EASD 2017 (European Association for the Study of Diabetes)

September 10-15, 2017; Lisbon, Portugal; Full Report – Draft

Executive Highlights

In this full report, we provide our complete coverage of the 53rd annual meeting of the European Association for the Study of Diabetes (EASD), held in Lisbon, Portugal from September 10-15, 2017. This year, 15,436 people were in attendance. To help you sort through our detailed full report, we’ve organized our content into eleven categories: (i) Themes, (ii) Outcomes Trials, (iii) GLP-1 Agonists, (iv) SGLT-2 Inhibitors adn Other Oral Agents, (v) Insulin Therapy, (vi) Novel Therapies, (vii) Diabetes Technology, (viii) Award Lectures and Additional Topics, (ix) Obesity, (x) Exhibit Hall, and (xi) The diaTribe Foundation's Annual Solvable Problems Forum. Each chapter is also available as a separate document. Titles highlighted in blue are new additions that were not mentioned in our daily updates from Lisbon, 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 53rd annual meeting. We’re already looking forward to next year: October 1-5, 2018 in Berlin, Germany.

Immediately below are our 16 key themes from the conference, followed by more than 200 pages of reporting (205 to be exact). Enjoy!

Table of Contents 

Themes

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 0.049 and another is 0.051, 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 Sessionswhich 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-TIMIEXAMINETECOSELIXAEMPA-REG OUTCOMELEADER, 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., ACCORDPistrosch 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.

Outcomes Trials

Symposium: Exenatide Study of Cardiovascular Event Lowering (EXSCEL): Primary Results

Study Rationale, Design, and Conduct

Robert Mentz, MD (Duke University, Durham, NC)

Dr. Robert Mentz discussed key aspects to the design and execution of EXSCEL for AZ’s GLP-1 agonist Bydureon (2 mg exenatide once-weekly). Like previous type 2 diabetes CVOTs, this study was double-blind and placebo-controlled (n=14,752, including 7,356 randomized to exenatide and 7,396 randomized to placebo). Unlike trials that have come before it, EXSCEL was meant to be a pragmatic outcomes study, more closely mimicking real-world conditions. As such, Bydureon treatment was integrated with usual care, and any concomitant anti-hyperglycemic therapy besides another GLP-1 agonist was allowed at the discretion of a patient’s usual diabetes care provider (rather than an HCP specially-appointed to execute EXSCEL). According to Dr. Mentz, annual calcitonin measurements were the only piece of data not collected from a usual care setting. We learned in a separate conversation with AZ’s VP of US Medical Affairs Dr. Jim McDermott that Bydureon was administered via single-dose reconstitution kits instead of the multi-use prefilled product pen. The more cumbersome dosing process could have contributed to lower medication adherence in this trial vs. LEADER for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) – otherwise, we might expect a once-weekly agent like Bydureon to show greater adherence numbers vs. a once-daily agent like Victoza. Moreover, this trial featured no run-in period, which typically identifies and excludes patients who are likely to show poor medication adherence. Median follow-up was 3.2 years, and study visits occurred at one week, two months, six months, and 12 months post-randomization, after which visits were every six months until end of treatment to minimize interference with usual care. Dr. Mentz further outlined how the trial included 70 days of safety follow-up immediately after the treatment period. He described inclusion criteria as broad: a wide range of CV risk was accepted, and there was no enrichment of the study population with elderly patients (participants were accepted down to age 18). Exclusion criteria included current or prior GLP-1 agonist use, eGFR <30 mL/min/1.73m2, prior pancreatitis, ≥two episodes of severe hypoglycemia in the past 12 months, calcitonin >40 ng/L, and personal or familial history of MEN-2. The primary endpoint was time to first occurrence of three-point MACE (non-fatal MI, non-fatal stroke, or CV death). Secondary endpoints were analyzed by conditional hierarchy, and included all-cause mortality, individual components of three-point MACE, hospitalization for acute coronary syndrome, and hospitalization for heart failure. The trial aimed for a minimum 1,360 primary endpoint events, and in the end collected 1,744. Lastly, Dr. Mentz established EXSCEL as a truly global study, enrolling 6,788 participants from Europe at 329 clinical sites (46%), 3,708 patients from North America at 190 sites (25%), 2,727 people from Latin America at 64 sites (18%), and 1,529 people from Asia Pacific at 104 sites (10%).

  • Simultaneous with the start of this EASD symposium, full EXSCEL results were published online in NEJM.

Participant Characteristics and Risk Factor Changes

Angelyn Bethel, MD (University of Oxford, UK)

Oxford’s Dr. Angelyn Bethel presented baseline characteristics of the study population, highlighting some key differences in this regard between EXSCEL and LEADER, Novo Nordisk’s positive CVOT for GLP-1 agonist Victoza (liraglutide). AZ’s trial enrolled 14,752 adults with type 2 diabetes, making it the largest diabetes CVOT completed to-date (notably, the company’s DECLARE CVOT for SGLT-2 inhibitor Farxiga will be even larger, with >17,000 participants, while LEADER enrolled 9,340 participants). At baseline, the average EXSCEL participant was 62 years-old with BMI 32 kg/m2, eGFR 76 ml/min/1.73m2, A1c 8%, and diabetes duration ~12 years. Metformin was the most common background diabetes drug (~75% of both treatment arms), followed by insulin and sulfonylureas, and ~12% of people were taking a DPP-4 inhibitor at study start – in contrast, people on a DPP-4 inhibitor were excluded from LEADER. As planned, EXSCEL enrolled a participant pool that was ~30% primary prevention, ~70% secondary prevention, making this a lower-risk group overall. More specifically, ~73% of both the exenatide and placebo arms had a prior CV event at baseline (53% had a history of coronary artery disease, 17% of cerebrovascular disease, 19% of peripheral arterial disease, and 16% of congestive heart failure). Both statins and anti-thrombotics/anti-coagulants were used in >70% of participants at baseline, while ~55% of individuals were on statin therapy and 40% were taking an ACE inhibitor/ARB. Median follow-up time was 3.2 years. Treatment discontinuation was quite high in both the exenatide and placebo groups, at 43% and 45%, respectively. Dr. Bethel didn’t comment extensively on this (underscoring instead the very small number of people lost to follow-up, at <0.5% total), but we imagine use of the Bydureon reconstitution kit rather than the easier-to-use pen had some contributing influence on dropout rates. To better understand what stimulated dropouts, we’d be curious to see any data on patient experience or quality of life in both LEADER and EXSCEL (and other diabetes outcomes studies, like EMPA-REG OUTCOME, CANVAS, and SUSTAIN 6, for that matter).

  • Dr. Bethel also shared data on changes in A1c, heart rate, body weight, blood pressure, and initiation of new therapies in EXSCEL. By the end of the study, there was a 0.5% A1c treatment difference between the Bydureon and placebo arms (p<0.001). Trial design aimed for glycemic equipoise, and people in both arms started from the same baseline A1c of 8%, but Dr. Bethel explained the significant difference by pointing out that HCPs were allowed to use any other diabetes drugs (with the exception of GLP-1 agonists) in treating their patients to target. Once again, she reinforced pragmatic trial design, and alluded to the fact that LEADER study protocol was more restrictive in what additional medications could be prescribed – no GLP-1 agonists, DPP-4 inhibitors, or pramlintide (AZ’s Symlin). As expected, heart rate increased by ~two beats/minute with exenatide therapy vs. placebo (p<0.001). From a baseline body weight just over 203 lbs, placebo-treated patients tended to gain weight by the end of follow-up while exenatide-treated patients experienced modest weight loss, leading to a significant ~3 lb treatment difference (p<0.001). Systolic blood pressure declined from a baseline ~136 mmHg in both arms, but Bydureon showed superior reductions by a mean ~2 mmHg (p<0.001).
  • Dr. Bethel reported a 33% risk reduction for the addition of any new diabetes therapy with Bydureon vs. placebo (HR=0.67, 95% CI: 0.63-0.71, p<0.05). Similarly, relative risk reduction for new initiation of insulin treatment was 39% with Bydureon (HR=0.61, 95% CI: 0.54-0.68, p<0.001). This finding is clinically-meaningful in terms of simplifying medication regimens for people with diabetes in the real world. Moreover, it suggests that participants randomized to placebo in this trial were treated more aggressively with other agents besides once-weekly exenatide, including SGLT-2 inhibitors, which have demonstrated cardioprotection in their own CVOTs (see our coverage of EMPA-REG OUTCOME for Lilly/BI’s empagliflozin and CANVAS for J&J’s canagliflozin). Indeed, SGLT-2 inhibitors were given open-label to 6.5% of patients in the Bydureon group vs. 9.4% of patients in the placebo group.

Safety Data

Bernard Zinman, MD (University of Toronto, Canada)

Dr. Bernard Zinman presented safety data from the EXSCEL trial. Serious adverse events were well-balanced across treatment arms, affecting 17% of participants in both the exenatide and placebo groups. There were 56 individuals in the exenatide arm (0.8%) and 38 in the placebo arm (0.5%) who reported serious adverse events related to treatment, and 108 (1.5%) and 104 (1.4%) participants respectively experienced serious adverse events leading to permanent treatment discontinuation. Severe hypoglycemia (requiring assistance) occurred numerically fewer times in the exenatide group (404 events) than the placebo group (450 events). Respectively, 247 (3.4%) and 219 (3.0%) participants experienced severe hypoglycemia, though this difference did not reach statistical significance. Acute pancreatitis – historically, a concern surrounding GLP-1 agonists – occurred in 26 participants in the exenatide group vs. 22 in the placebo group. Dr. Zinman noted that these very low rates of acute pancreatitis, and their near equivalence between the exenatide and placebo group, are extremely reassuring. Malignancy was also similar between groups, affecting 355 patients in the exenatide arm and 361 patients in the placebo arm (4.8% vs. 4.9%). Within this, there were 15 cases of pancreatic cancer in the exenatide arm (vs. 16 in the placebo arm) and 14 cases of thyroid cancer in the exenatide arm (vs. six in the placebo arm). Medullary thyroid cancer (MTC) occurred in two participants on exenatide and one on placebo; in all three cases, participants had an elevated calcitonin levels at baseline, a known risk factor for MTC. Dr. Zinman explained that most safety data in EXSCEL was collected via adverse event reporting – only acute pancreatitis and malignancy were confirmed by adjudication.

Cardiovascular Outcomes

Adrian Hernandez, MD (Duke University, Durham, NC)

Dr. Adrian Hernandez took the stage for the symposium’s main event: presentation of the CV outcomes data. Immediately, without wasting a breath, he unveiled the hazard ratio for three-point MACE of 0.91 (95% CI: 0.83-1.00, p<0.001 for non-inferiority, p=0.06 for superiority) trending toward exenatide, but missing the statistical threshold for superiority by a razor-thin margin. Talk about the “edge” of superiority with an upper bound of 1.00. These results trended in a much more positive direction than many may have thought after learning that EXSCEL had not met superiority from AZ’s topline announcement in May. The trial did not reach superiority for any individual component of the three-point MACE composite, but all of these secondary outcomes trended in favor of exenatide, with hazard ratios of 0.86 for non-fatal stroke (95% CI: 0.70-1.07), 0.95 for non-fatal MI (95% CI: 0.84-1.09), and 0.88 for CV death (95% CI: 0.73-1.05). Dr. Hernandez also presented several subgroup analyses that probed for possible heterogeneity of effect among different patient populations. Interestingly, there was a significant interaction for age (p=0.005 for interaction), whereby Bydureon was associated with statistically significant CV risk reduction in people older than 65 (HR=0.80, 95% CI: 0.71-0.91). The p-values for interaction were non-significant for sex, race, and geographical region (Europe, North America, Latin America, and Asia Pacific). Similarly, there was no significant interaction for various risk factors, including diabetes duration, baseline A1c, eGFR, BMI, background anti-hyperglycemic oral therapy, prior congestive heart failure, or a history of CV events.

  • Turning to secondary endpoints, Dr. Hernandez reported a hazard ratio for all-cause mortality of 0.86 (95% CI: 0.77-0.97, nominal p=0.016) favoring exenatide vs. placebo. By the trial’s pre-specified hierarchical testing structure, this can only be considered exploratory since exenatide did not meet superiority for its primary endpoint. Nevertheless, we find this suggestion of a 14% risk reduction for all-cause mortality to be noteworthy. No other secondary endpoints met superiority, but most had point estimates that trended in the “right” direction (to the left of unity), with a hazard ratio of 0.97 for fatal or non-fatal MI (95% CI: 0.85-1.10, p=0.622), 0.85 for fatal or non-fatal stroke (95% CI: 0.70-1.03, p=0.095), and 0.94 for hospitalization for heart failure (95% CI: 0.78-1.13, p=0.485). The secondary endpoint of hospitalization for acute coronary syndrome (ACS) trended in favor of placebo (HR=1.05, 95% CI: 0.94-1.18, p=0.402), but importantly, did not reach statistical significance.

Source: NEJM

Source: EXSCEL EASD presentation

EXSCEL in Perspective

Rury Holman, MD (University of Oxford, UK)

In a notable address, Dr. Rury Holman, first author on the EXSCEL paper published in NEJM, argued that this trial largely supports the CV benefits to the GLP-1 agonist class as a whole. He presented a meta-analysis of three GLP-1 agonist CVOTs (including EXSCEL, LEADER, and SUSTAIN 6 but excluding ELIXA for Sanofi’s lixisenatide because it evaluated four-point MACE as its primary outcome) showing a significant 12% risk reduction for three-point MACE with a GLP-1 agent vs. placebo (HR=0.88, 95% CI: 0.81-0.95, p=0.002). Dr. Holman reported a non-significant p-value for interaction of 0.28, suggesting no evidence for heterogeneity of effect between exenatide, liraglutide, and semaglutide. He called out that CV death accounts for two-thirds of all mortality in these large diabetes trials, and then discussed a similar meta-analysis looking specifically at CV death, which found a 13% relative risk reduction with GLP-1 agonist therapy (HR=0.87, 95% CI: 0.79-0.96, p=0.007). Here, the p-value for interaction was again non-significant at 0.43. Turning to all-cause death, Dr. Holman presented a meta-analysis showing 12% relative risk reduction with a GLP-1 agonist product (HR=0.88, 95% CI: 0.81-0.95, p=0.002). The p-value for interaction was 0.63, once more pointing to a lack of heterogeneity between these different GLP-1 agents. While it would be hard to assert that all GLP-1 agonists are identical in their effects – the variations in molecular structure are well-documented, and head-to-head studies like SUSTAIN 7 (semaglutide vs. dulaglutide) have demonstrated clinically-meaningful differences in A1c-lowering and weight loss – Dr. Holman’s overarching message was that Bydureon’s missing the mark on superiority had more to do with trial design and study population than with the exenatide molecule itself.

  • He proposed four specific differences between CVOTs that may have influenced outcomes: (i) baseline A1c (8.7% in LEADER and SUSTAIN 6 vs. 8.1% in EXSCEL), (ii) primary prevention cohort (19% in LEADER, 17% in SUSTAIN 6, and 27% in EXSCEL), (iii) median follow-up time (3.8 years, 2.1 years, and 3.2 years, respectively), and (iv) median drug exposure (3.5 years, 1.8 years, and 2.4 years, respectively). The inclusion of more participants facing lower CV risk at baseline may have muted the cardioprotective benefit to Bydureon vs. placebo. In fact, a major theme emerging at the FDA Advisory Committee for Victoza’s CV indication was liraglutide’s differing effects in lower- vs. higher-risk cohorts, and the FDA-approved label update applies only to type 2 diabetes patients with established CV disease. This isn’t to say that liraglutide, exenatide, or any GLP-1 agent doesn’t confer any cardioprotective value for those without a prior history of CV disease. Rather, it implies that CV benefit may take much longer to appear in a clinical trial enrolling low-risk patients, and that EXSCEL may have been “less powered” vs. LEADER in this regard. The hazard ratio for three-point MACE was 0.90 (95% CI: 0.82-1.00) in favor of Bydureon among EXSCEL participants with a prior CV event, 0.99 (95% CI: 0.77-1.28) among those without any history of CV disease. Dr. Holman’s discussion of less overall drug exposure in the present study vs. LEADER alluded to the less-than-ideal adherence to once-weekly exenatide injections. We might expect longer exenatide exposure to correlate with greater CV benefit, and to this end, we’re eager for more in-depth analysis of the adherence data from all GLP-1 agonist CVOTs side-by-side. While some have noted that Intarcia’s FREEDOM-CVO trial of ITCA 650 (implantable mini pump offering three-six months of continuous exenatide release, circumventing the adherence issue) was also neutral, showing CV safety but not efficacy vs. placebo, we also think that’s more about trial design and interest in speed to show safety.
  • Dr. Holman positioned EXSCEL as a reassuring safety dataset for Bydureon, as it should “dispel concerns” related to pancreatitis, pancreatic cancer, medullary thyroid cancer (MTC), and severe hypoglycemia. Moreover, he highlighted the 14% relative risk reduction for all-cause mortality in the trial (HR=0.86, 95% CI: 0.77-0.97). The pre-defined statistical testing plan precludes us from drawing conclusions about this as statistically significant, but all-cause death is clearly an important outcome (if not the most important outcome), and the lower frequency in exenatide vs. placebo arms is a valuable insight for clinical practice, according to Dr. Holman. We agree – this trial overall supports Bydureon as a safe and effective diabetes therapy, one that could benefit many patients in the real world (especially considering the very low proportion of the type 2 population that is on any GLP-1 agonist). While many questions remain about how Bydureon compares to Victoza and other in-class competitors, we pause to note incredibly important contributions from EXSCEL to the diabetes field: The study lends additional evidence in support of this advanced therapy class, and in our view, doesn’t conclusively refute (at least not yet) that CV benefits could be a GLP-1 class effect (in fact, we think it reinforces this).

Commentator

Francesco Giorgino, MD (University of Bari Aldo Moro, Italy)

Tasked with providing independent commentary on EXSCEL, Dr. Francesco Giorgino weighed positive and neutral results from the Bydureon CVOT, sharing a fairly balanced view overall. The suggestion of risk reduction for all-cause mortality (HR=0.86, 95% CI: 0.77-0.97) is certainly a positive, according to Dr. Giorgino, even though this finding cannot be deemed statistically significant because exenatide didn’t show superiority on the primary endpoint. He pointed to the neutral effect of Bydureon on heart failure hospitalization as another positive (HR=0.94, 95% CI: 0.78-1.13), given some lingering concerns in the diabetes community over incretin therapies and heart failure risk (this stems primarily from the SAVOR-TIMI CVOT of AZ’s DPP-4 inhibitor Onglyza, as neither LEADER nor SUSTAIN 6 found a significant signal for heart failure hospitalization). That the hazard ratio for individual components of three-point MACE (non-fatal MI, non-fatal stroke, and CV death) all trended in the right direction is also good news, as this offers a more compelling and comprehensive case for CV safety and falls in line with the CV efficacy data seen in LEADER for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). Indeed, Dr. Giorgino likened EXSCEL most closely to LEADER among all GLP-1 agonist CVOTs. He reported a number needed to treat (NNT) of 98 for liraglutide treatment over three years to prevent one death from any cause vs. an NNT of 106 for exenatide treatment over three years. As to why the primary endpoint result in EXSCEL missed superiority, Dr. Giorgino circled back to pragmatic trial design (no run-in period) and a larger primary prevention cohort (27% vs. 19% in LEADER, 0% in ELIXA for Sanofi’s lixisenatide, and 17% in SUSTAIN 6). He mentioned that while A1c-lowering was similar with Bydureon in EXSCEL and with Victoza in LEADER, the former demonstrated no significant risk reduction for severe hypoglycemia, which may have influenced observed outcomes (liraglutide was associated with a 20% risk reduction for confirmed hypoglycemia <54 mg/dl, p<0.001). Further, he reminded the audience that Bydureon reconstitution kits probably decreased adherence from where it would have been with a prefilled pen. That said, Dr. Giorgino found fault with some key arguments in defense of EXSCEL’s pragmatic design as well. For one, SGLT-2 inhibitors were also used at a similar rate in the placebo arm of SUSTAIN 6, which was positive for cardioprotection regardless. Moreover, investigators emphasized the infrequent clinical visits to minimize interference with usual care, but Dr. Giorgino pointed out that provider visits in LEADER were equally infrequent, once every six months after the first six months. These were important criticisms to be articulated, and we look forward to much more discussion on RCTs vs. the real world going forward. We’re eager for a more in-depth look at concomitant medications, patient/provider interactions, and adherence in all GLP-1 agonist CVOTs side-by-side.

  • Ultimately, Dr. Giorgino expressed his opinion that GLP-1 agonists are beneficial in terms of their CV effects, but it’s still unclear which target type 2 diabetes population is best. He described how the pleotropic effects of drugs in the class may lead to CV benefit, and outlined exenatide’s direct effects on the CV system including anti-inflammatory responses and anti-atherosclerotic responses. Glycemic efficacy has little to do with cardioprotection in EXSCEL or other diabetes CVOTs, in Dr. Giorgino’s view, since other large studies like ACCORD, ADVANCE, VADT, and UKPDS did not show a reduction in all-cause mortality despite substantial A1c drops.
  • Very notably, Dr. Giorgino did not give much credence to the argument dividing GLP-1 agonists into exendin-4-based molecules (exenatide, lixisenatide) and human GLP-1-based molecules (liraglutide, semaglutide). While the variations on molecular structure may result in products with slightly different signaling and biological effects, he explained that these variations are unlikely to cause meaningful differences in CV effects. We’ll be following this debate closely in the weeks and months ahead.

Close Concerns Questions

Q: How will the diabetes community respond to EXSCEL, a convincing demonstration of Bydureon’s CV safety and a narrow miss for CV benefit? Do these results add or subtract from the notion of a cardioprotective class effect for GLP-1 agonists?

Q: How big a role did poor adherence play in EXSCEL’s neutral result? Would the same CVOT using a prefilled exenatide pen (or better yet, the upcoming Bydureon autoinjector) yield a positive result?

Q: How did elements of pragmatic trial design influence outcomes in EXSCEL? What was the impact of SGLT-2 inhibitors prescribed to placebo-treated patients, and how does this compare to SGLT-2 use in SUSTAIN 6?

Q: Will the field move toward standardization of CVOT design? Will this start with FDA?

Q: In what form (if any) will EXSCEL data be incorporated onto the Bydureon product label? How will this affect AZ’s marketing around its GLP-1 agonist franchise?

Q: Is there a meaningful divergence in CV effects between exendin-4-based vs. human GLP-1-based molecules? What kind of study (mechanistic or outcomes) might investigate this further?

Q: If EXSCEL’s neutral result does in fact have more to do with pragmatic trial design than with the molecule itself, how can we explain the neutral findings from FREEDOM-CVO for Intarcia’s ITCA 650 (implantable exenatide mini pump)? 

Symposium: Insulin Degludec vs. Glargine Cardiovascular Safety in T2D: The DEVOTE Study

Impact of Glycemic Variability and Severe Hypoglycemia on Outcomes

Bernard Zinman, MD (University of Toronto, Canada); Thomas Pieber, MD (Medical University of Graz, Austria); John Buse, MD (UNC, Chapel Hill, NC)

We were treated to three new analyses from the DEVOTE CVOT of Novo Nordisk’s next-gen basal insulin Tresiba (insulin degludec) vs. Sanofi’s Lantus (insulin glargine): (i) Dr. Bernard Zinman correlated glycemic variability to severe hypoglycemia and all-cause death (paper published online in Diabetologia), (ii) Dr. Thomas Pieber showed a possible temporal relationship between severe hypoglycemia episodes and all-cause death (paper published online in Diabetologia), and (iii) Dr. John Buse discussed development of the DEVOTE hypoglycemia risk score and accompanying app (which we saw at Novo Nordisk’s booth in the exhibit hall).

  • (i) In DEVOTE 2, investigators found day-to-day glycemic variability to be significantly associated with all-cause mortality (HR=1.58, 95% CI: 1.23-2.03, p=0.0004). After adjusting for A1c and baseline characteristics, this finding retains its statistical significance with a hazard ratio of 1.33 (95% CI: 1.01-1.75, p=0.0432). Dr. Zinman presented additional data on glycemic variability and its relationship to severe hypoglycemia, which after adjusting for A1c and baseline characteristics, outputs a hazard ratio of 3.37 (95% CI: 2.52-4.50, p<0.0001). In contrast, he announced that there was no significant association between glycemic variability and three-point MACE after adjusting for A1c and baseline characteristics (HR=1.21, 95% CI: 0.98-1.49, p=0.0811). Dr. Zinman concluded that Tresiba’s benefits may arise from lower glycemic variability, which could substantially decrease frequency of hypoglycemia and risk for all-cause death, per this analysis. As a reminder, the relative risk reduction for severe hypoglycemia was 40% with Tresiba vs. Lantus in the original DEVOTE presentation at ADA 2017, while relative risk reduction for severe nocturnal hypoglycemia was even more impressive at 53%. In our view, hypoglycemia is a critical outcome beyond A1c and any therapy that reduces this risk is enormously valuable in our diabetes treatment arsenal. The hard evidence linking glycemic variability to hypoglycemia and all-cause death will also be valuable as we push for more consideration (from clinical trialists, regulators, patients, providers, and payers alike) of outcomes beyond A1c.
  • (ii) Next, Dr. Pieber presented the DEVOTE 3 analysis, showing a possible temporal relationship between severe hypoglycemia and all-cause death. In the 15 days following a severe hypoglycemia episode, hazard ratio for all-cause mortality in DEVOTE was 4.20 (95% CI: 1.35-13.09). In the first 30 days post-event, this hazard ratio was 3.66 (95% CI: 1.51-8.84). The increase in risk for all-cause death seems to decline as more time passes following a severe hypoglycemia episode (at one year – HR=2.78, 95% CI: 1.92-4.04). Dr. Pieber noted the wide confidence intervals, acknowledging that the temporal relationship of severe hypoglycemia and death is suggestive rather than conclusive at present. That said, severe hypoglycemia still showed a significant increase in risk for death from any cause at any time (HR=2.51, 95% CI: 1.79-3.50), and this is a very important finding. Severe hypoglycemia did not show statistically significant time course correlations with MACE events overall, but CV death was more likely following a severe low (HR=2.14, 95% CI: 1.37-3.35). These findings give yet another reason that hypoglycemia risk reduction is key in diabetes care – if the exceptionally high cost of hospitalizations and the quality of life impact wasn’t enough, this data now also shows a clear link to all-cause death.
  • (iii) Dr. John Buse discussed development of the DEVOTE hypoglycemia risk score and accompanying app. He reviewed rigorous analyses to show that the risk score is indeed accurate, predicting risk for severe hypoglycemia or a MACE event based on input variables such as age, A1c, duration of diabetes, gender, and insulin status (naïve, bolus, or basal-bolus). Dr. Buse suggested one potential application of the app in facilitating patient/provider conversations when it comes to insulin initiation – people with type 2 diabetes are often resistant to starting insulin treatment, but he showed how adding bolus insulin on the app only modestly changes hypoglycemia risk for certain other pre-set variables. All in all, though the purpose of this app is not definitely decided, we thought it was a brilliant tool, and we’re excited to see where Novo Nordisk goes with this.

Symposium: Canagliflozin Cardiovascular Assessment Study (CANVAS)

Design, Methods, and Patient Characteristics

Greg Fulcher, MD (University of Sydney, Australia)

Dr. Greg Fulcher reprised his role from ADA 2017, speaking first during this CANVAS symposium to review trial design and baseline characteristics of the study population. Notably, J&J’s CVOT for SGLT-2 inhibitor Invokana (canagliflozin) integrated data from two separate studies: (i) CANVAS (n=4,330), initiated in 2010, randomized type 2 patients to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, while (ii) CANVAS-R (n=5,812), initiated in 2014, randomized people to canagliflozin 100 mg that could be up-titrated to 300 mg, or to placebo. In total, the CANVAS program enrolled 10,142 participants across 30 countries and 667 clinical sites in North America, Latin America, Europe, and Asia Pacific. The primary endpoint was a three-point MACE composite (non-fatal MI, non-fatal stroke, and CV death), and mean follow-up time when taking the two trials together was 188 weeks (~3.6 years). In discussing patient characteristics/disposition in CANVAS, Dr. Fulcher focused on the mean age of 63 years-old in both canagliflozin and placebo groups, with a mean diabetes duration of 14 years. He shared that ~36% of participants were female, attributing the majority male subject pool to higher CV risk in the latter. According to Dr. Fulcher, ~90% of patients had hypertension at baseline, while ~14% had a history of heart failure and ~66% had some prior history of CV disease. Nearly 80% of individuals enrolled were white, and almost as many were on background metformin treatment (~50% on insulin, ~43% on sulfonylureas, ~12% on DPP-4 inhibitors). Baseline A1c was 8.2% in both arms, with a mean BMI of 32 kg/m2.

Effects on Intermediate Biomarkers and Beta Cell Function and CV Outcomes

David Matthews, MD (University of Oxford, UK)

Dr. David Matthews discussed the effect of canagliflozin on intermediate biomarkers and beta cell function in CANVAS. He revealed that canagliflozin dose (100 mg or 300 mg) had no effect on the previously-described mean A1c change of -0.6% with the drug vs. placebo. On the beta cell front, he reported that both doses of canagliflozin produced improvements in beta cell function as measured by HOMA2-%B after one year. From a baseline of ~56%, HOMA2-%B grew to 68% for canagliflozin 100 mg and 72% for canagliflozin 300 mg (vs. 60% for placebo, p<0.0001 for both comparisons). We are certainly intrigued by the potential for a beta cell protective effect with canagliflozin therapy, and we eagerly await longer-term data to determine whether this effect is real and endures over time. To our knowledge, this restoration of beta cell function has not been described in the SGLT-2 inhibitor class to-date, so we’re particularly keen to hear more commentary from thought leaders on how meaningful this is, and what the mechanism could be.

  • Without missing a beat, Dr. Matthews transitioned straight into the CV outcomes from the CANVAS trial. After reviewing the original results first presented at ADA 2017, he pointed to some baseline differences between the primary prevention (n=3,486) and secondary prevention (n=6,656) cohorts: Namely, the secondary prevention cohort had a higher baseline rate of heart failure (18% vs. 8%), as well as significantly higher use of cardioprotective agents like statins (81% vs. 63%), antithrombotic agents (87% vs. 49%) and beta blockers (64% vs. 33%). Background use of other diabetes therapies (metformin, insulin, SUs, DPP-4 inhibitors, and GLP-1 agonists), as well as RAAS inhibitors and diuretics did not differ significantly between the primary prevention and secondary prevention cohorts, nor did mean age, sex, diabetes duration, hypertension, or a variety of risk factors such as starting A1c, BMI, blood pressure, and cholesterol. We learned earlier that there was no heterogeneity of benefit for higher-risk vs. lower-risk participants in the CANVAS program (that is, the p-value for interaction was non-significant), but these baseline differences are still important to note as they could have skewed the results in some way. In all likelihood, this is not the last we’ll hear on subgroups in CANVAS, and we’ll keep our eyes and ears peeled for further detailed analyses.

Renal Outcomes

Dick De Zeeuw, MD (University Medical Center Groningen, The Netherlands)

Though CANVAS was primarily a cardiovascular outcomes trial, the microvascular findings on Invokana’s renal benefits packed quite a punch as well. Dr. Dick De Zeeuw summarized renal data from the integrated program (highlighting very similar values to EMPA-REG OUTCOME), shared new insights specific to CANVAS-R, and emphasized the importance of the ongoing CREDENCE trial (expected to complete in June 2019) to fully grasp canagliflozin’s impact in diabetic nephropathy. In CANVAS-R, canagliflozin was associated with an increase in eGFR in year two of treatment. In a subsequent off-treatment period (median time 30 days), Dr. De Zeeuw showed how this line continues on its upward slope, indicating further increase in eGFR even after people have stopped taking the oral SGLT-2 inhibitor. Right now, this data is merely “suggestive of a renal protective profile,” as Dr. De Zeeuw put it, but CREDENCE could draw more definitive conclusions about Invokana’s beneficial effects on kidney function. Interest in SGLT-2 inhibitors for kidney disease has essentially tripled of-late, with Lilly/BI and AZ launching their own dedicated studies of empagliflozin (Jardiance) and dapagliflozin (Farxiga) respectively in chronic kidney disease (CKD). At ESC 2017, Dr. David Fitchett hinted that patients with eGFR <60 ml/min/1.73m2 may actually stand to benefit the most from SGLT-2 inhibitor therapy in terms of renal and cardioprotection, and we’re excited about this new direction for an advanced diabetes therapy class.

Adverse Events and Safety Considerations

Bruce Neal, MD (The Georgia Institute for Global Health, Sydney, Australia)

Dr. Bruce Neal, first author on the CANVAS paper published in NEJM, shared new, more granular data on amputations occurring during the trial. This topic is of great interest to many in the diabetes field, including us, since it was revealed during the original CANVAS full results presentation at ADA that canagliflozin increased risk for lower limb amputations nearly two-fold vs. placebo (HR=1.97, 95% CI: 1.41-2.75, p<0.001). Dr. Neal discussed a dozen or so risk factors that were associated with lower-extremity amputations according to a univariate analysis of the CANVAS safety data, explaining that “by far the strongest relative risk came from having a prior amputation” (HR=21.4), though he also listed peripheral vascular disease (HR=2.5), neuropathy (HR=3.4), history of CV disease (HR=2.9), nephropathy (HR=2.2), baseline insulin use (HR=2.4), baseline A1c >8% (HR=2.0), male gender (HR=2.6), retinopathy (HR=2.3), use of loop diuretics (HR=2.1), baseline eGFR <45 ml/min/1.73m2 (HR=1.8), and diabetes duration ≥10 years (HR=1.6). His slides then advanced to display findings from a multivariate analysis: prior amputation (HR=20.9), peripheral vascular disease (HR=3.1), male gender (HR=2.4), neuropathy (HR=2.1), A1c >8% (HR=1.9), presence of CV disease at baseline (HR=1.5), and canagliflozin treatment (HR=1.8) remained as variables significantly increasing an individual’s amputation risk. Dr. Neal reinforced that canagliflozin treatment, independent of all other risk factors, still nearly-doubled amputation risk – in other words, these new results don’t explain away the amputation signal seen in CANVAS, attributing it to something other than the molecule, but they do pinpoint factors to consider as we push for more diligent monitoring and enhanced patient education around foot care in diabetes. Moreover, the multivariate analysis identifies possible reasons that CANVAS may have found an amputation signal not seen in EMPA-REG OUTCOME (in which, Dr. Neal reminded everyone, amputations were collected using a different process) – if, for example, Lilly/BI’s CVOT featured much less peripheral vascular disease, neuropathy, or prior history of amputations in its baseline study population (we’re eager to do a deeper dive on this). Looking ahead, Dr. Neal suggested that AZ’s DECLARE CVOT for Farxiga (dapagliflozin) will shed more light on SGLT-2 inhibitors and amputations. He underscored that other phase 3 trials of canagliflozin (not counting CANVAS) have reported only 10 lower-extremity amputation events total, in 8,114 participants, and that Truven observational results reflect no imbalance (HR=0.98, 95% CI: 0.68-1.41).

  • Moreover, Dr. Neal described common precipitating events that preceded lower limb amputations in CANVAS. Infection was the most common (67/140 amputations in the canagliflozin arm, 27/47 amputations in the placebo arm), followed by gangrene (53 and 13 events in the canagliflozin and placebo groups, respectively), peripheral arterial disease (46 and 13 events), ulcers (43 and 17 events), acute limb ischemia (18 and 3 events), and neuropathy (18 and 10 events). This fits with a recurring theme we’ve been hearing from several thought leaders – amputations are a soft endpoint (meaning patients/providers make a decision about whether or not to have one), and can often be avoided if care teams are diligently monitoring for these major precipitating factors. Once again, we note the tremendous opportunity here to improve foot care in real-world diabetes management (we’d love for J&J to show leadership in this initiative, alongside other SGLT-2 manufacturers), starting with education on what key features to monitor for.
  • On fractures, Dr. Neal discussed conflicting trends: More fractures were seen with canagliflozin vs. placebo in CANVAS, but fewer were seen in the SGLT-2 arm in CANVAS-R. Among adjudicated low-trauma fractures, there was no imbalance, but among all adjudicated fractures, canagliflozin was associated with significantly more vs. placebo across the integrated program (HR=1.26, 95% CI: 1.04-1.52). According to Dr. Neal, there is no clear reason for this discrepancy as of yet, and so uncertainty persists around canagliflozin and bone fractures. As he said at ADA, “I’m not easily persuaded by things happening by chance, but this is a weird result. We don’t see a fracture signal in EMPA-REG OUTCOME, nor in CANVAS-R, nor in any of the other CANVAS trials, so it’s possibly by chance.” He concluded this portion of his talk with a mention of CREDENCE – this upcoming outcomes trial of canagliflozin in diabetic kidney disease will hopefully help clarify the fracture trend.

Implications for Clinical Practice

Bruce Neal, MD (The Georgia Institute for Global Health, Sydney, Australia)

Dr. Bruce Neal remained on stage to contextualize CANVAS trial results, and this talk focused on a forthcoming publication from the George Institute that analyzes 82 SGLT-2 inhibitor studies in conjunction. The meta-analysis covers canagliflozin, empagliflozin (Lilly/BI’s Jardiance), and dapagliflozin (AZ’s Farxiga), as well as three agents developed and marketed in Japan (luseogliflozin [Taisho Pharmaceuticals’ Lusefi], ipragliflozin [Astellas’ Suglat], and phase 3 tofogliflozin [Chugai Pharma]). The results suggest a favorable risk/benefit profile for SGLT-2 inhibitors overall, with trends toward cardioprotection and renal benefit, plus minimal safety signals (except elevation in the risk for amputation and fracture). Dr. Neal described how the meta-analysis also shows some key differences between the various SGLT-2 inhibitors, mostly on the safety front, but he was careful to preface his remarks by cautioning that it is difficult to compare between trials that involved different populations and different methodologies.

  • The meta-analysis found an overall trend toward risk reduction for major CV events (HR=0.85, 95% CI: 0.77-0.93, p=0.504). Data from canagliflozin and empagliflozin indicates a significant risk reduction for CV death (HR=0.75, 95% CI: 0.65-0.87, p=0.024), as well as a trend toward risk reduction for non-fatal MI (HR=0.84, 95% CI: 0.73-0.98, p=0.648), for unstable angina (HR=0.95, 95% CI: 0.73-1.24, p=0.380), for heart failure hospitalization (HR=0.67, 95% CI: 0.55-0.80, p=0.936), and for all-cause death (HR=0.79, 95% CI: 0.70-0.88, p=0.110). Across all of these outcomes, Dr. Neal noted the “striking comparability” in individual point estimates for canagliflozin and empagliflozin, with two notable exceptions: CV death (which favored empagliflozin with a hazard ratio of 0.62 vs. 0.87 for canagliflozin) and non-fatal stroke (which favored canagliflozin with a hazard ratio of 0.91 vs. 1.24 for empagliflozin). He attributed these differences to chance, given the small number of events.
  • On renal outcomes, the meta-analysis showed a trend toward risk reduction for albuminuria progression (HR=0.72, 95% CI: 0.67-0.77, p=0.488) and serious decline in kidney function (HR=0.59, 95% CI: 0.49-0.71, p=0.793). This is based on data from canagliflozin and empagliflozin alone.
  • On safety, the meta-analysis revealed that the data thus far on the SGLT-2 inhibitor class shows no significant increase in the overall risk for cancer (HR=1.05, 95% CI=0.93-1.18, p=0.83), metabolic acidosis (HR=1.30, 95% CI=0.59-2.86, p=0.45), or thromboembolism (HR=0.91, 95% CI=0.62-1.34, p=0.68). On the other hand, the class is associated with an increased risk of fracture (HR=1.05, 95% CI=0.92-1.20, p=0.01) and amputation (HR=1.44, 95% CI=0.1.13-1.83, p=0.01). Furthermore, some interesting within-class differences emerged on the safety front, including:
    • A trend toward higher risk of metabolic acidosis with canagliflozin vs. empagliflozin and luseogliflozin;
    • A trend toward lower risk of thromboembolism with empagliflozin vs. canagliflozin, dapagliflozin, and luseogliflozin;
    • A trend toward higher risk of fracture with canagliflozin than dapagliflozin and empagliflozin;
    • And, famously, a trend toward higher risk of amputation with canagliflozin vs. empagliflozin.

Commentator

Ele Ferrannini, MD (University of Pisa, Italy)

In an engaging presentation to conclude EASD 2017 (this symposium was in the last Friday slot), University of Pisa’s Dr. Ele Ferrannini offered strong opinions on CVOT design and SGLT-2 inhibitor class effects. He suggested the field move away from three-point MACE as a primary outcome, referring to this endpoint as “a bit of a salad.” The field’s knowledge of SGLT-2 agents, for example, is complicated by the fact that canagliflozin and empagliflozin both showed 14% risk reduction for three-point MACE, while strokes trended in the wrong direction in EMPA-REG OUTCOME even though the relative risk reduction for CV death was greater (38% vs. 13% in CANVAS). Dr. Ferrannini also 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. Also, he pointed out that MACE lumps together MI and stroke, which have partially different sets of risk factors. Studies dedicated to MI alone, stroke alone, or heart failure alone might reveal more valuable and clinically-applicable information for diabetes practice, he argued. These are certainly clinical trials we’d like to see, and we’re glad Lilly/BI and AZ have launched dedicated investigations of their SGLT-2 inhibitor products in heart failure, but we also acknowledge the massive investment of time and resources that goes into a CVOT and the need for some practicality in selecting endpoints. Moreover, diabetes CVOTs published to-date are already exceptionally difficult to compare due to differences in study design and participant pool, and losing three-point MACE as a primary outcome might move us further away from standardization on this front (of course, this raises another debate over the advantages and drawbacks of CVOT standardization). Nonetheless, we thought this was a very interesting argument laid out by Dr. Ferrannini, and we look forward to collecting more insights and perspectives from other thought leaders. He continued his presentation by establishing the likelihood of cardioprotective and renal protective class effects among all SGLT-2 inhibitors, pointing to the congruence of findings between CANVAS and EMPA-REG OUTCOME on these key macrovascular and microvascular endpoints. Safety may be where SGLT-2 agents differ. That said, Dr. Ferrannini explained that amputations are a procedure-driven endpoint (or a soft endpoint, with decisions left up to patient/provider). He urged HCPs to look for precipitating factors (infection, gangrene, etc.) and to monitor carefully instead of shying away from Invokana (or worse yet, from all SGLT-2 inhibitor treatment options). We echo this view completely, and we also appreciated Dr. Ferrannini’s call for more real-world evidence on amputations, which could be most valuable in elucidating the signal.

Symposium: Acarbose Cardiovascular Evaluation (ACE): Primary Results

Cardiovascular, Glycemic, and Renal Outcomes

John McMurray, MD (University of Glasgow, Scotland); Rury Holman, MD (Oxford University, UK)

Alpha-glucosidase inhibitor acarbose (Bayer’s Glucobay) did not meet any of its CV endpoints in the Acarbose Cardiovascular Evaluation (ACE) CVOT, but did, very excitingly, show an 18% risk reduction vs. placebo for the secondary endpoint of new-onset type 2 diabetes (HR=0.82, 95% CI: 0.71-0.94, p=0.005) in a Chinese population with prediabetes and a previous history of CV events (n=6,526). In this multi-center, double-blind, secondary prevention CVOT, participants were randomized 1:1 to 150 mg acarbose vs. placebo after a five-week run-in period for optimization of background CV therapy, and were followed for a median of five years. University of Glasgow’s Dr. John McMurray outlined the ACE trial’s CV outcomes, showing no benefit for acarbose vs. placebo in this high-risk prediabetes population. There was definitively no relative risk reduction for the primary outcome of five-point MACE (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or hospitalization for heart failure; HR=0.98, 95% CI: 0.86-1.11, p=0.73) or for any of the secondary outcomes, including three-point MACE (HR=0.95 ,95% CI: 0.81-1.11, p=0.51), all-cause death (HR=0.95, 95% CI: 0.81-1.19, p=0.85), CV death (HR=0.89, 95% CI: 0.71-1.11, p=0.29), fatal or non-fatal MI (HR=1.12, 95% CI: 0.87-1.46, p=0.38), fatal or non-fatal stroke (HR=0.97, 95% CI: 0.70-1.33, p=0.83), hospitalization for unstable angina (HR=1.02, 95% CI: 0.82-1.26, p=0.87), and hospitalization for heart failure (HR=0.89, 95% CI: 0.63-1.24, p=0.48). On the bright side, acarbose appeared to reduce risk for new-onset type 2 diabetes by 18% (p=0.005 vs. placebo), and trial chairman Dr. Rury Holman (Oxford University, UK) revealed that this positive finding was accompanied by other beneficial metabolic outcomes, 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). Full results were simultaneously published in the Lancet.

Commentator

Chantal Mathieu, MD (KU Leuven, Belgium)

Dr. Chantal Mathieu closed this symposium by providing an independent perspective on the ACE trial results, illustrating (literally) her opinion of the results with an image of a glass half full. Although acarbose did not achieve its primary endpoint on CV outcomes, Dr. Mathieu positioned the drug’s significant prevention of new-onset diabetes as an extremely important result – particularly given the rising tide of prediabetes globally, and especially in China where the trial was conducted. As Dr. Jean-Louis Chiasson (University of Montreal, Canada) contextualized earlier in the symposium, many expected this trial to meet its primary endpoint based on acarbose’s known beneficial effect on markers of CV risk and postprandial glucose (which is associated with worse CV endpoints), as well as the promising suggestion of cardioprotection for acarbose in a 2003 meta-analysis of the 1998 STOP-NIDDM trial, in which the drug was associated with a significant relative risk reduction in the incidence of MI (HR=0.09, 95% CI: 0.01-0.72, p=0.03) and all CV events (HR=0.51, 95% CI: 0.28-0.95, p=0.03) in comparison to placebo in a majority white population with prediabetes and no CV history. Given all this, to the question of why ACE did not reach superiority, Dr. Mathieu’s answer was a resounding “I have no clue.” However, she did propose a variety of potential hypotheses to explain this underwhelming result: (i) the 150 mg dose range used in the trial doesn’t impact CV outcomes; (ii) acarbose’s primary effect on postprandial glucose isn’t sufficient to make a difference on wider CV risk; and (iii) limited epidemiological understanding of the prediabetes population. She left us 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 drug’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 preventive 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’s impressive glycemic outcomes will spur greater use in North America and Europe, in the diabetes and prediabetes populations alike.

Symposium: Evolocumab in Diabetes and Diabetes Risk: Novelties from the FOURIER Study

Cardiovascular Efficacy and Safety of Evolocumab in Diabetes and Risk of Development of Diabetes: An Analysis from the FOURIER Trial

Marc Sabatine, MD (Harvard University, Boston, MA)

A pre-specified sub-analysis of people with diabetes within the FOURIER trial revealed that the PCSK9 inhibitor evolocumab (Amgen’s Repatha) reduced risk for the composite primary endpoint (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization) by 17% (HR=0.83, 95% CI: 0.75-0.93, p<0.0008) and for the key secondary endpoint of three-point MACE (CV death, non-fatal MI, or non-fatal stroke) by 18% (HR=0.82, 95% CI: 0.72-0.93, p<0.0021). As outlined by Harvard’s Dr. Marc Sabatine, this is comparable to the 13% risk reduction (HR=0.87, 95% CI: 0.79-0.96, p=0.0052) for the primary endpoint and the 22% risk reduction (HR=0.78, 95% CI:0.69-0.89, p=0.0002) for three-point MACE for people without diabetes at baseline. Notably, the magnitude of this cardioprotective benefit appears to grow over time. Landmark analysis revealed a 13% relative risk reduction in three-point MACE after one year (HR=0.87, 95% CI: 0.73-1.04), which grew to a 25% relative risk reduction for the rest of the study (HR=0.75, 95% CI: 0.63-0.89). These new results are now published in The Lancet. Full coverage of the original FOURIER results (also presented by Dr. Sabatine) are available in our full report on ACC 2017.

  • Importantly, this significant reduction in CV risk occurred against the backdrop of overall higher risk for MACE events in people with diabetes. People with diabetes at baseline had 26% higher relative risk for the primary endpoint (HR=1.26, 95% CI:1.13-1.40, p<0.0001) – a 17% three-year risk of an event vs. 13% for people without diabetes. People with diabetes also had a 40% higher relative risk for the secondary outcome of three-point MACE (HR=1.40, 95% CI: 1.23-1.60, p<0.0001) – a 12% three-year risk of an event vs. 8% for their counterparts without diabetes. This elevated risk for CV events in people with diabetes underscores the importance of cardioprotective therapies for this population.
  • As in the original FOURIER analysis, evolocumab produced significant reductions in lipid levels in the subgroup of people with diabetes at baseline. Participants with diabetes showed an impressive 57% mean reduction in LDL cholesterol with evolocumab (p<0.0001), plunging from a baseline of 89 mg/dl to 31 mg/dl (vs. 85 mg/dl for placebo). This is comparable to the 60% mean reduction in LDL cholesterol in participants without diabetes. In people with and without diabetes, this LDL reduction was achieved rapidly, within the first six weeks, and was sustained throughout the duration of the trial. Evolocumab further produced significant reductions in other lipid parameters vs. placebo in people with diabetes: non-HDL cholesterol fell 50% (vs. -52% in people without diabetes), ApoB fell 45% (vs. -47% in people without diabetes), triglycerides fell 16% (vs. -16% in people without diabetes), and Lp(a) fell 27% (vs. -27% in people without diabetes).
  • There was no difference in new-onset diabetes with evolocumab vs. placebo (HR=1.05, 95% CI: 0.94-1.17), and this trend held true for participants with prediabetes at baseline (HR=1.00, 95% CI: 0.89-1.13). Among all participants without diabetes at baseline (in the evolocumab and placebo groups alike), the Kaplan-Meir rate of new-onset diabetes reached 4% after one year, 7% after two years, and 11%-12% after three years. Consistent with this, evolocumab was associated with no significant changes in A1c, fasting plasma glucose, or body weight vs. placebo – this held true across participants with diabetes, prediabetes, and no diabetes at baseline.
  • There were slight differences in baseline characteristics between FOURIER participants with and without diabetes, all of which were controlled for in this statistical analysis. Compared to the non-diabetes subgroup, the diabetes subgroup had fewer men (73% vs. 77%), higher incidence of hypertension (87% vs. 75%), lower incidence of smoking (22% vs. 32%), lower eGFR (74 vs. 76 ml/min/1.73m2), lower background use of ezetimibe (4% vs. 6%), and a different regional distribution.

Source: The Lancet

Symposium: J-DOIT3: A Multifactorial Intervention Trial for Prevention of Macrovascular Complications and Mortality

Background and Study Design

Kohjiro Ueki, MD (University of Tokyo, Japan)

The Japanese J-DOIT3 trial assessed the impact of multifactorial management of blood glucose, blood pressure, and lipids on the prevention of macrovascular complications and mortality in people with type 2 diabetes, comparing strict control vs. traditional management based on the current targets in Japanese guidelines. Dr. Kohjiro Ueki contextualized the rationale for the J-DOIT3 trial in terms of the 2008 Steno-2 study, which showed a significant reduction in five-year incidence of macrovascular complications and mortality in people with type 2 diabetes with intensive multifactorial therapy (glucose-lowering, blood pressure-lowering, and lipid-lowering simultaneously), but has limited generalizability because of its very small sample size (n=160) and low achievement of the target A1c of 6.5% (~15% achieved this, even in the intensive group). J-DOIT3 was designed to resolve these issues. A total of 2,542 participants (note the much larger sample size vs. Steno-2) across 81 sites in Japan were randomized 1:1 to intensive therapy (target A1c <6.2%, target blood pressure <120/75 mmHg, target LDL <80 mg/dl or <70 mg/dl with a CV history) vs. conventional therapy (target A1c <6.9%, target blood pressure <130/80 mmHg, target LDL <120 mg/dl or <100 mg/dl with a CV history). BMI goals were also lower in the intensive group (<22 kg/m2 vs. <24 kg/m2), as were triglyceride goals (<120 mg/dl vs. <150 mg/dl). Mean follow-up was 8.5 years.

  • Baseline characteristics were highly-similar across treatment arms: age 59, diabetes duration 8.5 years, A1c 8%, BMI 25 kg/m2, history of CV disease in 11% of participants, fasting plasma glucose 159 mg/dl, blood pressure 134/80 mmHg, LDL 125 mg/dl, and triglycerides 121-123 mg/dl. Very notably (this became a major theme of the symposium), the primarily Western audience audibly gasped at how well-controlled this Japanese population’s blood pressure and lipid levels were at baseline, compared to the norms in the US and Europe.

Data Analysis

Yasuo Ohashi, MD (Chuo University, Tokyo, Japan)

Dr. Yasuo Ohashi discussed outcomes and analyses in J-DOIT3, which changed somewhat as the study was developed. In the original trial design, the primary endpoint was occurrence of either MI, stroke, or death. Secondary outcomes included onset or progression of nephropathy, onset or progression of retinopathy, and lower limb vascular events (amputation or revascularization). The annual incidence of events in the conventional therapy arm was estimated at 4.4% initially (10% in those with a history of coronary artery disease and 2% in those without). To show a 30% risk reduction in the intensive arm at p<0.05 with 90% power, the required number of events was estimated at 328, giving a required 1,408 participants per arm for a 3.75-year observation period. However, after one year, the actual incidence of events was much lower (Dr. Ohashi alluded to the relatively healthy baseline population), and the necessary number of patients was reevaluated to be 3,338 total. Ultimately, the final number of participants (n=2,542), 11% of whom had a history of CV disease, fell short of goal. Thus, in January 2010, the primary endpoint was redefined: The initial primary endpoint became the main secondary endpoint, and the new primary endpoint became incidence of MI, stroke, death, or revascularization. Power was lowered to 80%, which required 250 events, and participants were followed until 80% power was reached.

  • There was a high rate of exclusion post-screening in J-DOIT3. Of 14,695 people judged eligible by screening, only 2,542 were randomized – 82.7% were excluded, of which 21.4% declined to participate and 61.3% were excluded for other reasons. Of 1,271 individuals randomized to conventional therapy, 8.7% discontinued, compared to 8% of 1,271 participants in the intensive therapy group. There was no comment on what might have led to such a high exclusion rate – it’s possible many patients were too well-controlled to meet inclusion criteria. It certainly seems that this study was significantly challenged by event rates in the background diabetes patient population in Japan.

Results and Interpretation

Kohjiro Ueki, MD (University of Tokyo, Japan)

After presenting background, Dr. Kohjiro Ueki came to the podium once again to review results, showing significant reductions in A1c, blood pressure, and lipids with intensive vs. conventional therapy over 8.5 years. Intensive treatment reduced mean A1c to 6.8% from a baseline 8%, corresponding to a 0.4% treatment difference vs. conventional therapy (95% CI: 0.43%-0.32%, p<0.001). Furthermore, intensive therapy reduced mean systolic blood pressure from 134 mmHg to 123 mmHg on average, and diastolic blood pressure from 80 mmHg to 74 mmHg on average. This culminated in a treatment difference of 5 mmHg and 3 mmHg, respectively (p<0.001 for both comparisons vs. conventional therapy). LDL dropped from 125 mg/dl to a mean 85 mg/dl with intensive therapy, and the 40 mg/dl reduction corresponded to an 18 mg/dl treatment difference from conventional therapy (p<0.001). These positive effects are especially impressive in light of the tight blood pressure and lipid control in both groups at baseline, before intervention. At the end of the study, BMI did not differ significantly from baseline in either treatment arm, despite an initial reduction with intensive control during the first year.

Outcomes

Takashi Kadawaki, MD (University of Tokyo, Japan)

Next, Dr. Takashi Kadawaki took the stage to present the study’s microvascular and macrovascular outcomes. Intensive therapy did not significantly reduce the cumulative incidence of the primary outcome of MI, stroke, all-cause death, or revascularization (HR=0.81, 95% CI: 0.63-1.04, p=0.094), though there was certainly a trend in favor of more aggressive control. Dr. Kadawaki attributed this result to lack of statistical power due to very low event rates overall, noting that this outcome did achieve significance after adjusting for base rate (HR=0.76, 95% CI: 0.59-0.99, p=0.042). Post-hoc analysis of individual component endpoints within the primary outcome revealed that intensive control did significantly reduce the risk of cerebrovascular events (HR=0.42, 95% CI: 0.24-0.74, p=0.0002), but not all-cause mortality or coronary events. Moreover, subgroup analysis revealed no significant interactions for the primary outcome or for cerebrovascular events on the basis of risk strata, sex, age, history of cardiovascular disease, baseline A1c, or diabetes duration. On secondary endpoints, intensive therapy narrowly missed significance for the main secondary outcome of MI, stroke, and death (HR=0.74, 95% CI: 0.54-1.01, p=0.055), but did significantly reduce the risk of nephropathy events (defined as albuminuria progression, serum creatinine levels elevated two-fold or more, or end-stage renal failure; HR=0.68, 95% CI: 0.56-0.82, p<0.0001) and retinopathy events (defined as retinopathy progression or loss of vision; HR=0.86, 95% CI: 0.74-1.00, p=0.046). Intensive therapy had no significant effect on lower limb vascular events (HR= 0.89, 95% CI: 0.36-2.20, p=0.80).

  • In Dr. Kadawaki’s view, these results are suggestive of a benefit for intensified multifactorial intervention for renal and retinal complications of diabetes, as well as cerebrovascular events. He argued that this data supports stricter treatment guidelines in Japan, more closely reflecting the targets in the intensive control arm of J-DOIT3. He also revealed that a follow-up observational study is ongoing to evaluate the legacy effect of intensive vs. conventional therapy on coronary events, cerebrovascular events, and mortality. We very much look forward to seeing if the effects observed here endure over an even longer time course.

Commentator

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

The great Dr. Per-Henrik Groop provided independent commentary on this important outcomes trial. He described how previously, the only multifactorial intervention targeting macrovascular complications with glucose, blood pressure, and lipid control simultaneously was Steno-2, a small but highly-cited Nordic study. While results from Steno-2 were positive, it remained to be seen whether these Nordic findings were generalizable in a larger, ethnically and culturally different population. Dr. Groop noted that the targets for A1c, blood pressure, LDL, BMI, and triglycerides in J-DOIT3 were more aggressive than those in Steno-2. However, baseline variables in J-DOIT3 participants were also better-controlled on the whole than in Steno-2. He established how Steno-2 achieved more impressive results: For the composite CV endpoint, intensive therapy was significantly beneficial over conventional therapy (HR=0.47, 95% CI: 0.24-0.73), compared to the modified primary outcome for J-DOIT3, which only became significant when adjusting for baseline risk factors (HR=0.76, 95% CI: 0.59-0.99, p=0.042). Still, Dr. Groop highlighted the positive effects of intensive therapy on kidney disease in J-DOIT3 as a particular bright spot (HR=0.68, 95% CI: 0.56-0.82, p<0.001). Ultimately, Dr. Groop emphasized that the well-controlled control group in J-DOIT3 created problems for the investigators, as did the unexpectedly low event rate. Despite the statistical hiccups, he maintained that targeting glycemia, blood pressure, and lipids simultaneously reduces risk for both micro and macrovascular complications, which should be the aim of best practice diabetes care everywhere.

Effects on the Incidence of Cardiovascular Events of the Add-On of Pioglitazone as Compared with a Sulfonylurea in Type 2 Diabetic Patients Inadequately Controlled with Metformin: The TOSCA.IT Study

Introduction

Gabriele Riccardi, MD (University of Naples, Italy)

Dr. Gabriele Riccardi introduced TOSCA.IT, a large (n=3,028) multicenter CVOT conducted across Italy to compare TZD pioglitazone head-to-head with sulfonylureas, including glimepiride, glibenclamide, and gliclazide. This effort was supported by the non-profit Italian Diabetes Association, which according to Dr. Riccardi, had been saying for >10 years prior that the diabetes field needs a pragmatic trial comparing sulfonylureas and TZDs in real-world clinical practice conditions. Indeed, these are two generic – and therefore low-cost – second-line therapy options after metformin for people with type 2 diabetes. While we’d love to see widespread access to SGLT-2 inhibitors and GLP-1 agonists with demonstrated cardioprotective benefit (from the recent EMPA-REG OUTCOME, LEADER, and CANVAS trials), we hear time and time again how cost is the main driver of diabetes treatment decision (this was a major theme at AADE 2017, it was unavoidable in conversations among diabetes educators). Given this, we absolutely see value in a comparison of outcomes between two accessible, widely-used generic drugs, and we applaud the Italian Diabetes Association for taking this on. The TOSCA.IT team set out with objectives to evaluate the long-term effects of pioglitazone vs. SUs on incidence of CV events and mortality, glucose control and its durability, and safety. 

  • Providing background, Dr. Riccardi presented mixed evidence from prior studies regarding sulfonylureas and CV risk, with some showing neutrality and others showing CV harm. Despite this uncertainty around CV effects, not to mention all the SU side-effects we do know with certainty (namely hypoglycemia), Dr. Riccardi explained that agents in this class are still prescribed in high volume due to their low cost and familiarity factor (“general practitioners feel more confident in sulfonylureas vs. newer drugs”).
  • On pioglitazone, he described minimal risk of hypoglycemia seen in previous clinical research and a mechanism of action that works against insulin resistance. Moreover, he mentioned the IRIS trial (published last year) as evidence that pioglitazone reduces risk for atherosclerosis CV events (stroke, MI), speculating that this may have something to do with a deceleration of carotid intima-media thickening (cIMT).

Design and Baseline Data

Olga Vaccaro, MD (Federico II University, Naples, Italy)

Dr. Olga Vaccaro outlined trial design and baseline characteristics of the study population, and was the first of several presenters to emphasize that TOSCA.IT enrolled patients with diabetes at relatively low risk for CV disease. On average, participants were 62 years-old with a BMI of 30 kg/m2, eight years diabetes duration, and baseline A1c 7.7%. Baseline LDL was ~103 mg/dl in both the pioglitazone (n=1,535) and sulfonylurea groups (n=1,493), while systolic blood pressure was a mean 134 mmHg and 17%-18% of participants were smokers. There were 187 people randomized to pioglitazone (12%) and 148 randomized to sulfonylureas (10%) with a prior CV event at baseline – looking at this another way, 89% of patients enrolled in the study did not have a history of CV disease. Moreover, Dr. Vaccaro remarked that nearly 70% of participants were on antihypertensive drugs, nearly 60% on lipid-lowering drugs, and nearly 40% on antiplatelet agents, highlighting that CV risk factors were “pretty optimally controlled” with other recommended therapies in this study population. In fact, risk for CV events was low enough that TOSCA.IT did not reach its pre-specified goal of collecting 498 primary endpoint events (non-fatal MI, non-fatal stroke, all-cause death, or urgent coronary revascularization). A futility analysis recommended that TOSCA.IT be terminated after 57.3 months (nearly five years) median follow-up, as it seemed unlikely that sufficient CV events would occur.

  • Within the sulfonylurea group, 50% of patients were on glimepiride, 49% on gliclazide, and <2% on glibenclamide. This is noteworthy, given commentary from some thought leaders that there are clinically-meaningful in-class differences to various SUs (though we still believe the class as a whole should be switched out in favor of safer, more effective therapies). Average daily metformin dose was 2,000 mg across both study arms, while mean dose of pioglitazone was 23 mg/day. This was an open-label trial, conducted in 57 different Italian clinics, which Dr. Vaccaro asserted is highly-representative of the clinical reality of diabetes care nationwide in Italy.

Efficacy on Blood Glucose Control and Cardiovascular Risk Profile

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

The great Dr. Stefano Del Prato presented glycemic results, including an A1c treatment difference of 0.06% after 60 months (p=0.01 for superiority). He emphasized that the trend is important here: sulfonylureas were associated with a greater initial drop in A1c, but based on rate-of-change data, the TZD pioglitazone demonstrated greater durability of glucose-lowering effect over time. Also on this point, treatment failure (defined as A1c >8% at two consecutive clinician visits) was 37% more likely for SU-treated patients vs. pioglitazone-treated patients over 60 months (HR=0.63, 95% CI: 0.52-0.75, p<0.0001), underscoring durability of effect for pioglitazone. Dr. Del Prato remarked that these durability findings are consistent with past RCTs. Fewer patients in the TZD arm required new initiation of insulin therapy vs. the SU arm, at 11% and 16%, respectively (p<0.0001). Dr. Del Prato paused to mention the double whammy of a drug class that heightens hypoglycemia risk and also increases need for insulin, although he acknowledged the alternative possibility, that greater hypoglycemia rates seen for SU-treated patients in TOSCA.IT were perhaps driven by more insulin use. Severe hypoglycemia (blood glucose <60 mg/dl, requiring assistance) occurred in 2% of SU-treated patients and in <0.2% of pioglitazone patients (p<0.0001), while moderate hypoglycemia (blood glucose <60 mg/dl, not requiring assistance) occurred in 32% of the SU group and only 10% of the TZD group (p<0.0001). There were no significant between-group differences on BMI (though weight tended to increase early on sulfonylurea therapy, later on pioglitazone therapy), LDL, blood pressure (systolic or diastolic), eGFR, UACR, or high-sensitivity c-reactive protein (a biomarker for inflammation). HDL cholesterol was mostly flat in the sulfonylurea arm, but rose slightly (~2 mg/dl) with pioglitazone over the course of the trial (p<0.0001), which Dr. Del Prato interpreted to mean that the TZD does change lipid profile for the better. He pointed out that triglycerides also declined slightly more, on average, with pioglitazone vs. sulfonylureas, though this did not reach statistical significance (p=0.29).

Cardiovascular Outcomes

Antonio Nicolucci, MD (Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy)

When the futility analysis recommended that the TOSCA.IT trial be stopped, 213 CV events had been adjudicated, and Dr. Antonio Nicolucci reported “absolutely no difference” in the primary outcome (non-fatal MI, non-fatal stroke, all-cause death, or urgent coronary revascularization) between pioglitazone and sulfonylureas (HR=0.96, 95% CI: 0.74-1.26, p=0.79). There was similarly no imbalance in any individual component of the composite endpoint. Dr. Nicolucci quickly reviewed post-hoc on-treatment analyses for each of these endpoints, all supporting the CV neutrality of pioglitazone vs. sulfonylureas in this particular study. However, an on-treatment analysis of a key secondary outcome (sudden death, fatal or non-fatal MI including silent MI, fatal and non-fatal stroke, above-the-ankle leg amputation, or any revascularization of the coronary, carotid, or leg arteries) did reflect a benefit to pioglitazone vs. sulfonylureas (HR=0.67, 95% CI: 0.47-0.96, p=0.03) – Dr. Nicolucci recognized that this must be “interpreted with caution.” Admittedly, we would have liked to see some hint of CV benefit to pioglitazone vs. SUs, for one because we want all people with diabetes to gain access to medicine better than sulfonylureas, and TZDs (also generic) circumvent the cost argument. Moreover, many diabetes thought leaders have touted IRIS trial results and the risk reduction for stroke/MI, recommending low doses of pioglitazone to real-world clinicians, and it would be tremendous to see a generic drug with some cardioprotective value for people with diabetes. Despite this disappointing result, some very clinically-meaningful and not-to-be overlooked differences appeared in the hypoglycemia and A1c durability data from this trial (see above).

Safety Profile of the Study Drugs

Aldo Maggioni, MD (ANMCO Research Center, Firenze, Italy)

Dr. Aldo Maggioni took the stage to discuss safety findings from the study, showing no significant difference in serious adverse events between pioglitazone (14%) and SU (13%) groups (p=0.69). He zoomed in on bladder cancer – the crux of a media storm that hit TZDs a few years ago, and a concern that still lingers in the minds of some HCPs – to highlight the reassuring absolute balance of a 1% event rate in both groups (p=1.00). Heart failure also occurred at a ~1% event rate across both arms (p=0.11). There was no difference in pathological fractures, macular edema, or new/worsening nephropathy between study drugs. Treatment discontinuation was substantially higher in the pioglitazone arm, at 28% vs. 16% in the sulfonylurea arm (HR=1.98, 95% CI: 1.67-2.34, p<0.0001), but this was attributed to the aforementioned media storm, which scared many patients away from the TZD class. During Q&A, Dr. Silvio Inzucchi corroborated how challenging it has been to conduct clinical trials of TZDs for this exact reason, and he praised the TOSCA.IT committee for pushing forward with this important outcomes research nonetheless. Dr. Maggioni also reiterated the hypoglycemia data, underscoring pioglitazone’s clear benefit on this relevant safety measure – and, we would add, a critical outcome beyond A1c. We also wonder about the link between sulfonylureas and beta cell burnout in TOSCA.IT, though this is an effect that may take much longer to appear – but is still such an important one, given how many type 2 patients are treated only with a sulfonylurea for the entire duration of their disease. Ultimately, the safety of pioglitazone vs. SUs on heart failure, fractures, and cancer is a reassuring finding from this study, and an important message, in our view, for the diabetes community to hear.

Implications for Clinical Practice

Enzo Bonora, MD (University of Verona, Italy)

Dr. Enzo Bonora reiterated that both pioglitazone and sulfonylureas are commonly used type 2 diabetes drugs around the world, suggesting that a head-to-head study like TOSCA.IT comparing the two generics was long overdue. He summarized that pioglitazone showed distinct advantage on A1c-lowering, durability of A1c-lowering, and hypoglycemia vs. sulfonylureas, and while there was no significant difference in terms of CV or all-cause death, the on-treatment analysis of key secondary outcome (HR=0.67, p=0.03) hints at a benefit to pioglitazone for ischemic CV disease (notably, this would fall in line with IRIS trial results). Dr. Bonora argued that changing the natural history of disease should be a key goal in diabetes management – this means counteracting insulin resistance, which TZDs are uniquely poised to do. Moreover, the superior A1c reductions with pioglitazone lasting over a longer term imply a decrease in microvascular disease (retinopathy, neuropathy, and nephropathy). This builds a fairly compelling case, in our view, that pioglitazone should be the generic agent of choice for second-line diabetes therapy after metformin. While we’re eager for the day when DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors go generic, we’d certainly advocate for pioglitazone over sulfonylureas when more advanced agents are simply unaffordable. We were also reminded of strong commentary in favor of pioglitazone from Drs. Steve Edelman and Robert Chilton on EASD day #2, and given the recent resurgence of interest in this agent that we’ve noticed in the field, we’re curious to see how TOSCA.IT will contribute to the conversation. On head-to-heads against sulfonylureas, Dr. Bonora also mentioned Lilly/BI’s ongoing CAROLINA CVOT of DPP-4 inhibitor Tradjenta (linagliptin) vs. glimepiride, which will provide key insight. 

  • Dr. Bonora warned against extrapolating these findings to a different, higher-risk patient population, meaning that the CV neutrality shown here wouldn’t necessarily apply in people with diabetes and established CV disease. A key exclusion criterion for this trial was a documented CV event in the prior six months. Would a more traditionally-designed diabetes CVOT, with an enriched study population to power faster event rate, would have shown a CV benefit to pioglitazone compared to sulfonylureas?

Commentator

Marja-Riitta Taskinen, MD (University of Helsinki, Finland)

Dr. Marja-Riitta Taskinen from the University of Helsinki provided independent commentary on TOSCA.IT, and reexamined the data through a rather critical lens. Her main point was calling into question whether this study population was truly “lower risk” for CV disease, since many participants were smokers, had baseline microalbuminuria, and/or started the trial with LDL levels >45 mg/dl. Plus, she articulated that diabetes itself confers a significantly higher CV risk compared to a background population, and she pointed out that there was no difference in LDL cholesterol, triglycerides, or hs-CRP between the two treatment arms. While true, we think the baseline population in TOSCA.IT looked remarkably different from the baseline population in EMPA-REG OUTCOME or LEADER, with a much larger proportion representing primary prevention. Dr. Silvio Inzucchi chimed in during Q&A, suggesting that the diabetes field perhaps needs two treatment algorithms, one for people with established CV disease and another for those without – we’d love to see these drafted. Dr. Taskinen also questioned the primary outcome of four-point MACE including all-cause death. Lastly, she referred to the on-treatment analysis for key secondary endpoint (the only positive, statistically significant CV finding in the trial) as “problematic” from a statistical perspective, and earlier in the symposium, Dr. Nicolucci cautioned against over-interpreting this.

  • On the whole, we still found many reasons from this data why HCPs should be writing far, far fewer SU prescriptions. A mix of three agents from this drug class showed high hypoglycemia risk and an attenuation of glycemic efficacy (in the real world, this might encourage providers to up-titrate, and higher doses of SUs may only exacerbate the hypoglycemia, weight gain, and beta cell burnout). Yes, sulfonylureas are cheap, but so are TZDs now that they’re generic. While the CV results were resoundingly neutral, the durability of A1c-lowering associated with pioglitazone in this study was intriguing, and we mention again the significantly lower risk of hypoglycemia (we can’t emphasize enough the importance of this outcome beyond A1c). Renowned cardiologist Dr. Robert Chilton, a well-respected voice in the field, said on Monday that he “can’t think of a better drug” in defense of pioglitazone, and we’d certainly be happy to see the generic diabetes market move away from sulfonylureas more toward pioglitazone.

Oral Presentations: The Failing Heart in Type 2 Diabetes

Risk of Heart Failure in Intensively Treated Patients with Type 2 Diabetes and Microalbuminuria: 21 Years Follow-Up in the Multifactorial Steno-2 Intervention

Jens Øllgaard, MD (Steno Diabetes Center, Copenhagen, Denmark)

Steno Diabetes Center’s Dr. Jens Øllgaard shared new post-hoc findings from the Steno-2 study, showing that multifactorial intervention (glucose-lowering, blood pressure-lowering, and lipid-lowering simultaneously) significantly reduces risk for heart failure vs. standard of care. The 21-year trial randomized 160 people with type 2 diabetes to intensive, multifactorial treatment or to standard care for 7.8 years, after which point all participants were offered the multifactorial intervention for 13 more years of follow-up. The relative risk reduction for heart failure hospitalization was a whopping 70% in favor of multifactorial treatment (HR=0.30, p=0.002) – 10 patients in the intensive arm (13%) experienced this primary heart failure endpoint vs. 24 conventionally-treated patients (30%). 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). These are highly-significant and impressive results, highlighting another reason we should consider more aggressive early approaches to diabetes management: Intensive control of glycemia, blood pressure, and lipids targets three major risk factors for CV morbidity/mortality, and we hope payers and providers in the field are compelled by this outcomes data showing fewer heart failure hospitalizations (which, of course, are quite costly). Dr. Øllgaard also pointed out that there’s no strict requirement from the FDA to evaluate heart failure in diabetes CVOTs, but that this outcome should under no circumstances be ignored, given the frequency of this complication in diabetes. We’re glad to see this happening, with Lilly/BI and AZ going one step further to launch dedicated outcomes trials of their respective SGLT-2 inhibitor products (Jardiance and Farxiga) in heart failure (the EMPEROR HF and Dapa-HF clinical programs).

Dapagliflozin is Associated with Lower Risk of Major Adverse Cardiovascular Events Compared to DPP-4 Inhibitors in Type 2 Diabetes Patients: Results from CVD-REAL Nordic

Anna Norhammar, MD (Karolinska Institute, Stockholm, Sweden)

Just weeks after presenting late-breaking data from CVD-REAL at ESC 2017, Dr. Anna Norhammar took the EASD stage to discuss a sub-analysis of participants starting new treatment with AZ’s SGLT-2 inhibitor Farxiga (n=6,362) or with any DPP-4 inhibitor (n=19,086). Farxiga (dapagliflozin) was associated with 30% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, CV death) vs. DPP-4 inhibitor therapy (HR=0.70, 95% CI: 0.55-0.89, p=0.004). Turning to the individual components of MACE, Dr. Norhammar reported non-significant hazard ratios still favoring dapagliflozin over DPP-4 agents: 0.75 for non-fatal MI (95% CI: 0.53-1.06, p=0.102), 0.8 for non-fatal stroke (95% CI: 0.56-1.15, p=0.222), and 0.74 for CV death (95% CI: 0.44-1.23, p=0.24s1). This analysis pulled data from national registries in Sweden and Norway, while the CVD-REAL dataset as a whole covers six countries (also the US, UK, Denmark, and Germany). The initial results from CVD-REAL, comparing all SGLT-2 inhibitors vs. other glucose-lowering drugs (DPP-4, insulin, GLP-1 agonists, etc.) were presented at ACC 2017, and the SGLT-2 class was associated with 39% relative risk reduction for heart failure hospitalization (p<0.001) and with 51% relative risk reduction for all-cause mortality (p<0.001). This more detailed look at Farxiga vs. DPP-4 inhibitors, specifically, bodes well for AZ’s DECLARE CVOT (dapagliflozin vs. placebo), expected to complete in 2H18. Only time will tell, of course, but we’re keeping our fingers crossed that this third SGLT-2 CVOT to report will bolster the notion of a cardioprotective class effect here.

Total Events of Hospitalization for Heart Failure in New Users of SGLT-2 Inhibitors: Real-World Data From 5 Countries and More Than 298,000 Patients: The CVD-REAL Study

Mikhail Kosiborod, MD (University of Missouri, Kansas City, MO)

Dr. Mikhail Kosiborod presented real-world data on the effect of SGLT-2 inhibitors on total events of hospitalization for heart failure. This compared to the primary presentation from CVD-REAL (also by Dr. Kosiborod, at ACC 2017), which focused on time-to-first-event analysis, rather than total events. This form of analysis yielded results that looked just as good. Real-world SGLT-2 inhibitor use led to a significant 45% reduction in total heart failure hospitalizations vs. other glucose-lowering drugs (p<0.001). The reduction did not depend on whether participants had a prior heart failure hospitalization before the trial. While we’ve heard some doubt about the likelihood of a true 30%-50% reduction (all observational research comes with certain limitations), the CVD-REAL results support the findings from CVOTs that the exciting new SGLT-2 inhibitor class has powerful CV disease-lowering effects. Although some countries from the CVD-REAL study were not included in this particular analysis, the results from this analysis did not appear to vary greatly between the countries that were included.

Questions and Answers

Q: I’m wondering if increased initiation of drugs like insulin in the comparator group may be implicated in increased rates of heart failure?

A: In the main paper, we did a sensitivity analysis by excluding comparator agents that could be implicated in increasing the risk of heart failure – like insulin, TZDs, and DPP-4 inhibitors. We sequentially took those out of the comparator group and it didn’t make any difference.

Q: What was the average time between the onset of medication and onset of heart failure in patients without previous episodes of heart failure?

A: The average duration of follow-up in this study was roughly nine months. If you look at clinical trial data on SGLT-2 inhibitors, the benefit for heart failure hospitalization emerges extremely early – within a few weeks of randomization.

Novel Biomarkers Predicting Heart Failure Hospitalization in People with Dysglycemia in the ORIGIN Trial

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

ORIGIN trial maestro Dr. Hertzel Gerstein presented an epidemiologic analysis drawing from ORIGIN biosamples, which identified six biomarkers that independently predicted hospitalization for heart failure in the study. Dr. Gerstein suggested that these biomarkers could provide insight into the pathophysiology of heart failure in diabetes and could inform the implementation of precision medicine in diabeto-cardiology.

  • The biomarkers identified to be independent predictors of heart failure hospitalization were:
    • High sensitivity troponin I (HR=1.38, 95% CI: 1.29-1.48)
    • NT-proBNP (HR=1.69, 95% CI: 1.53-1.88)
    • GDF15 (HR=1.28, 95% CI: 1.15-1.43)
    • Angiopoietin-2 (HR=1.17, 95% CI: 1.04-1.31)
    • Chromogranin A (HR=0.72, 95% CI: 0.65-0.80)
    • Cystatin C (HR=1.26, 95% CI: 1.14 – 1.41, became non-significant after factoring in serum creatinine)
  • Previous research using samples taken from the ORIGIN outcomes trial for Sanofi’s Lantus (insulin glargine) has already identified nine biomarkers that independently predicted the composite primary outcome of MACE, hospitalization for heart failure, and coronary revascularization. Out of the list of biomarkers that predicted heart failure hospitalization, high sensitivity troponin I, NT-proBNP, and GDF15 also predicted the MACE composite.

Questions and Answers

Q: Are these heart failure markers ready for primetime?

A: They are all not ready yet, but some are used already. NT-proBNP is a fairly commonly measured biomarker, as is troponin. We are going to be measuring more biomarker panels in our diabetes patients. The panels are becoming cheaper. Just like genetic testing has become cheaper, I think we are at the beginning of a new era.

Q: Did this study make a distinction between heart failure with preserved ejection fraction and heart failure with reduced ejection fraction?

A: We did not have ejection fraction data in ORIGIN so we couldn’t distinguish between them. Hospitalization for heart failure was ascertained by adjudication criteria.

Oral Presentations: SGLT-2 Inhibitors: New Opportunities

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

Dr. Silvio Inzucchi, a highly-respected voice on CVOTs, presented a new post-hoc analysis of the EMPA-REG OUTCOME trial assessing empagliflozin’s (Lilly/BI’s SGLT-2 inhibitor Jardiance) effect on a variety of heart failure-related composite outcomes. Compared to placebo, empagliflozin had a consistent beneficial effect on each of these composites, demonstrating a 34% risk reduction for hospitalization for heart failure/CV death (HR=0.66, 95% CI: 0.55-0.79, p<0.0001), a 38% risk reduction for hospitalization for heart failure/death due to heart failure (HR=0.62, 95% CI: 0.48-0.80, p=0.0002), a 37% risk reduction for hospitalization for heart failure/death due to heart failure/sudden death (HR=0.63, 95% CI: 0.51-0.79, p<0.0001), and a 35% risk reduction for hospitalization for heart failure/death due to heart failure/sudden death/presumed CV death (HR=0.65, 95% CI: 0.53-0.78, p<0.0001). Dr. Inzucchi pointed out that these risk reductions are similar to the famed 38% risk reduction for CV death from the EMPA-REG OUTCOME primary analysis, though he was careful to note that as a post-hoc analysis this should be interpreted with caution. We are eager to see direct data on empagliflozin in heart failure from the ongoing EMPEROR HF outcomes trials, initiated this year to evaluate the SGLT-2 inhibitor in people with heart failure with and without diabetes.

Oral Presentations: SGLT-2 Inhibitors: Clinical Utility

Empagliflozin (EMPA) Reduces Mortality in Analyses Adjusted for Control of Blood Pressure (BP), Low Density Lipoprotein Cholesterol (LDL-C) and HbA1c Over Time

David Fitchett, MD (University of Toronto, Canada)

Dr. David Fitchett presented a new analysis of EMPA-REG OUTCOME, demonstrating that empagliflozin’s significant risk reduction for CV and all-cause death was not driven by the SGLT-2 inhibitor’s beneficial effect on CV risk factors such as blood pressure, LDL cholesterol, and A1c. The hazard ratio of 0.62 for CV death in the trial’s primary analysis (corresponding to a 38% relative risk reduction) did not substantially change when adjusting for empagliflozin’s effect of reducing blood pressure (HR=0.61), LDL cholesterol (HR=0.59), A1c (HR=0.62), or all three of these CV risk factors together (HR=0.61). The same was true for the hazard ratio of 0.68 for all-cause mortality with empagliflozin (reflecting 32% relative risk reduction), which was essentially unchanged after adjustment for empagliflozin’s reductions in blood pressure (HR=0.67), LDL cholesterol (HR=0.66), A1c (HR=0.67), and all three together (HR=0.67).

  • Two years after the original presentation of the EMPA-REG OUTCOME results at EASD 2015 in Stockholm, the mechanism underlying empagliflozin’s famed cardioprotective effect remains unclear, though the notion of an overarching atherosclerotic effect (the hypothesized mechanism for GLP-1 agonists liraglutide and semaglutide based on LEADER and SUSTAIN 6 data) has been widely ruled out due to early rather than gradual divergence of Kaplan-Meir curves. At ADA 2016, Dr. Silvio Inzucchi presented a univariate mediation analysis of EMPA-REG OUTCOME, which attributed 52% of empagliflozin’s cardioprotection to volume contraction, as reflected by an increase in hematocrit. The same analysis attributed 24% to decreased uric acid concentration and only 3% to between-group A1c differences. At EASD 2016, we learned from Dr. Bernard Zinman that a multivariate analysis is underway – while a more complicated method to be sure, the multivariate analysis could offer more compelling information on empagliflozin’s CV mechanisms. Still, we recognize that it may be quite a while before we have a consensus around mechanism, and we underscore that we don’t think it’s crucial to understand mechanism before prescribing a drug for cardioprotection (particularly now that Jardiance has a CV indication on its label). As Dr. Juris Meier articulated at last year’s EASD congress, “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.”

Oral Presentations: Clinical Impact of Hypoglycemia

Weight Gain is Associated with Mild to Moderate Hypoglycemia in Patients with Type 1 Diabetes: Results from the DCCT

Anisoara Bumbu, MD (AP-HP, Paris, France)

Dr. Anisoara Bumbu presented an analysis of DCCT data showing that weight gain is correlated with increased mild to moderate hypoglycemia in patients with type 1 diabetes. The DCCT established that intensive glucose control prevents chronic complications, but the more aggressive approach also increased hypoglycemia risk and weight gain. In turn, Dr. Bumbu explained, weight gain lowers long-term therapy adherence and can increase the risk of other complications, including nephropathy and coronary artery disease. She reviewed data showing a weak association between severe hypoglycemia and weight gain in the DCCT, but described how less work has been done on more-frequent, less-severe hypoglycemia – until now. Using available data on the 1,441 patients with type 1 diabetes age 13-39 who participated in the DCCT (either conventional or intensive arm), a hypoglycemia score (number of blood glucose values <70 mg/dl divided by total number of blood glucose measurements) was calculated for each participant. Hypoglycemia scores were associated with severe hypoglycemia, but this new analysis also found a significant association between hypoglycemia score and total weight gain/average annual weight gain (R2=0.021, p<0.001). Over 7.5 years of follow-up, mean total weight gain in this sample was 16 lbs. When splitting hypoglycemia scores into tertiles, Dr. Bumbu showed a trend of increased weight gain: The third of lowest scores gained a total of 12 lbs on average vs. 18 lbs and 19 lbs for the second and first highest tertiles (p<0.008). When adjusting for age, sex, duration of diabetes, treatment arms, baseline A1c, and baseline BMI, inter-tertile differences remained highly significant (p<0.001). These results contribute to a growing body of evidence demonstrating the importance of avoiding hypoglycemia in patients with type 1 diabetes, and the meaningfulness of outcomes beyond A1c.

Corporate Symposium: Precision Medicine for Type 2 Diabetes (Sponsored by AZ)

From Clinical Trials to Real-World Evidence: New Dimensions in Type 2 Diabetes – Part One: Randomized Control Trials

Bernard Zinman, MD (University of Toronto, Canada)

Could EXSCEL’s design as a more “pragmatic” outcomes trial have played a role in its neutral result? While veteran clinical trialist Dr. Bernard Zinman didn’t explicitly pose this question, he did highlight that AZ’s outcomes trial for once-weekly GLP-1 agonist Bydureon (exenatide) was designed to be more reflective of real-world clinical practice than other more “traditional” CVOTs.

  • Dr. Zinman underscored that the enrollment criteria for EXSCEL were quite inclusive. Notable features included (i) enrolling patients with and without CV risk factors at baseline, (ii) allowing a wide range of concomitant medications, (iii) not enriching the study population with elderly patients, and (iv) not including a run-in period to rule out patients with low medication adherence. Perhaps an implied comparison is that the LEADER CVOT for Novo Nordisk’s Victoza (liraglutide) specifically targeted patients facing high CV risk, had a higher minimum age, excluded patients on DPP-4 inhibitors at baseline, and had a run-in period to establish adherence – though it did have a few “pragmatic” features as well. Notably, the FDA recently approved a new CV indication for Victoza reflecting reduced risk for adverse CV events, but this applies specifically to type 2 diabetes patients with established CV disease, in line with the high-risk participant pool in LEADER.

From Clinical Trials to Real-World Evidence: New Dimensions in Type 2 Diabetes – Part Two: Real-World Evidence

Richard Holt, PhD (University of Southampton, UK)

Dr. Richard Holt argued that while a randomized control trial shows that a drug can work, only real-world evidence demonstrates whether it will work. RCTs often suffer from poor generalizability, as a large proportion of type 2 diabetes patients have comorbidities that keep them out of RCTs. That said, he pointed out that real-world studies for drug classes like SGLT-2 inhibitors and DPP-4 inhibitors have generally been compatible with results from registrational RCTs.

Panel Discussion

Bernard Zinman, MD (University of Toronto, Canada); Richard Holt, PhD (University of Southampton, UK)

Q: Is it time for regulatory bodies to use real-world evidence like the CVD-REAL study?

Dr. Zinman: Yes, absolutely. Rich was spot on in saying that you need both. It’s not enough to have a randomized control trial. You need both the randomized control trial and real-world evidence. There are examples where in the RCT you get a particular outcome, but only when used in the real world do additional safety issues come up. The FDA and other regulators should look at both randomized control trials and real-world evidence.

Q: Can we continue to afford these randomized control trials?

Dr. Zinman: Absolutely, at least for me. The story everyone knows about rosiglitazone and concerns about CV safety led to the generation of data that puts healthcare providers, scientists, and patients with diabetes in a much better position. Look at how Angelo was able to present with such clarity about the paradigm shifts in the management of diabetes. We’re still unsure about sulfonylureas because nobody has done the randomized control trials. We were unsure about metformin until UKPDS. It’s only through carefully performed large-scale RCTs that we learn a lot about efficacy, safety – things like pancreatitis and pancreatic cancer – and we can move ahead. It’s money well-spent. We need science in diabetes management. At the end of the day, you need large numbers of patients exposed to any new therapy in a large RCT to evaluate a particular outcome, and certainly for safety.

Dr. Holt: I agree that we need to have randomized control trials, but there are times when an RCT shows a drug works but it doesn’t end up working in the real world. Think about the story of orlistat – very effective in trials, but in the real world people didn’t take it. We need to have both types of evidence. 

Is There More to Learn from GLP-1 Agonist Outcomes Trials?

Dr. Naveed Sattar echoed Dr. Bernard Zinman’s sentiments from this corporate symposium, adding that EXSCEL was a much larger trial with more than 14,000 patients (compared to LEADER’s n=9,340), with treatment according to “locally-accepted clinical practice,” and with no selection of patients with better adherence. Dr. Sattar estimated that <50% of patients in real-world practice would meet the strict CV disease inclusion criteria commonly used in “explanatory” CVOTs, praising AZ for attempting to create a more realistic and translatable trial by including a primary prevention cohort. In his opinion, we need more trials like EXSCEL to figure out what these new agents can do in a larger population. Nonetheless, Dr. Sattar praised the work done in previous CVOTs as well, for shifting the paradigm of diabetes management in patients with CV disease. We add that CVOTs are a massive investment of time and resources, which is one (understandable) reason for enrollment of higher-risk patients to meet a minimum number of CV events.

Corporate Symposium: 10 Years of DPP-4 Inhibition: New Science and Clinical Treatment for Patients with Type 2 Diabetes (Sponsored by MSD)

The Role of Cardiovascular Safety Trials and What They Can Tell Us About Patient Care

Daniel Drucker, MD (University of Toronto, Canada); Clifford Bailey, MD (Aston University, Birmingham, UK); Michael Nauck, MD (Diabeteszentrum Bad Lauterberg, Hanz, Germany)

This panel discussion offered incredible insights on the latest diabetes CVOTs, including AZ’s EXSCEL trial for GLP-1 agonist Bydureon (exenatide once-weekly), reported less than an hour before. Our favorite quote came from Dr. Daniel Drucker: “If one p-value is 0.049 and another is 0.051, do we worship the first drug over the second?” He was referring to Bydureon’s very narrow miss for CV superiority vs. placebo (HR=0.91, 95% CI: 0.83-1.00, p<0.001 for non-inferiority, p=0.06 for superiority). Dr. Michael Nauck chimed in that it’s important to read the text of these trials, not just the headlines, because of the nuances of study design and execution. Indeed, the EXSCEL results ended up trending in a much more positive direction than many people thought following the topline release in May, which announced CV safety but not efficacy. All three panelists acknowledged AZ’s effort to conduct a clinical trial more closely reflecting what happens in real-world treatment settings (i.e. there was no run-in period to exclude individuals with poor medication adherence). They also recognized the different populations enrolled in EXSCEL vs. Novo Nordisk’s LEADER trial for Victoza (liraglutide), in that AZ’s CVOT included a larger primary prevention cohort (27% vs. 19%). As Dr. Drucker put it, the era of CVOTs has led to a hyper-focus on high-CV-risk patients, which in reality represents only a small subset of the type 2 diabetes population. Dr. Clifford Bailey mentioned the “terrible gap between RCTs and the real world,” referring to the disconnect between clinical trial evidence for a therapy and real-world evidence for that same therapy. To this end, he praised EXSCEL’s pragmatic trial design, and expressed hope for many more efforts to “close the gap” in the future. If there’s one thing we learned at this year’s EASD meeting, it’s that CVOT design is a complicated issue (see our themes section of this full report). We fully appreciated all the commentary from this panel, and we agree that diabetes research should ideally apply to a very wide selection of the total patient population. On the other hand, we can’t honestly criticize the more “enriched” study population in LEADER. For one, CVOTs are massive investments and it makes sense that manufacturers would want to power these trials adequately to generate the necessary number of CV events. Moreover, it’s meaningful that Victoza (liraglutide) now has a CV indication on its product label, as supported by LEADER data and allowing Novo Nordisk to promote the drug for CV risk reduction. Lastly, many thought leaders have described how new medications (in other, non-diabetes therapeutic areas) almost always prove their efficacy in high-risk patients first, followed by lower-risk patients later on.

Reducing A1c – Why Do We Still Care?

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

Dr. Clifford Bailey argued that the diabetes field needs to stop putting microvascular and macrovascular complications in separate buckets. He emphasized that both stem from persistent hyperglycemia, and that lowering A1c is thus an important core strategy to prevent kidney disease and heart disease alike. Microvascular effects are most effectively addressed through simultaneous glucose-lowering and blood pressure-lowering, according to Dr. Bailey, while macrovascular effects are best treated through aggressive glucose-lowering and lipid-lowering side-by-side. Optimal, comprehensive diabetes management involves all three – glucose, blood pressure, and lipids – and it’s no coincidence that this multifactorial approach is what yielded fewer heart failure hospitalizations (70% risk reduction), longer life expectancy (by a median 7.9 years), and fewer adverse CV events (HR=0.36, p<0.001) vs. standard care in the Steno-2 study. Dr. Bailey’s talk was a great reminder that cardiologists, too, must attend to glycemia (a theme enforced by Dr. Lawrence Leiter at ESC 2017 a few weeks prior), despite most diabetes CVOTs using a glycemic equipoise design where A1c treatment difference is minimized between the active agent and control groups.

  • Should metformin still be first-line for type 2 diabetes? Dr. Drucker posed this question during the ensuing Q&A, and Dr. Bailey suggested that the answer is not so simple. “If you check a patient’s eGFR and you want to help them avoid hypoglycemia and further weight gain, there’s very good reason to use metformin first,” he began, later adding “there are certainly cases where a more considerable amount of weight needs to come off, maybe coupled with hypertension and even higher risk of hypoglycemia, and then you see where incretin therapies could be immediately advantageous, or where an SGLT-2 agent could be advantageous.” Dr. Bailey envisions the future of diabetes care as a move from risk stratification, to treatment individualization, and eventually to precision medicine; this is certainly an important goal. But in the meantime, he maintained that we shouldn’t undermine 60+ years of clinical experience with metformin. He encouraged providers to consider earlier intervention with combination therapies, prescribing metformin alongside a DPP-4 or an SGLT-2 – we’d love to see this take root in real-world clinical practice, so that more patients are more swiftly achieving target glycemic control.

The INDORSE Study: New Understanding of DPP-4 Inhibition

Daniel Drucker, MD (University of Toronto, Canada)

Dr. Daniel Drucker delivered a heavy-hitting lecture on the mechanism of action for DPP-4 inhibitors, showing how they work through GLP-1 and GIP, peptide hormones secreted from the gut in response to food consumption. The beauty of incretin-based therapies, in Dr. Drucker’s words, is that beyond extensive clinical trial data, we really understand how they work (in contrast to a drug like metformin), which allows us to predict efficacy and safety. Dr. Drucker reviewed that DPP-4 is an enzyme on the surface of many cells, shed as a soluble form, and that both the bound and soluble forms have catalytic activity. Blocking DPP-4 in mice, either with drugs or through genetic knockout, gives an increase in active GLP-1 and GIP, resulting in more insulin and less glucagon. He presented data from the recent INDORSE study, which found that sitagliptin (Merck’s DPP-4 inhibitor Januvia) preserves fractional sodium excretion in humans with type 2 diabetes. SDF-1, a chemokine, is a sitagliptin-sensitive DPP-4 substrate in people with type 2 diabetes. Plasma sitagliptin concentrations were correlated with fractional sodium excretion and SDF-1a, the latter of which was not degraded with sitagliptin on board. Blocking SDF-1 blocked the effects of DPP-4 inhibitors on the kidneys in mice. Dr. Drucker implied that this work is helping to piece together how different diabetes therapies act in the kidney, with many questions still unanswered about DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors.

Corporate Symposium: Individualized Diabetes Care Across the Ages – Keeping it Simple & Safe (Sponsored by Lilly/BI)

T2DM Disease Progression – Keeping an Eye on the Kidney

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

Dr. Per-Henrik Groop established links between renal impairment and CV risk, as well as renal impairment and hypoglycemia, advocating for an approach to diabetes management that focuses on the cardio-renal-glycemia triad. He spoke to the potential renal benefits of Lilly/BI’s DPP-4 inhibitor Tradjenta (linagliptin) and SGLT-2 inhibitor Jardiance (empagliflozin). 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%. Dr. Groop followed this slide with one on the ADVANCE trial showing a clear correlation between diabetic kidney disease (DKD) and frequency of CV events. He then shared data on 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. To sum up: “the more albumin that leaks into your urine, the more likely you are to experience a CV event.” Less well understood is the relationship between DKD and hypoglycemia, but Dr. Groop showed that this association undoubtedly exists. The incidence of severe hypoglycemia nearly doubles when chronic kidney disease (CKD) is added onto a diabetes diagnosis, and ~74% of sulfonylurea-induced severe hypoglycemia episodes occur in patients with reduced renal function. Dr. Groop suggested a couple mechanistic explanations for this renal/hypo link: (i) some insulin is excreted via the kidneys, so lower eGFR aligns with a higher amount of insulin left circulating in the blood, and (ii) there’s less compensatory glucogenesis from the kidneys (particularly overnight) with impaired renal function. On an optimistic note, Dr. Groop pointed to new diabetes drug classes – DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 agonists – that do not cause hypoglycemia and that may additionally offer cardio- and renal protection. We were so glad to hear this perspective on the importance of where glycemic control, CV risk mitigation, and kidney function intersect. How payers value improved outcomes is of course the question of the day. Diabetes management is moving, at an increasingly fast pace, toward an emphasis on outcomes rather than the biomarker of A1c, and it is beyond exciting that patients can now take medicine not just to lower blood glucose, but to prevent heart attacks, strokes, worsening kidney disease, and death. On CVOTs, Dr. Groop remarked: “We’re always asking for something extra in these outcomes trials. What else can this drug do for me?” In our view, this is exactly the right question to be asking as the bar continues to rise for diabetes therapies on outcomes beyond A1c.

  • While all DPP-4 inhibitors are safe in patients with renal impairment, Dr. Groop underscored that Tradjenta (linagliptin) is the only agent in this class that doesn’t have to be adjusted even with falling eGFR, as linagliptin is excreted via the gut instead of the kidneys. The 24-week MARLINA-T2D study, presented at ADA 2016 and published recently in Diabetes, Obesity and Metabolism, found a 6% decline in urine albumin to creatinine ratio (UACR) with linagliptin vs. placebo, though this did not reach statistical significance (p=0.1954). UACR decreased by a mean 10% on linagliptin vs. placebo for participants with baseline UACR <300 mg/gCr, and this finding neared statistical significance (p=0.059). While this data alone doesn’t support any renal protection associated with Tradjenta, Dr. Groop suggested that upcoming CARMELINA CVOT results will be more telling, since the kidney effects of linagliptin are believed to work via a longer-term, anti-fibrotic mechanism. According to ClinicalTrials.gov, CARMELINA is expected to complete in December 2017, and we’ll be eager to see the macrovascular and microvascular outcomes data next year.
  • Dr. Groop also touched upon the kidney benefits seen in EMPA-REG OUTCOME for SGLT-2 inhibitor Jardiance (empagliflozin), but encouraged everyone to “take two steps back” and keep in mind that this was not a dedicated investigation into renal outcomes. The good news is that Lilly/BI have a planned outcomes study for Jardiance specifically in people with CKD (with or without type 2 diabetes), which will reveal the full scale of empagliflozin’s renal effects. Interestingly, Dr. David Fitchett mentioned at ESC 2017 last month that diabetes patients with eGFR <60 ml/min/1.73m2 may actually reap the greatest benefits from SGLT-2 inhibitor treatment in terms of CV and renal risk reduction. The SGLT-2 class is poised to target all three aspects of the cardio-renal-glycemia triad, which we find extremely exciting, and we’re pleased to see continued investment from Lilly/BI to probe the full extent of these benefits (the companies have launched the EMPEROR HF program to investigate empagliflozin in heart failure as well). AZ also has ongoing studies of its SGLT-2 inhibitor Farxiga (dapagliflozin) in heart failure and CKD.

Corporate Symposium: Debating the New Epoch of Type 2 Diabetes Management – “The Good, the Bad, and the Ugly” (Sponsored by Novartis)

Evidence Matters but Must You Beat Me with Yet Another CVOT?

Marc Evans, MD (Cardiff University, Wales, UK); Päivi Paldánius (Novartis, Basel, Switzerland)

Drs. Mark Evans and Päivi Paldánius turned this provocatively-titled session into a pro-con debate on the value of CVOTs. Dr. Evans on the “pro” side argued that CVOTs provide information that is critical in informing development of treatment guidelines. As an aside, he shared that the two CVOT safety signals that most interest/concern him are retinopathy with Novo Nordisk’s semaglutide and amputations with J&J’s Invokana (canagliflozin). Taking over to present the “con” argument, Dr. Paldánius suggested that the whole 2008 FDA CV guidance was a case of “closing the barn door after the horse has bolted.” She highlighted the oft-raised points that results from many CVOTs are not generalizable to the broad type 2 diabetes patient population.

  • This talk got started with an interesting set of audience response questions. When asked which CVOT has most influenced their prescribing habits, EMPA-REG OUTCOME came in first with 33% of the vote, even beating out UKPDS at 29%. Interestingly, LEADER was a distant third with 13%, and CANVAS only had 2%. When asked later whether CVOTs raise more questions than they answer, 61% of the room said yes, 13% said no, and 26% said maybe.

People with Diabetes and Heart Failure are Special but You’re Breaking My Heart with Your Choice

Marc Evans, MD (Cardiff University, Wales, UK); Mark Cooper, MD (Baker IDI Heart and Diabetes Institute, Melbourne, Australia)

This Novartis-sponsored symposium followed one pro/con debate with another, this one on the utility of SGLT-2 inhibitors in heart failure. Dr. Marc Evans argued that SGLT-2 inhibitors should be first-line for type 2 diabetes patients with heart failure. He cited the European Society for Cardiology’s (ESC) relatively new recommendation that patients with type 2 diabetes and CV disease should get an SGLT-2 inhibitor early in the course of disease, backed by 2a-level evidence courtesy of EMPA-REG OUTCOME and CANVAS. Dr. Marc Cooper pushed back, making the point that the CVOTs that showed heart failure benefit were enriched for patients at high CV risk, and say little about recommendations for patients at lower baseline risk. He pointed out that in CANVAS there were roughly as many additional amputations as there were fewer hospitalizations for heart failure attributable to canagliflozin. He concluded by suggesting that there is not yet enough data to use SGLT-2 inhibitors widely in patients with heart failure, although he admitted that the drug class is a pretty exciting one overall.

Questions and Answers

Q: Do you think the amputation risk increase in CANVAS was a class effect or specific to canagliflozin?

Dr. Mark Cooper: We don’t really know. From what data we have from EMPA-REG, we didn’t see any increase, but they weren’t carefully evaluating that outcome. I still think it’s an open question. There is a possibility that canagliflozin is different, maybe because of slightly better A1c reduction or modest SGLT-1 action …  There is the potential that minor dehydration can alter peripheral blood flow, and it’s feasible that these drugs could have this problem. It’s still an open question.

Q: Why do we think there was no CV death improvement in CANVAS?

Dr. Marc Evans: There has been lots of discussion around this. The population was different than in EMPA-REG. The CANVAS program is not just one study. It was two studies. Maybe we are not seeing a cardiovascular death benefit from CANVAS because there wasn’t a long-enough follow-up because of the CANVAS-R component.

Q: What is the CV safety of sulfonylureas?

Dr. Cooper: There is not a lot of definitive safety evidence for SUs. Most of the data is historical and derived from real-world data. The linagliptin study vs. SUs had to be re-done because the regulators found that there may be potential harm in the SU arm. There’s no doubt that if SUs were launched now they’d go through a very rigorous CV safety evaluation.

Corporate Symposium: PCSK9 Inhibition in Diabetes – Making High Cholesterol History (Sponsored by Amgen)

The Lipid Lowering Story

Kausik Ray, MD (Imperial College London, UK)

Lipid expert Dr. Kausik Ray kicked-off this Amgen-sponsored session on the exciting new PCSK9 inhibitor class of biologic lipid-lowering drugs, which have demonstrated improvement in outcomes thanks to the FOURIER outcomes trial on Amgen’s Repatha (evolocumab). He highlighted that new data from FOURIER focusing on patients in the trial with diabetes, as well as the drug’s impact on diabetes risk, are to be presented in a dedicated session on the final day of EASD. His presentation focused on three central arguments: (i) cardiovascular risk reduction with lipid-lowering agents tends to be proportional to LDL reduction, (ii) diabetes patients are high risk patients and should be treated early with lipid lowering agents, and (iii) at least based on previous data, it’s reasonable to expect that cardiovascular risk reduction with PCSK9 inhibitors could easily be in the neighborhood of those seen with statins. On the latter point, he noted that while some people found the FOURIER trial’s 15% reduction in MACE “underwhelming,” the event reduction was comparable to the benefit seen with statins over the same relatively short amount of follow-up, and that we should expect the cumulative risk reduction with PCSK9 inhibitors to rise over time (as it does with statin therapy). 

  • During Q&A, Dr. Ray emphasized that PCSK9 inhibitors appears to be both safe and efficacious at very low final on-treatment LDL levels.
  • Why the lack of a mortality benefit in FOURIER? Dr. Ray argued that we are unlikely to see a benefit in mortality unless we follow people for longer than FOURIER did (median follow-up = 2.2 years).

GLP-1 Agonists

Symposium: Exenatide Study of Cardiovascular Event Lowering (EXSCEL): Primary Results

Study Rationale, Design, and Conduct

Robert Mentz, MD (Duke University, Durham, NC)

Dr. Robert Mentz discussed key aspects to the design and execution of EXSCEL for AZ’s GLP-1 agonist Bydureon (2 mg exenatide once-weekly). Like previous type 2 diabetes CVOTs, this study was double-blind and placebo-controlled (n=14,752, including 7,356 randomized to exenatide and 7,396 randomized to placebo). Unlike trials that have come before it, EXSCEL was meant to be a pragmatic outcomes study, more closely mimicking real-world conditions. As such, Bydureon treatment was integrated with usual care, and any concomitant anti-hyperglycemic therapy besides another GLP-1 agonist was allowed at the discretion of a patient’s usual diabetes care provider (rather than an HCP specially-appointed to execute EXSCEL). According to Dr. Mentz, annual calcitonin measurements were the only piece of data not collected from a usual care setting. We learned in a separate conversation with AZ’s VP of US Medical Affairs Dr. Jim McDermott that Bydureon was administered via single-dose reconstitution kits instead of the multi-use prefilled product pen. The more cumbersome dosing process could have contributed to lower medication adherence in this trial vs. LEADER for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) – otherwise, we might expect a once-weekly agent like Bydureon to show greater adherence numbers vs. a once-daily agent like Victoza. Moreover, this trial featured no run-in period, which typically identifies and excludes patients who are likely to show poor medication adherence. Median follow-up was 3.2 years, and study visits occurred at one week, two months, six months, and 12 months post-randomization, after which visits were every six months until end of treatment to minimize interference with usual care. Dr. Mentz further outlined how the trial included 70 days of safety follow-up immediately after the treatment period. He described inclusion criteria as broad: a wide range of CV risk was accepted, and there was no enrichment of the study population with elderly patients (participants were accepted down to age 18). Exclusion criteria included current or prior GLP-1 agonist use, eGFR <30 mL/min/1.73m2, prior pancreatitis, ≥two episodes of severe hypoglycemia in the past 12 months, calcitonin >40 ng/L, and personal or familial history of MEN-2. The primary endpoint was time to first occurrence of three-point MACE (non-fatal MI, non-fatal stroke, or CV death). Secondary endpoints were analyzed by conditional hierarchy, and included all-cause mortality, individual components of three-point MACE, hospitalization for acute coronary syndrome, and hospitalization for heart failure. The trial aimed for a minimum 1,360 primary endpoint events, and in the end collected 1,744. Lastly, Dr. Mentz established EXSCEL as a truly global study, enrolling 6,788 participants from Europe at 329 clinical sites (46%), 3,708 patients from North America at 190 sites (25%), 2,727 people from Latin America at 64 sites (18%), and 1,529 people from Asia Pacific at 104 sites (10%).

  • Simultaneous with the start of this EASD symposium, full EXSCEL results were published online in NEJM.

Participant Characteristics and Risk Factor Changes

Angelyn Bethel, MD (University of Oxford, UK)

Oxford’s Dr. Angelyn Bethel presented baseline characteristics of the study population, highlighting some key differences in this regard between EXSCEL and LEADER, Novo Nordisk’s positive CVOT for GLP-1 agonist Victoza (liraglutide). AZ’s trial enrolled 14,752 adults with type 2 diabetes, making it the largest diabetes CVOT completed to-date (notably, the company’s DECLARE CVOT for SGLT-2 inhibitor Farxiga will be even larger, with >17,000 participants, while LEADER enrolled 9,340 participants). At baseline, the average EXSCEL participant was 62 years-old with BMI 32 kg/m2, eGFR 76 ml/min/1.73m2, A1c 8%, and diabetes duration ~12 years. Metformin was the most common background diabetes drug (~75% of both treatment arms), followed by insulin and sulfonylureas, and ~12% of people were taking a DPP-4 inhibitor at study start – in contrast, people on a DPP-4 inhibitor were excluded from LEADER. As planned, EXSCEL enrolled a participant pool that was ~30% primary prevention, ~70% secondary prevention, making this a lower-risk group overall. More specifically, ~73% of both the exenatide and placebo arms had a prior CV event at baseline (53% had a history of coronary artery disease, 17% of cerebrovascular disease, 19% of peripheral arterial disease, and 16% of congestive heart failure). Both statins and anti-thrombotics/anti-coagulants were used in >70% of participants at baseline, while ~55% of individuals were on statin therapy and 40% were taking an ACE inhibitor/ARB. Median follow-up time was 3.2 years. Treatment discontinuation was quite high in both the exenatide and placebo groups, at 43% and 45%, respectively. Dr. Bethel didn’t comment extensively on this (underscoring instead the very small number of people lost to follow-up, at <0.5% total), but we imagine use of the Bydureon reconstitution kit rather than the easier-to-use pen had some contributing influence on dropout rates. To better understand what stimulated dropouts, we’d be curious to see any data on patient experience or quality of life in both LEADER and EXSCEL (and other diabetes outcomes studies, like EMPA-REG OUTCOME, CANVAS, and SUSTAIN 6, for that matter).

  • Dr. Bethel also shared data on changes in A1c, heart rate, body weight, blood pressure, and initiation of new therapies in EXSCEL. By the end of the study, there was a 0.5% A1c treatment difference between the Bydureon and placebo arms (p<0.001). Trial design aimed for glycemic equipoise, and people in both arms started from the same baseline A1c of 8%, but Dr. Bethel explained the significant difference by pointing out that HCPs were allowed to use any other diabetes drugs (with the exception of GLP-1 agonists) in treating their patients to target. Once again, she reinforced pragmatic trial design, and alluded to the fact that LEADER study protocol was more restrictive in what additional medications could be prescribed – no GLP-1 agonists, DPP-4 inhibitors, or pramlintide (AZ’s Symlin). As expected, heart rate increased by ~two beats/minute with exenatide therapy vs. placebo (p<0.001). From a baseline body weight just over 203 lbs, placebo-treated patients tended to gain weight by the end of follow-up while exenatide-treated patients experienced modest weight loss, leading to a significant ~3 lb treatment difference (p<0.001). Systolic blood pressure declined from a baseline ~136 mmHg in both arms, but Bydureon showed superior reductions by a mean ~2 mmHg (p<0.001).
  • Dr. Bethel reported a 33% risk reduction for the addition of any new diabetes therapy with Bydureon vs. placebo (HR=0.67, 95% CI: 0.63-0.71, p<0.05). Similarly, relative risk reduction for new initiation of insulin treatment was 39% with Bydureon (HR=0.61, 95% CI: 0.54-0.68, p<0.001). This finding is clinically-meaningful in terms of simplifying medication regimens for people with diabetes in the real world. Moreover, it suggests that participants randomized to placebo in this trial were treated more aggressively with other agents besides once-weekly exenatide, including SGLT-2 inhibitors, which have demonstrated cardioprotection in their own CVOTs (see our coverage of EMPA-REG OUTCOME for Lilly/BI’s empagliflozin and CANVAS for J&J’s canagliflozin). Indeed, SGLT-2 inhibitors were given open-label to 6.5% of patients in the Bydureon group vs. 9.4% of patients in the placebo group.

Safety Data

Bernard Zinman, MD (University of Toronto, Canada)

Dr. Bernard Zinman presented safety data from the EXSCEL trial. Serious adverse events were well-balanced across treatment arms, affecting 17% of participants in both the exenatide and placebo groups. There were 56 individuals in the exenatide arm (0.8%) and 38 in the placebo arm (0.5%) who reported serious adverse events related to treatment, and 108 (1.5%) and 104 (1.4%) participants respectively experienced serious adverse events leading to permanent treatment discontinuation. Severe hypoglycemia (requiring assistance) occurred numerically fewer times in the exenatide group (404 events) than the placebo group (450 events). Respectively, 247 (3.4%) and 219 (3.0%) participants experienced severe hypoglycemia, though this difference did not reach statistical significance. Acute pancreatitis – historically, a concern surrounding GLP-1 agonists – occurred in 26 participants in the exenatide group vs. 22 in the placebo group. Dr. Zinman noted that these very low rates of acute pancreatitis, and their near equivalence between the exenatide and placebo group, are extremely reassuring. Malignancy was also similar between groups, affecting 355 patients in the exenatide arm and 361 patients in the placebo arm (4.8% vs. 4.9%). Within this, there were 15 cases of pancreatic cancer in the exenatide arm (vs. 16 in the placebo arm) and 14 cases of thyroid cancer in the exenatide arm (vs. six in the placebo arm). Medullary thyroid cancer (MTC) occurred in two participants on exenatide and one on placebo; in all three cases, participants had an elevated calcitonin levels at baseline, a known risk factor for MTC. Dr. Zinman explained that most safety data in EXSCEL was collected via adverse event reporting – only acute pancreatitis and malignancy were confirmed by adjudication.

Cardiovascular Outcomes

Adrian Hernandez, MD (Duke University, Durham, NC)

Dr. Adrian Hernandez took the stage for the symposium’s main event: presentation of the CV outcomes data. Immediately, without wasting a breath, he unveiled the hazard ratio for three-point MACE of 0.91 (95% CI: 0.83-1.00, p<0.001 for non-inferiority, p=0.06 for superiority) trending toward exenatide, but missing the statistical threshold for superiority by a razor-thin margin. Talk about the “edge” of superiority with an upper bound of 1.00. These results trended in a much more positive direction than many may have thought after learning that EXSCEL had not met superiority from AZ’s topline announcement in May. The trial did not reach superiority for any individual component of the three-point MACE composite, but all of these secondary outcomes trended in favor of exenatide, with hazard ratios of 0.86 for non-fatal stroke (95% CI: 0.70-1.07), 0.95 for non-fatal MI (95% CI: 0.84-1.09), and 0.88 for CV death (95% CI: 0.73-1.05). Dr. Hernandez also presented several subgroup analyses that probed for possible heterogeneity of effect among different patient populations. Interestingly, there was a significant interaction for age (p=0.005 for interaction), whereby Bydureon was associated with statistically significant CV risk reduction in people older than 65 (HR=0.80, 95% CI: 0.71-0.91). The p-values for interaction were non-significant for sex, race, and geographical region (Europe, North America, Latin America, and Asia Pacific). Similarly, there was no significant interaction for various risk factors, including diabetes duration, baseline A1c, eGFR, BMI, background anti-hyperglycemic oral therapy, prior congestive heart failure, or a history of CV events.

  • Turning to secondary endpoints, Dr. Hernandez reported a hazard ratio for all-cause mortality of 0.86 (95% CI: 0.77-0.97, nominal p=0.016) favoring exenatide vs. placebo. By the trial’s pre-specified hierarchical testing structure, this can only be considered exploratory since exenatide did not meet superiority for its primary endpoint. Nevertheless, we find this suggestion of a 14% risk reduction for all-cause mortality to be noteworthy. No other secondary endpoints met superiority, but most had point estimates that trended in the “right” direction (to the left of unity), with a hazard ratio of 0.97 for fatal or non-fatal MI (95% CI: 0.85-1.10, p=0.622), 0.85 for fatal or non-fatal stroke (95% CI: 0.70-1.03, p=0.095), and 0.94 for hospitalization for heart failure (95% CI: 0.78-1.13, p=0.485). The secondary endpoint of hospitalization for acute coronary syndrome (ACS) trended in favor of placebo (HR=1.05, 95% CI: 0.94-1.18, p=0.402), but importantly, did not reach statistical significance.

Source: NEJM

Source: EXSCEL EASD presentation

EXSCEL in Perspective

Rury Holman, MD (University of Oxford, UK)

In a notable address, Dr. Rury Holman, first author on the EXSCEL paper published in NEJM, argued that this trial largely supports the CV benefits to the GLP-1 agonist class as a whole. He presented a meta-analysis of three GLP-1 agonist CVOTs (including EXSCEL, LEADER, and SUSTAIN 6 but excluding ELIXA for Sanofi’s lixisenatide because it evaluated four-point MACE as its primary outcome) showing a significant 12% risk reduction for three-point MACE with a GLP-1 agent vs. placebo (HR=0.88, 95% CI: 0.81-0.95, p=0.002). Dr. Holman reported a non-significant p-value for interaction of 0.28, suggesting no evidence for heterogeneity of effect between exenatide, liraglutide, and semaglutide. He called out that CV death accounts for two-thirds of all mortality in these large diabetes trials, and then discussed a similar meta-analysis looking specifically at CV death, which found a 13% relative risk reduction with GLP-1 agonist therapy (HR=0.87, 95% CI: 0.79-0.96, p=0.007). Here, the p-value for interaction was again non-significant at 0.43. Turning to all-cause death, Dr. Holman presented a meta-analysis showing 12% relative risk reduction with a GLP-1 agonist product (HR=0.88, 95% CI: 0.81-0.95, p=0.002). The p-value for interaction was 0.63, once more pointing to a lack of heterogeneity between these different GLP-1 agents. While it would be hard to assert that all GLP-1 agonists are identical in their effects – the variations in molecular structure are well-documented, and head-to-head studies like SUSTAIN 7 (semaglutide vs. dulaglutide) have demonstrated clinically-meaningful differences in A1c-lowering and weight loss – Dr. Holman’s overarching message was that Bydureon’s missing the mark on superiority had more to do with trial design and study population than with the exenatide molecule itself.

  • He proposed four specific differences between CVOTs that may have influenced outcomes: (i) baseline A1c (8.7% in LEADER and SUSTAIN 6 vs. 8.1% in EXSCEL), (ii) primary prevention cohort (19% in LEADER, 17% in SUSTAIN 6, and 27% in EXSCEL), (iii) median follow-up time (3.8 years, 2.1 years, and 3.2 years, respectively), and (iv) median drug exposure (3.5 years, 1.8 years, and 2.4 years, respectively). The inclusion of more participants facing lower CV risk at baseline may have muted the cardioprotective benefit to Bydureon vs. placebo. In fact, a major theme emerging at the FDA Advisory Committee for Victoza’s CV indication was liraglutide’s differing effects in lower- vs. higher-risk cohorts, and the FDA-approved label update applies only to type 2 diabetes patients with established CV disease. This isn’t to say that liraglutide, exenatide, or any GLP-1 agent doesn’t confer any cardioprotective value for those without a prior history of CV disease. Rather, it implies that CV benefit may take much longer to appear in a clinical trial enrolling low-risk patients, and that EXSCEL may have been “less powered” vs. LEADER in this regard. The hazard ratio for three-point MACE was 0.90 (95% CI: 0.82-1.00) in favor of Bydureon among EXSCEL participants with a prior CV event, 0.99 (95% CI: 0.77-1.28) among those without any history of CV disease. Dr. Holman’s discussion of less overall drug exposure in the present study vs. LEADER alluded to the less-than-ideal adherence to once-weekly exenatide injections. We might expect longer exenatide exposure to correlate with greater CV benefit, and to this end, we’re eager for more in-depth analysis of the adherence data from all GLP-1 agonist CVOTs side-by-side. While some have noted that Intarcia’s FREEDOM-CVO trial of ITCA 650 (implantable mini pump offering three-six months of continuous exenatide release, circumventing the adherence issue) was also neutral, showing CV safety but not efficacy vs. placebo, we also think that’s more about trial design and interest in speed to show safety.
  • Dr. Holman positioned EXSCEL as a reassuring safety dataset for Bydureon, as it should “dispel concerns” related to pancreatitis, pancreatic cancer, medullary thyroid cancer (MTC), and severe hypoglycemia. Moreover, he highlighted the 14% relative risk reduction for all-cause mortality in the trial (HR=0.86, 95% CI: 0.77-0.97). The pre-defined statistical testing plan precludes us from drawing conclusions about this as statistically significant, but all-cause death is clearly an important outcome (if not the most important outcome), and the lower frequency in exenatide vs. placebo arms is a valuable insight for clinical practice, according to Dr. Holman. We agree – this trial overall supports Bydureon as a safe and effective diabetes therapy, one that could benefit many patients in the real world (especially considering the very low proportion of the type 2 population that is on any GLP-1 agonist). While many questions remain about how Bydureon compares to Victoza and other in-class competitors, we pause to note incredibly important contributions from EXSCEL to the diabetes field: The study lends additional evidence in support of this advanced therapy class, and in our view, doesn’t conclusively refute (at least not yet) that CV benefits could be a GLP-1 class effect (in fact, we think it reinforces this).

Commentator

Francesco Giorgino, MD (University of Bari Aldo Moro, Italy)

Tasked with providing independent commentary on EXSCEL, Dr. Francesco Giorgino weighed positive and neutral results from the Bydureon CVOT, sharing a fairly balanced view overall. The suggestion of risk reduction for all-cause mortality (HR=0.86, 95% CI: 0.77-0.97) is certainly a positive, according to Dr. Giorgino, even though this finding cannot be deemed statistically significant because exenatide didn’t show superiority on the primary endpoint. He pointed to the neutral effect of Bydureon on heart failure hospitalization as another positive (HR=0.94, 95% CI: 0.78-1.13), given some lingering concerns in the diabetes community over incretin therapies and heart failure risk (this stems primarily from the SAVOR-TIMI CVOT of AZ’s DPP-4 inhibitor Onglyza, as neither LEADER nor SUSTAIN 6 found a significant signal for heart failure hospitalization). That the hazard ratio for individual components of three-point MACE (non-fatal MI, non-fatal stroke, and CV death) all trended in the right direction is also good news, as this offers a more compelling and comprehensive case for CV safety and falls in line with the CV efficacy data seen in LEADER for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). Indeed, Dr. Giorgino likened EXSCEL most closely to LEADER among all GLP-1 agonist CVOTs. He reported a number needed to treat (NNT) of 98 for liraglutide treatment over three years to prevent one death from any cause vs. an NNT of 106 for exenatide treatment over three years. As to why the primary endpoint result in EXSCEL missed superiority, Dr. Giorgino circled back to pragmatic trial design (no run-in period) and a larger primary prevention cohort (27% vs. 19% in LEADER, 0% in ELIXA for Sanofi’s lixisenatide, and 17% in SUSTAIN 6). He mentioned that while A1c-lowering was similar with Bydureon in EXSCEL and with Victoza in LEADER, the former demonstrated no significant risk reduction for severe hypoglycemia, which may have influenced observed outcomes (liraglutide was associated with a 20% risk reduction for confirmed hypoglycemia <54 mg/dl, p<0.001). Further, he reminded the audience that Bydureon reconstitution kits probably decreased adherence from where it would have been with a prefilled pen. That said, Dr. Giorgino found fault with some key arguments in defense of EXSCEL’s pragmatic design as well. For one, SGLT-2 inhibitors were also used at a similar rate in the placebo arm of SUSTAIN 6, which was positive for cardioprotection regardless. Moreover, investigators emphasized the infrequent clinical visits to minimize interference with usual care, but Dr. Giorgino pointed out that provider visits in LEADER were equally infrequent, once every six months after the first six months. These were important criticisms to be articulated, and we look forward to much more discussion on RCTs vs. the real world going forward. We’re eager for a more in-depth look at concomitant medications, patient/provider interactions, and adherence in all GLP-1 agonist CVOTs side-by-side.

  • Ultimately, Dr. Giorgino expressed his opinion that GLP-1 agonists are beneficial in terms of their CV effects, but it’s still unclear which target type 2 diabetes population is best. He described how the pleotropic effects of drugs in the class may lead to CV benefit, and outlined exenatide’s direct effects on the CV system including anti-inflammatory responses and anti-atherosclerotic responses. Glycemic efficacy has little to do with cardioprotection in EXSCEL or other diabetes CVOTs, in Dr. Giorgino’s view, since other large studies like ACCORD, ADVANCE, VADT, and UKPDS did not show a reduction in all-cause mortality despite substantial A1c drops.
  • Very notably, Dr. Giorgino did not give much credence to the argument dividing GLP-1 agonists into exendin-4-based molecules (exenatide, lixisenatide) and human GLP-1-based molecules (liraglutide, semaglutide). While the variations on molecular structure may result in products with slightly different signaling and biological effects, he explained that these variations are unlikely to cause meaningful differences in CV effects. We’ll be following this debate closely in the weeks and months ahead.

Close Concerns Questions

Q: How will the diabetes community respond to EXSCEL, a convincing demonstration of Bydureon’s CV safety and a narrow miss for CV benefit? Do these results add or subtract from the notion of a cardioprotective class effect for GLP-1 agonists?

Q: How big a role did poor adherence play in EXSCEL’s neutral result? Would the same CVOT using a prefilled exenatide pen (or better yet, the upcoming Bydureon autoinjector) yield a positive result?

Q: How did elements of pragmatic trial design influence outcomes in EXSCEL? What was the impact of SGLT-2 inhibitors prescribed to placebo-treated patients, and how does this compare to SGLT-2 use in SUSTAIN 6?

Q: Will the field move toward standardization of CVOT design? Will this start with FDA?

Q: In what form (if any) will EXSCEL data be incorporated onto the Bydureon product label? How will this affect AZ’s marketing around its GLP-1 agonist franchise?

Q: Is there a meaningful divergence in CV effects between exendin-4-based vs. human GLP-1-based molecules? What kind of study (mechanistic or outcomes) might investigate this further?

Q: If EXSCEL’s neutral result does in fact have more to do with pragmatic trial design than with the molecule itself, how can we explain the neutral findings from FREEDOM-CVO for Intarcia’s ITCA 650 (implantable exenatide mini pump)? 

Oral Presentations: Incretins: New Clinical Evidence

Individual HbA1c and Weight Responses to Exenatide QW or Placebo Added to Titrated Insulin Glargine in Type 2 Diabetes Uncontrolled After Insulin Optimization in the DURATION-7 Study

Juan Frias, MD (National Research Institute, Los Angeles, CA)

Dr. Juan Frias returned to the EASD stage to discuss a new post-hoc analysis of AZ’s DURATION-7 study, investigating GLP-1 agonist Bydureon (exenatide once-weekly) as an add-on to insulin glargine (Sanofi’s Lantus), following his presentation of the highly-anticipated full results at ADA 2017. According to Dr. Frias, 81% of participants in the Bydureon group (n=231 in an intent to treat analysis) experienced at least some reduction in A1c over the course of the 28-week trial, vs. only 60% of participants in the placebo group (n=230). Similarly, a higher proportion of patients on Bydureon (62%) vs. placebo (40%) experienced at least some reduction in body weight during DURATION-7. Dr. Frias presented very interesting scatter plots, with each dot representing a patient and placed in one of four quadrants: (i) increased A1c + increased body weight, (ii) decreased A1c + increased body weight, (iii) decreased A1c + decreased body weight, and (iv) increased A1c + decreased body weight. Quadrant no. 3 is where you’d want to be (reaping glycemic and weight loss benefits from once-weekly exenatide injections) and indeed, 51% of Bydureon-treated patients were in this lower left quadrant vs. 23% of placebo-treated patients, a quite noticeable difference. Conversely, only 7% of Bydureon-treated patients were in quadrant no. 1 (upper right, reflecting worsening A1c and body weight) vs. 23% of placebo-treated patients. That people receiving once-weekly exenatide were twice as likely to experience simultaneous improvements in A1c/body weight vs. placebo is quite clinically meaningful, Dr. Frias emphasized. He also summarized some key DURATION-7 data announced at ADA, including that 25% more participants on Bydureon vs. placebo achieved A1c target <7% by study end, and that 20% more people on Bydureon achieved the composite endpoint of A1c <7% with no severe hypoglycemia or weight gain. While AZ doesn’t have any insulin products in its diabetes portfolio or pipeline, combination therapy with a basal insulin/GLP-1 agonist is gaining more attention now that fixed-ratio combinations (Novo Nordisk’s Xultophy and Sanofi’s Soliqua) have been approved for type 2 diabetes. We certainly see value in demonstrating Bydureon’s benefits in the context of a basal insulin regimen, as it lends more evidence in support of safety/efficacy for basal insulin/GLP-1 combination treatment (whether simultaneous or sequential). Moreover, these results establish strong safety/efficacy for AZ’s once-weekly GLP-1 agonist in particular for the many real-world patients taking Lantus as standard of care. On the subject of “real-world,” HCPs in DURATION-7 were permitted to continue titrating glargine with an aim toward optimal glycemic control, even after the eight-week run-in period prior to Bydureon/placebo randomization, though it’s unclear how successfully this was done – Dr. Melanie Davies pointed out during Q&A that investigators could maybe have been proactive in encouraging optimal insulin titration throughout the study. That said, given how insulin is titrated far from optimally in real clinical settings, perhaps these clinical trial results underscoring Bydureon’s efficacy will actually translate better to the real world.

Semaglutide Provides Sustained Reductions in Body Weight Over 2 Years in Subjects with Type 2 Diabetes (SUSTAIN 6)

Agostino Consoli, MD (University of Chieti, Italy)

Dr. Agostino Consoli shared new data from Novo Nordisk’s SUSTAIN 6 trial of GLP-1 agonist semaglutide, demonstrating sustained weight loss over two years. While the 104-week study (n=3,297) was designed primarily to assess CV outcomes with once-weekly semaglutide vs. placebo – and indeed, showed significant 26% risk reduction for the primary MACE endpoint – the agent’s weight loss effects were also noteworthy. At week 104, 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). Looking at an even greater goal of ≥10% weight loss from baseline, 13% of people on 0.5 mg and 20% of people on 1.0 mg semaglutide achieved this vs. 6% and 7% of each placebo arm (p<0.0001 for both comparisons). Another impressive piece of data from this new analysis 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. Dr. Consoli further mentioned that the significance of weight loss results was maintained across baseline BMI categories. A separate post-hoc mediation analysis found that the impact of nausea and vomiting (common side-effects of GLP-1 agonists) on body weight was minimal – indirect weight loss effects mediated by nausea and vomiting were estimated at a mere ~0.3 lbs and ~0.09 lbs for the 0.5 mg and 1.0 mg doses, respectively. With these results, the SUSTAIN program extends its groundbreaking series of data, showing that semaglutide confers significant and clinically-meaningful reductions in weight and waist circumference over an extended treatment period in people with type 2 diabetes and high CV risk. Importantly, 5% weight loss seems to be the necessary level to delay new-onset type 2 diabetes, and semaglutide could have an impact in prediabetes if its efficacy is sustained in that population. The emphasis on positive body weight effects for semaglutide, in addition to profound A1c-lowering efficacy and cardioprotection, is fitting since Novo Nordisk is also conducting clinical trials of the potent GLP-1 agonist toward an obesity indication (phase 3 to begin in 1H18). Management reviewed remarkable phase 2 data on semaglutide in obesity during the company’s 2Q17 earnings call, and Chief Science Officer Dr. Mads Thomsen alluded to a “new level of efficacy” seen with semaglutide on weight loss. Once-weekly semaglutide has been submitted to the FDA for a type 2 diabetes indication, and a regulatory decision is expected in 4Q17. Needless to say, we’re very excited about this molecule and its enormous and diverse therapeutic potential …

Comparable Glycemic Control with Once-Weekly Dulaglutide vs. Insulin Glargine, Both Combined with Lispro, in Type 2 Diabetes and Chronic Kidney Disease (AWARD-7)

Katherine Tuttle, MD (University of Washington, Seattle, WA)

Dr. Katherine Tuttle presented an expanded analysis for a pre-specified secondary endpoint of impact on eGFR and albuminuria in the AWARD-7 trial. The original study evaluated the effect of GLP-1 agonist dulaglutide (Lilly’s Trulicity) vs. basal insulin glargine (Sanofi’s Lantus), both in combination with rapid-acting insulin lispro (Lilly’s Humalog) in people with type 2 diabetes and comorbid chronic kidney disease (either moderate or severe). The 52-week trial randomized 576 patients with eGFR between 15-60 ml/min/1.73m2 to either dulaglutide 1.5 mg, dulaglutide 0.75 mg, or titrated insulin glargine. Impressively, dulaglutide significantly reduced albuminuria, producing a 28% and 27% decrease in UACR (urine to albumin creatinine ratio) from baseline for the 1.5 mg and 0.75 mg doses, respectively, vs. a more modest 16% UACR reduction with insulin glargine (p<0.001 for both comparisons). As we first saw in a poster at ADA 2017, dulaglutide treatment appeared to mitigate further eGFR decline throughout the trial. While eGFR declined by an average of 1.9 ml/min/1.73m2 in the insulin glargine group at 26 weeks, eGFR only declined by 0.1 and 0.4 ml/min/1.73m2 in the 1.5 mg and 0.75 mg groups, respectively (from a baseline eGFR ~38 ml/min/1.73m2 in all treatment arms). By percent change from baseline, those in the insulin glargine group experienced an 8% decline in eGFR, while those in the dulaglutide 1.5 mg and 0.75 mg arms respectively experienced a 1% (p<0.05 vs. insulin glargine) and 3% decline in eGFR (p<0.05 vs. insulin glargine). As a reminder, dulaglutide met its primary endpoint of non-inferior A1c reduction vs. insulin glargine, and also produced substantial benefits in terms of weight loss and hypoglycemia risk reduction. From a safety standpoint, there were no significant differences between dulaglutide and insulin glargine, renal or otherwise, besides the expected nausea and GI adverse events expected with a GLP-1 agonist.

  • We’re intrigued by this suggestion of a renal benefit for dulaglutide, and we’d love to see this characterized further when the REWIND trial for Trulicity reports (expected to complete July 2018). Despite controversy over class effects vs. heterogeneity among GLP-1 agonist products, the renal benefit demonstrated by liraglutide in LEADER and by semaglutide in SUSTAIN 6 (both Novo Nordisk studies) piques our hope that dulaglutide will show similar positive effects on the kidneys. We note that like liraglutide and semaglutide, dulaglutide is also a human GLP-1-based molecule (though we’re growing less certain that this molecular distinction between human GLP-1 and exendin-4 has a very substantial impact on outcomes – we’re still collecting thoughts). We recently learned that the mortality rate of patients with comorbid diabetes and kidney disease is higher than the average mortality rate of all cancers (55% vs. 50% 10-year cumulative incidence, respectively), and it would be fantastic if GLP-1 agonists could be leveraged to address this unmet need.

Oral Presentations: Novel Therapies, Future Opportunities

IDegLira Improves Cardiovascular Risk Markers in Patients with Type 2 Diabetes Uncontrolled on Basal Insulin: Analyses of DUAL II and DUAL V

Tina Vilsbøll, MD (University of Copenhagen, Denmark)

Dr. Tina Vilsbøll presented a post-hoc analysis of two studies from the DUAL program for Novo Nordisk’s Xultophy (insulin degludec/liraglutide fixed-ratio combination). She focused on biomarkers of CV disease, showing how Xultophy is associated with superior weight loss, blood pressure reductions, and cholesterol-lowering vs. basal insulin monotherapy. In DUAL II, which compared Xultophy vs. insulin degludec (Novo Nordisk’s Tresiba), participants randomized to the combination achieved ~5.5 lbs more weight loss on average (p<0.0001), greater LDL-lowering (estimated treatment ratio 0.9, p<0.05), greater total cholesterol-lowering (estimated treatment ratio 1.0, p<0.05), and a greater margin of systolic blood pressure reduction (estimated treatment difference 3.7 mmHg, p<0.05). In DUAL V, people with type 2 diabetes were randomized to Xultophy or to monotherapy with insulin glargine (Sanofi’s Lantus). Once again, those on the combination experienced more weight loss (~7 lbs, p<0.05), LDL-lowering (estimated treatment ratio 0.9, p<0.05), total cholesterol-lowering (estimated treatment ratio 1.0, p<0.05), and systolic blood pressure reduction (estimated treatment difference 3.6 mmHg, p<0.05). In addition, the estimated treatment ratio for reductions in free fatty acids was 0.9 favoring Xultophy in DUAL V (p<0.0001). As expected for a drug containing a GLP-1 agonist, mean heart rate increased slightly with Xultophy vs. basal insulin alone in both DUAL studies (estimated treatment difference 2.9 and 3.7 beats/minute in DUAL II and DUAL V, respectively). Dr. Vilsbøll concluded that Xultophy confers a general improvement in CV biomarkers, most likely due to the liraglutide component, which demonstrated significant and clinically-meaningful CV risk reduction in the LEADER trial. Since Xultophy and Sanofi’s Soliqua (insulin glargine/lixisenatide) were both FDA-approved on the same day last November, we’ve thought that the benefit on CV outcomes associated with standalone liraglutide (branded Victoza) may give a slight competitive edge to Novo Nordisk’s product. The Victoza product label now boasts an indication for the reduction of adverse CV events as well, while the lixisenatide component of Soliqua showed neutral CV effects in the ELIXA CVOT. For now, it seems unlikely that Novo Nordisk will pursue a dedicated CV outcomes study for Xultophy. That said, we’ll be interested to see how CV effects come into the discussion around the combo product going forward, both at scientific meetings and in commercial promotions.

Beyond Topline Results for the Oral (Non-Peptide) GLP-1R Agonist TTP273 in Type 2 Diabetes: How Much and When?

Jennifer Freeman, PhD (vTv Therapeutics, High Point, NC)

In an important oral, Dr. Jennifer Freeman presented phase 2 data on vTv’s oral GLP-1 agonist candidate TTP273, indicating that lower doses might be more effective. In LOGRA, a phase 2 proof-of-concept study (n=174), TTP273 was well-tolerated, and after 12 weeks, A1c was 0.9% lower than placebo in the 150 mg once-daily arm and 0.7% lower than placebo in the 150 mg twice-daily arm (p<0.001 for both comparisons). Weight loss at three months was 2 lbs greater in the 150 mg once-daily arm and 1 lb greater in the 150 mg twice-daily arm vs. placebo, though these superior reductions in body weight did not reach statistical significance. Parsing the data by body weight and examining mg/kg dosing, Dr. Freeman showed how the greatest efficacy was seen at the lowest doses (<1.35 mg/kg), for both A1c and body weight reduction. For doses <1.35 mg/kg, margin of A1c drop neared 2% and weight loss was ~8 lbs vs. 0.3% A1c decline and 1 lb weight loss for doses >1.75 mg/kg. Thus, patients >22o lbs dosed once-daily experienced the greatest relative A1c and weight benefits. These patients also saw nearly 6 mmHg drops in systolic blood pressure and ~55 mg/dL in fasting plasma glucose. While we might expect patients at higher baseline body weight to benefit more from GLP-1 agonism, the disproportionate effects on glycemia among those receiving lower mg/kg doses are intriguing. Dr. Freeman noted that TTP273 is a functionally biased ligand and a small molecule, not a peptide, and signaling by TTP273 occurs through the neuroendocrine system via the GI tract, as well as by plasma concentration in the circulatory system. TTP273 does not activate the beta-arrestin pathway. Dr. Freeman hypothesized that high concentrations of TTP273 – particularly in the periphery, where the effect is desensitized more slowly – may alter the signaling dynamic of the molecule. A similar dose-response pattern was observed in a proof-of-concept study for TTP054, vTv’s other oral GLP-1 agonist candidate. More work will be needed to understand the mechanistic differences between peptide and small molecule GLP-1 agonists, but we continue to be excited about the impending arrival of oral GLP-1 agonists and the improved patient experience that will come with them. Closest-to-market in this area is Novo Nordisk’s oral semaglutide, in phase 3.

MEDI4166, a Novel Antibody (PCSK9)-Peptide (GLP-1) Fusion Molecule: Single-Ascending-Dose Study in Patients with Type 2 Diabetes

Meena Jain, MD (MedImmune, Cambridge, UK)

AZ discontinued its PCSK9/GLP-1 fusion candidate in 2Q17, and Dr. Meena Jain shared results from a phase 1/2 study (n=40) that shed some light on this decision. The agent, MEDI4166, was associated with more adverse events vs. placebo (67% vs. 50%, respectively), though the most common adverse events in both treatment arms were GI-related (17% vs. 30%, respectively). Notably, eight participants randomized to MEDI4166 (n=30) developed antidrug antibodies. Dr. Jain reported that these antidrug antibodies did not interfere with the agent’s PK/PD profile (for both the PCSK9 component or the GLP-1 component), but we imagine this may have come into play in the drug candidate’s discontinuation.

Oral Presentations: Incretins – Entry and Actions

Evaluation of the Effect of Food on the Pharmacokinetics of Oral Semaglutide

Jeanette Borregaard, MD (Novo Nordisk, Copenhagen, Denmark)

Novo Nordisk’s Dr. Jeanette Borregaard discussed the practical issue of how food affects the absorption of oral semaglutide, Novo Nordisk’s phase 3 GLP-1 agonist candidate. Healthy volunteers (n=78) received 10 mg oral semaglutide under three different experimental conditions: fed (high calorie, high fat breakfast 30 minutes pre-dose), fasting (overnight and four hours post-dose), and a reference condition (fasting overnight for at least six hours, 30 minutes post-dose fasting). Results indicated that the absorption of oral semaglutide is limited by prior food ingestion – 14 out of 25 subjects in the fed arm showed no detectable semaglutide exposure. Moreover, PK data revealed that the exposure of oral semaglutide was greater in the fasting group vs. the reference group, as reflected by a greater area under the concentration curve (AUC), though this did not reach statistical significance (p=0.080). On the basis of these findings, the dosing recommendation for oral semaglutide in the ongoing phase 3 PIONEER program was to take the drug with half a glass of water just after waking up, and to wait 30 minutes before eating or taking any other medications, Dr. Borregaard explained. Although it would be ideal if oral semaglutide could be taken at any time of the day without such specific stipulations, we note that this is still more convenient and adherence-friendly than an injection, as most GLP-1 agonists are administered.

Reduction of HbA1c with Dulaglutide in Type 2 Diabetes Patients Negative, Low Positive, or High Positive for GAD Antibodies – A Post-Hoc Analysis of AWARD-2, -4, and -5

Paolo Pozzilli, MD (Campus Bio-Medico University of Rome, Italy)

Anywhere between 5%-20% of patients with diagnosed type 2 diabetes may actually have latent autoimmune diabetes of the adult (LADA), which has an autoimmune component and is often characterized by anti-GAD antibodies and faster progression to insulin dependence. Dr. Paolo Pozzilli presented results of a post-hoc analysis from three of the AWARD trials for Lilly’s once-weekly GLP-1 agonist Trulicity (dulaglutide), focusing on patients with levels of anti-GAD antibodies suggestive of LADA. Out of the 2,466 AWARD patients assessed in this analysis, 7.6% were anti-GAD antibody positive, with 2.4% falling into a “high level” category and 5.3% falling into a “low level” category. Overall, dulaglutide provided statistically significant A1c reductions in the LADA group, comparable with what was found in non-LADA patients. There was perhaps a slight trend toward diminished efficacy in those with high levels of anti-GAD antibodies, but from an n=15 the difference was not statistically significant. Dulaglutide’s efficacy in LADA was consistent across the three AWARD trials used in this analysis, and was found to be greater than sitagliptin’s effect in LADA in AWARD-5. Hypoglycemia was not impacted by LADA status.

  • These results contrast with a study published in Diabetes Care last year that found diminished GLP-1 agonist (liraglutide or exenatide) efficacy in patients with raised GAD or IA2 autoantibodies. There was a smaller number of patients studied and the comparison was slightly different than in Dr. Pozzilli’s study, but it was striking that in the Diabetes Care paper the presence of islet autoantibodies diminished A1c-lowering efficacy by more than two-thirds. It remains to be seen if there is a meaningful difference in efficacy in LADA between dulaglutide and liraglutide/exenatide, or if the different finding was just a matter of study design.

Questions and Answers

Q: Did you get any measure of insulin secretion like fasting C-peptide?

A: Obviously that is a very important factor, but this was a post-hoc analysis and C-peptide data was not available.

Q: Why could there be a differential effect with dulaglutide vs. liraglutide and exenatide? We have a head-to-head study with liraglutide vs. dulaglutide – why didn’t you measure the GAD antibodies in that study? It would have answered the question of whether this is unique to dulaglutide and not liraglutide and exenatide.

A: We didn’t have the chance to measure GAD antibodies in AWARD-6. If you look at the data on exenatide and liraglutide published in Diabetes Care, the paper had a very small number of patients, and therefore was not really comparable with ours. New studies will have to be designed prospectively, though post-hoc studies like this one are useful in guiding what we study in the future.

Oral Presentations: What Can We Learn from Animal and In Vivo Models of Cardiorenal Complications?

Liraglutide Inhibits Vascular Smooth Muscle Cell Proliferation by Enhancing p-AMPK and Cell Cycle Regulation, and Delays Atherosclerosis in APO-E Deficient Mice

Toshie Iijima, PhD (Dokkyo Medical University, Japan)

Dr. Toshie Iijima presented data from atherosclerotic mice models that the GLP-1 agonist Victoza (Novo Nordisk’s liraglutide) reduces plaques in blood vessels, improves endothelial function, and delays angiotensin II mediated proliferation of vascular smooth muscle cells. This work builds on previous studies showing that GLP-1 agonists suppress the progression of atherosclerosis in animals. Dr. Iijima’s study used both genetics (an ApoE knockout) and a high fat diet to create a pro-atherosclerotic state, and then used multiple measures of atherosclerosis and endothelial function to assess liraglutide’s effect. The findings were consistently and broadly in favor of liraglutide, with reduced atherosclerotic plaque burden, reduced intimal-medial vessel wall thickness, and better blood vessel relaxation following stimulation with acetylcholine – in other words, healthier blood vessels. Dr. Iijima’s team found that liraglutide increased the phosphorylation of AMP-activated protein kinase (AMPK), which they hypothesized reduces vascular smooth muscle cell proliferation. We will be interested to see what sort of studies could confirm similar findings in humans.

Corporate Symposium: Recent Advances in GLP-1 Agonists: Glycemic Control and Beyond (Sponsored by Novo Nordisk)

Once-Weekly GLP-1 Receptor Agonists – How Do They Differ?

Daniel Drucker, MD (University of Toronto, Canada)

During Novo Nordisk’s symposium, Drs. Daniel Drucker and Ildiko Lingvay emphasized within-class differences to GLP-1 agonists, Dr. Lingvay calling them “the most heterogeneous class of diabetes drug therapy.” Perhaps the most patent example of this is the mix of neutral and positive CVOTs, with LEADER (for Novo Nordisk’s liraglutide) and SUSTAIN 6 (for Novo Nordisk’s once-weekly candidate semaglutide) showing significant CV risk reduction vs. placebo and EXSCEL (for AZ’s once-weekly exenatide, full results to be presented Thursday at this meeting), ELIXA (for Sanofi’s lixisenatide), and FREEDOM-CVO (for Intarcia’s ITCA 650, an implantable exenatide mini pump) demonstrating CV safety but not efficacy. Body weight effects also differ between various GLP-1 agents, as do glycemic effects. In fact, recent topline results from SUSTAIN 7, a head-to-head comparison of semaglutide vs. Lilly’s dulaglutide (Trulicity), showed a significant ~0.4% A1c treatment difference in favor of semaglutide plus an approximate doubling of weight loss benefit with semaglutide, despite both products being once-weekly, human GLP-1-based agents. Some have speculated that the divide between neutral and positive GLP-1 agonist CVOTs may be explained by molecular differences in exendin-4-based agents (exenatide and lixisenatide) vs. human GLP-1-based agents (liraglutide and semaglutide), while others have put more weight on variations in trial design – Thursday’s EXSCEL symposium will hopefully shed some light. While we don’t yet know with certainty what distinguishes one GLP-1 agonist from another, Dr. Drucker explored possibilities through a deep dive into the basic science of these compounds. He described semaglutide has having very similar features to native GLP-1, with a few slight but key differences from liraglutide: One amino acid substitution makes the once-weekly candidate more resistant to DPP-4 degradation, while another results in higher affinity binding to albumin. These small molecular changes underlie an improved GLP-1 agonist therapy: Semaglutide has demonstrated impressive potency across its phase 3 clinical program, and phase 2 studies in obesity imply superior weight loss efficacy vs. any obesity drug currently available (including Novo Nordisk’s market-leading Saxenda, a high-dose formulation of liraglutide). That said, Dr. Drucker acknowledged Trulicity’s weight loss efficacy as well. He pointed out that dulaglutide is a larger molecule that wouldn’t be able to enter the brain as rapidly as a smaller molecule like liraglutide, and still, dulaglutide is communicating effectively with the brain to suppress appetite and promote weight loss. He highlighted this as an interesting question for future studies. Dr. Drucker shared his view that differences between GLP-1 agonists are most likely explained by differences in molecule, though much more research is needed to provide definitive answers. On the bright side, he alluded to a tremendous opportunity for personalized medicine that we now have in the GLP-1 class, where patients/providers have a choice between therapies with different dosing regimens, different injection devices, and different effects on glycemia on outcomes beyond A1c. We appreciated this sentiment, and we hope it takes root in real-world clinical practice but are skeptical given how important formularies have become in determining what drugs patients take (outside the US, although they are not called formularies, it’s also often down to negotiation).

Cardiovascular Risk Management in Type 2 Diabetes: Where Are We?

Stephen Bain, MD (University of Swansea, UK)

Dr. Stephen Bain, one of the LEADER trial investigators, provided a brief review of the CVOT landscape and the results delivered to-date. He is willing to wager that the DPP-4 inhibitors are neutral from a CV perspective, and that SGLT-2 inhibitors are cardioprotective as a class. Regarding GLP-1 agonists, he noted that there are meaningful differences emerging in trials, and it will be important to learn whether differences in trial design or differences in the molecules themselves are the cause.

Further Insights into Cardiovascular Outcomes from LEADER

Neil Poulter, MD (Imperial College London, UK)

After breezing through the well-known topline results from the LEADER CVOT for Novo Nordisk’s Victoza (liraglutide) – in which just about “everything goes in the right direction” – Dr. Neil Poulter discussed analyses of five potential confounding factors and whether they influenced the CV risk reduction seen in LEADER. The five factors were: (i) prior MI/stroke, (ii) use of CV risk reduction medications at baseline, (iii) use of glucose-lowering drugs at baseline, especially insulin, (iv) introduction of various medications during the trial in the comparator group, and (v) severe hypoglycemia episodes during the trial. None of the five weakened the association between liraglutide treatment and reduced adverse CV events. Dr. Poulter also noted in his conclusion that the risk reduction seen in LEADER is unlikely to be fully explained by the observed differences in A1c, body weight, blood pressure, and lipids.

Insulin Degludec/Liraglutide (IDegLira) vs. Basal-Bolus Therapy in People with Type 2 Diabetes

Richard Holt, MD (University of Southampton, UK)

Dr. Richard Holt took the stage to present very impressive results from the DUAL VII trial that compared Novo Nordisk’s Xultophy (insulin degludec/liraglutide) vs. basal-bolus therapy for type 2 diabetes. These results were first presented at this year’s ADA. As a reminder, both treatment strategies brought mean A1c down to 6.7%, but Xultophy did so with around half as much daily insulin and a ~90% reduction in hypoglycemia (blood glucose-confirmed or symptomatic) and a ~3.5 kg (~8 lb) weight benefit – wow! One fact that Dr. Holt didn’t want the audience to forget is that Xultophy did all this with one injection a day instead of up to four with basal-bolus. Indeed, the decreased injection burden is just one of many benefits we see in the new fixed-ratio combination class – the same is true for Sanofi’s Soliqua.

Panel Discussion

Stephen Bain, MD (University of Swansea, UK); Neil Poulter, MD (Imperial College London, UK); Richard Holt, MD (University of Southampton, UK)

Q: We’ve seen great data from LEADER. In terms of the data on liraglutide and SGLT-2 inhibitors, which would you choose and where are the gaps in the evidence? And what about combining them?

Dr. Neil Poulter (Imperial College London, UK): Recently I’ve been talking with other cardiologists and they have been very impressed with the outcomes data for liraglutide and empagliflozin. They said that they consider it their job in terms of secondary prevention, if their patient is diabetic, for them to initiate therapy with an agent. Surprisingly, for most of them, an injection is too far – they would prefer that a GP or endocrinologist handle the injections. In the UK I can’t see may cardiologists initiating and injection. They are also frightened about hypoglycemia. The key thing is education of the cardiologists, so that they can work with GPs and endos. But cardiologists understand that there are benefits there.

Dr. Stephen Bain (University of Swansea, UK): Our cardiologists have no interest in insulin. I don’t think they’ll really be taking this to heart. It may be possible to infiltrate the cardiology guidelines. If price was no issue, I think metformin, SGLT-2 inhibitors, and GLP-1 agonists would be first line. Given that one is an injection, that one is third-line, but if we get oral GLP-1 agonists it would be a game changer.

Dr. Richard Holt (University of Southampton, UK): We’ve got two great classes of drugs now with outcomes data that will lower glucose effectively. We need to think of the side effect profile. Many people don’t fancy the SGLT-2 inhibitors because of mycotic infections and thrush. Others are okay with injections. We have to discuss the pros and cons with the patient.

Q: Why use a fixed-ratio combination?

Dr. Holt: It comes from the perspective of reducing the number of injections. One of the other advantages of IDegLira is the tolerability and nausea data. In studies of GLP-1 agonists given alone, there is often significant nausea and vomiting in early weeks. When we see this fixed-ratio combination allow patients to start with a lower dose of liraglutide, the tolerability is very good.

Q: Could you tell us what the absolute cardiovascular risk reduction was with liraglutide?

Dr. Bain: Absolutely, the event rate was 13% versus 14.9% with placebo. The number needed to treat was about 53.

Dr. Poulter: That is a very small number needed to treat. This is a huge swing, a fantastic benefit. Harping on about the absolute benefit being small is a bit disingenuous.

Q: One of the questions about liraglutide from LEADER was in patients without established cardiovascular disease, with risk factors only. Where do we sit in the management of those patients?

Dr. Poulter: That is why we did the analysis to stratify by prior MI or stroke. The numbers for pure primary prevention were small, so it is hard to say. The concern with any of these subgroup analyses is that for some of them you’ll come up with something by chance. We’re playing with frighteningly small numbers for primary prevention.

Q: Could you postulate on some of the reasons for the cardiovascular benefit in LEADER?

Dr. Poulter: Many things contributed a bit. The hypo story, and little bits of risk factors. My favorite is the fact that systolic blood pressure went down, but diastolic pressure went up a bit. For comparison, with a diuretic, and in EMPA-REG, both systolic and diastolic pressures went down. The pattern in LEADER may instead signify an improvement in arterial resistance.

Q: The data from DUAL VII [Xultophy vs. basal-bolus] were impressive. Is there still a place for basal bolus in type 2 diabetes?

Dr. Richard Holt (University of Southampton, UK): I think there is still a place for it. There is a need to individualize care and discuss options with patients. I think the results of DUAL VII are indeed impressive – that you can get people to target with a single injection of IDegLira. I’d be moving twards using IDegLira instead of basal bolus. Still, many individuals despite reaching the top dose of IDegLira were not at target. Basal bolus may be appropriate for where to go next in those patients.

Q: Was there interaction between hypoglycemia and cardiovascular death?

Dr. Poulter: As with the primary outcome, there was no interaction between hypoglycemia and CV death.

Corporate Symposium: Precision Medicine for Type 2 Diabetes (Sponsored by AZ)

What Can Precision Medicine Do for Type 2 Diabetes

Chantal Mathieu, MD (KU Leuven, Leuven, Belgium); Jiten Vora, MD (Royal Liverpool University Hospital, Liverpool, UK)

Co-emcees Dr. Chantal Mathieu and Dr. Jiten Vora kicked-off this corporate symposium that attracted an audience just shy of 1,000 attendees. Precision medicine is a hot topic in healthcare, though to-date it has not been applied as much in diabetes as in fields like cancer – a fact Dr. Vora lamented in his presentation. The presenter pair cited key recent data hinting that genetics plays a large role in the response to different glucose-lowering therapies, suggesting that there is at least potential for precision medicine to be helpful in diabetes. If a specific patient’s genetics predisposes them to respond to drug B but not drug A, it behooves the healthcare system to use precision medicine to get that patient onto drug B first, rather than setting them up for failure by starting them on drug A as part of a one-size-fits-all paradigm.

Early, Durable, Tailored Glycemic Control: Where Are We Now?

Angelo Avogaro, MD (University of Padova, Italy)

Dr. Angelo Avogaro’s main recommendations in this presentation were to (i) intensify glucose-lowering therapy early, and to (ii) strongly consider SGLT-2 inhibitors to do so. Dr. Avogaro made a strong case that SGLT-2 inhibitors are the treatment of choice for durable glycemic control starting early in the course of disease, citing lots of data on AZ’s Farxiga (dapagliflozin) – including CV risk reduction along a broad spectrum of baseline risk. All in all, Dr. Avogaro appeared fully supportive of the SGLT-2 inhibitors recent rise in favor, thanks in large part to excellent outcomes data from EMPA-REG OUTCOME and the CANVAS program, plus real-world data from CVD-REAL

  • Dr. Avogaro recommended GLP-1 agonists as a particularly effective way to intensify treatment in patients on an SGLT-2 inhibitor. He cited results from the DURATION-8 study showing that Farxiga (dapagliflozin) + Bydureon (exenatide once-weekly) was more efficacious with regard to A1c-lowering than either drug independently.
  • Audience response question: “What is the most important factor that you consider when choosing the first add-on to metformin?”
    • Potential cardiovascular benefits: 39%
    • Risk of hypoglycemia: 29%
    • Weight gain: 11%
    • Risk of non-hypoglycemia adverse events: 10%
    • Other: 9%
    • Potential renal benefits: 3%

From Clinical Trials to Real-World Evidence: New Dimensions in Type 2 Diabetes – Part One: Randomized Control Trials

Bernard Zinman, MD (University of Toronto, Canada)

Could EXSCEL’s design as a more “pragmatic” outcomes trial have played a role in its neutral result? While veteran clinical trialist Dr. Bernard Zinman didn’t explicitly pose this question, he did highlight that AZ’s outcomes trial for once-weekly GLP-1 agonist Bydureon (exenatide) was designed to be more reflective of real-world clinical practice than other more “traditional” CVOTs.

  • Dr. Zinman underscored that the enrollment criteria for EXSCEL were quite inclusive. Notable features included (i) enrolling patients with and without CV risk factors at baseline, (ii) allowing a wide range of concomitant medications, (iii) not enriching the study population with elderly patients, and (iv) not including a run-in period to rule out patients with low medication adherence. Perhaps an implied comparison is that the LEADER CVOT for Novo Nordisk’s Victoza (liraglutide) specifically targeted patients facing high CV risk, had a higher minimum age, excluded patients on DPP-4 inhibitors at baseline, and had a run-in period to establish adherence – though it did have a few “pragmatic” features as well. Notably, the FDA recently approved a new CV indication for Victoza reflecting reduced risk for adverse CV events, but this applies specifically to type 2 diabetes patients with established CV disease, in line with the high-risk participant pool in LEADER.

From Clinical Trials to Real-World Evidence: New Dimensions in Type 2 Diabetes – Part Two: Real-World Evidence

Richard Holt, PhD (University of Southampton, UK)

Dr. Richard Holt argued that while a randomized control trial shows that a drug can work, only real-world evidence demonstrates whether it will work. RCTs often suffer from poor generalizability, as a large proportion of type 2 diabetes patients have comorbidities that keep them out of RCTs. That said, he pointed out that real-world studies for drug classes like SGLT-2 inhibitors and DPP-4 inhibitors have generally been compatible with results from registrational RCTs.

Panel Discussion

Bernard Zinman, MD (University of Toronto, Canada); Richard Holt, PhD (University of Southampton, UK)

Q: Is it time for regulatory bodies to use real-world evidence like the CVD-REAL study?

Dr. Zinman: Yes, absolutely. Rich was spot on in saying that you need both. It’s not enough to have a randomized control trial. You need both the randomized control trial and real-world evidence. There are examples where in the RCT you get a particular outcome, but only when used in the real world do additional safety issues come up. The FDA and other regulators should look at both randomized control trials and real-world evidence.

Q: Can we continue to afford these randomized control trials?

Dr. Zinman: Absolutely, at least for me. The story everyone knows about rosiglitazone and concerns about CV safety led to the generation of data that puts healthcare providers, scientists, and patients with diabetes in a much better position. Look at how Angelo was able to present with such clarity about the paradigm shifts in the management of diabetes. We’re still unsure about sulfonylureas because nobody has done the randomized control trials. We were unsure about metformin until UKPDS. It’s only through carefully performed large-scale RCTs that we learn a lot about efficacy, safety – things like pancreatitis and pancreatic cancer – and we can move ahead. It’s money well-spent. We need science in diabetes management. At the end of the day, you need large numbers of patients exposed to any new therapy in a large RCT to evaluate a particular outcome, and certainly for safety.

Dr. Holt: I agree that we need to have randomized control trials, but there are times when an RCT shows a drug works but it doesn’t end up working in the real world. Think about the story of orlistat – very effective in trials, but in the real world people didn’t take it. We need to have both types of evidence. 

Is There More to Learn from GLP-1 Agonist Outcomes Trials?

Dr. Naveed Sattar echoed Dr. Bernard Zinman’s sentiments from this corporate symposium, adding that EXSCEL was a much larger trial with more than 14,000 patients (compared to LEADER’s n=9,340), with treatment according to “locally-accepted clinical practice,” and with no selection of patients with better adherence. Dr. Sattar estimated that <50% of patients in real-world practice would meet the strict CV disease inclusion criteria commonly used in “explanatory” CVOTs, praising AZ for attempting to create a more realistic and translatable trial by including a primary prevention cohort. In his opinion, we need more trials like EXSCEL to figure out what these new agents can do in a larger population. Nonetheless, Dr. Sattar praised the work done in previous CVOTs as well, for shifting the paradigm of diabetes management in patients with CV disease. We add that CVOTs are a massive investment of time and resources, which is one (understandable) reason for enrollment of higher-risk patients to meet a minimum number of CV events.

GLP-1 RAs: An Ideal First Injectable in Type 2 Diabetes?

Tina Vilsbøll, MD (University of Copenhagen, Denmark)

Dr. Tina Vilsbøll provided a compelling argument for the early use of GLP-1 agonists in treating type 2 diabetes. Of particular interest was her description of the differences between currently available GLP-1 agonists. As a class, these agents lower blood glucose, blood pressure, and body weight by addressing a range of the pathophysiologic defects associated with type 2 diabetes: They slow gastric emptying, lower inflammation, increase insulin secretion, lower appetite, and promote naturesis. However, Dr. Vilsbøll underscored that not all GLP-1 agonists are alike. In her words, short-acting agents like AZ’s Byetta (exenatide twice-daily) and Sanofi’s Adlyxin (lixisenatide once-daily) disproportionately affect postprandial glucose, while long-acting agents like AZ’s Bydureon (exenatide once-weekly), Novo Nordisk’s Victoza (liraglutide once-daily), Novo Nordisk’s once-weekly semaglutide, and Lilly’s Trulicity (dulaglutide once-weekly), have more of an effect on fasting plasma glucose and A1c. She drew a distinction between exendin-4-based agents (exenatide, lixisenatide) and human GLP-1-based agents (liraglutide, semaglutide, dulaglutide) – this argument has generated a fair amount of controversy in the field, as summarized in our themes section of this full report. Dr. Vilsbøll suggested that the exendin-4-based GLP-1 products may result in more antibodies vs. the human-GLP-1-based products. She also explained how large molecules (albiglutide, dulaglutide) cannot penetrate the brain as well, thus limiting their appetite-suppressing effects compared to small molecules (exenatide, liraglutide, lixisenatide, semaglutide).

  • Much to our delight, Dr. Vilsbøll promoted combination therapy of GLP-1 agonists with basal insulin. Fixed-ratio basal insulin/GLP-1 agonist combos are now on the market as Sanofi’s Soliqua (insulin glargine/lixisenatide) and Novo Nordisk’s Xultophy (insulin degludec/liraglutide). These products lower injection burden, but Dr. Vilsbøll pointed out that the two agents can also be dosed separately for superior benefits to either monotherapy. The complementary actions of GLP-1 agonists and insulin (the GLP-1 counteracts the weight gain from insulin, while delivery with insulin ameliorates some of the GI side-effects common with GLP-1 agonists) make this combination approach particularly attractive – we’ve heard this perspective from countless thought leaders, which is why it’s so disappointing that fixed-ratio products have been underutilized in their first few quarters on the market.

Corporate Symposium: Changing the Type 2 Diabetes Management Paradigm with Fixed-Ratio Combinations (Sponsored by Sanofi)

A Matter of Urgency: Simultaneous Intensification with Fixed-Ratio Combinations

James Gavin, MD (Emory University, Atlanta, Georgia)

In Sanofi’s late-morning session on fixed-ratio basal insulin/GLP-1 combinations, Dr. James Gavin established Soliqua (insulin glargine/lixisenatide) as a way to fill an unmet need for better postprandial glucose control in type 2 diabetes. He summarized findings from the DECODE and Diabetes Intervention Study (DIS) trials, both of which found an independent effect of postprandial hyperglycemia on CV and all-cause death. In the former, postprandial excursions were associated with a significantly increased risk for CV death across all subgroups of fasting plasma glucose. In the latter, mean postprandial glucose >180 mg/dl was associated with significantly heightened risk for fatal MI and for all-cause death vs. mean postprandial glucose between 80-145 mg/dl (p<0.05 for both comparisons). These were merely two examples – Dr. Gavin asserted that there’s an abundance of data on these adverse outcomes stemming from poor postprandial control – and yet a majority of diabetes drugs only address the fasting component of hyperglycemia. Products in the highly-anticipated new drug class of basal insulin/GLP-1 fixed-ratio combos simultaneously tackle fasting blood glucose (with the basal insulin piece) and post-meal glucose (with the GLP-1 agonist piece). Indeed, GLP-1 agonists have introduced competitive pressure for rapid-acting insulins on the market because of their positive postprandial effects, and it is our sense that Sanofi has long been emphasizing the benefits to short-acting GLP-1 agonists (like lixisenatide) on post-meal glycemia. We first heard Sanofi’s categorization of “prandial” GLP-1 agonists vs. “non-prandial,” longer-acting GLP-1 agonists years ago, and this characterization has been confirmed by further clinical evidence and KOL commentary. At EASD 2016, Dr. Boris Kovatchev presented a post-hoc analysis of LixiLan-O to emphasize how lixisenatide contributes to Soliqua’s overall A1c-lowering benefit by acting primarily on postprandial hyperglycemia. That said, Novo Nordisk’s Xultophy (insulin degludec/liraglutide) also contains a short-acting GLP-1 agonist component by this categorization, since both liraglutide (branded Victoza) and lixisenatide (branded Adlyxin) are indicated for once-daily injection. Dr. Gavin reviewed key phase 3 results on both products, revealing that Soliqua is weight neutral while Xultophy appears to promote weight loss. Moreover, we note that liraglutide’s demonstrated CV benefit in the LEADER trial and the recent FDA approval of a new CV indication for Victoza may lend further advantage to Xultophy. The SWITCH and DEVOTE studies have also shown lower hypoglycemia risk with insulin degludec vs. insulin glargine, another variable that may be meaningful for patients/providers choosing between the two advanced combinations. Of course, the most important takeaway from Dr. Gavin’s talk was how both Soliqua and Xultophy represent a leap forward in diabetes care: Both agents have shown superiority vs. component monotherapies, alongside a milder side-effect profile, and we so hope to see a boost in real-world uptake (whole class sales in 2Q17 were underwhelming at $34 million compared to billions for GLP-1 as a single-agent class). Dr. Gavin described the “urgency” that HCPs should feel in getting more of their type 2 patients on this class of combination therapy (especially those with baseline A1c >9% and/or those uncontrolled on two oral agents), and we couldn’t agree more.

Reflections on Injectables for Type 2 Diabetes: Let’s Move On!

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

Dr. Julio Rosenstock followed Dr. Gavin, launching off the discussion of postprandial control with an emphasis on the complementary effects of GLP-1 agonists and basal insulin that lead to superior glucose-lowering and fewer side-effects. Where insulin causes weight gain, GLP-1 agonists promote weight loss. When insulin is used to deliver the GLP-1 agonist, as in a fixed-ratio combination, it ameliorates GI side-effects that affect patient quality of life. Dr. Rosenstock shared data to support that side-effects of both monotherapies are not trivial. GLP-1 agonists, he explained, are plagued by discontinuation. One analysis found discontinuation rates after six months as high as 48% for exenatide (AZ’s Bydureon), 36% for liraglutide (Novo Nordisk’s Victoza), and 28% for dulaglutide (Lilly’s Trulicity). Moreover, 40%-50% of real-world withdrawal is due to nausea, vomiting, and diarrhea stemming from GLP-1 agonist treatment. Basal insulin is not without its side-effects, namely hypoglycemia risk and weight gain. It also comes with issues of low adherence to titration and low persistence: According to Dr. Rosenstock, 50%-60% of people have stopped insulin after a 12-month follow-up. He outlined three intensification options for patients uncontrolled on basal insulin: (i) rapid-acting insulin before the largest meal, (ii) a standalone GLP-1 agonist, and (iii) a switch to a fixed-ratio basal insulin/GLP-1 agonist combination. Dr. Rosenstock argued that the last is the most appealing, as it minimizes injection burden and co-pays, offering simplicity and the greatest chance at maximizing adherence. We found this to be another fascinating talk in favor of basal insulin/GLP-1 agonist fixed-ratios, and we hope real-world HCPs are similarly compelled by the ability to help their patients with medication adherence, improve glycemic control, and enhance patient quality of life with a milder side-effect profile.

Corporate Symposium: A Combined Approach to Treating Type 2 Diabetes (Sponsored by Sanofi)

Introduction

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

Dr. Julio Rosenstock provided a quick, commentary-rich intro to combination therapy in diabetes. He highlighted that fixed-ratio combinations like Sanofi’s Soliqua (insulin glargine/lixisenatide) and Novo Nordisk’s Xultophy (insulin degludec/liraglutide) provide more flexibility than fixed-dose combination pills, and allow for individualized titration based on patient response. Still, Dr. Rosenstock sees a prominent place for oral fixed-dose combinations, going so far as to prognosticate that SGLT-2 inhibitors + metformin will soon become the standard treatment for newly-diagnosed type 2 diabetes. Switching back to GLP-1 agonist/basal insulin combos, he characterized the efficacy demonstrated in phase 3 as “pretty much unprecedented.” He briefly critiqued the ADA/EASD diabetes drug guidelines as offering an overwhelming number of options, suggesting that providers could benefit from more guidance on preference between classes. He suggested a simplified guideline that still begins with metformin, has second tier consisting only of SGLT-2 inhibitors, GLP-1 agonists, and basal insulin, and moves quickly to combination therapy with those three drug classes. He concluded with a punchy tagline of “one pill, one shot – that’s all most patients need,” referring to a metformin+SGLT-2 inhibitor combination pill and a basal insulin+GLP-1 agonist combo injection.

The Combination for Control: LixiLan-O & LixiLan-L Study Results

Juan Frias, MD (National Research Institute, Los Angeles, CA)

Dr. Juan Frias, investigator in the phase 3 program for Sanofi’s Soliqua (insulin glargine/lixisenatide), provided a thorough presentation of the key results from LixiLan-O and LixiLan-L. We covered the initial presentation of those results in great detail, so we won’t rehash them here – check out the links above for full details. Dr. Frias’ high-level takeaway was that LixiLan reduced mean A1c significantly more than its components, got more patients to their A1c targets, did so without increases in body weight or symptomatic hypoglycemia, and with a favorable GI profile. As a result, he is optimistic that LixiLan could help facilitate early intensification of therapy in a big way.

Consistent Benefits in Early Intervention

Leigh Perreault, MD (University of Colorado, Aurora, CO)

Dr. Leigh Perrault of UC Aurora rounded out the presentation on LixiLan clinical trial results, pointing out that LixiLan delivers effective glycemic control in a number of important applications:

  • (i) Efficacy across the range of starting A1c: whether patients started at higher or lower starting A1c levels, LixiLan brought many patients down to a final A1c around 7%. 
  • (ii) Efficacy even in patients not at control on two or more oral glucose lowering drugs.
  • (iii) Early efficacy, with major changes in A1c as early as 12 weeks.
  • (iv) Improvements in quality of life, especially through glucose variability.

A Closer Look at Fixed-Ratio Combination Therapy

Francisco Javier Ampudia-Blasco, MD (Clinic University Hospital, Valencia, Spain)

Dr. Francisco Javier Ampudia-Blasco hammered home a few additional key points from Soliqua’s clinical trial program. He noted that Soliqua offers greater efficacy than its component parts while also drastically improving tolerability from a GI (i.e. nausea and vomiting) perspective. GI side-effects are one of the bigger barriers to initiating patients on GLP-1 agonists, so improvements on this front (thanks to slow dose up-titration with Soliqua) are a big win.

Posters

Simultaneous vs. Sequential Combination of Insulin Glargine and Lixisenatide in Type 2 Diabetes Uncontrolled on Metformin

J Rosenstock, F Ampudia-Blasco, F Giorgino, M Liu, R Perfetti, Y Handelsman

This exploratory analysis compared outcomes between a fixed-ratio combination of a basal insulin/GLP-1 agonist (as seen in the LixiLan-O trial of Sanofi’s Soliqua [insulin glargine/lixisenatide]) vs. the sequential add-on of its components (as seen in the GetGoal Duo-1 trial). The poster reported that the simultaneous administration of these agents has greater potential for A1c reduction. The present study used propensity score matching based on baseline age, race, BMI, A1c, fasting glucose, diabetes duration, and oral agent/metformin usage to create 87 matched pairs of participants between the LixiLan-O and GetGoal Dual-1 trials. The average A1c reduction among the LixiLan-O participants on Soliqua was 1.3% after 24 weeks vs. 0.7% for participants on lixisenatide added to insulin glargine in the GetGoal Duo-1 trial. This translates to a significant treatment difference of 0.6% in favor of Soliqua (p<0.0001). Furthermore, the proportion of patients achieving an A1c <7% at 24 weeks was 79% with Soliqua in the LixiLan-O study vs. only 51% with lixisenatide added to insulin glargine in the GetGoal Duo-1 study. The superiority of Soliqua over sequential combination of its monotherapies persisted for weight loss: The Soliqua group in the LixiLan-O trial experienced 1.2 kg (2.6 lbs) weight loss on average, compared to mean weight gain of 0.1 kg (0.2 lbs) for the add-on therapy group in GetGoal Duo-1. Both hypoglycemia and GI side-effects were lower with Soliqua vs. lixisenatide added to existing insulin glargine therapy. All together, these results support the superiority of simultaneous initiation of insulin glargine and lixisenatide over the sequential addition of lixisenatide to existing insulin glargine therapy in terms of glycemic control, weight, hypoglycemia, and GI side-effects. Although it is important to bear in mind that this is an indirect analysis, this study provides compelling evidence for initiating Soliqua earlier in the treatment algorithm, rather than the typical “treat-to-fail” paradigm of adding a GLP-1 agonist only after a patient has failed to meet goal on maximally-titrated basal insulin therapy.

Shorter Time to Glycemic Control with Fixed-Ration Combination of Insulin Glargine and Lixisenatide vs. Insulin Glargine Treatment Alone

J Frias, MP Domingo, L Meneghini, R Napoli, M Liu, ES Rak, VR Aroda

A poster authored by Dr. Juan Frias outlined compelling evidence that people with type 2 diabetes reach glycemic targets significantly faster with Sanofi’s fixed-ratio basal insulin/GLP-1 combination Soliqua (insulin glargine/lixisenatide) vs. standard of care Lantus (insulin glargine). This data, also highlighted in a Sanofi press release, comes from a post-hoc analysis of the phase 3 LixiLan-O (n=1,170) and LixiLan-L (n=736) trials, which showed superior A1c-lowering efficacy for Soliqua vs. Lantus in type 2 diabetes. In both trials, a significantly higher proportion of participants on Soliqua achieved A1c <7% vs. their counterparts in the Lantus arm at 12 weeks: 60% vs. 45% in LixiLan-O (p<0.0001), and 46% vs. 24% in LixiLan-L (p<0.0001). Moreover, the time required for study participants to collectively reach a median A1c <7% was significantly shorter with Soliqua than with Lantus: 85 vs. 166 days in LixiLan-O (HR=1.5, 95% CI: 1.3-1.7, p<0.0001) – this suggests that dosing intensification is required with Lantus. In LixiLan-L, Soliqua-treated patients took 153 days to achieve this median A1c level, whereas Lantus-treated patients did not collectively reach this goal by the end of the 30-week study (HR=2.0, 95% CI: 1.7-2.5, p<0.0001). In contrast, median time required to reach the fasting plasma glucose target <130 mg/dl was identical for participants treated with Soliqua and Lantus: 56 vs. 57 days in the LixiLan-O trial, and never for either group in the LixiLan-L trial. This suggests that the faster time to target A1c with Soliqua may be attributable to the product’s action on postprandial excursions in addition to fasting glucose, thanks to its short-acting GLP-1 agonist component. This study reinforces our enthusiasm for Soliqua as an agent that packs the punch of two drugs in one single injection. We are extremely moved by the notion that, beyond lowering A1c to a greater extent than standard of care Lantus, Soliqua gets patients to goal more rapidly. We hope that payers are taking note – the efficacy profile of Soliqua (and, indeed, its counterpart Xultophy [insulin degludec/liraglutide] from Novo Nordisk) represents a major advance over traditional basal insulin therapy, and access remains a major barrier preventing commercial uptake of these agents despite tremendous enthusiasm from diabetes thought leaders.

iGlarLixi Reduces HbA1c to a Greater Extent Than Basal Insulin Therapy Regardless of HbA1c Levels at Screening

E Niemoeller, E Souhami, Y Wu, KH Jensen

To complement the data covered directly above, a separate poster demonstrated that Soliqua reduces A1c to a greater extent than Lantus regardless of baseline A1c. This post-hoc analysis stratified existing data from the LixiLan-L trial based on entry A1c into three categories: (i) <8% (n=97), (ii) 8%-9% (n=161), and (iii) >9% (n=69). Soliqua lowered A1c to a significantly greater extent than Lantus across each of these categories, with a treatment difference of 0.56% (95% CI: 0.66-0.42, p<0.0001) for those with baseline A1c <8%, 0.4% (95% CI: 0.59-0.22, p<0.0001) for those with baseline A1c between 8%-9%, and 0.66% (95% CI: 0.93-0.39, p<0.0001) for those with baseline A1c >9%. For the entire study population overall, A1c-lowering was a mean 0.54% greater with Soliqua vs. Lantus (95% CI: 0.66-0.42, p<0.0001). Importantly, this superior glycemic control with Soliqua vs. Lantus came without an increased risk of hypoglycemia.

SGLT-2 Inhibitors and Other Oral Agents

Symposium: An Emerging and Innovative Therapeutic Approach in Type 1 Diabetes with Dual SGLT-1 and SGLT-2 Inhibition: The Sotagliflozin Clinical Program

The Unique Mechanism of Action of Sotagliflozin: A Dual SGLT-1 and SGLT-2 Inhibitor

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

Dr. Clifford Bailey kicked-off this star-studded symposium by reviewing the concept of SGLT-1 and SGLT-2 inhibition, the heterogeneity of the SGLT-2 inhibitor class, and the theorized and observed effects of dual SGLT-1/2 inhibition in patients with type 1 diabetes. SGLT-1 and SGLT-2 are both co-transporters that use the sodium gradient, created by Na+/KATPase, to carry glucose into cells, but SGLT-2 is concentrated almost entirely in the kidney while SGLT-1 is found in the small intestine, muscle, heart, and kidney. Moreover, SGLT-1 has a high affinity for glucose but low transport capacity, while SGLT-2 has a lower affinity for glucose and high transport capacity. When uninhibited, these transporters reabsorb nearly 100% of glucose from glomerular filtrate. SGLT-2 inhibitors increase kidney excretion by preventing this reabsorption. The concept of dual inhibition doubles down, also targeting SGLT-1 transporters in the gut to prevent the initial absorption of glucose into the bloodstream. This reduces initial glucose absorption, while SGLT-2 inhibition reduces reabsorption, for a greater cumulative lowering of the glucose profile via 60-90 g/day worth of glucosuria. Inhibitors vary in affinity for their transporters, and sotagliflozin is unique in its level of SGLT-1 affinity, with an IC50 of 36 nmol/L, rivaled only by canagliflozin at 663 nmol/L. For reference, dapagliflozin’s IC50 for SGLT-1 is 1,400 nmol/L. Sotagliflozin’s affinity for SGLT-2 is comparable to other approved SGLT-2 inhibitors.

  • Dr. Bailey noted that in type 2 diabetes, SGLT-2 inhibitors have consistently shown persistent glucosuria and A1c-lowering, with low hypoglycemia risk, sustained weight loss, and improved systolic blood pressure. In a small study (n=36) of sotagliflozin in patients with type 2 diabetes, sotagliflozin gave significant reductions in A1c and plasma glucose, and an increase in urinary glucose (as expected). Moreover, sotagliflozin increased GLP-1 in patients with type 2 diabetes, an effect of delayed glucose absorption to the later part of the small intestine. With the knowledge that dual SGLT-1/2 inhibitors act independently of insulin, and that they have glycemic benefits in type 2 diabetes, the question remained of their efficacy in helping to manage type 1 diabetes.

Unmet Medical Needs in Adult Patients with Type 1 Diabetes: Sotagliflozin and the Phase 2 Results of the inTandem Clinical Program

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

Building toward the highly-anticipated inTandem3 full results (a topline release in June announced that 400 mg sotagliflozin showed superiority on a primary endpoint of A1c <7% with no severe hypoglycemia or DKA), Dr. Julio Rosenstock emphasized the need for new adjunct therapies in type 1 diabetes. Despite advances in insulin analogs, glucose control in patients with type 1 diabetes remains difficult. Only about one-third of patients with type 1 diabetes are meeting glycemic goals, and CGM data shows that “good” A1c scores can mask wide fluctuations into hypo- and hyperglycemia. Severe hypoglycemia remains a major issue, and its frequency increases with diabetes duration.  T1D Exchange data indicates an overall 5% yearly risk of DKA for a background type 1 population, which peaks around 10% in teenage years. Further, patients with type 1 diabetes progressively gain weight and experience increased hypertension and CV risk 5-6x higher than the background population. Dr. Rosenstock sees limited value in off-label use of metformin as adjunct therapy in type 1 diabetes: He articulated how clinical trials have not convincingly demonstrated metformin’s benefits in type 1 diabetes in terms of long-term A1c decline or reduced insulin dose. While we see particular promise in both SGLT-1/2 dual inhibitors and SGLT-2 inhibitors as adjunct type 1 therapies, these drugs will have a difficult time reaching the vast majority of patients without an FDA indication. To this end, there’s clearly room – and unmet need – for a new non-insulin type 1 diabetes drug on the market. 

  • Dr. Rosenstock summarized phase 2 and proof-of-concept data on sotagliflozin as a launching pad for inTandem3. In phase 2, sotagliflozin showed dose dependent A1c reductions and postprandial glucose-lowering even in patients with type 2 diabetes and low eGFR (pointing to effective SGLT-1 action in the gut). An initial four-week proof-of-concept study in patients with type 1 diabetes on both MDI and pump therapy demonstrated significant A1c, body weight, and bolus insulin reductions, as well as reduced hypoglycemia. Most notably, time-in-range was increased from 56% to 68%. In four weeks, two cases of DKA occurred and were determined to be pump-related; neither case was euglycemic. Based on this positive data, sotagliflozin was advanced into phase 3 trials in type 1 diabetes. Full results from inTandem1and inTandem2 were presented at ADA 2017, while inTandem3 is Lexicon’s third and final trial for its phase 3 sotagliflozin program.

The Phase 3 inTandem Clinical Program: Efficacy and Safety of Sotagliflozin in Adults with Type 1 Diabetes

Melanie Davies, MD (University of Leicester, UK)

Professor Melanie Davies took the stage for the main event, announcing new inTandem3 findings, published simultaneously in the NEJM. This was a 24-week trial (n=1,402) investigating 400 mg sotagliflozin vs. placebo on a primary endpoint of the proportion of patients achieving target A1c <7% with no severe hypoglycemia or DKA. Of note, this was a global trial (whereas inTandem1 took place in the US/Canada and inTandem2 took place in Europe/Israel) without an insulin optimization period, making it closer to “real life.” The primary endpoint was met by 29% of people in the sotagliflozin arm vs. 15% 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). Notably, A1c was blinded throughout the 24 weeks, which may have led to less aggressive insulin adjustment. 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). These weight effects were particularly positive, as >70% of study participants had a BMI >25 kg/m2 at baseline. In patients with systolic blood pressure ≥130 mm Hg at baseline, sotagliflozin gave a treatment difference of 3.5 mmHg (p<0.002 vs. placebo) at 16 weeks. Treatment differences for total, basal, and bolus insulin doses were -5, -3, and -3 units/day, respectively (p<0.002 for all comparisons). 

  • There were four DKA events (0.6%) in the placebo group vs. 21 (3%) in the 400 mg sotagliflozin group, leading to 11 treatment discontinuations in the latter arm. In the sotagliflozin group, DKA was adjudicated in 4% of pump users and 2% of patients on MDI. In an NEJM editorial published alongside the inTandem3 paper, Dr. David Nathan gives a lot of weight to this DKA signal, arguing that this risk persisted despite trial protocol offering a high amount of patient education around DKA. We’re very curious to learn more about the nature of this education, but we also point out that there’s a lack of consensus in the field about best practices for managing DKA risk. We continue to believe this risk can indeed be managed (even if we haven’t optimized education/monitoring strategies just yet).
  • Prof. Davies presented additional safety data, with more serious adverse events seen in the sotagliflozin group (7%) vs. placebo (3%). She also noted incidence of diarrhea (4% vs. 2%, respectively) and genital mycotic infections (6% vs. 2%, respectively, and unsurprisingly). Severe hypoglycemia occurred in 3% of sotagliflozin-treated patients and 2% of placebo-treated patients, but documented hypoglycemia <55 mg/dl was significantly less frequent in the sotagliflozin group vs. the placebo group (11.8 events/person-year vs. 15.4 events/person-year, respectively).
  • Last week, Lexicon released positive pooled CGM data from inTandem1 and inTandem2. At week 24, patients treated with 200 mg and 400 mg doses of sotagliflozin spent an additional 5% and 12% of the day in-range (70-180 mg/dl), respectively, compared to those taking placebo (p=0.026 and p<0.001, respectively). These percentages translate to an additional 1.3 and 2.8 hours in-range, respectively –we feel confident saying that this additional time-in-range would be an enormous win for anyone with diabetes. This is time not spent in hypo- or hyperglycemia, meaning that patients can feel well for nearly three more hours each day – and not have to spend time trying to get back into range. It’s unfortunate that inTandem3 didn’t make use of CGM, given that time-in-range data may be a crux of the selling point for sotagliflozin. Lexicon is planning to file sotagliflozin with the FDA toward a type 1 indication in 1Q18.

Commentator

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

The renowned Dr. John Buse provided the discussant on inTandem3, bringing the symposium full circle with a description of the high unmet need for adjunct therapy in type 1 diabetes management. He reminded everyone that 3% of patients, according to the T1D Exchange, have reported at least one DKA event in the prior three months (alluding to the background rate of this type 1 complication). Dr. Buse shared his view that it is possible – even probable – that sotagliflozin’s dual inhibition provides distinguishable benefits vs. single SGLT-2 inhibition in type 1 diabetes. He expressed hope that there’s a clinical path forward for SGLT inhibition in type 1 diabetes management, with the caveat that communication around the issue of DKA is essential for people to feel comfortable with this therapy. That said, he also suggested that the DKA episodes observed in inTandem3 were less severe than what real-world clinicians normally see because patients were trained to more closely monitor for this – the flip side of this is that the absolute number of DKA events may have been inflated by the lower severity episodes. In a separate conversation with us, Dr. Buse remarked that the DKA-related education was probably not optimal in this study, despite what Dr. David Nathan refers to in his NEJM editorial as extra steps taken by the investigators to mitigate DKA risk. In addition, Dr. Buse pointed out that a large proportion of type 1 diabetes patients in the US are treated by an endocrinologist, likely offering better DKA-related education vs. a primary care physician.

  • In our view, Dr. Nathan’s editorial in NEJM minimized the profound glycemic and weight loss benefits seen in this sotagliflozin study, while overemphasizing the DKA signal. One of his main points alludes to the training of inTandem3 participants on ketone monitoring, and he argues that if there was still an imbalance in DKA after patients received concerted education, this safety issue will surely persist in the real world. Dr. Buse provided a rebuttal in his comment that DKA-related education in the trial was probably far from optimal, likely because there’s still a lack of consensus on what optimal DKA management should be. It would be a shame for a manageable safety issue to overshadow the glycemic and weight loss efficacy of sotagliflozin, and as Drs. Rosenstock and Buse clearly established, there is an unmistakable need for adjunct therapy in type 1 diabetes care. That sotagliflozin is an oral medication only adds to our excitement (AZ’s Symlin is an injectable adjunct type 1 treatment that has never quite taken off commercially). In Dr. Nathan’s closing paragraph, he suggests that automated insulin delivery (AID) will outpace pharmaceutical development for type 1, eventually making new, non-insulin drugs for this population unnecessary. To this, we respond that it’s a false reality to think AID will be affordable and accessible to everyone in the very near future – in the meantime, while the treatment options we have are just not good enough, sotagliflozin could be a significant stride.

Symposium: SGLT-2 Inhibitors, Novel Therapies for Type 1 Diabetes

Unmet Need and Adjunct Non-Insulin Therapies

Chantal Mathieu, MD (KU Leuven, Belgium)

Dr. Chantal Mathieu opened this symposium with an argument of what we should look for in adjunct type 1 diabetes therapies: (i) more stable glucose profiles, (ii) less weight gain, and (iii) less hypoglycemia. Equally important is what’s missing from this list, namely the reduction of insulin dose. While clinical trials in type 1 diabetes tend to report this (and while observers tend to focus on it), Dr. Mathieu maintained that decreasing insulin requirements should not be a goal independent of bringing down hypoglycemia risk. She outlined insulin’s key physiological role in suppressing hepatic glucose production, lipolysis, and lipogenesis. People with type 1 diabetes, whose beta cells aren’t secreting enough insulin, thus rely on exogenous insulin doses that shouldn’t necessarily be dramatically reduced even with adjunct treatment. Dr. Mathieu emphasized the importance of time-in-range and the value of CGM in clinical trials to analyze this (foreshadowing what DEPICT 1 CGM data would show…). Notably, she also chaired an earlier EASD symposium on Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin and the inTandem3 trial in type 1 diabetes. DKA was more common in the sotagliflozin arm (3%) vs. placebo (0.6%), a finding that has elicited mixed reactions, though in our view the efficacy data far outweighs this manageable safety risk. Dr. Mathieu shared her invaluable clinical perspective, that these agents (both dapagliflozin and sotagliflozin) could be highly-effective therapeutic tools for type 1 diabetes, but that they should be used in “expert hands,” with strong education on both the provider side and the patient side.

DEPICT 1: Study Design and Baseline Characteristics

Lars Hansen, MD (BMS, Princeton, NJ)

In this introduction to the trial, Dr. Lars Hansen provided an impressive amount of detail on baseline characteristics of the study population and study protocols (we were particularly interested in the recommendations around DKA, and appreciated the specificity). DEPICT 1 was conducted at 143 centers across 17 countries. At baseline, participants (n=833) had a mean A1c of 8.5%, mean age of ~42 years, mean diabetes duration of ~20 years, mean daily insulin dose of ~60 units, and mean BMI of 28 kg/m2 (indicating overweight) ­– we note that this pool was comprised of patients in definite need for further A1c reductions and weight loss. Participants were randomized 1:1:1 to dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), or placebo (n=260). All study drugs were on top of a patient’s background insulin regimen. After randomization, the study was designed to include a 24-week, double-blind treatment period, followed by an un-blinded 28-week treatment period. The 24-week data was presented and published today in the Lancet Diabetes & Endocrinology. The primary outcome was change in A1c at 24 weeks with dapagliflozin 5 mg or 10 mg vs. placebo, and secondary outcomes included changes in total daily insulin dose, body weight, mean 24-hour glucose, mean amplitude of glucose excursion (MAGE), time-in-range between 70-180 mg/dl, and proportion of patients achieving an A1c decrease of ≥0.5% without severe hypoglycemia. The study enrolled slightly more females than males, and >95% of participants were white. Moreover, ~60% of participants were from Europe and 27% from North America, the rest from Latin America and Asia-Pacific. Approximately 63% of participants were using MDI, with about 37% using an insulin pump; 33% of participants used CGM at baseline.

  • Based on a phase 2 pilot study of dapagliflozin in type 1 diabetes, and a post-hoc analysis splitting insulin dose adjustments above and below 20%, investigators decided to cap insulin dose reductions at 20% in DEPICT 1 to counter DKA risk. In the pilot, decreasing insulin by >20% was associated with an increase in ketogenesis. Following the first dose of dapagliflozin in DEPICT 1, patients/providers were recommended to reduce total daily insulin dose (including basal and bolus) up to but no more than 20%. Insulin adjustment followed throughout the treatment period. Study participants were given a combined meter for glucose/ketones and were instructed to fingerstick at least four times per day, as well as to check beta-hydroxybutyrate levels at any sign of DKA or illness, independent of SMBG values (we imagine this alerting of patients to early signs of possible DKA could be immensely valuable in the real world, though more much consensus is needed on how DKA should be most effectively monitored in real clinical practice settings).

DEPICT 1: Efficacy and Safety Data

Paresh Dandona, MD (State University of New York, Buffalo, NY)

Dr. Paresh Dandona presented the safety and efficacy data from DEPICT 1, both decidedly positive. Results were published simultaneously in the Lancet Diabetes & EndocrinologyBoth doses of dapagliflozin met the primary endpoint of change in A1c over 24 weeks: the 5 mg dose gave a 0.4% drop vs. placebo, while the 10 mg dose gave a 0.5% drop vs. placebo (both p<0.0001). A1c reduction was consistent across doses. Dr. Dandona pointed out that a 0.25% A1c decline was observed between the screening visit and randomization (he described this as unsurprising, because people experiencing challenges with their glucose management often show improvement with additional “attention,” i.e. enrollment in a clinical trial), with a clear additional benefit to dapagliflozin therapy after randomization. Total daily insulin dose fell 9% vs. placebo for the 5 mg dose of dapagliflozin and 13% vs. placebo for the 10 mg dose (both p<0.0001). Percent change in body weight vs. placebo was -3% for the 5 mg dapa dose and -4% for the 10 mg dose (both p<0.0001). Moreover, weight loss was continuous and there was very little flattening of the curve over six months, leading Dr. Dandona to conclude that more weight loss can be expected long-term (we eagerly await DEPICT 1 trial extension data to see for ourselves). Hypoglycemia was well-balanced across all treatment arms, and the proportion of patients with an A1c reduction of ≥0.5% without severe hypoglycemia was >50% for both SGLT-2 doses compared to ~25% for placebo.

  • CGM readings showed 52% (12.5 hours), 55% (13.2 hours), and 44% (10.6) time-in-range for 5 mg dapa, 10 mg dapa, and placebo, respectively. This translates to an extra ~2.2 hours in-range for low-dose dapagliflozin patients and an extra ~2.6 hours in-range for high-dose dapagliflozin patients vs. placebo – time spent feeling well, experiencing better quality of life (this is a tremendous increase!). In the placebo group, average adjusted interstitial glucose increased 5 mg/dl over 24 weeks; mean difference from placebo for the dapagliflozin groups was -15 mg/dl for 5 mg and -18 mg/dl for 10 mg (both p<0.001). Average adjusted MAGE at 24 weeks with placebo was 2 mg/dl; mean difference from placebo for the dapagliflozin groups was -17 mg/dl for low-dose and -19 mg/dl for high-dose (both p<0.0001).
  • 24-hour CGM data indicates a blood glucose reduction in the early morning hours. According to investigators, patients dosed dapagliflozin in the morning, and the greatest glucose-lowering effects seemed to occur near the end of the 24-hour dose cycle, around 7 am. This will require further analysis, and more study will be needed to fully comprehend the time-action profile of dapagliflozin in patients with type 1 diabetes, as well as how the “dawn effect” of early morning glucose increase is involved in this dynamic.
  • DKA has emerged as a key consideration in using SGLT-1/2 and SGLT-2 inhibitors in type 1 diabetes, but DEPICT 1 was reassuring on this front. There was an event rate of 1% in the 5 mg group (four patients – two due to insulin pump failure, one to missed insulin dose), 2% in the 10 mg group (five patients – one attributed to pump failure, three to missed insulin dose, and one to alcohol), and 1% in the placebo group (three patients – one due to pump failure, one to missed insulin dose, one to stress). At least some of the favorable DKA outcomes seem to be attributable to the study guideline that total insulin should only be reduced up to 20% – patients were advised to eat extra carbs and dose insulin if they weren’t taking a certain amount daily. It is our understanding that this lower limit of insulin reduction is paramount in preventing DKA, and we wonder if there was any cap on insulin reduction in any of the inTandem clinical trials for sotagliflozin.
  • The adverse event profile of dapagliflozin was otherwise as expected, with a greater frequency of genital mycotic infections (12%, 11%, and 3% in the 5 mg, 10 mg, and placebo arms, respectively). Urinary tract infections, fractures, and hypotension/dehydration were all evenly balanced and rarely occurred. Hypoglycemia occurred in 79% of participants on the 5 mg dapa dose, 79% of those on the 10 mg dapa dose, and 80% of those taking placebo, while severe hypoglycemia occurred in 8%, 6%, and 7% of participants, respectively. Adverse events led to 23 discontinuations in total: six from the 5 mg dose, 8 from the 10 mg dose, and 9 from placebo.

Commentator

Maciej Malecki, MD (Jagiellonian University Medical College, Cracow, Poland)

Dr. Maciej Malecki provided independent commentary, offering a very positive view on DEPICT 1 trial design and results overall. In fact, one of his final slides read that “the DEPICT 1 study gives hope for prompt registration of dapagliflozin as an adjunct type 1 therapy” – indeed, we’d love to see Farxiga move closer to the type 1 market, and we keep our fingers crossed that upcoming results from DEPICT 2 and the DEPICT 1 trial extension support the strong safety/efficacy profile seen here. According to Dr. Malecki, it’s a shame the DEPICT 1 investigators didn’t formally assess patient quality of life, because he predicts the result would’ve been quite positive, and we’d presume the same given significant improvements to time-in-range and body weight. He raised a question around dapagliflozin’s applicability in type 1 diabetes patients with lower baseline A1c, body weight, or total daily insulin dose, suggesting that in these circumstances, further decreases may not be desirable. On the other hand, we imagine ideal candidates for new adjunct treatments like dapagliflozin and sotagliflozin will be those type 1 patients in-need of additional glycemic control and weight loss, so it makes sense for AZ to investigate its SGLT-2 inhibitor in this particular patient population (somewhat elevated baseline A1c of 8.5%). It’s true, patients well-controlled and satisfied with their insulin therapy may not see the need for Farxiga to be introduced in pharmacies with a type 1 indication, but this is a small minority of the population – only one in three adults with type 1 diabetes in the US are meeting A1c goal.

  • Dr. Malecki added to Dr. Mathieu’s list of what we should look for in an adjunct therapy: Beyond more time-in-range, less weight gain, and less hypoglycemia, he also mentioned CV risk reduction. The excess risk for mortality in people with type 1 diabetes vs. the background population is almost entirely accounted for by CV death, he explained, arguing that we need better medicines to bring down this risk. DEPICT 1, of course, was not an outcomes trial, and we know it will likely be challenging to get all the funding/resources behind a large CVOT in type 1 diabetes. Dr. Malecki was optimistic, however, about the DECLARE CVOT for dapagliflozin in type 2 diabetes (he cited two positive SGLT-2 CVOTs so far, EMPA-REG OUTCOME and CANVAS). Positive DECLARE results wouldn’t support an indication specific to type 1, but at the very least, they would help spread awareness among patients/HCPs about the cardioprotective effects of SGLT-2 inhibitors, and word would certainly spread to the type 1 community as well. DECLARE is expected to complete in the second half of 2018.
  • During Q&A, Dr. Julio Rosenstock cautioned against a possible misinterpretation of DEPICT 1 in context with inTandem 3: “People need to be extremely careful not to run out of this room 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.” We agree that study design differences make comparisons difficult (and often futile). It is our view that both these phase 3 studies were actually positive.
  • One final word from us on DKA: The recommendation for no more than 20% insulin dose reduction was the most specific DKA-related study protocol we’ve heard, and we’re curious for more color on the DKA education and risk mitigation strategies in inTandem3. Similar to how the amputation signal in CANVAS highlighted the lack of proper education around foot care in real-world diabetes management, the inTandem program and clinical programs for SGLT-2 inhibitors in type 1 have brought the need for better DKA education to the forefront. As Dr. John Buse remarked in a separate conversation with us, the DKA-related education in inTandem3 was probably far from optimal, which begs the question: what is optimal DKA risk management? And, how can we spread it broadly in the real world? We’d love to collect more insights on this, and we’re hoping for some motion toward consensus, in time for sotagliflozin and dapagliflozin to reach the type 1 diabetes market (yes, we’re still very hopeful). None of this is to say that these safety concerns of amputations and DKA are trivial – far from it. Rather, it would be a sad story to see clinically-meaningful benefits like time-in-range and weight loss overshadowed by a manageable safety concern, especially when there is such high unmet need in the type 1 population for adjunct therapy.

Symposium: Acarbose Cardiovascular Evaluation (ACE): Primary Results

Cardiovascular, Glycemic, and Renal Outcomes

John McMurray, MD (University of Glasgow, Scotland); Rury Holman, MD (Oxford University, UK)

Alpha-glucosidase inhibitor acarbose (Bayer’s Glucobay) did not meet any of its CV endpoints in the Acarbose Cardiovascular Evaluation (ACE) CVOT, but did, very excitingly, show an 18% risk reduction vs. placebo for the secondary endpoint of new-onset type 2 diabetes (HR=0.82, 95% CI: 0.71-0.94, p=0.005) in a Chinese population with prediabetes and a previous history of CV events (n=6,526). In this multi-center, double-blind, secondary prevention CVOT, participants were randomized 1:1 to 150 mg acarbose vs. placebo after a five-week run-in period for optimization of background CV therapy, and were followed for a median of five years. University of Glasgow’s Dr. John McMurray outlined the ACE trial’s CV outcomes, showing no benefit for acarbose vs. placebo in this high-risk prediabetes population. There was definitively no relative risk reduction for the primary outcome of five-point MACE (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or hospitalization for heart failure; HR=0.98, 95% CI: 0.86-1.11, p=0.73) or for any of the secondary outcomes, including three-point MACE (HR=0.95 ,95% CI: 0.81-1.11, p=0.51), all-cause death (HR=0.95, 95% CI: 0.81-1.19, p=0.85), CV death (HR=0.89, 95% CI: 0.71-1.11, p=0.29), fatal or non-fatal MI (HR=1.12, 95% CI: 0.87-1.46, p=0.38), fatal or non-fatal stroke (HR=0.97, 95% CI: 0.70-1.33, p=0.83), hospitalization for unstable angina (HR=1.02, 95% CI: 0.82-1.26, p=0.87), and hospitalization for heart failure (HR=0.89, 95% CI: 0.63-1.24, p=0.48). On the bright side, acarbose appeared to reduce risk for new-onset type 2 diabetes by 18% (p=0.005 vs. placebo), and trial chairman Dr. Rury Holman (Oxford University, UK) revealed that this positive finding was accompanied by other beneficial metabolic outcomes, 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). Full results were simultaneously published in the Lancet.

Commentator

Chantal Mathieu, MD (KU Leuven, Belgium)

Dr. Chantal Mathieu closed this symposium by providing an independent perspective on the ACE trial results, illustrating (literally) her opinion of the results with an image of a glass half full. Although acarbose did not achieve its primary endpoint on CV outcomes, Dr. Mathieu positioned the drug’s significant prevention of new-onset diabetes as an extremely important result – particularly given the rising tide of prediabetes globally, and especially in China where the trial was conducted. As Dr. Jean-Louis Chiasson (University of Montreal, Canada) contextualized earlier in the symposium, many expected this trial to meet its primary endpoint based on acarbose’s known beneficial effect on markers of CV risk and postprandial glucose (which is associated with worse CV endpoints), as well as the promising suggestion of cardioprotection for acarbose in a 2003 meta-analysis of the 1998 STOP-NIDDM trial, in which the drug was associated with a significant relative risk reduction in the incidence of MI (HR=0.09, 95% CI: 0.01-0.72, p=0.03) and all CV events (HR=0.51, 95% CI: 0.28-0.95, p=0.03) in comparison to placebo in a majority white population with prediabetes and no CV history. Given all this, to the question of why ACE did not reach superiority, Dr. Mathieu’s answer was a resounding “I have no clue.” However, she did propose a variety of potential hypotheses to explain this underwhelming result: (i) the 150 mg dose range used in the trial doesn’t impact CV outcomes; (ii) acarbose’s primary effect on postprandial glucose isn’t sufficient to make a difference on wider CV risk; and (iii) limited epidemiological understanding of the prediabetes population. She left us 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 drug’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 preventive 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’s impressive glycemic outcomes will spur greater use in North America and Europe, in the diabetes and prediabetes populations alike.

Symposium: Update on the REMOVAL Trial

New Analyses from the REMOVAL Trial

John Petrie, MD (University of Glasgow, Scotland); Helen Colhoun, MD (University of Edinburg, UK); Peter Rossing, MD (Steno Diabetes Center, Copenhagen, Denmark); Coen Stehouwer, MD (Maastricht University Medical Center, The Netherlands)

In an update on the JDRF-sponsored REMOVAL trial, Glasgow’s Professor John Petrie, Edinburgh’s Professor Helen Colhoun, and other investigators presented new microvascular and safety data, as well as new subgroup analyses based on sex and BMI. The original results were presented in a dedicated symposium at ADA 2017: Three years of metformin therapy in adults with type 1 diabetes (n=428) had no significant effect vs. placebo on the primary endpoint of mean carotid intima-media thickness (cIMT), although there was a significant protective effect on the tertiary endpoint of averaged maximal cIMT (p=0.0093). Both are common CV biomarkers, surrogate measures for CV disease risk. Dr. Colhoun shared new findings on sex and BMI, neither of which showed a significant interaction with metformin treatment on the primary endpoint. She did report a significant three-way interaction (p<0.05) for treatment, time, and sex on maximal cIMT, with a greater slowing of slope for maximal thickness occurring in females vs. males, but qualified that this is “by no means conclusive evidence.” Metformin’s impact on reducing insulin requirements was driven by people with BMI <30 kg/m2, with daily dose actually increasing slightly among participants with BMI >30 kg/m2 (p=0.0443 for treatment interaction). That said, the overall decrease in daily insulin dose in REMOVAL was only ~2 units/kg for metformin vs. placebo (p=0.0018), which is not necessarily clinically-meaningful. As Dr. Julio Rosenstock pointed out during the ADA REMOVAL symposium, “two units is absolutely nothing in terms of reduced insulin dose.” Moreover, Dr. Colhoun shared that the A1c-lowering benefit to metformin was greatest among patients with BMI >30 kg/m2 (p=0.0019 for this subgroup on its own), although once again there was no significant three-way interaction. She concluded that these subgroup analyses do not change the message of the main REMOVAL paper, published in Lancet Diabetes & Endocrinology, in that metformin was found to be safe on the whole without exhibiting dramatic cardioprotection. Dr. Colhoun suggested that the lack of a significant interaction based on BMI calls into question that current diabetes treatment guidelines recommend metformin as an adjunct type 1 therapy for patients with overweight/obesity. However, it’s important to note that these algorithms take into account metformin’s weight loss effects, which were confirmed in REMOVAL (2.6 lbs treatment difference, p<0.0001). In our view, it seems there would still be a very distinct benefit to metformin in this population with type 1 diabetes/high BMI because of the benefits to body weight alone, regardless of CV risk management. In fact, this discussion also came up at ADA, and Dr. Partha Kar suggested that REMOVAL actually underscores current practice trends, with metformin as a helpful adjunct tool in people with type 1 diabetes who would benefit from weight loss.

  • Dr. Peter Rossing discussed new post-hoc analyses that employed different calculations of kidney function, confirming the hint from original REMOVAL results that metformin may confer renal benefit. In the original presentation, the eGFR secondary endpoint showed a treatment difference of 4 ml/min/1.73m2 in favor of metformin after 36 months (p<0.0001), mostly driven by a sharp initial rise in eGFR during the first three months that was maintained until the end of the study period. Initially, eGFR was calculated using the MDRD equation, but this latest analysis describes eGFR in terms of the CKD-EPI equation, which is tailored specifically to diabetes. Based on serum creatinine levels, eGFR (via the CKD-EPI equation) was an average of 2.5 ml/min/1.73m2 higher in the metformin group vs. placebo (95% CI: 1.21-3.78, p=0.0002). This trend persisted when eGFR was calculated using CKD-EPI based on cystatin C rather than creatinine: Here eGFR was an average of 2.9 ml/min/1.73m2 higher in participants treated with metformin vs. placebo (95% CI: 0.65-5.10, p=0.011). Unlike creatinine, cystatin C is not influenced by body weight, suggesting that metformin’s apparent ability to improve eGFR is a consequence of the drug’s direct action on the kidney, and not a mere byproduct of weight loss or a direct effect on tubular creatinine excretion. Moreover, progression to albuminuria tended to be slower in people treated with metformin: The drug showed a 37% reduction in time to onset of microalbuminuria (HR=0.63, 95% CI: 0.34-1.14), but this did not reach statistical significance (p=0.1275). With the assays and statistical analysis finalized just days ago, Dr. Rossing underscored that this is very preliminary data and that the findings cannot be “overstressed” until a more detailed analysis occurs based on rate of change in albuminuria excretion. That said, we are hopeful about the potential of a renal protective drug for the many people with type 1 diabetes at risk of kidney disease – no less one that is inexpensive, widely known, and widely available. Given the high cost of end-stage renal disease care and dialysis, even a moderately protective renal effect from metformin could have a substantial ROI. We keenly await the full analysis, which Dr. Rossing alluded will also include information on regression from albuminuria and rate of change in albuminuria excretion to provide a fuller picture of metformin’s effect on the kidney.
  • On safety, Dr. Coen Stehouwer reported a number needed to harm (NNH) of 13 for vitamin B12 deficiency (<150 pmol/L) from metformin use. This data from REMOVAL closely matches findings from the HOME study of metformin, further supporting that vitamin B12 monitoring is essential with long-term use of this agent. Indeed, the ADA’s 2017 Standards of Care calls attention to this need for B12 monitoring in the context of metformin therapy. Dr. Stehouwer underscored that the diabetes field has known for >50 years that metformin can induce vitamin B12 malabsorption, and Dr. Colhoun later chimed in that this safety issue should not be of enormous concern. There was a very slight decrease in hemoglobin levels seen in the REMOVAL trial (the key question here is “are the effects on B12 clinically-meaningful? Do they correlate with increased anemia risk?”), but according to Dr. Stehouwer, any risk of anemia is unlikely to be caused by B12 deficiency given a lack of effect on mean corpuscular volume (p=0.38). Further in-depth analysis into this topic is needed, and he assured that these more granular post-hocs will be done.
  • The panel emphasized how REMOVAL captures the need for more research into adjunct therapies for type 1 diabetes, and agreed that these results “will change practice, but exactly how has yet to be determined.” As Dr. Colhoun put it, conducting a large CVOT for metformin in type 1 diabetes was (and is) impractical, given the lack of industry investment behind a generic drug. That said, she urged pharmaceutical companies to focus more R&D on adjunct treatments in type 1 diabetes. The speakers also agreed that there’s a chance metformin may show greater benefits with longer-term use, or initiation earlier in the course of disease, perhaps in patients <18 years-old as opposed to adults with a mean 33 years diabetes duration as in REMOVAL. This is another practical challenge for pharmaceutical clinical research. Dr. Colhoun outlined other forthcoming pre-specified analyses that will be done on the REMOVAL primary cIMT endpoint: age, baseline cIMT, background CV disease, duration of diabetes, baseline A1c, smoking status, LDL levels, systolic blood pressure, insulin pump users (yes/no) – a list that looked like the rolling end credits after a movie. We so appreciate the commitment to gleaning as much insight as possible from this dataset, since it’s so true that the type 1 patient population is understudied and that there’s a lot we don’t understand about metformin. Having more definitive answers about metformin’s health effects, even if this study wasn’t entirely positive, is most valuable for the diabetes community.

Questions and Answers

Dr. Sanjoy Dutta (JDRF, New York, NY): Doing a study of this magnitude in type 1 diabetes is not easy, and the REMOVAL team (along with the CONCEPTT study team – that trial is being presented later at this meeting) is showing to the world that it is possible to do a large trial in type 1. Hopefully, pharma companies will take an opportunity to learn from this. After some time and additional analyses, will the panel (plus other investigators) put together some kind of guidance or learnings for how to successfully conduct a trial like this in such a non-abundant population? Can we write some kind of summary on this, offering tidbits that others can use to conduct large trials?

Dr. Petrie: It’s all about having a great team. There are always challenges, but if you have the right people, you can make it happen.

Dr. Colhoun: I agree with you – the pharma industry uses the excuse that it is difficult to run trials in type 1 as a reason for not examining drugs in this population. We need much greater ambition from them, and much greater support from that sector to realize insights.

Dr. Petrie: Trials with SGLT-2 inhibitors in type 1 diabetes, so far, have been run for six months or a year. These agents have potential, but we do need to see the effects on safety and complications in the long term. In my view, the regulators should need to see this also.

Dr. Dutta: Yes, that’s the point I was getting at – that it is, after all, quite possible to do a complications study. Another sidebar: How can we investigate in populations below 18 years of age? How do we design studies in adults that provide the necessary amount of safety information to go in populations <18, which in the context of type 1, is a critical population?

Dr. Hramiak: Keep in mind – this was a study of people who were survivors of type 1 diabetes. That point isn’t always emphasized enough in these presentations. If we are going to take your leadership from JDRF and translate that into studies that are practice-changing in the care of patients with type 1 diabetes, we have to start perhaps earlier than in our survivors, who in this case had a mean duration of diabetes of 33 years at study start. You’re right – maybe it has to start in teenagers. Those of us who look after patients with type 1, we see people struggle daily to achieve the level of control they need to prevent diabetes complications, and the tool we have in our hands are limited. Despite SGLT-2 and GLP-1 studies, we haven’t yet seen better than a 0.2% or 0.3% A1c-lowering effect. So, JDRF deserves some kudos, that they had the courage to do this trial with metformin. It will be practice-changing – we just don’t know how quickly, or in what direction.

Dr. Dutta: How does this change practice in type 1 diabetes care?

Dr. Petrie: I think in a sense, as chief investigator of a trial, you have a conflict of interest. You see the results through rose-tinted glasses, since you’ve worked on it for so long. In these people who have had type 1 for so many years, it’s quite tantalizing to see effects on the vascular wall, and it’s powerful that you see a reduction in weight and LDL (a potent biomarker for CV disease). This is only three years of their lives, even though they’ve had diabetes for so long and will have it for many more years after. What if they had been on metformin for longer? If we used statin therapy (the standard of care) more aggressively in this population, would this have more of an effect? Our participant pool used statins aggressively and we saw an effect.

Dr. Colhoun: An important question is whether or not we saw any dis-benefits to metformin. And, I think we can safely say no. We saw small effects on vitamin B12, but they are not of enormous magnitude. So that’s one thing, it’s useful to know. There’s no a priori reason, if you’re considering metformin as an adjunctive therapy in type 1, that you should limit it to people who have obesity. And we’ve learned that metformin is not a dramatic magic bullet for CV disease prevention. It may have accrued benefit over the long term, and some of the data collectively points that way, but would it compete as a cardioprotective agent against other diabetes drugs out there? The answer there is fairly clear: it wouldn’t. Where does that leave you therapeutically? Metformin is a safe drug. If you have a patient in front of you who is struggling to manage their glucose on insulin, it’s still worth giving metformin a try. Some patients will see weight loss and A1c reductions, and if your patient isn’t one of that group, you can always stop the drug. The results aren’t dramatic – rather, they’re more of a reassuring context for what you might consider for the individual patient with type 1 diabetes.

Dr. Dutta: How large does the evidence base have to be before we change our practice? Do we need a less detailed, larger RCT assessing outcomes? Is there observational data we can look back on?

Dr. Colhoun: I don’t think we have sufficiently unbiased observations to definitively answer this question. As for a CV prevention trial, it would certainly be worth trialing metformin in a factorial design. But as John and I know, to get a CV outcomes trial for a drug like metformin, which is off-patent, is nearly impossible.

Dr. Petrie: Right. We already wrote the protocol for a pragmatic trial – we just need the resources.

Oral Presentations: SGLT-2 Inhibitors: Clinical Utility

Safety and Efficacy of Ertugliflozin Compared to Glimepiride in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: The VERTIS SU Trial

Brett Lauring, MD (Merck, Kenilworth, NJ)

Merck’s Dr. Brett Lauring, subbing in for Dr. Patricia Hollander (Baylor, Dallas, TX), presented findings from VERTIS SU, a 52-week head-to-head trial of Merck/Pfizer’s SGLT-2 inhibitor candidate ertugliflozin vs. glimepiride (a sulfonylurea). Type 2 diabetes patients on a background of metformin therapy (≥1,500 mg/day) were randomized to treatment with a 5-mg daily tablet of ertugliflozin (n=448), with a 15-mg daily tablet of ertugliflozin (n=440), or with glimepiride that could be uptitrated to a maximum of 6 mg/day or 8 mg/day per local drug labels (n=437). In total, 1,326 participants completed a full year of treatment: 340 in the 5 mg ertugliflozin group, 357 in the 15 mg ertugliflozin group, and 348 in the sulfonylurea group. The higher dose SGLT-2 demonstrated non-inferiority vs. glimepiride on the primary endpoint of A1c-lowering – from a baseline 7.8%, mean A1c drop at the end of 52 weeks was 0.6% in the high-dose SGLT-2 arm vs. 0.7% in the SU arm, culminating in an A1c treatment difference of 0.1% (95% CI: 0.0-0.2). The criterion for non-inferiority was pre-defined as an upper bound of the 95% confidence interval <0.3, which wasn’t met by low-dose ertugliflozin (mean A1c drop of 0.6%, A1c treatment difference of 0.2%, 95% CI: 0.1-0.3). While we would not have expected to see non-inferior A1c reductions for the ertugliflozin doses (many clinicians have told us that the A1c lowering with SFUs is said to be very good for awhile and then falls off significantly – beta cell burnout to follow is expected), we did expect positive data on body weight, blood pressure, and adverse events and indeed, that’s what we saw in VERTIS SU. From a baseline ~192 lbs, body weight decreased by a mean ~8 lbs for patients on 15 mg ertugliflozin and by ~7 lbs for patients on 5 mg ertugliflozin, whereas participants taking glimepiride experienced 2 lbs weight gain on average (p<0.001 for both comparisons). This was unsurprising – weight gain is one of the commonly-cited disadvantages to sulfonylureas, while SGLT-2 inhibitors are known to promote weight loss – but still important to show differences on this key outcome beyond A1c (one that matters so much to patients) in a head-to-head clinical trial. Systolic blood pressure declined from a baseline ~130 mmHg by 4 mmHg and 2 mmHg in the 15 mg and 5 mg ertugliflozin arms, respectively, increasing by 1 mmHg over 52 weeks in the glimepiride group (p<0.001 for both comparisons). While adverse events on the whole were well-balanced across all three treatment arms, symptomatic hypoglycemia was significantly more common in patients on glimepiride (19%) vs. 15 mg ertugliflozin (5%, p<0.001 vs. SU) or 5 mg ertugliflozin (3%, p<0.001 vs. SU). Again, this is the result we would have expected given the well-known high hypoglycemia risk associated with sulfonylureas, but is still enormously valuable to see from a head-to-head clinical trial. Given that cost is the main line of defense for sulfonylureas currently (keeping these agents in diabetes treatment algorithms despite these side-effects, plus beta burnout and possible CV harm with longer-term exposure), we’d hope the increase in weight gain and especially hypoglycemia would sway payers toward newer, safer, better diabetes drugs – the cost of hypoglycemia-related hospital admissions is extremely high ($7 billion in claims in 2015 according to Truven data). Of course, regulators and payers are compelled by empirical evidence, and to this end, head-to-head studies against sulfonylureas (including VERTIS SU) are immensely important. The real prize may be in head-to-head outcomes trials, and for this we eagerly await results from CAROLINA, Lilly/BI’s CVOT comparing DPP-4 inhibitor Tradjenta (linagliptin) vs. glimepiride, expected to complete in March 2019.

  • For context, prior studies have shown canagliflozin (J&J’s SGLT-2 inhibitor Invokana) to offer superior A1c-lowering efficacy vs. glimepiride after one year and empagliflozin (Lilly/BI’s SGLT-2 inhibitor Jardiance) to offer superior A1c reductions vs. glimepiride after two years. Differences in trial design prevent us from deriving any meaningful conclusions from this regarding ertugliflozin’s differential benefits compared to other SGLT-2 agents already on the market, but we’ll be curious to learn more (especially from real-world data) on how the advanced SGLT-2 inhibitor class compares to sulfonylureas on A1c and outcomes beyond (including hypoglycemia episodes and CV events). Merck/Pfizer have filed ertugliflozin with the FDA and EMA (alongside fixed-dose combinations of ertugliflozin/metformin and ertugliflozin/ sitagliptin), and the companies are expecting regulatory decisions on all three products by year end.

Questions and Answers

Q: Did you see any signal for amputations?

Dr. Lauring: There were two in the trial, one occurring in the glimepiride group and one in the 15 mg ertugliflozin group. Both were toe amputations, in patients who had several baseline risk factors such as smoking, neuropathy, and peripheral arterial disease.

Q: For most of the 52-week period, it appears that glimepiride is actually superior on A1c. Should we not instead be using area under the curve to analyze this dataset?

Dr. Lauring: That’s a fair point. We have looked at the data that way, but I think a lot of practitioners are interested in what’s going to happen over time. (Editor’s note – we always have widely heard from clincians that SFU impact on A1c is very positive at the start and then “wears off” – we’d love to see longer-term data because this superiority sounds like it is not sustained but gets considerably worse in many cases).

Q: You say serious adverse events were uncommon – what were they, and were they more common with the low dose or the high dose?

Dr. Lauring: There was no particular pattern to serious AEs. They didn’t cluster into one disease area or biology of disease. We look at dozens of safety-related endpoints across lots of trials, and sometimes the 5 mg dose has more and sometimes the 15 mg dose has more, which is not surprising because both doses are near the top of the dose-response curve.

Q: What was the incidence of DKA?

Dr. Lauring: There was one case in the 15 mg ertugliflozin group. If I remember correctly, the patient had an episode of sepsis preceding DKA.

Dr. Chantal Mathieu: Your study nicely demonstrates that in people with A1c of 7.8%, if you hit them with an SU, you can really bring down A1c even though you have a price to pay in hypoglycemia. Did you adjudicate hypoglycemia? It also looks like you had two annoying severe hypoglycemia events in the ertugliflozin groups.

Dr. Lauring: There was general education around hypoglycemia, people were supplied with a meter and told how to record their symptoms. Keep in mind that when severe hypoglycemia is defined as requiring assistance, someone bringing you juice would then be defined as severe hypoglycemia, and it’s hard to get that number down to zero in a trial of ~1,300 patients, with ~440 per arm.

Empagliflozin (EMPA) Reduces Mortality in Analyses Adjusted for Control of Blood Pressure (BP), Low Density Lipoprotein Cholesterol (LDL-C) and HbA1c Over Time

David Fitchett, MD (University of Toronto, Canada)

Dr. David Fitchett presented a new analysis of EMPA-REG OUTCOME, demonstrating that empagliflozin’s significant risk reduction for CV and all-cause death was not driven by the SGLT-2 inhibitor’s beneficial effect on CV risk factors such as blood pressure, LDL cholesterol, and A1c. The hazard ratio of 0.62 for CV death in the trial’s primary analysis (corresponding to a 38% relative risk reduction) did not substantially change when adjusting for empagliflozin’s effect of reducing blood pressure (HR=0.61), LDL cholesterol (HR=0.59), A1c (HR=0.62), or all three of these CV risk factors together (HR=0.61). The same was true for the hazard ratio of 0.68 for all-cause mortality with empagliflozin (reflecting 32% relative risk reduction), which was essentially unchanged after adjustment for empagliflozin’s reductions in blood pressure (HR=0.67), LDL cholesterol (HR=0.66), A1c (HR=0.67), and all three together (HR=0.67).

  • Two years after the original presentation of the EMPA-REG OUTCOME results at EASD 2015 in Stockholm, the mechanism underlying empagliflozin’s famed cardioprotective effect remains unclear, though the notion of an overarching atherosclerotic effect (the hypothesized mechanism for GLP-1 agonists liraglutide and semaglutide based on LEADER and SUSTAIN 6 data) has been widely ruled out due to early rather than gradual divergence of Kaplan-Meir curves. At ADA 2016, Dr. Silvio Inzucchi presented a univariate mediation analysis of EMPA-REG OUTCOME, which attributed 52% of empagliflozin’s cardioprotection to volume contraction, as reflected by an increase in hematocrit. The same analysis attributed 24% to decreased uric acid concentration and only 3% to between-group A1c differences. At EASD 2016, we learned from Dr. Bernard Zinman that a multivariate analysis is underway – while a more complicated method to be sure, the multivariate analysis could offer more compelling information on empagliflozin’s CV mechanisms. Still, we recognize that it may be quite a while before we have a consensus around mechanism, and we underscore that we don’t think it’s crucial to understand mechanism before prescribing a drug for cardioprotection (particularly now that Jardiance has a CV indication on its label). As Dr. Juris Meier articulated at last year’s EASD congress, “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.”

Time to Next Therapy for Patients with Type 2 Diabetes in the UK: Canagliflozin Compared with Other Anti-Hyperglycemic Agents

Gill Hamilton, MD (Janssen, London, UK)

Kicking-off a series of oral presentations on the clinical utility of SGLT-2 inhibitors, Janssen’s Dr. Gill Hamilton shared findings from a retrospective cohort study conducted in the UK on time to next therapy for patients on Invokana (canagliflozin) vs. other diabetes drugs (including GLP-1 agonists, DPP-4 inhibitors, and other SGLT-2 inhibitors). Using the UK’s Clinical Practice Research Datalink, a sample of 46,349 patients who initiated a drug from one of these three classes between 2012-2015 was collected and analyzed for time to next therapy, including both add-on to existing regimen and switching to a new agent. Time to next therapy was significantly longer with canagliflozin vs. all DPP-4 inhibitors: Compared to sitagliptin (Merck’s Januvia), the hazard ratio was 1.43 (p<0.001), while these hazard ratios were even higher in comparison to saxagliptin (AZ’s Onglyza) and linagliptin (Lilly/BI’s Tradjenta), at 1.76 and 1.57, respectively (p<0.001 for both comparisons). J&J’s canagliflozin also showed significantly longer time to next therapy vs. AZ’s GLP-1 agonists Byetta (exenatide twice-daily) and Bydureon (exenatide once-weekly), with hazard ratios of 1.84 and 1.44, respectively (p<0.001 for both comparisons). The hazard ratio for time to next therapy was 1.43 in favor of canagliflozin vs. liraglutide (Novo Nordisk’s GLP-1 agonist Victoza) and was 2.46 in favor of canagliflozin vs. lixisenatide (Sanofi’s GLP-1 agonist Adlyxin, both p<0.001). Invokana did not show a statistically significant delay in next therapy when compared to in-class competitors, AZ’s Farxiga (dapagliflozin) and Lilly/BI’s Jardiance (empagliflozin). Dr. Hamilton shared that time to insulin therapy initiation was significantly longer with canagliflozin vs. linagliptin, short-acting exenatide, liraglutide, lixisenatide, and empagliflozin, but not for sitagliptin, saxagliptin, long-acting exenatide, or dapagliflozin. The real-world nature of this study limits definitive conclusions to some degree, but we found the suggestion notable that patients may benefit from canagliflozin (among other SGLT-2 inhibitors) in the sense of lower need for intensification with other agents, which adds treatment complexity, cost/co-pays, and may signify worsening glycemic control.

Oral Presentations: SGLT-2 Inhibitors: New Opportunities

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

Dr. Silvio Inzucchi, a highly-respected voice on CVOTs, presented a new post-hoc analysis of the EMPA-REG OUTCOME trial assessing empagliflozin’s (Lilly/BI’s SGLT-2 inhibitor Jardiance) effect on a variety of heart failure-related composite outcomes. Compared to placebo, empagliflozin had a consistent beneficial effect on each of these composites, demonstrating a 34% risk reduction for hospitalization for heart failure/CV death (HR=0.66, 95% CI: 0.55-0.79, p<0.0001), a 38% risk reduction for hospitalization for heart failure/death due to heart failure (HR=0.62, 95% CI: 0.48-0.80, p=0.0002), a 37% risk reduction for hospitalization for heart failure/death due to heart failure/sudden death (HR=0.63, 95% CI: 0.51-0.79, p<0.0001), and a 35% risk reduction for hospitalization for heart failure/death due to heart failure/sudden death/presumed CV death (HR=0.65, 95% CI: 0.53-0.78, p<0.0001). Dr. Inzucchi pointed out that these risk reductions are similar to the famed 38% risk reduction for CV death from the EMPA-REG OUTCOME primary analysis, though he was careful to note that as a post-hoc analysis this should be interpreted with caution. We are eager to see direct data on empagliflozin in heart failure from the ongoing EMPEROR HF outcomes trials, initiated this year to evaluate the SGLT-2 inhibitor in people with heart failure with and without diabetes.

Oral Presentations: The Failing Heart in Type 2 Diabetes

Dapagliflozin is Associated with Lower Risk of Major Adverse Cardiovascular Events Compared to DPP-4 Inhibitors in Type 2 Diabetes Patients: Results from CVD-REAL Nordic

Anna Norhammar, MD (Karolinska Institute, Stockholm, Sweden)

Just weeks after presenting late-breaking data from CVD-REAL at ESC 2017, Dr. Anna Norhammar took the EASD stage to discuss a sub-analysis of participants starting new treatment with AZ’s SGLT-2 inhibitor Farxiga (n=6,362) or with any DPP-4 inhibitor (n=19,086). Farxiga (dapagliflozin) was associated with 30% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, CV death) vs. DPP-4 inhibitor therapy (HR=0.70, 95% CI: 0.55-0.89, p=0.004). Turning to the individual components of MACE, Dr. Norhammar reported non-significant hazard ratios still favoring dapagliflozin over DPP-4 agents: 0.75 for non-fatal MI (95% CI: 0.53-1.06, p=0.102), 0.8 for non-fatal stroke (95% CI: 0.56-1.15, p=0.222), and 0.74 for CV death (95% CI: 0.44-1.23, p=0.24s1). This analysis pulled data from national registries in Sweden and Norway, while the CVD-REAL dataset as a whole covers six countries (also the US, UK, Denmark, and Germany). The initial results from CVD-REAL, comparing all SGLT-2 inhibitors vs. other glucose-lowering drugs (DPP-4, insulin, GLP-1 agonists, etc.) were presented at ACC 2017, and the SGLT-2 class was associated with 39% relative risk reduction for heart failure hospitalization (p<0.001) and with 51% relative risk reduction for all-cause mortality (p<0.001). This more detailed look at Farxiga vs. DPP-4 inhibitors, specifically, bodes well for AZ’s DECLARE CVOT (dapagliflozin vs. placebo), expected to complete in 2H18. Only time will tell, of course; it would certainly be positive for the class and field if this third SGLT-2 CVOT results bolster the notion of a cardioprotective class effect here.

Total Events of Hospitalization for Heart Failure in New Users of SGLT-2 Inhibitors: Real-World Data From 5 Countries and More Than 298,000 Patients: The CVD-REAL Study

Mikhail Kosiborod, MD (University of Missouri, Kansas City, MO)

Dr. Mikhail Kosiborod presented real-world data on the effect of SGLT-2 inhibitors on total events of hospitalization for heart failure. This compared to the primary presentation from CVD-REAL (also by Dr. Kosiborod, at ACC 2017), which focused on time-to-first-event analysis, rather than total events. This form of analysis yielded results that looked just as good. Real-world SGLT-2 inhibitor use led to a significant 45% reduction in total heart failure hospitalizations vs. other glucose-lowering drugs (p<0.001). The reduction did not depend on whether participants had a prior heart failure hospitalization before the trial. While we’ve heard some doubt about the likelihood of a true 30%-50% reduction (all observational research comes with certain limitations), the CVD-REAL results support the findings from CVOTs that the exciting new SGLT-2 inhibitor class has powerful CV disease-lowering effects. Although some countries from the CVD-REAL study were not included in this particular analysis, the results from this analysis did not appear to vary greatly between the countries that were included.

Questions and Answers

Q: I’m wondering if increased initiation of drugs like insulin in the comparator group may be implicated in increased rates of heart failure?

A: In the main paper, we did a sensitivity analysis by excluding comparator agents that could be implicated in increasing the risk of heart failure – like insulin, TZDs, and DPP-4 inhibitors. We sequentially took those out of the comparator group and it didn’t make any difference.

Q: What was the average time between the onset of medication and onset of heart failure in patients without previous episodes of heart failure?

A: The average duration of follow-up in this study was roughly nine months. If you look at clinical trial data on SGLT-2 inhibitors, the benefit for heart failure hospitalization emerges extremely early – within a few weeks of randomization.

Oral Presentations: Incretins: New Clinical Evidence

Time to Insulin in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)

Sam Engel, MD (Merck, Kenilworth, NJ)

EASD orals kicked-off with a new post-hoc analysis of Merck’s TECOS trial for DPP-4 inhibitor Januvia (sitagliptin), presented by Dr. Sam Engel. When added onto a background of metformin monotherapy (n=4,435) or metformin/sulfonylurea dual therapy (n=5,152), sitagliptin treatment significantly delayed insulin initiation for type 2 diabetes patients. Among CVOT participants only on metformin at baseline, the incidence of insulin initiation (defined as continuous use over at least three months) was 5.5% in the placebo arm vs. 3.8% in the DPP-4 arm over a median three years follow-up, which corresponds to a hazard ratio of 0.67 in favor of sitagliptin (95% CI: 0.51-0.89). Among patients on both metformin and a sulfonylurea at baseline, the incidence of insulin initiation was 20.4% in the placebo arm vs. 14% in the DPP-4 arm (HR=0.64, 95% CI: 0.56-0.73). Among those on baseline sulfonylurea monotherapy, a higher proportion started insulin treatment anew in the placebo arm (11.3%) vs. the DPP-4 arm (10.7%), corresponding to a hazard ratio of 0.96 in favor of sitagliptin (95% CI: 0.68-1.34), though this did not reach statistical significance since the upper bound of the 95% confidence interval is >1. Dr. Engel reviewed earlier findings showing Januvia’s association with a decreased likelihood of new insulin therapy start across the entire TECOS trial (542 patients on placebo vs. 744 patients on sitagliptin, p<0.0001). The more granular data he discussed today supports that Januvia can effectively delay the need for insulin in people with type 2 diabetes, which is not at all trivial – DPP-4 inhibitors are weight neutral where insulin promotes weight gain, they come with lower hypoglycemia risk compared to insulin, and they offer enhanced quality of life vs. insulin due to the weight neutrality, lower hypo risk, and reduced injection burden. 

Oral Presentations: Metformin – Oldie but Goodie

Delayed-Release Metformin Targeting the Lower Bowel Elicits Sustained Improvements in HbA1c and Fasting Glucose with Minimal Systemic Exposure

Juan Frias, MD (National Research Institute, Los Angeles, CA)

Dr. Juan Frias presented full results from a phase 2b study of Elcelyx’s Metformin Delayed Release (DR). These findings have been highly-anticipated since topline data from the study (n=542) was announced in November 2016 (also the subject of a late-breaking abstract at ADA 2017). After 16 weeks of treatment and from a baseline A1c of 8.6%, type 2 diabetes patients randomized to the highest tested dose of Metformin DR (1,500 mg) experienced a mean A1c reduction of 0.62% vs. a ~1.1% reduction with the comparator dose of metformin immediate release (IR) 2,000 mg (p<0.05). Fasting glucose reduction with Metformin DR was >75% of that observed with Metformin IR. PK analysis found that Metformin DR caused substantially lower plasma exposure (~1/3), as intended (this therapy candidate acts on the gut with an aim toward less systemic exposure than regular metformin immediate release or extended release). Taking into account the efficacy and exposure results, Dr. Frias reported that the glycemic improvement per amount of systemic drug exposure was actually higher with Metformin DR than with metformin IR. The safety/tolerability profile was superb, with clinically-meaningful and statistically significant ~50% reductions in GI adverse events vs. standard metformin IR 2,000 mg daily.

  • Elcelyx may pursue a targeted phase 3 program for Metformin DR in patients with type 2 diabetes and chronic kidney disease (CKD) stages 3B and 4 – in which metformin is currently restricted or contraindicated. This would be a letdown for the broader population that could benefit from the apparent GI tolerability benefit (if covered by payers), but isn’t entirely surprising in the challenging current regulatory and commercial climate for new diabetes drugs. In light of the modest efficacy but excellent tolerability and low systemic exposure in this study, Elcelyx is likely to test higher doses of Metformin DR in phase 3 than were tested in phase 2. The company de-risked this approach by conducting a pharmacokinetic (PK) study with population PK modeling (see below) showing that Metformin DR up to 2,100 mg daily should be safe in CKD stages 3B/4.

Questions and Answers

Q: We know metformin has some beneficial effects when in systemic circulation. What happens to those with metformin DR?

A: I’m not sure I have an answer for that, but it’s something to be considered.

Q: You focus on systemic exposure, but can you speculate about the mechanisms behind the differences between DR and IR metformin with regard to GI side-effects? Metformin has been shown to inhibit bile acid transporters, so the result may be spillover of bile acids into the colon. Did you measure bile acids?

A: I don’t think bile acids were measured. As far as the mechanism of the reduced GI side-effects, that was not assessed. Some of the difference may be due to difference in the systemic exposure.

Q: Normally we advise patients to take regular metformin with main meals. What is the recommended dosing for metformin DR?

A: The drug was taken with meals, once-daily in the morning. In this study, metformin IR was given twice-daily with meals, as is recommended.

Metformin Exposure with Gut-Restricted Delayed-Release Metformin in CKD Stage 4 Does Not Exceed That Of Current Metformin Used On-Label: Results From Population PK Modeling

Mark Fineman, PhD (Elcelyx Therapeutics, San Diego, CA)

A major takeaway from the modest efficacy but good tolerability observed with Elcelyx’s gut-restricted metformin DR (see above) was that higher doses could be considered for phase 3. To de-risk the testing of higher doses than were tested in phase 2b, Elcelyx conducted a population PK modeling study to see if serum exposure of metformin DR doses up to 2,100 mg would exceed already-approved levels of regular metformin IR in stage 2 or 3A chronic kidney disease (CKD). The model drew on data from metformin DR’s clinical program and other sources, and found that the 2,100 mg metformin DR dose would not be expected to cause greater serum drug levels than metformin IR 2,000 mg in CKD stage 2 or metformin IR 1,000 mg in CKD stage 3a. A simulated 2,400 mg metformin DR did not pass the test. A secondary simulation of what would happen in the case of acute kidney failure suggested that serum metformin levels would rise much more slowly with metformin DR 2,100 mg than with metformin IR. Elcelyx’s Dr. Mark Fineman, who presented the results, concluded that doses of metformin DR up to 2,100 mg daily would be justified for phase 3 study in patients with CKD stages 3B/4.

  • There is some risk inherently involved in testing doses of a drug in phase 3 that are higher than were tested in phase 2. We are modestly reassured by the fact that this is a new formulation of a well-understood drug, and Elcelyx has done a lot of work to characterize the PK profile and systemic exposure of the new formulation.

Questions and Answers

Q: It seems to me that the 2,100 mg dose is the safest DR dose. The slides presented previously showed that there was less effect with the 1,500 mg DR dose compared with 2,000 mg of metformin IR. Do you have a comparison of efficacy with the 2,100 mg DR dose to see if the efficacy benefit is similar?

A: Not as of yet. The results of the study presented in the last talk indicate that the 1,500 mg dose of metformin delayed release (DR) had less glucose-lowering effect than metformin immediate release 2,000 mg. This was just a PK modeling study to make sure that higher concentrations would be safe and justifiable to study.

Q: It’s well known that metformin has many advantageous effects independent of its glucose-lowering effect, such as anti-inflammatory effects. Is it known whether metformin DR will also have these effects?

A: We don’t have specific data on other potential effects of this metformin formulation other than gut-mediated glucose-lowering. That said, the main goal would be to use this formulation in patients in which too-high systemic concentrations are a risk. As we move into studies on CKD phase 3B/4, we expect gut exposure along the lines of what we have seen and systemic exposure that is not higher than what is seen in non-renally-impaired patients with metformin IR, but not zero. So if there are effects of metformin that are systemic and non-glycemic, this formulation may still address those as well.

Q: It’s nice that you can use metformin DR safely in these patients, but it also has to work in these patients. Based on the results presented previously, the fasting plasma glucose effect was smaller than expected. Have you explored the effect of this formulation on postprandial glucose measures?

A: We have done 24-hour glucose profiles earlier on after just a few days of dosing. The general pattern was that the postprandial effect appeared to be lower. We can’t tease out if there is a loss of postprandial glucose effect because we bypass the jejunum with the way the drug is formulated, or because the systemic exposure is lower.

Q: Have you looked at lactate levels with metformin DR?

A: Typically, lactate levels have not gone up very high in the studies we’ve done to-date, either with single or chronic dosing. With either DR or IR metformin, we’re not getting to high enough serum concentrations that would elicit the high lactate response. That said, in single-dose studies in various stages of renal impairment, we see small differentials between DR and IR/XR metformin, with a very strong correlation between plasma exposure and lactate response.

Metformin Potentiates Bile Acid-Induced GLP-1 Secretion in Patients with Type 2 Diabetes

Andreas Brønden, MD (Gentofte Hospital, Hellerup, Denmark)

With all the excitement about new formulations of metformin or the drug’s potential in preventing diabetes, it can be easy to forget that we know relatively little about how the drug works. Dr. Andreas Brønden presented results from a double-blind randomized crossover study (n=15) in type 2 diabetes, suggesting that metformin potentiates intestinal bile acids’ effect of stimulating GLP-1 secretion. Interestingly, metformin alone –without bile acids present – didn’t seem to have an effect on GLP-1 secretion. Past evidence suggests that bile acid receptors on L cells play a role in the induction of GLP-1, and Dr. Brønden’s results were consistent with these findings. Questions remain over whether metformin is changing the circulation of bile acids, whether it is impacting the sensitivity of L cells to bile acids, or whether it is doing something else entirely. Interestingly, although GLP-1 levels were increased by metformin following stimulated bile acid secretion, there was no change in insulin or glucagon. Full results were published in JCEM last month.

The Effect of Metformin on a Healthy Human Gut Microbiota

Trine Nielsen, MD (Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark)

A major article published in Nature a few months ago demonstrated that metformin induces changes in the composition of the gut microbiome in individuals with type 2 diabetes, contributing to the glucose-lowering effectiveness of the drug. This study presented at EASD by Dr. Trine Nielsen demonstrated that metformin can alter the gut microbiome in patients without diabetes. The drug meaningfully and reversibly altered levels of various types of bacteria in the gut. The therapeutic relevance is not immediately clear, but if (i) metformin acts in part by impacting the microbiome, and (ii) the effect on the microbiome isn’t limited to people with diabetes, then it’s very possible that the magic of metformin could apply to individuals without diabetes – especially prediabetes. 

Questions and Answers

Q: What is the presumed mechanism here?

A: Other studies have shown that when you give metformin in vitro, it inhibits the growth of some types of bacteria, and can cause changes in gene function. Changes in the microbiota could impact glucose tolerance through production of short chain fatty acids or maybe via GLP-1.

Oral Presentations: What Can We Learn from Animal and In Vivo Models of Cardiorenal Complications?

Empagliflozin, an SGLT2 Inhibitor, Improves Survival After Myocardial Infarction in Diabetic Rats by Up-Regulating Anti-Oxidative Stress Proteins

Hiroto Oshima, MD (Sapporo Medical University, Japan)

Is there a silver lining to the increase in ketones observed with SGLT-2 inhibitors? A research group from Sapporo suggested yes, based on evidence from a rodent study of Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin). In rat models of diabesity, higher ketone levels stimulated from empagliflozin treatment may provide a more efficient fuel source for the ailing heart after a heart attack, improving post-MI survival. In addition to serving as a better fuel source, the ketones appear to stimulate production of protective antioxidant proteins. The end effect was an improvement in 48-hour survival from 40% without empagliflozin to 70% with it. These findings could explain some of the improvement in CV outcomes – specifically CV death – seen in EMPA-REG OUTCOME. As with all animal studies, much more work needs to be done to prove this hypothesis, but it’s good to see progress being made towards exposing the mechanisms underlying empagliflozin’s cardioprotective effects. Moreover, we’re intrigued by ketone-based hypotheses since ketones have been a thorn in SGLT-2 inhibitors’ side from some perspectives since the specter of euglycemic ketoacidosis arose. From our view, this is such an incredibly important class that the field should focus more on reducing DKA risk and then treating it as well as possible – there’s a long way to go since so many patients are unaware of the risk, do not have ketone meters, and are not aware of healthy levels.

Questions and Answers

Q: From your perspective, which is more important, the energy hypothesis or the antioxidant hypothesis?

A: We think both are important.

Q: Did you have a chance to look at ER stress proteins?

A: No we did not in this study, but it is something we would like to do in the future.

Q: When you infused ketones, did you measure the blood pH and whether it changed?

A: We did a blood gas analysis and the pH did not change in this study.

Corporate Symposium: Precision Medicine for Type 2 Diabetes (Sponsored by AZ)

Early, Durable, Tailored Glycemic Control: Where Are We Now?

Angelo Avogaro, MD (University of Padova, Italy)

Dr. Angelo Avogaro’s main recommendations in this presentation were to (i) intensify glucose-lowering therapy early, and to (ii) strongly consider SGLT-2 inhibitors to do so. Dr. Avogaro made a strong case that SGLT-2 inhibitors are the treatment of choice for durable glycemic control starting early in the course of disease, citing lots of data on AZ’s Farxiga (dapagliflozin) – including CV risk reduction along a broad spectrum of baseline risk. All in all, Dr. Avogaro appeared fully supportive of the SGLT-2 inhibitors recent rise in favor, thanks in large part to excellent outcomes data from EMPA-REG OUTCOME and the CANVAS program, plus real-world data from CVD-REAL

  • Dr. Avogaro recommended GLP-1 agonists as a particularly effective way to intensify treatment in patients on an SGLT-2 inhibitor. He cited results from the DURATION-8 study showing that Farxiga (dapagliflozin) + Bydureon (exenatide once-weekly) was more efficacious with regard to A1c-lowering than either drug independently.
  • Audience response question: “What is the most important factor that you consider when choosing the first add-on to metformin?”
    • Potential cardiovascular benefits: 39%
    • Risk of hypoglycemia: 29%
    • Weight gain: 11%
    • Risk of non-hypoglycemia adverse events: 10%
    • Other: 9%
    • Potential renal benefits: 3%

Glucose-Lowering, Potential Cardiovascular Benefits: What’s Next in SGLT-2 Inhibition?

John McMurray, MD (University of Glasgow, UK)

UK cardiologist Dr. John McMurray began his heart failure-focused presentation guns blazing in defense of the FDA’s 2008 CV guidance for diabetes drugs: “In cardiology you usually need multiple outcomes trials for a drug, but the cupboard was bare in diabetes … Why weren’t these trials done earlier?” Echoing sentiments we’ve heard many times from cardiologists, he expressed dismay that heart failure was not part of the primary outcome assessed in CVOTs. He went so far as to say that heart failure is “without a doubt the most deadly complication of diabetes.” Focusing in on EMPA-REG OUTCOME, he noted that “he [could] think of very few studies in my lifetime that have created such surprise and amazement across different disciplines.” He noted that the heart failure benefit in the study emerged too early to be an affect of glucose reductions, so it was probably empagliflozin’s diuretic effect at work. He concluded with a CV rationale for combining SGLT-2 inhibitors and GLP-1 agonists, as the former drug class has the most benefit for heart failure (also renal dysfunction) whereas the latter drug class appears to work more on atherosclerosis – two complementary aspects of the CV disease picture (differential CV effects of SGLT-2 vs. GLP-1 also comprised a major theme at this year’s annual ESC congress).

Can the Mechanism of Action Become the Mechanism of Protection: Focus on the Kidney?

Hiddo Heerspink, PhD (University Medical Center, Groningen, Netherlands)

Dr. Hiddo Heerspink reviewed the current thinking on mechanism of action underlying SGLT-2 inhibitor therapy and renal protection. To-date, all reported CVOTs of an SGLT-2 inhibitor have shown evidence of renal protective effects: This includes a 39% relative risk reduction for diabetic nephropathy seen in the EMPA-REG OUTCOME trial of Lilly/BI’s empagliflozin, as well as a 40% risk reduction for the composite renal outcome (renal death, renal replacement therapy, or 40% reduction in eGFR) in the CANVAS trial of J&J’s canagliflozin. Still, as Dr. Heerspink pointed out, the precise mechanism underlying this beneficial effect remains a mystery. At present, there are three main (not mutually exclusive) hypotheses: (i) restoring tubuloglomerular feedback, (ii) restoring tubular hypoxia, and (iii) lowering glucotoxicity. The tubuloglomerular feedback hypothesis comes from evidence that SGLT-2 inhibitor treatment prevents the increase in levels of KIM-1, LFABP, and NGAL, well-known markers of subclinical tubular injury. The hypothesis regarding restoration of tubular hypoxia originates from evidence that dapagliflozin increases serum erythropoietin, reversing the phenomenon in diabetic kidney disease (DKD) whereby excessive glucose reabsorption in the kidney renders renal fibroblasts dysfunctional, producing a decrease in erythropoietin. Finally, the glucotoxicity-lowering hypothesis is based on the SGLT-2 inhibitor class’ well-known glucose-lowering effect (via urinary excretion).

  • Dr. Heerspink unveiled, to our surprise, that the mortality rate of patients with comorbid diabetes and kidney disease is higher than the average mortality rate of all cancers (55% vs. 50% 10-year cumulative incidence, respectively), a powerful illustration of the need for not only more DKD therapies but also a much greater focus on renal-protection.  No new DKD indications have been approved in the past 17 years, the most recent being irbesartan and losartan in 2000. SGLT-2 inhibitors represent a promising and long-awaited option. To this end, all three SGLT-2 inhibitors on the market have a dedicated renal outcomes trial either planned or ongoing: the CREDENCE trial for J&J’s canagliflozin (enrolling subjects with comorbid type 2 diabetes and CKD; completion expected June 2019), the Dapa-CKD trial for AZ’s dapagliflozin (enrolling subjects 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 subjects with CKD both with and without type 2 diabetes; timing not yet specified). Indeed, Dr. David Fitchett suggested at the recent ESC 2017 meeting in Barcelona 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.

The Evolving Safety Profile of SGLT2 Inhibitors: Knowledge Through Experience

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

Dr. Juris Meier offered new insights on the near-doubling of risk for lower limb amputations associated with SGLT-2 inhibitor canagliflozin (J&J’s Invokana) in CANVAS, describing potential impacts of SGLT-1 inhibition and of AMP-activated protein kinase. Dr. Meier noted that regulatory authorities have not viewed canagliflozin’s amputation signal as a class effect: While the EMA took a more conservative approach and recommended warnings be added to all SGLT-2 product labels, the labels for AZ’s Farxiga (dapagliflozin) and Lilly/BI’s Jardiance (empagliflozin) read, “It is unknown whether this constitutes a class effect.” The FDA issued a black box warning on all canagliflozin-containing medicines with the caveat that this “does not apply to dapagliflozin or other SGLT-2 inhibitors.” Dr. Meier summarized evidence to show the lack of an amputation signal in dapagliflozin or empagliflozin trials, contrasting this with a nonsignificant numerical imbalance in low-trauma bone fractures (HR=1.23 in favor of placebo, 95% CI: 0.99-1.52) and a near-doubling of lower-extremity amputations (HR=1.97, 95% CI: 1.41-2.75, p<0.001) in CANVAS. Naturally, this begs the question of what distinguishes the canagliflozin molecule from its in-class competitors, and Dr. Meier speculated. Canagliflozin has a longer half-life than the others, which keeps it circulating in the blood for an extended duration. J&J’s agent also has lower selectivity for the SGLT-2 receptor, since it also inhibits the SGLT-1 transporter abundantly expressed in endothelial cells, where it contributes to both glucose uptake and nitric oxide production. Thus, partial SGLT-1 inhibition may reduce endothelial nitric oxide synthase 3 (eNOS) activity and nitric oxide production in some blood vessels, hindering vasodilation and oxygen delivery to tissues. Moreover, in vitro studies have shown that canagliflozin, but not dapagliflozin or empagliflozin, induces AMP-activated protein kinase activity in human cells at concentrations measured in human plasma in clinical trials. While AMPK has positive effects, including the induction of lipid oxidation, it is also a negative regulator of osteoblastic and chondrogenic differentiation activation and has been shown to reduce cell proliferation and wound healing in vitro. While these explanations are, by Dr. Meier’s own admission, highly speculative, they do provide a mechanism that would hinder tissue healing and could conceivably lead to heightened amputation frequency with canagliflozin. While we continue to develop our understanding of SGLT-2 inhibitors as a class and as individual agents – adding to the immense learning we’ve done so far –  we appreciated Dr. Meier’s explanation on amputation signal grounded in basic science. We eagerly await results from DECLARE, AZ’s CVOT for Farxiga, expected to read out in 2H18, and from VERTIS CV, Merck/Pfizer’s CVOT for ertugliflozin, expected to complete in October 2019. These outcomes studies will shed more light on the SGLT-2 inhibitor class, hopefully building even more compelling evidence for a cardioprotective class effect while elucidating differential effects on lower limb amputations.

  • On this hypothesis, we have received some thought-provoking response. In particular, some KOLs pointed out that the SGLT-1 inhibiting effect of canagliflozin is about 1/2,000th of its SGLT-2 inhibiting effect, so this action may not be significant except perhaps in the gut where drug concentration is high before absorption – otherwise, canagliflozin would give a significant bump to urinary glucose excretion compared to other SGLT-2 inhibitors. There remains a lack of good data for empagliflozin and dapagliflozin on amputations, as EMPA-REG OUTCOME collected this data using a different process than CANVAS, and DECLARE is not expected to complete until the second half of 2018 (we’re not sure how amputations are being recorded in this latter, ongoing CVOT). Moreover, other thought leaders have mentioned that certain people have complete SGLT-1 deficiency (i.e. 100% inhibition), and are not known to have problems with amputations – though it is possible that risk factors associated with diabetes, including peripheral neuropathy, could play a crucial mediating role. 

Corporate Symposium: Individualized Diabetes Care Across the Ages – Keeping it Simple & Safe (Sponsored by Lilly/BI)

T2DM Disease Progression – Keeping an Eye on the Kidney

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

Dr. Per-Henrik Groop established links between renal impairment and CV risk, as well as renal impairment and hypoglycemia, advocating for an approach to diabetes management that focuses on the cardio-renal-glycemia triad. He spoke to the potential renal benefits of Lilly/BI’s DPP-4 inhibitor Tradjenta (linagliptin) and SGLT-2 inhibitor Jardiance (empagliflozin). 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%. Dr. Groop followed this slide with one on the ADVANCE trial showing a clear correlation between diabetic kidney disease (DKD) and frequency of CV events. He then shared data on 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. To sum up: “the more albumin that leaks into your urine, the more likely you are to experience a CV event.” Less well understood is the relationship between DKD and hypoglycemia, but Dr. Groop showed that this association undoubtedly exists. The incidence of severe hypoglycemia nearly doubles when chronic kidney disease (CKD) is added onto a diabetes diagnosis, and ~74% of sulfonylurea-induced severe hypoglycemia episodes occur in patients with reduced renal function. Dr. Groop suggested a couple mechanistic explanations for this renal/hypo link: (i) some insulin is excreted via the kidneys, so lower eGFR aligns with a higher amount of insulin left circulating in the blood, and (ii) there’s less compensatory glucogenesis from the kidneys (particularly overnight) with impaired renal function. On an optimistic note, Dr. Groop pointed to new diabetes drug classes – DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 agonists – that do not cause hypoglycemia and that may additionally offer cardio- and renal protection. We were so glad to hear this perspective on the importance of where glycemic control, CV risk mitigation, and kidney function intersect. How payers value improved outcomes is of course the question of the day. Diabetes management is moving, at an increasingly fast pace, toward an emphasis on outcomes rather than the biomarker of A1c, and it is beyond exciting that patients can now take medicine not just to lower blood glucose, but to prevent heart attacks, strokes, worsening kidney disease, and death. On CVOTs, Dr. Groop remarked: “We’re always asking for something extra in these outcomes trials. What else can this drug do for me?” In our view, this is exactly the right question to be asking as the bar continues to rise for diabetes therapies on outcomes beyond A1c.

  • While all DPP-4 inhibitors are safe in patients with renal impairment, Dr. Groop underscored that Tradjenta (linagliptin) is the only agent in this class that doesn’t have to be adjusted even with falling eGFR, as linagliptin is excreted via the gut instead of the kidneys. The 24-week MARLINA-T2D study, presented at ADA 2016 and published recently in Diabetes, Obesity and Metabolism, found a 6% decline in urine albumin to creatinine ratio (UACR) with linagliptin vs. placebo, though this did not reach statistical significance (p=0.1954). UACR decreased by a mean 10% on linagliptin vs. placebo for participants with baseline UACR <300 mg/gCr, and this finding neared statistical significance (p=0.059). While this data alone doesn’t support any renal protection associated with Tradjenta, Dr. Groop suggested that upcoming CARMELINA CVOT results will be more telling, since the kidney effects of linagliptin are believed to work via a longer-term, anti-fibrotic mechanism. According to ClinicalTrials.gov, CARMELINA is expected to complete in December 2017, and we’ll be eager to see the macrovascular and microvascular outcomes data next year.
  • Dr. Groop also touched upon the kidney benefits seen in EMPA-REG OUTCOME for SGLT-2 inhibitor Jardiance (empagliflozin), but encouraged everyone to “take two steps back” and keep in mind that this was not a dedicated investigation into renal outcomes. The good news is that Lilly/BI have a planned outcomes study for Jardiance specifically in people with CKD (with or without type 2 diabetes), which will reveal the full scale of empagliflozin’s renal effects. Interestingly, Dr. David Fitchett mentioned at ESC 2017 last month that diabetes patients with eGFR <60 ml/min/1.73m2 may actually reap the greatest benefits from SGLT-2 inhibitor treatment in terms of CV and renal risk reduction. The SGLT-2 class is poised to target all three aspects of the cardio-renal-glycemia triad, which we find extremely exciting, and we’re pleased to see continued investment from Lilly/BI to probe the full extent of these benefits (the companies have launched the EMPEROR HF program to investigate empagliflozin in heart failure as well). AZ also has ongoing studies of its SGLT-2 inhibitor Farxiga (dapagliflozin) in heart failure and CKD.

Corporate Symposium: Focus on the Future: Scientific and Clinical Understanding of Type 2 Diabetes and the Role of the Endocrinologist (Sponsored by MSD)

New Clinical Opportunities with DPP-4 Inhibitors for Patients with Type 2 Diabetes

Lawrence Leiter, MD (University of Toronto, Canada)

Dr. Lawrence Leiter made a case for the continued use of DPP-4 inhibitors despite the fact that these agents have not been shown to improve CV outcomes. He highlighted their efficacy, safety, tolerability, and ease of prescription/use, and he identified several target populations for whom DPP-4 inhibitors could be particularly valuable: (i) in-hospital management of diabetes, (ii) elderly patients, and (iii) patients with comorbid kidney disease. Dr. Leiter argued that people with diabetes without CV disease have not been well-studied in CVOTs to-date (we’d agree with this for the most part, as the largest primary prevention population has been 27% in EXSCEL). There are now several studies demonstrating benefits of DPP4 inhibitors for the in-patient management of diabetes, he explained. The largest, the Sita-Hospital trial (n=277 individuals admitted for surgery), found that DPP-4 inhibitor Januvia (sitagliptin) added to basal insulin offered nearly identical glycemic control vs. basal-bolus therapy, with a trend toward lower hypoglycemia (not to mention, the greater ease associated with the sitagliptin regimen). This study reminded us of one recently presented by Dr. Guillermo Umpierrez at AADE 2017, pointing to the potential use of DPP-4 inhibitors in inpatient settings. In the elderly, HCPs want to avoid the weight gain and hypoglycemia associated with sulfonylureas and insulin, and injectable insulin and GLP-1 agonists may be difficult to use, making DPP-4 inhibitors a solid choice. Moreover, Dr. Leiter highlighted that DPP-4 inhibitors have established safety/efficacy across all levels of renal function, and sitagliptin and linagliptin (Lilly/BI’s Tradjenta) have demonstrated similar A1c reduction across all stages of renal impairment.

Questions and Answers

Q: What are your thoughts on CAROLINA? Will it help us resolve the SU controversy?

A: CAROLINA includes the only active control of ongoing CVOTs, comparing linagliptin to glimepiride (a sulfonylurea), so it’s the first large, properly done RCT comparing two anti-hyperglycemic agents. The expectation is that it may show benefit of linagliptin, but will this be because linagliptin is good or because sulfonylureas are bad? A parallel study, CARMELINA, is comparing linagliptin vs. placebo, and most of us expect it will show safety.

Corporate Symposium: 10 Years of DPP-4 Inhibition: New Science and Clinical Treatment for Patients with Type 2 Diabetes (Sponsored by MSD)

The Role of Cardiovascular Safety Trials and What They Can Tell Us About Patient Care

Daniel Drucker, MD (University of Toronto, Canada); Clifford Bailey, PhD (Aston University, Birmingham, UK); Michael Nauck, MD (Diabeteszentrum Bad Lauterberg, Hanz, Germany)

This panel discussion offered incredible insights on the latest diabetes CVOTs, including AZ’s EXSCEL trial for GLP-1 agonist Bydureon (exenatide once-weekly), reported less than an hour before. Our favorite quote came from Dr. Daniel Drucker: “If one p-value is 0.049 and another is 0.051, do we worship the first drug over the second?” He was referring to Bydureon’s very narrow miss for CV superiority vs. placebo (HR=0.91, 95% CI: 0.83-1.00, p<0.001 for non-inferiority, p=0.06 for superiority). Dr. Michael Nauck chimed in that it’s important to read the text of these trials, not just the headlines, because of the nuances of study design and execution. Indeed, the EXSCEL results ended up trending in a much more positive direction than many people thought following the topline release in May, which announced CV safety but not efficacy. All three panelists acknowledged AZ’s effort to conduct a clinical trial more closely reflecting what happens in real-world treatment settings (i.e. there was no run-in period to exclude individuals with poor medication adherence). They also recognized the different populations enrolled in EXSCEL vs. Novo Nordisk’s LEADER trial for Victoza (liraglutide), in that AZ’s CVOT included a larger primary prevention cohort (27% vs. 19%). As Dr. Drucker put it, the era of CVOTs has led to a hyper-focus on high-CV-risk patients, which in reality represents only a small subset of the type 2 diabetes population. Dr. Clifford Bailey mentioned the “terrible gap between RCTs and the real world,” referring to the disconnect between clinical trial evidence for a therapy and real-world evidence for that same therapy. To this end, he praised EXSCEL’s pragmatic trial design, and expressed hope for many more efforts to “close the gap” in the future. If there’s one thing we learned at this year’s EASD meeting, it’s that CVOT design is a complicated issue (see our themes section of this full report, above). We fully appreciated all the commentary from this panel, and we agree that diabetes research should ideally apply to a very wide selection of the total patient population. On the other hand, we can’t honestly criticize the more “enriched” study population in LEADER. For one, CVOTs are massive investments and it makes sense that manufacturers would want to power these trials adequately to generate the necessary number of CV events. Moreover, it’s meaningful that Victoza (liraglutide) now has a CV indication on its product label, as supported by LEADER data and allowing Novo Nordisk to promote the drug for CV risk reduction. Lastly, many thought leaders have described how new medications (in other, non-diabetes therapeutic areas) almost always prove their efficacy in high-risk patients first, followed by lower-risk patients later on.

Reducing A1c – Why Do We Still Care?

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

Dr. Clifford Bailey argued that the diabetes field needs to stop putting microvascular and macrovascular complications in separate buckets. He emphasized that microvascular stems from persistent hyperglycemia and macrovascular is accentuated by persistent hyperglycemia, and that lowering A1c is thus an important core strategy to reduce kidney disease and heart disease alike. Microvascular effects are most effectively addressed through simultaneous glucose-lowering and blood pressure-lowering, according to Dr. Bailey, while macrovascular effects are best treated through aggressive glucose-lowering and lipid-lowering side-by-side (as well as good blood pressure control). Optimal, comprehensive diabetes management involves all three – glucose, blood pressure, and lipids – and it’s no coincidence that this multifactorial approach is what yielded fewer heart failure hospitalizations (70% risk reduction), longer life expectancy (by a median 7.9 years), and fewer adverse CV events (HR=0.36, p<0.001) vs. standard care in the Steno-2 study. Dr. Bailey’s talk was a great reminder that cardiologists, too, must attend to glycemia (a theme enforced by Dr. Lawrence Leiter at ESC 2017 a few weeks prior), despite most diabetes CVOTs using a glycemic equipoise design where A1c treatment difference is minimized between the active agent and control groups.

  • Should metformin still be first-line for type 2 diabetes? Dr. Drucker posed this question during the ensuing Q&A, and Dr. Bailey suggested that the answer is not so simple. “If you check a patient’s eGFR and you want to help them avoid hypoglycemia and further weight gain, there’s very good reason to use metformin first,” he began, later adding “there are certainly cases where a more considerable amount of weight needs to come off, maybe coupled with hypertension and even higher risk of hypoglycemia, and then you see where incretin therapies could be immediately advantageous, or where an SGLT-2 agent could be advantageous.” Dr. Bailey envisions the future of diabetes care as a move from risk stratification, to treatment individualization, and eventually to precision medicine (this is certainly an important goal). But in the meantime, he maintained that we shouldn’t undermine 60+ years of clinical experience with metformin. He encouraged providers to consider earlier intervention with combination therapies, prescribing metformin alongside a DPP-4 or an SGLT-2 – we’d love to see this take root in real-world clinical practice, so that more patients are more swiftly achieving target glycemic control.

The INDORSE Study: New Understanding of DPP-4 Inhibition

Daniel Drucker, MD (University of Toronto, Canada)

Dr. Daniel Drucker delivered a heavy-hitting lecture on the mechanism of action for DPP-4 inhibitors, showing how they work through GLP-1 and GIP, peptide hormones secreted from the gut in response to food consumption. The beauty of incretin-based therapies, in Dr. Drucker’s words, is that beyond extensive clinical trial data, we really understand how they work (in contrast to a drug like metformin), which allows us to predict efficacy and safety. Dr. Drucker reviewed that DPP-4 is an enzyme on the surface of many cells, shed as a soluble form, and that both the bound and soluble forms have catalytic activity. Blocking DPP-4 in mice, either with drugs or through genetic knockout, gives an increase in active GLP-1 and GIP, resulting in more insulin and less glucagon. He presented data from the recent INDORSE study, which found that sitagliptin (Merck’s DPP-4 inhibitor Januvia) preserves fractional sodium excretion in humans with type 2 diabetes. SDF-1, a chemokine, is a sitagliptin-sensitive DPP-4 substrate in people with type 2 diabetes. Plasma sitagliptin concentrations were correlated with fractional sodium excretion and SDF-1a, the latter of which was not degraded with sitagliptin on board. Blocking SDF-1 blocked the effects of DPP-4 inhibitors on the kidneys in mice. Dr. Drucker implied that this work is helping to piece together how different diabetes therapies act in the kidney, with many questions still unanswered about DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors.

Corporate Symposium: Influencing the Future of Type 2 Diabetes Management: Striving to Optimize Treatment (Sponsored by Takeda)

Pioglitazone Risk-Benefit Analyses: What’s New?

Robert Chilton, MD (University of Texas Health Science Center, San Antonio, TX); Steven Edelman, MD (UCSD, San Diego, CA)

During Takeda’s symposium, renowned cardiologist Dr. Robert Chilton offered a very optimistic review of TZDs, claiming that he can’t think of a better drug, that it should perhaps replace metformin as first-line therapy in type 2 diabetes in some cases, and that heart failure risk can be attenuated through a healthy lifestyle and diuretics. In the next talk, UCSD’s Dr. Steve Edelman agreed, positing that no class leads to longer or more durable glycemic changes. He directed blame for giving TZDs a bad name toward Cleveland Clinic’s Dr. Steven Nissen: “He was very wrong. It was a major disservice to the field. I give him no credit for making us do CVOTs. Yes, good things came out of it, otherwise we’d never see cardiologists at our meetings. Bottom line, it’s an important class of agents…it has a lot of baggage, but when used early in the natural history of type 2 diabetes, you don’t see the side-effects [Editor’s note: especially with a low dose].” In the aftermath of rosiglitazone’s link to increased risk of MI and CV death, Dr. Nissen played a major role in drafting the FDA’s 2008 guidance on diabetes CVOTs. While we, too, were negative on the required timing at first, we must acknowledge the wealth of learning that has come from these large outcomes studies, including four agents with demonstrated cardioprotection (GLP-1 agonists liraglutide and semaglutide, SGLT-2 inhibitors empagliflozin and canagliflozin). The bad reputation assigned to TZDs since the rosiglitazone scare does seem very real, and is perhaps unfounded given certain benefits seen with pioglitazone – last year’s IRIS trial, for example, showed CV benefits to low-dose pioglitazone. There were higher rates of heart failure in the RECORD and PROactive trials, but Dr. Chilton pointed out that PPARg works by increasing sodium and water retention – a fluid overload – not by damaging cardiocytes, so a diuretic would likely be an effective risk mitigation strategy. Even in the PROactive study, he underscored that fatal heart failure was not an issue. In-patient admissions for heart failure were higher, but many who were admitted went home on pioglitazone and a diuretic. Moreover, Dr. Chilton dismissed concerns of TZD-induced bladder cancer (“a consideration that’s pretty much dead”) and bone fracture (though TZDs are not the drug of choice for women with existing osteoporosis). Weight gain and edema are also potential side-effects, but relatively minor. This was a clear endorsement, to us, of a drug that had been held in contentious regard for many years. Takeda markets a branded formulation of pioglitazone called Actos, though the company has ceased breaking out sales in recent quarters, we imagine because most prescriptions go to generic versions. Indeed, the low cost of TZDs is an advantage that can’t be overlooked in modern diabetes management.

  • In the subsequent Q&A, a number of prominent clinician-researchers cautioned against panicking when a study picks up on an adverse signal. The initial question pertained to SUSTAIN 6, in which Novo Nordisk’s GLP-1 agonist semaglutide showed a profound CV benefit but also a 76% relative risk increase for retinopathy. Dr. Edelman replied brilliantly and succinctly: “Lantus caused breast cancer. Rosiglitazone, thanks to [Dr.] Steve Nissen, caused heart failure. The toe amputation in CANVAS needs to be looked at in not such a hysterical way. Same thing here. Society tends to focus on abnormalities, ignoring the benefits.” On the other hand, Dr. Chilton pointed out that there is some evidence that GLP-1 agonism stimulates VEGF – “it’s possible there could be a problem, but we won’t know until we look at it long-term.” Human nature forces us to be risk averse, latch on to outliers, and fall victim to negative framing. Dr. Chilton explained how he asked nurses in the coronary care unit if they would take drugs that might cause blindness or toe amputation, but might also reduce CV death. Fascinatingly, they said no.
  • The message from the panel was clear: As a field, we have to do a better job of not inducing a hysteria at every signal, because that could have a long-term detrimental effect on uptake of effective medicines. Pioglitazone, according to one audience member, is only taken by 3% of people with diabetes, despite its valuable action as an insulin sensitizer.

Corporate Symposium: 60 Years of Clinical Experience for a Better Tomorrow (Sponsored by Merck)

Role of Metformin in Global Diabetes Prevention

Marinella Temprosa, MD (George Washington University, Washington, DC)

In Merck’s symposium on “60 years of clinical experience with metformin,” Dr. Marinella Temprosa argued that the generic drug could be a cost-effective solution to the growing global prediabetes epidemic. She reviewed DPPOS results, noting the 31% reduction in diabetes development after ~three years on metformin and the 18% reduction in new-onset type 2 diabetes over 15 years. She also detailed data from the 2002 study published in Diabetes Care demonstrating 10-year cost-effectiveness of lifestyle intervention and metformin, concluding that both are good investments. We were reminded of Dr. John Buse’s talk at WCPD 2016, when he made a very compelling case for metformin as a population-level prediabetes intervention: It would cost a little over $4 billion to treat the entire US prediabetes population with metformin vs. >$1.2 trillion to treat this group with GLP-1 agonist liraglutide. Meanwhile, intensive lifestyle intervention as provided by the DPP costs ~$100/person/session – treating 86 million Americans with prediabetes would run a bill of ~$1.4 trillion. All in all, we’re convinced that metformin should be prescribed more readily for type 2 prevention, and were thus disappointed (though not entirely surprised) to hear from Dr. Temprosa that metformin uptake for this purpose in the US is quite low. She attributed this to an absence of a prediabetes indication (indeed, a key first step may be getting prediabetes recognized as a disease in and of itself) and failings in education. After surveying 15 treatment guidelines for people at high-risk for new-onset type 2 diabetes, Dr. Temprosa found that lifestyle is the preferred treatment option over metformin. Still, she is optimistic that diabetes prevention messages are being disseminated around the US, and she expressed hope that prevention practices (both lifestyle and metformin) will spread globally. Promisingly, DPP will be reimbursed by Medicare starting in 2018, although digital DPP will not be included (a major hit, given the potential gains in access). As of 2015, 84 million Americans were living with prediabetes, per CDC estimates (shockingly, only 12% were aware of their prediabetes status). In the words of Dr. Temprosa, “Do nothing? Is that really what we want to do? Diabetes can be prevented. It is not inevitable.”

  • Dr. Temprosa also alluded to Dr. David Nathan’s data from ADA 2017, showing that people with gestational diabetes continue to see greater benefits to metformin over 15 years follow-up. This supports greater use of metformin in gestational diabetes, which is a key population to consider in type 2 prevention. Indeed, several thought leaders have suggested risk stratification as a way to facilitate the introduction of metformin as a prediabetes therapy (in other words, start by prescribing the drug to those at highest-risk for type 2 diabetes). The gestational diabetes patient population could be a practical place to start, as this group is high-risk and more easily identified in clinical practice settings although there is always much worry about how therapies will impact pregnant women for obvious reasons.

Insulin Therapy

Symposium: Insulin Degludec vs. Glargine Cardiovascular Safety in T2D: The DEVOTE Study

Impact of Glycemic Variability and Severe Hypoglycemia on Outcomes

Bernard Zinman, MD (University of Toronto, Canada); Thomas Pieber, MD (Medical University of Graz, Austria); John Buse, MD (UNC, Chapel Hill, NC)

We were treated to three new analyses from the DEVOTE CVOT of Novo Nordisk’s next-gen basal insulin Tresiba (insulin degludec) vs. Sanofi’s Lantus (insulin glargine): (i) Dr. Bernard Zinman correlated glycemic variability to severe hypoglycemia and all-cause death (paper published online in Diabetologia), (ii) Dr. Thomas Pieber showed a possible temporal relationship between severe hypoglycemia episodes and all-cause death (paper published online in Diabetologia), and (iii) Dr. John Buse discussed development of the DEVOTE hypoglycemia risk score and accompanying app (which we saw at Novo Nordisk’s booth in the exhibit hall).

  • (i) In DEVOTE 2, investigators found day-to-day glycemic variability to be significantly associated with all-cause mortality (HR=1.58, 95% CI: 1.23-2.03, p=0.0004). After adjusting for A1c and baseline characteristics, this finding retains its statistical significance with a hazard ratio of 1.33 (95% CI: 1.01-1.75, p=0.0432). Dr. Zinman presented additional data on glycemic variability and its relationship to severe hypoglycemia, which after adjusting for A1c and baseline characteristics, outputs a hazard ratio of 3.37 (95% CI: 2.52-4.50, p<0.0001). In contrast, he announced that there was no significant association between glycemic variability and three-point MACE after adjusting for A1c and baseline characteristics (HR=1.21, 95% CI: 0.98-1.49, p=0.0811). Dr. Zinman concluded that Tresiba’s benefits may arise from lower glycemic variability, which could substantially decrease frequency of hypoglycemia and risk for all-cause death, per this analysis. As a reminder, the relative risk reduction for severe hypoglycemia was 40% with Tresiba vs. Lantus in the original DEVOTE presentation at ADA 2017, while relative risk reduction for severe nocturnal hypoglycemia was even more impressive at 53%. In our view, hypoglycemia is a critical outcome beyond A1c and any therapy that reduces this risk is enormously valuable in our diabetes treatment arsenal. The hard evidence linking glycemic variability to hypoglycemia and all-cause death will also be valuable as we push for more consideration (from clinical trialists, regulators, patients, providers, and payers alike) of outcomes beyond A1c.
  • (ii) Next, Dr. Pieber presented the DEVOTE 3 analysis, showing a possible temporal relationship between severe hypoglycemia and all-cause death. In the 15 days following a severe hypoglycemia episode, hazard ratio for all-cause mortality in DEVOTE was 4.20 (95% CI: 1.35-13.09). In the first 30 days post-event, this hazard ratio was 3.66 (95% CI: 1.51-8.84). The increase in risk for all-cause death seems to decline as more time passes following a severe hypoglycemia episode (at one year – HR=2.78, 95% CI: 1.92-4.04). Dr. Pieber noted the wide confidence intervals, acknowledging that the temporal relationship of severe hypoglycemia and death is suggestive rather than conclusive at present. That said, severe hypoglycemia still showed a significant increase in risk for death from any cause at any time (HR=2.51, 95% CI: 1.79-3.50), and this is a very important finding. Severe hypoglycemia did not show statistically significant time course correlations with MACE events overall, but CV death was more likely following a severe low (HR=2.14, 95% CI: 1.37-3.35). These findings give yet another reason that hypoglycemia risk reduction is key in diabetes care – if the exceptionally high cost of hospitalizations and the quality of life impact wasn’t enough, this data now also shows a clear link to all-cause death.
  • (iii) Dr. John Buse discussed development of the DEVOTE hypoglycemia risk score and accompanying app. He reviewed rigorous analyses to show that the risk score is indeed accurate, predicting risk for severe hypoglycemia or a MACE event based on input variables such as age, A1c, duration of diabetes, gender, and insulin status (naïve, bolus, or basal-bolus). Dr. Buse suggested one potential application of the app in facilitating patient/provider conversations when it comes to insulin initiation – people with type 2 diabetes are often resistant to starting insulin treatment, but he showed how adding bolus insulin on the app only modestly changes hypoglycemia risk for certain other pre-set variables. All in all, though the purpose of this app is not definitely decided, we thought it was a brilliant tool, and we’re excited to see where Novo Nordisk goes with this.

Oral Presentations: Improvement in Insulin Therapy

Effect of Food Intake on the Absorption of Oral Basal Insulin

Eric Zijlstra, PhD (Profil Institute, Neuss, Germany)

Dr. Eric Zijlstra presented phase 1 data on Novo Nordisk’s now-discontinued oral basal insulin candidate. The open-label crossover trial (n=42) found that patients can administer oral insulin 30 minutes prior to eating breakfast – in other words, a meal consumed in a fasting state 30 minutes-post oral dose did not affect absorption of the agent. Healthy male participants were given identical meals of chicken, whole grain pasta with tomato sauce, cheese, and fruit either 0, 30, 60, or 360 minutes following insulin dose on four separate study visits. There were no significant differences in mean serum insulin curves for the 30-, 60-, and 360-minute conditions. On the other hand, all three of these conditions showed much higher initial insulin concentrations and slower decreases vs. the condition of immediate eating. Those who ate immediately were exposed to only 36% of total insulin vs. those who waited 360 minutes. Time until maximum insulin concentration was also significantly shorter when the meal was eaten immediately. While these results are illuminating in terms of the practical possibilities surrounding oral basal insulin, we note that this trial didn’t enroll people with diabetes, and so we can’t necessarily extrapolate to how food might influence absorption in this target patient population. To our knowledge, Novo Nordisk discontinued this candidate not because of insufficient efficacy in phase 2, but more so because of the competitive pricing and other challenges plaguing the insulin market. With the right oral insulin molecule, might the company introduce a new candidate into its pipeline? We’re not quite ready to give up on prospects for oral insulin, though we understand the technical challenges: insulin’s narrow therapeutic range, complicated titration scheme, and inherent hypoglycemia risk.

Corporate Symposium: Perspectives on Basal Insulin Use in the Real World (Sponsored by Sanofi)

Consistency of Evidence from RCT to Real World with Insulin Glargine U300

Luigi Meneghini, MD (UT Southwestern Medical Center, Dallas, TX); Lori Berard (Consultant in Diabetes and Clinical Research, Winnipeg, Canada)

During a Sanofi-sponsored symposium on real-world evidence behind basal insulins, we were treated to an overview of Sanofi’s suite of real-world studies for Toujeo (insulin glargine U300), consisting of the four DELIVER studies as well as a project called LIGHTNING. A preliminary analysis from the DELIVER-D study comparing Toujeo vs. Novo Nordisk’s next-gen Tresiba (insulin degludec) in patients who switched over from Sanofi’s Lantus (insulin glargine U100) showed no statistically significant difference in A1c reduction or hypoglycemia between Toujeo and Tresiba arms, though hypoglycemia appeared to trend ever-so-slightly in Toujeo’s favor. We also got our first introduction to the intriguing LIGHTNING project, which will use machine learning on real-world data from 156,000 US patients from Humedia/Optum to compare Toujeo vs. Tresiba, Levemir (Novo Nordisk’s insulin detemir), and Lantus. Specific goals include: (i) finding patient segments in which Toujeo provides the greatest hypoglycemia differentiation vs. comparators, (ii) evaluating medical cost-savings for those segments, and (iii) estimating differences in glycemic control between Toujeo and the basal insulin competitors for those segments. Data is expected in the next 6-12 months, and we’ll keep our eyes and ears peeled. Although DELIVER and LIGHTNING are not RCTs, we think many providers – and possibly payers – would still be eager to hear the results. We also appreciate Sanofi’s emphasis on real-world evidence, especially when it comes to critical outcomes beyond A1c like hypoglycemia, and we certainly hope payers are compelled to improve reimbursement prospects for Toujeo as a highly-effective, next-generation basal insulin. Although findings from SWITCH 1SWITCH 2, and DEVOTE point to Tresiba’s hypoglycemia benefit over Toujeo, Toujeo’s benefits are substantial as well – far more so than Lantus and Levemir, to say nothing of NPH. All in all, Sanofi seems to be putting more commercial and clinical development resources behind its next-generation basal insulin product, which makes sense in light of waning sales of flagship product Lantus.

Panel Discussion

Stewart Harris, MD (Western University, Ontario, Canada); Timothy Bailey, MD (AMCR Institute, Escondido, CA); Luigi Meneghini, MD (UT Southwestern Medical Center, Dallas, TX); Lori Berard (Consultant in Diabetes and Clinical Research, Winnipeg, Canada); Kamlesh Khunti, MD (University of Leicester, UK)

Q: Some of the real-world data that we see presented comes from just one country. What is the applicability of real-world evidence sourced from just one country? Can you apply it to other jurisdictions?

Dr. Khunti: When we compare studies in different countries, we often see the same results everywhere.

Dr. Meneghini: Some drivers – or barriers – to adherence may be different between locations. As we think of setting up the tools of real-world evidence, we should try to keep that in mind so we can answer some specific questions.

Q: Could it be that patients who are not reaching goal by three months are the ones we neglect as not motivated?

Ms. Berard: There’s so many things that come into that. We should be sure we’re clearly providing patients with the targets, education, and support they need. Let’s think about whether we are doing our job, let alone if they are doing their job. We did a survey, and many providers felt that their patients weren’t motivated. But when we asked patients, they were willing to act but they wanted more of an understanding of why they were doing it.

Q: Are we really there with real-world evidence? Can we stand tall with the quality of the evidence?

Dr. Bailey: If you look at the progression over the last decade in terms of respectability, real-world evidence was not being talked about in journals, but today they’re becoming quite rigorous. There’s lots of aspiration for real-world evidence. Some of the tools are not yet mature, but it’s a new and promising thing – not just because we can be more inclusive of patients, but also because this type of evidence can reduce the per-patient cost of running trials and can increase the rapidity of results.

Corporate Symposium: Basal Insulins – Still Innovating After All These Years (Sponsored by Sanofi)

Enhancing Confidence with Newer Basal Insulins

Jeremy Pettus, MD (UCSD, San Diego, CA)

In a fast-paced presentation on next-generation basal insulins, Dr. Jeremy Pettus discussed improvements in the PK/PD profiles of Sanofi’s Toujeo (insulin glargine U300) and Novo Nordisk’s Tresiba (insulin degludec U100). According to Dr. Pettus, a perfect basal insulin would have a duration of action ≥24 hours to allow for flexible, once-daily dosing (several thought leaders have cited flexible dosing as an advantage to Tresiba). The perfect basal would come with a flat PK profile, providing evenly-distributed exposure over the course of a day, as well as a flat PD profile, with a peak-to-trough ratio near one to minimize hypoglycemia risk. Last but not least, Dr. Pettus’ perfect basal insulin would exhibit low between-day variability. He showed how both Toujeo and Tresiba, when compared to Lantus, have a more even distribution of glucose-lowering effect, with flatter PK/PD profiles. Moreover, both products last ~24 hours or more, allowing for more flexible dosing. In a head-to-head euglycemic clamp study of Toujeo vs. Tresiba, Sanofi’s product demonstrated a more even glucose infusion rate and lower fluctuation throughout the day.

  • Dr. Pettus also advocated for the use of CGM data to help providers better understand the patient experience on basal insulin. Four patients’ 24-hour CGM data was displayed: All had an A1c of 8.0%, but average blood glucose readings were 195 mg/dl, 195 mg/dl, 163 mg/dl, and 156 mg/dl, which would predict A1cs between 7.0% and 8.4%. Moreover, A1c can hide hypoglycemia – a patient with an A1c of 6.5% may be happily sent on their way by their doctor, because fingersticks don’t show daily lows that pull down A1c measurements. We absolutely agree about the value of time-in-range data, which can be provided by CGM, as opposed to A1c (for more, read our report on diaTribe’s Glycemic Outcomes Beyond A1c consensus conference). Certainly, more work needs to be done to make CGM data actionable and better utilized by regulatory authorities.

Corporate Symposium: Changing Diabetes Care: From Glycemia to Cardiovascular Disease (Sponsored by Novo Nordisk)

Prospects of Ultra-Fast Insulins in Pump Therapy

Bruce Bode, MD (Emory University, Atlanta, GA)

Dr. Bruce Bode gave an optimistic talk on use of Novo Nordisk’s faster-acting aspart (Fiasp) in insulin pumps, noting that results from the large Onset 5 study are expected in 2018. Dr. Bode covered two published studies (Heise et al., Diabetes Obes Metab 2017 and Bode et al., DTT 2017) and the in-press Onset 4 study (Zjilstra JDST 2017) showing that Fiasp in pumps works faster than aspart (especially in the first 30-60 minutes), might lessen hypoglycemia (“we don’t know for sure yet”), and is stable in insulin pump tubing. Interestingly, a slide comparing PK profiles suggested that Fiasp has a bigger speed advantage over aspart when delivered via pump – a 26-minute faster time to peak PK in pump vs. a smaller 7-minute advantage with injections (see picture below). Dr. Bode wondered if Fiasp’s excipients give it this larger advantage when it is infused continuously rather than as single bolus injection doses. Looking ahead, the “definitive” Onset 5 trial will share results in 2018, as the last patient came out of the trial this past month. The multi-national study enrolled ~450 adults with type 1 diabetes in a randomized, blinded comparison between Fiasp and aspart in pumps. The primary endpoint is change in A1c at 16 weeks, though we’re excited to see the CGM data on time <70 mg/dl. Dr. Bode closed with his view on hybrid closed loop, which he called “a “gamechanger” – “You as a professional don’t adjust insulin.” He hopes to study use of faster aspart in hybrid closed loop in the “near future,” as many 670G users still report post-meal glucose values that rise up to ~180-200 mg/dl. As a reminder, Novo Nordisk’s 2Q17 update confirmed that an FDA decision on Fiasp (next-gen faster-acting insulin aspart) is anticipated in 3Q17 (this month!), following a Class II resubmission in March 2017. The next-gen mealtime insulin is already approved in Europe and Canada, and we continue to hear resounding positive feedback.

  • Dr. Bode said that “over 50,000” people have signed up to get on hybrid closed loop in the US (i.e., 670G), and “over 25,000” are already on it – these numbers are overestimates based on what we heard in Medtronic’s 2Q17 earnings call (~2.5 weeks ago). At the time, management shared that “close to 35,000” patients were in the Priority Access Program to eventually get on the 670G (i.e., less than “50,000”), with shipments to all of these customers expected to complete later this fall. It’s possible that more have signed up for the priority access program since that time, though we doubt an additional 15,000 have come on in the past couple weeks. Meanwhile, far fewer than 25,000 are likely on the MiniMed 670G right now, as only ~1,000 patients were on it as of late July and the ongoing sensor shortage has slowed new 670G shipments (not expected to resolve until April 2018). Read more in Medtronic 2Q17.

Posters

Efficacy and Safety of Fast-Acting Insulin Aspart Are Maintained Over 52 Weeks: Comparison with Insulin Aspart in Onset 1

C Mathieu, B Bode, D Russell-Jones, E Franek, L Rose, T Graungaard, A Phillis-Tsimikas, A Oesterskov

A Novo Nordisk poster displayed one-year results from the Onset 1 trial comparing next-generation mealtime insulin Fiasp (faster-acting insulin aspart) vs. NovoLog (insulin aspart). The company issued a press release alongside presentation of this data, and very notably, Fiasp was FDA-approved just a couple weeks later. Dr. David Russell-Jones presented 26-week data from Onset 1 at ADA 2016 (n=761), showing modest but statistically significant A1c improvements with Fiasp vs. NovoLog. This superiority was maintained at 52 weeks: A1c declined a mean 0.1% with faster-acting insulin aspart, but was essentially flat with insulin aspart boluses (estimated treatment difference 0.1%, 95% CI: 0.19%-0.0%). The estimated treatment difference for one-hour postprandial glucose was 16 mg/dl in favor of Fiasp (95% CI: 25 mg/dl-7 mg/dl). The estimated treatment difference for two-hour postprandial glucose was 8 mg/dl in favor of Fiasp, though this did not reach statistical significance (95% CI: 20 mg/dl-+5 mg/dl). There were no between-group differences in weight change or adverse events, including episodes of blood glucose-confirmed hypoglycemia. The conclusions of the poster were two-fold: (i) There were no long-term safety issues associated with faster-acting insulin aspart (which is crucial, since the FDA issued a Complete Response Letter for Novo Nordisk’s first submission of the candidate), and (ii) glycemic control was significantly improved with Fiasp vs. NovoLog over one year of treatment. We’re enormously excited for a more advanced prandial insulin product to soon be available to people with type 1 and type 2 diabetes in the US. According to Novo Nordisk management, Fiasp will launch in the US late this year or early next.

Simultaneous vs. Sequential Combination of Insulin Glargine and Lixisenatide in Type 2 Diabetes Uncontrolled on Metformin

J Rosenstock, F Ampudia-Blasco, F Giorgino, M Liu, R Perfetti, Y Handelsman

This exploratory analysis compared outcomes between a fixed-ratio combination of a basal insulin/GLP-1 agonist (as seen in the LixiLan-O trial of Sanofi’s Soliqua [insulin glargine/lixisenatide]) vs. the sequential add-on of its components (as seen in the GetGoal Duo-1 trial). The poster reported that the simultaneous administration of these agents has greater potential for A1c reduction. The present study used propensity score matching based on baseline age, race, BMI, A1c, fasting glucose, diabetes duration, and oral agent/metformin usage to create 87 matched pairs of participants between the LixiLan-O and GetGoal Dual-1 trials. The average A1c reduction among the LixiLan-O participants on Soliqua was 1.3% after 24 weeks vs. 0.7% for participants on lixisenatide added to insulin glargine in the GetGoal Duo-1 trial. This translates to a significant treatment difference of 0.6% in favor of Soliqua (p<0.0001). Furthermore, the proportion of patients achieving an A1c <7% at 24 weeks was 79% with Soliqua in the LixiLan-O study vs. only 51% with lixisenatide added to insulin glargine in the GetGoal Duo-1 study. The superiority of Soliqua over sequential combination of its monotherapies persisted for weight loss: The Soliqua group in the LixiLan-O trial experienced 1.2 kg (2.6 lbs) weight loss on average, compared to mean weight gain of 0.1 kg (0.2 lbs) for the add-on therapy group in GetGoal Duo-1. Both hypoglycemia and GI side-effects were lower with Soliqua vs. lixisenatide added to existing insulin glargine therapy. All together, these results support the superiority of simultaneous initiation of insulin glargine and lixisenatide over the sequential addition of lixisenatide to existing insulin glargine therapy in terms of glycemic control, weight, hypoglycemia, and GI side-effects. Although it is important to bear in mind that this is an indirect analysis, this study provides compelling evidence for initiating Soliqua earlier in the treatment algorithm, rather than the typical “treat-to-fail” paradigm of adding a GLP-1 agonist only after a patient has failed to meet goal on maximally-titrated basal insulin therapy.

Novel Therapies

Symposium: An Emerging and Innovative Therapeutic Approach in Type 1 Diabetes with Dual SGLT-1 and SGLT-2 Inhibition: The Sotagliflozin Clinical Program

The Unique Mechanism of Action of Sotagliflozin: A Dual SGLT-1 and SGLT-2 Inhibitor

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

Dr. Clifford Bailey kicked-off this star-studded symposium by reviewing the concept of SGLT-1 and SGLT-2 inhibition, the heterogeneity of the SGLT-2 inhibitor class, and the theorized and observed effects of dual SGLT-1/2 inhibition in patients with type 1 diabetes. SGLT-1 and SGLT-2 are both co-transporters that use the sodium gradient, created by Na+/KATPase, to carry glucose into cells, but SGLT-2 is concentrated almost entirely in the kidney while SGLT-1 is found in the small intestine, muscle, heart, and kidney. Moreover, SGLT-1 has a high affinity for glucose but low transport capacity, while SGLT-2 has a lower affinity for glucose and high transport capacity. When uninhibited, these transporters reabsorb nearly 100% of glucose from glomerular filtrate. SGLT-2 inhibitors increase kidney excretion by preventing this reabsorption. The concept of dual inhibition doubles down, also targeting SGLT-1 transporters in the gut to prevent the initial absorption of glucose into the bloodstream. This reduces initial glucose absorption, while SGLT-2 inhibition reduces reabsorption, for a greater cumulative lowering of the glucose profile via 60-90 g/day worth of glucosuria. Inhibitors vary in affinity for their transporters, and sotagliflozin is unique in its level of SGLT-1 affinity, with an IC50 of 36 nmol/L, rivaled only by canagliflozin at 663 nmol/L. For reference, dapagliflozin’s IC50 for SGLT-1 is 1,400 nmol/L. Sotagliflozin’s affinity for SGLT-2 is comparable to other approved SGLT-2 inhibitors.

  • Dr. Bailey noted that in type 2 diabetes, SGLT-2 inhibitors have consistently shown persistent glucosuria and A1c-lowering, with low hypoglycemia risk, sustained weight loss, and improved systolic blood pressure. In a small study (n=36) of sotagliflozin in patients with type 2 diabetes, sotagliflozin gave significant reductions in A1c and plasma glucose, and an increase in urinary glucose (as expected). Moreover, sotagliflozin increased GLP-1 in patients with type 2 diabetes, an effect of delayed glucose absorption to the later part of the small intestine. With the knowledge that dual SGLT-1/2 inhibitors act independently of insulin, and that they have glycemic benefits in type 2 diabetes, the question remained of their efficacy in helping to manage type 1 diabetes.

Unmet Medical Needs in Adult Patients with Type 1 Diabetes: Sotagliflozin and the Phase 2 Results of the inTandem Clinical Program

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

Building toward the highly-anticipated inTandem3 full results (a topline release in June announced that 400 mg sotagliflozin showed superiority on a primary endpoint of A1c <7% with no severe hypoglycemia or DKA), Dr. Julio Rosenstock emphasized the need for new adjunct therapies in type 1 diabetes. Despite advances in insulin analogs, glucose control in patients with type 1 diabetes remains difficult. Only about one-third of patients with type 1 diabetes are meeting glycemic goals, and CGM data shows that “good” A1c scores can mask wide fluctuations into hypo- and hyperglycemia. Severe hypoglycemia remains a major issue, and its frequency increases with diabetes duration.  T1D Exchange data indicates an overall 5% yearly risk of DKA for a background type 1 population, which peaks around 10% in teenage years. Further, patients with type 1 diabetes progressively gain weight and experience increased hypertension and CV risk 5-6x higher than the background population. Dr. Rosenstock sees limited value in off-label use of metformin as adjunct therapy in type 1 diabetes: He articulated how clinical trials have not convincingly demonstrated metformin’s benefits in type 1 diabetes in terms of long-term A1c decline or reduced insulin dose. While we see particular promise in both SGLT-1/2 dual inhibitors and SGLT-2 inhibitors as adjunct type 1 therapies, these drugs will have a difficult time reaching the vast majority of patients without an FDA indication. To this end, there’s clearly room – and unmet need – for a new non-insulin type 1 diabetes drug on the market. 

  • Dr. Rosenstock summarized phase 2 and proof-of-concept data on sotagliflozin as a launching pad for inTandem3. In phase 2, sotagliflozin showed dose dependent A1c reductions and postprandial glucose-lowering even in patients with type 2 diabetes and low eGFR (pointing to effective SGLT-1 action in the gut). An initial four-week proof-of-concept study in patients with type 1 diabetes on both MDI and pump therapy demonstrated significant A1c, body weight, and bolus insulin reductions, as well as reduced hypoglycemia. Most notably, time-in-range was increased from 56% to 68%. In four weeks, two cases of DKA occurred and were determined to be pump-related; neither case was euglycemic. Based on this positive data, sotagliflozin was advanced into phase 3 trials in type 1 diabetes. Full results from inTandem1and inTandem2 were presented at ADA 2017, while inTandem3 is Lexicon’s third and final trial for its phase 3 sotagliflozin program.

The Phase 3 inTandem Clinical Program: Efficacy and Safety of Sotagliflozin in Adults with Type 1 Diabetes

Melanie Davies, MD (University of Leicester, UK)

Professor Melanie Davies took the stage for the main event, announcing new inTandem3 findings, published simultaneously in the NEJM. This was a 24-week trial (n=1,402) investigating 400 mg sotagliflozin vs. placebo on a primary endpoint of the proportion of patients achieving target A1c <7% with no severe hypoglycemia or DKA. Of note, this was a global trial (whereas inTandem1 took place in the US/Canada and inTandem2 took place in Europe/Israel) without an insulin optimization period, making it closer to “real life.” The primary endpoint was met by 29% of people in the sotagliflozin arm vs. 15% 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). Notably, A1c was blinded throughout the 24 weeks, which may have led to less aggressive insulin adjustment. 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). These weight effects were particularly positive, as >70% of study participants had a BMI >25 kg/m2 at baseline. In patients with systolic blood pressure ≥130 mm Hg at baseline, sotagliflozin gave a treatment difference of 3.5 mmHg (p<0.002 vs. placebo) at 16 weeks. Treatment differences for total, basal, and bolus insulin doses were -5, -3, and -3 units/day, respectively (p<0.002 for all comparisons). 

  • There were four DKA events (0.6%) in the placebo group vs. 21 (3%) in the 400 mg sotagliflozin group, leading to 11 treatment discontinuations in the latter arm. In the sotagliflozin group, DKA was adjudicated in 4% of pump users and 2% of patients on MDI. In an NEJM editorial published alongside the inTandem3 paper, Dr. David Nathan gives a lot of weight to this DKA signal, arguing that this risk persisted despite trial protocol offering a high amount of patient education around DKA. We’re very curious to learn more about the nature of this education, but we also point out that there’s a lack of consensus in the field about best practices for managing DKA risk. We continue to believe this risk can indeed be managed (even if we haven’t optimized education/monitoring strategies just yet).
  • Prof. Davies presented additional safety data, with more serious adverse events seen in the sotagliflozin group (7%) vs. placebo (3%). She also noted incidence of diarrhea (4% vs. 2%, respectively) and genital mycotic infections (6% vs. 2%, respectively, and unsurprisingly). Severe hypoglycemia occurred in 3% of sotagliflozin-treated patients and 2% of placebo-treated patients, but documented hypoglycemia <55 mg/dl was significantly less frequent in the sotagliflozin group vs. the placebo group (11.8 events/person-year vs. 15.4 events/person-year, respectively).
  • Last week, Lexicon released positive pooled CGM data from inTandem1 and inTandem2. At week 24, patients treated with 200 mg and 400 mg doses of sotagliflozin spent an additional 5% and 12% of the day in-range (70-180 mg/dl), respectively, compared to those taking placebo (p=0.026 and p<0.001, respectively). These percentages translate to an additional 1.3 and 2.8 hours in-range, respectively –we feel confident saying that this additional time-in-range would be an enormous win for anyone with diabetes. This is time not spent in hypo- or hyperglycemia, meaning that patients can feel well for nearly three more hours each day – and not have to spend time trying to get back into range. It’s unfortunate that inTandem3 didn’t make use of CGM, given that time-in-range data may be a crux of the selling point for sotagliflozin. Lexicon is planning to file sotagliflozin with the FDA toward a type 1 indication in 1Q18.

Commentator

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

The renowned Dr. John Buse provided the discussant on inTandem3, bringing the symposium full circle with a description of the high unmet need for adjunct therapy in type 1 diabetes management. He reminded everyone that 3% of patients, according to the T1D Exchange, have reported at least one DKA event in the prior three months (alluding to the background rate of this type 1 complication). Dr. Buse shared his view that it is possible – even probable – that sotagliflozin’s dual inhibition provides distinguishable benefits vs. single SGLT-2 inhibition in type 1 diabetes. He expressed hope that there’s a clinical path forward for SGLT inhibition in type 1 diabetes management, with the caveat that communication around the issue of DKA is essential for people to feel comfortable with this therapy. That said, he also suggested that the DKA episodes observed in inTandem3 were less severe than what real-world clinicians normally see because patients were trained to more closely monitor for this – the flip side of this is that the absolute number of DKA events may have been inflated by the lower severity episodes. In a separate conversation with us, Dr. Buse remarked that the DKA-related education was probably not optimal in this study, despite what Dr. David Nathan refers to in his NEJM editorial as extra steps taken by the investigators to mitigate DKA risk. In addition, Dr. Buse pointed out that a large proportion of type 1 diabetes patients in the US are treated by an endocrinologist, likely offering better DKA-related education vs. a primary care physician.

  • In our view, Dr. Nathan’s editorial in NEJM minimized the profound glycemic and weight loss benefits seen in this sotagliflozin study, while overemphasizing the DKA signal. One of his main points alludes to the training of inTandem3 participants on ketone monitoring, and he argues that if there was still an imbalance in DKA after patients received concerted education, this safety issue will surely persist in the real world. Dr. Buse provided a rebuttal in his comment that DKA-related education in the trial was probably far from optimal, likely because there’s still a lack of consensus on what optimal DKA management should be. It would be a shame for a manageable safety issue to overshadow the glycemic and weight loss efficacy of sotagliflozin, and as Drs. Rosenstock and Buse clearly established, there is an unmistakable need for adjunct therapy in type 1 diabetes care. That sotagliflozin is an oral medication only adds to our excitement (AZ’s Symlin is an injectable adjunct type 1 treatment that has never quite taken off commercially). In Dr. Nathan’s closing paragraph, he suggests that automated insulin delivery (AID) will outpace pharmaceutical development for type 1, eventually making new, non-insulin drugs for this population unnecessary. To this, we respond that it’s a false reality to think AID will be affordable and accessible to everyone in the very near future – in the meantime, while the treatment options we have are just not good enough, sotagliflozin could be a significant stride.

Symposium: SGLT-2 Inhibitors, Novel Therapies for Type 1 Diabetes

Unmet Need and Adjunct Non-Insulin Therapies

Chantal Mathieu, MD (KU Leuven, Belgium)

Dr. Chantal Mathieu opened this symposium with an argument of what we should look for in adjunct type 1 diabetes therapies: (i) more stable glucose profiles, (ii) less weight gain, and (iii) less hypoglycemia. Equally important is what’s missing from this list, namely the reduction of insulin dose. While clinical trials in type 1 diabetes tend to report this (and while observers tend to focus on it), Dr. Mathieu maintained that decreasing insulin requirements should not be a goal independent of bringing down hypoglycemia risk. She outlined insulin’s key physiological role in suppressing hepatic glucose production, lipolysis, and lipogenesis. People with type 1 diabetes, whose beta cells aren’t secreting enough insulin, thus rely on exogenous insulin doses that shouldn’t necessarily be dramatically reduced even with adjunct treatment. Dr. Mathieu emphasized the importance of time-in-range and the value of CGM in clinical trials to analyze this (foreshadowing what DEPICT 1 CGM data would show…). Notably, she also chaired an earlier EASD symposium on Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin and the inTandem3 trial in type 1 diabetes. DKA was more common in the sotagliflozin arm (3%) vs. placebo (0.6%), a finding that has elicited mixed reactions, though in our view the efficacy data far outweighs this manageable safety risk. Dr. Mathieu shared her invaluable clinical perspective, that these agents (both dapagliflozin and sotagliflozin) could be highly-effective therapeutic tools for type 1 diabetes, but that they should be used in “expert hands,” with strong education on both the provider side and the patient side.

DEPICT 1: Study Design and Baseline Characteristics

Lars Hansen, MD (BMS, Princeton, NJ)

In this introduction to the trial, Dr. Lars Hansen provided an impressive amount of detail on baseline characteristics of the study population and study protocols (we were particularly interested in the recommendations around DKA, and appreciated the specificity). DEPICT 1 was conducted at 143 centers across 17 countries. At baseline, participants (n=833) had a mean A1c of 8.5%, mean age of ~42 years, mean diabetes duration of ~20 years, mean daily insulin dose of ~60 units, and mean BMI of 28 kg/m2 (indicating overweight) ­– we note that this pool was comprised of patients in definite need for further A1c reductions and weight loss. Participants were randomized 1:1:1 to dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), or placebo (n=260). All study drugs were on top of a patient’s background insulin regimen. After randomization, the study was designed to include a 24-week, double-blind treatment period, followed by an un-blinded 28-week treatment period. The 24-week data was presented and published today in the Lancet Diabetes & Endocrinology. The primary outcome was change in A1c at 24 weeks with dapagliflozin 5 mg or 10 mg vs. placebo, and secondary outcomes included changes in total daily insulin dose, body weight, mean 24-hour glucose, mean amplitude of glucose excursion (MAGE), time-in-range between 70-180 mg/dl, and proportion of patients achieving an A1c decrease of ≥0.5% without severe hypoglycemia. The study enrolled slightly more females than males, and >95% of participants were white. Moreover, ~60% of participants were from Europe and 27% from North America, the rest from Latin America and Asia-Pacific. Approximately 63% of participants were using MDI, with about 37% using an insulin pump; 33% of participants used CGM at baseline.

  • Based on a phase 2 pilot study of dapagliflozin in type 1 diabetes, and a post-hoc analysis splitting insulin dose adjustments above and below 20%, investigators decided to cap insulin dose reductions at 20% in DEPICT 1 to counter DKA risk. In the pilot, decreasing insulin by >20% was associated with an increase in ketogenesis. Following the first dose of dapagliflozin in DEPICT 1, patients/providers were recommended to reduce total daily insulin dose (including basal and bolus) up to but no more than 20%. Insulin adjustment followed throughout the treatment period. Study participants were given a combined meter for glucose/ketones and were instructed to fingerstick at least four times per day, as well as to check beta-hydroxybutyrate levels at any sign of DKA or illness, independent of SMBG values (we imagine this alerting of patients to early signs of possible DKA could be immensely valuable in the real world, though more much consensus is needed on how DKA should be most effectively monitored in real clinical practice settings).

DEPICT 1: Efficacy and Safety Data

Paresh Dandona, MD (State University of New York, Buffalo, NY)

Dr. Paresh Dandona presented the safety and efficacy data from DEPICT 1, both decidedly positive. Results were published simultaneously in the Lancet Diabetes & EndocrinologyBoth doses of dapagliflozin met the primary endpoint of change in A1c over 24 weeks: the 5 mg dose gave a 0.4% drop vs. placebo, while the 10 mg dose gave a 0.5% drop vs. placebo (both p<0.0001). A1c reduction was consistent across doses. Dr. Dandona pointed out that a 0.25% A1c decline was observed between the screening visit and randomization (he described this as unsurprising, because people experiencing challenges with their glucose management often show improvement with additional “attention,” i.e. enrollment in a clinical trial), with a clear additional benefit to dapagliflozin therapy after randomization. Total daily insulin dose fell 9% vs. placebo for the 5 mg dose of dapagliflozin and 13% vs. placebo for the 10 mg dose (both p<0.0001). Percent change in body weight vs. placebo was -3% for the 5 mg dapa dose and -4% for the 10 mg dose (both p<0.0001). Moreover, weight loss was continuous and there was very little flattening of the curve over six months, leading Dr. Dandona to conclude that more weight loss can be expected long-term (we eagerly await DEPICT 1 trial extension data to see for ourselves). Hypoglycemia was well-balanced across all treatment arms, and the proportion of patients with an A1c reduction of ≥0.5% without severe hypoglycemia was >50% for both SGLT-2 doses compared to ~25% for placebo.

  • CGM readings showed 52% (12.5 hours), 55% (13.2 hours), and 44% (10.6) time-in-range for 5 mg dapa, 10 mg dapa, and placebo, respectively. This translates to an extra ~2.2 hours in-range for low-dose dapagliflozin patients and an extra ~2.6 hours in-range for high-dose dapagliflozin patients vs. placebo – time spent feeling well, experiencing better quality of life (this is a tremendous increase!). In the placebo group, average adjusted interstitial glucose increased 5 mg/dl over 24 weeks; mean difference from placebo for the dapagliflozin groups was -15 mg/dl for 5 mg and -18 mg/dl for 10 mg (both p<0.001). Average adjusted MAGE at 24 weeks with placebo was 2 mg/dl; mean difference from placebo for the dapagliflozin groups was -17 mg/dl for low-dose and -19 mg/dl for high-dose (both p<0.0001).
  • 24-hour CGM data indicates a blood glucose reduction in the early morning hours. According to investigators, patients dosed dapagliflozin in the morning, and the greatest glucose-lowering effects seemed to occur near the end of the 24-hour dose cycle, around 7 am. This will require further analysis, and more study will be needed to fully comprehend the time-action profile of dapagliflozin in patients with type 1 diabetes, as well as how the “dawn effect” of early morning glucose increase is involved in this dynamic.
  • DKA has emerged as a key consideration in using SGLT-1/2 and SGLT-2 inhibitors in type 1 diabetes, but DEPICT 1 was reassuring on this front. There was an event rate of 1% in the 5 mg group (four patients – two due to insulin pump failure, one to missed insulin dose), 2% in the 10 mg group (five patients – one attributed to pump failure, three to missed insulin dose, and one to alcohol), and 1% in the placebo group (three patients – one due to pump failure, one to missed insulin dose, one to stress). At least some of the favorable DKA outcomes seem to be attributable to the study guideline that total insulin should only be reduced up to 20% – patients were advised to eat extra carbs and dose insulin if they weren’t taking a certain amount daily. It is our understanding that this lower limit of insulin reduction is paramount in preventing DKA, and we wonder if there was any cap on insulin reduction in any of the inTandem clinical trials for sotagliflozin.
  • The adverse event profile of dapagliflozin was otherwise as expected, with a greater frequency of genital mycotic infections (12%, 11%, and 3% in the 5 mg, 10 mg, and placebo arms, respectively). Urinary tract infections, fractures, and hypotension/dehydration were all evenly balanced and rarely occurred. Hypoglycemia occurred in 79% of participants on the 5 mg dapa dose, 79% of those on the 10 mg dapa dose, and 80% of those taking placebo, while severe hypoglycemia occurred in 8%, 6%, and 7% of participants, respectively. Adverse events led to 23 discontinuations in total: six from the 5 mg dose, 8 from the 10 mg dose, and 9 from placebo.

Commentator

Maciej Malecki, MD (Jagiellonian University Medical College, Cracow, Poland)

Dr. Maciej Malecki provided independent commentary, offering a very positive view on DEPICT 1 trial design and results overall. In fact, one of his final slides read that “the DEPICT 1 study gives hope for prompt registration of dapagliflozin as an adjunct type 1 therapy” – indeed, we’d love to see Farxiga move closer to the type 1 market, and we keep our fingers crossed that upcoming results from DEPICT 2 and the DEPICT 1 trial extension support the strong safety/efficacy profile seen here. According to Dr. Malecki, it’s a shame the DEPICT 1 investigators didn’t formally assess patient quality of life, because he predicts the result would’ve been quite positive, and we’d presume the same given significant improvements to time-in-range and body weight. He raised a question around dapagliflozin’s applicability in type 1 diabetes patients with lower baseline A1c, body weight, or total daily insulin dose, suggesting that in these circumstances, further decreases may not be desirable. On the other hand, we imagine ideal candidates for new adjunct treatments like dapagliflozin and sotagliflozin will be those type 1 patients in-need of additional glycemic control and weight loss, so it makes sense for AZ to investigate its SGLT-2 inhibitor in this particular patient population (somewhat elevated baseline A1c of 8.5%). It’s true, patients well-controlled and satisfied with their insulin therapy may not see the need for Farxiga to be introduced in pharmacies with a type 1 indication, but this is a small minority of the population – only one in three adults with type 1 diabetes in the US are meeting A1c goal.

  • Dr. Malecki added to Dr. Mathieu’s list of what we should look for in an adjunct therapy: Beyond more time-in-range, less weight gain, and less hypoglycemia, he also mentioned CV risk reduction. The excess risk for mortality in people with type 1 diabetes vs. the background population is almost entirely accounted for by CV death, he explained, arguing that we need better medicines to bring down this risk. DEPICT 1, of course, was not an outcomes trial, and we know it will likely be challenging to get all the funding/resources behind a large CVOT in type 1 diabetes. Dr. Malecki was optimistic, however, about the DECLARE CVOT for dapagliflozin in type 2 diabetes (he cited two positive SGLT-2 CVOTs so far, EMPA-REG OUTCOME and CANVAS). Positive DECLARE results wouldn’t support an indication specific to type 1, but at the very least, they would help spread awareness among patients/HCPs about the cardioprotective effects of SGLT-2 inhibitors, and word would certainly spread to the type 1 community as well. DECLARE is expected to complete in the second half of 2018.
  • During Q&A, Dr. Julio Rosenstock cautioned against a possible misinterpretation of DEPICT 1 in context with inTandem 3: “People need to be extremely careful not to run out of this room 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.” We agree that study design differences make comparisons difficult (and often futile). It is our view that both these phase 3 studies were actually positive.
  • One final word from us on DKA: The recommendation for no more than 20% insulin dose reduction was the most specific DKA-related study protocol we’ve heard, and we’re curious for more color on the DKA education and risk mitigation strategies in inTandem3. Similar to how the amputation signal in CANVAS highlighted the lack of proper education around foot care in real-world diabetes management, the inTandem program and clinical programs for SGLT-2 inhibitors in type 1 have brought the need for better DKA education to the forefront. As Dr. John Buse remarked in a separate conversation with us, the DKA-related education in inTandem3 was probably far from optimal, which begs the question: what is optimal DKA risk management? And, how can we spread it broadly in the real world? We’d love to collect more insights on this, and we’re hoping for some motion toward consensus, in time for sotagliflozin and dapagliflozin to reach the type 1 diabetes market (yes, we’re still very hopeful). None of this is to say that these safety concerns of amputations and DKA are trivial – far from it. Rather, it would be a sad story to see clinically-meaningful benefits like time-in-range and weight loss overshadowed by a manageable safety concern, especially when there is such high unmet need in the type 1 population for adjunct therapy.

Symposium: Generation of Stem Cell-Derived Beta Cells from Type 1 Diabetes Patients (Sponsored by EASD/JDRF)

The Quest to Make Fully Functional Human Pancreatic Beta Cells from Embryonic Stem Cells: Climbing Mountains in the Clouds

James Johnson, MD (University of British Columbia, Vancouver, Canada)

UBC’s Dr. James Johnson (Site Head for the new Novo Nordisk Research Centre Oxford), while impressed by how far the field has come, is “not really sure when we’ll get” to converting human embryonic cells to true beta cells. When displaying a timeline of progress in efforts to generate beta cells, he placed a question mark over the true beta cell where the year should go and commented “Notice I didn’t even put a century there, but that might just be me being pessimistic.” He later said that we’re on the right track towards making mature beta cells, but the question is when. He proceeded to outline a number of the barriers blocking progress, first calling on the field to reconsider experimental design and rigor. To some, transplantation of beta-like cells into a mouse and thereby curing diabetes is the gold standard, he said. Poking holes in that logic, he then showed a graph of improved glycemia in a mouse brought on by an insulin pump or pellet – “a pump or pellet can rapidly reverse diabetes in mice. Reversal should not be considered a high bar or gold standard for assessing cells.” Instead, Dr. Johnson advocated for transplantation of the cells into mouse eyes, where they can be visualized at the individual level. In Q&A, he expanded his recommendations – “electron microscopy, super-resolution, live-cell…You name it, we need it.” Another barrier to progress is unknowns about source human islets – are they the ideal comparison for in vitro differentiated cells? What is the normal insulin response to glucose and other nutrients? Beta cells are so heterogeneous, both inter- and intra-individually – what parameters should we be aiming to recreate? On top of that, islets from cadaveric donors have all sorts of factors making them unnatural/un-generalizable. “We need to think carefully about what we need to make. We need to build heterogeneity into the system.” Because of this heterogeneity, Dr. Johnson implored scientists to stop showing single cell traces in studies, calling the tactic a cop-out (and arguably a scientifically dishonest one at that). He called for an online database of pooled data where one could look up every studied human islet and how they respond to certain stimuli – and he believes this should all be public information, even offering to be the host. We’d love to see this move forward as well – in vitro-generated beta cells should be compared to a standard; not whatever cells came in the mail that day.

  • In Q&A, prominent beta cell biologist Dr. Decio Eizirik asked if we should focus on completely recapitulating the islet, or simply generating a population of cells that responds to glucose in a near-physiological manner, leading to a decrease in A1c. Dr. Johnson agreed that helping the patient is the bottom line, but he only focused on heterogeneity in his talk because he fears it may be necessary for proper functioning. We found this to be the perfect answer, and we hope, for the sake of time, that scientists don’t have to generate every beta cell phenotype to be successful.
  • Dr. Johnson left the audience with an important thought on expectation-management: “This is really exciting stuff, but we need to be measured as scientists – we can’t get so excited that we lead patients down false roads of hope. We’re working on it, but there’s a lot left to do.” This was and remains a major concern with hybrid closed loop systems. We believe the messaging around them is improving, but some still expect the MiniMed 670G to be a true “artificial pancreas” that requires no user input.
  • Other barriers to progress mentioned by Dr. Johnson include: (i) It seems that the more beta-like a cell is, the less chance it survives implantation due to a stronger immune response. Is there a happy medium where the cell is beta-like enough to approximate physiological function but avoid a hefty immune assault? (ii) Generating the beta cell is just the first step! From there, it has to evade the immune system by a mechanism involving immune suppression, encapsulation, cloaking, etc; something Viacyte’s de-prioritization of its ambitious phase 1/2 PEC-Encap therapy demonstrates is equally non-trivial.

White Adipose Tissue as a Drug Target

Rudolf Zechner, PhD (University of Graz, Austria)

Pharmacological researcher Dr. Rudolf Zechner discussed work his group has been doing in rodents with an inhibitor of adipose triglyceride lipase (ATGL). The compound reduces lipolysis from white adipocytes, fat storage cells that we increasingly realize do much more than just store fat. The mouse-specific ATGL inhibitor atglistatin, which acts preferentially on adipose tissue and the liver while appearing to avoid dangerous effects of lipolysis inhibition elsewhere in the body, led to a beneficial metabolic phenotype. This included reduced fatty acid levels, improved insulin sensitivity, and less insulin secretion. Atglistatin does not work on human ATGL, but Dr. Zechner suggested that a human-specific compound would work if it does not target cardiac lipolysis, and if human lipolysis reacts similarly to mouse lipolysis – which he admits is no small “if.” Still, his group’s early-stage but exciting work has apparently already appealed to industry, as Dr. Zechner noted as an aside that he has “lots of pharma companies getting in touch with him” – a good sign!

  • When weighing pharmacological inhibition of lipolysis, the main factor in favor is that inhibiting lipolysis appears to cause resistance to obesity in animals on high-fat diets, as well as better glucose tolerance. However, overly broad inhibition of lipolysis can cause ectopic fat accumulation elsewhere in the body. This is especially catastrophic in the heart, and mice with a complete body-wide knockout of adipose triglyceride lipase rarely make it to 24 weeks of life before they die of severe cardiac steatosis.
Antonio Vidal-Puig, MD (University of Cambridge, UK)

Dr. Antonio Vidal-Puig discussed his fascinating hypothesis that adipose tissue reaching the limit of its fat-storing capacity is what tips the scale in an individual patient toward metabolic dysfunction. He began his presentation by reminding the audience that adipose tissue consists of more than just adipocytes (fat storage cells) – there are also blood vessels that must grow as fat tissue grows, immune cells that manage adipocytes and take up loose fatty acids, and structural support requirements. The “adipose tissue expandability hypothesis” suggests that while the risk of metabolic dysfunction increases linearly with adipose tissue gain on a population level, an individual patient has an adipose tissue threshold beyond which the tissue stops being able to buffer additional nutrient excess, causing metabolic compromise. The takeaway from this theory would be to focus on improving adipose tissue functionality by increasing its capacity. Though his theory suggests that the body can compensate for adipose tissue gain until it hits its threshold, during Q&A Dr. Vidal-Puig pushed back against a dichotomy of healthy obesity vs. unhealthy obesity. “A person is seen as a healthy obese individual until they develop their first complication… Assuming that you can tell anyone that they are “healthy obese” and can do anything they want is a bad idea.”

Oral Presentations: Novel Therapies, Future Opportunities

Beyond Topline Results for the Oral (Non-Peptide) GLP-1R Agonist TTP273 in Type 2 Diabetes: How Much and When?

Jennifer Freeman, PhD (vTv Therapeutics, High Point, NC)

In an important oral, Dr. Jennifer Freeman presented phase 2 data on vTv’s oral GLP-1 agonist candidate TTP273, indicating that lower doses might be more effective. In LOGRA, a phase 2 proof-of-concept study (n=174), TTP273 was well-tolerated, and after 12 weeks, A1c was 0.9% lower than placebo in the 150 mg once-daily arm and 0.7% lower than placebo in the 150 mg twice-daily arm (p<0.001 for both comparisons). Weight loss at three months was 2 lbs greater in the 150 mg once-daily arm and 1 lb greater in the 150 mg twice-daily arm vs. placebo, though these superior reductions in body weight did not reach statistical significance. Parsing the data by body weight and examining mg/kg dosing, Dr. Freeman showed how the greatest efficacy was seen at the lowest doses (<1.35 mg/kg), for both A1c and body weight reduction. For doses <1.35 mg/kg, margin of A1c drop neared 2% and weight loss was ~8 lbs vs. 0.3% A1c decline and 1 lb weight loss for doses >1.75 mg/kg. Thus, patients >22o lbs dosed once-daily experienced the greatest relative A1c and weight benefits. These patients also saw nearly 6 mmHg drops in systolic blood pressure and ~55 mg/dL in fasting plasma glucose. While we might expect patients at higher baseline body weight to benefit more from GLP-1 agonism, the disproportionate effects on glycemia among those receiving lower mg/kg doses are intriguing. Dr. Freeman noted that TTP273 is a functionally biased ligand and a small molecule, not a peptide, and signaling by TTP273 occurs through the neuroendocrine system via the GI tract, as well as by plasma concentration in the circulatory system. TTP273 does not activate the beta-arrestin pathway. Dr. Freeman hypothesized that high concentrations of TTP273 – particularly in the periphery, where the effect is desensitized more slowly – may alter the signaling dynamic of the molecule. A similar dose-response pattern was observed in a proof-of-concept study for TTP054, vTv’s other oral GLP-1 agonist candidate. More work will be needed to understand the mechanistic differences between peptide and small molecule GLP-1 agonists, but we continue to be excited about the impending arrival of oral GLP-1 agonists and the improved patient experience that will come with them. Closest-to-market in this area is Novo Nordisk’s oral semaglutide, in phase 3.

Weight Loss Unrelated to Decrease in Calorie Intake After a Single Dose of a Bispecific Antibody to FGFR1/Klothoβ in Obese Subjects

Puneet Arora, MD (Genentech, San Francisco, CA)

Genentech’s Dr. Puneet Arora summarized promising weight loss data from the first in-human study of the company’s bispecific FGFR1/Klothoβ antibody, currently in development for obesity and type 2 diabetes. People with obesity (n=71), at mean baseline body weight 218 lbs, were randomized to receive one of seven single escalating doses of the injectable candidate BFKB8488A (ranging from 3 mg to 681 mg). Dr. Arora described a significant dose-dependent decrease in body weight observed after just one week (p<0.01 for interaction). Body weight fell a mean of 0.3% with a 3 mg dose, 0.9% with a 10.5 mg dose, 0.9% with a 39 mg dose, 1% with a 111 mg dose, 1% with a 171 mg dose, 2% with a 342 mg dose, and 2% with a 681 mg dose. In comparison, weight loss was <0.3% from baseline with placebo. Thigh injections appeared to be especially potent: here, 171 mg and 250 mg doses produced a mean body weight reduction of 2% and 1%, respectively. Though these are small effects, this is quite an impressive degree of weight loss for only one week. We would be very interested to see whether this effect is durable in longer-term studies. Notably, BFKB8488A was not associated with any loss of appetite or caloric intake, suggesting that the candidate’s weight loss benefit is not attributable to a simple decrease in eating behavior and may be instead acting to increase energy expenditure. Past studies – including a presentation by UT Southwestern’s Dr. Steven Kliewer at ENDO 2017 – corroborate this, providing compelling evidence that FGF receptor activation has a direct effect on adipose tissue (“the fire”) which is complemented by indirect action in the hypothalamus and hind brain, triggering a cascade of downstream effects to support increased energy expenditure (“the fuel”).

  • Genentech’s bispecific antibody binds to both FGF receptor 1 (FGFR1) and the Klothoβ protein, thus accelerating the formation FGFR1/Klothoβ complexes in adipose tissue. This stands in contrast to other FGF-targeting therapies in development, the majority of which are analogs of the FGF21 protein. Novo Nordisk announced in its 4Q16 update that it has initiated a phase 1 trial of a new once-daily FGF21 analog (NN9499) in obesity, which will enroll 56 male participants with overweight or obesity and has an expected completion date of October 2017, according to ClinicalTrials.gov. Novo Nordisk is usually very smart about its product pipeline and this addition is a strong vote of confidence in the FGF pathway as a therapeutic target. That said, Pfizer and Lilly have discontinued their FGF21 candidates after underwhelming glucose-lowering efficacy, though these candidates were in development for type 2 diabetes, not obesity. We will continue to closely watch this exciting arena within the larger obesity drug competitive landscape, with a particular eye toward whether there is a difference in efficacy between the FGF21 analog approach vs. the FGFR1/Klothoβ antibody approach.

MEDI4166, a Novel Antibody (PCSK9)-Peptide (GLP-1) Fusion Molecule: Single-Ascending-Dose Study in Patients with Type 2 Diabetes

Meena Jain, MD (MedImmune, Cambridge, UK)

AZ discontinued its PCSK9/GLP-1 fusion candidate in 2Q17, and Dr. Meena Jain shared results from a phase 1/2 study (n=40) that shed some light on this decision. The agent, MEDI4166, was associated with more adverse events vs. placebo (67% vs. 50%, respectively), though the most common adverse events in both treatment arms were GI-related (17% vs. 30%, respectively). Notably, eight participants randomized to MEDI4166 (n=30) developed antidrug antibodies. Dr. Jain reported that these antidrug antibodies did not interfere with the agent’s PK/PD profile (for both the PCSK9 component or the GLP-1 component), but we imagine this may have come into play in the drug candidate’s discontinuation.

Oral Presentations: Incretins: New Clinical Evidence

The Effects of GIP/GLP-1 Receptor Co-Activation on Appetite and Food Intake in Overweight/Obese Subjects

Natasha Bergmann (University of Copenhagen, Denmark)

Ms. Natasha Bergmann presented somewhat disappointing results demonstrating that the addition of GIP on top of existing GLP-1 agonist therapy does not produce any further reductions in food intake or appetite suppression in people with obesity. In fact, she showed, it may reduce the potency of GLP-1 agonist monotherapy. In this study, 18 male participants with obesity (average BMI 33 kg/m2, no type 2 diabetes or prediabetes) were given repeated isoglycemic glucose infusions with the addition of GLP-1, GIP, both GLP-1/GIP, and placebo, after which their food intake was measured at an unlimited buffet. Expectedly, food intake was significantly reduced with GLP-1 vs. placebo (~396 calories, p=0.035), but food intake with GIP and GLP-1/GIP did not differ significantly from placebo. Thus, Ms. Bergmann suggested that not only is GLP-1/GIP dual activation not superior to GLP-1 activation alone, but it seems to be inferior. A similar trend persisted for the secondary outcome of appetite suppression, which was reported on a subjective scale. Compared to placebo, GLP-1 produced less reported hunger (p<0.0001), a higher degree of satiety (p<0.05), and lower prospective food consumption (p<0.0001). GIP and GLP-1/GIP, by contrast, did not significantly differ from placebo on these metrics. The additional secondary endpoint of resting energy expenditure (REE) was unchanged in all experimental conditions. It’s important to keep in mind that this data pertains only to food intake and subjective appetite measures, to say nothing of the effect of GLP-1/GIP dual activation on outcomes like weight loss and glycemic control. That said, this investigation, though small, suggests that the efficacy of GLP-1/GIP dual agonists does not come from the drugs’ effect on appetite and eating behavior. The growing GLP-1/GIP competitive landscape currently contains phase 1 candidates from Lilly, Sanofi, and Novo Nordisk, in addition to a preclinical candidate from Zealand.

Oral Presentations: Incretins – Entry and Actions

Evaluation of the Effect of Food on the Pharmacokinetics of Oral Semaglutide

Jeanette Borregaard, MD (Novo Nordisk, Copenhagen, Denmark)

Novo Nordisk’s Dr. Jeanette Borregaard discussed the practical issue of how food affects the absorption of oral semaglutide, Novo Nordisk’s phase 3 GLP-1 agonist candidate. Healthy volunteers (n=78) received 10 mg oral semaglutide under three different experimental conditions: fed (high calorie, high fat breakfast 30 minutes pre-dose), fasting (overnight and four hours post-dose), and a reference condition (fasting overnight for at least six hours, 30 minutes post-dose fasting). Results indicated that the absorption of oral semaglutide is limited by prior food ingestion – 14 out of 25 subjects in the fed arm showed no detectable semaglutide exposure. Moreover, PK data revealed that the exposure of oral semaglutide was greater in the fasting group vs. the reference group, as reflected by a greater area under the concentration curve (AUC), though this did not reach statistical significance (p=0.080). On the basis of these findings, the dosing recommendation for oral semaglutide in the ongoing phase 3 PIONEER program was to take the drug with half a glass of water just after waking up, and to wait 30 minutes before eating or taking any other medications, Dr. Borregaard explained. Although it would be ideal if oral semaglutide could be taken at any time of the day without such specific stipulations, we note that this is still more convenient and adherence-friendly than an injection, as most GLP-1 agonists are administered.

Oral Presentations: Metformin – Oldie but Goodie

Delayed-Release Metformin Targeting the Lower Bowel Elicits Sustained Improvements in HbA1c and Fasting Glucose with Minimal Systemic Exposure

Juan Frias, MD (National Research Institute, Los Angeles, CA)

Dr. Juan Frias presented full results from a phase 2b study of Elcelyx’s Metformin Delayed Release (DR). These findings have been highly-anticipated since topline data from the study (n=542) was announced in November 2016 (also the subject of a late-breaking abstract at ADA 2017). After 16 weeks of treatment and from a baseline A1c of 8.6%, type 2 diabetes patients randomized to the highest tested dose of Metformin DR (1,500 mg) experienced a mean A1c reduction of 0.62% vs. a ~1.1% reduction with the comparator dose of metformin immediate release (IR) 2,000 mg (p<0.05). Fasting glucose reduction with Metformin DR was >75% of that observed with Metformin IR. PK analysis found that Metformin DR caused substantially lower plasma exposure (~1/3), as intended (this therapy candidate acts on the gut with an aim toward less systemic exposure than regular metformin immediate release or extended release). Taking into account the efficacy and exposure results, Dr. Frias reported that the glycemic improvement per amount of systemic drug exposure was actually higher with Metformin DR than with metformin IR. The safety/tolerability profile was superb, with clinically-meaningful and statistically significant ~50% reductions in GI adverse events vs. standard metformin IR 2,000 mg daily.

  • Elcelyx may pursue a targeted phase 3 program for Metformin DR in patients with type 2 diabetes and chronic kidney disease (CKD) stages 3B and 4 – in which metformin is currently restricted or contraindicated. This would be a letdown for the broader population that could benefit from the apparent GI tolerability benefit (if covered by payers), but isn’t entirely surprising in the challenging current regulatory and commercial climate for new diabetes drugs. In light of the modest efficacy but excellent tolerability and low systemic exposure in this study, Elcelyx is likely to test higher doses of Metformin DR in phase 3 than were tested in phase 2. The company de-risked this approach by conducting a pharmacokinetic (PK) study with population PK modeling (see below) showing that Metformin DR up to 2,100 mg daily should be safe in CKD stages 3B/4.

Questions and Answers

Q: We know metformin has some beneficial effects when in systemic circulation. What happens to those with metformin DR?

A: I’m not sure I have an answer for that, but it’s something to be considered.

Q: You focus on systemic exposure, but can you speculate about the mechanisms behind the differences between DR and IR metformin with regard to GI side-effects? Metformin has been shown to inhibit bile acid transporters, so the result may be spillover of bile acids into the colon. Did you measure bile acids?

A: I don’t think bile acids were measured. As far as the mechanism of the reduced GI side-effects, that was not assessed. Some of the difference may be due to difference in the systemic exposure.

Q: Normally we advise patients to take regular metformin with main meals. What is the recommended dosing for metformin DR?

A: The drug was taken with meals, once-daily in the morning. In this study, metformin IR was given twice-daily with meals, as is recommended.

Metformin Exposure with Gut-Restricted Delayed-Release Metformin in CKD Stage 4 Does Not Exceed That Of Current Metformin Used On-Label: Results From Population PK Modeling

Mark Fineman, PhD (Elcelyx Therapeutics, San Diego, CA)

A major takeaway from the modest efficacy but good tolerability observed with Elcelyx’s gut-restricted metformin DR (see above) was that higher doses could be considered for phase 3. To de-risk the testing of higher doses than were tested in phase 2b, Elcelyx conducted a population PK modeling study to see if serum exposure of metformin DR doses up to 2,100 mg would exceed already-approved levels of regular metformin IR in stage 2 or 3A chronic kidney disease (CKD). The model drew on data from metformin DR’s clinical program and other sources, and found that the 2,100 mg metformin DR dose would not be expected to cause greater serum drug levels than metformin IR 2,000 mg in CKD stage 2 or metformin IR 1,000 mg in CKD stage 3a. A simulated 2,400 mg metformin DR did not pass the test. A secondary simulation of what would happen in the case of acute kidney failure suggested that serum metformin levels would rise much more slowly with metformin DR 2,100 mg than with metformin IR. Elcelyx’s Dr. Mark Fineman, who presented the results, concluded that doses of metformin DR up to 2,100 mg daily would be justified for phase 3 study in patients with CKD stages 3B/4.

  • There is some risk inherently involved in testing doses of a drug in phase 3 that are higher than were tested in phase 2. We are modestly reassured by the fact that this is a new formulation of a well-understood drug, and Elcelyx has done a lot of work to characterize the PK profile and systemic exposure of the new formulation.

Questions and Answers

Q: It seems to me that the 2,100 mg dose is the safest DR dose. The slides presented previously showed that there was less effect with the 1,500 mg DR dose compared with 2,000 mg of metformin IR. Do you have a comparison of efficacy with the 2,100 mg DR dose to see if the efficacy benefit is similar?

A: Not as of yet. The results of the study presented in the last talk indicate that the 1,500 mg dose of metformin delayed release (DR) had less glucose-lowering effect than metformin immediate release 2,000 mg. This was just a PK modeling study to make sure that higher concentrations would be safe and justifiable to study.

Q: It’s well known that metformin has many advantageous effects independent of its glucose-lowering effect, such as anti-inflammatory effects. Is it known whether metformin DR will also have these effects?

A: We don’t have specific data on other potential effects of this metformin formulation other than gut-mediated glucose-lowering. That said, the main goal would be to use this formulation in patients in which too-high systemic concentrations are a risk. As we move into studies on CKD phase 3B/4, we expect gut exposure along the lines of what we have seen and systemic exposure that is not higher than what is seen in non-renally-impaired patients with metformin IR, but not zero. So if there are effects of metformin that are systemic and non-glycemic, this formulation may still address those as well.

Q: It’s nice that you can use metformin DR safely in these patients, but it also has to work in these patients. Based on the results presented previously, the fasting plasma glucose effect was smaller than expected. Have you explored the effect of this formulation on postprandial glucose measures?

A: We have done 24-hour glucose profiles earlier on after just a few days of dosing. The general pattern was that the postprandial effect appeared to be lower. We can’t tease out if there is a loss of postprandial glucose effect because we bypass the jejunum with the way the drug is formulated, or because the systemic exposure is lower.

Q: Have you looked at lactate levels with metformin DR?

A: Typically, lactate levels have not gone up very high in the studies we’ve done to-date, either with single or chronic dosing. With either DR or IR metformin, we’re not getting to high enough serum concentrations that would elicit the high lactate response. That said, in single-dose studies in various stages of renal impairment, we see small differentials between DR and IR/XR metformin, with a very strong correlation between plasma exposure and lactate response.

Oral Presentations: Impact of Exercise on Metabolism

Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes

Michael Rickels, MD (University of Pennsylvania, Philadelphia, PA)

University of Pennsylvania’s Dr. Michael Rickels presented compelling data (n=15) demonstrating that 150 ug of Xeris’ soluble mini-dose glucagon (G-Pen mini) prevents exercise-induced hypoglycemia more effectively than a basal rate reduction and with less hyperglycemia than seen with glucose tablets. In the small Helmsley Charitable Trust-funded crossover study, 15 people with well-controlled type 1 diabetes (baseline A1c: 7.1%; duration ≥2 years; on pumps; regular exercisers) each participated in four moderate exercise sessions consisting of brisk uphill treadmill walking at 50%-55% VO2 max for 45 minutes. Five minutes before beginning exercise, patients received in separate trials: (i) sham basal reduction and placebo glucagon injection; (ii) 50% basal rate reduction and placebo injection; (iii) 20 grams oral glucose five minutes before the start of the exercise and another 20 grams 30 minutes after the start of exercise; and (iv) sham basal reduction and a 150 ug subcutaneous injection five minutes before the start of exercise. The figure below shows that, after onset of exercise, blood glucose levels in both the control and basal reduction groups drop and remain low through recovery – the glucose tab and glucagon conditions both elevate similarly during exercise, but the glucagon intervention causes glucose to plateau after exercise, while glucose tabs caused levels to increase further during recovery. At a high-level, ~33% of control and basal reduction cases saw hypoglycemia (“a few serious”), while none of the glucose tabs or glucagon experiments saw a glucose go below 70 mg/dl. On the other end of the spectrum, hyperglycemia was present in ~73%  (>250 mg/dl) occurred with glucose tabs than with glucagon (five to one). Following exercise, patients ate a standardized meal and were monitored for the rest of the day and overnight. After the meal, glucose levels in all groups converged around 180 mg/dl, and there were no differences in CGM metrics between the conditions that night. These findings suggest that 150 ug mini-dose glucagon given before moderate aerobic exercise is safe and an effective alternative for preventing hypoglycemia – Dr. Rickels concluded that the findings warrant longer-term investigation. We’re not sure if the choice of a flat 20 grams of glucose tabs, dosed twice, was really a fair comparator in this study. Arguably it should have been individualized based on the person – 40 grams of glucose tabs was likely overkill for many, given that this was treadmill walking for 45 minutes. An n=1 example: Adam finds 40 grams of glucose tabs raise his blood glucose by roughly +200 mg/dl (on average), while 45 minutes of brisk walking would drop his blood sugar anywhere from -45 to -90 mg/dl (on average). In the context of this experiment, 40 grams would have been more than double what he would need to counteract walking.

  • When asked about glucagon dosing in Q&A, Dr. Rickels said that it needs to be investigated in future protocols, but 150 ug has been shown to be more effective than 75 ug at correcting hypoglycemia after a recent bolus. The question was raised due to a figure that depicted super-physiologic levels of glucagon after glucagon injection. We hope a mini-dose glucagon pen would allow for smaller/larger doses, depending on circumstances – e.g., down trending arrow, small child, heavy exercise, etc. This seems like the kind of drug that should allow for individualization, rather than a flat dose.
  • Xeris’ mini dose glucagon is in phase 2 and no timing has been shared on a phase 3 trial. The phase 3 for Xeris’ G-Pen auto-injector for severe hypoglycemia rescue is currently recruiting participants, with an expected completion date this month. See the ClinicalTrials.gov posting here and our glucagon competitive landscape for more information.

Questions and Answers

Prof. Stephanie Amiel (King’s College London): Am I correct in thinking that glucagon has really dealt well with immediate hypoglycemia, but we need a strategy for delayed nocturnal hypoglycemia?

A: We didn’t see any nocturnal hypoglycemia in this study. That’s probably the case because of how well-controlled we conducted the study so the conditions could be comparable. The participants took part in fasting exercise in morning, and the patients had to start out with good glucose before the study. There’s certainly a greater risk for nocturnal hypoglycemia following afternoon or evening hypoglycemia – that should be studied in the future.

Oral Presentations: Fat in the Liver – How It Gets In, How It Gets Out

Non-Alcoholic Fatty Liver Disease and Risk of Mortality and Cardiovascular Disease Among People with Type 2 Diabetes: A National Retrospective Cohort Study

Sarah Wild, PhD (University of Edinburgh, UK)

Dr. Sarah Wild presented results from a sizable retrospective cohort study from Scotland that underscored the significant independent connection between non-alcoholic fatty liver disease (NAFLD) and multiple causes of mortality – especially CV disease – in individuals with type 2 diabetes. The unmet need in this area remains extremely high, as there are currently no approved treatments for NAFLD or the related NASH. Out of the cohort of 133,312 type 2 diabetes patients in Scotland between the ages of 40-89, 1.5% had a hospitalization for NAFLD. The patients who had been hospitalized for NAFLD had a 62% increased risk for CV events, 39% increased risk for CV death, 111% increased risk for all-cause mortality, and 42x increased risk of hepatocellular cancer mortality compared to those with type 2 diabetes who had not been hospitalized for NAFLD (aforementioned increases in risk were all statistically significant). Cancer mortality excluding hepatocellular cancer was not significantly increased. For more on this area, see our NAFLD/NASH competitive landscape, which gives the big picture on drugs in development toward these indications.

  • It’s important to note that NAFLD diagnoses in Dr. Wild’s study were assessed by hospital admissions. This suggests that the group being studied here was type 2 diabetes patients with severe NAFLD, whereas there may be patients in the comparator group who had milder NAFLD that did not require hospitalization. It also suggests that this study likely underestimated the overall prevalence of NAFLD in the population.
  • Dr. Wild emphasized the need for early intervention to prevent NAFLD progression, given the observed risks associated with severe NAFLD in this study. The early stages of NAFLD respond to lifestyle changes similar to those recommended for type 2 diabetes.

Questions and Answers

Q: How secure was the diagnosis of NAFLD in this study? Were you able to adjust for alcohol consumption and differences in BMI?

A: We could not validate the diagnoses of NAFLD in this study. This study came from Scotland, a population known to like its alcohol, and we can’t be sure that we’ve excluded excessive alcohol intake as we don’t have a way to assess that in this registry. We did adjust for differences in BMI.

Effectiveness of Dapagliflozin in Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Patients Compared to Sitagliptin and Pioglitazone

Anastasios Koutsovasilis, MD (General Hospital of Nikaia, Athens, Greece)

This study assessed changes in multiple markers of liver damage when 247 patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) were treated with AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin), Takeda’s TZD Actos (pioglitazone), or Merck’s DPP-4 inhibitor Januvia (sitagliptin) in addition to metformin. It was not clear how participants were allocated between groups – there was no mention of randomization – and the study was open-label. Both pioglitazone and dapagliflozin led to significant improvements in APRI index, a validated lab-based measure of liver fibrosis – the improvement with pioglitazone was roughly double the improvement with dapagliflozin. Sitagliptin did not yield a statistically significant improvement in this index. Ultrasound assessment also found improvements in liver fat with dapagliflozin and pioglitazone. Body weight improved significantly with dapagliflozin but not pioglitazone or sitagliptin. Although the liver fibrosis findings appeared greatest with pioglitazone, Dr. Anastasios Koutsovasilis appeared most enthusiastic about dapagliflozin due to the beneficial effect on body weight. In his mind, the beneficial change in liver fibrosis with dapagliflozin was likely mediated by the improvements in body weight. He suggested in his conclusion that “body weight gain, observed in the pioglitazone group, could exacerbate liver inflammation and other metabolic disorders” – which one audience member took issue with during Q&A, noting that recent clinical evidence on pioglitazone in NAFLD is fairly reassuring. 

Questions and Answers

Q: In your conclusion you mentioned the weight gain with pioglitazone could increase inflammation and CV risk – I don’t think that is fair.

A: Well, I said that the increase in body weight could have an effect.

Comment: Well it has not been proven that the increase in body weight with pioglitazone increases those risks.

Q: What was the usual daily dosage of pioglitazone you used in the study?

A: Most patients were on the 30 mg dose.

Q: Is the beneficial effect of dapagliflozin on the liver direct, or might it be due to the change in body weight?

A: Our assumption is that it is probably because body weight decreased.

Corporate Symposium: Innovating Beyond Glucose Control in Diabetes Care (Sponsored by Sanofi)

Unmet Needs in Adult Patients with Type 1 Diabetes That Could Be Addressed with An Oral Agent and the Sotagliflozin Clinical Development Program

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

In a heartfelt talk, Dr. Anne Peters characterized the heavy demands of type 1 diabetes management as a psychological and physiological battle between hypo and hyperglycemia. She positioned Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin as a future adjunct option to address the needs unmet by insulin therapy alone, namely time-in-range. Dr. Peters vividly described the phenomenon of diabetes distress, which involves feelings of powerlessness, management fatigue, and fear of hypoglycemia – all related to the constant variability in blood glucose that characterizes type 1 diabetes. In the Lexicon-led inTandem clinical trial program, sotagliflozin has shown a promising ability to increase time-in-range and reduce glycemic variability in people with type 1 diabetes (in addition to A1c-lowering, weight loss, and minimal risk of DKA). Dr. Peters argued that time-in-range is a key clinical feature to improve patient quality of life in type 1 diabetes. We couldn’t agree more with her emphasis on this important outcome beyond A1c, and we’re excited by the prospect of an oral adjunct type 1 treatment that address time-in-range – long overdue for people with type 1 diabetes. To this end, recent data from dQ&A highlights time-in-range as the defining factor in patients’ daily lives, and Dr. Peters underscored that this crucial outcome should be elevated to a position of much higher importance in clinical trial design and regulatory decision-making.

  • Agreement on how to standardize this and other outcomes beyond A1c is the first step toward this goal, and Dr. Peters alluded to a soon-to-be-published consensus statement from the “endocrine world” (that is, AACE, ADA, the Endocrine Society, JDRF, the Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange – all of which took part in a recent gathering organized by The diaTribe Foundation called “Glycemic Outcomes Beyond A1c: Standardization & Implementation”) that will do precisely this. On hypoglycemia, the consensus statement proposes a classification system encompassing level 1 (70-54 mg/dl), level 2 (<54 mg/dl), and level 3 (altered mental state and/or requiring assistance). Notably, this is free of subjective adjectives like “mild” or “moderate” since no experience of hypoglycemia is mild from the patient’s point of view.  The consensus statement further defines time-in-range as the percentage of blood glucose readings between 70-180 mg/dl per unit of time, and DKA as either elevated serum ketones or evidence of acidosis (serum bicarbonate <15 mol/L or blood pH <7.3). Our eyes will be peeled for forthcoming publications in Diabetes Care.

Dual SGLT-1 and SGLT-2 Inhibition: Of Mechanisms and Men

Thomas Danne, MD (Kinderkrankenhaus, Hannover, Germany)

In a similar vein, Dr. Thomas Danne discussed the potential of sotagliflozin in the type 2 diabetes population – particularly those with kidney dysfunction. Unlike SGLT-2 inhibitors, which are not currently indicated for type 2 diabetes patients with renal impairment since the drug is filtered through the kidneys (though Dr. David Fitchett’s comments at ESC 2017 suggest there may be some need to change this), sotagliflozin maintains its efficacy even in patients with lower eGFR levels, thanks to its additional inhibition of SGLT-1 transporters in the small intestine. To this end, following promising reductions in A1c, body weight, and blood pressure with sotagliflozin in phase 2 trials, a Sanofi-led phase 3 program for sotagliflozin in type 2 diabetes is ongoing, with new trials slated to begin in 2H17. We appreciated Dr. Danne’s framing of the potential DKA risk with this agent (albeit a smaller issue in type 2 vs. type 1 diabetes) as a solvable problem: “No one wanted to discontinue insulin because of the risk of hypoglycemia, so I certainly hope SGLT-2 and SGLT-1/2 development isn’t hindered by the issue of DKA.” We very much agree that DKA is preventable with proper patient education, and represents a manageable risk when considered in light of the strong benefits of SGLT-2 and SGLT-1/2 dual inhibition from a glycemic perspective, as well as a variety of outcomes beyond A1c, including weight loss, blood pressure reduction, and increased time-in-range.

Enriching Diabetes Care: Technology and New Models for Intervention

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

For Dr. Boris Kovatchev, the future of diabetes technology will revolve around the concept of a “digital twin,” a virtual image of an individual patient incorporating the person’s condition, genetic information, and data from various sensors – a sort of n=1 model that describes someone’s physiology. Dr. Kovatchev said suggested that all digital twins would be stored in a database, periodically updated with lab records and physician opinions so as to constantly improve the representation. In this way, a global precision treatment ecosystem would be stablished, which physicians could use to glean information. In just one example of this database’s far-reaching applications, a new treatment or algorithm could be optimized by testing it across the ecosystem. Dr. Kovatchev also foresees a local ecosystem surrounding each individual comprised of data updated every five minutes from sensors, which could be used to facilitate decision support, predictive algorithms, and closed-loop management.

  • Dr. Kovatchev detailed the pathway to closed loop systems, crediting the UVA/Padova simulator as a key step in reducing time and cost. According to Dr. Kovatchev, “diabetes is the best quantified disease – no one else is even close.” Oh the irony that patients are not doing better, especially insulin users! Dr. Kovatchev and his team developed a computer simulator for type 1 diabetes, which he presented to the FDA in 2007. This project helped significantly accelerate the closed-loop field and served as an alternative to animal studies during early trials of automated insulin delivery algorithms. Testing in humans moved much faster from that point. We wonder how a “digital twin” database in the future could similarly accelerate development of new therapies and technologies.
  • Dr. Kovatchev briefly reviewed three recent artificial pancreas studies (Medtronic 670G, JDRF Pilot trial, home use of bihormonal bionic pancreas) and was impressed with the low rates of hypoglycemia and substantial time in range. He noted that time spent in hyperglycemia still needs to be improved. Dr. Kovatchev found the skiing studies conducted in Virginia and Colorado heartening (ADA 2016), and expressed optimism that closed loop systems will continue to work in real-life settings. 

Integrating Diabetes Care

David Kerr, MD (Bournemouth Diabetes and Endocrine Centre, UK)

Dr. David Kerr’s message was clear: integration of diabetes care cannot be achieved without accurate patient segmentation. To this end, Dr. Kerr, believes technology will be critical. He asserted that smart insulin pens will revolutionize healthcare, and also mentioned the Apple Watch and Garmin Watch as noteworthy devices. Dr. Kerr predicted an explosion in the use of telehealth and foresees expanded use of robots/algorithms, including things like diabetes help chat bots. Dr. Kerr and his team are hoping to work on creating a ride share program using geolocation to match patients with their A1c test appointments, essentially “uberizing” the process– how amazing. (As an aside, at an Aspen Institute session earlier this year, we heard that what was most requested among an AARP session of those over 65 was “Uber by regular phone” where people could call Uber rather than summon it by app.)  This system will have a greater impact on A1c control, he said, than introduction of a new therapy. If we had to guess, we’d agree – the field is certainly not lacking for tools, but better and more intelligent use of them. Still, Dr. Kerr cautioned against creating a digital divide and stressed access and affordability. For him, the current status of diabetes care is inadequate, as evidenced by the racial divide in the US, in which minority populations are disproportionately affected. Differentiating by type 1 vs. type 2 is simply not enough, and all five determinants of health must be considered including: (i) genetics (many products are based on evidence that fails to include minority populations who suffer the greatest disease burden); (ii) biology (variations for absorption and action exist); (iii) behavior (adherence, lifestyle); (iv) psychology (diabetes distress, fear of hypoglycemia); and (v) society (affordability, stigma). The bottom line, according to Dr. Kerr, is that if we continue on the same track, we’re going to bankrupt health systems around the world. Value needs to become the main currency, which Dr. Kerr defines as the sum of quality and experience of care divided by cost.

  • With an eye towards the future, Dr. Kerr detailed several fascinating diabetes tech solutions on the horizon. He described a hypothetical system in which a patient’s glucose readings are interpreted by an algorithm stored within a device and explained to the patient by a projected virtual physician. He also predicted that Amazon and Google will become major healthcare players in the future, and proposed the potential of a “doctor in the house” using voice tools like Amazon Echo or Ok Google to provide on-demand support, advice, and education. In addition to a digital/automated physician, Dr. Kerr foresees each patient having a virtual population clinician, who can evaluate all the patient’s data recorded from various sensors and make recommendations, which are then automatically implemented via smart devices.

Corporate Symposium: Precision Medicine for Type 2 Diabetes (Sponsored by AZ)

Multiple Targets, One Drug – The Future of Combination Therapy

Christina Rondinone, PhD (Medimmune-AstraZeneca, Washington, DC)

Dr. Christina Rondinone of MedImmune, AZ’s biologics R&D arm, positioned GLP-1/glucagon dual agonists as the future of type 2 diabetes treatment – or rather, the future of therapy for cardio-renal-metabolic syndrome. Dr. Rondinone explained how NASH, type 2 diabetes, CV events, and insulin resistance are all interconnected. Each may be a separate disease state, but she emphasized that “we’re talking about one patient – the cardio-renal-metabolic patient.” The next generation of pharmaceutical medicines should go beyond treating the individual diseases and treat the syndrome more holistically, and according to Dr. Rondinone, a dual peptide combining GLP-1 agonism with glucagon holds the most multifaceted potential. Clinical and real-world data has established, rather convincingly, that GLP-1 agonists lower A1c very effectively and promote weight loss via suppressed appetite and greater gastric emptying. Glucagon offers additional weight loss, plus improvements in lipid levels and liver fat. Studies of bariatric surgery have found that oxyntomodulin levels rise post-procedure. This is the same gut hormone secreted after meals to decrease appetite and increase energy expenditure, and it’s thus an intriguing therapeutic target for diabetes, obesity, and related comorbidities. Several companies have oxyntomodulin analogs in the GLP-1/glucagon dual agonist competitive landscape, including OPKO Health (for obesity) and Lilly (for type 2 diabetes and NASH); AZ’s MEDI0382 is a GLP-1/glucagon dual agonist in phase 2 for type 2 diabetes and obesity. Dr. Rondinone went on to review preclinical data on GLP-1/glucagon dual agonists demonstrating decreasing insulin requirements, conversion of white fat to brown fat, and improvements in glucose tolerance. In animal models of NASH, specifically, these dual peptide agents have shown reduced steatosis, reduced fibrosis, and dramatic drops in liver triglycerides. Given Dr. Rondinone’s enthusiasm for this emerging therapy class, it’s great to see a robust competitive landscape, with many candidates in preclinical development, phase 1, or phase 2. We’d certainly like to see faster forward progress. We also love this concept of cardio-renal-metabolic syndrome, an idea also touched upon by Dr. Per-Henrik Groop during a Lilly/BI sponsored symposium, and one receiving increasing attention of late. The outcomes beyond A1c movement goes hand-in-hand with a focus on diabetes comorbidities and complications – it’s no longer acceptable to treat glycemia in isolation, without attending to CV disease, renal disease, NASH, etc.

Posters

Nasal Glucagon for the Treatment of Moderate-to-Severe Hypoglycemic Episodes in Children and Adolescents with Type 1 Diabetes (T1D) in Home or School Settings

L Deeb, H Dulude, M Zhang, S Zhang, B Reiner, C Piché, C Guzman

Lilly presented exciting real-world data on its phase 3 nasal glucagon candidate at ADA, and followed-up with two posters at EASD. On this first poster, we saw how 33 episodes of moderate hypoglycemia (n=14 type 1 patients age 4-18) were all resolved within 30 minutes with nasal glucagon treatment at home or at school. There were no 911 emergency calls, and 15 minutes following nasal glucagon treatment, blood glucose levels rose from a mean 56 mg/dl (moderate hypoglycemia) to 114 mg/dl (range from 79 mg/dl to 173 mg/dl). Adverse events consisted of nausea, vomiting, nasal discomfort, watery eyes, and headache, but these side-effects, reported by a caregiver, were said to be mild/moderate and tended to resolve within one-two hours. Treatment satisfaction scores for Lilly’s nasal glucagon were impressively high: 94% of caregivers endorsed being “relatively satisfied” to “very satisfied.” Although this was a rather small study, it is encouraging to see positive results for nasal glucagon in children and adolescents, a population who could particularly use an alternative to subcutaneous injection and a complicated glucagon reconstitution process.

Nasal Glucagon for the Treatment of Moderate-to-Severe Hypoglycemic Episodes in Real-World Settings in Adults with Type 1 Diabetes

E Seaquist, H Dulude, M Zhang, E Rampakakis, R Rabasa-Lhoret, G Tsoukas, R Conway, SJ Weisnagel, G Gerety, V Woo, S Zhang, D Caballo, M Triest, C Piché, C Guzman.

This second poster determined Lilly’s nasal glucagon candidate (in phase 3) to be successful in treating hypoglycemia in adults with type 1 diabetes (n=69) in the real world. Of 157 hypoglycemia events counted, 96% met the primary objective of return to in-range blood sugar within 30 minutes. There were six instances where this did not happen, and the poster clearly displays how five of these events were resolved within 45 minutes with nasal glucagon treatment. No 911 emergency calls were made, and safety/satisfaction data was also strong. The most common adverse events were nasal irritation (experienced by 82% of participants) and headache (experienced by 54% of the study population), but a majority of these symptoms (60%) lasted one hour or less and were of mild/moderate severity. When asked about satisfaction, 83% of caregivers reported being satisfied or very satisfied. To our knowledge, Lilly plans to submit this nasal glucagon candidate for the treatment of hypoglycemia to FDA in 1H18.

Duodenal Mucosal Resurfacing Demonstrates Sustained Improvement in Glycemic Parameters in Type 2 Diabetes: 12 Month Data

A van Baar, M Nieuwdrop, L Crenier, A Mertens, R Batterham, F Holleman, P Vignolo, G Costamagna, J Deviere, R Haidry, L Rodriguez, MG Neto, J Bergman, and G Mingrone

This poster detailed one-year data from the Revita-1 trial of Fractyl’s Revita DMR (duodenal mucosal resurfacing) procedure, meant to restore insulin sensitivity in people with type 2 diabetes. The intervention was associated with significant and clinically-meaningful reductions in A1c, fasting plasma glucose, and HOMA-IR 52 weeks after a single procedure (involves endoscopic ablation of a portion of the duodenal mucosa). In this single arm, open label study, participants with type 2 diabetes either with (n=15) or without (n=27) preserved beta cell function underwent one DMR procedure, and were evaluated for key endpoints at three, six, nine, and 12 months. Significant A1c reductions were seen after one year, with mean A1c falling 0.9% (p<0.05) in the cohort with no residual beta cell function and 1.4% in the cohort with preserved beta cell function (p<0.05), from baselines of 8.7% and 8.9%, respectively. For both groups, peak A1c reductions occurred at the nine-month mark, reaching study-wide lows of ~7.6% and ~7.4%, respectively. In slight contrast, fasting plasma glucose dropped sharply in the first three months of the study and remained plateaued at this low level. At one year, from a baseline of ~190 mg/dl, fasting sugars fell a significant 37 mg/dl for the cohort with no residual beta cell function (p<0.001) and fell 49 mg/dl for the cohort with preserved beta cell function (p<0.001). HOMA-IR, a measure of insulin resistance, followed a similar pattern, falling from a baseline of 9.0 to 6.0 after one year in the cohort with no residual beta cell function (p<0.05) and from 12.5 to 6.5 in the cohort with preserved beta cell function (p<0.001). The DMR procedure also produced significant decreases in body weight, but the absolute differences were slight. After one year, average BMI fell from 32.5 kg/m2 to 32 kg/m2 in the cohort with no residual beta cell function (peaking at 31 kg/m2 after nine months) and from 33 kg/m2 to 32.5 kg/m2 in the cohort with preserved beta cell function (peaking at 32 kg/m2 after three months).

  • These results support the benefit of DMR for glycemia and insulin resistance in particular, though we are slightly underwhelmed by the magnitude of these improvements. Previous data from the first in-human trial of Revita DMR showed a more impressive 2.1% A1c reduction at six months, after peak efficacy of 3.5% decline at three months – still, even less than we might have hoped, given the high baseline A1c of ~9%. Follow-up for the Revita-1 study will continue until January 2019, according to ClinicalTrials.gov, and we look forward to learning longer-term data to gauge durability of metabolic effects.
  • Notably, the larger (n=110) Revita-2 trial was launched by Fractyl in May 2017 to more rigorously assess the efficacy of this procedure in a placebo-controlled setting, randomizing participants to DMR endoscopies vs. a sham procedure. The study is estimated to run until April 2019, with primary completion in October 2018.
  • In a separate call with our team, Fractyl CMO Dr. David Maggs emphasized that the DMR procedure is very patient-friendly: It’s a one-time treatment that circumvents the issue of medication adherence. That Revita-1 trial participants experienced significant glycemic improvements after a single procedure is certainly noteworthy, in our view. Moreover, we were pleased to learn from Dr. Maggs that ongoing and future studies may collect patient-reported outcomes and quality of life metrics, as we imagine this data could be quite strong in favor of Fractyl’s intervention. “Both type 1 and type 2 diabetes confer a massive daily burden,” Dr. Maggs stated, “and this is a way to possibly regain some metabolic control without a big effort on the patient’s part.” We’re intrigued by this potential, and though issues of cost and reimbursement will be critical as this therapy candidate approaches the commercial market, we’re glad to see continued forward progress from this innovative approach to insulin resistance and type 2 diabetes.

Crossover Study Comparing Bioavailability of a Capsule Formulation of the Glucagon Receptor Antagonist LGD-6972 to an Oral Solution Formulation in Healthy Subjects

J Pipkin, E Vajda, L Biernat, D Klein, Y Li, M Zangmeister, R Zhou, L Zhi, and K Marschke

In this phase 1 study, a new capsule formulation of Ligand’s glucagon receptor antagonist LGD-6972 demonstrated bioequivalence to the original solution formulation on a number of PK parameters. Ultimately, this poster data supports the use of this patient-preferred capsule formulation in ongoing and future phase 2 studies. In a crossover design, participants with type 2 diabetes (n=12) were randomized to receive a single 15 mg dose of LGD-6972 in the form of either three 5 mg capsules or 4 ml of 3.75 mg/ml solution. Following an 18-day washout period, participants received a second single dose of the other LGD-6972 formulation. The two formulations were virtually identical in terms of blood plasma exposure (as measured by area under the concentration curve), as well as time to maximum concentration (six hours) and half-life (38-40 minutes). Only maximum concentration differed slightly between the two formulations (348 ng/ml for the capsules vs. 322 ng/ml for the solution), due to high inter-subject variability. Furthermore, as was confirmed in past phase 1 studies, no serious adverse events were reported and only five participants reported any study drug-related adverse events (GI discomfort, chest discomfort, and fatigue). Ligand announced positive topline data from a phase 2 trial of this candidate in early September, and management has previously suggested that the company will seek a dedicated partner before initiating phase 3.

Diabetes Technology

Symposium: Continuous Glucose Monitoring Before and During Pregnancy in Women with Type 1 Diabetes: Results from CONCEPTT; a Multicentre Multinational Randomized Controlled Trial

Results

Rosa Corcoy, MD, PhD (Hospital de la Santa Creu i Sant Pau, Barcelona, Spain) Denice Feig, MD (Mount Sinai Hospital, Toronto, Canada) Elisabeth Mathiesen, MD (University of Copenhagen, Denmark) Helen Murphy, MD (Cambridge University NHS Foundation, Cambridge, UK)

The JDRF-funded CONCEPTT RCT testing CGM in pregnant women (n=215) showed positive neonatal outcomes with Medtronic’s older Guardian CGM. Though not the primary endpoint, significantly improved neonatal outcomes were the headline – CGM drove a significant reduction in the incidence of large for gestational age (OR=0.51, p=0.02), 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). The numbers needed to treat (NNT) were compelling – NNTs of just 6-8 women with CGM to prevent one of those negative outcomes. The primary A1c endpoint showed a small -0.2% A1c advantage for CGM at 34 weeks (p=0.02). However, 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 per day in hypoglycemia (3% vs. 4%; p=0.1). Results were published in The Lancet, a major visibility win!

As expected with the older Guardian sensor, wear time was lower than in more recent CGM studies – 70% of pregnant participants used CGM for 75%+ of the time. In addition, ~80% of women reported frustrations with the CGM device. We brought this limitation up in Q&A (it was not mentioned), and would guess the trial probably underestimated current CGM’s potential benefit in pregnancy. What would outcomes have looked like with G4/G5, FreeStyle Libre, or Guardian Sensor 3? Since the trial took three years to run, a year to plan, and spanned six countries (Canada, UK, Spain, Italy, Ireland, and the US), getting the latest devices in was obviously a challenge. The study concludes that “CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy” – hear, hear! According to The Lancet publication, it’s also the first study to indicate potential for improvements in non-glycemic health outcomes from CGM use. Nice!

There were a few big surprises from this trial: (i) pump+CGM outcomes looked worse on a few notable endpoints vs. MDI+CGM outcomes (see below); (ii) CGM had no significant benefit on severe hypoglycemia; and (iii) the difference in outcomes was quite large between some countries (a fascinating source of commentary from Dr. Elisabeth Mathiesen). See more details below. We look forward to cost-effectiveness data when it is published. The trial also included a second arm testing CGM in women planning pregnancy, but showed no A1c benefit at 24 weeks or conception.

  • An editorial from Dr. Satish Garg in The Lancet was very positive, with a nice beyond-A1c mention: “We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes and ; thus endocrine and obstetric medical societies could consider advocating or recommending revising their guidelines accordingly.” We wonder if this study could help validate time-in-range as a meaningful surrogate endpoint, independent of A1c. The study follows a very positive hybrid closed loop study during labor/pregnancy from Dr. Helen Murphy and colleagues at Cambridge, which was published in NEJM in 2016 – automation is a definitely an exciting frontier for pregnancy, along with use of next-gen devices! Dr. Murphy did mention in Q&A that a FreeStyle Libre in pregnancy study is ongoing.
    • Neonatal outcomes – paramount in a diabetes pregnancy study – were very positive in favor of the CGM group. Babies from mothers who wore CGM were less likely to be large for gestational age (LGA; >90th percentile – 53% in CGM group vs. 69% in control group; p=0.02), lower incidence of neonatal hypoglycemia requiring IV glucose (15% vs. 28%; p=0.03), were less likely to require NICU admissions >24 hours (27% vs. 43%; p-0.02), and had significantly lower median customized centile (a measure of birthweight standardized for maternal ethnicity, height, weight, and neonatal sex and gestational age at delivery – 92% vs. 96%; p=0.05). Further, infants from mothers in the CGM group had hospital stays reduced by nearly a full day (3.1 days vs. 4.0 days; p=0.02). Co-PI Dr. Denice Feig pointed out that not only were the median customized centiles lower in the CGM group (across each of the four study sites), but the lower portion of the box plot was much wider, indicating that many more babies were closer to the normal weight range than in the control group. The numbers needed to treat (NNT) were quite compelling: Six women with CGM prevented one event of LGA; eight women with CGM to prevent one event of neonatal hypoglycemia; and six women with CGM to prevent one NICU admission over 24 hours. 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. There were no differences in serious adverse pregnancy outcomes (miscarriage, stillbirth, termination, or congenital anomaly), obstetric outcomes (hypertensive disorders in pregnancy, C-section, maternal weight gain, maternal length of hospital stay), or gestational age at delivery between groups.
    • We would’ve loved to see primary outcomes beyond A1c, but a JDRF representative told us that a primary neonatal outcome would’ve required much more statistical power – he estimated 10,000 participants, compared to the 215 pregnant women in this study! We’re not all that familiar with pregnancy outcomes and their frequency, but in this case, it seems to have made sense to not power for neonatal events. The same rep also mentioned that there will be some follow-up of both baby cohorts to look for long-term impacts of maternal CGM use on offspring development.
  • A subgroup analysis of pump vs. MDI CGM users revealed that pump users achieved lower reductions in A1c (-0.32% vs. -0.55%; p=0.001) and slightly less time spent in hypoglycemia (according to the speaker, though we didn’t notice a large difference in the publication’s appendix) However, pumpers had concerning higher rates of gestational hypertension (14.4% vs 5.2%; p=0.02), preterm delivery (43.2% vs 36.2%; p=0.04), and NICU admissions for greater than 24 hours (44.5% vs. 29.6%; p=0.01) than MDI users. This result was surprising, especially since pumpers at baseline seemed to be more engaged with their health (lower rates of smoking, take preconception vitamins, booked appointments earlier, …). Infants of pump users also experienced higher rates of hypoglycemia requiring IV dextrose (31.8% vs. 19.1%; p=0.03), although once adjusted (not specified, but presumably for baseline maternal characteristics), the difference was no longer significant. There were no other observed significant differences in diabetes status or neonatal outcomes. These results are disappointing for pump users, as it is more expensive therapy that did not deliver better outcomes in this study. Why? We wonder if pumps psychologically loosen eating restrictions, while the hassle of injections might make expectant mothers more likely to hesitate before eating or choose different foods (pure speculation on our part). We look forward to seeing the cost-effectiveness data, and certainly, this is very positive news for MDI+CGM.
    • Could higher proportions of MDI users in clinics that tend to have better outcomes (see Dr. Mathiesen’s call to “Learn from Spain” below) underlie MDI vs. pump discrepancies? In other words, Spain had a significantly lower rate of LGA than a number of other countries (even in the control group vs. other countries’ CGM groups) – were Spanish patients simply more likely to be on MDI?  
  • The 0.2% A1c advantage for CGM at 34 weeks was characterized as “small,” and in our view, outweighed by the time-in-range and time-in-hyperglycemia data. We must go Beyond A1c in studies like this! CGM users saw a 0.54% decline in A1c by 34 weeks (baseline: 6.8%) vs. a 0.35% decline in the control group (baseline: 6.95%) – the 0.2% difference was statistically significant (p=0.034), though it missed the goal for a 0.5% difference and comes in smaller than recent studies like DiaMonD and GOLD. Strangely, ~20% of A1c samples were missing, though the investigators do not believe it impacted results. The time in range (63-140 mg/dl) data were very strong: pregnant women on CGM spent 100 more minutes per day in the tight target range and 72 fewer minutes per day in hyperglycemia relative to the control group at 34 weeks. Time in hypoglycemia did not statistically favor CGM (~14 minutes better with CGM), given low rates in both groups (3% vs. 4%; p=0.1). Coefficient of variation favored the CGM group at 34 weeks (32% vs. 34%), but just barely missed statistical significance (p=0.058).
  • Despite raising a number of concerns about the study, and especially, diabetes pregnancy care overall, Dr. Elisabeth Mathiesen (Head of Diabetes Treatment at the Copenhagen Centre for Pregnant Women with Diabetes) concluded that CGM “is the future” and that the CONCEPTT study “will change the future for pregnant women with diabetes.” She began by acknowledging that CGM proved effective in the study, reducing A1c greater than in the control group and preventing many adverse neonatal events. However, she found the lack of an effect on maternal severe hypoglycemia “a little disturbing” and pointed to the downsides of using CGM (80% of users reported problems and 30% used the sensors less than 75% of the time) – again, we believe the use of a better sensor would’ve made a difference on both of these points. Other points of weakness for Dr. Mathiesen were generalizability (the study took three years to enroll at 31 centers) and moderate endpoint data collection (86% of A1c values; 77% of sensor data). In light of this data, will Dr. Mathiesen implement CGM in all pregnant women as suggested by the study authors? In favor of “yes,” she said, many will ask for it, the study recommends it, and her “stomach feeling” is that CGM is the future. On the other hand, she questioned the quality of treatment in the study overall (more in first bullet below), and worried that the cost of CGM will prompt reduction in other aspects of care –  “the cost of CGM use in 20 pregnant women is the cost of the salary of one working nurse.” Conversely, if CGM prevents expensive neonatal outcomes, it should drop healthcare resource – it is an upfront investment with upside, especially in pregnancy, when there are two bodies who can benefit. In our opinion, pregnant women with diabetes, who clearly have a lot at stake and are asked to keep their blood glucose levels to very tight ranges (63-140 mg/dl in this study), need access to their glucose values at all times to stay in range most of the day . The glycemic findings from this trial were not as strong as some would have hoped, but they still suggest definite benefit (+100 minutes/day), in tandem with improved neonatal outcomes. We hope that economic analysis and/or follow-up studies with more accurate and user-friendly sensors will tip consensus more toward an unequivocal “yes.”
    • Dr. Mathiesen pointed out the care that pregnant women were getting in the trial, even in the CGM group, presenting a slide with the simple question: “Treatment of Excellence?” She questioned whether a lack of A1c guidelines for pregnancy in the two main countries of this study (Canada and UK) impacted quality of care. In the CGM group of CONCEPTT, A1c late in pregnancy was 6.4%, there was a 38% rate of preterm delivery, and 53% rate of LGA. While these figures compared favorably to the control group, “routine results” from her center in Copenhagen are significantly better: In pre-publication data from this clinic (n>400), A1c late in pregnancy is 6.1%, preterm delivery rate is 17%, and LGA rate is 38%. Dr. Mathiesen then showed a figure from earlier in the presentation depicting LGA rates from the control and CGM groups in Canada, the UK, Italy, and Spain (below), and the clear message “Learn from Spain.” Indeed, the rate of LGA in the Spanish control group was less than half that in the other countries’ control groups, and even lower than that of the CGM groups in two of the three other countries! This discrepancy, to her, is “probably more important” than the influence of CGM on pregnancies. She implored attendees to “please listen to how [Dr.] Rosa [Corcoy] (an endocrinologist in Barcelona) is treating her patients. It probably has to do with diet – carb counting, weight gain, and attitude.”
  • Dr. Murphy gave the perfect response to Dr. Mathiesen’s criticism: “No doubt, if we could clone Dr. Mathiesen and put her in every center, we could get much better glucose control. This took place in 31 centers. What we have is generalizable. A1c, with all standardizations, is still different. It’s not correct to compare a single center to labs across 31 sites.
    • During Q&A, Dr. Feig noted that we don’t know the relative contributions of glucose control throughout the whole pregnancy vs. in the 24-48 hours pre-delivery on neonatal outcomes. Existing literature, she said, is “quite variable” about the contribution during labor, but she believes it may contribute a little. It’s an interesting scientific question, especially as we think about automated insulin delivery and the previous finding from Dr. Murphy’s NEJM study. Theoretically, better glucose control with less hypoglycemia would be good for the mother, so even if 100% of the contribution on neonatal glycemia were from the labor period and just prior, we still hope that the mother could be given access to CGM.
  • Dr. Mathiesen began her commentary by applauding the PIs – Drs. Feig and Murphy – for their bravery in forging ahead and conducting an RCT in pregnancy. “Until these two women dared to take it on, no one would dare. These women are truly brave.” Hear, hear!

Symposium: Achieving Improved Compliance to Diabetes Care: The Common Task for Care Providers, Health Systems and People with Diabetes

Healthcare Provider Perspective: How Mobile Applications Contribute to Improving Compliance

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

Mills-Pensinsula Medical Center's Dr. David Klonoff discussed the factors that will augment digital health adoption and suggested how to lower patient and HCP barriers. He broke down the primary factors that each stakeholder looks for in digital health products: Usability (for patients), clinical benefit (for healthcare providers), economic benefit (for payers), security (to satisfy product regulators), and data privacy (to satisfy legal regulators) – of course, there is plenty of overlap in this list. He went into more detail on how to make these products more appetizing for patients and providers: Providers look for interoperability with digital systems (something he believes the market will enforce in the long run), EMR compatibility, compatibility with professional standards, and safety in a mobile platform environment (Does the phone/software prioritize the medical app while you’re playing Angry Birds?.. Something FDA is certainly aware of and taking into consideration as companies seek to use phones as primary displays and control device functions from apps). Dr. Klonoff believes patients look for easy log-in (though noted simplicity must be balanced with security), simplified data and alert displays, no increase in (or less) work, time, and cost, coupled with improved outcomes and “no friction.” We think all of these can be boiled down to a slightly modified version of his third bullet: Patients will widely adopt digital health for diabetes if the quality of life and/or health benefits outweigh the burden of using them. As that balance improves, more will adopt and use the products. He went on to speak briefly about the quality of digital health clinical data, a lack of research into the benefits of social media (prominent patient advocate Mr. Bastian Hauck pushed back), and pharma’s growing involvement in digital therapeutics.

  • Dr. Klonoff listed a number of common flaws he sees in mHealth data generation and analysis: “mHealth clinical trials have produced good outcomes, but aren’t necessarily producing the best data of all time.” He advised audience members to first ask whether or not the data was generated via a randomized controlled trial. “Some digital health companies advocate for getting rid of RCTs – they say that once the trial is done, analyzed, and published, the technology is out of date and a next-gen product is on market. Make sure you’re looking at good data.” He didn’t offer many alternatives, except for doing n=1 trials at scale, wherein one patient and all his/her possible confounds are examined at a time, and then all conclusions from all patients are analyzed – sort of like a meta-analysis of individual level data. RCTs are certainly still needed, but we do see value in complementing them with real-world data (as does FDA), since the technology innovation cycle is rapid and apps are often multi-modular and therefore difficult to study in a simple RCT.
    • We agreed wholeheartedly with Dr. Klonoff’s caveat to look out for a small n, big p, and small t. Indeed, it is fallacious to draw definitive conclusions from studies with small sample sizes, statistically insignificant differences, and/or performed over a short time period. Dr. Klonoff suggested that trials in digital health have to be at least a year, but then suggested products must constantly be refreshed to maintain engagement.” We assume the only way for companies to navigate this balance is to choose one side, or do one-year studies with built-in product updates throughout.  
  • Patient advocate and active #dedoc member, Mr. Bastian Hauck – thinking that Dr. Klonoff had denigrated social media during his talk – pushed back during Q&A. Dr. Klonoff later clarified via email that he believes research into the benefits of social media on treatment adherence is lacking – he didn’t comment on overall benefit. To be clear, Dr. Klonoff doesn’t discourage social media use – he just doesn’t outright encourage it either based on the evidence he has seen. Mr. Hauck’s passionate comments were worth sharing anyhow: “The counterpoint is, we always talk about social media without defining it. We’re not doing anything new. We don’t need RCTs here, in my opinion. We have a lot of evidence showing peer-to-peer support, getting patients together to talk things through, is helpful. Social media is just a new means of communication. Same community work, just at a much faster pace. We’re always trying to scale things up and make things digital, and we’re not there yet in many cases, like AI, but with social media, we are already there. Making it faster and scaling. Yet we’re still getting so many counterpunches. We don’t need evidence to prove that communication is going to work.” The only reason we can think of for performing an “RCT” of social media use is to demonstrate benefit so that hesitant healthcare providers would more actively direct their patients to try it. On the other hand, social media is free, so there’s little barrier to access, and therefore little need to convince payers that it’s effective (though perhaps they could financially incentivize people to use social media).
  • When Dr. Klonoff first became a doctor, he noted that every innovation at big meetings was a drug. “Now, what really gets the buzz is new software and digital therapeutics,” he said. He pointed to Lilly’s FDA-cleared Go Dose, Novo Nordisk and Glooko’s recently-launched Cornerstones4Care, and Sanofi’s partnership with Evidation Health to mine behavioral trends and outcomes for insights into new product design and how to deploy current products. The list goes on – and this digital explosion is only starting to take off. Where will it be in five years?

Patient Perspective: How Mobile Applications Contribute to Improving Compliance

Kyle Jacques Rose (mySugr, Vienna, Austria)

mySugr’s Mr. Kyle Jacque Rose shared insights from IDF Europe’s 16-page position paper on mobile apps in diabetes, stressing the fallibility of the “one-size-fits-all” model. Patients require vastly different levels of specificity from their apps on their journey from prediabetes diagnosis to familiarity with one's chronic condition – a concept Mr. Rose illustrated through carb counting apps. During prediabetes, learning how to begin evaluating lifestyle habits including food choice is an important prevention step like what is offered in Accu-Chek View or Omada's programs. When first diagnosed, just tracking total carbs would be a victory for most patients, a feature offered by simple nutrition databases. From there, Mr. Rose suggested that patients might move on to an application like Calorie King, which allows users to track whole nutrition (macronutrients). As acquaintance with the disease increases further, patients can begin to identify interactions between nutrition choices and blood glucose – “interactive problem solving” – with the help of an app such as Meal Memory. (Dexcom recently hired Meal Memory founder Doug Kanter, a very big win.) And finally, deep data analysis (e.g., Medtronic’s CareLink + IBM Watson) might help patients to figure out how to handle “all foods.” We often consider that one app may not be designed optimally for every person, but we appreciated this perspective that needs across the diabetes journey change just as drastically as between individuals, and found it to be a good argument for the open digital ecosystem Mr. Rose described. On the one hand, there were 165,000 health care-related apps as of March 2016 – plenty to fill every niche imaginable – though a vast majority are not validated. Mr. Rose also surveyed the different functions of diabetes apps, touched on their functions beyond improving glycemia (adherence, motivation/inspiration, logging), and suggested that cost is a major hurdles to access in some cases, and emphasized that there are important differences between apps that are important for both patients and HCPs to recognize. We believe FDA guidance is fairly well laid out for what counts as a mobile medical app vs. not, though perhaps there is still plenty of nuance overall, especially on decision support and device connectivity.

  • A big point of excitement for Mr. Rose is the potential for smart pens to “bring the connected cloud to the mainstream.” He alluded to his experience in numerous automated insulin delivery trials, sharing that giving up control to a system is very exciting, but scary for many – when he was in a Montpellier trial with Prof. Eric Renard, it took him a few days to stop performing fingersticks and trust the system. Soon after, he felt like he was in good hands! Automated insulin delivery systems, he continued, are particularly compelling if national insurers provide access, but otherwise, this technology may only be available to a select few. Even if national insurers do get on board, connected pen-based automated insulin titration systems will likely expand access to the broader population, both for those who can’t afford pumps and for those who would prefer to not wear one. It will fascinating to see how payers compare these two options, and whether automated insulin pump-based systems show superior outcomes to automated insulin pen-based systems. And if so, what incremental outcomes will encourage payers to reimburse for a pump over MDI?

Symposium: Advances in Infusion Sets and Insulin Pumps

Glucose Monitoring and Insulin Delivery: a Single Device?

William Tamborlane, MD (Yale School of Medicine, New Haven, CT, USA)

Dr. William Tamborlane reviewed much of the back half of his lecture from AACE back in May, spelling out the “Inconvenient Truth” of today’s diabetes management (poor), illuminated the light at the end of the tunnel (new tools, including adjunct therapies), and shared a 670G wish list from two colleagues who were in the pivotal study. Dr. Tamborlane, a diabetes technology pioneer, was enthusiastic about adjunctive therapies in type 1 diabetes – “they’re obviously not a cure, but there’s lots of excitement at this meeting, particularly about SGLT-2 inhibitors in type 1.” He was of course referencing DEPICT 1 (AZ’s trial of Farxiga (dapagliflozin) in type 1 diabetes) and inTandem 3(Lexicon’s SGLT-1/2 inhibitor, sotagliflozin.) We hope to see Dr. Tamborlane’s Yale group study SGLT-2s on top of closed loop, something his colleague Dr. Eda Cengiz has mentioned in the past. Dr. Tamborlane later shared some MiniMed 670G feedback provided by two of his colleagues who were in the pivotal trial: They’d like to: (i) be exited from closed loop (Auto Mode) less often; (ii) adjust target glucose levels (it’s fixed at 120 mg/dl); (iii) manually set temporary basal rates for periods of stress; (iv) manually give correction doses that correct to glucose levels <150 mg/dl; and (v) track glucose and insulin delivery remotely on smartphone apps. We note that this list has grown by one since we last heard him speak at AACE, with the latest addition of “fewer exits.”

Oral Presentation: Improvements in Insulin Therapy

The Effect of an Automated Bolus Calculator on Glucose Control, Glucose Variability and Quality of Life in Patients with Type 1 or 2 Diabetes Treated with Insulin Pumps

Lian van Meijel, PhD (Radboud University Medical Centre, Nijmegen, Netherlands

A randomized controlled trial (n=32) found that use of an automated bolus calculator improves glycemic variability, but does not change A1c, instances of hypoglycemia, quality of life, or glucose levels in type 1 adults with good A1c control and pump experience. While previous studies have shown that automated bolus calculators can reduce A1c and improve quality of life, the majority have consisted of patients new to pumps and with high A1c values. In this four-month study, 32 type 1 adults who had used pumps for at least six months and with A1c <10% (a bit high to constitute “reasonable control” in our view), were randomized to receive either an automated bolus calculator or continue with standard care. All participants received instructions on carb counting and took an exam prior to randomization. Although glucose variability did significantly improve in the experimental group while it remained unchanged in the control, there were no observed significant differences in glucose levels, LBGI and HBGI scores, hypoglycemia frequency, and quality of life both within and between groups. It’s interesting that improvements in glycemic variability were achieved, yet this did not impact anything else – we can’t recall seeing that in a study before. This was a small study and both groups consisted of experienced pumpers with verified carb counting ability, so it’s perhaps not surprising that the calculator didn’t augment A1c or other parameters drastically. We expect that the meal dosing paradigm is going to change quite drastically in the coming years with automated insulin delivery – what’s the best way optimize the patient-automated algorithm interface to achieve maximum time-in-range? Meanwhile, how will bolus calculators benefit MDIs when they are more widely integrated into apps paired with smart pens? Interestingly, the researchers had originally intended to enroll type 2 adults as well, but they were only able to find two eligible participants and therefore decided to exclude them.

Corporate Symposium: Dexcom Continuous Glucose Monitoring: Clinical Outcomes and Next Generation Technology (Sponsored by Dexcom)

Introduction to the Next Generation Dexcom CGM Technology

Jake Leach (Dexcom, San Diego, CA)

Dexcom SVP Mr. Jake Leach shared two new updates on the pipeline: (i) the next-gen follow-on to G5 in Europe will not be called “G6” (it goes beyond the US version of G6 to include “additional features”); and (ii) there is ongoing work to integrate smart pens with Dexcom’s G5 app, Clarity, and Share (two pictures included for the first time). We also heard enthusiasm for smartwatches, and new adhesive study results. Mr. Leach’s closing comment summarized the pipeline vision nicely: “Imagine a world where fingersticks are completely eliminated, CGM is the first tool for all newly diagnosed patients, and insulin delivery is optimized using CGM-integrated smart pens and automated insulin delivery systems.” See the details below!

  • In discussing the next-gen pipeline for the EU audience, Mr. Leach did not once use the term “G6.” He revealed in Q&A (we asked!) that the EU follow-on to G5 will actually not be called “G6” – it will have “additional features” beyond the US version of G6. (The latter will be submitted to the FDA by the end of this month and include 10-day wear, one calibration per day, a one-button inserter, a 30% smaller profile wearable, and acetaminophen blocking.) Mr. Leach confirmed that the next-gen Dexcom product for Europe “depends on regulatory and clinical studies,” suggesting it is indeed still in progress. We’d infer factory calibration is a clear additional EU feature for the G5 follow-on, given all the mentions of it in the pipeline (e.g., showing the G6 pre-pivotal data from DTM 2016). We’d guess 14-day wear is also in the cards, as there was a separate mention of this today (“we are now examining sensor performance out to 14 days”) and previous expectations for G6/Verily. Both features are strategically smart for Dexcom to incorporate in the immediate next-gen in Europe, as it must stay competitive with Abbott’s 14-day, factory calibrated FreeStyle Libre – waiting a bit of time to get these features in makes sense. We’re not sure what other “additional features” will be included, though Mr. Leach did discuss a new sensor adhesive we’ve never heard about before (more below). In the US, 14-day wear and factory calibration are expected in the first-gen Dexcom/Verily product (timing update to come in the 3Q17 call).
  • On the smart pen front, Mr. Leach confirmed that Dexcom has smart pen “partners” (none disclosed) and is currently working on integrating insulin injection data straight into the G5 app, Dexcom Clarity, and Dexcom Share. The blue pen shown on the slide was not branded (see below), though it looks fully disposable and without any add-ons. A separate slide with smart pens showed Lilly’s Luxura and Novo Pen Echo (see second picture below). This was the deepest confirmation yet of Dexcom’s commitment to this critical area, and the first suggestion that it could potentially partner with Novo Nordisk and Lilly (our speculation). Which of the three insulin companies will get there first with a compelling, easy-to-use smart pen?

  • Mr. Leach spent more time than ever on Dexcom’s commitment to additional wearable displays, including Apple Watch, Android Wear, Fitbit Ionic (announced last week), and direct CGM transmitter-to-watch communication (“untethered,” meaning no nearby phone needed). We were glad to hear the latter following Apple’s plans for WatchOS4 and Dexcom CGM shared in June. To be clear, Dexcom has never given timing on launching direct CGM-to-Apple Watch transmission, presumably because the regulatory path is under discussion. (This “Native Core Bluetooth” feature in WatchOS4 will launch this fall.) We see this direct CGM-to-watch communication as highly compelling for CGM users, especially once Watches have Wifi and cellular built in (e.g., pediatrics could wear a watch alone and still use Dexcom Share). Mr. Leach shared definite excitement for the brand-new Fitbit Ionic integration partnership, but did not offer further details beyond our coverage last week. As we’ve come to expect, a big R&D goal remains “building an ecosystem of devices compatible with Dexcom CGM.”
  • We also heard some compelling marketing claims for the next-gen, one-button sensor applicator that will now launched with G6: 76% of pediatric subjects rated the applicator as “didn’t feel anything” vs. 30% for G5. In addition, 98% of pediatric subjects rated the new applicator system as “very easy” or “Somewhat easy” compared to 59% for G5.
  • Mr. Leach shared a never-before-seen 14-day adhesive patch survival study (n=21 adults). With the new patch, Dexcom found a 20% improvement in survival at 14 days vs. its current G5 patch (~90% vs. ~75%). The curves started to separate at day 10, and this also suggests 14-day wear is very much on the radar. Mr. Leach said this new adhesive will be included in “next-gen devices,” though it wasn’t clear if this will also apply to the soon-to-be-submitted G6 in the US. We wonder if this new adhesive will also reduce site reactions that prevent some from using CGM.
  • We’ve long known acetaminophen blocking is planned for G6, though Mr. Leach showed a 24-patient study that confirmed the benefit relative to G5. Dexcom gave participants a 1000mg dose of extra strength acetaminophen (paracetamol), showing a +60 mg/dl peak bias for G5 and little-to-no change for the next-gen sensor. Said Mr. Leach, “We have high confidence in the superior interference.” This will also help with FreeStyle Libre competition, as Abbott’s sensor doesn’t have acetaminophen interference.
  • Dexcom is “excited” with the Verily partnership progress, and more information is expected at “upcoming meetings” as Dexcom “starts to move into clinical trials and feasibility studies.” Mr. Leach showed the same slide we’ve seen throughout the year, with two generations of Verily systems both expected to be 14-day wear, real-time CGM, and factory calibrated (low-cost expected in gen two). The 2Q17 call did not give a firm timing update on Verily gen one (previously planned for end of 2018); an update should come in the 3Q17 call.

Corporate Symposium: Shaping the Future of Integrated Diabetes Management Solutions (Sponsored by Roche)

Features and Performance of the New Eversense Implantable CGM System

Tim Juergens (Roche, Basel, Switzerland)

Roche’s Tim Juergens showed attendees the company’s open diabetes management ecosystem (“available soon”), heavily featuring Senseonics’ Eversense implantable CGM, recently-acquired mySugr, and even a reusable smart pen available in cooperation with Pendiq in Germany in 2H17 (per an under-the-radar German press release). The company’s own Accu-Chek Insight CGM was absent from the forward-looking slides, and a rep told us Roche will not launch further versions of Insight. Presumably it will stay on the market in its current limited launch form, but the focus moving forward will be Eversense. Roche’s own Accu-Chek Insight underwent a limited launch in the EU last year (we’re not sure of the size), but a Roche scientist noted that, while it performs up to par with the competition, it doesn’t add anything novel, unlike the implantable 90-180-day Eversense. As a reminder, Roche currently distributes Eversense widely, invested ~$30 million in the company in May, and is supplying the Accu-Chek Insight pump for the development of an automated insulin delivery system with Senseonics and TypeZero. We wonder if Roche might even buy the implantable CGM manufacturer, as Senseonics’ current market cap of ~$300 million arguably puts it in M&A reach. Also included in Roche’s proposed open diabetes ecosystem are Roche solutions (Emminens eConecta, Accu-Chek Smart Pix, mySugr, BGM, pumps,), third party solutions (Senseonics Eversense, Pendiq connected pen), and the data backbone (perhaps in reference to the new, slightly vague partnership with Accenture).

  • Mr. Juergens presented a visually-appealing depiction of a “day-in-the-life” with Roche’s integrated diabetes ecosystem. You can see our photos of the slides here. We definitely recommend taking a look – you’ll see the Eversense sensor and mySugr prominently displayed, examples of feedback from a mySugr-affiliated diabetes nurse educator (“Your blood glucose went a bit low just before you woke up. Having looked at your data, I recommend your normal breakfast but cover it with a smaller insulin bolus”), automated insulin dose titration/connected pen, automated carb counting, support through a smartwatch (“Please stop running…arrhythmia detected…Your doctor will reach out to you”), payer and pharmacy integration, care delivery, and caregiver communication. This was a mock-up and seems to be in the concept stage, but we like the vision – acquiring elements and forging partnerships to create a seamless diabetes care experience. This is surely a far cry from the product-based business model , but theoretically the direction we’ll see more diabetes tech companies head. Of course, executing on this vision and getting payers to buy in is the truly hard part. Can Roche pull it off? Also in this model, Mr. Juergen indicated that Roche will push forward with prevention programs, early diagnosis, and decision support, in addition to value-based payment models.

  • The positive stated ambition of this ecosystem is to “enable people with diabetes to spend more time in range and experience true relief.” Nice outcomes beyond A1c! According to Mr. Juergen, this care delivery redirection is necessitated by more engaged and informed patients – higher health literacy, increased use of smart personalized health apps, and online education.

Features and Performance of the New Eversense Implantable CGM System

Lynne Kelley, MD (Senseonics Holdings, Inc., Germantown, MD)

In a Roche-sponsored symposium, Senseonics CMO Dr. Lynne Kelley shared that the implantable Eversense CGM has now been tested in over 500 patients to date (>100,000 sensor wear days). Subtracting the 161 EU and US pivotal trial participants, that means that over 340 patients have been implanted in the EU since the limited launch began last June. This patient base is in line with revenue, which totaled $800,000 in 2Q17 (<$2 million cumulatively). The company expects availability in 14 countries by the end of the year and a pretty big uptick in sales: $4-$6 million expected for 2H17. As a reminder, active discussions with FDA continue – management still expects there will be an advisory committee panel in late fall with approval hopefully soon after (the last update projected a 4Q17 approval). Dr. Kelley also provided a timing update on the clinical study for the Senseonics/Roche/TypeZero automated insulin delivery system, hoping that it will begin prior to the end of this year (moved up from “early 2018” timing shared on the 2Q17 call). Elsewhere on the pipeline front, Dr. Kelley showed the Eversense Apple Watch display and indicated that the company is “looking toward compatibility on a variety of other mobile devices.”

  • According to Dr. Kelley, there have been very few reports of irritation due to the transmitter adhesive across the launch and trials. Skin irritation is still an issue with other systems that are worn for multiple days – it is encouraging to hear that Eversense may avoid this hurdle, though the tradeoff is daily-adhesive changes. Perhaps the adhesive formulation is also less irritable on the body, since it doesn’t have to stick for six days or more.
  • The average total clinic time for an insertion procedure (including patient intake, etc.) is 15-20 minutes, with the actual Eversense insertion taking 2.5-4 minutes. This is faster than we would have guessed. Further, Dr. Kelley suggested it takes ~2-3 rounds for physicians to feel comfortable with the insertion and removal procedures. As a reminder, there was only one SAE in PRECISE II (the US pivotal trial), and it was due to a sensor that was placed too deep. Otherwise, it seems like the procedure is rather easy to learn and perform. Scaling this product will require buy-in from HCPs, so we’ll be interested to see if these early sentiments carry to a broader population of prescribers. 

Corporate Symposium: Focus on the Future: Scientific and Clinical Understanding of Type 2 Diabetes and the Role of the Endocrinologist (Sponsored by MSD)

Evolving Role of the Endocrinologist in the Care of Patients with Type 2 Diabetes in a Changing Digital Environment

Partha Kar, MD (Portsmouth Hospitals NHS Trust, Portsmouth,UK)

A diverse panel of physicians moderated by Dr. Partha Kar, Clinical Director of Diabetes at Portsmouth Hospitals NHS Trust, discussed their views on digital health, exposing a surprising lack of knowledge and substantial fear regarding regulation, additional provider burden, and adverse effects. Dr. Lawrence Leiter noted that insulin adjustment apps make him particularly nervous, as he believes some have been validated but many have not. Dr. Steven Kahn echoed these sentiments, questioning the evaluation process behind insulin titration apps and worrying that patients will choose free options that likely lack sufficient regulation and maintenance. On the other hand, Dr. Michael Nauck said that basal insulin titration could eventually be supported by an app, but stipulated that the process shouldn’t be “too autonomous” and that, “you have to also involve a healthcare professional, otherwise things may have a chance to go wrong.” We’d note here that the FDA has already cleared three basal-only titration apps (Voluntis’ Insulia, Sanofi’s My Dose Coach, and Amalgam Rx’s iSafge Rx), which must meet a fairly high bar and do require prescriptions and HCP setup (though after that, they run on their own). Dr. Kahn expressed concern regarding the time commitment digital health tools require of providers, stating that, “these interactions become loops that never stop,” and Dr. Nauck feared that patients will become so attached to their apps that they will forget to see their physician and discuss their diabetes in person. We find the likelihood of the latter highly doubtful – the time patients spend with their providers is extremely limited and digital health should help provide support between visits. Dr. Kar acknowledged this opportunity, finding that digital technology is most effective when used to bolster self-management. Dr. Nauck also expressed fear that apps could produce adverse responses, which may go unreported. This panel discussion reinforced the need for companies to engage physicians and prove the value of their tools. While digital health is often consumer focused, providers are still gatekeepers, and having their buy-in could go a long way. While early digital health efforts in diabetes were mostly disappointing, we believe the bar has risen and companies are quickly moving to gather medical device data passively and offer decision support. These products will be more useful and will, by necessity, need to secure regulatory clearance. 

  • Although fearful of the potential for mHealth utilization to go awry, the panelists did express some optimism. Dr. Nauck sees value in technology that reinforces standard training courses, and Dr. Leiter said digital health brings “wonderful potential” to enhance patient-provider communication and involve the entire healthcare team. Dr. Leiter called for studies evaluating apps, but emphasized that they must consider outcomes beyond A1c, claiming that even apps that don’t improve A1c but do boost patient involvement and behavioral modifications can be positive – we agree! A1c also won’t capture value from apps that reduce both highs and lows. Plus, by the time a study is enrolled and a single A1c endpoint is gathered at 3 months, the app might have evolved in a meaningful way. Dr. Leiter also noted the potential of social support and experiential apps to be educational tools.
  • We were surprised by the lack of digital health knowledge on this panel, with participants questioning whether any regulatory body was responsible for approving mHealth apps. There is clearly more that can be done to educate providers on mHealth options. At one point, Dr. Nauck asked: “Who is guiding this process of scrutinizing [mHealth apps]? Do they get approval or do they just appear?” None of the panel members responded – not even the moderator! Obviously the answer to this question depends on whether the app qualifies as a medical device, though the pathway is pretty clear in the US. Similarly, when an audience member asked which organizations control health apps and whether apps will be treated as a medical product, Dr. Kar noted that “there will come a responsibility for all healthcare provider bodies to ensure it’s safe” and advised physicians to “put faith” in apps that companies like Roche and Dexcom have partnered with. We’d note that valid apps like BlueStar and mySugr can come from small companies, but have also received regulatory approval. FDA guidelines for digital health continue to be updated, including the recent pre-cert program and Digital Health Innovation Plan.  Indeed, to the surprise of Dr. Nauck, one audience member mentioned that BlueStar is approved and can be prescribed and reimbursed. Dr. Nauck, who had never heard of the app, asked: “Is that true, or is that going too far?” Neither the panelists nor Dr. Nauck responded. Of note, this was an international panel, and we wonder how attitudes and knowledge would differ if panelists were based in the US – FDA seems to be particularly forward-thinking on digital health regulation (and possibly education thereof).

Corporate Symposia: The Omnipod® System: Real World Use and Future Innovation

Trang Ly, PhD (Insulet, Billerica, MA, USA); Thomas Danne, MD (Kinderkrankenhaus, Hannover, Germany); Lalantha Leelarathna, PhD (University of Cambridge, Cambridge, UK); Shacey Petrovic (Insulet, Boston, MA, USA)

Insulet’s corporate symposium shared real-world Omnipod user data from over 38,000+ Glooko users, German/Austria DPV registry members, and outcomes with different pumps at Manchester Diabetes Center. The takeaway was clear – Omnipod outcomes and retention look similar to other pumps, if not slightly better. Overall, there was nothing truly compelling or shocking in the cross-sectional, retrospective, observational data (see key outcomes below), but it does show what is possible with direct device data downloads – characterizing real-world outcomes, understanding populations, and benchmarking. The Glooko partnership is clearly going to become a bigger Insulet asset over time, helping the company keep up with Medtronic’s CareLink. Indeed, Insulet-provided Glooko is now in 2,800+ clinics, with over 50,000 users uploading. There were no big pipeline updates, though the Horizon Automated Glucose Control system has now been tested in 113 patients (n=7,104 hours), up notably from 92 patients (n=4,584 hours) as of AADE in August. Medical Director Dr. Trang Ly did not give a timing update on Horizon, though did confirm that a pre-pivotal study is the next step after the ongoing five-day hotel study is complete. She did show a CGM trace from one 10-year-old participant in the hotel study, who entered with a mean A1c of 9.8%; on day #4, mean glucose had dropped to ~144 mg/dl, predicting an estimated A1c drop to ~6.7% (an impressive 82% time-in-range). No other days or participants were shown, though this was an encouraging n=1 plot in one user, and we look forward to full outcomes from this first outpatient study with Horizon. Presumably the previous timing is on track for a pivotal in 2018 and launch in 2019, though this was not confirmed. Otherwise, President Shacey Petrovic confirmed that Lilly U500 Omnipod clinical/development work is complete, data analysis is in progress, and Insulet is “preparing for submission” and running human factors studies. (A launch is expected in 2019, per 2Q17.)  As of AADE, Dr. Trang Ly hoped data from this phase 3 study (VIVID; n=416) could be shared at ADA 2018. U200 work remains in “technical development” and an FDA submission is expected in the “next 1-1.5 years,” in line with the planned 2020 launch. There was no update on the Dash PDM beyond what we saw at AADE and ADA; as of the 2Q17 call, FDA submission was expected in 4Q17. On the commercial front, there was definite excitement from Ms. Petrovic concerning Insulet’s move to directly distribute Omnipod in Europe, starting in mid-2018 with the Ypsomed agreement expiration (see our previous coverage).

  • Dr. Trang Ly shared data from 38,778 Omnipod patients in the US with at least three months of data downloaded using Insulet-provided Glooko. The average glucose level was 186 mg/dl, equivalent to an estimated A1c of 8.1%. Dr. Ly emphasized that this “compares favorably” to data from the T1D Exchange Registry, where A1c is 8.4%. The more interesting analysis showed data in a subset of Omnipod CGM users (n=3,394) vs. non-CGM users (n=35,384) – those using CGM had a slightly higher percentage of glucose tests in-range (52% vs. 48%), a slightly lower estimated A1c (8.1% vs. 7.8%), and a lower total daily insulin dose. Dr. Ly mentioned that this data likely underestimates CGM use in Insulet’s user base, since it does not include G5/Glooko integration. A separate slide showed a subset of Insulet users with self-reported demographic data, which included a notable n=496 type 2s– they were slightly older (mean age: 56 years), but had a lower estimated A1c (7.8%) and higher daily insulin dose (59 units per day) than the full cohort. This certainly bodes well for Insulet’s U500 and U200 work! We’ve include both slides below.
  • Drs. Thomas Danne (DPV registry) and Lalantha Leelarathna (Manchester Diabetes Center) provided reassuring real-world Omnipod data from Europe – outcomes with Omnipod looked very similar to other pumps. The DPV registry showed increasing use of Omnipod since 2012, with the highest use in youth with type 1 diabetes (10-15 years). A1c of Omnipod users in DPV was an encouraging 7.2%-7.7% (depending on age group); it was not compared to other pumps. On average, <10% of patients stopped using Omnipod in the DPV, retention in line with what Insulet has shared historically. At the Manchester Diabetes Center, Omnipod retention at three years was an impressive 99%, better than Medtronic (96%), Animas (96%), and Roche (81%). Said Dr. Danne, “For people who say Omnipod has a delivery problem – we don’t see this with the data and with the retention rate. We can feel good about it.” Dr. Danne concluded that “switching to a tubeless pump appears to be an effective alternative to MDI.” 

Corporate Symposium: Changing Diabetes Care: From Glycaemia to Cardiovascular Disease (Sponsored by Novo Nordisk)

Prospects of Ultra-Fast Insulins in Pump Therapy

Bruce Bode, MD (Emory University, Atlanta, GA)

Dr. Bruce Bode gave an optimistic talk on use of Novo Nordisk’s faster-acting aspart (Fiasp) in insulin pumps, noting that results from the large Onset 5 study are expected in 2018. Dr. Bode covered two published studies (Heise et al., Diabetes Obes Metab 2017 and Bode et al., DTT 2017) and the in-press Onset 4 study (Zjilstra JDST 2017) showing that Fiasp in pumps works faster than aspart (especially in the first 30-60 minutes), might lessen hypoglycemia (“we don’t know for sure yet”), and is stable in insulin pump tubing. Interestingly, a slide comparing PK profiles suggested that Fiasp has a bigger speed advantage over aspart when delivered via pump – a 26-minute faster time to peak PK in pump vs. a smaller 7-minute advantage with injections (see picture below). Dr. Bode wondered if Fiasp’s excipients give it this larger advantage when it is infused continuously rather than as single bolus injection doses. Looking ahead, the “definitive” Onset 5 trial will share results in 2018, as the last patient came out of the trial this past month. The multi-national study enrolled ~450 adults with type 1 diabetes in a randomized, blinded comparison between Fiasp and aspart in pumps. The primary endpoint is change in A1c at 16 weeks, though we’re excited to see the CGM data on time <70 mg/dl. Dr. Bode closed with his view on hybrid closed loop, which he called “a “gamechanger” – “You as a professional don’t adjust insulin.” He hopes to study use of faster aspart in hybrid closed loop in the “near future,” as many 670G users still report post-meal glucose values that rise up to ~180-200 mg/dl. As a reminder, Novo Nordisk’s 2Q17 update confirmed that an FDA decision on Fiasp (next-gen faster-acting insulin aspart) is anticipated in 3Q17 (this month!), following a Class II resubmission in March 2017. The next-gen mealtime insulin is already approved in Europe and Canada, and we continue to hear resounding positive feedback.

  • Dr. Bode said that “over 50,000” people have signed up to get on hybrid closed loop in the US (i.e., 670G), and “over 25,000” are already on it – these numbers are overestimates based on what we heard in Medtronic’s 2Q17 earnings call (~2.5 weeks ago). At the time, management shared that “close to 35,000” patients were in the Priority Access Program to eventually get on the 670G (i.e., less than “50,000”), with shipments to all of these customers expected to complete later this fall. It’s possible that more have signed up for the priority access program since that time, though we doubt an additional 15,000 have come on in the past couple weeks. Meanwhile, far fewer than 25,000 are likely on the MiniMed 670G right now, as only ~1,000 patients were on it as of late July and the ongoing sensor shortage has slowed new 670G shipments (not expected to resolve until April 2018). Read more in Medtronic 2Q17.

Corporate Symposium: Innovating Beyond Glucose Control in Diabetes Care (Sponsored by Sanofi)

Enriching Diabetes Care: Technology and New Models for Intervention Strategie

Boris Kovatchev, PhD (University of Virginia School of Medicine, Charlottesville, Virginia)

For Dr. Boris Kovatchev, the future of diabetes technology will revolve around the concept of a “digital twin,” a virtual image of an individual patient incorporating the person’s condition, genetic information, and data from various sensors – a sort of n=1 model that describes someone’s physiology. Dr. Kovatchev said suggested that all digital twins would be stored in a database, periodically updated with lab records and physician opinions so as to constantly improve the representation. In this way, a global precision treatment ecosystem would be stablished, which physicians could use to glean information. In just one example of this database’s far-reaching applications, a new treatment or algorithm could be optimized by testing it across the ecosystem. Dr. Kovatchev also foresees a local ecosystem surrounding each individual comprised of data updated every five minutes from sensors, which could be used to facilitate decision support, predictive algorithms, and closed-loop management.

  • Dr. Kovatchev detailed the pathway to closed loop systems, crediting the UVA/Padova simulator as a key step in reducing time and cost. According to Dr. Kovatchev, “diabetes is the best quantified disease – no one else is even close.” Oh the irony that patients are not doing better, especially insulin users! Dr. Kovatchev and his team developed a computer simulator for type 1 diabetes, which he presented to the FDA in 2007. This project helped significantly accelerate the closed-loop field and served as an alternative to animal studies during early trials of automated insulin delivery algorithms. Testing in humans moved much faster from that point. We wonder how a “digital twin” database in the future could similarly accelerate development of new therapies and technologies.
  • Dr. Kovatchev briefly reviewed three recent artificial pancreas studies (Medtronic 670G, JDRF Pilot trial, home use of bihormonal bionic pancreas) and was impressed with the low rates of hypoglycemia and substantial time in range. He noted that time spent in hyperglycemia still needs to be improved. Dr. Kovatchev found the skiing studies conducted in Virginia and Colorado heartening (ADA 2016), and expressed optimism that closed loop systems will continue to work in real-life settings. 

Integrating Diabetes Care

David Kerr, MD (Bournemouth Diabetes and Endocrine Centre, Bouurnemouth, UK)

Dr. David Kerr’s message was clear: integration of diabetes care cannot be achieved without accurate patient segmentation. To this end, Dr. Kerr, believes technology will be critical. He asserted that smart insulin pens will revolutionize healthcare, and also mentioned the Apple Watch and Garmin Watch as noteworthy devices. Dr. Kerr predicted an explosion in the use of telehealth and foresees expanded use of robots/algorithms, including things like diabetes help chat bots. Dr. Kerr and his team are hoping to work on creating a ride share program using geolocation to match patients with their A1c test appointments, essentially “uberizing” the process– how amazing. (As an aside, at an Aspen Institute session earlier this year, we heard that what was most requested among an AARP session of those over 65 was “Uber by regular phone” where people could call Uber rather than summon it by app.)  This system will have a greater impact on A1c control, he said, than introduction of a new therapy. If we had to guess, we’d agree – the field is certainly not lacking for tools, but better and more intelligent use of them. Still, Dr. Kerr cautioned against creating a digital divide and stressed access and affordability. For him, the current status of diabetes care is inadequate, as evidenced by the racial divide in the US, in which minority populations are disproportionately affected. Differentiating by type 1 vs. type 2 is simply not enough, and all five determinants of health must be considered including: (i) genetics (many products are based on evidence that fails to include minority populations who suffer the greatest disease burden); (ii) biology (variations for absorption and action exist); (iii) behavior (adherence, lifestyle); (iv) psychology (diabetes distress, fear of hypoglycemia); and (v) society (affordability, stigma). The bottom line, according to Dr. Kerr, is that if we continue on the same track, we’re going to bankrupt health systems around the world. Value needs to become the main currency, which Dr. Kerr defines as the sum of quality and experience of care divided by cost.

  • With an eye towards the future, Dr. Kerr detailed several fascinating diabetes tech solutions on the horizon. He described a hypothetical system in which a patient’s glucose readings are interpreted by an algorithm stored within a device and explained to the patient by a projected virtual physician. He also predicted that Amazon and Google will become major healthcare players in the future, and proposed the potential of a “doctor in the house” using voice tools like Amazon Echo or Ok Google to provide on-demand support, advice, and education. In addition to a digital/automated physician, Dr. Kerr foresees each patient having a virtual population clinician, who can evaluate all the patient’s data recorded from various sensors and make recommendations, which are then automatically implemented via smart devices.

Corporate Symposium: Can Connectivity Drive Sustained Behavior Change? (sponsored by Ascensia)

Ascensia Announced Global Innovation Competition – €200,000 for Winning DIgital Solutions that Address Type 2 Diabetes

Michael Kloss (Ascensia, Parsippany, NJ)

At the end of an excellent Ascensia symposium on behavioral change, CEO Mr. Michael Kloss took over the mic to announce a global innovation competition (The Ascensia Diabetes Challenge) – €200,000 in cash prizes are available for digital solutions that improve the lives of people with type 2 diabetes. He began by thanking the panelists for “pointing out that our technology is frustrating for patients,” and cited this fact as the reason for the competition. Submissions will be welcome from Europe, the Americas, and Asia Pacific with entries opening on October 1 for Europe and November 6, 2017 for Asia Pacific and the Americas. Finalists will then be announced in early 2018, with a finalist event in spring 2018 and winner announced in June 2018. The expert panel of judges will include UCSD’s Dr. Bill Polonsky, Dr. Masood Nazir (a GP from the UK), and Robin Swindell (a person with type 2 and on the board of Diabetes UK) – nice! Criteria includes user experience, innovation, efficacy, sustainability, and scalability. The challenge is done in partnership with yet2, an innovation and technology consultant that has run several similar efforts. We’ll be interested to see who applies, what ultimately wins, and whether it comes to market or stimulates further innovation inside Ascensia. Prize competitions create nice financial incentives for applicants, though we wonder how entrepreneurs think about them – Do they worry about making their ideas public? Are they excited by the chance to bring an idea to a big company and do something with it? Of course, this also sends a big message to Ascensia’s internal team that innovation can come from anywhere, including outside of the company’s walls. In a press conference on the challenge, we asked whether the competition and associated cash prize bring any strings attached. We were referred to the challenge's terms and conditions (fine print), which do seem pretty hands off – “the winner will also have the opportunity to work with Sponsor on the development of their solution, using the expertise and resources from the company to help towards bringing their solution to market.  Such collaboration is subject to a mutually agreed upon business relationship with mutually agreeable terms.” Ascensia does not automatically get any IP from ideas, which is great to see. We’re glad to see the standalone company trying to broaden and think differently, as relying on the BGM+strips market will not prove sustainable long term.  

  • Will we see more of these innovation challenges moving forward? These seem like a great deal for companies to crowdsource innovation, assuming the ideas are solid and applicant quality is high. Amazon/Merck launched the Alexa Diabetes Challenge in April, and we’ll be at the Demo Day to see the finalist voice-enabled solutions for type 2 diabetes. We wonder what the IP parameters are for contests like this – does the winning content automatically belong to the funding company? Or is the winner independent, just with some extra cash in pocket? Or somewhere in between?

Driving Sustained Behavioral Change: Digitizing an Evidence Based Diabetes Program

Osama Hamdy, MD, PhD (Joslin Diabetes Center, Boston, MA); William Polonsky, PhD (UCSD, San Diego, USA)

The respected Dr. Osama Hamdy gave an overview of Healthimation’s weight management program (using animation, gaming, and leveraging Joslin’s Why WAIT program), which he co-founded, sharing that the platform now integrates with device data. Pictured on the slide were a connected scale, a smartwatch, and a series of Ascensia meters. An Ascensia rep later told us that the picture did not denote an exclusive relationship, though the talk did come in an Ascensia symposium. We’re glad to see Healthimation pushing forward with connectivity, and of course, to see Ascensia embracing up-and-coming digital tools that expand its addressable market. Based on Dr. Hamdy’s remarks, the company aims to create an ecosystem, in which “every part of a day is connected.” The original WhyWAIT intervention has shown encouraging data, driving average weight loss of 6.4% at five years, 21% of enrollees stopping insulin, and 50%-60% experiencing a reduction in their diabetes medications. The question is, can this program translate to the digital setting with the help of machine-learning assisted personalization, Hollywood style animation and gaming, and coaching? How will it stack up to Virta’s approach? No outcomes were shared today, which was disappointing following the beta launch in December. According to the website, the product is available as a free seven-day trial, with a steep direct-to-consumer price of $49.99 per month. Many attempts to turn weight management virtual have fallen short because the programs aren’t sticky, but Dr. Hamdy firmly believes that “Lena,” the fit, young, quirky avatar that guides users through the course and the Hollywood magic (surprises, new games, etc.) will keep people from getting bored – we like the out-of-the-box thinking and hope he is right. Following the presentation, UCSD’s Dr. William Polonsky plainly said that “most apps we see in type 2 diabetes are pretty darn boring.” He (naturally) didn’t seem as positive about Healthimation as its founder did, but if it can provide the right mix of cheerleading, connectivity, and support to make sense of data, then Dr. Polonsky believes it can be successful.

Corporate Symposium: Real-World Challenges in Type 2 Diabetes: Why a Paradigm Shift is Needed

Luc Van Gaal, MD, PhD (Antwerp University Hospital, Antwerp, Belgium); Steven Edelman, MD (UCSD, San Diego, USA); Richard O’Brien, MD, PhD (University of Melbourne, Melbourne, Australia); William Polonsky, PhD (UCSD, San Diego, USA); Eduard Montanya, MD, PhD (University of Barcelona, Barcelona, Spain)

Melbourne’s Prof. Richard O’Brien, UCSD’s Dr. William Polonsky, and Barcelona’s Prof. Eduard Montanya discussed real- world challenges in type 2 diabetes, identifying adherence as the primary driver for the gap between outcomes observed in clinical trials versus real life. Dr. O’Brien cited a recent study (from Dr. Polonsky’s group) demonstrating that 75% of the differences in A1c reductions seen in clinical trials for GLP-1 agonists vs. real-world data can be explained by non-adherence. For DPP-4 inhibitors, the paper suggests that 72% is due to non-adherence. Dr. O’Brien urged physicians to discuss adherence with their patients, citing that one third of prescriptions for diabetes medications are never filled. Dr. Polonsky took adherence a step further, diving into critical patient beliefs surrounding medication. The issue, he said, is that diabetes medications lack short-term, tangible benefits, while cons such as burden and real/imagined adverse effects are plentiful – we wonder if VR, simulation, and higher tech education might help close this gap. For example, here’s what happens to the body when glucose levels are high, here’s how you will age when glucose levels are high, etc. Dr. Polonsky provided the telling example of an exercise he performs with type 2 patients, in which he shows them the profiles of two hypothetical patients, one of whom has at-goal A1c but takes two medications and is on insulin, while the other has a high A1c, but is not on any medications. When asked which patient is doing better, the vast majority say it’s a tough question. In other words, some people with diabetes equate more medication with failure. Yikes! The onus for this misconception is largely on providers, who sometimes threaten patients with more medication if they don’t improve behavior. Dr. Polonsky emphasized working on the patient-provider relationship, citing several studies demonstrating that improved trust is associated with greater adherence. So how do we shift the paradigm? Dr. Montanya mentioned a study demonstrating that triple combination therapy immediately following diagnosis (instead of a step-wise add-on approach over four months) conferred a greater A1c improvement. His argument was in favor of early combination therapy, but this could also tie in to adherence: Presumably, a stepwise approach is perceived as consecutive failures, while the immediate intensification is simply a medication regimen that drives right to success, so patients are more likely to stick to it. Dr. Montanya also suggested telemedicine as a potential approach to improve adherence, although acknowledged that meta-analyses yield mixed results and tend to demonstrate only short-term efficacy. He, and many thought leaders we’ve heard from recently, are particularly excited about ITCA 650, the six-month implantable exenatide pump from Intarcia. He discussed the FREEDOM-1 and -2 trials demonstrating significant reductions in A1c and body weight, and sees real potential in the pump to drive adherence. Once implanted, it works! We also see very high potential in novel ways to take and track medication, such as the super brilliant Pill Pack(“Pharmacy Simplified”). Poor adherence is a complicated affair, one that costs the health system huge sums of money – addressing it will take a carefully-crafted combination of support, technology, and design.

Questions and Answers

Q: What is the best way to approach a patient about being adherent?

A: Dr. Polonsky: What we see is healthcare providers will say, “I don’t know this data regarding adherence, I don’t see that.” That probably has to do with how we ask the question. It’s common for providers to say: “Look you haven’t had any problems managing your meds, have you?” The patient is almost guaranteed to answer no. There’s an opportunity to normalize the situation. Instead say, “I know people struggle taking medication, what kind of trouble do you have with your medication?” It’s important to open up the door to normalize the issue. Bravo!

Posters

Positive Clinical Outcome of Belgian Reimbursement of Real-time Continuous Glucose Monitoring for Type 1 Diabetes Patients on Insulin Pump Therapy

S Charleer, C De Block, R Radermecker, E Weber, C Vercammen, L Crenier, Y Taes, F Nobels, B Keymeulen, C Mathieu, P Gillard

A very compelling poster shared 12-month healthcare outcomes from a national Belgian reimbursement of CGM in 515 insulin pump users (RESCUE). The hospitalization and work absenteeism outcomes were outstanding and a tremendous win for CGM. This academic study tracked outcomes in the 12 months prior to CGM initiation and then in the 12 months following CGM in a population of type 1 adults on pumps. Most 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. We’re not sure if this cost estimate included the price of CGM, but saving this many days from work and hospitalizations is very encouraging for CGM’s cost-effectiveness. Notably, the observed A1c reduction of approximately 0.3% (baseline: 7.6%) with CGM over 12 months would have significantly understated these outcomes. As we’ve seen in other CGM studies, the benefit was slightly larger for those with higher A1c levels at baseline. CGM drove an improvement in quality of life (SF-36, though numerical numbers were not given), and both fear of hypoglycemia (HFS-Worry) and emotional burden due to diabetes (PAID-SF) improved significantly. It was not clear from the poster or the ClinicalTrials.gov page what CGM device(s) were used in this study. What a victory for the field and something we hope to see repeated in other countries and health systems!

  • This was a real-world, observational study of CGM, meaning there are some limitations. First, there seemed to be some patient dropout between the pre-post evaluation – n=515 were enrolled, n=496 had 12-month data before CGM, and then n=379 had 12-month data post-CGM. (This is why we focused on percentage of patients and not number of events in the above.) We’re not sure if this was a lost data issue or if people actually stopped wearing CGM. There is likely some selection bias from no inclusion criteria or randomization – patients for CGM were “selected by the diabetes teams.” Last, the study only enrolled pumpers at specialized diabetes centers, meaning generalizability is a question. We’re not sure how these limitations would influence the impressive results.
  • The ClinicalTrials.gov page notes that Belgian CGM reimbursement was granted for an initial period of three years, with this study serving as an evaluation of the decision. This trial will continue out to 24 months, meaning we should see follow-on data at some point. If outcomes are positive, we’d have to assume reimbursement will be extended.

Insulin Treated Patients Titrated to HbA1c Target Require Insulin Dose Titration Every 39 Days on Average to Maintain Glucose Control

Andrew Rhinehart, MD (Glytec, Waltham, MA, USA), John Clarke, RN, CDE (Glytec, Waltham, MA, USA), Robby Booth (Glytec, Waltham, MA, USA)

12-month data from Glytec’s outpatient Glucommander decision support system demonstrated a significant A1c drop, sustained with adjustments every ~57 days after goal was reached. 74 patients with insulin-dependent diabetes (baseline A1c: 10.3%; 78% type 2; average age = 56 years) were included in the non-randomized, uncontrolled study. At three months, A1c had dropped 2.3% points to 8.0%; at six months, A1c stayed flat at 8.0%; at nine months, A1c crept up to 8.3%; and at 12 months, A1c fell to 7.8%, representing a 2.5% absolute drop from the high baseline of 10.3%. The magnitude of this drop closely resemble that shown in six-month data from a separate study (presented at ATTD 2o17). Over the course of the study, mean blood glucose dropped from 214 mg/dl to 162 mg/dl. Impressively, the median time to goal (three consecutive days with average blood glucose <180 mg/dl) was just seven days. These rapid and sustained improvements in glycemia came at a very low risk of SMBG-detected hypoglycemia. The percentage of readings <54 mg/dl was o.37%, and the percentage <40 mg/dl was 0.05% – no episodes required assistance. These values were captured in a mean 3.0 fingersticks per day in the first three months, and 2.5 per day in the final three months. It’s impressive that Glytec can titrate insulin with so little glucose data; how would it look with CGM? After the first three months of treatment, Glucommander recommended a dose update every ~57 days – the poster reasons that the best-case three-to-four months between in-person clinic visits doesn’t meet the titration needs of most patients, and we would add that software is likely better at adjusting insulin than a provider with limited time. Average total daily dose per kg rose by 38% (0.66 U/kg to 0.91 U/kg), reflecting a failure to intensify prior to the intervention. Interestingly, the percent of daily dose coming in the form of basal fell from 50% to 31% - this ratio of basal:bolus continues to vary widely in studies and we hope the field moves away from one-size-fits-all expectations for 50%/50%. The poster notes that larger prospective RCTs are needed to confirm these results – great to hear since a number of studies have shown solid data but with no control group – and also that Glucommander will be used to treat over 100,000 patients in 2017.

  • We would have loved to see CGM in this study, at least in a subset of participants, to truly capture time spent in hypoglycemia (especially overnight). Richer CGM data could also be leveraged to guide the titration software more precisely. Glytec has existing BGM integrations with Roche, Livongo, Agamatrix, and Telcare.
  • Participants were given a Telcare cellular-enabled meter and asked to check four times a day. Blood glucose data was automatically sent to the clinic, where patients due for titration were flagged in the Glytec software so that a nurse could make the recommended adjustment, which appeared either on the patient’s meter or via text message.

A Prospective Pragmatic Clinical Trial in Type 2 Diabetes to Compare the V-Go Insulin Delivery Device with Standard Treatment Optimisation

M Cziraky, S Abbott, M Nguyen, P Strange, T Wasser, L Nowalk, K Larholt

In a four-month, multicenter, pragmatic clinical trial, use of the V-Go insulin delivery device induced significant reductions in A1c amongst adults with type 2 diabetes (n=415), alongside significant decreases in total daily dose of insulin (TDD). 52 participating clinical sites across the US were randomized to offer either the V-Go or continue offering standard care to their patients (we’re not sure how enrollment was determined within a clinic assigned to V-Go). Overall, the V-Go group saw a significantly greater A1c decrease than the control group (0.95% vs. 0.46%; P=0.002), though from a higher baseline A1c (9.9% vs. 9.3%). Presumably, this reflects some selection bias in prescribing – those given V-Go were more likely to be having a harder time with their diabetes. There was a 32% decrease in the number of V-Go patients with A1c greater than 9% vs. a 17% reduction in the control group, though the higher baseline A1cs with V-Go makes comparative conclusions challenging. Indeed, by the study’s end, the control group actually had lower average A1cs than did the V-Go group (8.8% vs. 9.0%). Average TDD decreased significantly in V-Go patients by 0.2 U/kg (baseline: 71.3 units), while TDD in the control group remained unchanged. Similar results were achieved in a sub-population of MDI users, with V-Go patients achieving significantly larger decreases in A1c (-1.0% vs -0.4%; p=0.006) alongside declines in TDD. Again, baseline A1c levels were significantly greater in the V-Go group. An interesting A1c vs. TDD density plot for the overall study population (below) shows leftward and downward shifts in the solid blue line (V-Go group at end of the study) compared to the dotted blue line (V-Go at the beginning of the study) – this indicates a lower A1c with less insulin. Meanwhile, the control group only saw the red dotted line (pre-study) shift down slightly (to the solid red line), reflecting improved A1c without decreased TDD. Promisingly, a questionnaire administered to patients at the end of the study indicated that 94% of patients used V-Go as directed, and 85% intend to continue using V-Go. Valeritas has published a number of positive posters and studies in the recent past showing declines in A1c and TDD, and we’ll be interested to see if the newly public company can scale adoption and reimbursement. 

Performance of a Non-invasive Glucose Monitoring Device for People with Prediabetes and Type 2 Diabetes

T Lin, E Naidis, A Rozner, A Gal, A Drexler, K Bahartan

A single-arm study (n=32) sponsored by Integrity Applications found that there were no significant differences in the accuracy of the GlucoTrack, the company’s non-invasive blood glucose monitoring device, between people with prediabetes (n=7; MARD=18.3%), people newly diagnosed with type 2 diabetes (duration 5 years; n=9; MARD=15.6%), and people with long-duration type 2 diabetes (duration >5 years; n=16; MARD=16.6%). Participants wore the ear-clip GlucoTrack for a “calibration day,” comprised of three measurements every 10 minutes, followed by a trial day consisting of a pre-prandial measurement, standardized breakfast, and six additional measurements every 30 minutes. All groups demonstrated similar proportions of measurements in the A and B zones of the Consensus error grid (at least 92% of the measurements were in Zone A across all groups). The sample sizes are small, so we’re not sure how results would look in a more robust pivotal study. If the main application is for people with prediabetes and those on orals, is this accuracy good enough? GlucoTrack is already CE marked and has launched in China, South Korea, Turkey, and some European countries, according to a rep in the exhibit hall. There is still a lot to prove here. The product’s non-invasive aspect is appealing (after a few calibration fingersticks twice a year), but the ear clip is bulky and attached to an industrial-looking handheld by a wire, and each reading takes one minute to register. The form factor and user friendliness aspects are lacking at the moment (save for the lack of fingersticks), while the likes of Dexcom and Abbott continue to move quickly on innovating subcutaneous sensors – slimmer on the body, less painful to insert, more integrated with consumer electronics, and lower cost. Until GlucoTrack becomes more discreet and less time-consuming to use, adoption will likely be difficult.

The Effects of Local Subcutaneous Inflammation on Insulin Pharmacokinetics

M Novak, R Radford, K Riley, J Alarcón, A Harvey, R Pettis

A BD poster showed that local inflammation, mimicking that seen from extended infusion set wear and insulin excipients, alters insulin PK profile in a large animal model. Swine (n=5) were given bolus subcutaneous injections of lipopolysaccharide (LPS; a documented activator of inflammatory cascades) or saline. 24 hours later, four units of U100 insulin lispro was injected into the same site. Plasma measurements recorded over the following six hours demonstrated significantly less total circulating insulin over the first 60 minutes, significantly lower peak plasma insulin concentration, and significantly slower time to peak in the LPS condition. This means that local inflammation may cause decreased and slower insulin absorption into the vasculature. The poster claims that this is the first time that local subcutaneous inflammation has been shown to significantly alter insulin PK, and BD is interested in looking more representatively at the effects of device- and insulin excipient-induced insulin. This has obvious implications in extended infusion set wear, often called the Achilles heel of pump therapy. A number of groups, including BD with funding from JDRF, are currently looking at ways to extend set wear time to seven days or beyond. JDRF is also funding TJU/Capillary Biomedical’s efforts ($1.5 million) to develop a novel seven-day wear set,  and last June, Medtronic shared that it is also working on an extended wear set that it is hoping to launch “in the next three years.” Addressing this issue with novel mechanical or molecular approaches will greatly reduce hassle associated with pump wear, and make a single-site CGM/pump closed loop system more realistic.

Award Lectures and Additional Topics

Award Lectures

Recurrent Hypoglycemia in Diabetes: The Long-Term Complications

Brian Frier, MD (University of Edinburgh, UK)

In the very prestigious (and absolutely packed) Camilo Golgi lecture, University of Edinburgh’s Professor Brian Frier gave a whirlwind overview of everything hypoglycemia, arguing that “while there’s no definitive proof that recurrent hypoglycemia causes cardiovascular disease, aggregating evidence suggests that it may be more than a minor inconvenience.” His hypothesis is that as the natural history of diabetes progresses, hyperglycemia underlies a steady increase in the prevalence of vascular complications. Then, after 10 years or so, the effects of hypoglycemia kick in and cause a rapid uptake in complication rate. The data supporting the impact of hypoglycemia on microvascular complications in type 1 diabetes is circumstantial – rapid improvement of glycemic control has been shown to cause acute worsening of retinopathy, and severe hypoglycemia coupled with a surge in blood pressure can leave patients more susceptible to renal disease than those who had severe hypoglycemia without a blood pressure surge. On the other hand, an analysis of DCCT data found no link between severe hypoglycemia frequency and retinopathy/nephropathy risk (of course severe hypoglycemia is not the only concern, so is “regular” hypo – to say nothing of retinopathy/nephropathy risk not being the only concern related to severe hypoglycemia). On the macrovascular side, there is correlational data suggesting that arteries may thicken, lose elasticity, and fill with calcium, and a retrospective cohort study (Zhao et al., 2012) indicated that patients with higher rates of hypoglycemia develop more micro- and macro-vascular complications. A separate study from a group in Spain suggested that suggests that hypoglycemia may actively promote atherosclerosis – a finding Prof. Frier called "disconcerting." Given the pathophysiology underlying hypoglycemia (which looks spookily similar to that underlying hyperglycemia) and the lasting metabolic effects of a single episode of hypoglycemia – longer than Prof. Frier believes has been realized in the past – we wouldn’t be surprised to eventually find that hypoglycemia (biochemical+severe) contributes to CV disease. That said, in DEVOTE, Tresiba was non-inferior to Lantus on CV outcomes, while reducing hypoglycemia by 40% (53% overnight), though 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.  Similarly, hypoglycemia was ruled out as a mediating factor between liraglutide and reduced risk for three-point MACE (non-fatal MI, non-fatal stroke, and CV death) in LEADER. There hasn’t been a study inducing recurrent hypoglycemia over the long term and studying outcomes for obvious ethical reasons, but recent secondary outcomes data makes a convincing case against a link. 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.

  • Professor Frier indicated that consensus has been reached on thresholds for clinically relevant hypoglycemia bins – at 3.9 mmol/L (70 mg/dl; “alert level hypoglycemia”) and at 3.0 mmol/L (54 mg/dl; “significant hypoglycemia”). See the slide below for a visual. When we last heard discussion on hypoglycemia “bins” at the diaTribe Foundation’s Glycemic Outcomes Beyond A1c meeting in July, a breakout session moderated by Profs. Frier and Stephanie Amiel at that meeting expressed agreement on the cut-offs of <70 mg/dl and <54 mg/dl to divide the different classes of hypoglycemia, though had less unanimity on terminology. Prof. Frier’s told us that the International Hypoglycemia Study Group has agreed on how to call these bins since then but awaits consensus with other groups. It’s so important for all stakeholders to get on the same page so we can move on with standardizing the measurement and reporting of hypoglycemia in clinical trial and real world data.

  • According to Prof. Frier, the Clark and Gold surveys are sensitive to IAH, but have a number of limitations, so an expert committee (including Profs. Frier and Simon Heller) developed the HypoA-Q for use in the HYPO-COMPaSS trial. The HypoQ-A is a 33-item (seven-minute) questionnaire that has undergone psychometric validation, performing with sensitivity and predictive ability for IAH. “It looks like this is the way moving forward, but we need a longitudinal prospective validation study now.” It would be excellent to see consensus develop around an IAH detection instrument, because as Prof. Frier pointed out, there isn’t even an internationally-recognized definition at this point – IAH means different things to different people and is ignored in many studies of new insulins.
  • The detrimental effects of hypoglycemia on the individual are notable, and notably, Prof. Frier reminded attendees that caregivers of patients with impaired hypoglycemia awareness also require support. This was extraordinary to hear so much attention paid to this area in such a prestigious lecture – as well, we would note that although he didn’t name patient-reported outcomes, the impact on the family is critical for most individuals. Caregiver support is important across the spectrum of diabetes, but extremely crucial when the patient has impaired awareness. Caregivers often feel that their lives are restricted because they always have to treat lows, that their loved one has a sort of “Jekyll and Hyde” syndrome, that they have difficulty treating some events, that they too have fear of hypoglycemia, and that there is a major unmet need for information and support.

Rising Star Symposium (Sponsored by Novo Nordisk)

Gustaf Cristoffersson, MD (Uppsala University, Sweden); Teresa Mezza, PhD (Cattolica University, Rome, Italy); Andrew Wood, MD (University of Exeter, UK); Hanieh Yaghootkar, MD (University of Exeter, UK)

It was an absolute pleasure to attend the Novo Nordisk-sponsored Rising Star Symposium, which featured some of the best and brightest young minds in diabetes research today. As one of the very last sessions of the week, we cannot think of a more fitting end to the conference than learning from the newest generation of diabetes scientists. This year’s brilliant recipients were Drs. Gustaf Cristoffersson (Uppsala University, Sweden), Teresa Mezza (Cattolica University, Rome, Italy), Andrew Wood (University of Exeter, UK), and Hanieh Yaghootkar (University of Exeter Medical School, UK) who discussed their work in immunology, islet plasticity, genetic and environmental interactions on BMI, and favorable adiposity respectively. See below for some of our major takeaways from this fascinating symposium.

  • Dr. Christoffersson detailed his work leveraging video microscopy to examine the cell to cell immune response in type 1 diabetes. He found that only 1%-2% of the CD8+ T-cells shown to cluster around beta cells in a diabetes mouse model are actually specific for islet antigens. By tagging islet-specific T-cells red and non-islet-specific T-cells green, Dr. Cristofferson discovered that these non-islet-specific T-cells can actually suppress the immune response, potentially by limiting trafficking or proliferation. These findings hint at a new avenue for developing immunotherapies combatting diabetes closer to the source.
  • Dr. Mezza presented her work investigating the relationship between beta cell function and islet morphology in hopes of identifying new therapeutic targets to preserve beta cell mass in diabetes patients and prevent beta cell degeneration in those at risk. She found that islet size is inversely correlated with glucose uptake – the more insulin resistant a patient is, the larger the islet. Not surprisingly, insulin sensitivity is inversely related with alpha cell area, with five-times greater alpha cell mass in insulin resistant patients indicating a decrease in beta cells. Additionally, she found an increase in small islets in insulin resistant patients, suggesting that insulin resistance prompts the production of new islets as part of a compensatory mechanism. This is further supported by the observation that insulin sensitivity is inversely correlated with the proportion of double cells (cells that include markers for alpha and beta function), indicating proliferation. Importantly, duct cells in particular were found to secrete both insulin and glucagon, suggesting that they may be progenitors for endocrine cells. Dr. Mezza hopes to investigate potential regulators of duct and alpha cell trans-differentiation to identify how to intercept the conversion from duct to alpha cell and potentially redirect the process to generate more beta cells.
  • Next up was Dr. Wood, who sought to determine whether genetic effects on BMI are accentuated given specific behaviors. It’s important to investigate this area, because it’s possible that we’re underestimating the contribution of genetics to obesity risk, which is currently estimated at 40%-70%. Dr. Wood described a Gene x Behavior interaction study (GxB) recently published by Tyrrell et al. in the International Journal of Epidemiology demonstrating that watching TV and self-reported activity exhibit an interaction between genetics and the environment. We know that watching more TV is associated with a greater BMI, but Tyrrell et al. were able to find that this difference in BMI actually increases by 35% as the genetic risk increases, showing that the environment is able to enhance genetic risk. Likewise, self-reported low activity exacerbates genetic susceptibility to a high BMI. Dr. Wood is currently conducting a GxB study examining interactions due to sleep patterns and physical activity data derived from wearable accelerometers. The researchers haven’t been able to identify evidence of interactions with interrupted sleep patterns, although self-reported data suggest it is a significant factor. This area of research could be critical in curbing the global obesity epidemic, as it may serve to identify which environmental factors have the greatest impact on BMI.
  • Wrapping up the symposium, Dr. Yaghootkar discussed her research examining the physiological and molecular basis for why some people with obesity never develop type 2 diabetes, a condition which is termed “favorable adiposity.” Using data from the UK Biobank, Dr. Yaghootkar identified genetic variants associated with body fat percentage and then tested the genetic variance against multivariable metabolic outcomes using summary statistics from published GWASs (genome-wide association studies). These analyses revealed 620 independent genetic loci associated with body fat percentage and 24 alleles associated with favorable adiposity. These favorable adiposity alleles were shown to be associated with reduced risk of type 2 diabetes, heart disease, and hypertension. Interestingly, favorable alleles are associated with more lower body fat in women (corresponding to a pear body-type) and fat all over in men (corresponding to an apple body-type). Still, when looking at individual alleles, Dr. Yaghootkar noted heterogeneous effects in body shape, clouding the pciture. Dr. Yaghootkar hopes to use the genetic variance to understand the role of favorable adiposity on non-metabolic disease outcomes. As a parting teaser, she mentioned that favorable adiposity is associated with a higher risk of depression in women – which we find surprising at first glance because people with diabetes are more susceptible to depression, but then again, that certainly has a lot to do with the environment (stigma, etc.).

DNA Switches, Beta Cells, and Diabetes

Jorge Ferrer, PhD (Imperial College London, UK)

The brilliant Dr. Jorge Ferrer delivered the 11th Albert Renold Lecture, detailing the complex and largely unchartered territory of regulatory genomics as it relates to diabetes. Consider Dr. Ferrer’s metaphor: Diabetes genetics is like the London coliseum theater – there’s wonderful engineering, and when something fails, the regulatory switchboard is likely the culprit. Such is the case with diabetes. Dr. Ferrer was motivated to enter the field of regulatory genomics because he finds current type 2 drugs inefficient. By cultivating a better understanding of the molecular causes of type 2 diabetes, he hopes to eventually develop precision medicine therapies intercepting specific pathways, promising a completely new class of treatment. With recent advances in genome and epigenome sequencing, as well enhanced manipulation via CRISPR/Cas9, this goal seems within reach, but will require enormous effort, given that the number of mapped regulatory elements is on the order of one million. Regulatory elements such as enhancers (locations on the genome where transcription factors can bind to upregulate expression of nearby genes) can be mapped using Chip-Seq. Dr. Ferrer and his team generated a map of human enhancers contributing to early pancreas development and were able to identify enriched sequence motifs. Through this process, they determined that the well-known transcription factor TEAD, which was previously not associated with pancreas development, is essential for the proliferation of pancreatic progenitors. They also conducted GWAS and identified >100 loci that influence the risk for developing type 2. Interestingly, they found blocks of associated variants, most of which did not affect proteins, hinting at a regulatory role. Indeed, Dr. Ferrer found that tissue-specific activity in pancreatic islets is driven by clusters of regulatory elements known as super-enhancers. This fascinating research is still in its earliest stages and several questions: What role do the enhancers play? Which genes do they regulate? Are the variants responsible for activating and/or inhibiting genes? Ideally, Dr. Ferrer would like to be able to track the impact of regulators on beta cell pathways for type 2 diabetes, which would allow for a more targeted molecular therapy.

  • Dr. Ferrer discussed several ongoing research projects aimed at better understanding the genetics of diabetes. Several groups are investigating the role of long, non-coding RNAs (lncRNAs) in diabetes. Currently, we know that there are lncRNAs highly specific to pancreatic islets, and that they are abnormally regulated in type 2. Some efforts are now focused on determining whether lncRNAs are involved in islet gene regulation. In one example, a team of investigators used RNAi and CRISPRi to identify a critical structural interaction between PLUTO, a lncRNA, and PDX1, a transcription factor, both of which are downregulated in type 2. When PLUTO is knocked down, nearby enhancers are prevented from appropriate interaction with PDX1, clogging the regulatory network. Another group identified a cross-regulatory feedback circuit contributing to appropriate islet proliferation involving genes known to be associated with monogenic diabetes. Another ongoing project, which has enrolled >1,000 patients to-date, is screening for the presence of penetrant islet enhancer mutations in “mutation negative” diabetes patients. Causal genetic variants can be found in only about half of the population with diabetes, suggesting a pool of patients likely to harbor regulatory mutations. The researchers hope to identify new nodes of defects underlying diabetes and to distinguish connections in the regulatory network. These nodes could potentially be prime targets for developing therapeutics.
  • We appreciated that Dr. Ferrer closed his lecture with a slide depicting the reality of diabetes in refugee camps. While cutting-edge research is undoubtedly thrilling, it’s important to remember and respect the urgent need that is happening right now (especially in areas with deplete resources).

EASD/Novo Nordisk Foundation Diabetes Prize for Excellence

Philipp Scherer, PhD (UT Southwestern Medical Center, Dallas, TX)

Dr. Philipp Scherer detailed his impressive work investigating two main questions: (i) What goes wrong in adipose tissue when we gain weight? (ii) How can we pharmacologically intervene? While the field is still a long way from being able to fully answer these questions, Dr. Scherer shared exciting updates regarding the role of adiponectin and ceramides in type 2 diabetes, articulating how further exploration into these topics will yield major ground for pharmacological intervention. At a basic level, vasculature is responsible for maintaining appropriate oxygenation and nutrient supply of adipose tissue. When fat is gained quickly, vascularization sometimes struggles to keep up, and hypoxia can occur, resulting in what Dr. Scherer referred to as the “ominous triad of adipose tissue dysfunction” – inflammation, fibrosis, and impaired angiogenesis. Eventually, this dysfunction amounts to insulin resistance. Interestingly, Dr. Scherer noticed that adiponectin, a peptide produced by adipose tissue, is the only hormone secreted from adipocytes with levels inversely related to fat mass (more hormone correlates with less fat mass). Adiponectin is also associated with remodeling of the extracellular matrix, which has been shown to be instrumental for the metabolic health of fat tissue. Dr. Scherer’s interest in adiponectin led him to investigate ceramides, a group of lipids known to be elevated in those with diabetes, contributing to cell death, insulin resistance, and inflammation, and correlating with non-alcoholic fatty liver disease (NAFLD). In a major win for the field, Dr. Scherer found that adiponectin decreases ceramide levels in the liver, and that when adiponectin is eliminated in mice, insulin resistance develops. Additionally, an overexpression of adiponectin receptors in mice clears up ceramides and improves glucose tolerance. Further supporting the role of adiponectin in lowering ceramides, treatment with TZD pioglitazone improves insulin sensitivity and is known to depend on the presence of adiponectin – in fact, it’s the most potent inducer of adiponectin that we’re aware of. In patients treated with pioglitazone, ceramide levels are lowered. These results could be incredibly clinically relevant, as Dr. Scherer believes anyone with type 2 diabetes will have increased levels of ceramides, although he noted that further tests are needed. We’ll keep an eye out, as we’re very intrigued by this area of research.

  • Huge congratulations to Dr. Scherer for winning this prestigious prize! This was a fascinating lecture overall, and we appreciated the deep dive into basic science.

A Glucose-Centric View on Diabetes Pathogenesis: From Islet Biology to Integrated Physiology and Precision Medicine

Bernard Thorens, PhD (University of Lausanne, Switzerland)

Although we think of glucose regulation as a primarily hormonal phenomenon, Dr. Bernard Thorens – honored with this year’s prestigious Claude Bernard lecture – provided a fascinating reminder of the neurological side of glucose sensing and regulation. Dr. Thorens participated in some of the foundational work in cloning beta cell GLP-1 and Glut2 receptors. His work in rodent models demonstrates that neurons in key parts of the body and brain can sense glucose directly via the Glut2 receptor, and in turn modulate beta cell activity, release of gluco-regulatory hormones, and glucose-seeking behavior. Interestingly, knocking out the Glut2 receptor in these glucose sensing pathways essentially causes a prediabetic state in mouse models. Better understanding of the body’s complex glucose sensing neural network – and the ways it is impacted by genetic variations – could contribute to precision medicine in diabetes.

  • Dr. Thorens’ presentation focused on three key glucose sensing networks:
    • Hepato-portal glucose sensing: Sensory neurons in the hepatic portal vein – which carries freshly absorbed glucose and nutrients from the intestine to the liver – plays a key role in the body’s adaptation to incoming glucose. Signals from these neurons help stimulate the first phase of insulin secretion, playing a bigger role in the first phase than the beta cells’ direct sensing of glucose (at least in mice). It also increases muscle glucose uptake and decreases feeding behavior.
    • Pre-autonomic neurons: Another glucose-sensing network of neurons, this one in the brain, modulates activity of the autonomic nervous system. This in turn stimulates beta cell proliferation and glucagon secretion. We appreciated that some of Claude Bernard’s seminal work involved stimulation of these brain areas. 
    • Dopaminergic reward system: Glut2 receptors found in the brain’s reward pathway – which plays a role in addiction – stimulates sugar-seeking behavior. Interestingly, this system is unable to sense artificial sweeteners and fructose, which may play a role in overeating or sugar craving associated with consumption of beverages sweetened with these substances.
  • Dr. Thorens is a coordinator of the RHAPSODY public-private partnership that aims to better understand the progression from prediabetes to type 2 diabetes. The Innovative Medicines Initiative (IMI) supports the project and Sanofi is a co-leader. RHAPSODY hopes to define “disease trajectories” for type 2 diabetes and build a database of biosamples that can help identify biomarkers for assessing risk of diabetes progression.

Targeting Therapy in Diabetes: Insights from Genetics

Ewan Pearson, PhD (University of Dundee, UK)

Dundee’s Dr. Ewan Pearson provided optimism and pragmatism in equal doses as he delivered his prestigious Minkowski Lecture on the role of genetics in diabetes management. He shared the story of patient diagnosed with type 1 diabetes at age 18, only for it to be discovered at age 87 that she had robust C-peptide and in fact had MODY. He argued that C-peptide measurements should become standard of care for type 1 diabetes, as genetic diagnoses of diabetes can change lives (the patient in his story switched off of insulin to a sulfonylurea and is doing well). Genetics plays an important role in type 2 diabetes as well, and Dr. Pearson believes that in ten years, patients’ genetic sequences will be a part of their electronic health records, allowing for the creation of response prediction calculators that would factor in demographics, genotype, and biomarkers to predict a given patient’s likelihood of response and risk of side-effects with different therapeutic options (i.e. an output like “Patient A is X% likely to respond and Y% likely to have an adverse reaction to an SGLT-2 inhibitor”). That strikes us as a fantastic way to make PCPs’ jobs more manageable and make targeted therapy in type 2 diabetes a reality, instead of expecting already-overwhelmed PCPs and endos to process these vast amounts of data singlehandedly.

Symposium: Hypoglycemia Revisited

The Case for a New Classification of Hypoglycemia in Clinical Trials: A Regulator's View

Bart Van der Schueren, MD (University of Leuven, Belgium)

Dr. Bart Van der Schueren (University of Leuven) provided an EMA perspective on measuring hypoglycemia in trials. Notably, the Agency’s updated diabetes drug guideline will be open for public comment soon, confirming his remarks at the Outcomes Beyond A1c meeting in August. In the draft guideline (no timeline on release), EMA is leveraging recommendations from the International Hypoglycemia Study Group – “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 admitted that use of the “less than or equal to” will likely be a source of public comment: “I don’t know why we did that, but we might get comments on that!” We hope it is changed to simply “less than” so that it aligns with the consensus achieved at the Outcomes Beyond A1c meeting in August: <54 mg/dl and <70 mg/dl. (This may seem small, but it is very critical for the field to agree on.) Dr. Van der Schueren mentioned that if a drug shows less of these non-severe hypoglycemia events, it “will be taken into account” in the review – we assume such CGM data would be reported in the label, just like severe hypoglycemia for products like Tresiba. He echoed his August comments that “better analytic tools have changed what we can measure” – his slide showed a picture of time-in-range on FreeStyle Libre and the FDA press release approving Dexcom’s G5 for non-adjunctive use. We love seeing this CGM enthusiasm from EMA and we seriously hope FDA gets the message. Dr. Van der Schueren highlighted patient-reported outcomes as an area where more consensus is needed, since “a lot of questionnaires are not sufficiently validated.” The upcoming EMA guideline will not recommend a specific PRO, though EMA did include the hypoglycemia fear survey and diabetes therapy-related quality of life questionnaire in the Trulicity label (see page 16 here). Last, he reprised his comments from August on composite/co-primary endpoints, which are difficult for regulators – they typically mix efficacy and safety endpoints within the same statement (e.g., achieving A1c <7% without episodes of severe hypoglycemia or DKA). “It becomes difficult to disentangle that into a primary indication,” said Dr. Van der Schueren. The EMA is seeing more of these outcomes proposed for adjunctive therapies in type 1 diabetes (e.g., SGLT-2s), and we’ll be interested to see how companies and regulators cope with them for benefit-risk decisions and product labels. 

The Case for a New Classification of Hypoglycemia in Clinical Trials: A Researcher’s View

Stephanie Amiel, MD (King’s College London, UK)

Dr. Stephanie Amiel (King’s College London) 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, Dr. 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., ACCORDPistrosch 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). The paper has already been cited 20 times! Dr. Amiel again noted that 70 mg/dl is an “alert level,” meaning it is the lower limit of the target range (Dr. Amiel said this level was “usually asymptomatic”) and alerts patients that they need to do something. Interestingly, in many of the studies Dr. Amiel covered, <70 mg/dl was NOT linked to the host of adverse outcomes like <54 mg/dl. We thought her summary of the data was compelling and wonder how FDA will interpret all the evidence linking <54 mg/dl to meaningfully negative outcomes. Will further validation be needed? Hopefully, the field will start to use CGM widely to capture the occurrence of hypoglycemia in trials, further building a case. Ultimately, we hope non-severe hypoglycemia data (e.g., <54 mg/dl) makes it into product labels, changes incentives for drug development, and even redefines the bar for reimbursement.

Symposium: Diabetic Hypoglycemia: New Thinking, New Tools (Sponsored by the International Hypoglycemia Study Group)

Summary

Ulrik Pedersen-Bjergaard, MD (Diabetes Research Foundation, Copenhagen, Denmark); Bastiaan de Galan, MD (Radboud University Medical Center, The Netherlands); Rory McCrimmon, MD (University of Dundee, UK)

The International Hypoglycemia Study Group hosted an information-packed symposium at EASD, imparting some of their endless knowledge on hypoglycemia prevalence, pathogenesis, therapeutic pipeline, and more.

  • Hypoglycemia is certainly recognized to be a huge problem, but statistics presented by Dr. Ulrik Pedersen-Bjergaard were still alarming. These figures demonstrate how, even though hyperglycemia hospitalizations have gone down and overall A1c has decreased, hypoglycemia remains a big limitation to better therapy. As CGM use rises further, we expect a lot more hypoglycemia that has traditionally gone undetected will surface, hopefully adding more urgency to the discussion. Could we ever see a day where drugs are indicated for the reduction of hypoglycemia (independent of A1c)?
  • Severe Hypoglycemia

Mild Symptomatic Hypoglycemia

Asymptomatic Hypoglycemia

Nocturnal Hypoglycemia

T1D: at least one episode per patient-year; 20% with recurrent episodes

T1D: up to two episodes per patient-week

Up to 75% of all events in T1D

 

Increasingly evident from CGM

~16% of patients reported nocturnal hypoglycemia in the past month (probably an underestimate)

 

Although reduced by the use of long-acting insulin analogues – still frequent

Insulin-treated T2D: Occurrence ~1/3 of that in T1D

Insulin-treated T2D: Occurrence ~1/3 of that in T1D

  • Denmark’s Dr. Pedersen-Bjergaard emphasized that the correlation between hypoglycemia and A1c is not strong, likely due to differential glycemic variability from patient-to-patient. In the DCCT, intensive control did increase the risk of severe hypoglycemia relative to the control arm, but people with recurrent hypoglycemia or impaired awareness of hypoglycemia were excluded from the study. Recently, the HAT study demonstrated that the association between A1c and severe hypoglycemia is actually much less significant in the broader population – there is a slightly significant relationship (with a small effect size) between A1c and any hypoglycemia in type 1, but not in type 2. Nocturnal and severe hypoglycemia were not associated with A1c at all. 2017 data from EDIC, the DCCT follow-up, now shows that the relationship between lower A1c and increased rate of severe hypoglycemia is blunted, even though in the same cohort of patients. Why? Dr. Pedersen-Bjergaard suggested that treatment improvements may underlie the differences, though patients outside of the intensive arm may have developed impaired hypoglycemia awareness or other risk factors.
    • Audience members seemed confused by this counterintuitive tenet, as one asked for clarification during Q&A. The panel dismissed explanations including glycemic variability, a “disengagement with one’s own self-management,” and a clustering of risk factors in a few individuals. We believe the evidence against a solid relationship between A1c and hypoglycemia should be preached from the mountain tops, as it is the best argument against relaxing glycemic control in hypoglycemia-prone individuals.
  • Nocturnal hypoglycemia actually reduces sleep efficiency, increasing delta power and slow wave sleep at the cost of decreased REM sleep, increased wakes, and increased sleep latency (time to sleep) once awoken. This is why people with diabetes often feel exhausted when they wake in the morning, and why morning exhaustion is a possible indicator of prior hypoglycemia. Belgium’s Dr. Bastiaan de Galan also contested the “myth” of the Somogyi effect (elevated blood glucose in the morning as an indication of nocturnal hypoglycemia, or “posthypoglycemic hyperglycemia”). Low fasting glucose in the morning is still an accepted possible sign of nocturnal hypoglycemia, but the morning glucose rebound is no longer widely accepted.
  • Scotland’s Dr. Rory McCrimmon showed data demonstrating that impaired awareness of hypoglycemia prevalence hasn’t changed in the last 30 years (~25%), and skimmed the surface of ongoing mechanistic and therapeutic research. The field hasn’t yet determined the main biological culprit(s) behind IAH, but it may involve glucose transport, alternate fuels (glycogen/lactate), glucose sensing (GK/AMPK/KATP), peripheral signals (opiates/steroids/cytokines), and/or neurotransmitter release. Whatever the mechanism, the net result is an increase in GABAergic (inhibitory) tone and a decrease in glutamatergic (excitatory) tone from glucose-sensing neurons. He showed preliminary evidence that IAH is a product of habituation to some repeated stimulus (a logical hypothesis): in a rodent model, his group was able to dis-habituate and restore physiological response to recurrent hypoglycemia with high-intensity exercise. There are countless other novel approaches to restore hypoglycemia awareness currently under investigation: (i) oral dehydroepiandrosterone; (ii) inhaled formoterol; (iii) opioid receptor blockade; (iv) naltrexone; (v) somatostatin type 2 antagonism; and (vi) oral diazoxide (K+ channel activator). Having a toolkit of agents that improve hypoglycemia awareness, and a pharmacogenomics approach that dictates which work best in which patients, would be a true game-changer. Of course, we also hope to see CGM and automated insulin delivery better studied in those with impaired hypoglycemia and high risk of severe hypoglycemia.
  • Dr. Pedersen-Bjergaard introduced the IHSG patient and provider hypoglycemia risk stratification infographic tool, which will be available here soon. The tool separates patients by low, moderate, and high risk, offers solutions for each risk range, describes acute and long-term outcomes and risk factors, and providers risk-reduction strategies. This could be a very helpful resource, especially for those who aren’t seen after by one of the luminaries of the IHSG.
  • Two days prior, IHSG member Prof. Brian Frier was given the honor of delivering the Camilo Golgi lecture, in which he indicated that consensus has been reached on thresholds for clinically relevant hypoglycemia bins – at 3.9 mmol/L (70 mg/dl; “alert level hypoglycemia”) and at 3.0 mmol/L (54 mg/dl; “significant hypoglycemia”). When we last heard discussion on hypoglycemia “bins” at the diaTribe Foundation’s Glycemic Outcomes Beyond A1c meeting in July, a breakout session moderated by Profs. Frier and Stephanie Amiel at that meeting expressed agreement on the cut-offs of <70 mg/dl and <54 mg/dl to divide the different classes of hypoglycemia, though had less unanimity on terminology. Prof. Frier told us that the International Hypoglycemia Study Group has agreed on how to call these bins since then but awaits consensus with other groups.
  • Dr. McCrimmon explained why hypoglycemia may only be deleterious in the context of hyperglycemia, not on its own. Chronic hyperglycemia is an inflammatory stimulus that depletes the anti-oxidative response. When hypoglycemia comes along, it causes tremendous oxidative stress, but there are fewer reserves of anti-oxidants to restore homeostasis. This makes sense in theory, and was supported in a rodent study: Control mice performed fine on novel object recognition task (testing memory) after intermittent hypoglycemia, while STZ mice (who have chronic hyperglycemia) struggled immensely following the same intervention (while STZ mice not exposed to hypoglycemia did fine). At a molecular level, the STZ mice who had undergone the hypoglycemia treatment had significantly higher protein carbonylation, a biomarker of oxidative activity. Might eating a diet rich in anti-oxidants help to dampen the deleterious effects of hypoglycemia? The idea that the recovery from hypoglycemia and the control leading into it could be just as important as the event itself is fascinating.

Symposium: Role of Alirocumab in Lipid Management of Individuals with Type 1 and Type 2 Diabetes at High CV Risk: ODYSSEY DM Program

PCSK9 and Diabetes: What is Currently Known?

Bertrand Cariou, MD (Institut du Thorax, Nantes, France)

Dr. Bertrand Cariou provided an excellent overview of the connections between PCSK9 and diabetes, and outlined the key questions about PCSK9, lipids, and diabetes that Sanofi/Regeneron’s ODYSSEY DM program for Praluent (alirocumab) set out to answer. Reviewing data that has already been presented on alirocumab and Amgen’s PCSK9 inhibitor Repatha (evolocumab), Dr. Cariou noted no deteriorations in A1c, worsening of other markers of glucose homeostasis, or increase in diabetes incidence with use of PCSK9 inhibitors. Both type 1 and type 2 diabetes patients have been found to have elevated PCSK9 levels on average, with higher A1c predicting higher PCSK9 levels even after adjusting for traditional CV risk factors. This relationship raises an important question: Are PCSK9 inhibitors less effective in diabetes, because they have more substrate to overcome? Dr. Cariou noted that data so far (including from the ODYSSEY DM program) does not suggest that PCSK9 inhibitors are any less effective in diabetes patients.

Overview of the ODYSSEY DM Program

Kausik Ray, MD (Imperial College London, UK)

Before the presentation of results – old and some new – from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, Dr. Kausik Ray provided an extensive walkthrough of the trials’ design, highlighting the ways in which they were unprecedented. ODYSSEY DM-INSULIN was the first trial to examine PCSK9 inhibitor efficacy specifically in insulin-treated diabetes patients facing high CV risk. ODYSSEY DM-DYSLIPIDEMIA was the first PCSK9 inhibitor trial in diabetes to use non-HDL cholesterol as a primary endpoint (most other PCSK9 inhibitor trials have used LDL as the primary outcome).

Alirocumab in Insulin-Treated Individuals with Type 1 and 2 Diabetes: ODYSSEY DM-INSULIN

Helen Colhoun, MD (University of Edinburgh, UK)

New data from Sanofi/Regeneron’s ODYSSEY DM-INSULIN study demonstrated a 52% reduction in LDL cholesterol with PCSK9 inhibitor Praluent (alirocumab) vs. placebo in people with type 1 diabetes (p<0.0001), comparable to the 49% placebo-adjusted LDL reduction previously reported at ADA 2017 for the subgroup with type 2 diabetes. This double-blind, 24-week study randomized 517 insulin-treated patients (441 with type 2 diabetes, 76 with type 1 diabetes) with starting LDL levels >70 mg/dl despite maximally-tolerated statins to alirocumab 75 mg or to placebo in a 2:1 fashion. Alirocumab dose was titrated up to 150 mg at 12 weeks for patients who did not achieve an LDL cholesterol <70 mg/dl at week 8. University of Edinburgh’s Dr. Helen Colhoun presented the results specific to type 1. The impressive 52% drop from baseline LDL 121 mg/dl translated to a mean 62 mg/dl decline (as we understand it, this is very clinically-meaningful). Notably, 63% of participants achieved this LDL reduction with the lower, 75 mg dose of alirocumab, while 37% of participants were titrated up to 150 mg. In terms of the time course for LDL reduction, a massive drop occurred by week eight, after which point levels largely plateaued. Dr. Colhoun pointed out that 70% of participants with type 1 diabetes achieved LDL goal of <70 mg/dl with Praluent vs. 76% of people with type 2 diabetes (who came in with a lower mean baseline LDL of 110 mg/dl, and a smaller variance). Similarly, high levels of target achievement were seen for the non-HDL cholesterol goal of <100 mg/dl with Praluent – 71% for type 1 participants and 79% for type 2 participants. Overall, we are thrilled to see a dedicated analysis of type 1 diabetes in this clinical trial program, and we’re even more pleased that Praluent’s potent LDL-lowering effect also spans to this often under-studied population (in addition, of course, to type 2 diabetes). Given that CV disease is the main cause of morbidity and mortality in people with diabetes, we see great potential for Praluent as an effective tool for lipid management in this patient population. We are eagerly awaiting results from the ODYSSEY OUTCOMES CVOT of Praluent, expected to complete in December 2017 with results anticipated early 2018, to learn whether this LDL-lowering effect translates to a lower incidence of CV events. In the FOURIER CVOT, Amgen’s Repatha (evolucmab) recently became the first PCSK9 inhibitor to report a cardioprotective effect (demonstrating a 15% risk reduction the composite primary endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization), and we think this bodes well for Praluent’s CVOT results.

  • Beyond the primary endpoint of superior LDL-lowering with Praluent vs. placebo, the trial’s type 1 diabetes subgroup also met several key secondary endpoints: placebo-adjusted, alirocumab was associated with a 43% reduction in non-HDL cholesterol (p<0.0001), a 29% reduction in total cholesterol (p<0.0001), a 39% reduction in ApoB (p<0.0001), a 19% reduction in Lp(a) (p=0.0039), and a 40% reduction in LDL particle number (p<0.0001). Dr. Colhoun highlighted the Lp(a) reduction as particularly exciting, since this key risk factor for peripheral vascular disease is not affected by statin therapy. Consistent with the rest of the ODYSSEY program, adverse event rates were low, with no appreciable differences between the alirocumab and placebo arms.

Alirocumab Versus Usual Care in Diabetes with Mixed Dyslipidemia: ODYSSEY DM-DYSLIPIDEMIA

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

Dr. Stefano Del Prato presented new results from a sub-analysis of the ODYSSEY DM-DYSLIPIDEMIA trial, specifically comparing alirocumab with fenofibrate, another lipid-lowering drug. Results from the whole trial were presented at this year’s ADA so we won’t revisit them again here except to say that alirocumab performed as well as expected in type 2 diabetes patients with mixed dyslipidemia (high triglycerides, low HDL). The high level takeaway from the new analysis was that alirocumab looked great when compared with fenofibrate, one of the existing “usual care” drugs for mixed dyslipidemia. Even setting aside the comparison vs. alirocumab, fenofibrate didn’t really appear to be particularly effective in this trial (9% reduction in non-HDL cholesterol vs. a much more impressive 42% reduction with alirocumab). Fenofibrate trended toward a slightly better reduction in triglycerides (-24% from baseline vs. -15% with alirocumab), but the difference was not statistically significant. No new, specific, or worrying safety signals arose with alirocumab. These new results said more about fenofibrate than alirocumab, since we already saw how alirocumab did in the overall trial. Importantly, neither alirocumab nor fenofibrate disrupted glucose control as measured by A1c, fasting plasma glucose, or a number of glucose-lowering medications.

The US Experience

Edward Gregg, PhD (CDC, Atlanta, GA)

The CDC’s highly respected Dr. Edward Gregg shared fascinating insights on the changing character of the US diabetes epidemic: A diversification of complications and maintained cumulative incidence and secondary events.

  • The first factor that Dr. Gregg believes may be underlying these trends is progress in the treatment of older adults, thanks to improvements in clinical and public health efforts. As a consequence, we are likely seeing greater reductions in macrovascular complication and decreased mortality, which could cause reduced competing risk (i.e. allowing other complications to manifest) and extended exposure (i.e. people have diabetes longer).
  • Dr. Gregg suggested that factor #2 contributing to the observed trends is an increase in type 2 diabetes in youth and young adults in virtually all ethnic groups except for non-Hispanic whites. He explained that the improvements we’ve seen in the care of older adults are not apparent in youth (this is probably because research in this demographic is sorely lacking). Millennials (born between 1980-2000) are the most obese generation yet; within this generation, smoking prevalence is higher in people with diabetes than in those without diabetes; these patients are most likely to have very poor glycemic control; and youth have seen the smallest improvements in CVD hospitalization and mortality.
  • Taken together, diagnosis at young age plus a lack of quality care leads to extended exposure. We found this analysis to be particularly interesting, and on the whole, a positive outlook. Improved outcomes in adults speaks for itself – our tools and drugs are getting better. While the trends in young people are heading in the wrong directions, we believe that studying this at-risk cohort in greater depth would yield improved preventative and care measures. Dr. Gregg believes the field has hit a tipping point, as everyone in behavioral research and otherwise is talking about behavioral research/intervention and healthy environment design. This is terrific, of course – we’re still wary that most numbers we see on the “most” obese are getting worse.
  • Overall diabetes complication incidence in the US has been ~flat since 2010. There hasn’t been much of a decline in the last four years in CV hospitalization rates; over time, as long as they were reimbursed, the advent of cardioprotective diabetes drugs will bend that curve meaningfully. On a quite worrisome note from our view, there has actually been an increase in amputations in the past four years, largely driven by men, and by toe amputations.
  • Diabetes appears to take a larger toll on disability-free life than overall life-expectancy. A recent study showed that if a woman has diabetes and is 50 years old, she can expect disability onset (on average) at age 70, and then live to 80 years. Meanwhile, a 50-year-old woman without diabetes can expect to live disability-free until she’s 79, and then live to 86 years. That’s a nine-year difference in disability-free living, and just a six-year gap in life expectancy. It’s clearly not enough to just make patients live longer, because we risk creating a population of elderly unwell who will not only have compromised qualities of life, but also cost the healthcare system boatloads.
  • Increased incidence + decreased mortality = increased lifetime risk. The average 60-year-old man spent 15 years with diabetes in the 1990s; 18 years in the 2000s. Put in a population context, the total years spent with diabetes for the average community of 1,000 was 5,463 years in the 1990s; in the 2000s, it was 12,199 years. That’s more than a doubling of exposure to diabetes. Even if diabetes management continues to improve dramatically and complication rates continue to drop, there will still be a huge burden attributable to the sheer size of the epidemic and longer lifespans.

Symposium: Precision Medicine in Diabetes: How Close are We?

Precision Medicine in Common Diabetes

Angus Jones, PhD (University of Exeter School of Medicine, UK)

Dr. Angus Jones considers the differentiation between type 1 and type 2 to be a major error of practice in diabetes management. With this bold statement, he set the stage for this precision medicine symposium. Dr. Jones argued that the type 1 vs. type 2 divide creates a one-size-fits-all situation with high stakes, as all future management decisions are based on that initial checkbox. In reality, hyperglycemia has more nuance to it, Dr. Jones explained, aptly noting that “patients behave like their endogenous secretions, not like their BMI or diagnosis.” To provide a more precise diagnosis, Dr. Jones and his team have created a model which integrates an individual’s clinical features, antibody results, and insulin-related biomarkers to generate a predicted diagnosis. This group, the UK MASTERMIND consortium, takes precision medicine one step further – the aim of more specific diagnoses is to better predict which patients will be successful on which diabetes therapies. Dr. Jones is leveraging electronic health record data to identify clinical predictors for therapy response. Excitingly, he has found that females with obesity are more likely to respond positively to TZDs and negatively to sulfonylureas vs. females without obesity. No such differences exist for males by BMI. Dr. Jones performed a similar analysis comparing DPP-4 inhibitors vs. SGLT-2 inhibitors: Lower BMI and triglyceride levels are independently associated with a better response to DPP-4 inhibitors, while higher BMI and good renal function seem to predict a positive response to SGLT-2 inhibitors. Dr. Jones cautioned that it’s unlikely a prediction model will ever be able to recommend a single therapy. Instead, he hopes for more tailored treatment options, with models outputting a few select choices more likely to be successful, which HCPs can then review with their patients. Dr. Jones also emphasized the need to replicate these preliminary findings in real-world and clinical trials to minimize false positives.

  • Dr. Jones has released a free diagnostic app on iTunes and Google Play, called Diabetes Diagnostics. As of now, the app takes clinical features as inputs to distinguish between type 1 and type 2 diabetes for individuals. Dr. Jones shared plans to incorporate insulin biomarkers into the model within the next year. His team is also working on creating diagnosis prediction calculators integrated directly into EHR, and is beginning to create provider-facing tools for predicting therapy response.

Symposium: Achieving Improved Compliance to Diabetes Care: The Common Task for Care Providers, Health Systems, and People with Diabetes

The Diabetes Team: How to Improve Cohesion

Dario Rahelic, MD (Dubrava University Hospital, Zagreb, Croatia); Sophie Hindkjaer (IDF, Denmark); Iryna Vlasenko, PhD (IDF, Ukraine)

Three speakers representing the interdisciplinary diabetes management team provided their perspective on how best to optimize diabetes treatment, emphasizing metrics beyond cost, mutual respect between patients and providers, and pharmacists as integral community healthcare members. For Dr. Dario Rahelic, an IDF board member and President of the Croatian Society for Diabetes and Metabolic Disorders, diabetes therapy is not just about direct cost. When evaluating a new therapy, he considers the broader impact, making sure to assess indirect effects like loss of productivity, quality of life, life years gained, and hospital visits. From the patient perspective, Ms. Sophie Hindkjaer, an IDF Young Leader living with type 1 diabetes, found that her doctor visits markedly improved once she viewed herself as an expert in her own diabetes. While her initial clinic visits felt like exams and were comprised solely of reviewing blood glucose numbers, after participating in the IDF youth leadership camp, she realized that her physician should not be scolding her, but rather working with her to improve her life. She began having productive conversations with her healthcare team by supplying and asking for context surrounding her glucose numbers. In her own words, “if you only focus on the numbers, you might miss the whole picture.” We love the idea of the empowered patient, but not everyone will have the opportunity to learn in the IDF context, so we hope to see more efforts go toward teaching providers how to be more effective.  Just as the patient should be considered an essential member of the healthcare team, so, as argued by IDF board member Dr. Iryna Vlasenko, should pharmacists. Pharmacists are often overlooked by physicians, yet they can educate patients about proper therapy use, recommend ancillary products and services, help maintain glycemic control, and prevent complications, all within a community setting. Dr. Vlasenko finds that pharmacists are underutilized, largely due to poor social and professional acceptance. Stigma doesn’t only apply to the people living with diabetes…

  • Dr. Rahelic urged the audience to avoid thinking exclusively in terms of direct cost. For a patient population whose numbers exceed those of HIV/AIDS, tuberculosis, and malaria combined, solutions can only be reached by thinking creatively. Dr. Rahelic provided the example of when he negotiated with the Croatian Ministry of Health and national insurance to make modern insulin available to type 2 patients in his country. While both entities were quick to dismiss the proposal at first due to expenses, Dr. Rahelic pointed out that the costs of hypoglycemia and weight gain associated with premixed insulin outweigh savings. Ultimately, he was able to reach a compromise, in which type 2 patients could receive modern basal insulin analogues for a more reasonable co-payment of 10-20 EUR. Up-front investment in tools that enable better glycemic control is a no-brainer, since the alternative is costly hypoglycemia and/or complications down the road.
  • We were pleased to hear Dr. Rahelic mention that diabetes management encompasses more than just medication. He stressed the effects of stigma, empathy, and the amount of time patients spend with physicians, which he finds to be insufficient. In his home country of Croatia, there are only 140 diabetologists and 2,500 general practitioners, each of whom are tasked with seeing 40-60 patients per day (aka 8-12 minutes/patient). To this end, Dr. Rahelic noted the importance of nurse educators, and we add that remote and AI coaching will likely fill huge gaps in care. 
  • Dr. Vlasenko detailed several studies showing the benefits of pharmaceutical intervention by pharmacists. A study published in the International Journal of Clinical Pharmacy suggested that pharmacists can reduce medical expenses and contribute to safety and efficacy, estimating the total cost savings associated with 500 interventions to be over $200,000 – more than half of the interventions helped prevent adverse drug reactions. A randomized control trial of elderly patients with diabetes and hypertension found that pharmaceutical care significantly improved health outcomes and did not increase total direct healthcare costs significantly, designating pharmaceutical intervention as a cost-effective option.
  • Ms. Hindkjaer emphasized the need for patient trust. Patients are expected to talk to their healthcare team about topics they might not even be ready to discuss with their families. As an example, women with diabetes are asked to make decisions regarding pregnancy very early on. This kind of trust can only be achieved through confidentiality and shared respect. Ms. Hindkjaer also noted that providers should be open to including the patient’s support network during visits, although acknowledged that not every patient will be ready for this step immediately, if at all. IDF Europe President-elect Dr. Niti Pall later added that the patient-provider relationship comes down to four factors: trust, empathy, expertise, and information. “If you don’t get trust and empathy right, they’ll never take your expertise and information.”
  • Dr. Rahelic proposed several solutions to ease the global burden of diabetes, including increasing awareness, involving politicians, facilitating cooperation between healthcare providers and national diabetes programs, and thinking globally yet acting locally. The last concept is particularly relevant given disparities across healthcare systems regarding access, technology, and reimbursement. Even in Europe, which is generally associated with high-quality care, people in Albania pay for all diabetes therapies out of pocket. There is no one-size-fits-all solution, though Dr. Pall strives for the “holy grail” that is elimination of all user fees and co-payments in medicine across the globe.

How Can Mobile Applications Contribute to Improving Compliance?

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

Mills-Pensinsula Medical Center's Dr. David Klonoff discussed the factors that will augment digital health adoption and suggested how to lower patient and HCP barriers. He broke down the primary factors that each stakeholder looks for in digital health products: Usability (for patients), clinical benefit (for healthcare providers), economic benefit (for payers), security (to satisfy product regulators), and data privacy (to satisfy legal regulators) – of course, there is plenty of overlap in this list. He went into more detail on how to make these products more appetizing for patients and providers: Providers look for interoperability with digital systems (something he believes the market will enforce in the long run), EMR compatibility, compatibility with professional standards, and safety in a mobile platform environment (Does the phone/software prioritize the medical app while you’re playing Angry Birds?.. Something FDA is certainly aware of and taking into consideration as companies seek to use phones as primary displays and control device functions from apps). Dr. Klonoff believes patients look for easy log-in (though noted simplicity must be balanced with security), simplified data and alert displays, no increase in (or less) work, time, and cost, coupled with improved outcomes and “no friction.” We think all of these can be boiled down to a slightly modified version of his third bullet: Patients will widely adopt digital health for diabetes if the quality of life and/or health benefits outweigh the burden of using them. As that balance improves, more will adopt and use the products. He went on to speak briefly about the quality of digital health clinical data, a lack of research into the benefits of social media (prominent patient advocate Mr. Bastian Hauck pushed back), and pharma’s growing involvement in digital therapeutics.

  • Dr. Klonoff listed a number of common flaws he sees in mHealth data generation and analysis: “mHealth clinical trials have produced good outcomes, but aren’t necessarily producing the best data of all time.” He advised audience members to first ask whether or not the data was generated via a randomized controlled trial. “Some digital health companies advocate for getting rid of RCTs – they say that once the trial is done, analyzed, and published, the technology is out of date and a next-gen product is on market. Make sure you’re looking at good data.” He didn’t offer many alternatives, except for doing n=1 trials at scale, wherein one patient and all his/her possible confounds are examined at a time, and then all conclusions from all patients are analyzed – sort of like a meta-analysis of individual level data. RCTs are certainly still needed, but we do see value in complementing them with real-world data (as does FDA), since the technology innovation cycle is rapid and apps are often multi-modular and therefore difficult to study in a simple RCT.
    • We agreed wholeheartedly with Dr. Klonoff’s caveat to look out for a small n, big p, and small t. Indeed, it is fallacious to draw definitive conclusions from studies with small sample sizes, statistically insignificant differences, and/or performed over a short time period. Dr. Klonoff suggested that trials in digital health have to be at least a year, but then suggested products must constantly be refreshed to maintain engagement.” We assume the only way for companies to navigate this balance is to choose one side, or do one-year studies with built-in product updates throughout.  
  • Patient advocate and active #dedoc member, Mr. Bastian Hauck – thinking that Dr. Klonoff had denigrated social media during his talk – pushed back during Q&A. Dr. Klonoff later clarified via email that he believes research into the benefits of social media on treatment adherence is lacking – he didn’t comment on overall benefit. To be clear, Dr. Klonoff doesn’t discourage social media use – he just doesn’t outright encourage it either based on the evidence he has seen. Mr. Hauck’s passionate comments were worth sharing anyhow: “The counterpoint is, we always talk about social media without defining it. We’re not doing anything new. We don’t need RCTs here, in my opinion. We have a lot of evidence showing peer-to-peer support, getting patients together to talk things through, is helpful. Social media is just a new means of communication. Same community work, just at a much faster pace. We’re always trying to scale things up and make things digital, and we’re not there yet in many cases, like AI, but with social media, we are already there. Making it faster and scaling. Yet we’re still getting so many counterpunches. We don’t need evidence to prove that communication is going to work.” The only reason we can think of for performing an “RCT” of social media use is to demonstrate benefit so that hesitant healthcare providers would more actively direct their patients to try it. On the other hand, social media is free, so there’s little barrier to access, and therefore little need to convince payers that it’s effective (though perhaps they could financially incentivize people to use social media).
  • When Dr. Klonoff first became a doctor, he noted that every innovation at big meetings was a drug. “Now, what really gets the buzz is new software and digital therapeutics,” he said. He pointed to Lilly’s FDA-cleared Go Dose, Novo Nordisk and Glooko’s recently-launched Cornerstones4Care, and Sanofi’s partnership with Evidation Health to mine behavioral trends and outcomes for insights into new product design and how to deploy current products. The list goes on – and this digital explosion is only starting to take off. Where will it be in five years?

Symposium: The Beta Cell in Type 2 Diabetes – What Are the Changes and Are They Reversible?

Human Islet Cell Heterogeneity and Changes in Type 2 Diabetes

Jesper Gromada, PhD (Regeneron, Tarrytown, NY)

Dr. Jesper Gromada presented data on islet cell subpopulations obtained using a technique that allows for isolation and mRNA sequencing of individual cells. This exquisite level of granularity yielded some fascinating findings. In samples from people without diabetes, Dr. Gromada’s team was able to identify a subpopulation expressing high levels of cellular stress genes. Many of these cells produced only low levels of insulin and/or had upregulation of unfolded protein response (UPR) genes. These findings support a model whereby beta cells under stress first begin showing stress markers, then turn off their insulin secretion and upregulate the UPR response to try and cope, then slowly recover. Although some stressed cells may die if overly stressed, Dr. Gromada’s study did not find upregulation of genes that cause apoptosis, otherwise known as programmed cell death.

  • Dr. Gromada’s team is now examining cells from individuals with type 2 diabetes. While there have not been enough samples collected yet to allow for full analysis of islet cell subtypes, the team has already identified 245 genes that exhibit different regulation vs. individuals without diabetes – most associated with islet growth and function. One major benefit of the technique Dr. Gromada’s team is using is that it can target changes in gene regulation to specific cell populations (alpha vs. beta vs. delta vs. other), eliminating some mechanistic guesswork.

Questions and Answers

Q: I have a question about kinetics. How fast do you think the cycle from unstressed to stress, to downregulated insulin production, to recovery happens? Every day, every meal, or only occasionally?

A: I have no idea but it cannot be that common. Our working hypothesis is that there is an increase in the proportion of stressed insulin-producing cells in type 2 diabetes – that diabetes pushes cells faster into the high-insulin stressed group, and they recover only slowly. Since we have low replication and more cells pushed out, that’s how we theorize beta cell mass slowly goes down, though we don’t have the data to support that yet.

Q: Did you check to see if the same islet cell subpopulations existed in type 2 diabetes islets?

A: In the type 2 diabetes data we have, we don’t have enough cells to thoroughly analyze subpopulations, but from the limited donors we have, we do seem to be seeing the same subpopulations of cells.

Durable Reversal of Beta Cell Failure by Calorie Restriction

Roy Taylor, MD (Newcastle University, UK)

Dr. Roy Taylor, a proponent of the controversial fat-centric “twin cycle” hypothesis of type 2 diabetes mediated by excess liver and pancreatic fat, reviewed his previous work and provided an update on his current project: the DiRECT trial of extreme low-calorie diet for diabetes remission. He disclosed that 12-month data from the study will be presented at IDF this December. We of course will be interested to see whether a weight loss intervention delivered in primary care can yield diabetes remission in the >300 type 2 diabetes patients enrolled. It is definitely ambitious, although Dr. Taylor’s previous COUNTERPOINT study did demonstrate a sustained rebound in beta cell health in patients who underwent a short-duration extreme low calorie diet – at least in patients with more recently diagnosed diabetes. We admire Dr. Taylor’s dedication to evaluating the “twin cycle” and diabetes-remission-by-extreme-weight-loss hypotheses, and we look forward to seeing whether they will be borne out by the DiRECT trial. Even if the theory is right, there is fair skepticism about how scalable his extreme caloric restriction interventions may be.

  • For background, the twin cycle hypothesis implicates excess liver and pancreatic fat in the pathophysiology of type 2 diabetes. The two cycles are (i) positive calorie balance causing liver fat to increase, causing insulin resistance and increased insulin output. This creates a vicious cycle of fatty liver disease. (ii) The spillover fat (as triglycerides) is taken up by pancreatic islets causing insulin resistance and another vicious cycle, which culminates in an acute insulin crisis, beta cell de-differentiation, and the diagnosis of type 2 diabetes.

Questions and Answers

Q: What differentiated the responders from non-responders in COUNTERPOINT?

A: As a group, they were indistinguishable clinically apart from the duration of their diabetes. The responders were almost all short duration – less than 10 years. Over 11 years duration, we generally observed no response.

Q: I am reminded of a study published by Dr. Ralph DeFronzo’s group in 2003 that found that lipid infusion reduced glucose-stimulated insulin secretion in people with a family history of type 2 diabetes.

A: Yes, that was an important study – one I mentioned in my grant application for my current study. It demonstrates the importance of lipids in initiating this process.

Q: You ascribe what you see to pancreatic fat via imaging. Have you looked at circulating markers like glucose, fatty acids, and amino acids?

A: Plasma fatty acids increased during starvation, which is no surprise. At one week after the resumption of feeding, there was normalization of hepatic insulin sensitivity despite the increase in plasma fatty acids. Fatty acids in plasma don’t impinge much on beta cell metabolism. The payload from VLDL and LPL is the big bomb on the pancreas. The glucose normalizes of course and will have an affect on beta cell function, but it’s relatively modest. Removing fat from the beta cell environment decreases VLDL secretion.

Comment: Well I think glucose lowering is important, too. Work in China has shown that acute short-term reductions in glucose can cause diabetes remission.

Q: I’m questioning whether we should have so much emphasis on fat. It could be that you are only reducing the glucose load and in that way relieving stress on beta cells.

A: We’ve considered that, though the time course seems to favor the importance of fat. Type 2 diabetes has to start with a trigger … there has to be an etiological buildup. As soon as glucose rises, the glucose will play an important role, but if measurement of pancreatic fat is done precisely, we can rely on that, and the time course seems in favor of fat playing an important role.

Q: To preserve the weight loss after the caloric restriction period is over, was there a specific diet, or did you just tell people to avoid weight gain?

A: It’s very important to avoid diets. People were advised to eat whatever they found most agreeable and pleasant to keep their weight down. For most, it was a low-ish carb pattern. The key was portion size, and we did tell people to avoid takeaway meals. But the final arbiter is the weight scale.

Q: Where is the fat located in the pancreas?

A: We can’t be definitive, but most likely it is intracytoplasmic within islets. 

Bariatric Surgery and the Beta Cell: Where Does the Miracle Occur?

David D’Alessio, MD (Duke University, Durham, NC)

Bariatric surgery expert Dr. David D’Alessio drew upon recent and ongoing research to suggest a model explaining bariatric surgery’s impact on the beta cell and glucose regulation. He focused on forms of bariatric surgery that expedite nutrient delivery to the gut: Roux-en-Y gastric bypass and vertical sleeve gastrectomy. At baseline, candidates for bariatric surgery with obesity and type 2 diabetes are hyperinsulinemic, with a normal or decreased incretin effect. Immediately post-op, beta cell function increases markedly, likely driven by an augmented incretin effect. Over time, however, with weight loss and increased insulin sensitivity, the insulin secretion rate and beta cell sensitivity to glucose and incretins gets dialed back.

  • Dr. D’Alessio argued that instead of looking to the progressive pathophysiology of type 2 diabetes to inform drug development, it would be better to examine bariatric surgery, which in many ways is the disease progression in reverse. Also on the topic of therapeutic relevance, he suggested that beta cell responses to bariatric surgery – and the variation in response between different patients – might help explain why some patients’ diabetes responds well to bariatric surgery (i.e. remission) while other patients’ diabetes responds poorly (i.e. recurrent hyperinsulinemic hypoglycemia). 

Questions and Answers

Q: Is the improvement in beta cell function after bariatric surgery dependent more on the specific surgical approach, or on the level of weight loss achieved?

A: Vertical sleeve gastrectomy and Roux-en-Y gastric bypass do different things than procedures like gastric banding that behave more like dieting and don’t cause an increase in insulin secretion early on. Procedures that increase gut nutrient flux behave differently than ones that are restrictive.

Symposium: Cognitive Impairment and Alzheimer’s Disease in the Type 2 Diabetes Patient

Diabetes as an Accelerator of Alzheimer’s Disease: Underlying Mechanisms and Potential Treatments

Fernanda De Felice, PhD (Queen’s University, Kingston, Canada)

Dr. Fernanda De Felice summarized the latest research on the link between Alzheimer’s Disease and diabetes, a topic that’s quickly gaining attention as Alzheimer’s Disease becomes a public health issue in its own right, and as thought leaders increasingly refer to it as “type 3 diabetes.” Insulin expression in the brain is lower in people with Alzheimer’s Disease compared to a background population. Insulin receptors are downregulated due to the action of toxins associated with Alzheimer’s. Accordingly, this condition increases the risk of type 2 diabetes and vice versa, leading Dr. De Felice to strongly urge providers to track blood glucose levels in people at risk for cognitive disorders. Given the growing number of young people with type 2 diabetes, Dr. De Felice also emphasized the need to find earlier indicators of Alzheimer’s. By the time this cognitive condition manifests clinically, it’s most often too late to treat. Dr. De Felice described an interaction between endoplasmic reticulum (ER) stress, obesity, insulin action, and type 2 diabetes, and then pointed out how the same markers for ER stress are observed in the brains of Alzheimer’s mice. The similarities between these two diseases don’t end there – both begin with inflammation, which activates the cell stress pathway, eventually resulting in insulin resistance. In the brain, this stress is also related to synaptic malfunctioning and cognitive decline.

  • Researchers are hard at work leveraging the parallel pathways of type 2 diabetes and Alzheimer’s Disease to design new therapies. Wake Forest’s Dr. Suzanne Craft is currently leading a large clinical trial SNIFF (the Study of Nasal Insulin in the Fight against Forgetfulness), investigating the potential protective effect of insulin on synapses. The study has identified that GLP-1 agonist liraglutide (Novo Nordisk) can attenuate loss of neuronal insulin receptors in monkeys, preserving appropriate synapse morphology. Dr. De Felice also detailed the role of irisin, a newly-discovered hormone released by the muscle upon exercise. Irisin is also expressed in the brain, associated with metabolic effects, and found to be reduced in both human and mice Alzheimer’s brains. When Alzheimer’s mice are treated with irisin, memory is improved, suggesting a potentially powerful therapeutic target.  

Lifestyle in Cognitive Impairment and Type 2 Diabetes: Is There Ground for Joint Prevention?

Jaakko Tuomilehto, MD (University of Helsinki, Finland)

As the prevalence of Alzheimer’s Disease steadily rises (by 2047, experts predict Alzheimer’s prevalence will be 8x what it is today), prevention efforts are becoming paramount. Prevention expert Dr. Jaakko Tuomilehto took the stage to discuss the role of lifestyle, describing similar interventions as those prescribed for prediabetes. He highlighted findings from the Finish Diabetes Prevention Study (DPS), in which dementia risk correlated with a lower intake of total fat and saturated fat, as well as with increased physical activity. Likewise, preliminary data from the FINGER study published in the Lancet demonstrated that a multi-domain lifestyle intervention (diet, exercise, cognitive training, and vascular risk monitoring) in an at-risk elderly population is associated with significant improvements in executive functioning and processing speed. Good glycemic control was not sufficient to preserve cognitive function, but these lifestyle changes were promising. It’s estimated that a 10%-25% reduction in all seven risk factors for Alzheimer’s Disease (diabetes, hypertension, obesity, depression, inactivity, smoking, and cognitive activity) could prevent 1.1-3.0 million cases worldwide. Moreover, a five-year delay in the onset of Alzheimer’s would decrease prevalence by 50%. Dr. Tuomilehto’s talk outlined a compelling case for lifestyle prevention strategies, as they could impact individual health outcomes/quality of life as well as the state of Alzheimer’s from a public health perspective.

Oral Presentations: Clinical Impact of Hypoglycemia

Weight Gain is Associated with Mild to Moderate Hypoglycemia in Patients with Type 1 Diabetes: Results from the DCCT

Anisoara Bumbu, MD (AP-HP, Paris, France)

Dr. Anisoara Bumbu presented an analysis of DCCT data showing that weight gain is correlated with increased mild to moderate hypoglycemia in patients with type 1 diabetes. The DCCT established that intensive glucose control prevents chronic complications, but the more aggressive approach also increased hypoglycemia risk and weight gain. In turn, Dr. Bumbu explained, weight gain lowers long-term therapy adherence and can increase the risk of other complications, including nephropathy and coronary artery disease. She reviewed data showing a weak association between severe hypoglycemia and weight gain in the DCCT, but described how less work has been done on more-frequent, less-severe hypoglycemia – until now. Using available data on the 1,441 patients with type 1 diabetes age 13-39 who participated in the DCCT (either conventional or intensive arm), a hypoglycemia score (number of blood glucose values <70 mg/dl divided by total number of blood glucose measurements) was calculated for each participant. Hypoglycemia scores were associated with severe hypoglycemia, but this new analysis also found a significant association between hypoglycemia score and total weight gain/average annual weight gain (R2=0.021, p<0.001). Over 7.5 years of follow-up, mean total weight gain in this sample was 16 lbs. When splitting hypoglycemia scores into tertiles, Dr. Bumbu showed a trend of increased weight gain: The third of lowest scores gained a total of 12 lbs on average vs. 18 lbs and 19 lbs for the second and first highest tertiles (p<0.008). When adjusting for age, sex, duration of diabetes, treatment arms, baseline A1c, and baseline BMI, inter-tertile differences remained highly significant (p<0.001). These results contribute to a growing body of evidence demonstrating the importance of avoiding hypoglycemia in patients with type 1 diabetes, and the meaningfulness of outcomes beyond A1c.

Corporate Symposium: Real-World Challenges in Type 2 Diabetes (Sponsored by Servier)

Why a Paradigm Shift is Needed

Luc Van Gaal, MD (Antwerp University, Belgium); Steven Edelman, MD (UCSD, San Diego, CA); Richard O’Brien, MD (University of Melbourne, Australia); William Polonsky, PhD (Behavioral Diabetes Institute, San Diego, CA); Eduard Montanya (University of Barcelona, Spain)

Melbourne’s Prof. Richard O’Brien, UCSD’s Dr. William Polonsky, and Barcelona’s Prof. Eduard Montanya discussed real-world challenges in type 2 diabetes, identifying adherence as the primary driver for the gap between outcomes observed in clinical trials versus real life. Dr. O’Brien cited a recent study (from Dr. Polonsky’s group) demonstrating that 75% of the differences in A1c reductions seen in clinical trials for GLP-1 agonists vs. real-world data can be explained by non-adherence. For DPP-4 inhibitors, the paper suggests that 72% is due to non-adherence. Dr. O’Brien urged physicians to discuss adherence with their patients, citing that one third of prescriptions for diabetes medications are never filled. Dr. Polonsky took adherence a step further, diving into critical patient beliefs surrounding medication. The issue, he said, is that diabetes medications lack short-term, tangible benefits, while cons such as burden and real/imagined adverse effects are plentiful – we wonder if VR, simulation, and higher tech education might help close this gap. For example, here’s what happens to the body when glucose levels are high, here’s how you will age when glucose levels are high, etc. Dr. Polonsky provided the telling example of an exercise he performs with type 2 patients, in which he shows them the profiles of two hypothetical patients, one of whom has at-goal A1c but takes two medications and is on insulin, while the other has a high A1c, but is not on any medications. When asked which patient is doing better, the vast majority say it’s a tough question. In other words, some people with diabetes equate more medication with failure. Yikes! The onus for this misconception is largely on providers, who sometimes threaten patients with more medication if they don’t improve behavior. Dr. Polonsky emphasized working on the patient-provider relationship, citing several studies demonstrating that improved trust is associated with greater adherence. So how do we shift the paradigm? Dr. Montanya mentioned a study demonstrating that triple combination therapy immediately following diagnosis (instead of a step-wise add-on approach over four months) conferred a greater A1c improvement. His argument was in favor of early combination therapy, but this could also tie in to adherence: Presumably, a stepwise approach is perceived as consecutive failures, while the immediate intensification is simply a medication regimen that drives right to success, so patients are more likely to stick to it. Dr. Montanya also suggested telemedicine as a potential approach to improve adherence, although acknowledged that meta-analyses yield mixed results and tend to demonstrate only short-term efficacy. He, and many thought leaders we’ve heard from recently, are particularly excited about ITCA 650, the six-month implantable exenatide pump from Intarcia. He discussed the FREEDOM-1 and -2 trials demonstrating significant reductions in A1c and body weight, and sees real potential in the pump to drive adherence. Once implanted, it works! We also see very high potential in novel ways to take and track medication, such as the super brilliant Pill Pack(“Pharmacy Simplified”). Poor adherence is a complicated affair, one that costs the health system huge sums of money – addressing it will take a carefully-crafted combination of support, technology, and design.

Questions and Answers

Q: What is the best way to approach a patient about being adherent?

Dr. Polonsky: What we see is healthcare providers will say, “I don’t know this data regarding adherence, I don’t see that.” That probably has to do with how we ask the question. It’s common for providers to say: “Look you haven’t had any problems managing your meds, have you?” The patient is almost guaranteed to answer no. There’s an opportunity to normalize the situation. Instead say, “I know people struggle taking medication, what kind of trouble do you have with your medication?” It’s important to open up the door to normalize the issue. Bravo!

Posters

Low Income Predicts Cardiovascular Event Risk Independently from the Presence of Type 2 Diabetes and Pre-Existing Coronary Artery Disease

R Saely, A Vonbank, C Saely, C Lins, D Zanolin, A Leiherer, A Schuler, A Muendlein, A Mader, P Schwerzler

A diverse research team from Austria, Liechtenstein, and the US presented a poster demonstrating that low income is an independent risk factor for CV events, regardless of a patient’s diabetes status or pre-existing coronary artery disease (coronary stenosis with lumen narrowing 50%).While it’s known that low socioeconomic status is associated with increased CV risk, low-income populations also show disproportionately high rates of type 2 diabetes and related complications (including macrovascular events). It was not known whether the association between low socioeconomic status/CV risk was independent of type 2 diabetes. Out of a cohort of 389 individuals referred to coronary angiography for the evaluation of established or suspected stable coronary artery disease, those in a higher income bracket were 32% less likely to experience a CV event (HR=0.68, 95% CI: 0.51-0.92, p=0.011) over eight years, after adjusting for age, gender, smoking, LDL, HDL, hypertension, BMI, waist circumference, type 2 diabetes, and baseline coronary artery disease. The incidence of CV events for those earning <€20,000/year was 62% vs. 5% among those with an annual income >€35,000. The poster did not specify whether the patient cohort was established from multiple countries, and we wonder whether differences exist on a geographic basis related to differing healthcare systems and access. There’s clearly a lot of work to be done here to assist this under-served population, requiring multidisciplinary efforts. 

Obesity

White Adipose Tissue as a Drug Target

Rudolf Zechner, PhD (University of Graz, Austria)

Pharmacological researcher Dr. Rudolf Zechner discussed work his group has been doing in rodents with an inhibitor of adipose triglyceride lipase (ATGL). The compound reduces lipolysis from white adipocytes, fat storage cells that we increasingly realize do much more than just store fat. The mouse-specific ATGL inhibitor atglistatin, which acts preferentially on adipose tissue and the liver while appearing to avoid dangerous effects of lipolysis inhibition elsewhere in the body, led to a beneficial metabolic phenotype. This included reduced fatty acid levels, improved insulin sensitivity, and less insulin secretion. Atglistatin does not work on human ATGL, but Dr. Zechner suggested that a human-specific compound would work if it does not target cardiac lipolysis, and if human lipolysis reacts similarly to mouse lipolysis – which he admits is no small “if.” Still, his group’s early-stage but exciting work has apparently already appealed to industry, as Dr. Zechner noted as an aside that he has “lots of pharma companies getting in touch with him” – a good sign!

  • When weighing pharmacological inhibition of lipolysis, the main factor in favor is that inhibiting lipolysis appears to cause resistance to obesity in animals on high-fat diets, as well as better glucose tolerance. However, overly broad inhibition of lipolysis can cause ectopic fat accumulation elsewhere in the body. This is especially catastrophic in the heart, and mice with a complete body-wide knockout of adipose triglyceride lipase rarely make it to 24 weeks of life before they die of severe cardiac steatosis.
Antonio Vidal-Puig, MD (University of Cambridge, UK)

Dr. Antonio Vidal-Puig discussed his fascinating hypothesis that adipose tissue reaching the limit of its fat-storing capacity is what tips the scale in an individual patient toward metabolic dysfunction. He began his presentation by reminding the audience that adipose tissue consists of more than just adipocytes (fat storage cells) – there are also blood vessels that must grow as fat tissue grows, immune cells that manage adipocytes and take up loose fatty acids, and structural support requirements. The “adipose tissue expandability hypothesis” suggests that while the risk of metabolic dysfunction increases linearly with adipose tissue gain on a population level, an individual patient has an adipose tissue threshold beyond which the tissue stops being able to buffer additional nutrient excess, causing metabolic compromise. The takeaway from this theory would be to focus on improving adipose tissue functionality by increasing its capacity. Though his theory suggests that the body can compensate for adipose tissue gain until it hits its threshold, during Q&A Dr. Vidal-Puig pushed back against a dichotomy of healthy obesity vs. unhealthy obesity. “A person is seen as a healthy obese individual until they develop their first complication… Assuming that you can tell anyone that they are “healthy obese” and can do anything they want is a bad idea.”

Oral Presentations: Incretins: New Clinical Evidence

Semaglutide Provides Sustained Reductions in Body Weight Over 2 Years in Subjects with Type 2 Diabetes (SUSTAIN 6)

Agostino Consoli, MD (University of Chieti, Italy)

Dr. Agostino Consoli shared new data from Novo Nordisk’s SUSTAIN 6 trial of GLP-1 agonist semaglutide, demonstrating sustained weight loss over two years. While the 104-week study (n=3,297) was designed primarily to assess CV outcomes with once-weekly semaglutide vs. placebo – and indeed, showed significant 26% risk reduction for the primary MACE endpoint – the agent’s weight loss effects were also noteworthy. At week 104, 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). Looking at an even greater goal of ≥10% weight loss from baseline, 13% of people on 0.5 mg and 20% of people on 1.0 mg semaglutide achieved this vs. 6% and 7% of each placebo arm (p<0.0001 for both comparisons). Another impressive piece of data from this new analysis 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. Dr. Consoli further mentioned that the significance of weight loss results was maintained across baseline BMI categories. A separate post-hoc mediation analysis found that the impact of nausea and vomiting (common side-effects of GLP-1 agonists) on body weight was minimal – indirect weight loss effects mediated by nausea and vomiting were estimated at a mere ~0.3 lbs and ~0.09 lbs for the 0.5 mg and 1.0 mg doses, respectively. With these results, the SUSTAIN program extends its groundbreaking series of data, showing that semaglutide confers significant and clinically-meaningful reductions in weight and waist circumference over an extended treatment period in people with type 2 diabetes and high CV risk. Importantly, 5% weight loss seems to be the necessary level to delay new-onset type 2 diabetes, and semaglutide could have an impact in prediabetes if its efficacy is sustained in that population. The emphasis on positive body weight effects for semaglutide, in addition to profound A1c-lowering efficacy and cardioprotection, is fitting since Novo Nordisk is also conducting clinical trials of the potent GLP-1 agonist toward an obesity indication (phase 3 to begin in 1H18). Management reviewed remarkable phase 2 data on semaglutide in obesity during the company’s 2Q17 earnings call, and Chief Science Officer Dr. Mads Thomsen alluded to a “new level of efficacy” seen with semaglutide on weight loss. Once-weekly semaglutide has been submitted to the FDA for a type 2 diabetes indication, and a regulatory decision is expected in 4Q17. Needless to say, we’re very excited about this molecule and its enormous and diverse therapeutic potential …

The Effects of GIP/GLP-1 Receptor Co-Activation on Appetite and Food Intake in Overweight/Obese Subjects

Natasha Bergmann (University of Copenhagen, Denmark)

Ms. Natasha Bergmann presented somewhat disappointing results demonstrating that the addition of GIP on top of existing GLP-1 agonist therapy does not produce any further reductions in food intake or appetite suppression in people with obesity. In fact, she showed, it may reduce the potency of GLP-1 agonist monotherapy. In this study, 18 male participants with obesity (average BMI 33 kg/m2, no type 2 diabetes or prediabetes) were given repeated isoglycemic glucose infusions with the addition of GLP-1, GIP, both GLP-1/GIP, and placebo, after which their food intake was measured at an unlimited buffet. Expectedly, food intake was significantly reduced with GLP-1 vs. placebo (~396 calories, p=0.035), but food intake with GIP and GLP-1/GIP did not differ significantly from placebo. Thus, Ms. Bergmann suggested that not only is GLP-1/GIP dual activation not superior to GLP-1 activation alone, but it seems to be inferior. A similar trend persisted for the secondary outcome of appetite suppression, which was reported on a subjective scale. Compared to placebo, GLP-1 produced less reported hunger (p<0.0001), a higher degree of satiety (p<0.05), and lower prospective food consumption (p<0.0001). GIP and GLP-1/GIP, by contrast, did not significantly differ from placebo on these metrics. The additional secondary endpoint of resting energy expenditure (REE) was unchanged in all experimental conditions. It’s important to keep in mind that this data pertains only to food intake and subjective appetite measures, to say nothing of the effect of GLP-1/GIP dual activation on outcomes like weight loss and glycemic control. That said, this investigation, though small, suggests that the efficacy of GLP-1/GIP dual agonists does not come from the drugs’ effect on appetite and eating behavior. The growing GLP-1/GIP competitive landscape currently contains phase 1 candidates from Lilly, Sanofi, and Novo Nordisk, in addition to a preclinical candidate from Zealand.

Oral Presentations: Novel Therapies, Future Opportunities

Weight Loss Unrelated to Decrease in Calorie Intake After a Single Dose of a Bispecific Antibody to FGFR1/Klothoβ in Obese Subjects

Puneet Arora, MD (Genentech, San Francisco, CA)

Genentech’s Dr. Puneet Arora summarized promising weight loss data from the first in-human study of the company’s bispecific FGFR1/Klothoβ antibody, currently in development for obesity and type 2 diabetes. People with obesity (n=71), at mean baseline body weight 218 lbs, were randomized to receive one of seven single escalating doses of the injectable candidate BFKB8488A (ranging from 3 mg to 681 mg). Dr. Arora described a significant dose-dependent decrease in body weight observed after just one week (p<0.01 for interaction). Body weight fell a mean of 0.3% with a 3 mg dose, 0.9% with a 10.5 mg dose, 0.9% with a 39 mg dose, 1% with a 111 mg dose, 1% with a 171 mg dose, 2% with a 342 mg dose, and 2% with a 681 mg dose. In comparison, weight loss was <0.3% from baseline with placebo. Thigh injections appeared to be especially potent: here, 171 mg and 250 mg doses produced a mean body weight reduction of 2% and 1%, respectively. Though these are small effects, this is quite an impressive degree of weight loss for only one week. We would be very interested to see whether this effect is durable in longer-term studies. Notably, BFKB8488A was not associated with any loss of appetite or caloric intake, suggesting that the candidate’s weight loss benefit is not attributable to a simple decrease in eating behavior and may be instead acting to increase energy expenditure. Past studies – including a presentation by UT Southwestern’s Dr. Steven Kliewer at ENDO 2017 – corroborate this, providing compelling evidence that FGF receptor activation has a direct effect on adipose tissue (“the fire”) which is complemented by indirect action in the hypothalamus and hind brain, triggering a cascade of downstream effects to support increased energy expenditure (“the fuel”).

  • Genentech’s bispecific antibody binds to both FGF receptor 1 (FGFR1) and the Klothoβ protein, thus accelerating the formation FGFR1/Klothoβ complexes in adipose tissue. This stands in contrast to other FGF-targeting therapies in development, the majority of which are analogs of the FGF21 protein. Novo Nordisk announced in its 4Q16 update that it has initiated a phase 1 trial of a new once-daily FGF21 analog (NN9499) in obesity, which will enroll 56 male participants with overweight or obesity and has an expected completion date of October 2017, according to ClinicalTrials.gov. Novo Nordisk is usually very smart about its product pipeline and this addition is a strong vote of confidence in the FGF pathway as a therapeutic target. That said, Pfizer and Lilly have discontinued their FGF21 candidates after underwhelming glucose-lowering efficacy, though these candidates were in development for type 2 diabetes, not obesity. We will continue to closely watch this exciting arena within the larger obesity drug competitive landscape, with a particular eye toward whether there is a difference in efficacy between the FGF21 analog approach vs. the FGFR1/Klothoβ antibody approach.

Corporate Symposium: Obesity and Diabetes (Sponsored by Novo Nordisk)

A Global Syndemic

Donna Ryan, MD (Pennington Biomedical Research Center, Baton Rouge, LA); Melanie Davies, MD (University of Leicester, UK); Luc Van Gaal, MD (Antwerp University, Belgium)

In this Novo Nordisk-sponsored symposium, Drs. Donna Ryan, Melanie Davies, and Luc Van Gaal discussed obesity as a global syndemic. If you’ve never heard the term “syndemic,” you’re not alone – we hadn’t either! A syndemic is a combination of “synergistic” and “epidemic,” where components (in this case, obesity and diabetes) interact to amplify disease burden. Dr. Ryan defined the term as a biological interaction with underlying social forces resulting in excess disease burden within a population. Obesity and diabetes are known to be biologically related, sharing common pathophysiology, but they are also clustered in the same populations, implying that the two diseases act at a community level rather than an individual level. To illustrate her point, Dr. Ryan described the make-up of Louisiana and Colorado. Louisiana has high rates of obesity and the highest prevalence of diabetes in the US, whereas in Colorado, diabetes rates are much lower and obesity prevalence is the lowest in the US (the CDC’s recent state-by-state obesity data supports this). According to Dr. Ryan, Louisiana and Colorado also feature distinct cultural, physical, and work environments, as well as differences in social/demographic factors, education, incarcerations rates, and mental health rankings. “Obesity and diabetes are twins,” she established. Dr. Ryan urged diabetes care providers to address weight with concerted interventions, as “good weight management is good diabetes management.” Even a minor weight loss can have major implications in metabolic health, and Dr. Ryan issued a call-to-action for HCPs to double as advocates for better built environments, food environments, and work environments to this end.

  • Antwerp’s Dr. Luc Van Gaal examined obesity through the lens of diabetes prevention, noting that prediabetes risk doubles for each five-point increase in BMI. Dr. Gaal cited studies of Diabetes Prevention Programs (DPP) from the US, Finland, and China, demonstrating that intensive lifestyle intervention significantly reduces risk for new diabetes development. He supplied an easy (and compelling) statistic to remember from the DPP: Four kilos lost over four years reduces risk for new-onset diabetes by 58%. He showed impressive findings on how intense dietary restriction can normalize beta cell function and reduce fat accumulation in the pancreas and liver in people with type 2 diabetes. Dr. Gaal also reviewed available obesity medications to be used when lifestyle alone is insufficient in achieving results. He drew attention to the SCALE study of Novo Nordisk’s Saxenda (liraglutide 3.0 mg), in which the high-dose GLP-1 agonist caused ~7% body weight loss sustained over three years, dropping the proportion of those developing diabetes from 11% to just 3%. Still, with a nod toward adherence issues, Dr. Gaal cautioned that drugs will correct situations but cannot be considered cures – their effects will only present if taken consistently. Dr. Gaal recommended bariatric surgery for those with extreme obesity and those who have already developed type 2 diabetes.   
  • Professor Melanie Davies predicted upcoming trends in diabetes/obesity pharmacotherapy, emphasizing combination treatments. Per her clinical experience and previous research, Professor Davies has found single agents to be disappointing. She emphasized that multiple redundant pathways in the human body resist long-term weight loss, which is why combination approaches offer the best chance at success. According to Professor Davies, therapies will have to target two or more pathways to yield long-term weight benefits, and she suggested that GLP-1 agonists should be at the center of action. Possible combo therapies include hybrids (molecules bound together) and chimeras (a secondary activity is designed into the existing drug peptide backbone). Professor Davies also expressed excitement for a GLP-1/GIP/glucagon tri-agonist, which in rats has shown 25% weight loss while also improving and maintaining reductions in blood glucose. The triple combination therapy was further shown to reduce cholesterol and reverse fat accumulation in the liver. We were pleased to get such comprehensive education on obesity pharmacotherapy from a Novo Nordisk symposium, suggesting that the company is focused not only on its current market-leader in Saxenda, but on pipeline products that could be effective in obesity care. Indeed, Novo Nordisk has seven candidates that we’re aware of in the obesity drug competitive landscape, the closest-to-market being once-weekly GLP-1 agonist semaglutide (phase 3 obesity studies are slated to start in the first half of 2018).

Questions and Answers

Q: What data is needed to convince more countries to classify obesity as a disease?

Dr. Ryan: When people argue about whether obesity is a disease, they’re arguing about a definition. We have these definitions used by epidemiologists and we classify a BMI of 25-30 kg/m2 as overweight and 30 kg/m2 or higher as obese. We correlate BMI with risk for CV outcomes, all-cause mortality, cancer, etc., and on a population basis that works well. But the diagnosis of obesity is clinical, and according to the World Health Organization, it’s an abnormal accumulation of excess body fat associated with ill health. It’s not a number. We treat patient health, we don’t treat cosmetics. It’s understanding what obesity is, the definition, its health effects, and the fact that we have some treatments that can improve obesity.

Q: Do you think the environment can cause epigenetic changes that make the syndemic worse?

Dr. Ryan: Once obesity develops, it’s difficult to reverse. There are demonstrated changes in the hypothalamus, which could be considered epigenetic. Once mothers develop obesity and diabetes, there’s definitely evidence of transmission of risk to their offspring if they’re gaining too much weight or have type 2 diabetes during pregnancy. The trans-generational effect is very concerning.

Posters

The MetAP2 Inhibitor ZGN-1061 Improves Glycemia in High Fat Diet-Induced Obese Mice

B Burkey, J Vath, M Wyman, S Vickers, S Cheetham, K Dickinson, G Birmingham, T Hughes

In this preclinical study, Zafgen’s next-generation MetAP2 inhibitor ZGN-1061 showed dose-dependent improvements in weight loss, glycemic control, and insulin sensitivity after four weeks in mice with diet-induced obesity. These mice were treated with either ZGN-1061 at doses of 0.03 mg/kg, 0.1 mg/kg, or 0.3 mg/kg, with Zafgen’s now-discontinued first-generation MetAP2 inhibitor beloranib, or with placebo for 28 days (n=10 per group). ZGN-1061 dose-dependently reduced body weight by 4%, 17%, and 30%, respectively. For comparison, beloranib achieved 32% weight loss – comparable to the highest dose of ZGN-1061. On the glycemia front, the ascending doses of ZGN-1061 additionally reduced baseline fasting glucose by 12%, 16%, and 27% relative to placebo (vs. 24% for beloranib) and reduced glucose excursions in an oral glucose tolerance test by 21%, 27% and 33% (vs. 33% for beloranib). Furthermore, ZGN-1061 doses reduced insulin excursions by 25%, 44%, and 60% and showed a reduction in insulin resistance, as measured by HOMA-IR, ranging from 40% at the lowest dose to 82% at the highest dose. Interestingly, these metabolic improvements were disassociated from food intake, which transiently decreased with ZGN-1061 (and beloranib) after 16 days, but did not significantly differ between any of the experimental groups by the end of the study. This data provides preliminary evidence that ZGN-1061 has a comparable weight loss and glycemic control profile to beloranib and is a potential treatment for both obesity and type 2 diabetes. To this end, a phase 2 trial (n=~120) is ongoing investigating the safety/efficacy of ZGN-1061 in people with overweight and obesity and type 2 diabetes – Zafgen announced this new study while we were still on the ground in Lisbon. We see potential for the MetAP2 inhibitor class, but note that it will be absolutely critical for Zafgen to provide compelling, reassuring safety (in addition to efficacy) data given that its former flagship product beloranib was discontinued after two thrombosis-related deaths in phase 3 trials.

Single and Multiple Dose Evaluation of a Novel MetAP2 Inhibitor: Results of a Randomized, Double-Blind, Placebo-Controlled Clinical Trial

J Malloy, D Zhuang, T Kim, D Kim, and K Taylor

This poster presented promising safety and PK data a phase 1 study of Zafgen’s second-generation MetAP2 inhibitor ZGN-1061, showing no notable safety or tolerability signals and, importantly, no evidence of pro-thrombotic effects (the reason for the discontinuation of Zafgen’s first-genMetAP2 inhibitor beloranib from phase 3). The study was composed of a single ascending dose (SAD) phase investigating the absorption and clearance of a one-time dose (0.2, 0.6, 1.2, 2.4, 3.6, and 4.8 mg) of ZGN-1061 in healthy participants (n=39) followed by a multiple ascending dose (MAD) phase investigating the effect of twice-weekly doses (0.2, 0.6, and 1.8 mg) of the drug in people with obesity for 28 days (n=29). The SAD study phase indicated rapid absorption and clearance of ZGN-1061: Mean maximum plasma concentration of ZGN-1061 increased linearly with dose, ranging from 0.5-18.7 ng/ml, and peaked within 30 minutes of dosing, with a half-life of one hour or less, making the drug undetectable after 12 hours. In the MAD phase, all three doses of ZGN-1061 showed an impact on body weight, producing weight loss ranging from ~2 lbs to ~5 lbs over 28 days. Finally, ZGN-1061 was well-tolerated across the doses tested. No serious adverse events occurred in either the SAD or MAD phases, and the most common adverse events reported were headache, mild GI issues, and injection site irritation (this occurred with no relationship to dose size). Very importantly, there was no evidence of venous thromboembolism (VTE), both in terms of VTE events and elevations in the D-dimer biomarker, though this signal will be important to continue to monitor closely in future studies, given that Zafgen’s former flagship product beloranib was discontinued after two thrombosis-related deaths in phase 3 trials. Together, these results support the further evaluation of ZGN-1061 in larger and longer trials. To this end, a phase 2 trial (n=~120) is ongoing investigating the safety/efficacy of ZGN-1061 in people with overweight and obesity and type 2 diabetes – Zafgen announced this new study while we were still on the ground in Lisbon.

Exhibit Hall

Exhibit Hall – Diabetes Technology

Abbott

The bustling Abbott booth, tucked into the corner of the hall, showed off the real world and clinical data (both from adults and pediatrics) of FreeStyle Libre, along with the slogan “You can view it – Anytime, anywhere.” The “anywhere” part of that phrase is becoming more literal by the day – Abbott has caught up to Dexcom, with Libre availability in 41 countries, and full or partial reimbursement in 17 of them. The big news today was the achievement of reimbursement status in the UK – see our report here. The other recent milestone was national reimbursement in Japan, and a rep told us that she believes FreeStyle Libre Pro will enter the French market in 2018 (Libre consumer has already secured national reimbursement). The public figure for user base stands at “over 300,000,” but we’re hoping for another update in the 3Q17 call. FreeStyle Libre remains under FDA review after its 3Q16 submission. As typically shown at Abbott’s booths, there were a slew of patient testimonials on the device: “Discovering FreeStyle Libre was like someone turning the light on.” “FreeStyle Libre has also washed away my parents’ anxious feelings overnight.” “It’s allowed me to do things that I would have never considered.”

Ascensia

The Ascensia booth advertised the Contour Next One and Next Plus BGMs (identical meters branded differently for separate markets). Representatives shared that they were receiving lots of questions surrounding the Contour Next One, mostly on how the new system functions. Visitors were also curious to learn more about Contour NextLink, which is available with Medtronic’s MiniMed 670G in the US (630G and 670G pumps) and in the MiniMed 640G outside the US. The booth bore the following campaign message: “Confidence in calibration: Recommend the highly accurate Contour Next Link 2.4 meter to calibrate their compatible CGM device and help avoid hypoglycemia.” This is a smart move for Ascensia, given Contour’s widely appreciated accuracy and the new partnerships with Dexcom (Medicare bundle) and Insulet (OmniPod Dash). As a reminder, Medtronic’s next-gen Bluetooth-enabled pumps will switch to Roche’s Accu-Chek Guide.

  • Today, Ascensia announced a new technology partner: The Contour Next One BGM system will connect via Bluetooth to the CE-marked Balansio Mobile app and directly plug glucose readings into the app’s CE-certified class IIb bolus calculator. The integration is already complete and available in Finland, Sweden, and the UK, where Balansio has launched (Balansio has plans to launch in more countries soon). We have never heard of this app, and according to Google Play, it has 1,000-5,000 downloads (a strong 4.2/5 stars). To receive a bolus recommendation, users will simply have to enter the carbohydrates they plan to eat. Balansio can also automatically collect physical activity data to help users better understand the effects of activity on blood glucose. We wonder if Ascensia will also integrate with mySugr, as the Logbook’s bolus calculator has a much wider user base to help. mySugr is still an independent company, even though Roche now owns it.

Cellnovo

The Cellnovo patch pump system is now available in 10 countries (including the UK, Australia, Italy, France, Spain, Israel, the Netherlands, and Greece), but a previously proposed 4Q17 US launch has now been pushed back. A 510(k) submission was filed with FDA in November 2016, but the company shared last week that the Agency has requested a second set of further information. No updated timing was shared, just that it will be delayed. This is a blow to the company, though commercializing in the competitive US market would be quite a challenge for the company right now anyway. In other news, a remote-upgradable Android handset will launch in the next month with international technology standards for Bluetooth and Android (the handset was previously a locked-down Windows phone), and a handout indicated that “Large-scale, automated production” of the new insulin cartridge is now available – good to hear, since acceleration in pump shipments has been severely hindered by the manufacturing handover to Flex. Will the product finally scale and start bringing in meaningful revenue before cash runs out? Elsewhere in the small booth, there was a mannequin wearing the pump on its arm, and the messaging for “simplicity” was prevalent. We asked about the two closed loop programs in which Cellnovo is involved, but received no updates. Diabeloop’s system presented with promising data at ADA, and the companies have since launched a CE mark pivotal trial with results expected by end of 2017 (launch possible in 2018). In April, Cellnovo and TypeZero separately announced a non-exclusive worldwide licensing agreement, giving Cellnovo the right to commercialize TypeZero’s automated insulin delivery technology within a Cellnovo patch pump (possible launch in 2018, presumably in Europe). The latter is starting to seem less likely at this stage.

Dexcom

The most notable update in Dexcom’s booth was a slide that flashed across a large plasma screen: “Collaborations developing new insulin delivery products (closed loop systems, smart pens & more).” Listed on the slide were 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. Though we’ve long known Dexcom CGM would be used in diabeloop’s CE Mark pivotal trial, it was great to see the French company on a Dexcom slide. The OHSU team under Dr. Jessica Castle has long used Dexcom CGM in closed-loop studies, though we cannot recall the institution appearing on a Dexcom slide. The focus of the booth was G5 on Android, with phones around the booth demoing the app. A slogan at the back of the booth proudly proclaimed that Dexcom is the “first and only” CGM on both mobile operating systems. Reps in the booth seemed very excited about the new Apple Watch Series 3 and WatchOS4 – read our coverage of those here.

EOFlow

Korea-based EOFlow advertised its disposable insulin patch pump EOPatch, which a rep described as the Omnipod but, “thinner, narrower, and lighter.” The Bluetooth-enabled EOPatch is pending regulatory approval in Korea, which the company expects to receive next month. A Korean launch is expected by the end of 2017 or start of 2018. Previous guidance from ADA 2017 called for a launch in 2017. The company is also working on CE mark and FDA clearance, and hopes for decisions in the first half of 2o18 and late 2018, respectively. It would be surprising if the company could get all those submissions in at once. It plans on working with distribution partners in Europe and the US, and wants to troubleshoot any kinks before attempting a launch in larger markets such as France or Germany. EOFlow also hopes to include the EOPatch in a closed-loop system with Chinese CGM company POCTech for a launch as early as late 2018 in Korea. (See our comments below on POCTech, which are very low-confidence.) Long-term, the company is reportedly developing an integrated closed-loop system (sensor+pump+algorithm all in one patch), with a launch timing hoped for in 2021. We would be shocked if EOFlow figures out how to align infusion set and CGM wear times and build everything into small device. Heavy skepticism is all we could leave this booth with…

Glooko

A Glooko rep reinforced that the new touchscreen, NFC- and Ethernet-enabled transmitter (see picture of a prototype), which is currently piloting in Sweden, is expected to launch later this year. She told us that many stoppers-by were unaware of the Glooko/Diasend merger (more of the EU audience had heard of Diasend), but were excited to hear of the additional software solutions that Glooko has added on top of both companies’ vast device compatibility (160+ devices!). Glooko also has lots happening on the decision support, remote monitoring, population health, and a patient-facing app. We’re equally enthused by the merger – see why in our report from exactly a year ago today!

IDx

At the IDx booth, we learned that the multi-center FDA clinical trial (n>1,000) testing the company’s diabetic retinopathy screening software, IDx-DR, has wrapped up, aligning nicely with the company’s timeline released earlier this summer. IDx is currently preparing the data, and hopes to submit to the FDA by the beginning of 2018. The software has already received its CE mark as a class IIa medical device, and the representatives cited multiple European customers. In addition to filing with the FDA, IDx is focused on applying the screening software for other diseases, especially Glaucoma. Reps told us they even hope to expand applications even further to include cardiovascular events and Alzheimer’s (yes, with eye screening). The representative predicted that a test for Glaucoma will be available in “October or November.” We see automated diabetic retinopathy screening tools having the potential to massively improve care, especially for those living in remote areas, as per NIDDK Director Dr. Judith Franklin’s inspiring talk given at this year’s ADA.

J&J - OneTouch

The LifeScan/Animas booth was buzzing with questions surrounding timing for the OneTouch Via bolus-only patch delivery device. Unsurprisingly, the representatives were unable to provide any timeline details, nor could they share news pertaining to the US launch. As a reminder, the OneTouch Via has received FDA clearance, but has yet to launch in the US. Representatives said that they’re working to ramp up manufacturing at the Calibra plant in Puerto Rico and are in discussions with payers, but couldn’t say for sure when we might expect a rollout. It does sound close. We did learn that the last patient has completed the major multi-center clinical trial investigating changes in A1c, glycemic variability, and patient reported quality of life in type 2 patients using the OneTouch Via for boluses vs. bolus insulin pens, and the company hopes to publish sometime next year. Representatives were unable to comment on the OneTouch Vibe Plus with Dexcom G5 –FDA and Health Canada approval was announced in December, but no launch timing has ever been shared. The Dexcom booth didn’t even list LifeScan/Animas as a partner, so it’s hard to imagine this is ever coming to market. We also were unable to receive updates on the WellDoc integration.

Kaleido

The colorful patch pump company had an expansive booth – arguably outsized, given that it still doesn’t have a product on the market. Following a CE Mark in 2016, a Netherlands launch is now expected by the end of 2017/early 2018, and a UK launch will follow sometime in 2018. This is about ~1-2 years delayed from the “end of 2016” launch timeline given at EASD 2016. The company has integrated feedback from ~30 users, making pretty small changes to the user interface (e.g., temp basal in %, using hours instead of minutes, bolus calculator tweaks, adding Glooko/Diasend integration). The company has “a long waiting list” to get on the pump, and the rep told us it has 98% reimbursement in the Netherlands. With the massive delays at this stage and Cellnovo’s own struggles, it’s hard to be optimistic about Kaleido’s prospects. The company has a nice “consumer” feel, though it’s hard to build a pump company on this alone. Can it scale and compete in an increasingly competitive market?

Medtronic - Absent from the Exhibit Hall

The biggest tech gossip in the exhibit hall was Medtronic’s absence, which surprised many attendees. The pump+CGM giant was nowhere to be found, 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. At JPM, Medtronic expected an international launch of the MiniMed 670G in May-October, a timeline that is fast-approaching. We would not be surprised to see this delayed, given the ongoing sensor supply shortage that has slowed MiniMed 670G shipments in the US (see 2Q17). Many in the hall were also gossiping about the new infusion set recall, announced on Monday. Upon further reflection, we wonder if the adverse events stem from the waterproof MiniMed 630G/670G – perhaps more Medtronic pumps are being used around water now, leaving higher chances of water getting on top of the reservoir during the set change process. 

One Drop

One Drop made its first exhibit hall appearance at EASD, and the team was especially excited about the new Apple announcements on Watch and iOS 11. CEO Jeff Dachis told us that direct Chrome BGM-to-Watch transmission (no nearby phone needed) will launch in 4Q17 – this will likely be the first meter to take advantage of WatchOS4’s Core Bluetooth addition, something we hope many diabetes devices will move to. Notably, One Drop is also the only diabetes app shown on the Apple Watch Series 3 “Health Tools” page, an impressive vote from Apple (see picture below). One Drop reps were also excited about AR Kit (augmented reality) and ML Kit (machine learning), which will launch with iOS 11 next week and give app developers even more tools to implement in next-gen products. Imagine looking at your diabetes data in augmented reality! The One Drop team is now up to 27 people, including recent hire Dr. Lindsay Sears joining the clinical team with Dr. Chandra Osborn.

POCTech/Diamesco

The POCTech and Diamesco booths were merged, as the latter will apparently market the Chinese-developed CGM. The booth proudly displayed a CE Mark certificate for the POCTech CGM, which looked to have come through in August. Commercialization is reportedly expected in 2018 in France, Spain, and Italy; as we have in the past, it is hard to take this company seriously based on what we’ve seen thus far. The seven-day wear CGM reportedly needs one calibration per day, and a brochure advertised an MARD of 8.7% vs. venous blood glucose (n=73). No study details or protocol were shared (e.g., Was it in people with diabetes? How many matched pairs? Percent of points in hypoglycemia?). The CGM sends data to a receiver or smartphone and collects a value every three minutes. To say we are skeptical would be an understatement. Meanwhile, Diameso advertised a new reusable smartpen (DiaPen) and clunky-looking tubed pump (i-Jet). The rep said both products will launch in “Fall 2017” in Europe, though the i-Jet poster said is is already “distributed in major European countries.” We’re not holding our breath.

Roche - Diabetes Care

Roche’s Diabetes Care booth was absolutely packed with attendees hoping to hear more about the company’s “integrated diabetes ecosystem” (which we learned a lot about earlier this week – see demo slides here). The ecosystem, which will leverage Accu-Chek BGMs, the mySugr app, GoCarb (an AI carb quantification app), Accu-Chek Connect app, Eversense CGM, Accu-Chek View (a digital diary with HCP data sharing portal for prediabetes), the connected Pendiq pen, and other pieces, will “hopefully” be available before next year’s EASD. We look forward to learning about the business model and making this experience truly seamless. In the booth, we haven’t sensed this much excitement from Roche reps in a long time. One said “this is a very exciting moment for us. It’s a little fuzz, but we’re going to an open ecosystem, and this is the direction we need to go.” Open ecosystem, she added, means that the platform – whatever business model it is based upon – will be device agnostic in 1.5-2 years. As we understand it, individual pieces of the ecosystem are rolling out: mySugr has been available for quite some time now (used by over one million patients; Pro bundle reimbursed by a large payer in Germany), Accu-Chek View is already available in Germany, Pendiq will be available in Germany starting in late September, and GoCarb should launch next year (more work is needed to optimize its machine learning algorithms). It’s great to see the Roche diabetes business appear so revitalized, when there were (believable) rumors of divestment just seven months ago. The transition from a product-focused business to a service/digital health-based one will not be automatic for a large company, but it is the right move and all about bravery and execution.

  • We learned more details about how Roche is moving forward with the Accu-Chek Insight CGM: On Monday, we heard that Roche will not launch further versions of Insight. Today, we confirmed that the sensor will stay in existing limited launch markets (“specialized diabetes centers” in the Netherlands, Norway, Denmark, and Sweden), but the rep wasn’t sure if Roche would expand the offering to other countries. We ultimately think the decision to focus on 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.
  • Roche hopped on the VR train at this meeting, sitting visitors down in a chair (both real and virtual) and having them watching videos telling the stories of patients and how the Roche ecosystem can help them. When will we see virtual reality leveraged outside of an exhibit hall to help patients? How far away is for product training and diabetes education?

Roche mySugr

mySugr launched a direct-to-consumer (DTC) Pro bundle in the US just yesterday morning! The package consists of unlimited test strips delivery, an Accu-Chek Guide BGM, the mySugr app, and 24/7 CDE access for $39.99 per month. Nice! The mySugr bolus calculator, offered in Europe, is obviously not included in the bundle and a rep we spoke to wasn’t sure it has been submitted in the US. As a reminder, the all-in package is reimbursed by a large payer in Germany and mySugr has noted that it is talking to payers in other markets – presumably including the US – but this launch is exclusively direct-to-consumer. We like this move, and the $39.99/month pricing is quite competitive. For comparison, Livongo’s DTC offering is $65/month (which may be explained by higher touch, more hands-on coaching), and One Drop’s Premium plan launched in December with unlimited strips at a slightly less expensive $33-$39.95 per month. It was great to see mySugr featured so prominently in the Roche booth – when we first arrived, a mySugr rep was giving a talk about the platform in front of a sizable crowd, and there was a lime green corner of the large booth dedicated to mySugr.

Roche Senseonics

The glucose monitoring section of the Roche Diabetes Care exhibit was bustling – despite the absence of the Insight CGM – due to live demos of Senseonics Eversense insertions. Eager attendees crowded around a Roche rep as she slid the inserter into a mock piece of tissue (see the demo kit below). We overheard many say that they’ve “heard very good reviews” and all wanted to know when the sensor would be available in their respective countries. Per the 2Q17 call, Senseonics expects availability in 14 countries by the end of the year. One woman from France asked about availability, to which the rep replied, “we’re hoping we’ll have it in France by the end of the year, probably with reimbursement. Maybe we need more study results, I don’t know. It would be a missed opportunity, I think.” At the moment, there has been a very slow rollout in the EU, with >340 implantations thus far (outside of trials). We wonder if the now CE marked 180-day indication, just announced yesterday, will ready Eversense’s launch to ramp up. Roche has been heavily featuring Eversense of late, and it seems like this is the sensor it will pour resources into, as opposed to its own Accu-Chek Insight (see more in the Roche Diabetes Care booth write-up).

Valeritas

The Valeritas booth was unstaffed when we stopped by, but we were able to grab a flier advertising the basal-bolus patch insulin delivery device, V-Go. The pamphlet emphasized simplicity (no batteries or programming), comfort (user rating: 8.7/10), patch form-factor, positive outcomes (published data demonstrate V-Go lowers A1c with less insulin), and no need for accessory needles or pens. The pamphlet also indicated that nine out of ten patients who try V-Go want to stay on it, although this statistic was cited only as “Data on File.” We were hoping to receive updates on the connected “V-Go Link” and a pre-filled V-Go. Valeritas’ quarterly sales have now been almost exactly flat for the past two years – what will it take for this device, which has encouraging health and economic data, to ramp? The one-day wear and device clunkiness may be limiting appeal, though awareness and accessibility (solvable problems) are likely the biggest issues.

Ypsomed

A portion of Ypsomed’s sprawling booth was still dedicated to Insulet’s Omnipod, which Ypsomed will continue to distribute internationally only through June 30, 2018 – perhaps ironically, the slogan was, “Enjoy Freedom,” relevant to both the pump and the partnership. The expiration of the agreement will definitely challenge Ypsomed’s business, as international Omnipod sales have seen YOY growth of 63%35%, and 33% over the last three half-year reports. Ypsomed now plans to launch its own patch pump, the YpsoPod, in the second half of 2020 (calendar year), though this was obviously not discussed in the booth. Elsewhere, reps were excited to share the vision for the near future: A connected network of proprietary devices/software that include the durable YpsoPump, Unio BGM, mylife app, and mylife desktop software. There was no specific time horizon shared. CGM integration with the YpsoPump is on the roadmap, according to the FY17 update, but reps indicated that it will not be an internally-developed CGM. Presumably this means Dexcom, Abbott, or Senseonics will be used. Ypsomed will obviously need to move towards automation fairly quickly to stay competitive.

Exhibit Hall – Diabetes Therapy

AstraZeneca

AZ’s booth held a significant amount of real estate at the north side of the exhibit hall, where the company opted for an earthy bright white and wood grain display with touches of artificial grass. Bydureon (exenatide once-weekly) and Farxiga (dapagliflozin) were most prominently featured on either front corner, alternately promoted with the slogans “Bydureon first…insulin later” (an adage we’re hearing applied frequently to GLP-1 agonists) and “glucose out, results in.” Touch screens and headphones were readily available to learn more about each product. DPP-4 inhibitor Onglyza (saxagliptin) was less prominently featured on a changing display. Grass-lined couches and low white chairs led attendees through a door in the booth’s middle wall, which had coffee bars on either side. The back side of AZ’s booth hosted purple couches and white coffee tables, with a large TV screen and a panel dedicated to EXSCEL results, promoting their Thursday announcement and noting that it’s the largest CV outcomes trial, conducted in >14,000 patients across 687 sites, with a pragmatic trial design including patients at a wide range of CV risk. This side also dedicated a wall to the DapaCare clinical program, investigating the CV and renal effects of dapagliflozin in patients with and without diabetes. There was no mention of Qtern (dapagliflozin/saxagliptin) anywhere in AZ’s booth and representatives had little to offer, which is disappointing because the drug (approved but not yet marketed in the US) is actually available in Europe, where it was first-to-market in this SGLT-2/DPP-4 class.

J&J – Janssen

About half of J&J’s booth was dedicated to SGLT-2 inhibitor Invokana (canagliflozin), the remainder focused on the company’s diabetes device business. Both standalone Invokana and Invokamet (canagliflozin/metformin fixed-dose combination) were advertised, and one banner announced that more than one million patients globally have been treated with Invokana. On interactive screens, booth visitors could review the safety/efficacy data on canagliflozin, and graphs particularly emphasized weight loss and blood pressure-lowering.

Lilly

Located right at the main entrance to the exhibit hall, Lilly’s large booth dedicated nearly half its square footage to BI-partnered SGLT-2 inhibitor Jardiance (empagliflozin) and GLP-1 agonist Trulicity (dulaglutide). The bright display, set atop large white tiles, promoted Trulicity as a “simple approach to a first injection,” highlighting the GLP-1 agonist’s patient-friendly, IDEO-designed pen. Another slogan read, “for those who are reluctant, Trulicity can help make it click.” BI-partnered DPP-4 inhibitor Tradjenta (linagliptin) had a smaller presence, but was still actively promoted as “Simple. Every day,” on a set of displays along the main walkway. A display on Lilly’s “Streetwise” program, which produces informational pamphlets for teens and young adults with diabetes, accompanied another on Lilly’s partnership with Disney, which has produced materials and resources designed for families with young children who have diabetes. Around the back of the booth, we found a timeline of developments at Lilly, starting with its 1876 founding (and detailing an amazing history of pharmaceutical advances). A decently-sized corner of Lilly’s booth was dedicated to the company’s insulin offerings: Visitors could compare each of the five pen options for rapid-acting insulin Humalog, and also had the chance to learn more about biosimilar basal insulin Basaglar (this product is also partnered with BI, and we saw lots more on the biosimilar in Lilly/BI’s combined exhibit).

Lilly/BI

Across the way from Lilly’s booth, BI’s exhibit featured interactive attractions around Jardiance and EMPA-REG OUTCOME. Attendees could play a Wii-based game in which they slashed a sword to choose trivia answers about Jardiance and the groundbreaking CVOT, and a moving arrow advertised 38% relative risk reduction in CV death. This was very similar to the messaging we saw around Lilly/BI’s SGLT-2 inhibitor in the ESC exhibit hall last month. Notable square footage was devoted to Basaglar in a soothing light blue and green style, where insulin initiation was likened to an airplane flight, promoting the product’s patient support kit and featuring stuffed baby animals in suitcases to ease the “turbulence” of insulin initiation. Large picnic tables drew guests to the coffee bar, next to a bean bag toss game where you could answer questions about Basaglar by throwing a bean bag through a specific hole.

MSD

MSD boasted a large booth along the edge of the exhibit hall, dedicated entirely to DPP-4 inhibitor Januvia (sitagliptin) and fixed-dose combination Janumet (sitagliptin/metformin). Curving teal carpets surrounded a round hardwood floor at the center of the company’s large, open space, where tall white stools and colorful sofas drew a sizeable crowd of conference-goers relaxing in between sessions. MSD’s exhibit once again celebrated the 10th anniversary of Januvia, launched in 2006.

Mylan

Mylan’s mid-size booth was positioned in the middle of the exhibit hall, swathed in the company’s typical light blue and white color scheme. As a nod to the company’s impending entrance into diabetes with Biocon-partnered biosimilar insulin glargine (submitted to the EMA in 3Q16, FDA submission pending after several delays), the booth’s entrance featured an array of touchscreens containing a survey about HCP awareness of biosimilars. Adjacent to a popular espresso bar and circle of comfortable white lounge chairs, handouts featured descriptions of the INSTRIDE 1 and INSTRIDE 2 trials of the candidate in type 1 and 2 diabetes. If approved, this biosimilar insulin glargine could be the third-to-market biosimilar insulin glargine in the US, after Lilly/BI’s Basaglar and Merck’s tentatively-approved Lusduna Nexvue.

Novartis

Novartis’ sizeable booth at the front of the exhibit hall was dedicated largely to DPP-4 inhibitor Galvus (vildagliptin), in contrast to last year’s display in which the company’s diabetic retinopathy drug Lucentis (intravitreal ranibizumab) took center stage. We attribute this enthusiasm for Galvus to the fact that 2017 marks 20 years since the agent was invented – a milestone that Novartis commemorated with a winding corridor bisecting the exhibit, leading attendees on a tour of the milestones in the history of DPP-4 inhibitor development. On one side of this divider, modern while panels ensconced a calm circle of plush gray chairs where attendees could rest between sessions. On the other side of the divider stood a 10-foot tall hourglass, which attendees could enter to partake in a virtual reality experience consisting of a video defining the problem of clinical inertia, and the urgency of addressing diabetes before complications like CV disease, renal disease, and blindness take hold. Consistent with this hourglass imagery, messaging emphasized that “the time is now” and when time is running out, patients with diabetes should turn to Galvus.

Novo Nordisk

At Novo Nordisk’s booth, we got to try out a new, in-progress app based on the DEVOTE dataset. You input variables such as age, A1c, diabetes duration, and insulin status (naïve, basal, or basal-bolus therapy), and the app outputs your risk for hypoglycemia and MACE events (MI, stroke, CV death). While the precise purpose of this app is still being decided (it’s not yet available to the public), company reps described this project as an effort to make hard scientific data more patient-friendly, which could encourage people to better understand data at the frontline of advances in diabetes care. Moreover, the app could facilitate and enrich patient/provider conversations to determine optimal treatment. Regardless, we thought this was very cool, and we’ll be excited to see a real-world product come out of a clinical outcomes trial – on an easy-to-use digital platform, no less. The DEVOTE CVOT, first presented at ADA 2017, showed Novo Nordisk’s Tresiba (basal insulin degludec) to be non-inferior to Sanofi’s Lantus (insulin glargine, and largely the standard of care) on CV outcomes but far superior on hypoglycemia (40% relative risk reduction for severe hypoglycemia, 53% relative risk reduction for severe hypoglycemia overnight). New analysis of DEVOTE will be presented Friday morning at this meeting, and you can bet we’ll be in the front row.

We also noticed more space dedicated to Xultophy (insulin degludec/liraglutide fixed-ratio combination) in Novo Nordisk’s EASD booth compared to conferences past. The product was featured on a colorful sign hanging from the ceiling, and messaging presented Xultophy as a “simple intensification treatment” to improve diabetes care. We were drawn to this, given previous statements from Novo Nordisk management and reps that Xultophy would be less of a commercial priority in the near-term vs. standalone insulin degludec (Tresiba) and standalone liraglutide (GLP-1 agonist Victoza). Perhaps the “near-term” is over – we’d certainly love to see the company put more commercial resources behind Xultophy, especially because we’ve been underwhelmed by early numbers for prescription volume and quarterly sales. This class of basal insulin/GLP-1 combos (also including Sanofi’s Soliqua) posted only $19 million in 1Q17 and $34 million in 2Q17, even though it represents a major advance in diabetes therapy. Novo Nordisk’s obesity drug Saxenda (liraglutide 3.0 mg) was hosted in its own nearby booth, and reps were on hand to discuss three-year SCALE data showing 80% risk reduction for new-onset type 2 diabetes with Saxenda vs. placebo.

Sanofi

Sanofi’s expansive booth was divided into sections for each of its major diabetes products (plus PCSK9 inhibitor Praluent), including – for the first time – its newly-approved biosimilar Insulin lispro Sanofi. EMA-approval came in July, and earlier this month, the FDA granted tentative approval pending resolution of patent disputes (from Lilly, over Humalog). A tall video monitor summarized data from SORELLA 1 and 2, demonstrating non-inferiority of Sanofi’s biosimilar mealtime insulin vs. Humalog, and one poster read, “Everything you’d expect from a mealtime insulin, without the brand name.” Messaging around this new product also emphasized sustainable cost, availability in SoloStar pens (which are familiar to patients), and the company’s long history of expertise in diabetes and insulin manufacturing. We were happy to see a substantial presence from Insulin lispro Sanofi in Sanofi’s booth, a quick turnaround following EMA-approval in July, and we hope this is indicative of the company’s commitment to swift commercial rollout, getting this lower-cost biosimilar mealtime insulin into the hands of as many patients as possible.

Takeda

Takeda’s colorful puzzle piece booth made a re-appearance in this year’s exhibit hall. Large puzzle piece shapes in red, purple, and blue were suspended from the ceiling and placed around the corners of the booth, amidst tall white stools and sleek low-slung couches. To complement the puzzle theme, catchy messaging for the company’s DPP-4 inhibitor Vipidia (alogliptin, Nesina in the US) read “every piece counts when managing type 2 diabetes.” Signage also emphasized other members of the alogliptin franchise – Vipdomet (alogliptin/metformin, Kazano in the US) and Incresync (alogliptin/pioglitazone, Oseni in the US) – with large screens scrolling through the clinical data for these products.

The diaTribe Foundation's 4th Annual Solvable Problems in Diabetes Forum

At The diaTribe Foundation’s fourth annual Solvable Problems in Diabetes gathering, attendees were treated to a wide-ranging panel discussion with Dr. Daniel Drucker (Lunenfeld-Tanenbaum Research Institute), Prof. Melanie Davies (University of Leicester), and Prof. David Matthews (Oxford). The panelists, known largely for their clinical and basic research, surprised many by focusing largely on how behavior change might augment diabetes drugs in real-world use. See our top themes from the night directly below, and read on for some of our favorite quotes from the evening.

  • Dr. Drucker was particularly passionate about behavior change, claiming that if he were beginning his career today, he might choose behavioral science over basic science – “that’s where I think we can make a big difference.” Dr. Drucker argued passionately that the diabetes community has failed to think creatively to drive adherence. He urged innovators to borrow from market strategists and learn how to design effective incentives, referencing how teens spend 30-60 minutes each day on social media, yet pediatric clinical trials struggle with recruiting. Taking the perspective of a payer or pharma company, Dr. Drucker said he would focus on improving adherence and accessibility before attempting to push out yet another novel drug. We’re certainly beginning to see more enthusiasm for going beyond the pill – e.g., coaching, education, digital dose titration, but agree that not nearly enough progress has been made here, particularly from the big players. Until real-world outcomes start to match those seen in clinical trials, there is still work to be done.
  • Prof. Davies acknowledged that behavior change incentives are “interesting,” but diabetes is long-term and requires continuous psychological support – not just short-term incentives. To her, an equally, if not more, important application of behavioral intervention is to ease diabetes distress, loneliness, and guilt over the long haul. Everyone recognizes these issues are overlooked and critical, and we look forward to more tangible wins on this front. Which health systems are doing a great job at managing this? What can we take from the depression treatment literature (e.g., cognitive behavioral therapy, or CBT) and translate into diabetes?
  • Prof. Matthews agreed that changing behavior to improve adherence and outcomes – while difficult – is possible. For him, communication must improve if we are going to see big changes in adherence. If people with diabetes don’t appreciate the urgency of a diagnosis – or aren’t getting screened in the first place – taking drugs consistently will remain a major roadblock. Indeed, the latest drugs or technology won’t make a difference if diabetes is taken lightly. He astutely noted that endocrinologists are never acknowledged in an obituary like oncologists.
  • There was notable enthusiasm for technology, device engineering, and far better use of data to drive outcomes. Dr. Drucker claimed that innovations in drug delivery (e.g., Intarcia’s ITCA 650 implantable GLP-1 agonist micropump) have very strong potential, and his money continues to be on the engineers in the next few years – not biologists. Prof. Davies has her sights set on personalizing technology and providing actionable information right from diagnosis, which continues to be a challenge in a field where data is not sufficiently captured and how-to’s are often missing. Prof. Matthews expressed interest in personalized combination therapies – traditional fixed-ratios can’t hit the mark, he said, as they lack flexibility to appeal to different individuals. Dr. Drucker was hesitant on the role of artificial intelligence, cautioning endocrinologists in the room that their days in business may be numbered. As moderator Ms. Kelly Close noted, however, we see AI and pattern recognition as very positive developments for our time-crunched, data-analysis-poor field – machines can crunch disparate data sets far better than humans, freeing up physicians to focus on other things (or simply freeing them up to avoid burnout).
  • Prof. Matthews also commented on the amputation signal detected in the CANVAS trial, for which he was a principal investigator. In alignment with the emerging consensus, he called the signal “sufficiently robust,” and diverted attention to the next logical question: Is this a class effect or canagliflozin-specific? 

Quotable Quotes

On Behavioral Intervention and Supporting People with Diabetes

  • “We really need to get a grip on how to apply the stuff that the marketers know to drive behavior. There’s no reason why we couldn’t drive better behavior in public health; we’ve just lagged behind. And we need to catch up quickly. To me this is the greatest opportunity: cradle to grave buy-in of understanding your consumer, which is a mixture of the healthcare provider and patient. Design incentives to make the drug or device really attractive to prescribe, use, and not stop. We need to think differently about how to achieve goals. That doesn’t mean stop doing research, but we must completely change how we think about goals and sustained consumer/patient satisfaction and adherence every step along the way.” – Dr. Daniel Drucker
  • If I were starting today, I might not go into basic science, but I’d go into behavioral science. That’s where I think we can make a big difference. – Dr. Drucker
  • “When I was a medical student, they told us you can change knowledge, not behavior. I believed this for many years, until the Irish government said that it was illegal to smoke in Irish pubs. I thought, ‘my goodness, no one will ever go and drink Guinness in an Irish pub again.’ And that lasted about 24 hours. [Laughter] You can change people’s behavior, but it’s difficult. Technology is the way we can change this part of society.” – Prof. David Matthews
  • “An intervention is needed in type 1 focused on self-compassion, on feeling better and less guilty. We have to apply similar scientific robustness in behavior change intervention as we do with drugs and devices.” – Prof. Melanie Davies
  • “We say to patients, ‘you need to be engaged in your health.’ But we also have to be able to say, ‘if you are engaged, we can deliver things that will allow you to transform your lives.’” – Prof. Matthews
  • “For most people with type 1 diabetes, you don’t need to convince them of the importance of taking insulin. Most of the folks get it and they are really benefitting from these huge advantages. Type 2 is a very different disease. I do some meetings where I have folks in the room treating cancer. I talk about persistence and adherence: Only 50% of people with diabetes are taking drugs – e.g., people take drug holidays. Oncologists look at you and ask, “What world are you living in?” – Dr. Drucker
  • “You can’t blame people with type 2 diabetes. We need to understand the messaging, behavior, and motivation to treat the disease. People don’t associate diabetes as the serious illness that drove them to heart attack or stroke. We have failed our patients. We haven’t communicated effectively, and until we learn how to do so, it’s going to be a missing part. We can make stem cell-derived beta cells and new co-agonists, but if our patients don’t get the message – that this disease is going to kill and disable them – then they’re going to continue not to take the latest and greatest.” – Prof. Matthews
  • Is it so difficult to do these trials in kids? We just need to do stuff differently. Kids spend 30-60 minutes per day on social media; are you telling me we can’t figure out how to get two to three minutes of that time to deliver better health? We’ve failed as a community to think out of the box. Get on the phone and say to these folks designing the trials that it’s a crime that we don’t have pediatric labeling because “recruiting is difficult.” We can’t keep failing in the same way, we have to think differently. We’re such a conservative, slowly-moving group of folks.” – Dr. Drucker
  • “Behavior change around incentives is interesting, but there’s a whole issue around depression, diabetes distress, social isolation, and social deprivation. There are a lot of other aspects that, at some point, may be solved by incentivizing and making treatment simpler, but diabetes is a long-term condition requiring long-term support.” – Prof. Davies
  • We just did a structured education program where we looked at a number of patients and most didn’t think type 2 diabetes was a lifelong disease. Most didn’t associate that diabetes would shorten their life.” – Prof. Davies

On Where the Field is Going or Should Go

  • As a biologist, the engineers have kicked our butts over the last 15 years in type 1 diabetes. That’s where all the advances have come from in type 1 diabetes. Glucose-sensitive beta cells for safe and sustained prime time clinical use are far away. As a biologist, my money over the next five years is still on the engineers.” – Dr. Drucker
  • I think we should definitely have self-management and education, but I think giving good information and support right from diagnosis is important. We also need to make drugs and therapies more accessible to patients more quickly and increase access to multi-professional teams. We need really good dieticians, specialist nurses, and psychologists – not just physicians.” – Prof. Davies
  • If you’re a payer, why not look at available data critically and decline to pay a premium in the absence of sustained long-term efficacy? Here you come with a fancy drug, wanting a 10%-20% premium, and people are not even using current drugs properly. Until we start to help them use what they have more effectively, don’t come to me with yet another new drug. If I were running a reimbursement scheme, that’s how I might react.” – Dr. Drucker
  • “We as patients want to feel normal; diabetes is a lonely disease. Being able to look at your blood glucose on an iPhone or swipe your arm and not feel stupid (or worried that blood might accidentally shoot into the air, as everyone with diabetes has experienced) has made a big difference for those lucky enough to access technology like Loop and FreeStyle Libre. I’m optimistic about what we can see data deliver if we invest more in technology and interpretation.” – Ms. Kelly Close
  • “I’m pretty disappointed in the fact that the persistence, adherence, and A1c that we’re delivering with all these new drugs is kind of abysmal in type 2 diabetes. It doesn’t make sense to put a huge amount of effort in making new drugs even better without new thinking around and tools to show how we get patients to use the last group of drugs we developed more effectively.” – Dr. Drucker
  • “I think there’s a huge gap between the specialists reading the latest outcomes study and immediately thinking the entire world will change. Primary care doctors who do the lion’s share of diabetes management are unbelievably focused on safety and not being burdened by new drugs. The primary care doctors are much more concerned about not getting caught out yet again with a promise of fantastic new benefits that are elusive or are yanked away from them due to safety concerns. Primary care doctors stick with what they know that’s safe and hasn’t hurt them, because we’ve betrayed some of their trust before.” – Dr. Drucker
  • On a clinical basis, people’s lives are absolutely transformed by technology. Sometimes it is difficult to measure that. We do have ways to measure these benefits, but in many trials, we don’t use measures of self-efficacy very much. We need to calculate the economic benefit. Just as we personalize drugs, we can personalize technology and other interventions.”  – Prof. Davies
  • “People have trouble taking tablets and injections. It’s partly why bariatric surgery is effective. People cannot cheat. If we can make drug delivery much more effective – like pills that go in the stomach and dissolve over six months or lung peptide delivery. It’s about making it easier for people to follow through. Engineering, that’s where we can make the biggest breakthrough.” – Dr. Drucker
  • “The problem with fixed combinations is I cannot change one vs. another. If you need 75 mg of aspirin, and you need this amount of statin, and you need an ACE inhibitor, the pharma companies should plug that together for you. That’s personalized medicine, and it’s very different from a fixed-dose combination. On a related note,  insulin and GLP-1 combinations are giving very good results.” – Prof. Mathews
  • The system doesn’t work well. We need to talk about integration. We’re not very good at collecting data, reflecting on it, and improving on it. Quality improvement has been around for decades. The system hasn’t worked well – it’s not very integrated.” – Prof. Davies

On Artificial Intelligence

  • “Once we have AI algorithms, endocrinologists managing glucose fluctuations might be out of business. A human won’t be in the business of looking at numbers.” – Dr. Drucker
  • “It’s SO much better to have a machine running the numbers. My doctor and I have been trying to figure out for 20 years what my basal rates should be … but based on my experience with automated insulin delivery, optimal basal rates change every day. The idea that we thought we could figure this out when a computer can do it so much better – that blows me away. There’s plenty to still talk about with my doctor. Having artificial intelligence ‘in charge’ of the numbers could make doctors feel and be more successful as they’d have more space to address other major problems [wellness measures like Adam Brown talks about in Bright Spots & Landmines – food, mindset, exercise, sleep – short- and long-term complications, emotional well-being, etc.]” – Ms. Close

On CANVAS

  • “That data about amputation in CANVAS is sufficiently robust. There are uncertainties, but the science is good and that’s what we need to keep saying. Now we have another question, is this a class effect or not?” – Prof. Matthews
  • “Every time a patient says they have an amputation and are on SGLT2-inhibitors, you make that report. If someone else comes along and their toe is black for any number of reasons, you send them on their way without even thinking of reporting. That’s reporting bias, which is horrendous in real world data.” – Prof. Matthews

Panel Discussion

Melanie Davies, MD (Professor of Diabetes Medicine, University of Leicester, UK); Daniel Drucker, MD (Senior Investigator, Lunenfeld-Tanenbaum Research Institute, Toronto, ON); David Matthews, MD (Professor of Diabetic Medicine, University of Oxford, UK); Kelly Close (Founder, The diaTribe Foundation; President, Close Concerns, San Francisco, CA)

Dr. Daniel Drucker (Senior Investigator, Lunenfeld-Tanenbaum Research Institute, Toronto ON): I’m torn between really cool advancements in basic science, making drugs better, even in my narrow field of gut peptides there’s lots of potential, but as a clinician (a poser clinician really), I’m pretty disappointed in the fact that the persistence, adherence, A1c, that we’re delivering with all these new drugs is kind of abysmal in type 2 diabetes. It’s one thing to put a huge amount of effort in making new drugs even better if we can’t even get patients to use the last group of drugs we developed more effectively. Innovation is great, let’s spend some time thinking about how to better treat type 2 diabetes because we’re not doing a very good job. You may disagree with me…

Prof. Melanie Davies (Professor of Diabetes Medicine, University of Leicester, UK): I think that’s right I think the issue around what happens in real life in terms of access to therapies and taking and continuing therapies is a real challenge I’ve had so much time and obsession around glp1 and that’s most of the data in the last 2 days and there is progress around glp1 and data around weight loss and 1ac and combo therapies is exciting but it’s how we translate those benefits in RCTs into practice and understanding a bit more about clinical benefit and safety concerns and we have seen safety concerns that we need to understand better.

Prof. David Matthews (Professor of Diabetic Medicine, University of Oxford, UK): I’ve spent a lot of my life in CVOTs, initially UKPDS latter in CANVAS. My daughter is a physician in infectious disease. In the 1800s, John Snow in London spotted outbreak of cholera. He managed to plot the epidemiology in two ways. He plotted where everybody was, but not just geography, it’s how long it takes you to get to a certain water point that also matters. Mathematics was advanced at the time and he was able to demonstrate that there clearly was one source of cholera. This was really advanced epidemiology, he could have written it in NEJM. But he went and took the handle of the pump. As endocrinologists, we sit behind desks and wait for patients to come to door. We need another diabetologist. We can’t cope. We don’t take the handle off the pump. When I was a medical student, we learned that you can change knowledge, not behavior. I believed this for many years. until the Irish government said that it was illegal to smoke in Irish pubs. And in Irish pubs you could just barely see through the door. I thought, ‘My goodness, no one will ever go and drink Guiness again. We’re not going to the pub.’ And that lasted about 24 hours. {laughter] You can change people’s behavior, but it’s difficult. If you look at the CDC chart, it goes up and up, and in 1995, it takes another turn upwards. Brilliant data. Everyone says, you can do something about it. It’s about technology, that’s the way we can change this part of society. Fitbit, all sort of things, electronic feedback. Application. There are two things we need to be doing, better molecules for physicians behind desks, but we also need to be out there. The majority of the cost is type 2 diabetes, and it’s preventable predicated on lifestyle.

Ms. Kelly Close (Founder, The diaTribe Foundation; President, Close Concerns, San Francisco, CA): Dr. Drucker, how would you respond to that?

Dr. Drucker: I don’t disagree with the opportunity. So smoking is a very binary thing. Changing people’s lifestyles is not a binary decision. If you look at the science around behavioral economics and health – a lot of the work, if you think incentives and penalties are useful, the results often surprise you. Not predictable. Just starting to realize that understanding the behavioral economics surround opportunity to intervene in HT, dyslipidemia, MI, just starting to look at it that there’s where we need to go. That and how do we get drugs in people’s hands, increase access. It’s not just patients. It’s providers, payers, regulators.  If I were starting today, I might not go into basic science, but I’d go into behavioral science, because that’s where I think we can make a big difference.

Prof. Davies: I think one of the issues is we have great pathways for looking at drugs and devices and we have a way of testing them and focusing and reviewing the data but we don’t have a very robust way of researching behavioral changes and cost effectiveness. In the UK it’s very frustrating that there are lot of technology and apps looking at behavior changes and we have no idea if they’re being tested and regulated in a similar way as devices. We need fantastic drugs and devices but they need to be regulated in a way that we can test on how best to optimize them to really improve. We need to focus on self-compassion in type 1 regarding an intervention in feeling better and less. We have to apply similar robustness through behavior change intervention as we do with drugs and devices as well.

Ms. Close: If we think about self-compassion it’s what makes our lives easier. For the first few years I didn’t want to check my blood glucose because to be worried about that you just feel so stupid. I wonder if you think about tools today and as BGM is getting easier, we’ve made a lot of progress not just for the tools and access. How would you think about that for clinical research?

Prof. Davies: On a clinical basis, people’s lives are absolutely transformed by technology. Sometimes it is difficult to measure that. We do have ways to measure that, in many trials, but we don’t use self-efficacy very much. We calculate the economic benefit. We should be looking at robust research to help to target those research to the right people. Just as we personalize drugs, we can personalize technology and other interventions.

Dr. Drucker: I’m a libertarian. I’d love for every person who’s a partner in this discussion – the manufacturer, healthcare provider, the patients – I’d like them to have more skin in the game. Whether that is a mixture of incentives or penalties for outcomes, that’s where the science need to come. Right now, we have all these siloes folks make technology, and not tied to outcomes derived from technology. Providers write prescriptions, but not tied economically to outcomes. Patients themselves, you’d think they’d be tied to outcomes, but a little different in type 2 diabetes. We need to do a better job of breaking down silos and making so everyone works together to drive in the right direction. More skin in the game. Get people to use drugs by giving it to people for free, then they get a good result, then they’ll start to pay. Serious about changing way we deliver technology and having much more of the partners responsible. 

Prof. Matthews: I don’t know whether you remember the old slides we used to make and I always used to the night before lecturing put one extra slide and I’d desperately be making these at home. I recently threw away all of my slides from college, and one of the slides I threw away was a slide I made that said: what we need is smart agents. When you talk about smart agents, things have changed quite dramatically in the last decades in terms of agents that work when blood glucose goes high like the GLP-1 and SGLT-2 inhibitors –these drugs work when blood glucose is high and stop when blood glucose comes back to normal. The use of smart agents means that for type 2 I’m really pleased to be living in a society where we’ve started to get smart pharmaceuticals. And there’s more to come with implantable pumps and glucose-dependent insulin. The glucose sensing stuff we have for type 1 is going through dramatic changes. We’ll see progressively that people can control blood glucose without the downside of hypoglycemia. We need to also think about glucose centricity. This is about the progress being made in clinical care, in pharma delivery, and in brilliant tech. We need to capitalize on that and lots are interested – this will transform diabetes management. We can’t just say to our patients, ‘You need to be engaged in your health,” you also have to be able to say, “if you are engaged we can deliver things that will allow you to transform your lives.’

Ms. Close: The balancing act, it’s the brain and the body. Regarding behavior, where do we go from here?

Dr. Drucker: The Claude Bernard lecture was lovely. Type 1 diabetes is a very, very different disease for many obvious reasons. For most people with type 1 diabetes, you don’t need to convince them of the importance of taking insulin. For most of the type 1 folks, their teenage years are difficult, but they get it and they are really benefitting from these huge advantages. Type 2 is a very different disease. I do some meetings where I have folks in the room treating cancer. I talk about persistence and adherence, how only 50% of people are taking drugs and some people taking drug holidays. Oncologist looks at you and say, “What world are you living in?” But we can’t blame people with type 2 diabetes. We need to understand the messaging, behavior, motivation to treat disease. Someone with cancer equates the disease with death. When you have type 2 diabetes, death isn’t the first thing you think o