September 10-15, 2017; Lisbon, Portugal; Themes – Draft

EASD 2017 was packed with new data and commentary from some of the most eminent diabetes thought leaders. To help digest this incredible six days of learning, we’ve put together this report of major themes from the meeting, spanning diabetes therapy, diabetes technology, big picture topics, and obesity.

On the therapy side, questions over CVOT design and GLP-1 agonist class effects were inescapable. AZ’s EXSCEL CVOT for GLP-1 agonist Bydureon (exenatide) was at the heart of both these sets of discussions: Bydureon demonstrated compelling CV safety, just missing the threshold for superiority vs. placebo (HR=0.91, 95% CI: 0.83-1.00, p=0.06). Speakers proceeded to debate whether this neutral result had more to do with pragmatic trial design or with exenatide being an exendin-4-based molecule (as opposed to a human GLP-1-based molecule like liraglutide). We hadn’t expected the “protection” results would be as close to superiority as they were and this lent credence to the notion that it is truly a cardioprotective class – whether some molecules are more or less cardioprotective is a major question. Notably, at EASD this year, we also observed a greater emphasis on renal outcomes in diabetes, and saw very positive data on two potential adjunct therapies for type 1 – Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin and AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin). We were thrilled to see these results given how much help is needed on the type 1 front.

As usual, and we hope to see some changes over time here, it was a light conference on the tech side, but there were a couple victories for CGM. First, the JDRF-sponsored CONCEPTT trial in pregnancy was a big success, demonstrating compelling neonatal and glycemic outcomes with Medtronic’s old Guardian sensor. Imagine what the data will be with better sensors! No one should be pregnant and have diabetes without wearing CGM. We were also struck by a compelling cost-effectiveness poster from the Belgian experience with CGM. Medtronic was notably absent from the exhibit hall and industry symposia, though we did hear some valuable pipeline commentary from Dexcom and Roche.

Big picture, hypoglycemia and outcomes beyond A1c had a strong presence at this meeting, continuing the momentum from the July 21, 2017 “Glycemic Outcomes Beyond A1c” gathering in Washington DC and the August 29, 2016 “Diabetes Outcomes Measures Beyond A1c” workshop at FDA. Notably, brand new analyses from the DEVOTE Tresiba trial established a strong correlation between glycemic variability/all-cause mortality, and between severe hypoglycemia /all-cause mortality. We also heard that EMA’s upcoming draft diabetes drug guideline will be open for comment soon – we’re glad to hear it will continue to encourage use of CGM, especially for measuring non-severe hypoglycemia.

Without further ado, our 15 themes from EASD 2017…

Diabetes Therapy

How to Design a CVOT

• One of the primary discussion topics emerging from the EXSCEL full results symposium was CVOT design and the role of “real-world” elements. From day #1 of EASD 2017, Drs. Bernard Zinman and Naveed Sattar defended AZ’s pragmatic trial design for GLP-1 agonist Bydureon (exenatide once-weekly) and emphasized points of contrast to Novo Nordisk’s LEADER for Victoza (liraglutide once-daily). There was no run-in period to EXSCEL, which is typically used to exclude individuals showing poor medication adherence – LEADER included a two-week run-in phase for precisely this purpose. Moreover, participants were given the single-use Bydureon reconstitution kit which is decidedly less patient-friendly (some would say adherence-friendly) than the multi-use Bydureon pen or the upcoming Bydureon autoinjector (expecting an FDA decision in 2H17). Patients continued to see their usual care providers, who were allowed to prescribe any concomitant medications except another GLP-1 agonist (the LEADER protocol also prohibited DPP-4 inhibitors). Similarly, a wide range of concomitant medication use at baseline was allowed in EXSCEL, and ~12% of participants were taking a DPP-4 inhibitor at study start, whereas LEADER excluded anyone on a baseline DPP-4 agent. The primary prevention cohort, comprised of individuals without a history of CV events at baseline, was ~27% in EXSCEL vs. ~19% in LEADER, which suggests that the latter study population was significantly sicker, while the former more closely resembles the real-world type 2 diabetes patient population. During Thursday’s EXSCEL symposium, several speakers (including first author Dr. Rury Holman and independent commentator Dr. Francesco Giorgino) attributed the neutral CV findings to this pragmatic trial design. Given Bydureon’s extremely narrow miss for superiority (HR=0.91, 95% CI: 0.83-1.00, p=0.06), it does seem quite likely to us that study design skewed the results, and we’re not ready to give up on the idea of a cardioprotective class effect for GLP-1 agonists. Of course, this debate over class effect is just one of many interesting questions that arises from this discussion of CVOT design, though all the answers seem equally elusive right now. To boot, the degree of cardioprotection may differ by molecule – of course there would need to be one big CVOT to assess this.
  
  • Which study design – pragmatic like EXSCEL or “enriched” like LEADER – is more valuable for the diabetes field? On the one hand, there’s an ever-present gap between RCTs and the real world, and pragmatic trial designs could offer a better sense of how these therapies will translate. After all, the ultimate goal of manufacturers, regulators, HCPs, and payers alike is to help real-world patients achieve better health outcomes, outside the context of a clinical trial. On the other hand, Victoza now has an FDA-approved indication for CV risk reduction, which may be less likely for Bydureon based on the EXSCEL dataset though ultimately some assumptions may be made about the class “in real life”. Labels dictate whether or not manufacturers can promote products for CV prevention, and raising awareness of the diabetes/CV disease overlap is incredibly important from a public health perspective. This is one reason we’d love to see an “all-brand” CVOT with GLP-1 and SGLT-2 and some combination therapies – although people “shake their head” when they hear this idea, we think it is a great idea for a foundation to fund or other philanthropy given the upside of knowing the answers.
• Despite the many new questions with elusive answers for now, one fact was clear following EASD sessions on EXSCEL and CANVAS: The field lacks guidance on standard CVOT design at present. There were profound differences in the baseline characteristics of participants in EXSCEL vs. LEADER, and the two trial protocols were markedly different as well. Amputations were recorded in a rigorous, prospective manner in the CANVAS study for J&J’s SGLT-2 inhibitor Invokana (canagliflozin), but were collected via a different process (the specifics are still unclear) in EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin). This makes it exceptionally difficult – if not impossible ­– to compare trials, or to compare molecules within the same class. We can’t determine with certainty whether liraglutide offers CV benefits distinct from exenatide, or whether canagliflozin is associated with an amputation risk completely missing from empagliflozin. On both efficacy and safety, thought leaders are limited in what conclusions can be drawn about these therapeutic agents relative to one another, which means patients/providers receive less-than-optimal insights to guide treatment decisions. With each new CVOT to report, it seems it’s even harder to compare between them. Of course, there are advantages to different trial designs as characterized above, and we understand that manufacturers may have different motivations underlying their CVOTs (often, the primary objective is to demonstrate CV safety). Some of the differences in trial design may have been more accidental. We do see major value in head-to-head outcomes trials, and although a massive investment would be required, we do hope the field considers this as it looks ahead to changing guidelines and what “could” be known that would impact public health. By the same token, it might be worthwhile for FDA to consider some standardization of CVOT design.
• In providing the discussant on new CANVAS data, Dr. Ele Ferrannini questioned the use of three-point MACE (non-fatal MI, non-fatal stroke, or CV death) as the primary outcome in CVOTs. Each of these components has its own set of risk factors, and treating them as one creates “a bit of a salad,” in Dr. Ferrannini’s words. While it’s exciting to see how a drug reduces risk for three-point MACE, he argued that it would be more clinically-valuable to understand how an agent impacts MI alone, stroke alone, or heart failure alone. In a separate conversation with us, he acknowledged the massive investment of time and resources that goes into a CVOT, and suggested that this is precisely why manufacturers should want to find their product’s most profound benefits. Lastly, he alluded to some irony in the fact that a non-fatal MI counts as “plus one” in terms of a CV event but “minus one” in terms of avoiding a CV death. All of this was really stirring food for thought. We’re intrigued by the prospect of having some diabetes therapies ideal for patients at high risk for heart failure, others ideal for patients at high risk for stroke, or MI – this would be a notable stride forward in personalized medicine for diabetes. While there’s been some discussion of SGLT-2 inhibitors as better for preventing heart failure and GLP-1 agonists as better for their anti-atherosclerotic effects, only dedicated studies can confirm this; Lilly/BI’s Jardiance and AZ’s Farxiga are now being investigated in chronic heart failure, but those clinical trials enroll patients with and without diabetes. That said, increasing the specificity of primary endpoint moves us further away from standardization of CVOT design, and we’re eager to collect more expert opinions on how valuable/important this is for the diabetes field. EASD 2017 raised the question time and time again of how CVOTs should be designed, and while we’re still not sure of the “right” answers, we found this to be an engaging discussion throughout the meeting – a discussion to be continued.

GLP-1 Agonists and the Reach/Limitations of Class Effects

• The debate over human GLP-1-based molecules vs. exendin-4-based molecules gained steam at EASD 2017. Dr. Daniel Drucker emphasized this distinction during a Novo Nordisk-sponsored symposium early in the agenda. He highlighted that all human GLP-1-based agents have yielded positive CVOT data thus far (liraglutide in LEADER and semaglutide in SUSTAIN 6), while exendin-4-based agents have demonstrated CV safety but not efficacy (lixisenatide in ELIXA, continuous release exenatide in FREEDOM-CVO, exenatide once-weekly in EXSCEL). Other thought leaders have expressed little confidence in this explanation for the diverging CVOT results within the GLP-1 class – this is the tune we heard from AZ’s VP of US Medical Affairs Dr. Jim McDermott and from Dr. Francesco Giorgino, who provided independent commentary on EXSCEL. Dr. Giorgino attributed EXSCEL’s neutral result predominantly to its pragmatic trial design. He acknowledged that human GLP-1-based molecules and exendin-4-based molecules may exhibit slightly different signaling and biological effects, but argued that these variations are unlikely to explain meaningful differences in CV outcomes. In contrast, Dr. Drucker called attention to other ways in which GLP-1 agonists differ to build a likely case for diverging CV effects. Some agents in this class seem to be more potent than others, with greater A1c-lowering and weight loss seen in phase 3. The SUSTAIN 7 topline results show semaglutide’s superiority to dulaglutide (Lilly’s Trulicity) in head-to-head data, with a ~0.4% A1c treatment difference and an approximate doubling of weight loss benefit favoring semaglutide, despite both these once-weekly agents being human GLP-1-based. Whether or not a difference in potency translates to a difference in CV outcomes remains to be sorted out through further research, and we’re eager to see mechanistic studies on human GLP-1-based vs. exendin-4-based molecules, which could be quite illuminating.
• In our view, EXSCEL results do more to support the notion of a cardioprotective class effect than to refute it, given the compelling CV safety findings, the very narrow miss on superiority, and the details of “real-world” trial design (particularly the lower risk population and the adherence issues). Dr. Drucker even spoke to the statistical piece shortly after the EXSCEL presentation, during an MSD corporate symposium: “If one p-value is 0.49 and another is 0.51, do we worship the first drug over the second?” Moreover, Dr. Rury Holman presented a meta-analysis to underscore a cardioprotective class effect based on all the GLP-1 CVOTs published to-date (12% risk reduction for three-point MACE with GLP-1 agent vs. placebo, p=0.002). It’s also becoming increasingly clear, however, that agents within the GLP-1 class are not interchangeable – the differences in glycemic efficacy and weight loss seem real (could these lead to differences in CV effects?), and there are also notable product differences (how patient-friendly/adherence-friendly is the drug, how high is the injection burden?). We don’t anticipate this debate quieting anytime soon, but for now, we’re glad that new data on GLP-1 agonists coming out of EASD supports the overall benefits to this advanced therapy class.

Adjunct Therapies for Type 1 Diabetes Make Leaps and Bounds

• EASD 2017 was a particularly exciting moment for adjunct type 1 therapies. Not only did we see positive results from Lexicon’s inTandem3 trial of SGLT-1/2 dual inhibitor sotagliflozin, but this was followed by extremely strong efficacy/safety data from AZ’s DEPICT 1 study of SGLT-2 inhibitor Farxiga (dapagliflozin) in type 1 diabetes. inTandem3 (n=1,402) was a global trial designed to more closely reflect real-world clinical circumstances, with no insulin optimization period. Sotagliflozin continued its track record of efficacy (see our coverage of inTandem1 and inTandem2, presented first at ADA). The primary endpoint, defined as A1c <7% with no severe hypoglycemia or DKA, was met by 29% of patients in the 400 mg sotagliflozin arm vs. 15% of those in the placebo arm (p<0.001). Mean A1c reduction was 0.8% with sotagliflozin vs. 0.3% with placebo, culminating in a treatment difference of 0.5% (p<0.001). Sotagliflozin was associated with ~5 lbs weight loss vs. ~2 lbs weight gain for participants on placebo, for a treatment difference of ~7 lbs (p<0.001). There were four DKA events (0.6%) in the placebo group vs. 21 (3%) in the sotagliflozin group, leading to 11 treatment discontinuations in the latter. Just before EASD began, Lexicon released pooled CGM data from inTandem1 and inTandem2, reporting that patients on 400 mg sotagliflozin spent an additional 12% of the day in-range at the end of 24 weeks (p<0.001 vs. placebo). This corresponds to an additional 2.8 hours, and we feel confident saying that this extra time-in-range would be an enormous win to anyone with diabetes. DEPICT 1 (n=833) was the first phase 3 study of a marketed SGLT-2 inhibitor to report. From a baseline 8.5%, mean A1c declined 0.4% with dapagliflozin 5 mg vs. placebo and 0.5% with dapagliflozin 10 mg vs. placebo (both p<0.001). CGM readings showed 52% (12.5 hours), 55% (13.2 hours), and 44% (10.6 hours) time-in-range for 5 mg, 10 mg, and placebo, respectively. Weight loss was 3%-4% greater with dapagliflozin vs. placebo (p<0.0001). There was no imbalance in confirmed DKA, with event rates of 1% (four patients), 2% (five patients), and 1% (three patients) in the 5 mg, 10 mg, and placebo groups, respectively. Before we go any further, we want to emphasize that this discussion of inTandem3 and DEPICT 1 side-by-side is meant to reflect our enthusiasm for both these candidates. We left EASD with hope for a new generation of adjunct treatments in type 1 diabetes, which are sorely lacking right now (AZ’s Symlin is injectable rather than oral, and though it helps with postprandial spikes, it has not been shown to reduce A1c, plus it’s poorly reimbursed and hasn’t taken off commercially – we’d love to see a co-formulation and a study that looks at time in zone rather than only A1c). Our outlook reflects two positive phase 3 readouts: Both DEPICT 1 and inTandem3 demonstrate that dapagliflozin and sotagliflozin, respectively, can be safely given to patients with type 1 diabetes to lower A1c and increase time-in-range without causing hypoglycemia (and with a DKA risk that we believe should ultimately prove manageable). It should be underscored that these studies were designed differently, with different protocols for insulin adjustment (among other things). In the words of Dr. Julio Rosenstock: “People need to be extremely careful not to run and say dapagliflozin is safe and sotagliflozin is not. These are two separate studies, with more MDI in DEPICT 1. People on MDI had less chance of DKA than people on pumps in the inTandem studies.”
• Another key takeaway from these trials is that the diabetes field lacks clarity/consistency on best practice DKA management. DEPICT 1 protocol recommended no more than 20% reduction in total daily insulin dose (this upper cap was based on a post-hoc of an earlier phase 2 study of dapagliflozin in type 1). Dr. Chantal Mathieu highlighted during the DEPICT 1 symposium that lowering insulin dose should not be a primary goal for adjunct therapy, because insulin serves important functions beyond countering acute hyperglycemia. It also suppresses hepatic glucose production, lipolysis, and lipogenesis, so Dr. Mathieu argued that even with adjunct treatment, people with type 1 diabetes will have significant exogenous insulin needs. We’re not aware of any attempts by inTandem3 investigators to cap insulin reductions, but we’d be keenly interested in a post-hoc analyzing how changes in insulin dose correlate with DKA risk. While Dr. David Nathan refers to the inTandem3 study population as highly-educated on DKA in his NEJM editorial (we thought this was overly-critical and on the whole, unfair – and, in fact, untrue that the population was highly educated), the content and quality of this education remain unclear. According to Dr. John Buse, the DKA-related messaging was probably far from optimal, which begs the question: What should the message to patients be? How do we disseminate best practices on monitoring and managing DKA risk? What are those best practices? We can’t claim to know these answers, but the dominant opinion from thought leaders seems to be this: DKA is a serious safety concern that should not be minimized, but with diligent monitoring, proper patient selection, and strong education, the risk can be controlled, and shouldn’t deter patients who could experience tremendous benefit from sotagliflozin or dapagliflozin in addition to their insulin regimen. We have said for some time that the “average” patient doesn’t know much about DKA at all. Lexicon is targeting 1H18 for FDA and EMA submission of sotagliflozin. AZ has not yet shared a timeline for dapagliflozin’s potential type 1 indication.

The Importance of Renal Protection for People with Diabetes and New Applications of SGLT-2 Inhibitors in CKD

• EASD 2017 abounded with commentary on the importance of addressing renal complications of diabetes. We noticed an uptick in the words “kidney” and “renal” at this year’s meeting, and while this is purely our impression rather than rigorously-adjudicated data, it signals to us a greater focus on renal outcomes in best practice diabetes management. Why should diabetes care providers attend to the kidneys? Dr. Per-Henrik Groop provided a compelling answer early on in the conference, noting that where diabetes alone increases premature death by 4.1% over 10 years vs. a background population, albuminuria increases premature death by 17.8%, impaired eGFR by 23.9%, and albuminuria plus impaired eGFR by 47%. He outlined a clear correlation between diabetic kidney disease (DKD) and frequency of CV events, and showed how DKD on top of type 2 diabetes essentially doubles risk for all-cause death, peripheral vascular disease, acute MI, and stroke/transient ischemic attack. “The more albumin that leaks into your urine, the more likely you are to experience a CV event,” Dr. Groop established. Dr. Hiddo Heerspink echoed this sentiment in a separate session with the surprising statistic that the mortality rate of patients with comorbid diabetes/kidney disease is higher than the average mortality rate of all cancers (55% vs. 50% 10-year cumulative incidence, respectively). These statistics powerfully illustrate the need for more renal-focused therapies in diabetes – an especially urgent matter given that no new DKD indications have been approved in the past 17 years, the most recent being irbesartan and losartan in 2000. On the (very) bright side, recent CVOTs reveal that already-approved drugs from the SGLT-2 and GLP-1 classes could act as renal protective agents in their own right. We credit these large trials in part for the shift from A1c-centric diabetes care to treatment that really targets outcomes, both CV and renal. And, we’re pleased to see this transition happening at an increasingly fast pace (it’s a good sign to hear so much conversation on renal outcomes at a major scientific meeting like EASD). There appears to be particular enthusiasm right now for the renal protective effects of SGLT-2 inhibitors. Dr. Heerspink reviewed how all reported CVOTs of an SGLT-2 agent to-date have shown evidence for renal protection: This includes a 39% relative risk reduction for diabetic nephropathy seen in the EMPA-REG OUTCOME trial of Lilly/BI’s Jardiance (empagliflozin), as well as a 40% risk reduction for the composite renal endpoint (renal death, renal replacement therapy, or 40% reduction in eGFR) in the CANVAS trial of J&J’s Invokana (canagliflozin). Moreover, all three SGLT-2 inhibitors on the market have a dedicated renal outcomes trial either planned or ongoing: the CREDENCE trial for canagliflozin (enrolling participants with comorbid type 2 diabetes and CKD; completion expected June 2019), the Dapa-CKD trial for AZ’s dapagliflozin (enrolling participants with CKD both with and without type 2 diabetes; completion expected November 2020); and a soon-to-begin trial of Lilly/BI’s empagliflozin (enrolling people with CKD both with and without type 2 diabetes). Dr. David Fitchett suggested at ESC 2017 that diabetes patients with eGFR <60 ml/min/1.73m² may actually stand to benefit the most from treatment with an SGLT-2 inhibitor, in terms of CV and renal outcomes alike – the truth will lie in outcomes data, and we look very forward to that. This spotlight on the kidneys leads into another concept that seemed to gain steam at EASD, one that also requires admitting the limitations of A1c as a biomarker, in order to address more concrete health outcomes… we’re talking about reframing diabetes as “cardio-renal-metabolic syndrome,” and we have much more on this directly below.

Reimagining Diabetes as Cardio-Renal-Metabolic Syndrome

• Several speakers at EASD 2017 discarded the term “diabetes” altogether, instead focusing their remarks on “cardio-renal-metabolic syndrome.” Diabetes has always been about more than hyperglycemia, with its multitude of microvascular and macrovascular complications, but we’re noticing more emphasis placed on CV disease and kidney disease at recent meetings (we imagine this trend has something to do with positive CV and renal findings from EMPA-REG OUTCOME, LEADER, SUSTAIN 6, and CANVAS). Regardless of cause, we were glad to hear thought leaders deliberately expand the scope of discussion in Lisbon. A patient could have NASH, type 2 diabetes, CV disease, and/or insulin resistance, but no matter, Dr. Christina Rondinone of MedImmune (AZ’s biologics R&D arm) described this individual as “the cardio-renal-metabolic patient.” In line with this rebranding, she advocated for a more comprehensive approach to treatment for cardio-renal-metabolic syndrome, and spoke to the promise of GLP-1/glucagon dual agonists in AZ’s pipeline (click here for the full competitive landscape). This combination therapy could offer effective A1c-lowering, greater weight loss (via appetite suppression and gastric emptying), and improvements in lipid levels and liver fat, according to Dr. Rondinone. Earlier that same day, Dr. Per-Henrik Groop explained how this era of CVOTs is leading people to ask an all-important question about anti-hyperglycemic agents: What else can this drug do for me? In our view, this is exactly the right question to be asking as the bar rises for new diabetes drugs, and as the field moves at an increasingly fast pace toward an emphasis on outcomes rather than the biomarker of A1c. Dr. Groop urged diabetes care providers to attend to the kidneys (“if you don’t remember anything else from my talk today, please remember to screen regularly for renal function”), but framed his presentation with the overarching message that diabetes is more than high blood sugar – it’s really cardio-renal-metabolic syndrome. We’ll be curious to see how far this term goes, and we’ll certainly keep our ear to the ground for further mentions at upcoming scientific meetings. Thinking bigger, we wonder how this diabetes rebranding might be used to influence payers, or to overcome clinical inertia by encouraging HCPs to intervene earlier with combination treatment regimens. For now, we don’t think the average patients thinks about this much at all and certainly doesn’t see the primary or even “a” purpose of medicine as protective (cardio or renal) – some may see incretins or DPP-4 inhibitors as preventing hypoglcyemia, but there are enormous access problems related to getting these medicines.

The Case Against Sulfonylureas Mounts in Head-to-Head Trials

• The only good defense of sulfonylureas – with their associated hypoglycemia risk, weight gain, beta cell burnout, and possible CV harm – is low cost. Several thought leaders have suggested that these generic agents will fall out of favor as data accumulates showing their inferiority to alternatives (especially another generic like TZDs). EASD 2017 offered great data to this end. Although, the real prize may come when CAROLINA reports, Lilly/BI’s CVOT comparing DPP-4 inhibitor Tradjenta vs. glimepiride, expected to complete in March 2019.
  
  • The TOSCA.IT CVOT (n=3,028), sponsored by the Italian Diabetes Association, compared TZD pioglitazone head-to-head against three sulfonylureas: glimepiride (50%), gliclazide (49%), and glibenclamide (<2%). Pioglitazone demonstrated non-inferiority vs. SUs on the primary composite CV endpoint (HR=0.96, 95% CI 0.74-1.26, p=0.79), but more importantly, showed superiority on glycemic outcomes. After 60 months, the mean A1c treatment difference between pioglitazone vs. sulfonylureas was a significant 0.06% (p=0.01), and the durability of the glucose-lowering effect was better over the course of the trial with the TZD. SUs were 37% more likely to result in two consecutive A1c measurements >8% (HR=0.63, 95% CI: 0.52-0.75, p<0.0001). Severe hypoglycemia occurred in 2% of SU-treated patients and in <0.2% of pioglitazone patients (p<0.0001), while moderate hypoglycemia occurred in 32% of the SU group and only 10% of the TZD group (p<0.0001). This hypoglycemia data is particularly compelling, in our view, and should move payers, too. The cost of a hypoglycemia hospitalization is astronomical, and any agent that increases this risk is likely to rack up an expensive medical bill over the long term. The availability of generic, low-cost pioglitazone makes the continued use of sulfonylureas puzzling. The new TOSCA.IT data may cast a shadow over IRIS findings (low-dose pioglitazone was associated with significantly reduced risk for stroke/MI in people without diabetes but with insulin resistance), but we think it presents a crystal-clear argument for pioglitazone over sulfonylureas.
  • Dr. Brett Lauring presented VERTIS SU, a 52-week head-to-head trial (n=1,326) of Merck/Pfizer’s SGLT-2 inhibitor candidate ertugliflozin vs. glimepiride. The higher dose of ertugliflozin (15 mg) was non-inferior to glimepiride on A1c, with an end-of-study treatment difference of 0.1% favoring the SU (95% CI: 0.0-0.2). This is unsurprising, since we hear that A1c-lowering by SUs is very good but drops off quickly, as beta cell burnout occurs. The most notable outcomes were on body weight and adverse events. In contrast to 2 lbs weight gain with glimepiride, 5 mg ertugliflozin was associated with a mean ~7 pounds weight loss, 15 mg ertugliflozin with a mean ~8 pounds weight loss (p<0.001 for both comparisons). Ertugliflozin also gave significantly greater reductions in systolic blood pressure at both doses. Symptomatic hypoglycemia was significantly more common with glimepiride (19%) vs. 15 mg ertugliflozin (5%) and 5 mg ertugliflozin (3%, p<0.001 for both comparisons). Body weight, blood pressure, and hypoglycemia are all incredibly clinically-relevant in diabetes care. That ertugliflozin shows benefits over glimepiride on these key outcomes beyond A1c should be taken seriously. The cost of hypoglycemia-related hospital admissions has been listed at >$7 billion/year (in 2015), and any agents that minimize that risk should be viewed by payers as well worth the cost.
  • A striking poster displayed hypoglycemia frequency and cost data for patients on a DPP-4 inhibitor vs. an SU. Annual rates of hypoglycemia among adult patients with type 2 diabetes who started new therapy with either DPP-4 inhibitors (n=176,786) or sulfonylureas (n=245,201) between 2007-2013 were collected from a claims database. Hypoglycemia events were consistently higher among patients on SUs vs. DPP-4 inhibitors. Reported outpatient hypoglycemia rates per 100 person-years increased from 4.4 to 9.2 for those on sulfonylureas (between 2007 and 2013), and from 3.0 to 6.0 for those on DPP-4 inhibitors. Similarly, overall hypoglycemia rates from 5.4 to 10.4 with SUs and from 3.0 to 6.4 with DPP-4 inhibitors. Cost per hypoglycemia event was consistently lower for the DPP-4 inhibitor group vs. the SU group, possibly indicating lower severity of hypoglycemia with a DPP-4 vs. SU agent. The poster also estimated cost-savings associated with DPP-4 inhibitors due to their decreased risk for hypoglycemia compared to sulfonylureas – $750 million for the study period. In an interview with the poster’s lead author, Dr. Swapnil Rajpathak, he argued that this is one of many studies, including CVOTs and other RCTs, that can help to change prescriber and payer behavior.

A “Light” Meeting for Insulin Therapy

• We noticed a decline in the amount of new insulin data at EASD 2017, especially compared to this year’s ADA Scientific Sessions, which featured full DEVOTE data on Novo Nordisk’s next-gen basal Tresiba (CV outcomes as well as remarkable hypoglycemia benefits) and lots of clinical evidence on advanced rapid-acting options (Lilly’s phase 2 ultra-rapid-acting candidate, Adocia’s ultra-rapid BioChaperone Lispro, and Novo Nordisk’s Fiasp). There was valuable follow-up on these agents at EASD, including (i) post-hoc analyses of DEVOTE linking glycemic variability to all-cause death, (ii) creation of a new hypoglycemia risk score app based on DEVOTE results (see our big picture themes for more on both of these), and (iii) one-year safety/efficacy findings from Onset 1 on Fiasp (faster-acting insulin aspart). That said, other advanced therapy classes like GLP-1 agonists, SGLT-2 inhibitors, and GLP-1 agonist/basal insulin combos seemed to account for more air time in Lisbon, in terms of oral presentation slots and the poster hall. Our sense of-late is that groundbreaking news on insulin therapy is coming from the regulatory scene (i.e. Fiasp was FDA-approved in late September, Novo Nordisk has filed with the FDA and EMA for Tresiba’s hypoglycemia claim based on DEVOTE results) and from real-world evidence (Sanofi dedicated an entire symposium to Toujeo/RWE, which was a most-fascinating session), though of course there’s much more exciting research up ahead. We eagerly await further progress on ultra-rapid-acting insulins, and we’re excited to see what comes from Sanofi’s LIGHTING project: This new endeavor will use machine learning on records from 156,000 US patients to compare outcomes between Toujeo (insulin glargine U300), Tresiba (insulin degludec), Levemir (insulin detemir), and Lantus (insulin glargine U100), in an effort to identify patient segments where Toujeo could provide the greatest hypoglycemia benefit vs. in-class competitors. LIGHTING also aims to evaluate medical cost-savings with reduced hypoglycemia (we cannot stress enough how important this is to quantify!), and we applaud Sanofi’s investment in garnering insights from real-world evidence. The first readouts from LIGHTING are expected in the next 6-12 months. If you notice we missed anything major in our insulin-related coverage from EASD 2017, please write us!

Promise for PCSK9 Inhibitors in Diabetes

• The LDL-lowering PCSK9 inhibitor class made waves at EASD, with new data supporting the efficacy of these agents in diabetes populations specifically. We heard exciting findings pertaining to both PCSK9 inhibitors on the market: A new sub-analysis of the FOURIER CVOT revealed a 17% relative risk reduction in the primary composite CV endpoint and an 18% relative risk reduction in three-point MACE with Amgen’s Repatha (evolocumab) in people with type 2 diabetes (this is on par with the 15% and 20% relative risk reductions seen for the whole participant pool, with or without diabetes). New data from the ODYSSEY DM-INSULIN study showed a mean 52% reduction from baseline LDL with Sanofi/Regeneron’s Praluent (alirocumab) in people with type 1 diabetes. The ODYSSEY DM program presented the first clinical data on PCSK9 inhibitors in diabetes at ADA 2017 (alirocumab was associated with a mean 49% LDL drop in people with type 2, which is on par with the lipid-lowering benefits seen overall). We’re thrilled to see momentum in this area of clinical research, with even more new results on PCSK9 in diabetes shared at EASD. Effective lipid-lowering is critical for best practice diabetes management, and given that CV disease is the leading cause of death in this patient population, we’re hopeful that people with diabetes will also reap the benefits from this advanced therapy class (provided the issues of high cost and poor reimbursement are eventually settled). As Dr. Bertrand Cariou noted in one session at this meeting, there were some earlier concerns that PCSK9 inhibitor products wouldn’t be as efficacious in people with diabetes, given the correlation between higher A1c and elevated levels of circulating PCSK9 (meaning the drugs would have more substrate to overcome). Dr. Cariou asserted that this hasn’t played out in the clinical data so far, which is great news.

Drugs for Prediabetes? Continuing Support of Metformin, New Possibilities in Acarbose

• We were pleased to see alpha-glucosidase inhibitor acarbose (Bayer’s Glucobay) join the ranks of metformin as a potential prediabetes therapy. The Acarbose Cardiovascular Evaluation (ACE) CVOT (n=6,526 patients in China) was presented on Wednesday at EASD, and the agent’s positive results in delaying new-onset type 2 diabetes came as a pleasant surprise. Despite being resoundingly neutral on all of its CV endpoints, acarbose showed an impressive 18% risk reduction vs. placebo for the secondary endpoint of type 2 diabetes incidence (HR=0.82, 95% CI: 0.71-0.94, p=0.005). This exciting finding was accompanied by other beneficial metabolic effects, including a small but significant 0.07% reduction in mean A1c with acarbose vs. placebo (95% CI: -0.04 to -0.10, p<0.0001), a 0.24 mmol/L (~4 mg/dl) reduction in 2-hour postprandial glucose (95% CI: -0.16 to -0.32, p<0.0001), a 0.09 mmol/L (~2 mg/dl) reduction in triglycerides (95% CI: -0.07 to -0.12, p<0.0001), and 0.64 kg (~1.4 lbs) weight loss (95% CI: -0.53 to -0.75, p<0.0001). Independent commentator Dr. Chantal Mathieu contextualized these results with an optimistic message: Prediabetes evolves to diabetes, and we now have extremely solid evidence for a drug that can prevent this. We agree with Dr. Mathieu that the agent’s ability to prevent the onset of diabetes in this high CV risk prediabetes population represents a major win. We can’t help but imagine what this could mean from a public health perspective if acarbose was used more widely for diabetes prevention. Even if this preventative effect is specific only to the very homogenous study population, the potential ROI for acarbose is massive given that an astonishing half of the adult population (500 million people) in China has prediabetes. To-date, acarbose (and alpha-glucosidase inhibitors in general) is most commonly prescribed in Asia, and we are curious whether the ACE trial will spur greater use in North America and Europe, in the diabetes and prediabetes populations alike.
• We heard compelling commentary in support of metformin for diabetes prevention as well. Dr. Marinella Temprosa argued that the generic drug could be a cost-effective solution to the growing global prediabetes epidemic. She reviewed DPPOS results and the 2002 study published in Diabetes Care demonstrating 10-year cost-effectiveness of lifestyle intervention and metformin, concluding that both are good investments. Dr. Clifford Bailey gave a resounding endorsement of metformin’s safety/efficacy, hinting that its niche may be even earlier in the progression of hyperglycemia. Metformin is still considered the first-line treatment for type 2 diabetes in most major guidelines, but perhaps its glycemic and weight loss effects would have clinically-meaningful impact in people with prediabetes, while those diagnosed with type 2 should be more swiftly treated with an advanced therapy (a DPP-4 inhibitor, SGLT-2 inhibitor, or GLP-1 agonist). We appreciated and agreed with this defense of metformin from both experts. Despite this clinical enthusiasm, however, Dr. Temprosa pointed out that real-world uptake of metformin for prediabetes is quite low. If we have strong, published evidence to this end, what are the remaining obstacles? Foremost, Dr. Temprosa alluded to the absence of a prediabetes indication (indeed, a key first step may be getting prediabetes recognized as a disease in and of itself). Still, she concluded her talk with optimism that diabetes prevention messages are being disseminated around the US, and she expressed hope that prevention practices (both lifestyle and metformin) will spread globally. “Do nothing?” she challenged. “Is that really what we want to do? Diabetes can be prevented. It is not inevitable.”

Multifactorial Interventions and an Argument for Earlier Use of Combination Therapy

• Data from multifactorial intervention trials presented at EASD – namely, Steno-2 and J-DOIT3 – supported the need for earlier, more aggressive treatment in type 2 diabetes, perhaps with combination therapy. New 21-year findings from Steno-2 showed how simultaneous glucose-, blood pressure-, and lipid-lowering significantly reduces risk for heart failure hospitalization by 70% vs. standard care (HR=0.30, p=0.002). For the composite endpoint of heart failure hospitalization/CV death, the relative risk reduction was 62% in favor of multifactorial treatment (HR=0.36, p=0.006), and for the composite endpoint of heart failure hospitalization/all-cause death, the relative risk reduction was 49% in favor of multifactorial treatment (HR=0.51, p=0.001). On the last day of EASD, we heard the first data readouts from the Japan Diabetes Optimal Integrated Treatment (J-DOIT3) study (n=2,542). Participants were randomized to conventional (A1c target <6.9%, BMI ≤24 kg/m²) or intensive therapy (A1c target <6.2%, BMI ≤22 kg/m²). While there was no significant difference between treatment groups on the primary composite endpoint (MI, stroke, death, or revascularization), results trended in favor of intensive therapy (HR=0.81, 95% CI: 0.63-1.04, p=0.094). The data did show significance on this endpoint after adjusting for baseline factors (HR=0.76, 95% CI: 0.59-0.99, p=0.042). Over a median duration of 8.5 years, the intensive treatment group achieved an average A1c of 6.8% vs. 7.2% for the conventional group (p<0.001). The intensive treatment group also experienced 5 mmHg greater decreases in systolic blood pressure, 18 mg/dL lower LDL, and 2.5 mg/dL higher HDL (all p<0.001). Intensive treatment was also superior to conventional care on the secondary outcome of nephropathy (HR=0.68, 95% CI: 0.56-0.82, p<0.0001). There’s been some speculation that J-DOIT3 results were skewed by the relatively healthy conventional care group (these participants were well-controlled per Japanese treatment guidelines for hyperglycemia, which are rather strict). Regardless, the overall findings reveal plenty of reasons that HCPs might consider more aggressive glucose, blood pressure, and lipid control for better health outcomes. In a way, both these trials support earlier use of combination therapy. Given how much real-world reluctance there has been to uptake of new fixed-ratio combo products (Novo Nordisk’s Xultophy and Sanofi’s Soliqua), we see a definite need to educate patients/HCPs broadly on the benefits to earlier intervention with combination therapy.

New Data Galore

• We noticed a particularly high number of simultaneous journal publications this year, with a new scientific paper(s) released alongside a symposium announcing new data. NEJM has picked up all the major diabetes CVOTs to-date (SAVOR-TIMI, EXAMINE, TECOS, ELIXA, EMPA-REG OUTCOME, LEADER, SUSTAIN 6, CANVAS, DEVOTE), and EXSCEL joined these ranks with the full results published online in NEJM shortly after 5:15 PM local time on Thursday, September 14 (just as Dr. Robert Mentz was introducing study rationale, design, and execution). Other simultaneous publications from this year’s EASD were inTandem3 results (in NEJM, alongside an overly-critical, some would say absurd, editorial by Dr. David Nathan), two new analyses from DEVOTE (published here and here in Diabetologia, alongside commentary by Dr. Martin Rutter), DEPICT 1 results (in Lancet Diabetes & Endocrinology, alongside a positive editorial by Dr. John Petrie), the TOSCA.IT CVOT comparing TZD pioglitazone head-to-head vs. sulfonylureas (in Lancet Diabetes & Endocrinology), the ACE CVOT for Bayer’s Glucobay (acarbose, in Lancet Diabetes & Endocrinology), and a new post-hoc of FOURIER focusing on participants with diabetes (in Lancet Diabetes & Endocrinology). It is a new world compared to 15 years ago when we felt lucky to see an occasional reference to diabetes in NEJM or JAMA. Now, for all these publications to make a real difference in the real world! So much must go into this and we hope to see far more collaboration here among various stakeholders. If it is published and doesn’t make a difference to patients and HCPs, does it matter that it was published?  
• EASD is always a data-heavy meeting, and the 2017 conference was especially so. Individual studies aside (whether positive, negative, or neutral), this signals an abundance of new data on diabetes therapies being presented, discussed, deliberated. We want to acknowledge the enormous effort that goes into each of these trials, and to appreciate this commitment to and investment in diabetes research overall, which leaves us hopeful for continued advances in diabetes care. The breadth of research presented at this year’s EASD meeting was also impressive: We saw plenty of new outcomes data in type 2 diabetes (including EXSCEL, the DEVOTE analyses, and TOSCA.IT), in addition to exciting findings on adjunct type 1 therapies (inTandem3, DEPICT 1) and new results in prediabetes (acarbose lowered type 2 diabetes incidence by 18% vs. placebo, p=0.005). Historically, more of EASD has related to studies originally announced at ADA in our view – this is definitely not any longer the case.

Diabetes Technology

A Strong Case for CGM in Pregnancy (CONCEPTT) and Big Cost Benefits in Belgium (RESCUE)

• Results from the JDRF-funded CONCEPTT RCT (n=215) made a strong case for CGM use in pregnant women, even with Medtronic’s older (!) Guardian CGM driving significant reductions in the incidence of large for gestational age or LGA (OR =0.51, p=0.01), fewer NICU admissions lasting 24+ hours (OR=0.48, p=0.02), fewer incidences of neonatal hypoglycemia (OR=0.45, p=0.03), and one-day shorter length of hospital stay (p=0.01). Wow! While not the primary endpoint, we find these neonatal outcomes extremely compelling, as did the study authors, who concluded that “CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy.” We’d go so far as to say that although this study didn’t test a much broader population, these results are strong enough to encourage CGM use for any women with diabetes who are pregnant, period (there’s a lot of controversy on when women with gestational diabetes should go on insulin if at all – we would not want to see these women not set up for success with CGM, particularly now that CGM use is expanding overall. As for the primary maternal glycemic outcomes, there was a small 0.2% A1c advantage for CGM at 34 weeks (p=0.02). More importantly, mothers on CGM spent a significant 100 more minutes/day in range (68% vs. 61%, p=0.003), 72 fewer minutes/day in hyperglycemia (27% vs. 32%, p=0.03), and a non-significant ~14 fewer minutes/day in hypoglycemia (3% vs. 4%, p=0.1). As expected with the older Guardian sensor, wear time was lower than in more recent CGM studies – just 70% of pregnant participants used CGM for 75%+ of the time, and ~80% reported frustrations with the device. Due to the length and scope of the trial, updating to a more recent sensor would have proved challenging, but we can’t help but speculate what the results may have looked like if a newer device had been used.
  
  • The numbers needed to treat (NNT) were compelling: Six women with CGM to prevent one event of LGA (large gestational age); eight women with CGM to prevent one event of neonatal hypoglycemia; and six women with CGM to prevent one NICU admission over 24 hours. This last one was particularly compelling short-term and of course the first one is profoundly important when thinking about prevention over the long term. Economic analysis wasn’t presented, but we’d guess that 72-96 months of CGM use (nine months per pregnancy * NNT) would be cost-effective relative to those expensive negative events. 
  • A sub-group analysis suggested that MDI+CGM had a bit of an advantage over pump+CGM for a few outcomes. Pumpers had higher rates of gestational hypertension, preterm delivery, and NICU admissions for 24+ hours. Pump users also had lower A1c reductions, though they spent slightly less time in hypoglycemia. This is clearly very positive news for CGM+MDI, and we wonder how it would compare to automated insulin delivery during pregnancy and delivery. We also doubt that one can just say flatly that MDI is “better” however – it may be that those using pumps had more complications overall, etc. We can imagine however that perhaps those on pumps had less disciplined dietary habits because it is “easier” to take insulin using a pump – hard to know!
  • Interestingly, there were fairly significant differences in large for gestational age across countries, leading commentator Dr. Elisabeth Mathieson to exclaim “learn from Spain!” This discrepancy, to her, is “probably more important” than the influence of CGM on pregnancies. It was a good point – as we focus on technology, we cannot forgot the obvious opportunities for quality improvement in comparing different healthcare systems.
• We also saw convincing evidence of CGM’s health- and cost-efficacy in an incredibly valuable poster sharing 12-month outcomes from national Belgian CGM reimbursement in 515 insulin pump users (RESCUE). This most-valauble academic study tracked outcomes in the 12 months prior to CGM initiation and then in the 12 months following CGM. Notably, the percentage of patients experiencing a hypoglycemia/DKA hospitalization declined by a striking 75% following CGM initiation (16% of patients without CGM to 4% with CGM; p<0005). Meanwhile, CGM drove a 64% decline in the percentage of patients experiencing a work absence (25% to 9%; p<0005). From these data, the poster estimates a nationwide cost reduction of €345,509 – assuming this was calculated from the sub-set of 379 users with 12-month CGM data, it implies €911 saved per person! CGM use also drove improved quality of life, improved fear of hypoglycemia, and improved emotional burden due to diabetes. This is exactly the kind of data we hope to see more of, providing a strong case for CGM reimbursement that will hopefully convince other healthcare systems to perform similar analyses. We’d also love to better understand how healthcare costs look on CGM+MDI vs. CGM+pump….

Industry News: Dexcom Pipeline, Roche Reinvented, & No Medtronic in Exhibit Hall

• In a corporate symposium, Dexcom SVP Mr. Jake Leach shared two updates on the pipeline: (i) The next-gen CGM in Europe will not be called “G6,” as it has “additional features”; and (ii) there is ongoing work to incorporate smart pens with the G5 app, Clarity, and Share. Though Mr. Leach didn’t specify, we imagine that factory calibration will be a logical add-on feature for the G5 follow-on, as well as possible 14-day wear. Both of these amenities will keep pace with Abbott’s FreeStyle Libre, which now has more than 400,000 users worldwide (just approved in the US for 10-day wear). With respect to smart pens, Mr. Leach confirmed that Dexcom has smart pen “partners” – none were disclosed, but slides included images of Lilly and Novo Nordisk pens. Which of the three insulin companies will get there first with a compelling, easy-to-use, widely accessible smart pen? Or perhaps smaller players will drive this field like Bigfoot, Companion Medical, and Common Sensing? Dexcom’s booth featured a slide touting collaborations with Tandem, TypeZero, Insulet, Beta Bionics, and the University of Virginia, with first-time-appearances (that we’ve seen) for Diabeloop and Oregon Health and Science University. 
• After a notable absence from the ADA exhibit hall, Roche came to EASD with new-look diabetes business prospects and pieces at EASD. At the corporate symposium and exhibit hall, the company touted a new “integrated diabetes ecosystem,” which will include Accu-Chek connected BGMs and Connect app, the recently acquired mySugr app, GoCarb (an AI-powered carb counting app), Senseonics’ Eversense CGM (in lieu of Roche’s in-house Insight CGM), the connected Pendiq pen, and other pieces will “hopefully” be available before next year’s EASD. A rep told us that the “open ecosystem” means that the platform will be device-agnostic in 1.5-2 years – and Roche will push forward with prevention programs, early diagnosis, and decision support, in addition to value-based payment models. It’s a refreshing and bold change from the pump- and BGM-centric business we were talking about even a year ago!
  
  • Notably, Roche does not plan to launch further versions of the Accu-Chek Insight CGM. The sensor will stay in existing limited launch markets (“specialized diabetes centers” in the Netherlands, Norway, Denmark, and Sweden), but it sounds like Roche will not expand the device to other countries. We ultimately think the decision to prioritize Senseonics’ Eversense is a prudent one, otherwise the company would be competing against itself to some degree – plus we’ve long wondered how the Insight sensor would have stacked up against Dexcom and Abbott sensors that have strong user experiences and deep pipelines.
  • While we were at EASD, mySugr launched a direct-to-consumer Pro bundle in the US, including unlimited test strips delivery, an Accu-Chek Guide BGM, the mySugr app, and 24/7 CDE access for $39.99 per month. The mySugr bolus calculator, offered in Europe, is not included in the bundle, but we’ve since learned – at Health 2.0 last week - that it is currently under FDA review.
• Medtronic didn’t make an appearance in the exhibit hall, giving conference-goers plenty of fodder for gossip. The pump+CGM giant was absent, and only two posters on the 670G were shared in the hall (both cuts of the pivotal data, but nothing highly notable). Medtronic’s international business is really carrying the company’s sales (see 2Q17), so it was even more surprising to see the absence – particularly in Europe where the 640G has been doing well. There is still no word on the MiniMed 670G in the US, which we had previously expected to launch this year. Many in the hall were gossiping about the sensor supply shortage that has slowed MiniMed 670G shipments in the US, as well as the infusion set recall reported earlier in the conference.

Real World Issues in Digital Health

• Can digital health improve medication and regimen adherence? In a panel discussing real-world challenges in type 2 diabetes, Dr. William Polonsky identified worrisome patient beliefs surrounding medication, like the tendency for patients to equate more drugs with a more severe prognosis, as critical drivers in non-adherence. Commenting on Healthimation’s virtual weight management program, Dr. Polonsky said he believes it can be successful if it provides the right mix of cheerleading, connectivity, and support to make sense of data, frankly adding that “most apps we see in type 2 diabetes are pretty darn boring.” We wonder if VR, simulation, and higher tech education might help to close the adherence gap – lots still to prove there. During The diaTribe Foundation’s Fourth Annual Solvable Problems gathering, Professor David Matthews discussed how type 2 patients don’t typically appreciate the full severity of their disease. Clear messaging is going to be crucial to help patients comprehend the seriousness of a diabetes diagnosis. Technology can help, he added – beyond serving as an education tool, technology that brings patients closer to their providers may also help drive adherence. According to Professor Eduard Montanya, telemedicine may be useful, although the literature is mixed at this point. We were excited to hear that Ascensia is launching a global innovation competition for digital solutions that improve the lives of people with type 2 diabetes – a promising sign that this BGM company is trying to broaden, in addition to its growing partnerships. We see the greatest potential for digital health in capturing data seamlessly, driving more continuous HCP care and education, providing more in-the-moment feedback, more intelligently titrating insulin, and helping users see the interaction between glucose and other factors.  
• It was also clear that not everyone is ready to jump on board the digital health bandwagon. A diverse panel of EU physicians moderated by Dr. Partha Kar, Clinical Director of Diabetes at Portsmouth Hospitals NHS Trust, expressed a surprising lack of knowledge and substantial fear regarding regulation, additional provider burden, and adverse effects surrounding digital health. Insulin titration apps and bolus calculators were of particular concern, with Dr. Lawrence Leiter worrying that many insulin adjustment apps have not been validated, Dr. Steven Kahn believing that free options will lack sufficient regulation and maintenance, and Dr. Michael Nauck nervous that the process will become “too autonomous” (not involving providers enough). None of the physicians on the panel had heard of WellDoc’s BlueStar type 2 diabetes management app and were shocked to learn from an audience member that it is an FDA-cleared, prescribed, reimbursed digital therapeutic. Wow! Several questioned whether there were even regulatory bodies to evaluate digital health apps. This was, of course,  an international panel, and it would be interesting to see how attitudes and knowledge might differ if some US participants had been included. FDA guidelines continue to be updated, but the regulatory pathway for digital health apps feels more straightforward. However, there’s a lot more needed to spread awareness and validate apps in the eyes of providers. As positive outcomes mount and providers realize that digital health can reduce their burden, we hope adoption will take off. As one example, a Glytec poster showed how use of the outpatient Glucommander decision support system resulted in an astounding 2.5% A1c drop from a high baseline of 10.3%. The improvement was sustained with adjustments every ~57 days after goal was reached. With risk stratification and automatic alerts when insulin should be titrated along with recommended adjustments, Glucommander – and other products like it – should save providers time and allow them to focus on the whole person.

Big Picture

Hypoglycemia Takes Center Stage – Regulatory + Biology – Plus New DEVOTE Analysis

• We were delighted to attend two fantastic symposia and the Camillo Golgi lecture, all dedicated to hypoglycemia, from the regulatory to the biological. How fantastic to hear from such world experts. In the first symposium, CHMP member Dr. Bart Van der Schueren (University of Leuven) provided an EMA perspective on measuring hypoglycemia in trials. In the draft diabetes drug guideline (open for comment soon), EMA is leveraging recommendations from the International Hypoglycemia Study Group (IHSG) – “clinically important hypoglycemia” will be defined as <54 mg/dl, while a “glucose alert level” will be <70 mg/dl (but does not have to measured routinely in trials). Dr. Van der Schueren acknowledged that use of the “less than or equal to” will likely be a source of public comment, and we hope it is changed to “less than” so it aligns with the consensus from the Outcomes Beyond A1c meeting in August: <54 mg/dl and <70 mg/dl. In his packed Golgi award lecture that we write much more about below, IHSG member and notable global hypoglycemia expert Prof. Brian Frier (University of Edinburgh) referred to 70 mg/dl as “alert level,” in alignment with Dr. Van der Schueren, but his slide also referenced 54 mg/dl as “significant hypoglycemia,” a bit different from the terminology Dr. Van der Schueren used. Still, we’re elated that tiny points, such as “or equal to” and terminology are all that’s left – the field has come so far to reach consensus in so short a time!
  
  • King’s College London’s Prof. Stephanie Amiel provided a compelling snapshot of why <54 mg/dl (<3 mmol/l) is an evidence-based cutoff for serious/clinically important hypoglycemia. As she did at the August 29 outcomes beyond A1c meeting, Prof. Amiel shared study after study showing the link between negative health outcomes and glucose levels <54 mg/dl – impaired cognitive function (e.g., Gonder-Frederick Diabetes Care 2009), strong correlation with severe hypoglycemia (e.g., DAFNE data), and evidence for CV harm and arrhythmias (e.g., ACCORD, Pistrosch et al., Acta Diabetol 2015). Much of the evidence is summarized in the International Hypoglycemia Study Group paper, published in Diabetologia and Diabetes Care earlier this year (see the reference section for many of the studies she covered). Of note, in many of the studies Dr. Amiel reviewed, <70 mg/dl was NOT linked to the host of adverse outcomes like <54 mg/dl. We wonder how FDA will view the <54 mg/dl data, and how much more validation, if any, it will need to see before considering it when evaluating diabetes therapies.
  • A fascinating IHSG Symposium featured alarming data on the prevalence of hypoglycemia, an explanation for why the correlation between A1c and hypoglycemia is weak, an in-depth look at nocturnal hypoglycemia, therapeutic research in hypoglycemia unawareness, and more. It’s excellent to see this group of clinicians and researchers advocating for more recognition of hypoglycemia!
• New analyses from DEVOTE presented by Drs. Bernard Zinman and Thomas Pieber established the strong correlation between glycemic variability/all-cause mortality, and between severe hypoglycemia/all-cause mortality. This CVOT for Novo Nordisk’s basal insulin degludec (Tresiba) found a remarkable 40% risk reduction for severe hypoglycemia with the next-gen product vs. standard of care insulin glargine (Sanofi’s Lantus). Dr. Zinman showed how day-to-day glycemic variability in the trial was significantly associated with all-cause death (HR=1.58, 95% CI: 1.23-2.03, p=0.0004) across both treatment groups. Dr. Pieber discussed a possible temporal relationship between severe hypoglycemia and all-cause death, with a greater risk for mortality in the first 15 days post-hypoglycemia episode (a whopping HR=4.20, 95% CI: 1.35-13.09) compared to the 365 days post-event (HR=2.78, 95% CI: 1.92-4.04). It’s great to have this hard evidence linking glycemic variability and hypoglycemia to outcomes – as if we didn’t already know the value of these metrics beyond A1c, we now see their association with an outcome everyone cares about: death.
  
  • Notably, Professor Brian Frier’s highly-praised Golgi Lecture warned that recurrent hypoglycemia may be more than a “minor inconvenience” with respect to CV disease. He alluded to a number of studies that suggest links between hypoglycemia and micro- and macrovascular complications, but recent evidence has gone in the opposite direction. In DEVOTE, for example, Tresiba was non-inferior to Lantus on CV outcomes, while reducing hypoglycemia by 40% (53% overnight). However, Prof. Frier pointed out that that conclusions are limited by the facts that the number of severe hypoglycemic events was low and the study was not powered to examine an effect of hypoglycemia on cardiovascular events. Even in the absence of solid evidence at present, hypoglycemia is a huge driver of diabetes quality of life at the very least, so interventions should aim to reduce it, regardless of CV effects. We’d still love to see more evidence on CV effects, since this would be

Obesity

New Energy for Obesity R&D

• There was more obesity content at EASD 2017 compared to last year’s meeting, which was good to see in light of ever-climbing obesity rates, particularly on the severe and morbid obesity sides. Perhaps the most impressive showing came from Novo Nordisk’s GLP-1 agonist candidate semaglutide, in development for both type 2 diabetes (submitted to FDA and EMA) and obesity (phase 2, with phase 3 to begin in 1H18). New data from the SUSTAIN 6 CVOT showed continued weight loss with semaglutide over two years. In this 104-week study (n=3,297), 0.5 mg and 1.0 mg doses of semaglutide gave a mean weight loss of ~8 lbs and ~11 lbs, respectively, compared to ~1.5 lbs and ~1.1 lbs for the corresponding placebo doses (p<0.0001 for both comparisons). Waist circumference fell a significant 2.7 cm with semaglutide 0.5 mg and 4.2 cm with semaglutide 1.0 mg vs. 0.6 cm and 0.9 cm with each placebo dose (p<0.0001 for both comparisons). Moreover, 36% of participants on lower-dose and 47% of participants on higher-dose semaglutide achieved ≥5% weight loss from baseline by the end of SUSTAIN 6. These values were approximately double the proportion of patients on low- and high-dose placebo reaching ≥5% body weight loss, at 18% and 19%, respectively (p<0.0001 for both comparisons). We can only imagine what impact might be seen with combination approaches that include behavioral approaches. Another impressive piece of data was that 77% of the 0.5 mg semaglutide group and 81% of the 1.0 semaglutide group experienced no weight gain at two years vs. 52% and 53% of the corresponding placebo groups. Needless to say, we’re very excited about this molecule and its potential applications in obesity care, and we’re happy to note Novo Nordisk’s strong commitment to its obesity clinical program for semaglutide in addition to the type 2 diabetes program. This is a big deal since particularly for obesity, perhaps even more so than for diabetes, a once-weekly shot may be far better for patients than a once-daily, even forgetting the other incredible benefits. Novo Nordisk’s focus on obesity was also apparent in its exhibit hall presence, with one entire booth dedicated to market-leading Saxenda (liraglutide 3.0 mg). EASD 2017 also featured two posters with new safety/efficacy findings on Zafgen’s second-generation MetAP2 inhibitor ZGN-1061. A phase 1 PK and dose-ranging study found no notable safety/tolerability signals for ZGN-1061. Importantly, this trial also showed no evidence of pro-thrombotic effects (the reason for the discontinuation of Zafgen’s first-gen MetAP2 inhibitor beloranib from phase 3). Moreover, ZGN-1061 showed a rapid impact on body weight, producing weight loss between ~2 lbs and ~5 lbs over 28 days. To complement this, a preclinical study demonstrated dose-dependent improvements in not only body weight but also glycemic control and insulin sensitivity in mice with diet-induced obesity. In line with these data, Zafgen announced the initiation of a new phase 2 trial of ZGN-1061 in people with type 2 diabetes while we were on the ground in Lisbon. We’re pleased to see this forward progress and a growing appreciation for the need to develop effective therapies to support chronic weight management, both for obesity as an independent chronic condition and within the context of diabetes and prediabetes.

-- by Payal Marathe, Adam Brown, Ann Carracher, Abigail Dove, Brian Levine, Maeve Serino, and Kelly Close