinking about characteristic menopause symptoms – hot flashes, etc. – then there were no increases. We didn’t observe any mood changes or psychological differences.

Q: How does canagliflozin cause weight loss in people who already have normal blood glucose?

A: The molecule lowers the renal threshold, so patients do excrete more glucose, regardless of their baseline glycemia.

Q: I understand that these patients were without diabetes, but perhaps some of them had prediabetes. Have you thought about analyzing the effects of canagliflozin/phentermine on individuals with prediabetes vs. participants with truly normal glycemia?

A: That’s a fantastic question. People with A1c up to 6.5% were enrolled in this study, so there was indeed a small number of patients with prediabetes signed-up, but in our analysis we didn’t see any difference in weight loss for this subset of participants.

Comparable Efficacy and Safety of Liraglutide 3.0 mg for Weight Management Across Baseline BMI Subgroups: Results from the SCALE Obesity and Prediabetes Trial

Sten Madsbad, MD (University of Copenhagen, Denmark)

Dr. Sten Madsbad (University of Copenhagen, Denmark) described glycemic control, body weight, and safety endpoints from a post-hoc analysis of the SCALE trial focused on obesity and prediabetes. While the initial analysis showed that treatment with liraglutide 3.0 mg (Novo Nordisk’s Saxenda) causes significant weight loss and significant delays in the onset of type 2 diabetes, this new post-hoc divided participants from the study into four baseline BMI subgroups: 27-29.9 kg/m² (n=62); 30-34.9 kg/m² (n=624); 35-39.9 kg/m² (n-737); ≥40 kg/m² (n=831). There were no signals for BMI-specific intermediate factors. In other words, the post-hoc analysis found no significant interaction between treatment and baseline BMI in terms of weight loss (p=0.48), change in fasting plasma glucose (p=0.55), or regression to normoglycemia (p=0.92) over three years – the effects of Saxenda on these parameters were sustained across all four BMI sub-groups. The interaction between treatment and baseline BMI did reach near statistical significance for A1c reduction (p=0.06), with a smaller A1c difference between liraglutide vs. placebo in the lowest BMI subgroup (0.01% difference in A1c-lowering). Dr. Madsbad also pointed out the lack of noticeable pattern in treatment-related adverse events (including GI side-effects and hypoglycemia episodes) across baseline BMI subgroups. Overall, he positioned this post-hoc as confirming the efficacy of Saxenda in managing obesity and prediabetes.

Weight Loss (%)

BMI (kg/m2)	Liraglutide 3.0 mg	Placebo	Estimated Difference
27-29.9	5.7	1.8	3.9
30-34.9	6.5	1.7	4.8
35-39.9	6.2	1.8	4.4
>40	5.9	2.1	3.8

Regression to Normoglycemia (%)

BMI (kg/m2)	Liraglutide 3.0 mg	Placebo	Estimated Difference
27-29.9	67	36	31
30-34.9	67	34	33
35-39.9	70	40	30
>40	63	33	30

A1c Reduction (%)

BMI (kg/m2)	Liraglutide 3.0 mg	Placebo	Estimated Difference
27-29.9	0.29	0.28	0.01
30-34.9	0.34	0.14	0.2
35-39.9	0.36	0.13	0.23
>40	0.36	0.14	0.22

Questions and Answers

Q: During three years of this trial, did you find any problems with renal function?

A: No. I haven’t shown this data, but we’ve had a great experience with GLP-1 agonists – and liraglutide, especially – and kidney safety.

Combined Actions of PYY and GLP-1 Contribute to Weight Loss after Roux-en-Y Gastric Bypass

Maria Svane, MD (University of Copenhagen, Denmark)

Sweden’s Dr. Maria Svane (University of Copenhagen, Denmark) showed how the appetite-inhibiting hormones GLP-1 and PYY act in concert to decrease food intake following a patient’s Roux-en-Y gastric bypass (RYGB) surgery. In a small study (n=12 individuals following RYGB, with normal glucose tolerance, mean age 36, mean BMI 33.5 kg/m²), participants were given four treatments on four different days: (i) an injection of GLP-1 antagonist Exendin 9-39 and a sitagliptin (Merck’s Januvia) pill; (ii) an injection of Exendin 9-39 and a placebo pill; (iii) a saline infusion and a sitagliptin pill; and (iv) a saline infusion and a placebo pill. Dr. Svane explained how Exendin 9-39 can differentially suppress action of the GLP-1 hormone, and how the hormone DPP-4 is required to activate PYY – thus, a DPP-4 inhibitor like sitagliptin keeps PYY inactive. This strategic study design allowed researchers to isolate and compare the appetite-inhibiting effects of GLP-1 and PYY post-gastric bypass (on average, participants were enrolled ~5 months after a procedure). Food intake increased 19.5% when patients were treated with both active agents (thus inhibiting both GLP-1 and PYY) vs. placebo (p=0.04). Participants’ food intake also increased slightly when they were given Exendin 9-39 alone (inhibiting just GLP-1) or sitagliptin alone (inhibiting just PYY) vs. placebo, but these increases were not statistically significant. Dr. Svane emphasized the critical takeaway that there are no significant or clinically meaningful effects seen for GLP-1 or PYY alone (as evidenced by the fact that inhibiting one or the other doesn’t markedly increase food intake), but acting in tandem, these hormones effectively suppress a patient’s appetite following gastric bypass surgery. The synergistic effects of GLP-1 and PYY could explain successful maintenance of weight loss post-gastric bypass, and Dr. Svane suggested excitedly that this finding presents new drug targets for obesity pharmacotherapies that can mimic the metabolic effects of bariatric surgery without the same level of risk or invasiveness. Novo Nordisk currently has a PYY candidate (PYY 1562 [NN9747/8]) in its phase 1 pipeline for both diabetes and obesity and the company has shared that the candidate could be co-formulated with once-weekly GLP-1 agonist semaglutide. This study certainly lends support for the efficacy of this approach and we believe it’s likely that Novo Nordisk will pursue this further.

Questions and Answers

Q: I see that you’ve shown how GLP-1 and PYY are important for food intake, but I’m not sure how this shows the mechanism of weight loss via bypass surgery. What would this same study show if healthy people or obese people pre-surgery were enrolled?

A: I’m not aware of a study that has used the same combination of agents in un-operated participants. Studies with infusion of Exendin 9-39 in un-operated subjects have shown that the agent doesn’t increase food intake, but also that PYY secretion is upregulated, so I think ultimately infusion of Exendin-939 would be difficult to interpret.

Q: It seems paradoxical that sitagliptin, which is known to be weight-neutral, has a weight-lowering effect here. Are you aware of any data on the combination of a high-dose GLP-1 agonist with sitagliptin?

A: The weight-neutral effect of DPP-4 inhibitors could be happening through this suppression of PYY. I’m not aware of any studies using the particular combination you mention, but that could be a very interesting approach.

Q: There’s also an increase in GLP-1 hormone when individuals are sleep-deprived, so do you think sleep deprivation has a similar effect?

A: It’s not completely clear whether the same effects occur after sleep. Hormone concentration does consistently increase after sleep, so I think the same mechanisms are operating after bariatric surgery-induced weight loss.

Beneficial Effects of Canagliflozin on Energy Metabolism and Visceral Fat Volume through a Possible Mechanism of Fatty Acid Oxidation in an Animal Model of Obese Type 2 Diabetes

Hiroharu Mifune, MD (Kurume University School of Medicine, Japan)

SGLT-2 inhibitors, and particularly canagliflozin, have shown a pronounced weight loss benefit in individuals without hyperglycemia. Canagliflozin (J&J’s Invokana) can reduce body weight without actually improving glycemic status, and this study in mice was designed to figure out why, according to Dr. Hiroharu Mifune (Kurume University, Japan). Dr. Mifune described how mice with induced obesity and mild hyperglycemia were dosed with either 10 mg/kg of canagliflozin or placebo daily. Canagliflozin treatment resulted in a significant reduction in visceral fat vs. placebo after 14 days (p<0.05). Subcutaneous fat also declined for canagliflozin-treated mice over two weeks, but this reduction was not statistically significant vs. placebo. While this study didn’t yield conclusive evidence on the SGLT-2 inhibitor’s mechanism for weight loss, Dr. Mifune ended his talk with a detailed, multifaceted hypothesis: (i) The drug decreases glucose reabsorption by the kidneys, which in turn leads to greater urinary excretion of glucose and calorie loss – the essential precursor to weight loss; (ii) Excess urinary excretion of glucose makes fat the body’s primary fuel resource, increasing lipolysis and thus lowering adipose tissue volume – another precursor to weight loss; (iii) Increased lipolysis spurs more beta-oxidation and greater synthesis of ketone bodies, which decreases a mouse’s food intake during the light phase – the smaller calorie intake contributes directly to weight loss. On the other hand, the increase in carbohydrate intake among humans on SGLT-2 inhibitors has been well-characterized, so we’re curious how Dr. Mifune’s hypothesis may translate to humans.

Award Lectures and Additional Topics

Award Lectures

Uncomplicating Diabetes: Interactions between Metabolic and Hemodynamic Signaling Pathways in the Pathogenesis of Diabetic Complications

Mark Cooper, MD (Baker IDI Heart and Diabetes Institute, Melbourne, Australia)

After being presented with the Claude Bernard medal – one of the most prestigious awards in diabetes, granted for innovative leadership and lifetime achievement in diabetes research – Dr. Mark Cooper delivered an outstanding lecture exploring some of the possible hemodynamic and metabolic mechanisms underlying diabetic complications. “Glucose control alone is not enough to prevent complications,” he said, “but the way we lower glucose [see EMPA-REG OUTCOME and LEADER] could confer benefit. By working that out, we can optimize our approach to tackling complications.” He went on to detail some of the highlights from his impressive basic science career to date: On the hemodynamic side, he told the story of how ACE inhibitors protected renal function in a diabetic rat model with genetic hypertension, and also reduced atherosclerosis in a diabetes-accelerated atherosclerosis APO-E knockout mouse strain – ACE inhibitors are now used in diabetes treatment for kidney and heart outcomes. On the metabolic side, he focused on reactive dicarbonyl intermediates, glycation byproducts that directly play a role in complications. In an experimental animal model, scavengers of these byproducts effectively reduced renal injury. When ACE inhibitors were combined with these scavengers, Dr. Cooper and colleagues observed a synergistic reduction in complication burden in the animals, suggesting that hemodynamic and metabolic factors work in concert in the development of diabetic complications, and multiple drugs should therefore be combined to address both sides of the equation. Dr. Cooper shared similar stories relating to AGEs (advanced glycation endproducts) and their receptors, ROS (reactive oxygen species; produced by both hemodynamic and metabolic cascades), and TGF-β. Many of his findings have gone on to be therapeutically relevant, and others are on the way; the JDRF just funded an Australian study to investigate whether a NOX1-, NOX4-, and NOX5-selective inhibitor (NOXs produce ROSs) would slow or reverse diabetic kidney disease in type 1 patients with existing albuminuria. Dr. Cooper’s impressive, hypothesis-driven science has carried him a long way, and he has improved the lives of so many people through his work. Huge congratulations to him!

• Dr. Cooper is also investigating the role of epigenetics in the legacy effect. Thus far, his group has found that mTOR, a protein commonly involved in cancer pathology, is methylated less and less as chronic kidney disease progresses. In vitro studies have hinted at a causal relationship, as assaulting endothelial cells with high concentraitons of glucose directly reduces mTOR methylation and leads to an increase in mTOR expression and activity. In addition, Dr. Cooper’s team found that transient hyperglycemia (in vitro) causes persistent histone methylation, even after normal glucose levels have been restored. This work is putting metabolic karma in context, helping the field understand why a period of poor glycemic control can put an individual at risk for complications later on.

Rising Star Symposium

Sander Kooijman, MD (University of Oxford, UK); Francesca D’Addio (San Raffaele Hospital, Milan, Italy); Niina Sandholm, MD (Folkhälsan Research Centre, Helsinki, Finland); Angus Jones, MD (University of Exeter, UK)

Every year, one of our favorite EASD features is the Novo Nordisk-sponsored Rising Star Symposium, which caps off the meeting by bringing promising young investigators to the stage to present the past, present, and future of their research. Drs. Sander Kooijman (University of Oxford, UK), Francesca D’Addio (San Raffaele Hospital, Milan, Italy), Niina Sandholm (Folkhälsan Research Centre, Helsinki, Finland), and Angus Jones (University of Exeter, UK) won the prestigious prize this year and expertly explained their work in physiology, immunology, genetics, and precision medicine, respectively. The session was an absolute pleasure to watch, not only because it represented the next generation of great diabetes scientists who promise to improve the lives of countless patients, but mainly because the work was simply top-notch. See below for our major takeaways from each talk.

• Up first was Dr. Kooijman, who posed an important question: “Should we take cold showers in the morning or in the evening?” “Huh?” was our initial reaction as well, but Dr. Kooijman went on to clarify through data: It is well known that cold exposure enhances fatty acid clearance by brown fat, and that brown fat activation protects from metabolic disorders. It has also been shown that brown fat levels fluctuate cyclically throughout the year, such that there is more in the cold months. Dr. Kooijman keenly observed that the amount of brown fat levels also correlates, perhaps even better, with seasonal night length. A series of experiments in mice have indicated that brown fat activity does, indeed, show strong circadian rhythms, with the highest activity at wakening. Dr. Kooijman concluded by returning to his question, which he hopes to address in the future: Should you shower with cold water in the morning or in the evening? Would it be more beneficial to supplement the activity of already active brown fat when waking, or to activate it when it is relatively dormant (or, we might add, would it be detrimental to alter this cycle at all)?
• Dr. D’Addio gave a rapid-fire presentation on the role of B lymphocytes, specifically regulatory B cells (Bregs) in type 1 diabetes. Though the role of Bregs is often debated (are they involved in the pathology of the disease? If yes, are they protective or harmful?) she posited that naturally occurring Bregs endowed with immunoregulatory properties exist and may protect from diabetes. Further, she suggested that infusion of ex vivo or newly-generated Bregs will likely be feasible, providing a new potential immunotherapy – nice!
• Dr. Sandhoolm reviewed just a few of her incredible findings regarding the genetic background of diabetic nephropathy in type 1 diabetes. She and her colleagues have identified a number of genes that may predispose a person with diabetes to the complication – such important work in the interest of identifying those at risk and intervening. This is an area of high unmet need and we’re glad to see rising stars working to elucidate its genetic basis and pathophysiology – we certainly hope this work can eventually translate into interventional therapies.
• Dr. Jones, a disciple of the 2016 EASD/Novo Nordisk Prize for Excellence winner Dr. Andrew Hattersley (if you didn’t know this fact, you could’ve easily surmised it from observing the beaming Dr. Hattersley in the audience), advocated for the treatment of diabetes patients based not solely on clinical diagnosis, but on C-peptide levels. His premise is simple: Some type 1 patients produce a lot of insulin, and some type 2 patients produce little to no insulin, so the paradigm of assuming that all type 1 patients and very few type 2 patients should be on insulin therapy is flawed. He explained that there are now easy and inexpensive ways to measure C-peptide, and doing so would so would be an efficient way to personalize treatment. For example, patients with low C-peptide levels have markedly reduced responses to GLP-1 agonists, and combining exogenous insulin with medium to high levels of endogenous insulin can put a patient at risk for hypoglycemia. We’re intrigued by the call to better harness C-peptide results to individualize therapy. We’ve also heard ADA Chief Medical Officer Dr. Bob Ratner similarly speak to the commonalities behind type 1 and type 2 diabetes and advocate for a unified view of diabetes pathophysiology.

EASD/Novo Nordisk Foundation Diabetes Prize for Excellence

Andrew Hattersley, MD (University of Exeter, UK)

After accepting the 2016 EASD/Novo Nordisk Foundation Diabetes Prize for Excellence, the brilliant Dr. Andrew Hattersley (University of Exeter, UK) asserted that precision medicine in diabetes is a reality now, though widespread implementation into clinic practice is more challenging than the science itself. Current professional society guidelines call for the tailoring treatments to the severity of diabetes (A1c), not the root cause. Dr. Hattersley illustrated, via a series of case studies, that shifting this paradigm to define and treat the causes of an individuals’ diabetes can improve care. Each story began with a person who was diagnosed with type 1, type 2, or gestational diabetes (one was new British PM Theresa May!), and did not improve on insulin therapy. Each story concluded with an alternate diagnosis and proper treatment leading to better outcomes. For a large number of the cases, the patients actually had forms of monogenic diabetes, and could be easily controlled with an oral medication, diet adjustment, or even the cessation of treatment. For the less cut-and-dry, polygenic varieties of diabetes, Dr. Hattersley is banking on Big Data sets to help elucidate which genetic factors, or even clinical characteristics, correlate with which types of diabetes and which treatment to pair with each diagnosis. He cited MASTERMIND, a consortium that looked at ~50,000 patients in the UK, with preliminary findings that obese people and females see better outcomes on TZDs, while non-obese people and males have better outcomes on sulfonylureas. Indeed, when the GSK ADOPT trial was sub-analyzed, obese females displayed better and prolonged control using TZDs vs. sulfonylureas, while non-obese males showed the reverse (for about three years, after which the therapies appear equally effective). While there has been tremendous progress in the science of precision medicine in diabetes, people are still constantly misdiagnosed. This is in part because a lot of the monogenic forms are so rare that Dr. Hattersley believes some providers aren’t considering them when evaluating patients, and in part because the medical education system has been teaching diabetes simply as type 1, type 2, and gestational for too long. Huge congratulations to Dr. Hattersley on winning the prestigious Prize for Excellence – precision medicine is an exciting but very early field at the moment, and we hope the reality eventually lives up to the hype.

Symposium: New Paths to Tight Glycemic Control

From the Start: Combination Therapy

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

Dr. Stefano Del Prato (University of Pisa, Italy) framed his talk on early combination therapy with a compelling slide to show what is at stake – an estimated ~170 million people with diabetes globally with neuropathy, ~160 million with retinopathy, ~150 million with overt nephropathy, ~80 million with coronary heart disease, and ~25 million with stroke (based on prevalence estimates and the global population of patients). He gave many strong arguments in favor of early combination therapy: pathogenetic complexity of type 2, complementary treatment modes of action, balances efficacy and side effects, potentially more sustained efficacy (to reduce the risk of long-term complications), and better therapy individualization. Dr. Del Prato highlighted “extra-glycemic properties” too, in the wake of cardiovascular benefit from LEADER and EMPA-REG and kidney function benefits for empagliflozin (Wanner et al., NEJM 2016). He urged caution in applying the high-risk population results to newly diagnosed individuals, but was clear that “we have to start factoring these results in.” His talk ran through many combination therapies, but was not prescriptive – in Q&A he recommended clinicians choose the right combination based on the patient in front of them. (Admittedly this is extremely difficult, and the curious clinician seemed a bit let down.) Dr. Del Prato concluded that the field needs to change the type 2 diabetes treatment paradigm to start treating patients much earlier – no argument there.

Clinical Profiling as a Key to Optimal Drug Selection

John Wilding, MD (University of Liverpool, UK)

Dr. John Wilding (University of Liverpool, UK) gave this session on combination therapy a reality check – it is extremely difficult for clinicians to know what drug to choose for a particular patient at a given point in time. The guidelines don’t give enough tools to make precision estimates, do not consider recent outcome trials (they aren’t updated frequently enough), and don’t account for variability of response to treatment. As just one example, Dr. Wilding pointed out the remarkable spectrum of individual patient responses in a dapagliflozin trial: weight change ranged from -15 kg to +10 kg, while A1c changes ranged from -2% to +4%! He also showed a slide with 21 different factors to consider when choosing a drug (see below), an overwhelming task even for the best clinicians. Like Dr. Del Prato, Dr. Wilding seemed to lean towards greater use of SGLT-2s and GLP-1s, given the cardioprotective results (EMPA-REG, LEADER) and weight loss without hypoglycemia. We appreciated his insightful concluding series of questions, (see below) particularly the suggestion that we need more n=1 trials in diabetes – what is best for me based on my data? We think greater use of CGM in type 2 diabetes would help a lot here, particularly something as low-hassle as FreeStyle Libre Pro, which seems ideally designed as a companion diagnostic for prescribing type 2 diabetes drugs. Dr. Wilding noted that prospectively testing every combination and sequence of drugs would not be practical, but pharmacogenomics, other biomarkers (C-peptide), and big data may help HCPs make better treatment choices in the future. We hope digital tools from tech-pharma partnerships (IBM Watson/Novo Nordisk, Sanofi/Verily) can make serious progress on this front.

Key Questions Low weight/accelerated progression. Can we accurately identify those who will need insulin early? Glucose lowering drugs in obese/overweight type 2 diabetes. Should we prioritize weight losing/neutral medications early – is the evidence strong enough? Variability in response: How do we know which is the right drug for each patients (n of 1 trials)? Optimal sequencing of treatment: which drug 1st, 2nd, 3rd? Complications: at what point to modify targets? Can we extrapolate from cardiovascular outcomes studies to lower risk populations?

Factors to Consider When Selecting Appropriate Drugs for Type 2 Diabetes

Patient Characteristics	Co-morbidity	Healthcare System
Patient Preference Age Gender BMI Ethnicity Driving? Disease Duration Occupation/hobbies Lives alone? Social support?	Renal Function Blood Pressure CVD Liver Function Pancreatitis Osteoporosis Cognitive Function Frailty Cancer	Affordability Formulary/Guidelines Education/training

Pre-Conference Sessions

Adherence to Treatment: From Concept to Practice

Gérard Reach, MD (Paris 13 University, Bobigny, France); Kamlesh Khunti, MD (University of Leicester, UK); Klara Pickova (Ambit Media, Prague, Czech Republic); Bastian Hauck, MD (Abenteur Diabetes, Denmark); Guusje Neijens (Diabetescentrum ISALA Zwolle, Netherlands); Joao Raposo (Diabetes Education Study Group, Portugal)

The annual Diabetes Education Study Group (DESG) symposium featured healthcare professional and patient voices on clinical inertia, lack of high-quality diabetes education, and their role in adherence to treatment. Dr. Gérard Reach (Paris 13 University, Bobigny, France) partly attributed less-than-ideal medication adherence to patients’ non-adherence and doctors’ clinical inertia, or patient/provider reluctance to add additional drugs and especially insulin to a treatment regimen. He cited a study published the week prior in Diabetes Care which reported early treatment intensification in only 69% of type 2 diabetes patients with an A1c >7.5% and only 72% of type 2 patients with an A1c >8%. Dr. Reach explained how delaying insulin can give patients the false sense that their disease is not so severe and how it contributes to the misconception that needing insulin is a sign of patient failure, in both cases decreasing medication adherence. He also discussed poor drug adherence in terms of psychological loss aversion – immediate side-effects are given greater mental weight than long-term therapeutic benefits. Dr. Kamlesh Khunti (University of Leicester, UK) elaborated on clinical inertia, advocating for more research on ways to overcome the issue and going so far as to posit that we don’t need new molecules in diabetes care: “We have really good drugs, but we’re just not starting them early enough.” While we don’t agree with this entirely, we did appreciate SO much Dr. Khunti’s emphasis on reducing clinical inertia and his advocacy for high-quality diabetes education programs – we’d love to hear more from AADE and other international educational professional organizations on what is possible. He drew a strong parallel between drugs and education – you wouldn’t buy a drug that hasn’t been rigorously tested for quality, so we shouldn’t sell diabetes education unless it’s of the highest quality. Expanding access to high-quality education programs should be a top priority, in his view. Even where these programs exist, however, patient uptake remains low at ~50%, to which Dr. Khunti argued that we must value diabetes education to the same extent that we value drug therapy.

• “A clinician wants a patient to adhere to treatment, but a person with diabetes wants diabetes to adhere to her life.” Ms. Klara Pickova (Ambit Media, Prague, Czech Republic), a patient with type 1 diabetes, captured wonderfully the major miscommunication that occurs when providers use almost-accusatory words like “non-adherence” or “compliance,” putting undue burden on people who have other stressors beyond diabetes in their lives. The conception of “adherence” as a patient’s responsibility to stick to a treatment regimen, taking the right medications and always eating healthy and exercising, is narrow and reductive. We loved Ms. Pickova’s expansion of the “adherence” definition to make it more productive in helping patients achieve the best possible health outcomes – in her view, solutions to improve patient engagement rest on healthcare professionals identifying what’s important to a real-world patient and aligning diabetes care with those goals. Like us, many in the room found this quote powerful. In fact, Dr. Bastian Hauck (Abenteur Diabetes, Denmark) shared that he felt compelled to tweet the quote immediately, and that the online diabetes community was reacting to it almost instantaneously.
• Pharmaceutical companies must play a role in enhancing education programs, according to Portugal’s Dr. Joao Raposo. He suggested that pharma might present the ideal opportunity for enhanced diabetes education. For a new diabetes drug to be successful today, Dr. Raposo explained, companies have to sell not only the medicine but a slew of support services to make the product attractive and user-friendly. “Now is the moment for people interested in education to approach pharma and make sure they’re selling quality-assured education programs.” We were very intrigued by Dr. Raposo’s idea – how fantastic would it be for companies with the resources for quality assurance to provide the diabetes education necessary to help patients understand their condition and to motivate them to remain engaged in their diabetes care over the long term?
• Dr. Hauck’s talk highlighted the potential for social media to provide round-the-clock support for patients with diabetes. He shared several anecdotes to illustrate this: For example, a 19-year-old patient wakes up in the middle of the night with hypoglycemia and drinks orange juice, but is still wondering whether it’s okay to go back to sleep, whether he should take insulin, etc. The patient can feasibly get answers to these questions from other members of his online diabetes community, living in another time zone halfway around the world. Dr. Hauck underscored the value of real-time information and support. In response to a question about the accuracy of online information, he clarified that social media will never replace medical advice, but that we can increase the validity of this information by encouraging healthcare professionals to also participate.
• Ms. Guusje Neijens (Diabetescentrum ISALA Zwolle, Netherlands) made a strong case for the role of diabetes coaches in adherence. She pointed out that knowledge isn’t enough – people are aware that exercise is good for you, but not everyone partakes every day. A diabetes coach can provide essential motivation and psychosocial support to a patient juggling diabetes among many other real-life stressors. Ms. Neijens remarked that coaching is unfortunately not well-reimbursed and that few can make diabetes coaching their full-time job. We’ve heard much commentary lately about the need for better reimbursement of diabetes coaches, as recently as AADE 2016 in August.

Diabetes and Bone Symposium

Richard Eastell, MD (University of Sheffield, South Yorkshire, UK); Serge Ferrari, MD (Geneva University Hospital, Geneva, Switzerland); Claus Glüer, MD (Kiel University, Kiel, Germany); Martina Rauner, MD (Technical University of Dresden, Dresden, Germany); Nicola Napoli, MD (Campus Bio-Medico University, Rome, Italy)

This intimate pre-conference symposium provided a lively discussion of increased fracture risk in people with diabetes – an issue the interdisciplinary panel of both diabetes and bone specialists agreed is seriously “undertreated and overlooked.” Bone density is an excellent predictor of fracture risk, but Dr. Richard Eastell (University of Sheffield, South Yorkshire, UK) explained that this bone density/fracture risk profile is shifted in people with diabetes, such that for the same level of bone density, people with diabetes have a greater risk of fracture than people without diabetes (accounting for fall risk), and the trend is even stronger for people with diabetes on insulin. Furthermore, people with diabetes recover poorly from fractures: following fracture, diabetes is associated with longer hospital stays and increased risk of delayed healing and non-union of the bone. Dr. Serge Ferrari (Geneva University Hospital, Geneva, Switzerland) went on to explain that the correlation between diabetes and fracture risk is not well-understood, and the phenomenon is quite nuanced, differing between type 1 and type 2 diabetes. Paradoxically, while both type 1 and type 2 diabetes are associated with elevated fracture risk (increased by 200% for type 1 and up to 70% for type 2), type 1 and 2 diabetes have opposing effects on bone mineral density (BMD): people with type 1 diabetes tend to have low BMD, whereas people with type 2 diabetes tend to have high BMD. How diabetes increases fracture risk and why this occurs independently of bone density remains mysterious to orthopedists and endocrinologists alike. Perhaps an even greater mystery, according to Dr. Ferrari, is why fracture risk is “not yet recognized as a major complication of diabetes,” given the “overwhelming” evidence on this phenomenon.

• A theme throughout the symposium was the need for “endocrinologists of the bone,” or diabetes doctors who understand how various diabetes drugs will affect patients at risk of fracture. Indeed, diabetes drugs have variable effects on fracture risk:
  
  • GLP-1 agonists: No known effect on bone health.
  • DPP-4 inhibitors: Possible preventative effect on bone health according to meta-analyses.
  • SGLT-2 inhibitors: May be detrimental to bone health. Dapagliflozin non-significantly reduces bone mineral density and canagliflozin is associated with increases in CTX markers, a biomarker of bone degradation.
  • Insulin: Increases fracture risk.
  • TZDs: May increase fracture risk in women.
• “The skeleton is one of the largest glucose-consuming organs of the body, and it is being completely overlooked in the context of diabetes.” Indeed, preliminary evidence suggests that diabetes alters bone structure, chemical composition, and cell signaling pathways within the skeleton. This complication of diabetes is highly under-investigated and under-discussed (it often plays second fiddle to the well-characterized micro- and macrovascular complications of diabetes), and we appreciate the increased attention it received at EASD.  
• Among people with diabetes, emerging evidence suggests an association between the severity of their microvascular diabetes complications and the magnitude of microstructural alterations to the bones. This suggests that diabetes’ effect on the skeleton may fundamentally originate from an altered supply of blood to the skeleton. We’re intrigued by this connection and hope that future research will delve into the relationship further.

Corporate Symposium: Facing New Horizons: Optimism & Opportunities in Diabetes Management (Sponsored by Sanofi)

Debate: Sequential vs. Simultaneous Intensification – A New Management Paradigm

Julio Rosenstock, MD (UT Southwestern, Dallas, TX); Neil Skolnik, MD (Temple University, Philadelphia, PA)

A heated debate featuring Dr. Julio Rosenstock (UT Southwestern, Dallas, TX) and Dr. Neil Skolnik (Temple University, Philadelphia, PA) unraveled the controversy over whether diabetes combination therapies should be implemented simultaneously or sequentially:

• Dr. Rosenstock staunchly argued that an aggressive, simultaneous approach to beginning a combination therapy regimen will produce better diabetes outcomes. He characterized the current AACE/ACE and ADA/EASD diabetes treatment guidelines – both of which follow the broad pattern of metformin as first-line therapy, followed by the gradual addition of other agents – as unhelpfully promoting a “treat-to-fail” paradigm whereby therapy is intensified only after patients begin failing to meet their treatment goals.  He envisions a future in which it is standard to treat everyone with “one pill of metformin and SGLT-2 inhibitor and one injection of insulin and GLP-1 agonist” – what a vision indeed (and one that would likely do away with complex diabetes treatment algorithms)! We think it’s a hassle for patients to be constantly switching from one therapy or other and believe that for many (but not all) patients, greater consideration of combination therapy, now that so much more is available, would be very helpful. Dr. Rosenstock drew support for the superiority of simultaneous initiation of combination therapy by comparing the results of his own GetGoal Duo 1 study, in which lixisenatide is added sequentially on top of an existing insulin glargine regimen, to the LixiLan-O and LixiLan-L trials, in which lixisenatide and insulin glargine were administered in a fixed-ratio coformulations. Though the study populations were similar, the sequential GetGo Duo 1 trial produced an average A1c of 7%, as opposed to an “unprecedented” 6.4% and 6.5% respectively in LixiLan-O and LixiLan-L.
• Taking the opposite position, Dr. Skolnik reminded the audience that no clinical trial to date has been designed to directly compare the efficacy of a simultaneous versus sequential approach to diabetes combination therapy. “The cure for clinical inertia is not throwing more medications at patients,” Dr. Skolnik argued, insisting that monotherapies can be effective so long as titration is done effectively. This, of course, is much easier said than done – clearly, today, for a broad population of patients, it is being done poorly. His comments were also murky – throwing “more” drugs is the last thing Dr. Rosenstock was arguing – the entire beauty of combo therapy is giving patients less to think about (one drug not too) and presumably switching far less often. Dr. Skolnik surmised his position with a quote from Mark Twain: “What gets us into trouble is not what we don’t know. It’s what we know for sure that just ain’t so.” In his view, though the idea of combatting the progression of diabetes with an aggressive combination of complementary drugs is intuitively appealing, there simply is no empirical data to support the superiority of simultaneous versus sequential therapy. Ironically, though the entirety of this Sanofi-sponsored symposium on GLP-1 agonist/insulin fixed-ratio combinations was overwhelmingly dominated by strong sentiments on the pro-simultaneous combination therapy side, Dr. Skolnik’s argument in favor of a sequential approach gained a fair amount of audience support – it isn’t surprising from our view that this “theory” is “theoretically” appealing but in practicality doesn’t work for so many patients. Symposium attendees took a blinded poll on simultaneous versus sequential approaches to diabetes combination therapy both before the debate began and after hearing Dr. Rosenstock’s and Dr. Skolnik’s competing arguments. Prior to the debate 80% of the audience voted in favor of initiating a combination therapy regimen simultaneously, and although this fell to 60% at the symposium’s end, we still believe there is major support for combo approaches – particularly when the “real world” outcomes are considered. Although we are skeptical of the effectiveness of delaying the initiation of a more potent and aggressive treatment regimen, especially given the existing long delays in diabetes treatment escalation, Dr. Skolnik brings up points that undoubtedly payers will – from our view, that is the biggest worry that payers won’t want to reimburse the therapies that clearly work well.  While Dr. Skolnik’s point that the field must be careful not to let our clinical decision-making extend past the available evidence is well-taken theoretically, we think additional trials and big data will continue to show better outcomes with the approaches that have greater potency and less hassle.

How Close Are We to Revolutionizing Diabetes Management?

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

Dr. William Cefalu discussed recent developments in diabetes to answer the question of whether we are on the verge of a revolution in diabetes treatment. In regard to "precision medicine", he suggested “not quite yet”, but with new technology, computational power, etc., small steps are being taken each year. He also went through an exercise as to what treatment guidelines would look like today if we "wiped the slate clean” and based only on recent evidence as opposed to changing current diabetes treatment guidelines for a true paradigm shift. He reviewed a series of exciting developments in the diabetes field, including the individualization of A1c targets, a greater push to counteract clinical inertia through aggressive sequential therapy intensification or early use of simultaneous combination therapy, the increasingly mainstream acceptance of bariatric surgery as a legitimate diabetes treatment for some patients, and the use of precision medicine to both potentially identify which patients will best respond to lifestyle therapy and to create targeted pharmacogenetic therapies for specific subtypes of diabetes. Despite these exciting new developments, Dr. Cefalu acknowledged that current diabetes treatment hasn’t been “revolutionized” (defined as “changed radically or fundamentally”) yet, but emphasized that each year brings small steps toward a true paradigm shift. In fact, Dr. Cefalu suggested that in 10-15 years, diabetes treatment could be well on its way toward this goal. Turning to the current diabetes treatment algorithm paradigm, Dr. Cefalu proposed a new goal-oriented treatment paradigm (see below). Most notably, Dr. Cefalu’s algorithm called into question metformin’s long-standing position as the go-to first-line diabetes therapy for patients with type 2 diabetes and suggested that while it may remain preferred for many patients, other diabetes drug classes could also be considered as first-line options. Dr. Cefalu acknowledged that physicians such as Dr. Skyler have previously argued against the use of metformin as the first-line treatment for the majority of patients. In addition, Dr. Cefalu’s schematic strongly emphasizes therapy intensification if A1c is greater than 7% and explicitly offers initial combination therapy initiation with either insulin and oral agents, GLP-1 agonists and oral agents, or a combination of oral agents. Aggressive goal-oriented treatment intensification and the option to use combinations of diabetes drugs has a role in the current ADA/EASD and AACE/ACE guidelines as well, though Dr. Bailey’s graphic brings these two points front and center. Still, the point is well-taken – perhaps it’s time for a bottom-up redesign of treatment algorithms as opposed to periodic and fairly minor updates.

Corporate Symposium: Type 2 Diabetes: Beyond the Beta Cell (Sponsored by AZ)

Hormonal Dysregulation: What is the Impact on Glycemic Control and the Broader Pathophysiology?

Daniel Drucker, MD (Mount Sinai Hospital, Toronto, Canada)

The always-eloquent Dr. Daniel Drucker (Mount Sinai Hospital, Toronto, Canada) called attention to the role of glucagon and the alpha cell (often overshadowed by the beta cell) in diabetes and expressed enthusiasm for combination and bihormonal therapies around the corner. According to Dr. Drucker, tackling the alpha cell may be just as important as preserving the beta cell in successful approaches to diabetes. He pointed out that alpha cell function is disrupted fairly early on in the progression of this disease, which leads to irregular endogenous glucagon secretion. The precise cause of these alpha cell effects is unknown, but Dr. Drucker explained that the causative factor is likely insulin-independent because research in type 1 diabetes shows that a patient’s abnormal glucagon profile is unimproved even after insulin treatment lowers A1c. Thus, skewed glucagon levels may have an impact on diabetes independent of insulin sensitivity and blood glucose. While diabetes drugs don’t receive much attention for their alpha cell/glucagon effects, Dr. Drucker outlined how GLP-1 agonists (including long-acting, once-weekly exenatide [AZ’s Bydureon]), DPP-4 inhibitors (such as vildagliptin [Novartis’ Galvus]), and amylin analogs are actually quite effective in reducing, and then sustaining low levels of glucagon and in decreasing hepatic glucose production. He described amylin analogs as a “very potent inhibitor of glucagon” which unfortunately haven’t seen much success in global or US markets, perhaps because the product requires multiple daily injections. Notably, SGLT-2 inhibitors increase glucagon levels and hepatic glucose production, but Dr. Drucker qualified that this issue can be easily managed by prescribing a DPP-4 inhibitor alongside an SGLT-2 inhibitor. Fixed-dose combinations of SGLT-2 inhibitors and DPP-4 inhibitors are mechanistically and clinically intriguing, though Lilly/BI’s Glyxambi (empagliflozin/linagliptin) has not appeared to gain significant traction in the US thus far – we believe that could well be due to payers, not to appetite for combo therapy. AZ’s Qtern (saxagliptin/dapagliflozin) was recently approved in the EU and we’re curious if the combination of the two classes will prove more popular in Europe (though we expect reimbursement will be a major challenge in many countries). We felt that Dr. Drucker’s talk provided another strong argument for combination therapies – they can offer multifactorial biological effects and holistic care that matches the complicated molecular machinery underlying diabetes, not to mention greater convenience for patients. Furthermore, Dr. Drucker remarked that while pump devices have mostly relied on insulin so far, the future is bright for bihormonal pump therapy. He concluded with an optimistic statement: “We’re on the cusp of treating diabetes with bihormonal agents.”

Should glycaemic control be central to the management of Type 2 diabetes?

Tina Vilsbøll, MD (University of Copenhagen, Denmark)

Dr. Tina Vilsbøll spoke to the landscape-altering effects of cardiovascular outcomes trials (CVOTs), which are paving the way for a future in which patients can be treated for both hyperglycemia and macrovascular complications with just one or two drugs. She particularly expressed excitement over the EMPA-REG OUTCOME, LEADER, and SUSTAIN 6 results – but acknowledged that these trials were performed in largely populations with existing cardiovascular disease, which precludes generalizability to the wider population (although almost a fifth of participants in both LEADER and SUSTAIN 6 were over 60 years of age and at high risk, but did not have a history of cardiovascular disease). On the other hand, ongoing CVOTs, such as the DECLARE trial for AZ’s Farxiga (dapagliflozin; expected completion by April 2019, according to ClinicalTrials.gov), are also examining medications in even lower risk, younger (aged 40 and over) “primary prevention” populations. Dr. Vilsbøll underscored that 20% of patients with diabetes already have (usually) irreversible microvascular complications at diagnosis, and over 50% will develop them over the course of the disease. The ability of GLP-1 agonists and SGLT-2 inhibitors to apparently address both hyperglycemia and cardiovascular concerns leads Dr. Vilsbøll to believe that this is a particularly exciting and pivotal time for the management of diabetes. Of course, the success seen in CVOTs isn’t the end of the line; more work needs to be done to elucidate the mechanism underlying the therapies’ cardioprotective effects and to identify the patient populations most suited to particular agents. That said, even if the mechanism isn’t well understood, we don’t think that’s a reason not to use it – the mechanism for metformin, as just one example, also isn’t particularly well understood.  

Treating Today, Managing for the Future

Marcus Schindler, MD (AstraZeneca, Stockholm, Sweden)

AZ’s head of Cardiovascular and Metabolic Disease Development Dr. Marcus Schindler offered an exciting glimpse into AZ’s areas of focus in terms of promising early-stage diabetes therapies. Echoing executives from other pharmaceutical companies, Dr. Schindler emphasized the need for differentiation for new diabetes candidate therapies – new therapies must provide added value for patients, payers, and society or else payers are unlikely to reimburse them. With this framework in mind, Dr. Schindler highlighted five particularly promising avenues that AZ has invested in: (i) beta cell regeneration; (ii) thermogenesis; (iii) mimic bariatric surgery; (iv) heart failure; and (v) precision medicine. See below for details on AZ’s efforts in each of these areas. We appreciated this look at the future of diabetes therapy from AZ’s perspective and share the excitement over the potential of many of these strategies.

• Beta cell regeneration: Dr. Schindler underscored AZ’s interest in developing a deeper understanding of the beta cell, facilitated by its partnership with Harvard Medical School’s Dr. Doug Melton to produce an unlimited supply of human beta cells for study (and, eventually, for use therapeutically). In Q&A, Dr. Schindler asserted that understanding beta cell biology will be key to decoding type 2 diabetes pathophysiology and to the future of diabetes therapy.
• Thermogenesis: Dr. Schindler expressed optimism on the potential of transforming normal human white adipose tissue into metabolically-active “beige” tissue by inducing upregulation of UCP1. He shared that AZ has identified a small molecule compound that is able to dramatically increase UCP1 in human adipose tissue in vitro and suggested that, as a therapy, this compound could perhaps induce both potent insulin sensitization and weight loss. This is the first that we’ve heard of this candidate and, while it’s clearly very early-stage, we’re intrigued by AZ’s investment in this area and look forward to its fruits.
• Mimic bariatric surgery: Regarding the use of gut hormones to pharmacologically replicate the metabolic effects of bariatric surgery, Dr. Schindler especially highlighted AZ/MedImmune’s phase 1 GLP-1 agonist/glucagon dual agonist MEDI0382. New preclinical data for MEDI0382 will be presented at EASD on Wednesday, September 14 and promising phase 1 results were presented at ADA 2016 this past June. In Q&A, Dr. Schindler suggested that, in the near-term, the most-talked about novel diabetes drug class in the pipeline will be the GLP-1 agonist/glucagon dual agonists. The flurry of industry investment, as illustrated by ourcompetitive landscape, would certainly support Dr. Schindler’s point. Dr. Schindler also noted that there is some interest in FGF21 to pharmacologically achieve the metabolic effects of bariatric surgery, though he felt that the data on the impact of FGF21 on glucose thus far was less compelling than the data on its impact on lipids.
• Heart failure: Dr. Schindler noted that there is significant interest in the use of SGLT-2 inhibitors in heart failure. He further emphasized that the Cardiovascular and Metabolic Disease unit at AZ is focused on multiple, interlinked co-morbidities of diabetes, including heart failure, NASH, and chronic kidney disease. We think it’s very smart of AZ to look at diabetes and its co-morbidities as a cohort – drugs like SGLT-2 inhibitors certainly hint at the potential for pharmacotherapies to address multiple conditions and indications.
• Precision medicine: Dr. Schindler discussed the potential of precision medicine to develop very targeted therapies. In particular, he highlighted the company’s phase 1 anti-microRNA AZD4076, which targets upregulated miR-103/107 in patients with NASH. Thus, it will hopefully eventually be possible to target this therapy to patients with higher levels of miR-103/107. Dr. Schindler also shared that this compound is an insulin sensitizer as well and could be a treatment for both diabetes and obesity and confirmed that this candidate will be injectable. Overall, Dr. Schindler was very optimistic on the prospects of the microRNA field, calling it the “next wave of innovation.” We’ve heard little about concrete precision medicine-based therapies for diabetes and we’re glad to see the promise of harnessing individual characteristics for target treatment coming into fruition and materializing into actual therapeutic candidates.

Posters

Cost of Severe Hypoglycemia among Patients with Type 2 Diabetes in the UK, by Treatment Regimens

T Holbrook, K Tunceli, J Williams, R Das, Y Tang, R Shankar, J Chen, L Radican, and J Piercy

This study looked at the frequency and cost of hypoglycemia-related hospitalizations in the UK between 2008-2014, and found that both insulin and sulfonylureas were associated with high hypoglycemia hospitalization rates, while no severe hypoglycemic events were seen in patients treated solely with a DPP-4 inhibitor or with metformin plus a DPP-4 inhibitor. The results were based on data on 110,206 patients with type 2 diabetes, compiled from the Clinical Practice Research Datalink. The event rate for hypoglycemia hospitalizations was greatest for insulin only treatment regimens at 16.8/1,000 person-years, followed by insulin plus non-sulfonylurea oral agents at 12.1/1,000 person-years. Monotherapy with sulfonylureas corresponded to a hypoglycemia hospitalization rate of 7.8/1,000 person-years. The researchers also examined average length of hospital stay and mean cost. Patients on sulfonylurea monotherapy who experienced severe hypoglycemia were in the hospital for 7.3 days on average, followed by insulin monotherapy at a close second of 7.1 days per hospitalization. When excluding excess bed days, all instances of severe hypoglycemia were expensive, with an overall mean cost of 1,351£ ($1,722). Average cost was highest for sulfonylurea-only regimens, at 1,576£ ($2,008). Notably, individuals >80 years-old were most affected by hypoglycemia regardless of treatment regimen, experienced a mean 7.2-day hospital stay for an episode of severe hypoglycemia (vs. 6.4 days for those 65-79 and 3.6 days for those <65), and cost the healthcare system 1,486£ ($1,894) per hospitalization (vs. 1,374£ or $1,751 for those 65-79 and 883£ or $1,125 for those <65).

• These results further underscore the health economic argument in favor of non-insulin alternatives to sulfonylureas. While the older generic class remains an unfortunate popular option for patients without access newer branded medications, the downstream costs of SU-induced hypoglycemia – not to mention the impact on patient safety and quality of life – are unconscionable for many patients. We hope data like this can help convinced payers to offer better coverage of safer alternatives for those at high risk for hypoglycemia and severe hypoglycemia, such as DPP-4 inhibitors for those early in disease progression, SGLT-2 inhibitors, and/or GLP-1 agonists.
• Regarding the insulin results, we’d be curious to see a breakdown of the hypoglycemia costs associated with use of human insulin versus insulin analogs (Sanofi’s Lantus [insulin glargine] or Lilly’s Humalog [insulin lispro], for instance) or next-generation insulin analogs (Novo Nordisk’s Tresiba [insulin degludec] or Sanofi’s Toujeo [U300 insulin glargine]). We suspect that newer basal insulins with longer, flatter profiles of action will have lower downstream costs associated with hypoglycemia, especially given the recent SWITCH 1 and 2 data for Tresiba demonstrating significant reductions in severe, symptomatic confirmed, and nocturnal hypoglycemia.

Health Economic Impact of Hypoglycemia Among 7289 Insulin-Treated Patients with Diabetes: Results from an International Survey in Nine Countries

S-Y Goh, S Abusnana, R Emral, R Mirasol, A Murphy, F Pathan, A Rudijanto, V Chan, A Jain, CA Yepes Cortés

This six-month retrospective, four-week prospective study probed for the real-world implications of hypoglycemia around the world, gathering data on patients (n=7,289) with type 1 or type 2 diabetes diabetes from Bangladesh, Colombia, Egypt, Indonesia, the Philippines, Singapore, South Africa, Turkey and the United Arab Emirates. Rate of hypoglycemia was 4.8 events per-person/per-month for type 1 diabetes patients during the retrospective period and 6.9 events per-person/per-month during the prospective period. The greatest direct impact of hypoglycemia was increased blood glucose monitoring, which occurred in 44% of type 1 patients and in 20% of type 2 patients in the four weeks of follow-up. Hypoglycemia also increased the frequency of telephone contacts with a healthcare team member, clinic appointments, and hospital admissions and led patients to avoid exercise, reduce their insulin dose, and skip insulin injections. The authors list indirect impacts of hypoglycemia as well, including reduced punctuality or more absences at work or school, reported by 6% of type 1 diabetes patients and by 4% of type 2 diabetes patients.

Daytime napping and the risk of metabolic diseases: dose-response meta-analysis

Y Tomohide, N Shojima, T Yamauchi, T Kadowaki

A poster by Dr. Yamada Tomahide and colleagues (University of Tokyo, Japan) described the results of a recent study (n=307,237) demonstrating that long daytime naps of 60 minutes or longer are associated with a 45% increased risk of developing type 2 diabetes. A pooled meta-analysis of 21 sleep study results showed a J-shaped relation: there was no effect of napping on diabetes risk for naps up to about 40 minutes a day, but a sharp increase in risk occurred at longer times, becoming clinically significant for naps lasting 60 minutes and onward. The authors postulate that daytime napping might be a consequence of nighttime sleep disturbance such as obstructive sleep apnea (OSA), which is independently linked to heart attacks, stroke, and other cardiovascular events that may be correlated with type 2 diabetes risk. Furthermore, long daytime naps may signify nighttime sleep deprivation, which is linked to changes in leptin and ghrelin levels in addition to increased hunger and impaired carbohydrate metabolism. There is also the possibility of reverse causality – the people taking long daytime naps could be more likely to be ill and have various risk factors for diabetes, morbidity, or mortality. Of course, this is an observational study that does not point toward any causal relationship between type 2 diabetes and hour-long naps. In fact, the authors pointed out that existing research suggests that short naps – especially ones fewer than 30 minutes – might even have beneficial effects on diabetes: short naps are known to modify a variety of endocrine abnormalities, although the mechanisms of this phenomenon are unclear and a specific benefit for diabetes has yet to be demonstrated. Clearly further research is required to dissect this complex, duration-dependent relationship between sleep and diabetes. Our interest is piqued and we await updates in future studies, particularly with regard to the direction of causality – does diabetes risk modify sleep, or does sleep instead play a role in diabetes risk?

Exhibit Hall

Exhibit Hall – Diabetes Technology

Abbott

Upon entering the exhibit hall, Abbott’s setup immediately caught our eye with shiny yellow branding and a lengthy queue of excited attendees waiting to take home their very own (free) FreeStyle Libre sensors. The company also focused heavily on the LibreLink Android app (currently available in Sweden, the Netherlands, Germany, Italy, and the UK) – as we arrived, a packed lecture about the app was just wrapping up in the middle of the exhibit, and the buzz was extremely positive as attendees filed out. The clever “You Can Do It” marketing campaign was extended to LibreLink: “Patients can do it with their phone,” featuring a cyclist happily swiping the Libre sensor. This is a very appealing campaign. Reps were very enthusiastic about the Lancet publication of data from the IMPACT trial and partnerships with mySugr and Social Diabetes (coverage here). In terms of presentation, one corner of the booth featured a touchscreen with rotating pictures of people and their accompanying testimonials about the Libre. Our personal favorite? “Just keep calm, flash and carry on!!” Reps did not have any FDA updates on FreeStyle Libre, though the Pro version was approved shortly after EASD and the real-time consumer version was submitted to FDA in August.  

Ascensia

Ascensia’s futuristic, white booth mainly focused on the Contour Next One Bluetooth-enabled BGM – currently available in Switzerland and Poland, with more EU launches planned for later this year (it was cleared in May). We got to demo one of the meters ourselves (using sugary food coloring), and then explore the Contour app both in real life and in virtual reality. For the latter, a rep situated us in a sound-dampening egg-shaped chair and fitted us with VR glasses, and we were transported to what looked like a typical den, only with a giant floating app interface before us. We were led through the process of testing our blood glucose, logging a picture of the sushi that we had just “eaten,” and examining a trend graph. Cool! Even though the app hasn’t reached holographic status just yet in the real world, we still commend Ascensia for it’s easy-to-use interface.

BD

BD’s showed off its most highly anticipated pipeline product (with partner Medtronic), the MiniMed Pro-set with BD FlowSmart technology – this was the first time we’ve seen it on European soil, and only the second time in an exhibit hall (following AADE last month). Reps maintained that the set is slated for a limited (at least 1,000 patients) launch in the US and France to collect user feedback, followed by a full-scale, global launch around December. [Read our coverage of the early October launch here and our initial test drive of the set here.]. New to us was the soon-to-be launched patient education website “BD and Me.” The site intends to “bring diabetes education to life” by offering eight online video courses on the newly released FITTER-based injection recommendations. This is excellent to see, as one of the main comments on the recent FITTER publications (Mayo Clinic Proceedings) noted the challenge of wide dissemination. There are so many learnings from FITTER that we think so many patients don’t know (as well as HCPs) so this should be very positive. Starting this December in the UK, and soon thereafter in other countries (eventually it will be global), providers will be able to refer patients to these video lessons for quick and easy instruction and refreshers – nice! In light of FITTER’s commentary on needle length and sharps disposal, the booth also had a demo table with the compelling AutoShield safety 4-mm pen needles – we continue to see this as an example of very meaningful “low tech” innovation that still makes a huge difference for patients.

Dexcom

Dexcom’s sported a small but busy booth with a lineup of iPhones displaying the G5 app. Handouts highlighted the positive CGM reimbursement decision in Germany (see our June coverage), though despite Dexcom’s press release last week (that was a bit confusing to us), we confirmed that the company still has to negotiate pricing and contract with payers – but hearing that it will be reimbursed in Germany was a massive win! Dexcom’s 2Q16 call noted that a revenue impact from German reimbursement won’t come until 2017, and we assume that is still the case. Nevertheless, this news has been referenced in many sessions at EASD and is a tremendous victory for the field in one of the world’s most challenging reimbursement environments. In short, it is a statement that says CGM is cost-effective, and hopefully a sign of more positive things to come in other markets. Abbott’s cash-pay FreeStyle Libre has done very well in Germany, an indication that demand is high for easy and convenient and discreet glucose sensing and eliminating fingersticks. This positive decision for CGM will clearly expand the German market, and we look forward to seeing the size of its impact on Dexcom’s still fairly small international sales base (~13% of sales in 2Q16 – so much room for upside!).

Diasend/Glooko

This booth boasted the major tech news of the day: Diasend has merged with Glooko to form a unified company under the Glooko name and headed by Glooko CEO Rick Altinger. The two Diasend reps and one Glooko rep at the booth were up for discussing the merger, which was great – it is aimed at building the “World’s Premier Diabetes Management Platform.” The merger is incredibly symbiotic in nature in our view: Diasend brings existing integration with 140+ devices, a sizable global footprint (23 countries), and reimbursement expertise in a wide variety of markets, while Glooko brings strong user interface, great data analytics and reporting, and population tracking. See our detailed thoughts on the merger and an interview with the Glooko and Diasend teams.

Emperra

The tiny booth sported the recently launched Bluetooth-enabled, reusable Esysta connected pen. According to the rep, the pen is reimbursed by insurance in Germany, though the cash pay price is very expensive: 192 euros for a single pen and 616 euros (!) for a pen and meter. The company says it works with any insulin, as plastic adaptors convert any insulin cartridge to fit in the pen. We thought these were clunky and did not find them confidence inspiring (picture below). The button on the pen was more difficult to press down than manual pens, though we liked that the dose calculator gave a countdown timer on screen. We are elated to see more interest in Bluetooth-enabled pens, though are not confident that Emperra is the real deal at this stage. See our October coverage of Patients Pending’s Timesulin Dose Capture device for a smart pen/cap landscape review.

 

EOFlow

New to us, Korea-based EOFlow showed off a disposable patch pump, EOPatch. It looks similar in size to the original OmniPod and communicates with a snappier looking handheld touchscreen controller. According to the company’s two-line press release last week, the pump has been submitted for verification and validation and will be available “in the global market in 2017.” The on-body patch and handheld do have Bluetooth and can communicate with CGM. According to the EOFlow’s website, the company started at a university incubation center in Seoul, Korea in 2011. The booth and website are not confidence inspiring, though we’ll be interested to see if the product is indeed commercialized. The pump market is very competitive and not for the faint of heart …

Inside BioMetrics

We stopped by the Inside Biometrics booth to have a first look at the Bluetooth-enabled Keya Smart System, a meter that measures both blood glucose and ketone levels using the same strip. The device is about the size of a pack of cards (see picture below), has a very easy-to-use interface, and functions like a normal BGM, but alerts operators when their ketones are high. It received a CE mark back in May, and a UK launch is expected by the end of the year, with Germany to follow soon thereafter. FDA clearance is expected next year, though it has not yet been filed. Reps told us that the company has an existing integration agreement with Diasend (now merged with Glooko), and is working on an app that would offer actionable analytics – they seemed particularly excited about this because so little is known about the interactions between glucose and ketone levels. When asked about the possibility of a flash or continuous monitoring system, reps told us to keep an eye out for gen 2. Inside Biometrics will soon be ramping up, growing their team from ~45 to ~60 people, outsourcing manufacturing of the meter (but not the strips), and establishing a branch in California. BGM is a very tough market for startups, but we are happy to see some novel innovation and a product that could conveniently address DKA – most patients don’t even know what their ketone levels should be, let alone have the supplies to measure them – and the issue is important as SGLT-2s are used in type 1. We like the convenience of a normal meter that can measure ketones in the background, reducing the hassle of Abbott’s Precision Xtra meter that requires separate strips.

• Reps were thrilled with the reception from the EASD crowd. The small booth was frequently busy, Dr. Lutz Heinemann gave the meter a shoutout during an oral session, and the reps related that some unspecified pharma companies had asked them if they could perform a trial with the meter, while other companies approached them with hopes of assisting in the development of the app. 

Kaleido

We first saw Kaleido at last year’s EASD, and the company received a CE Mark earlier this year. The very colorful patch pump is expected to launch in the Netherlands and UK by the end of this year. The approach resembles Cellnovo, giving patients two reusable pump units, a wireless controller handheld, and an insulin cartridge that connects to a short on-body infusion set (5 cm or 30 cm). Unlike Cellnovo or the OmniPod, the handheld doesn’t have a built-in blood glucose meter, though the company recently added a bolus calculator. The body-worn pump and iPod-like handheld are both quite slim (measurements here), and the company has put a major emphasis on customizable color offerings. This is direct competition for Cellnovo, who has had a fairly slowly launch ramp in Europe.  

Medtronic

Medtronic’s booth focused overwhelmingly on demoing Guardian Connect, it’s CE Marked Bluetooth-enabled, standalone CGM. Reps said the product will launch in Europe in mid-November, on the very early side of the updated timing shared in the 2Q16 call (~Nov 2016-Jan 2017). The booth had scores of Apple devices running the Guardian Connect iOS app, which has a very clean interface and design that will give Dexcom’s G5 a competitive run for its money. We learned that the Bluetooth-enabled transmitter will backfill up to eight hours of data if the phone is out of range, on par with FreeStyle Libre (and well ahead of G5, which does not backfill data at this point). The Guardian Connect app will launch initially on iOS in Europe with a “Today View” widget (swipe down from the home screen to view data – essential for patient convenience in our view), though it will not initially post to HealthKit or have a Watch app. “Care Partners” will be able to get customizable text message notifications for out-of-range values, including predicted lows and highs. As a reminder, this will launch with Enlite 2 (Enlite Enhanced) outside the US; the US version of Guardian Connect with Enlite 3 is currently under FDA review, with launch expected by April 2017. The MiniMed 640G – now available for more than a year outside the US – was a minor part of the booth, but still drew some interest from curious attendees. Patients on the 640G we’ve run into here absolutely love it, and it has certainly shown in Medtronic’s recent international revenue performance. 

POCTech

China-based POCTech was back again at this EASD with more bold claims, advertising a seven-day, Bluetooth-enabled CGM requiring just one calibration per day. A handout boasted a 9.6% MARD vs. fingersticks in a 73-patient study in two medical centers – there were not enough study details listed to know if the trial was robust, though we assume it was not based on the sparse information and amateur handout. The product actually has a CE Mark in Europe, though the company has resubmitted to update the transmitter to add Bluetooth (approval expected by end of year). The company is seeking a European partner to go to market following approval. The CGM is under review in China for use in the hospital, though the rep said it is 6+ months away from approval (behind the EASD 2015 expectation for Chinese approval by the end of 2016).

Roche

We were delighted to see Roche demoing its soon-to-launch Accu-Chek Insight CGM, branded as “the 7^th sense that helps your patients get it right.” Insight is currently in CE Mark approval trials and on track to launch in Denmark, Sweden, the Netherlands, and Norway by the end of the year (see our Day #1 coverage). This initial limited launch will occur at specialized diabetes centers and last 6-9 months so that Roche can gather feedback before fully rolling it out in more countries in 2017. We wonder if this will also give time for manufacturing to scale. In person, the on-body transmitter appeared bulky to us (roughly ~2x the size of Dexcom’s G5), and the single-use inserter was a little intimidating (though reps cited data suggesting otherwise). The preliminary accuracy data presented at EASD, however, was encouraging (MARD: 10.5%), and it will be interesting to see how uptake goes in the increasingly competitive EU market (Abbott FreeStyle Libre, Dexcom G5, Medtronic’s 640G and upcoming Guardian Connect, Senseonics Eversense). Roche’s Bluetooth-paired app is, at the moment, limited to a dedicated Android phone solely used for the Insight CGM, which is obviously a complete hassle – reps noted that this is only temporary, and iOS and Android apps should be available by the end of the year. The CGM data will not sync with mySugr at launch, but it will eventually if all goes as planned.

• Roche also showed off the Smart Pix software, a platform to visualize and analyze Insight CGM data. The display contains an AGP-like trace, and a CGM traffic light system that indicates degree of success in a number of categories pertinent to glycemic control over a two-week period. Smart Pix also has what looked like a standard high/low pattern-recognition feature. A rep commented that pilot users’ only complaint was that other meters won’t integrate with it.

YPSOMED

Ypsomed’s expansive green booth deftly balanced demos of the tubeless mylife OmniPod and its own touchscreen durable YpsoPump. According to the rep, the YpsoPump is currently launching in the Netherlands and UK, with Germany expected later this year – this is right on with the timing shared in June when the pump received EMA approval for use with Novo Nordisk’s NovoRapid prefilled insulin cartridges. We had a chance to demo the pump and speak with a patient using it, and both experiences left us positive on the key features: (i) prefilled NovoRapid insulin cartridges for faster set changes (about 15 seconds to load and prime); (ii) touchscreen (capacitive) with an OLED display that is easy to see in the dark; (iii) a fully icon-driven display that has no words (language neutral for Europe); (iv) very light weight (83 g) and small size in the hand; and (v) built-in Bluetooth. Read our full list here of the pump’s strengths, weaknesses, opportunities, and threats.

Exhibit Hall – Diabetes Drugs

AstraZeneca

AstraZeneca’s sizeable maroon and gold booth was certainly one of the exhibit hall’s most interactive displays. At one corner, an artist stood before a crowd of people, sprinkling white sugar over a glass panel and, in a clever play on the pharmacological idea of glucose removal, effortlessly whisked the sugar away to create elaborate designs. Adjacent to this was a popular game involving detailed figurines of patients that visitors could place on a high-tech glass table, which would light up to reveal that individual’s unique diabetes profile, as well as how they could benefit from AZ’s selection of diabetes drugs. Approximately equal square footage was dedicated to the SGLT-2 inhibitor Forxiga (dapagliflozin), the DPP-4 inhibitor Onglyza (saxagliptin), and the GLP-1 agonist Bydureon (exenatide once weekly), with some mention of Xigduo (dapagliflozin/metformin) and the anti-platelet drug Brilique (ticagrelor) as well. Across the booth, beneath a commanding archway entirely composed of flatscreens panning through the logos of AZ’s impressive lineup of diabetes and cardiovascular therapies, was a bustling coffee bar and lounge area. Signage declared AZ’s excitement about its “next wave of scientific innovation” – a nod to the company’s impressive lineup of emerging diabetes therapies, including the antiplatelet agent Brilinta (ticagrelor), the phase 1/2 PCSK9 inhibitor/GLP-1 agonist combination MEDI4166, and a saxagliptin/dapagliflozin fixed-dose combination (just approved in Europe under the trade name Qtern). Furthermore, colorful dangling panels declared AZ’s commitment to “understanding the cardiovascular and renal profile” of diabetes specifically. This is certainly a timely message at what promises to be a CVOT and renal outcomes-heavy EASD, and in an era when diabetes drugs must offer benefits beyond glycemic reductions in order to set themselves apart.

GI Dynamics

GI Dynamics occupied a small booth near one edge of the exhibit hall. A large painting as well as two 3D models displayed how the EndoBarrier therapy for obesity acts on the stomach. Three clinical effects of EndoBarrier relevant to the treatment of both diabetes and obesity were listed on the wall: (i) restores healthy glycemic levels; (ii) produces significant weight loss; (iii) lessens cardiovascular risk. Many different informational handouts were also available, including one that described EndoBarrier as the first endoscopically-delivered treatment for patients with type 2 diabetes and obesity. The obesity market is challenging and we wish it were easier for companies doing the very hard work to try to help patients on this front.

GSK

GSK’s booth was small and off to a side wall of the exhibit hall. The entire booth was essentially a medical affairs stand with no outright promotion of the company’s one diabetes product, GLP-1 agonist Tanzeum (albiglutide).

Intarcia

Intarcia’s booth featured two stations demonstrating implantation of the company’s Medici subcutaneous osmotic mini-pump drug delivery system (the device used to deliver a continuous stream of GLP-1 agonist exenatide in the company’s phase 3 ITCA 650). In between these two stations, a spinning, lighted glass case showcased the matchstick-sized mini-pump. The booth with its intriguing demonstration and bold, colorful graphic designs drew a steady stream of curious attendees. It’s clear that Intarcia’s booth is very much focused on attracting potential partners for future applications of the Medici system: the back wall of the booth stated that the company is looking to identify proteins, peptides, antibody fragments, and “other high potency small molecules” suitable for delivery via the system – this is very exciting from our view. Interestingly, the materials also emphasized that the company is particularly interested in oncology, inflammatory diseases, and metabolic disorders (in that order) – we’re a little surprised that oncology would come first in promotional materials at a diabetes conference, though perhaps it is not too surprising that the company is looking to diversify beyond diabetes given the current challenging payer environment and high bar for new diabetes drugs – this is all speculative at this point. There has never been higher interest in increasing adherence and all eyes are on Intarcia as it moves toward regulatory approval.

j&J/Janssen

Like last year, Janssen’s tile-floored exhibit emphasized clinical data showing SGLT-2 inhibitor Invokana’s (canagliflozin) superiority over DPP-4 inhibitor Januvia (sitagliptin). These results and claims were displayed prominently – superior A1c reductions vs. sitagliptin, greater improvements in blood pressure and weight loss vs. sitagliptin, well-tolerated with low frequency of hypoglycemia (~4% of patients treated with Invokana as monotherapy or with Invokana added on to metformin as dual therapy). The exhibit also featured interactive iPads and bright monitors with patient stories on both Invokana and Invokamet (canagliflozin/metformin), calling on people to “change the conversation” surrounding diabetes. Overall, Janssen didn’t seem to deviate very much from what we’ve seen of the company’s exhibit hall presence at other recent conferences, whether US-based or international, although there was less overt promotion of the Check Your Numbers Tracker App compared to ADA 2016 and AADE 2016.

Lilly

Lilly’s large booth was summed up by the large projection of the tagline “A wide range of therapies” projected on the back wall of the booth, just behind the popular espresso bar – indeed, they have the broadest portfolio around! Approaching the booth, the space was flanked with sections devoted to its GLP-1 agonist once weekly Trulicity (dulaglutide) and its BI-partnered SGLT-2 inhibitor Jardiance (empagliflozin), followed by sections devoted to BI-partnered basal insulin Abasaglar (biosimilar insulin glargine), BI-partnered DPP-4 inhibitor Trajenta (linagliptin), and mealtime insulin Humalog, finally culminating in sections devoted to support programs for type 1 diabetes and observational studies. The Jardiance, Trajenta, and Abasaglar sections were essentially miniaturized versions of their space in the Lilly/BI joint booth next door (see below). The purple-and-green Trulicity section evoked the colors of the products extremely patient-friendly IDEO-designed pen while the Humalog section emphasized the product’s 20 years (!) on the market. We were particularly impressed by the “Streetwise” educational materials within the “Support for Type 1 Diabetes” section aimed at young adults living with diabetes – the pamphlets touched on a wide range of topics from exercise and traveling with diabetes to body piercings/tattoos, drinking, and emotional well-being with diabetes. We think the Trulicity app is really something and expect to see it highlighted more in the future.

Lilly/BI

Lilly/BI’s joint booth featured its signature wood-paneled rustic-chic aesthetic in full force – complete with long communal wood picnic tables in which participants could rest on their “hike” through the partnership’s diabetes products. The booth was anchored on one side by biosimilar insulin glargine Abasaglar and on the other by the Jardiance (empagliflozin) SGLT-2 inhibitor and the Trajenta (linagliptin) DPP-4 inhibitor franchises. On the Abasaglar side, Lilly/BI likened insulin initiation to an airplane flight, extolling the virtues of an Abasaglar patient support kit – with injection guides and other educational materials – to ease the “turbulence” of insulin initiation. Further playing on this theme, the area featured several colorful suitcases with stuffed baby animals (the area also featured large pictures of baby animals and the inviting opener “Now that we’ve got your attention…”) and with clinical trial findings on how to ease the anxieties surrounding insulin initiation that many patients face. On the other side, the section devoted to Jardiance and combination Synjardy (empagliflozin/metformin) featured a beanbag toss game highlighting the connection between diabetes and cardiovascular events. The Trajenta and Jentadueto (linagliptin/metformin) section featured futuristic virtual reality headsets (these seem to be popping up everywhere in exhibit halls!) with which participants “walked” through a landscape with pop-up text emphasizing the products’ administration simplicity and its effectiveness at different stages of renal function.

MSD

MSD’s exhibit very much celebrated the 10th anniversary of DPP-4 inhibitor Januvia (sitagliptin), first introduced in 2006. One large wall proudly announced this 10th anniversary and in bold, eye-catching text, emphasized our extensive experience with Januvia as well as the product’s reliable safety profile. Curving teal carpets surrounded a round hardwood floor at the center of the company’s large, open space. The exhibit featured informational handouts on what it means to be an incretin-enhancer, among other topics, and the slogan “Support your patient with confidence. Choose Januvia first as a partner to metformin.” The highlight of MSD’s booth was a high-tech, hologram-like display in one corner explaining how incretins relate to the pathophysiology of type 2 diabetes. We weren’t surprised that the company (Merck’s international equivalent) chose to underscore familiarity and safety as advantages to Januvia, especially with many other exhibits comparing products from newer drug classes to sitagliptin. We were interested by the offering of more general, scientific background on incretin-based drugs (which includes both DPP-4 inhibitors and GLP-1 agonists). There is great interest in Merck’s work ahead with Pfizer on the SGLT-2 and DPP-4/SGLT-2 combination fronts.

Mylan

Mylan boasted a decently-sized booth, swathed in the company’s typical light blue and white color scheme. As a nod to EASD’s thematic emphasis on the cardiovascular complications of diabetes, the booth’s signage was mostly dedicated to Mylan’s cardiovascular drugs, including Lipanthyl (fenofibrate) and Cholib (fenofibrate/simvastatin) for cholesterol and Verapamil (isoptin) for hypertension. To signify the company’s impending entrance into the diabetes arena, touchscreen displays featured descriptions of the  INSTRIDE 1 andINSTRIDE 2 trials of Biocon-partnered biosimilar insulin glargine in type 1 and 2 diabetes showing that the trial met its primary and secondary endpoints. If approved, this biosimilar insulin glargine will be the third-to-market biosimilar insulin glargine in the US. We were disappointed to see no trace of Mylan’s Biocon-partnered development programs for oral Insulin Tregopil, biosimilar insulin aspart (Novo Nordisk’s NovoLog), or biosimilar insulin lispro (Lilly’s Humalog). The periphery of the booth was occupied by towering signs showing images of the diverse range of patients taking Mylan’s drugs. “How do we care for 7 billion people? One person at a time,” the panels read. While some Americans speculated that this strong, patient-centric messaging may be a strategy to rebuild the company’s reputation in the aftermath of the recent outrage over the pricing of Mylan’s EpiPen, we doubt this given the timing needed to create this material – on the other hand, they certainly need something to help. We think patient outrage over pricing generally speaking is only going to become further intensified.    

Novartis

Novartis divided its expansive exhibit into one half dedicated to DPP-4 inhibitor Galvus (vildagliptin) and the other focused on Lucentis (intravitreal ranibizumab) – though the latter was far flashier. The company promoted its diabetic macular edema drug alongside ViaOpta DETECT, a platform to enable early identification of eye complications and referral of patients for timely intervention. A slogan for the platform was featured prominently: collaborate, educate, screen, refer. Notably, by putting on black goggles, you could partake in a virtual reality experience, seeing the world as someone with diabetic retinopathy would. Meanwhile, a large monitor showed what the person in virtual reality was seeing. This attraction drew much attention from conference attendees walking through the exhibit hall, who then stayed to learn more about the fight to preserve vision through interactive monitors and colorful displays. In fact, the crowd at Novartis’ exhibit rivaled that of Novo Nordisk directly adjacent. While more understated, the side of the booth dedicated to DPP-4 inhibitor Galvus was also highly interactive. Patient case stories emphasized the message that when time is running out, patients with diabetes should turn to Galvus. The dominant image of an hourglass on the wall was a powerful, memorable reminder of the time theme.

Novo Nordisk

Novo Nordisk’s commanding booth dominated the exhibit hall, in terms of both attendance and square footage. Approximately equal space was dedicated to Tresiba (basal insulin degludec), Xultophy (insulin degludec/liraglutide), and Victoza (liraglutide), each of which boasted a semi-circular theater area with low slung white benches, a large touchscreen display, and a color-coordinated team of Novo Nordisk representatives giving an interactive presentation on each drug’s efficacy, action profile, and dosing information (all three had a line of physicians waiting to be seated!). The green Tresiba displays advertised the drug’s ability to “get A1c down with control,” a notion that was echoed in the imagery of parachutes “falling” along with A1c. The bright pink Xultophy displays framed the drug as “a step further with one injection per day,” itemizing three of the new drug’s most important benefits: (i) easy; (ii) confident drug delivery ratios; and (iii) preferred by patients.” It’s smart in our view to emphasize composite benefits – that worked very well for liraglutide when building the GLP-1 market (Victoza is now Novo Nordisk’s biggest product!)  The emphasis on Tresiba and Xultophy reflects Novo Nordisk’s clear enthusiasm for its new arrivals, but Victoza received a great deal of attention as well. Sleek maroon signage emphasized Victoza’s status as the “most prescribed GLP-1 agonist” and, perhaps as a nod to the increasing competition in the GLP-1 space, highlighted its “seven years of experience” on the market.

Sanofi

Sanofi’s sleek, white and green booth was one of the exhibit hall’s largest and most well-attended. As was true at recent conferences and last year’s EASD, Toujeo (insulin glargine U300) was the clear focal point, dominating 90% of the booth’s square footage. Signage reminded the booth’s visitors that Toujeo has a “more stable and prolonged action profile than Lantus,” subtly encouraging physicians to switch their patients from the dominant (and off-patent) Lantus to a regimen involving the similar but more advanced Toujeo. We certainly continue to hear great enthusiasm for both Toujeo as well as Novo Nordisk’s next-gen basal insulins. Sanofi’s booth functioned as a thriving social space, with modern white workstations bustling with physicians and a packed movie theater area showing a short film titled “The Challenge,” depicting a group of people with diabetes on a rugged, five-day mountain climbing expedition. Wow! The story was intended to parallel the challenge of combatting diabetes stigma – a message that certainly resonated with us! Two small podiums at the very edge of the booth highlighted Lantus (insulin glargine) and Lyxumia (lixisenatide), but these drugs are clearly not the emphasis of Sanofi’s EASD advertising campaign, presumably due to Lantus’ patent expiry and the fact that Lyxumia is not available in Germany.

Sanofi/Regeneron

Regeneron displayed a decently-sized booth near the entrance to the exhibit hall, dedicated entirely to its PCSK9 inhibitor Praluent (alirocumab). A small crowd was clustered in the booth’s intimate seating area, surrounded by towering, six foot tall statues of blue and green arrows, pointed down toward the ground to parallel Praluent’s LDL cholesterol-lowering action. Signage surrounding the booth’s perimeter emphasized Praluent’s efficacy and ease of use, posting large statistics boasting the drug’s “more than 60% LDL reduction” and the fact that “up to 80% of patients achieved their goal” when taking Praluent. With an eye toward personalization, Regeneron’s advertisements also emphasized the fact that Praluent comes in two different pens, a 75 mg/dl dose and a 150 mg/dl dose for “more power if you need it.”

Takeda

Takeda’s booth stood out at this year’s exhibit hall, with its playful puzzle theme and emphasis on the patient’s point of view. Colorful puzzle pieces – red, purple, neon green – were suspended from the ceiling. Conference attendees were invited to align their feet with footprints on the carpet to symbolize adopting a patient’s perspective, and from that angle exactly, you could see that four hanging puzzle pieces together made-up a photograph of a patient’s smiling face. The company seemed to be highlighting its investment in fulfilling the most pressing patient needs with DPP-4 inhibitor Vipidia (alogliptin, Nesina in the US), Vipdomet (alogliptin/metformin, Kazano in the US), and Incresync (alogliptin/pioglitazone, Oseni in the US). On-theme, even the coffee break tables within the exhibit were shaped like puzzle pieces, and a catchy slogan for Vipidia read “Every piece counts.”

-- by Adam Brown, Abigail Dove, Helen Gao, Brian Levine, Payal Marathe, Sarah Odeh, and Kelly Close