June 22-26, 2018; Orlando, FL; Full Report – Draft

In this report, we provide our full coverage of diabetes/obesity therapy, diabetes technology, and big picture topics from the ADA’s 78th Scientific Sessions. Dive into different topics, from GLP-1 and type 1 adjuncts, to automated insulin delivery and CGM – and everything in between. Talk titles highlighted in yellow denote the presentations and commentary that we found particularly notable. Titles highlighted in blue represent new coverage that wasn’t included in our daily highlights (day #1, day #2, day #3, day #4, or day #5) or the first edition of our full report. Note that some talks may appear in multiple sections (e.g. content on basal insulin/GLP-1 fixed-ratio combinations appears under the “GLP-1” category as well as the “insulin” category).

Our sections proceed as follows (you can navigate through these using our table of contents below):

Themes

GLP-1 Agonists

SGLT Inhibitors

Adjunct Treatments for Type 1 Diabetes

Insulin Therapy

Treatment Algorithms and Strategies

Novel Therapies

Automated Insulin Delivery, Pumps, and Pens

CGM and BGM

Digital Health and Connected Care

Beyond A1c and Hypoglycemia

Obesity, Prediabetes, and Remission

Type 1 “Cure” Therapies and Pathophysiology

Diabetes Complications

Policy and Reimbursement

Epidemiology and Education

Award Lectures and Additional Topics

TCOYD/The diaTribe Foundation 12th Annual Diabetes Forum

The diaTribe Foundation's Third Annual Musings Under the Moon: Next-Gen Diabetes

Interview with New ADA CEO Ms. Tracey Brown

Exhibit Hall

…

Happy reading!

Themes

Diabetes Therapy

Adjunct Therapy for Type 1 Diabetes Takes Center Stage: New Data Galore on SGLTs, GLP-1s, Metformin in T1D; Consensus Meeting Brings ~30 Thought Leaders Together to Discuss DKA; Potential for Type 1 CVOT?

• ADA 2018 was by far the biggest conference to-date for adjunct therapies (and especially SGLT inhibitors) in type 1 diabetes. It started with a Friday morning gathering of ~30 thought leaders discussing DKA risk minimization (this was organized by ATTD and Prof. Thomas Danne). Then, in no particular order, we covered:

  • 24-week DEPICT-2 results on AZ’s SGLT-2 Farxiga (dapagliflozin);

  • one-year data from DEPICT-1, inTandem 1, and inTandem 2 on Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin (intended brand name Zynquista);

  • topline data (i.e. no numbers) from the phase 3 EASE program for Lilly/BI’s SGLT-2 Jardiance (empagliflozin); and

  • pooled CGM data from DEPICT and inTandem.

The very last symposium of ADA 2018 – the only one in its timeslot – was  “SGLT Inhibition for Type 1 Diabetes Mellitus Management―How Far Have We Gone?”. We were genuinely impressed by the attendance and engagement in this final session; there were few empty seats in the largest convention center ballroom, and audience members formed long lines at the microphone to ask questions. Prof. Danne noted that every single person invited to the closed ATTD meeting accepted his invitation, which “goes to show how people feel about these agents, and wanting to get them distributed to patients with type 1 diabetes safely.” Indeed, it seems the diabetes community is energized and enthusiastic about the prospect of these first oral agents as adjunct to insulin in type 1 diabetes. We echo these feelings of excitement (because to be sure, adjunct therapy and therapy in general for type 1 is a severe unmet need), though we can’t ignore the heightened DKA risk associated with these drugs. To this end, we’re glad to see thought leaders getting organized in establishing best practices for DKA prevention and treatment for patients taking an SGLT on top of insulin. This risk is manageable, but real-world HCPs/patients need support in how to manage it before sotagliflozin and dapagliflozin (and eventually, empagliflozin) are approved for type 1 diabetes (Sanofi/Lexicon have filed sotagliflozin with FDA and EMA, while AZ has so far filed dapa in Europe and Japan – eventually we also hope to see BI/Lilly and J&J jump in as well). Dr. Jeremy Pettus read our minds when he remarked, at The diaTribe Foundation & TCOYD’s 12^th Annual Diabetes Forum, “there’s no doubt these drugs work to increase time-in-range and lower A1c, weight, and blood pressure, but they do increase risk of DKA. We need to focus on the risk/benefit profile and on mitigating DKA. These drugs make a difference in lives and help manage a disease that, quite frankly, really sucks. Any drug that can help is an improvement.”

• With an accumulation of data from the inTandem and DEPICT clinical programs (the latest coming at this ADA), the benefits of SGLTs in type 1 are well-established: 1-3 more hours in-range each day, A1c-lowering of 0.3%-0.4%, meaningful weight loss (up to 10 lbs at 52 weeks with 400 mg sotagliflozin, according to inTandem1), and lower total daily insulin dose. By and large, healthcare providers and patients are recognizing the metabolic and quality of life benefits that SGLTs offer.

• The field is slowly but encouragingly moving toward consensus on DKA risk mitigation and treatment. On Friday, we attended ATTD’s consensus meeting on the issue, and heard universal enthusiasm for the utility of these agents as well as agreement on the need for patient- and provider-facing education, careful patient selection (e.g. engaged patients who will check ketones regularly, not people on low-carb diets, etc.), and widespread knowledge of how to treat DKA (as counterintuitive as it may seem, this requires eating carbs and injecting insulin). On the other hand, the meeting ended without clear agreement on the specifics of ketone monitoring methodology (urine or blood?) and frequency, the exact ketone level that should cause concern or prompt treatment, what insulin dose should be decreased (basal or bolus?) and by how much, and whether or not there should be an upper A1c cutoff for eligible patients. According to Prof. Danne, a consensus manuscript should be published by year-end, or before the first regulatory meetings take place (we anticipate an FDA Advisory Committee gathering in early 2019). We’re eager to see what precise recommendations the group settles on.

• Lilly/BI threw a curveball in the very last hour of ADA 2018, when Dr. Julio Rosenstock suggested that there may be a low dose of empagliflozin (2.5 mg) that gives all the advantages of adjunct therapy without any of the DKA risk. In the phase 3 EASE program (n=1,680 across EASE-2 and EASE-3), 2.5 mg daily empagliflozin did not increase DKA vs. placebo, but it did offer significant improvements in A1c and body weight without affecting hypoglycemia. The 10 mg and 25 mg doses of empagliflozin also met all efficacy endpoints but did significantly raise DKA frequency vs. placebo. Dr. Rosenstock specified that efficacy was similar with 2.5 mg and 10 mg Jardiance, although without any specific numbers on A1c, weight loss, or time-in-range (they weren’t ready by ADA’s deadline for abstract submission), we can’t confidently determine what or whether an efficacy tradeoff might come with a lower SGLT-2 dose. Our sense from DEPICT and inTandem is that efficacy and safety are both dose-dependent; that is, a higher dose means greater glycemic benefits and more weight loss, alongside a more elevated risk for DKA. Will 2.5 mg Jardiance – one quarter of the lowest dose available for type 2 diabetes – be “enough” for type 1s to notice a difference in their diabetes management? Importantly, EASE-3 was the only study to include 2.5 mg empagliflozin, and it didn’t include a trial extension past 24 weeks – recall that DEPICT-1 found no DKA imbalance between dapagliflozin and placebo at 24 weeks, but a difference did appear at one year. We wouldn’t at this stage conclude from EASE-3 topline results alone that no DKA risk exists with lowest-dose empagliflozin – rather,, we’d note our excitement about EASD and full EASE results that are set to be presented there on the morning of Thursday, October 4, the second-to-last day of EASD 2018 in Berlin. While it’s technically unclear if any other data will be released before then, we would doubt it.

• We also saw promising data for GLP-1 agonist liraglutide (Novo Nordisk’s Victoza) in type 1 diabetes, which was even called out by ADA in a press release and press conference. Nearly three years ago, in August 2015, Novo Nordisk discontinued its program for liraglutide in type 1 based on mixed efficacy results, but Dr. Paresh Dandona (whose work apparently prompted Novo Nordisk’s original studies) presented a small (n=46), independent study showing a 0.6% placebo-adjusted A1c drop (p=0.006) and ~6 lbs placebo-adjusted weight loss (p=0.041) over one year. Without affecting average insulin dose or hypoglycemia rates, liraglutide offered improved glycemic control and weight loss, on par with SGLT inhibitors (see above). That said, Novo Nordisk’s CMO in North America Dr. Todd Hobbs told us it’s highly unlikely the company will re-start its Victoza for type 1 program. He explained that in the ADJUNCT studies, there was substantial heterogeneity across participants in terms of how much insulin dose adjustment was required (if any) and what liraglutide dose each individual responded to. When investigators prescribed the same dose adjustments across a larger sample, they had problems with some patients experiencing hypoglycemia. Still, Dr. Hobbs acknowledged that many HCPs/patients are using liraglutide off-label, making Dr. Dandona’s research immensely valuable. We continue to see a role for GLP-1s as adjunct therapy in type 1 diabetes, though SGLTs are certainly generating more buzz right now. We’re curious to learn more about this new trial from Dr. Dandona: What aspects of trial design or study population might have made it seemingly more successful than the ADJUNCT studies? Is success largely dependent on striking the optimal balance between insulin and liraglutide doses, and individualizing this ratio for each patient? Perhaps these results might encourage more experienced practitioners to use more GLP-1s off-label in type 1 diabetes, but we don’t expect widespread use without an official indication. With Victoza’s patent expiring in 2022/2023, liraglutide could soon become a much more accessible option for type 1s and type 2s alike.

• Finally, results from the EMERALD study pointed to a potential CV benefit from metformin in youth with type 1 diabetes. While also small (n=49), this study found improvements in insulin resistance, aortic function, carotid intima media thickness (cIMT), and body composition with metformin in type 1s 12-21 years-old. There were no effects of metformin on A1c, lipids, or blood pressure. Metformin is already a very common off-label therapy in type 1 diabetes, though notably, the much larger, JDRF-sponsored REMOVAL trial (presented at last year’s ADA) found no positive impact of metformin on cIMT over three years. Of course, REMOVAL enrolled adults, and we wonder if earlier intervention with metformin may offer different results. We’d love to see long-term CV outcomes studies investigate metformin, GLP-1s, and SGLT-2s in type 1; in fact, Dr. David Cherney called for a type 1 CVOT during the final talk of ADA 2018 (what a way to end!). There’s no doubt that type 1s face increased CV risk, and these patients need better options to manage that risk. Whether initiated by manufacturers or funded through public-private partnerships as Dr. Cherney suggested, we see a moral imperative to investigate these new and old options to improve quality and length of life for people with type 1 diabetes.

In CVOT Era, ADA/EASD Consensus Statement Emphasizes CV Risk Assessment, Recommends GLP-1s & SGLT-2s, Positions GLP-1s as First-Injectable Before Insulin

• In 2018, ADA and EASD will update their consensus statement on the management of type 2 diabetes. The writing committee presented a draft of the position statement on Tuesday morning – watch the full symposium here. Since the last update to this consensus document in 2015, the diabetes field has seen numerous positive CVOTs, which have shifted the treatment paradigm from glucose-centric to outcomes-centric (namely, avoiding adverse CV events). Accordingly, the committee encourages HCPs to first and foremost assess a patient’s CV risk when designing a type 2 diabetes treatment plan. The draft recommends that GLP-1s and SGLT-2s be added as second-line therapy in any patient with established CV disease not meeting her personal glycemic target (notably, the document doesn’t endorse any one particular A1c or other glycemic goal). A softer recommendation to add or switch to a GLP-1 or SGLT-2 stands for patients with CV disease who are meeting their personal glycemic targets. The committee specifically recommends GLP-1 over SGLT-2 when atherosclerosis is dominant, vice-versa when heart failure is dominant. Going even further, the committee has endorsed liraglutide over semaglutide over exenatide (within GLP-1), and empagliflozin over canagliflozin (within SGLT-2), which makes sense based on current FDA and EMA approved indications and safety warnings (e.g. amputations with canagliflozin). That said, Prof. Philip Home pointed out during Q&A that a handful of additional CVOTs will read out over the next year, including DECLARE for AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin), which is expected by year-end. In response, ADA’s Dr. William Cefalu proposed that the consensus statement could be a “living document” as is the ADA’s Standards of Care (starting in 2018), though this is harder to organize when two professional organizations are involved instead of just one. Separately, the consensus has also promoted GLP-1s to first-line injectable therapy, before basal insulin, when a patient is not meeting targets with oral agents. Writing committee members highlighted a GLP-1 agonist’s benefits on weight loss and hypoglycemia; we echo an audience member in calling this change a “long time coming.” We also noted a renewed emphasis on patient-centered care and shared decision-making throughout the session’s presentations, including the draft’s aim to provide recommendations on how to reach glycemic targets rather than to offer pre-specified targets for groups of people. We’re huge fans of this last point; there’s no doubt that talking about patient-centered care (and criticizing the new ACP guidelines) is in vogue, but we imagine patient outcomes will be better if/when providers start personalizing care and care goals, with an emphasis on individual risk factors. 

• The writing committee maintained more conservative stances in other domains of diabetes care. Metformin remains first-line, “foundational” therapy in this draft (alongside lifestyle change). The speakers acknowledged that this was highly-debated internally, but ultimately, the committee decided to stick to the status quo given metformin’s strong safety/tolerability and the high cost of polypharmacy. Dr. John Buse made an interesting comment in closing the session, questioning whether SGLT-2s might be foundational therapy if they had been discovered decades ago instead of metformin. Moreover, the committee did not find sufficient evidence to recommend initial combination therapy, unless someone is ≥1.5% above his A1c target. For comparison, ADA’s 2018 Standards of Care calls for initial dual therapy whenever a patient has baseline A1c >9%, while AACE is expectedly more aggressive, recommending initial dual therapy for anyone with baseline A1c ≥7.5% and triple therapy for anyone with baseline A1c >9% plus symptoms. In the end, we return to the importance of personalization and focusing more on how glucose is lowered, but we would also love to see a greater push toward earlier, faster intensification of treatment (given the persistent challenge of clinical inertia in diabetes care). Patients are spending too much time not doing well on metformin; even though current guidelines recommend against this, they clearly aren’t working. We understand the need for consensus statements and guidelines to be grounded in evidence, but how can they most efficiently overturn the treat-to-fail paradigm that’s so ingrained in real-world practices?

• For a deeper dive on the ADA/EASD draft consensus statement, read our full coverage and please do check out the webcast.

Growing Emphasis on Next-Generation Insulins, Particularly Hypoglycemia Benefits (Toujeo, Tresiba, Fiasp, Afrezza)

• We noticed a strong showing from next-generation insulins at ADA, both during oral presentations/symposia and in the poster hall. Next-gen insulins include Sanofi’s Toujeo (insulin glargine U300) and Novo Nordisk’s Tresiba (insulin degludec) on the basal side, plus Novo Nordisk’s Fiasp (faster-acting insulin aspart) and MannKind’s Afrezza (inhaled insulin) on the prandial side (both of these are considered ultra-rapid-acting). We continue to believe that Toujeo and Tresiba are a major leap above the basal insulin analogs that came before them (Sanofi’s Lantus and Novo Nordisk’s Levemir), and to this end, we were pleased to see abundant data not only on their safety/efficacy, and emphasizing hypoglycemia benefit and cost-effectiveness.

  • Next-gen basal insulins: Sanofi’s BRIGHT study (n=929) comparing Toujeo vs. Tresiba head-to-head found significantly less hypoglycemia with insulin glargine U300 vs. insulin degludec during the titration phase (the first 12 weeks of the 24-week trial). There was no significant difference in hypoglycemia rate between groups during the maintenance phase (the second 12 weeks of the 24-week trial), nor was there a significant difference overall. While these results certainly highlight Toujeo’s clinical benefits, we don’t think they convincingly demonstrate that one of these advanced basals is better than the other. Another late-breaking poster featured results from the real-world CONFIRM study (n=4,056) suggesting that hypoglycemia and treatment discontinuation are both more common with Toujeo vs. Tresiba. Two oral presentations by the highly-respected Prof. Simon Heller and Dr. Richard Pratley, respectively, underscored Tresiba’s significant hypoglycemia benefit vs. Lantus in the elderly; these were post-hoc analyses of SWITCH 2 and DEVOTE. (Notably, DEVOTE results showing CV safety and risk reduction for severe hypo are now part of Tresiba’s product label in the US and Europe.) On cost-effectiveness, a new analysis of Sanofi’s DELIVER 2 showed that switching to Toujeo from another basal insulin conferred an estimated $1,439 of healthcare savings per patient per year, driven by lower hypoglycemia-related healthcare utilization – namely, hospitalizations, ER visits, and outpatient care. Our takeaway from ADA is that both next-gen basal insulins boast a strong efficacy/safety profile, and that as a class, these agents could lessen the cost of diabetes on the health system. While head-to-head RCTs are interesting, it’s important to recognize that there’s more than enough room for both of these products to be successful on the market – and in fact, greater uptake of both products would be great news for the diabetes population on the whole, because more patients would be taking a basal insulin that’s more effective, safer, and easier-to-use.

  • Ultra-rapid-acting mealtime insulins: Fiasp and Afrezza also had their time in the spotlight at ADA 2018. Dr. Satish Garg presented results from the STAT study (n=60 type 1s) comparing Afrezza vs. Novo Nordisk’s NovoLog (insulin aspart) head-to-head. According to CGM readings, Afrezza offered a 12% increase (1.5 hours) in time-in-range vs. NovoLog (p<0.005), and postprandial glucose excursions were 15% smaller (-20 mg/dl) with the inhalable bolus vs. the injectable bolus (p<0.05). Both these metrics are meaningful to patient quality of life, and we applaud MannKind for using CGM to unveil these key benefits (albeit, in a relatively small trial). The unique ability to take quick, booster boluses with Afrezza (incredibly rapid onset of action within ~12 minutes) goes hand-in-hand with CGM – this was highlighted in MannKind’s exhibit hall booth – and we imagine STAT could have important implications for the Afrezza business moving forward. In the poster hall, we saw a post-hoc analysis of AFFINITY-1 and noted a lower risk of severe hypoglycemia with Afrezza (22% incidence) vs. NovoLog (31% incidence). Another late-breaker showcased pooled data from Onset 1 and Onset 2: Severe nocturnal hypoglycemia was significantly less common with Fiasp vs. NovoLog (HR=0.84, 95% CI: 0.72-0.98, p=0.02), while severe daytime hypoglycemia was balanced across groups (HR=0.96, 95% CI: 0.86-1.07, p=0.46). In our view, hypoglycemia risk reduction and enhanced time-in-range are likely to be the most meaningful advantages to faster-acting mealtime insulins, and ADA offered compelling data to this end. As we see it, prandial insulin is one of the areas within diabetes care with the most room for improvement, given how fear of hypoglycemia and uncertainty around meals directly interfere with patient quality of life.

Peptides Gone Oral: Novo Nordisk Leads Oral GLP-1 Competitive Landscape, Reports Positive PIONEER 1 Results; Research Continues on Oral Insulin

• Peptides gone oral was a major theme at ADA 2018, with Novo Nordisk’s oral GLP-1 semaglutide stealing the show. Late-breaking data from PIONEER 1 (oral sema vs. placebo in 703 type 2s) was presented on a poster. After 26 weeks, the highest dose (14 mg) gave a mean 1.4% placebo-adjusted A1c drop (p<0.001) and ~6 lbs placebo-adjusted weight loss (p<0.001). Additionally, 44% of people on 14 mg oral semaglutide experienced ≥5% weight loss vs. 16% of people taking placebo (p<0.001). The composite outcome of A1c <7% without weight gain or hypoglycemia was achieved by 73% of participants on 14 mg semaglutide vs. 27% of those on placebo (p<0.001); the composite of ≥1% A1c decline and ≥3% weight loss was seen in 54% and 11%, respectively (p<0.001). These are impressive efficacy results (note that these numbers are pulled from the PIONEER 1 on-treatment analysis), and 14 mg is most likely the dose that Novo Nordisk will commercialize, with an NDA planned for 2019 after all 10 trials in the phase 3 PIONEER program report this year. As for safety, 7% of the 14 mg semaglutide group (13 individuals) prematurely discontinued treatment due to an adverse event vs. 2% of the placebo group (four individuals). Nausea and other GI symptoms do seem to be dose-dependent with oral semaglutide, but as with all GLP-1 agonists, these tend toward mild-to-moderate and usually subside over time. It’s shaping up to be a very big year for oral semaglutide, and that started with ADA and PIONEER 1. Novo Nordisk has also released topline results from PIONEER 2, 3, 4, and 7. The company’s North America CMO Dr. Todd Hobbs told us he’s most looking forward to PIONEER 6 CVOT results, given the importance of showing cardioprotection and other beyond-A1c benefits for a new diabetes therapy to be successful today.

  • We’ve heard some speculation that the fasting requirements around oral semaglutide will impose undue burden on patients. As stated on the poster, PIONEER 1 participants were instructed to take their dose in a fasting state every morning and to refrain from eating for another 30 minutes thereafter. While this could be perceived as a nuisance by some patients, we think that many others will decide the glucose-lowering and weight loss are well worth it; plus, oral semaglutide is an appetite-suppressant, which could ease the post-dose fasting. Non-adherence to this protocol would undercut the efficacy of oral semaglutide. Based on the compelling efficacy data from PIONEER 1, we suspect adherence was fairly strong, but we’d love specific details on this. Moreover, since adherence is always lower outside the context of an RCT, we’ll be curious to see if Novo Nordisk invests in any support tools – digital or otherwise – to aid real-world engagement.

  • Ultimately, we’re optimistic that Novo Nordisk can make oral semaglutide into an easy-to-take commercial product although it won’t be exactly the same – and no problem on that front! We can’t emphasize enough how meaningful it could be for patients to have all the potency and efficacy of a GLP-1 agonist without any of the injection burden that some (by no means all) perceive. We’ve heard from many a thought leader that oral administration is the next frontier for GLP-1 therapy, and we’re now closer than ever with positive PIONEER results. Questions certainly remain – around pricing, side-effect management, positioning within the diabetes treatment paradigm, etc. – but for the moment, oral GLP-1 is an R&D victory to celebrate.

• Oral insulin also had some airtime at this meeting, though there seem to be more hurdles here relative to oral GLP-1. As a reminder, Novo Nordisk discontinued its oral basal insulin candidate from phase 2 back in 3Q16. Vanderbilt’s Dr. Mary Moore presented a study in dogs showing that this candidate can yield smaller postprandial glucose excursions and enhanced postprandial hepatic glucose disposal, but the issue remains developing a carrier to increase bioavailability of the oral insulin so that the commercial product can be reasonably priced. During the same session, SUNY’s Dr. Harold Lebovitz shared new data on Biocon’s mealtime oral insulin candidate Insulin Tregopil. This was a small PK/PD study (n=18 type 2s), and Insulin Tregopil showed peak action within 37-47 minutes, suggesting that this bolus works about as fast as MannKind’s ultra-rapid-acting inhalable Afrezza. (Afrezza had its own moment in the spotlight at ADA, when the STAT study found superior postprandial control and more time-in-range vs. Novo Nordisk’s NovoLog.) We imagine that Insulin Tregopil (like all insulin products) will encounter intense pricing pressure as well, and we remain somewhat skeptical about the technical viability of an oral prandial insulin. Nonetheless, Biocon’s development program is one to watch, and we eagerly await data from larger clinical trials.

• One Saturday afternoon symposium reviewed alternative (non-injectable) delivery routes for peptide therapies, going beyond oral to discuss implantables as well. Intarcia’s implantable exenatide mini pump was a key highlight during this session, though across the board, this was a relatively quiet meeting for ITCA 650. FDA issued a Complete Response Letter (CRL) for this GLP-1 agonist candidate in September 2017, and Intarcia is now working to resubmit (management has given no sense of the timeline for this, though presumably, it’s as soon as possible). We do want to call attention to three posters on ITCA 650, highlighting consistent efficacy across subgroups, safe patient switching from liraglutide (Novo Nordisk’s Victoza) to the implantable mini pump without up-titration, and strong safety/efficacy across a pooled analysis of phase 3 studies. Despite the CRL roadblock, we’re optimistic about the potential for ITCA 650 to boost penetration of the GLP-1 agonist class and to improve real-world adherence to GLP-1 therapy, though it may be more work than originally expected to get this drug/device combo approved.

New Data Emphasizes Favorable Benefit/Risk Profile of Combination Therapy (Novo Nordisk’s Xultophy, AZ’s Qtern, & More); Exploring Roles for GLP-1 + SGLT-2 Co-Administration in Diabetes Care

• We saw abundant data at ADA supporting that combination therapy performs better than monotherapy on both efficacy and safety endpoints. Novo Nordisk presented DUAL IX (n=420) comparing fixed-ratio Xultophy (insulin degludec/liraglutide) to basal insulin Lantus (Sanofi’s insulin glargine) in patients on a background SGLT-2 inhibitor. After 24 weeks, A1c declined by a mean 1.9% with Xultophy vs. 1.7% with Lantus (baseline 8.3%). Xultophy was associated with a 58% lower risk of symptomatic or severe hypoglycemia (!), and 85% of patients on the fixed-ratio combo reached A1c <7% compared to 71% of patients on basal insulin without GLP-1. Xultophy had no impact on body weight over 24 weeks, while Lantus caused ~4 lbs weight gain from a baseline ~194 lbs. Thus, DUAL IX adds to the compelling dataset on Xultophy’s efficacy and mild side-effect profile (no weight gain or even modest weight loss, much less hypo). Plus, participants in DUAL IX were already on a potent anti-hyperglycemic therapy (SGLT-2), which makes the glucose-lowering from Xultophy all the more remarkable. AZ presented two positive studies on fixed-dose combination Qtern (dapagliflozin/saxagliptin), one comparing the SGLT-2/DPP-4 to Lantus and another comparing it to glimepiride (a sulfonylurea). Qtern was non-inferior to Lantus (p=0.118) and superior to glimepiride (p=0.001) on A1c-lowering. Body weight decreased with Qtern across both trials, but increased with Lantus and with glimepiride, and the fixed-dose combination treatment offered comparatively lower hypoglycemia risk. Again, these results highlighted superior efficacy and milder side-effects with a combination therapy vs. commonly-prescribed standalone diabetes drugs. In our view, fixed-ratio and fixed-dose combinations are both under-utilized in diabetes care today given their favorable benefit/risk profile, which was only confirmed by what we saw at this ADA.

• Despite these numerous positive readouts, we noted continuing debate on when to initiate combination regimens – this is so frustrating given other therapeutic areas like cancer where barely anyone (!) starts on monotherapy. The writing committee for the new ADA/EASD consensus statement on type 2 diabetes management did not find sufficient evidence to recommend starting all patients on a combination from the get-go, but on the flip side, six-year EDICT results showed long-lasting benefits to triple combo therapy (metformin + TZD pioglitazone + GLP-1 agonist exenatide) in newly-diagnosed patients. EDICT participants randomized to the triple combination maintained an A1c around 5.8% after six years, while those randomized to standard care had an A1c around 6.7% (p<0.0001). Importantly, hypoglycemia was 10x as common in the standard care group vs. the triple combination group. Dr. Hertzel Gerstein advocated fiercely for early combination therapy in a separate ADA talk, for improved patient outcomes (and maybe even diabetes remission). All this said, EDICT’s sample size after six years was down to 30%-40% of the original participant pool, which was small to begin with (n=217), and the ADA/EASD writing committee evaluated a comprehensive evidence base. We can’t reasonably make a judgment on the ideal timing to initiate combination therapy in everyone with type 2 diabetes, but we do feel that the average real-world patient isn’t treated aggressively enough, given delayed diagnosis and pervasive clinical inertia (stemming from the provider-side as well as the patient-side). With new fixed-ratio and fixed-dose combination products (like Xultophy and Sanofi’s Soliqua, Qtern and Lilly/BI’s Glyxambi and Merck/Pfizer’s Steglujan), patients can take multiple agents in one convenient injection or tablet, paying only one co-pay and seeing greater A1c reductions and/or weight loss with a milder side-effect profile. We understand this may not be a cost-effective at the population level in terms of short term (for now), and as Dr. Silvio Inzucchi has pointed out, the conventional therapy arm in EDICT didn’t have access to more advanced drugs like SGLT-2 inhibitors (that is to say, perhaps SGLT-2 monotherapy would perform better than metformin + pioglitazone + exenatide – though we doubt it). Even after the sum of positive data we saw at ADA, some still perceive combination therapy as a complicated beast. Going forward, we hope to see better guidance for real-world HCPs on how to match the right combination to the right patient at the right time – and this is a task for precision medicine as much as it is for professional medical organizations. We do feel strongly that HCPs having a bit more time to work this out short-term would benefit virtually all patients longer term – and they’ll need to know how to do it eventually, when cost isn’t an issue.

• There was noticeable buzz at these ADA Scientific Sessions around GLP-1 + SGLT-2 co-administration. After all, these are arguably the two most advanced therapy classes available to treat diabetes today: Could combining them into one medication regimen lead to greater A1c reductions, greater weight loss, greater cardioprotection? UT’s Dr. Muhammad Abdul-Ghani presented findings from a small study (n=45) comparing GLP-1 monotherapy (liraglutide) vs. SGLT-2 monotherapy (canagliflozin) vs. GLP-1/SGLT-2 co-administration. After four months, combo therapy conferred more than additive weight loss – this was remarkable to see though not surprising given what we’ve been hearing as hallway chatter at other gatherings like CODHy. Body weight fell ~8 lbs in the canagliflozin group, ~4 lbs in the liraglutide group, and ~14 lbs with both GLP-1 and SGLT-2 together. (If weight loss was exactly additive, we’d expect a ~12 lbs reduction in the combo group – this seems synergistic!) A1c reductions were less than additive, but were still greater with the combination (-1.9%) vs. either monotherapy (-1.1% with canagliflozin, -1.6% with liraglutide). Notably, this weight loss and A1c data matches that of DURATION-8 (n=695), AZ’s larger clinical trial evaluating Bydureon (exenatide) + Farxiga (dapagliflozin) co-administration. Seven-month DURATION-8 results were presented at EASD 2016, one-year data was shared at ADA 2017, and two-year results were the subject of a poster at ADA 2018. From the data collected to-date, it seems like prescribing GLP-1 and SGLT-2 together could be a particularly effective strategy to promote weight loss, even if the combination gives “underwhelming” A1c results (Dr. Abdul-Ghani’s words). The additive cardioprotection question has yet to be explored in a large RCT; we’d be keen to see that study. The ADA/EASD consensus statement writing committee endorsed this combination as safe, recommending GLP-1 on top of SGLT-2 or vice versa when patients have comorbid CV disease and continue above their personal glycemic targets. While a GLP-1 agonist and an SGLT-2 inhibitor do have opposing effects on glucagon response (the former inhibits glucagon secretion, the latter increases plasma glucagon concentration), thought leaders don’t appear to be particularly worried about this from a safety perspective; we are interested to learn more about if/how these contradictory effects on glucagon lead to sub-additive glycemic efficacy.

CANVAS One Year Later: Understanding the Risk/Benefit Profile of J&J’s Invokana (Canagliflozin) and CV/Renal Class Effects of SGLT-2 Inhibitors

• ADA 2018 offered lots of follow-up on CANVAS, the headliner of ADA 2017, which leant evidence for cardioprotection and renal protection as SGLT-2 class effects, and presented what some perceive as a complicated risk/benefit profile for J&J’s Invokana (canagliflozin). As a reminder, this CVOT found a nearly doubled risk for lower limb amputations with Invokana vs. placebo (HR=1.97, 95% CI: 1.41-2.75). In a particularly notable ADA poster this year, J&J shared results from OBSERVE-4D, a real-world observational analysis of >700,000 patients. OBSERVE-4D found no increased amputation risk with canagliflozin vs. other SGLT-2s (empagliflozin and dapagliflozin, in this analysis) or vs. other glucose-lowering drugs excluding metformin (intent-to-treat HR=1.01, 95% CI: 0.93-1.10, p=0.71; on-treatment HR=0.75, 95% CI: 0.40-1.41, p=0.25). Dr. John Buse, who co-authored the paper on this study, considered these findings very reassuring with regard to canagliflozin’s safety in real-world practice. On the other hand, Dr. Mikhail Kosiborod later emphasized that the majority of patients in OBSERVE-4D were very low risk relative to those enrolled in CANVAS (~75% did not have baseline CV disease), and the amputation signal in CANVAS was likely amplified by high-risk patients. That said, in a post-hoc analysis, canagliflozin was found to independently ~increase amputations even after controlling for history of CV events. Though, OBSERVE-4D found no heightened amputation risk in the ~25% of participants with baseline CV disease, either. Dr. Kosiborod also noted that the six-month duration of OBSERVE-4D was probably not long enough to detect an amputation signal, and indeed, we’d like to see a longer follow-up on this cohort. In the end, these results don’t drastically shift how we think about Invokana/amputations: Our sense is that most thought leaders believe in amputations as a risk inherent to the canagliflozin molecule, but that this is only problematic if the patient is otherwise at high-risk for amputations, since base rate of this complication is very low (even in a diabetes patient population). Prescribing Invokana thus becomes a challenge of proper patient selection. We don’t think amputation risk should undermine the tremendous glucose-lowering, weight loss, CV, and renal benefits to this SGLT-2 inhibitor, especially since some thought leaders have noted greater A1c and weight reductions with Invokana vs. Jardiance or Farxiga. Dr. Jim Gavin pointed out that OBSERVE-4D can offer a data-driven narrative to combat some of the hysteria surrounding amputations. He also described how some good has come out of this CANVAS signal: HCPs were re-focused on monitoring the feet and checking for amputation risk factors in patient care – we were very glad to hear about this.

• An oral presentation by Dr. Dick de Zeeuw showed consistent CV/renal benefits to Invokana across baseline eGFR subgroups in CANVAS. Notably, the A1c-lowering efficacy of canagliflozin was attenuated as eGFR dropped (from ≥90, to 60-90, to 45-60, to <45 ml/min/1.73m²), but it didn’t matter – the SGLT-2 inhibitor continued to decrease risk for three-point MACE, heart failure hospitalization, and the renal composite outcome (40% reduction in eGFR, end-stage renal disease, or renal death). This was an incredibly exciting 15 minutes for us, because these data confirm not only that cardioprotection is robust with Invokana (and likely with all SGLT-2s), but that the CV benefit occurs independent of glucose control. It’s meaningful that canagliflozin continues to protect against adverse CV outcomes despite less glucose-lowering – this reaffirms that the CV benefit in CANVAS was not driven by changes in A1c (but rather, is inherent to the molecule), and it raises exciting possibilities about SGLT-2 as CV or renal medicine independent of diabetes. Indeed, thought leaders like Dr. David Fitchett have speculated that patients with renal dysfunction may stand to benefit the most from SGLT-2 inhibitors in terms of cardio and renal protection, and it’s ironic that FDA currently doesn’t recommend these drugs for people with eGFR below 45 ml/min/1.73m² because of attenuated glycemic efficacy. These results bode well for CREDENCE, J&J’s ongoing outcomes trial which has a composite primary endpoint of end-stage renal disease, doubling of serum creatinine, and renal or CV death and has enrolled patients with type 2 diabetes and an eGFR ≥30 to <90 ml/min/1.73 m2 (expected to complete in June 2019). Additionally, AZ and Lilly/BI also have outcomes trials for their SGLT-2 inhibitors in people with or without diabetes (Dapa-CKD and EMPA-KIDNEY, respectively).

• While the lack of a major CVOT presentation gave ADA 2018 a different feel from those of recent years, the enthusiasm for positive CV and renal outcomes data is as loud and strong as ever. SGLT-2 inhibitors (as well as GLP-1 agonists) are at the heart of this excitement. In addition to follow-up data on CANVAS, we sensed tremendous anticipation for the DECLARE trial (for AZ’s SGLT-2 Farxiga), which is scheduled to complete in July 2018 and to report results by year-end. Very notably, DECLARE includes heart failure hospitalization in a co-primary endpoint, and it features a large primary prevention cohort in that 60% of participants had no history of CV events at baseline.

Reflecting on 10 Years of FDA-Mandated Diabetes CVOTs: Ample Discussion on Trial Design & How to Maximize Insights

• This year marks the 10th anniversary of FDA’s famed 2008 CVOT guidance, and fittingly, ADA was rife with discussion on how these large outcomes trials should be designed. We gathered a general consensus from thought leaders that while CVOTs are a massive investment (occasionally deterring a company from developing a diabetes drug), they’ve been worthwhile for all the insights gained: GLP-1s and SGLT-2s are cardioprotective; these classes might also offer renal benefit; and SGLT-2s could be indicated for heart failure and CKD outside the context of diabetes. The field is now faced with the task of making CVOTs more feasible for manufacturers (so as not to dis-incentivize diabetes R&D) without sacrificing on insights.

  • Drs. Steven Marso and Darren McGuire discussed ideal CVOT design during a Friday afternoon “debate” (in quotes only because the two brilliant cardiologists agreed on many key points!). They proposed that future CVOTs incorporate heart failure as a primary endpoint and enroll a larger primary prevention cohort – notably, AZ’s DECLARE trial for SGLT-2 Farxiga does both, and we look forward to those results in 2H18. Drs. Marso and McGuire also suggested more studies in non-diabetes populations, including obesity (e.g. Novo Nordisk’s SELECT for GLP-1 semaglutide), heart failure (e.g. Lilly/BI’s EMPEROR, AZ’s Dapa-HF), and CKD (e.g. AZ’s Dapa-CKD, Lilly/BI’s EMPA-KIDNEY, J&J’s CREDENCE). In many ways, this next wave of diabetes CVOTs is already underway.

  • Making CVOTs more feasible will largely depend on FDA and what the agency will accept to indicate the CV safety or efficacy of a given drug. Will FDA loosen requirements for a new product where cardioprotection is considered a class effect (e.g. SGLT-2 inhibitors)? Could positive CVOT data support claims on combination therapy product labels (e.g. LEADER and DEVOTE results on the label for Novo Nordisk’s Xultophy)? Will FDA require a separate, post-market CVOT for oral semaglutide even after SUSTAIN 6 and PIONEER 6 (assuming Novo Nordisk would aim for a cardioprotection indication on that product label)? As we understand it, many of these conversations have been launched between FDA and different manufacturers, though it’s unclear how far along these discussions are. For example, Novo Nordisk has filed requests with FDA to include LEADER and DEVOTE data on the Xultophy (liraglutide/insulin degludec) label. It’s unclear whether the company will move forward with plans for the SOUL CVOT of injectable semaglutide in type 2 diabetes, or whether FDA will accept SUSTAIN 6 results as sufficient to support a CV claim, or whether the company will shift focus anyway to oral semaglutide’s CV efficacy. Questions abound, and the only thing we can say with any degree of certainty is that CVOT design is evolving. We’ll be very interested to revisit this theme at ADA 2019, to note what changes have been made and how the field is continuing to refine the design and conduct of large outcomes trials.

  • We do hope that evolution in CVOT design culminates in more standardization. It’s already challenging to compare between CVOTs given differences in study population, study design, study protocol, etc., as became exceptionally clear when EXSCEL (AZ’s GLP-1 Bydureon) reported at EASD 2017. We implore that in re-envisioning the diabetes CVOT, the field pushes toward more standardization, because this further enhances insights gained and could support treatment decisions. For example, Dr. Marso alluded to greater heart failure benefit with SGLT-2s vs. greater impact on atherosclerosis with GLP-1s; both therapy classes have shown compelling cardioprotection, and now we should help providers identify the patients most likely to benefit from each so that we can improve real-world outcomes.

Remission of Type 2 Diabetes is Becoming a Reality – But for Whom?

• We’ve noticed growing interest of late to not only treat, but reverse type 2 diabetes, and ADA offered new data and analyses that elucidated what makes remission more likely for some patients as opposed to others. When one-year results from DiRECT were presented at IDF 2017, we were impressed: The intensive weight loss intervention gave 46% remission with a protocol administered through primary care providers. In Orlando, Prof. Roy Taylor showed that responders/non-responders were differentiated by the ability of their beta cells to recover, and the only significant difference between these groups was mean duration of diabetes – 2.7 years vs. 3.8 years (p<0.05). In other words, shorter duration of diabetes predicted a greater likelihood of remission with the intervention at hand (~800 calories/day for three-five months, withdrawal of anti-hyperglycemic and anti-hypertensive drugs, stepped food reintroduction, and structured support for long-term weight maintenance). Both responders and non-responders lost similar amounts of weight in the initial study period, pointing to an inherent difference in ability of beta cells to recover function.

  • In a separate oral, Prof. Mike Lean emphasized that the factors predicting weight loss and remission were different in DiRECT (even though remission was much more likely – 86% – among participants who lost at least 15 kg). Remission was predicted by lower A1c, fewer background diabetes medications, and older age, while weight loss was predicted by higher body weight, BMI, male sex, and a shorter duration of diabetes. Prof. Taylor’s analysis also revealed a numerical but non-significant benefit to having lower A1c and lower fasting plasma glucose. It seems as if the field is coming to understand a phenotype of patients who have enough preserved beta cell function that they can achieve diabetes remission with enough weight loss. That is, there’s a window, moderated by a number of baseline factors, in which type 2 diabetes can be much more easily sent into remission.

• A 95-person Virta Health study in prediabetes underscored the importance of earlier intervention. In this trial of a high-fat/low-carb diet combined with tech-enabled remote care, Virta demonstrated 61% reversion to normoglycemia at one year and zero progression to diabetes with a mean 11.5% weight loss. This builds on strong type 2 diabetes remission data (n=262) announced earlier this year; Virta’s intervention gave a similar 60% “reversal” rate with 12% weight loss and a 1.3% A1c drop after one year. Notably, Virta’s intervention costs ~$370/month and is currently accessed through out-of-pocket payments or employer-based coverage. We certainly think the value proposition is a good one. We’re eager to see longer-term data from Virta as well as the DiRECT study. Two-year data collection for DiRECT is almost complete and 2.5-year diabetes data from Virta is forthcoming as well. Both longer-term readouts will be critical in demonstrating the long-term sustainability of diabetes remission via intensive lifestyle intervention. For now, we remain very excited and optimistic about the scalability of these programs (again, DiRECT was administered in a usual care setting) and the impact they could have on long-term outcomes and diabetes-associated costs.

• On a much less encouraging note, RISE Peds found that the rapid decline in beta cell function that occurs among youth with type 2 continues despite treatment with metformin or basal insulin glargine (Sanofi’s Lantus). Our understanding is that ~5,000 youth are diagnosed with type 2 diabetes in the US each year; that’s only ~one-quarter the number diagnosed with type 1, but the rising tide of childhood obesity (up to 19% in 2015-2016) suggests that prediabetes and type 2 diabetes in youth is an important (and in Dr. John Buse’s words, “scary”) public health concern. Moreover, the pathophysiology of type 2 in youth is poorly understood: We know that beta cell function falls off more quickly than it does in adults with new-onset type 2, but we don’t know why, and we don’t know how to stop or reverse it with any available drugs, since neither metformin nor insulin glargine were effective in RISE Peds. DiRECT results would lead us to believe that rapid decline in beta cell function makes it very difficult to reverse type 2, since Prof. Roy Taylor described beta cell vitality as the differentiating factor between responders/non-responders. Other largescale trials, including the DPPOS and SCALE, have demonstrated efficacy of medications including metformin, acarbose, liraglutide, and insulin on preserving the beta cell and improving the progression of dysglycemia in adults, but that doesn’t seem to apply in younger patients. As such, Dr. Buse emphasized the need to address childhood obesity/type 2 diabetes as a public health problem; he called for aggressive public health action, including campaigns against marketing from the food industry that targets children. All in all, while ADA offered several exciting “wins” for type 2 diabetes remission strategies in adults, the situation is bleak for youth. Read more about RISE Peds directly below.

Major Symposia – VADT-f, RISE, TEDDY – Offer Neutral Data at Best, Negative at Worst; Biggest Takeaway is Knowing How Much We Don’t Know

• With no CVOT presenting this year, we looked to other symposia for major influential data, the data we’d be talking about in the year ahead. Sadly, these symposia – from VADT-f to RISE to TEDDY – reported mostly negative or neutral results. The VADT 15-year follow-up found no significant micro or macrovascular benefit to intensive glucose control (an aim to lower A1c 1.5% from baseline). The hazard ratio for the primary composite CV outcome was 0.91 trending toward intensive control (95% CI: 0.78-1.06, p=0.23), and for the renal composite outcome was 0.90 trending toward intensive control (95% CI: 0.63-1.27, p=0.55). For eye events, the hazard ratio was 0.84 (95% CI: 0.70-1.00, p=0.053), again favoring intensive control but missing statistical significance. RISE Peds found that neither insulin glargine (Sanofi’s Lantus) nor metformin can preserve or improve beta cell function in children/adolescents with type 2 diabetes or prediabetes: Both steady-state C-peptide and ACPRmax (arginine at maximal glycemic potentiation) declined over the course of the trial, reflecting continually worsening beta cells. Finally, TEDDY struggled to pin down the environmental triggers of type 1 diabetes; neither childhood GI infection nor maternal vitamin D or omega-3 supplementation were significantly correlated with onset of autoimmunity. In other words, these trials primarily highlighted what we don’t know about type 1 and type 2 diabetes – the controversy continues over whether tight A1c control is optimal for CV risk reduction, no drugs in our current toolkit seem to address the underlying pathophysiological defects of type 2 diabetes in youth, and environmental stimulants of type 1 diabetes remain a mystery.

• That said, we walked away from these symposia with important takeaways nonetheless.

  • On VADT-f, speakers speculated that these findings may not be relevant in an era of cardioprotective diabetes drugs, because A1c-lowering shouldn’t be the focus of modern diabetes management – we should first and foremost target CV risk. Dr. Peter Reaven, a VADT investigator, argued that treatment decisions should consider CV effects as seriously as glycemic effects, and he noted that SGLT-2s and GLP-1s are used infrequently in the VA patient population. Independent commentator Dr. Hertzel Gerstein emphasized that maintaining good glucose control is probably just as important as achieving it. He also shared findings from a meta-analysis of VADT, ACCORD, ADVANCE, and UKPDS supporting that A1c <7% does significantly lower microvascular risk overall. We loved Dr. Gerstein’s plug for personalized glycemic targets: “Please put your hand up if you’re average. Nobody is average!” he asserted. “Clinical trials do not tell you how to treat the patient in front of you, because they just say what works on average.” Indeed, when asked what A1c goal they set for their patients today, none of the panelists could give a clear answer – because it always depends.

  • On RISE Peds, independent commentator Dr. John Buse advocated that we address childhood obesity as a public health crisis (even more so than a medical one). He argued that we should demand marketing restraint from the food industry, suggested we explore more aggressive public health policy, and highlighted that research should continue evaluating therapeutic and surgical approaches to obesity, type 2 diabetes, and prediabetes in youth. We too took this as the most important learning from RISE Peds, and we’d particularly like to see more investment in the built environment (it should be conducive to physical activity) and in access to healthy food. In terms of research, we hope to see more rigorous investigation to identify public health strategies that work. For now, we imagine the greatest ROI may come if we approach population-level obesity in youth as a public health problem rather than a medical challenge.

  • On TEDDY, Dr. Riitta Veijola reported that having a second degree relative with type 2 diabetes delayed progression from autoimmunity to type 1 diabetes vs. those without a family history of type 2 (HR=0.61, 95% CI: 0.44-0.86, p=0.003). This analysis was adjusted for class II HLA, age at seroconversion, first-degree relatives with type 1, IAA and IA-2A titers, and seven SNPs. There were no notable differences based on first-appearing autoantibody. Dr. Veijola called these results “quite intriguing,” and we agree.

Next-Generation Glucagon from Xeris, Zealand, Lilly Poised to Revolutionize Hypoglycemia Treatment

• Hypoglycemia was a major focus at this meeting overall, and within that realm, we noticed particular enthusiasm for imminent innovation in glucagon rescue therapy. Dr. Mark Christiansen presented results from a phase 3 trial (n=80) of Xeris’ glucagon autoinjector (intended brand name “MyGluca”) in type 1 diabetes. The autoinjector showed equivalent efficacy to Lilly’s glucagon emergency kit in raising blood glucose and improving patient-reported neuroglycopenic and autonomic symptoms. Importantly, this equivalent efficacy also came with greater ease-of-use in the autoinjector arm, since Lilly’s kit requires a lengthy, error-prone reconstitution process. Indeed, a human factors study found that 99% of trained and untrained users were able to successfully administer the full glucagon dose with Xeris’ autoinjector. The primary issue with current glucagon reconstitution kits is that they are cumbersome and not user-friendly, particularly for those unfamiliar with diabetes, syringes, etc., and an autoinjector – enabled by the liquid-stable glucagon inside of it – is an elegant solution to this problem, ultimately offering an improvement in patient safety. We also got a full look at phase 2 results (n=17) on Zealand’s liquid-stable dasiglucagon (to be commercialized as the HypoPal autoinjector), following a topline release in May. Dasiglucagon demonstrated equivalency to Novo Nordisk’s GlucaGen in raising blood glucose. We now eagerly await phase 3 data on dasiglucagon from both a pivotal study as a single-dose rescue therapy vs. GlucaGen and an immunogenicity trial, for which positive topline results have been released. Our attention is now turning to the submission and market entry of these candidates: Xeris is targeting 3Q18 for FDA submission, while Zealand is targeting 2019; Lilly also plans to file an NDA for its nasal glucagon candidate by end of 2018. While questions remain surrounding future reimbursement, pricing, and market size, we’re beyond excited about these much-needed innovations in this much under-served area of diabetes therapy.

Increasing Attention on Access, Affordability, & Cost-Effectiveness (Analyses on Sanofi’s Next-Gen Toujeo, Steno-2/Multifactorial Treatment)

• ADA 2018 was chock-full of cost-effectiveness data, pointing to the compelling ROI of newer diabetes drugs as well as more intensive, multifactorial approaches to treatment. A cost-effectiveness analysis from Sanofi’s DELIVER 2 study found that switching to Toujeo (insulin glargine U300) from another basal insulin led to ~$1,439 saved per patient per year. In line with the original DELIVER 2 findings (switching to Toujeo reduced the risk of hypoglycemia in a real-world setting), these cost-savings were driven by lower hypoglycemia-related healthcare utilization, including fewer hospitalizations (2.8% of people on Toujeo vs. 4.3% of people on other insulins, p=0.037); a smaller proportion of people visiting the ER (3.1% vs. 5.1%, p=0.007); and fewer patients requiring outpatient care (12.5% vs. 15.4%, p=0.011). Similarly, a cost-effectiveness analysis of Steno-2 showed >$1,500 in healthcare savings per patient per year with multifactorial treatment (simultaneous glucose-lowering, blood pressure-lowering, and lipid-lowering) vs. conventional therapy (p=0.045) in a Danish population with type 2 diabetes. The lion’s share of these savings (>$1,000 per patient per year) was attributable to reduced costs for inpatient services due to CV complications (~$1,550 vs. ~$2,580/patient/year, p=0.002). This illustrates an additional economic incentive for more intensive diabetes therapy, in addition to its compelling clinical benefits (in Steno-2, intensive therapy gave ~50% microvascular risk reduction after four years, ~53% macrovascular risk reduction after eight years, 46% risk reduction in mortality after 13 years, and an average of nearly 8 years of life gained after 21 years). We only hope that these numbers resonate with payers and providers, as we continue to believe that more aggressive and/or advanced diabetes therapy should be viewed not as a cost, but as an investment in greater health and safety.

• We were also pleased to see hard data on access/affordability (because it’s one thing to note that these are issues in diabetes care, and another to quantify them so that we can build a case for improving access). Yale’s Ms. Darby Herkert presented a survey (n=199) to show that one in four patients with diabetes underuse insulin due to cost constraints. This 25% of patients is 3x as likely to have an A1c above 9%, which clearly links medication expense to utilization to outcomes. As another example, ADA and IBM Watson Health conducted a study using insurance claims data from >300,000 Americans with type 2 diabetes. Of this cohort, 31% of patients had altogether discontinued their diabetes medications after three months; this grew to 44% by six months and 58% by one year. Virtually all patients in the database started with metformin as first-line, and the few who didn’t discontinue therapy were most likely to remain on metformin monotherapy one year later. Only a vanishingly small fraction of the patient population intensified therapy after one year, and even then, this intensification was to metformin/SU combos, metformin/DPP-4 inhibitor combos, or standalone SUs and DPP-4s (as opposed to more efficacious options like SGLT-2 inhibitors or GLP-1 agonists, with weight loss and CV benefits to boot). In our view, these findings are inextricable from the challenge of poor reimbursement/access to more advanced diabetes drugs.

Mixed Results on Disease-Modifying Treatments for T1D: TrialNet Study Finds Promise in Low-Dose ATG for Recently-Diagnosed Type 1s; Two-Year Data on ViaCyte’s PEC-Encap; Negative Data from TEDDY, Kamada

• While there were a fair number of presentations at ADA about “curing” or preventing type 1 diabetes, our overall sense of this field was not drastically changed – there’s a lot of passion and enthusiasm for disease-modifying type 1 therapies, but we’re a long road away from a commercial product. We saw positive data from both ViaCyte (the PEC-Encap system) and TrialNet (investigating low-dose ATG in recent-onset diabetes). University of Florida’s Dr. Michael Haller discussed the TrialNet data (n=84), emphasizing the benefits of low-dose antithymocyte globulin (ATG) therapy on C-peptide levels in people with disease duration <100 days. After one year, participants on placebo experienced a ~0.45 mmol/L decline in C-peptide levels, which was attenuated to only ~0.1 mmol/L decline with ATG monotherapy (p=0.0003) and ~0.25 mmol/L decline with a combination regimen of ATG + granulocyte colony stimulating factor (GCSF, p=0.031). These improvements in C-peptide were accompanied by improvements in A1c: From a baseline 7.5%, A1c fell to 6.5% with ATG monotherapy (p=0.002) and trended downward to 7% with ATG/GCSF combination therapy (p=0.011). Neither treatment produced meaningful reduction in insulin dose, but this was a relatively short duration of follow-up. Two-year data collection will be completed this Fall, and we look forward to learning whether these promising effects are durable. Dr. Haller memorably referred to these ATG and ATG/GCSF cocktails as “Brazil Lite,” since they’re meant to be a more tolerable version of the Brazil Cocktail (also known as the Voltarelli Cocktail), which used more intensive doses of ATG to produce insulin independence in ~60% of subjects, but at the cost of severe side-effects and immune-compromization. We’re cautiously optimistic that “Brazil Lite” will have at least “lite” efficacy with a much better safety/tolerability profile. But again, this is early-stage research and we must manage expectations when it comes to a type 1 “cure.” UC San Diego’s renowned Dr. Robert Henry shared ViaCyte’s data, framing PEC-Encap as safe and well-tolerated overall. In the first cohort of patients from the phase 1/2 STEP ONE trial (n=19), the device successfully preserved insulin-producing function from the encapsulated beta cells. Dr. Henry highlighted that cell survival and engraftment was strongest in areas where PEC-Encap experienced strong host tissue integration and vascularization. After two years, the larger PEC-Encap device (STEP ONE evaluated two sizes, VC-01-250 and VC-01-20) was found to contain mature insulin- and glucagon-secreting cells with no immune response detected. We are certainly excited about PEC-Encap and about ViaCyte’s entire pipeline of beta cell encapsulation therapies, though questions remain about how long PEC-Encap can evade foreign body response. Moreover, these candidates are all in the earlier stages of clinical development. Once again, we think it’s essential to keep enthusiasm in check so that we’re managing expectations for a type 1 “cure” (and no results reported at ADA suggested that this disease-modifying product is close on the horizon).

• Kamada’s phase 2 trial of serine protease inhibitor AAT was also presented at ADA, by Israel’s Dr. Yael Lebenthal. This study (n=70 newly-diagnosed type 1s, ages 8-25) failed to meet its primary endpoint of a significant reduction in C-peptide area under the curve (AUC), although a subgroup analysis showed a significant effect for participants 12-18 years-old. In this cohort, the 120 mg/kg AAT dose lowered C-peptide AUC by 0.18 pmol/ml (p=0.20). For all ages, there appeared to be a dose-dependent relationship between AAT and A1c-lowering: After one year, patients on 120 mg/kg AAT had a mean A1c of 6.7% vs. 7.8% with 60 mg/kg AAT and 8.2% with placebo. Moreover, a higher proportion of participants who received the higher dose of AAT reached A1c <7% (75%) vs. lower dose AAT (27%) and placebo (25%). Kamada must now decide whether to continue the development program for AAT in newly-diagnosed type 1s 12-years and up. While it’s difficult to imagine a business model for a future drug that’s only effective in such a narrow population, we do wonder if these business models will be rolled out over time, since Kamada’s candidate isn’t the only one to show efficacy in only a subgroup of type 1 diabetes patients.

• Findings from the TEDDY study, presented during a Saturday afternoon symposium, were similarly underwhelming. TEDDY aimed to identify environmental triggers of type 1 diabetes, and found that neither childhood GI infection nor maternal vitamin D or omega-3 supplementation were significantly correlated with onset of autoimmunity. The most intriguing observation was that having a second degree relative with type 2 diabetes delayed progression from autoimmunity to type 1 diabetes vs. those without a family history of type 2 (HR=0.61, 95% CI: 0.44-0.86, p=0.003). Our optimism for disease-modifying therapies is measured given our still incomplete understanding of type 1 pathogenesis and the practical limitations of a treatment that must be delivered in a short, specific window after diagnosis. To be sure, adjunct therapies for type 1 diabetes shined brighter at ADA compared to disease-modifying “cure” or prevention therapies (see above). In general, we see more short-term promise in adjunct therapies and technology (CGM, closed loop systems) when it comes to improving quality of life for people with type 1 diabetes. That said, the competitive landscape for type 1 cure and prevention approaches remains incredibly robust, and we’re so glad that researchers are fiercely committed to this endeavor. Indeed, Lilly and Novo Nordisk each recently announced expanded programs to develop beta cell encapsulation therapies, so the march will continue on for a strategy that effectively “cures” type 1 diabetes.

Growing Interest in Psychosocial Care for People with Diabetes; Call to Include Mental Health Providers on Diabetes Care Teams

• By our count, more than 20 abstracts at ADA 2018 addressed the psychosocial aspects of diabetes care, which continues a trend of increasing focus on distress and depression as diabetes complications. Last year’s Sci Sessions marked the first year the conference placed a specific emphasis on this topic, and we sensed deepened interest in 2018. On Friday, Dr. Mary de Groot (who co-authored the ADA Position Statement on Psychosocial Care) opened a symposium on mental health disorders and diabetes distress by describing the prevalence and severity of depression and anxiety in patients with diabetes. Dr. de Groot mentioned that one in four people with diabetes will have depression in their lifetime. She reviewed evidence establishing a definitive association between depression and poorer glycemic control, lower adherence, more complications, and higher mortality. It’s telling that Dr. de Groot – a veritable leader in this field – is still set to the task of discussing the existence of a diabetes/mental health link instead of possible solutions for the individual and for the entire patient population. This signals low awareness of these complications, despite efforts from ADA and others to expand knowledge. That said, at ADA 2017, Dr. de Groot presented results from Program ACTIVE II (n=150) to show that exercise and/or behavioral therapy helped improve symptoms of depression while also lowering A1c.

• Speakers also stressed that diabetes and depression have a bidirectional relationship – either one can pave the way for the other. To this point, Dr. de Groot referenced a 2013 study that found a hazard ratio of 1.43 (95% CI: 1.16-1.77) for diabetes predicting depression and a hazard ratio of 2.02 (95% CI: 1.80-2.27) for depression predicting diabetes; while this association is likely more correlative than causative, it’s an important relationship to unpack nonetheless. In a later talk on best practices for mental health management, Dr. Mark Williams cited a separate finding that diabetes increases relative risk of depression by 25%. He argued that diabetes and depression should be treated with some form of collaboration between PCPs and psychiatrists; with all the talk of multidisciplinary care teams, let’s not forget the importance of mental health providers on those teams. In the same session, Dr. John Newcomer addressed the use of antipsychotic medications and urged clinicians to be careful about which medications they prescribe. According to a 2017 meta-analysis, nearly all antipsychotics induce statistically significant weight gain – part of the reason that they have an FDA class warning for hyperglycemia and diabetes risk. Unfortunately, Dr. Newcomer commented that no new pharmacotherapies to manage antipsychotic-induced weight gain are coming in the foreseeable future, meaning that clinicians must instead focus on prioritizing lower risk medications and emphasizing prevention and intervention with their patients.

Inspiring Award Lectures Share Lens into the Future: A Better Understanding of Type 2 Diabetes Pathophysiology + Drugs That Target the Brain to Improve Metabolism

• As always, we were incredibly inspired by ADA’s lineup of award lectures. We discuss just a few examples here, and you can read about many more in our full conference report. Yale’s Dr. Gerald Shulman received the prestigious Banting Medal for Scientific Achievement, and his award lecture was a tour-de-force on the physiology of insulin resistance. He summarized a decades-long body of work into the following framework: Under circumstances of caloric imbalance, fat storage shifts from adipocytes to muscle and liver, leading to insulin resistance in all of these tissues. This insulin resistance interrupts two of insulin’s major effects: (i) direct action on liver cells to increase glycogen synthesis, and (ii) indirect action on adipocytes to decrease gluconeogenesis. The disruption of glycogen synthesis and the disinhibiting of gluconeogenesis spells increased glucose production, leading to hyperglycemia and eventually the development of type 2 diabetes. Dr. Shulman’s lab is currently exploring a liver-targeted mitochondrial uncoupling agent (still in preclinical development), which undoes these consequences of insulin resistance; phase 1 trials could begin soon. Dr. Mark Atkinson and Ms. Carol Atkinson received ADA’s Humanitarian Award for their tireless efforts to support the diabetes communities in Texas, Florida, Puerto Rico, and the Caribbean following hurricanes Harvey, Irma, and Maria. Ms. Atkinson and Dr. Atkinson respectively serve as the Director and President of the Board of Directors for Insulin for Life USA, a non-profit dedicated to providing diabetes medications and supplies to people with diabetes in the US and worldwide who lack access for a multitude of reasons ranging from natural disasters to financial limitations. They led emergency relief efforts to deliver an astounding >4,600 lbs of diabetes supplies to thousands in need. University of Aberdeen’s Dr. Lora Heisler won this year’s Outstanding Scientific Achievement Award, and in her lecture, she discussed the neurobiology of metabolic disease, positioning the brain as the next frontier of drug development for type 2 diabetes. Dr. Heisler has mapped the mechanism of action for obesity drugs D-fenfluramine (now discontinued due to CV side-effects) and lorcaserin (Arena/Eisai’s Belviq): Both agents mimic the action of serotonin on the 5HT-2C receptor in the brain, which then stimulates the release of α-MSH, which in turn binds to MC4R receptors, thereby activating the appetite-suppressing pro-opiomelanocortin pathway. Dr. Heisler contextualized that when her research career first began, the notion of drugs that act in the brain to improve metabolism was completely unheard of, and funding for research into this topic was hard to come by. Fast forward to today, and GLP-1 agonists (which have targets in both the brain and the gut) are all the rage for the treatment of diabetes and obesity, and the obesity drug competitive landscape abounds with neural-acting candidates like FGF-21 analogs, MetAP2 inhibitors, and MC4R agonists (which, like lorcaserin, act on the pro-opiomelanocortin pathway).

Diabetes Technology

Major New Devices Debut at ADA, Propelled by FDA and Accelerating Progress in CGM, AID, Apps, and Interoperability

• In a sign of diabetes technology’s accelerating pace, the FDA approved three major PMAs on the meeting’s eve: Medtronic’s MiniMed 670G pediatric indication (7-13 years), Senseonics’ Eversense 90-day implantable CGM, and Tandem’s Basal-IQ/Dexcom G6 (PLGS) – read coverage here, here, and here. One of those would have been a big day, but three in one day on the eve of ADA was truly remarkable! This complemented ADA debuts for DreaMed/Glooko’s Advisor Pro clinical decision support software (cleared a week before ADA), Insulet’s touchscreen Omnipod Dash touchscreen PDM (cleared in early June), Dexcom’s no-calibration G6 CGM (cleared in March), Medtronic’s Guardian Connect and Sugar.IQ app (approved in March), and of course Abbott’s FreeStyle Libre real-time (approved last September). To cap off the meeting with another approval on Monday, Medtronic announced a CE Mark for the MiniMed 670G/Guardian Sensor 3 in 7+ years, enabling the first hybrid closed loop launch outside the US in 10 EU countries this fall – and with pediatric approval from the start.

• Every diabetes device product theater we attended was absolutely packed at ADA, reflecting more interest than we’ve ever seen in diabetes technology. Companies are certainly raising their game, much to attendees delight – Insulet’s Omnipod Dash was widely cited as a terrific example of user-centric design, Dexcom’s G6 received praise for its strong no-calibration accuracy and new FDA iCGM pathway, Abbott’s FreeStyle Libre was frequently called a gamechanger among providers in attendance (especially related to cost and pharmacy access), Medtronic’s MiniMed 670G was lauded for delivering strong time-in-range (>70%) and securing a pediatric approval, and Senseonics’ Eversense and Tandem’s Basal-IQ were noted as excellent new options in AID and CGM.

• By any measure, the year-over-year progress in diabetes technology has been remarkable. At ADA 2017, there was only one standalone real-time CGM in the US (Dexcom G5); now there are four more with Abbott’s FreeStyle Libre real-time, Medtronic’s Guardian Connect, Senseonics’ Eversense, and Dexcom’s G6 entering the market! One year ago, there were zero factory-calibrated real-time CGMs in the US; now there are two with G6 and FreeStyle Libre. CGM interoperability was certainly of interest at ADA 2017, but there was no pathway besides the traditional, lengthy PMA route; this year, Dexcom marketed the first “integrated CGM” (G6) and Tandem showed why it matters with the unexpected early approval of Basal-IQ with G6 – the first iCGM-compatible pump and clear sign of things to come. We believe interoperability will increasingly become a key feature advantage, enabling companies to move faster, iterate more quickly, and integrate more seamlessly with the growing ecosystem of diabetes devices and apps. Korea-based SOOIL even announced plans to submit an open protocol pump to the FDA, hoping to commercialize a device tailored for the DIY community by ADA 2019. During the JDRF/NIH/HCT Closed-Loop Research night, Dr. Aaron Kowalski praised this move and shared strong enthusiasm for the non-profit’s Open Protocol initiative – this did not even exist at ADA 2017! As noted below, the DIY community had its strongest presence ever at ADA, and we fully expect the pace of technology to continue accelerating over the next year – particularly as the regulatory process becomes more streamlined with iCGM (and potentially iPump?), as FDA’s Digital Health PreCert program beta launches at the end of this year, as the DIY community pushes industry faster, and as more companies push innovation to software and move to consumer-grade hardware. Perhaps most of all, the higher level of competition will continue to drive the entire diabetes technology field forward!

Automated Insulin Delivery Commercial Progress from Medtronic, Insulet, Diabeloop, Tandem; Industry-DIY Start to Blend; Compelling Research from Cambridge Inpatient, McGill on Pramlintide, Bionic Pancreas

• In automated insulin delivery (AID), we saw progress on several commercial systems, alongside a greater presence for the DIY community and promising academic research on other hormones and populations. Highlights included Insulet’s Omnipod Horizon five-day hotel studies in 6+ years; Medtronic’s MiniMed 670G real-world data (including in former MDIs), a CE Mark, and a bold outcomes-based $25,000 guarantee for payers; FDA approval of Tandem’s Basal-IQ/Dexcom G6 PLGS system (launch in August) and the Control-IQ pivotal finally getting underway; and new Diabeloop data. Though Medtronic is still the only company to have an approved hybrid closed loop product on the market, momentum is certainly building for other companies’ products – even if they are quite a bit behind Medtronic. Though this ADA had no huge pivotal studies or long-term data, we expect to see much more by ADA 2019.     

  • Insulet presented three strong abstracts from five-day studies of the Omnipod Horizon hybrid closed loop in adults, adolescents, and pediatrics. The studies compared 96 hours of hybrid closed loop with a tablet computer and Dexcom G4 CGM to seven days of patients’ standard therapy. In adults, Horizon drove a robust +2.7 hour/day improvement in the range of 70-180 mg/dl (74% vs. 63%), a dramatic 63% reduction in time <70 mg/dl (-46 mins/day: 1.9% vs. 5.1%), and a one-hour per day reduction in time >250 mg/dl (-58 mins/day: 4.5% vs. 8.5%). In adolescents and pediatrics, the improvement was far more striking: impressive +3-4-hour/day improvements in time-in-range (!) and two-hour/day reductions in time >250 mg/dl, reflecting far more hyperglycemia in the younger age groups. Overnight outcomes looked similar or slightly better, depending on the group. In an encouraging sign for commercial use, Horizon users were in closed loop ~98% of time – and this was not even a commercial-ready platform. Insulet is being very methodical in the testing of its system, though the algorithm seems strong and the Omnipod’s tubeless form factor is unparalleled. We hope the company moves quickly to a pre-pivotal and to a pivotal (no timing shared). Presumably a ~2020 launch is still on track.

  • Medtronic presented a host of data describing MiniMed 670G’s US performance in the real world (100,000+ systems shipped in the US). The population-wide data have been positive enough for Medtronic to offer a bold $25,000 outcomes guarantee for payers. At the top of our list of real-world 670G outcomes were those in former MDI users (n=241). Relative to the pivotal trial and a bigger real-world 670G data set from 30,337 users, these 241 former MDI users had similar Auto Mode outcomes on the MiniMed 670G: 73% time-in-range (70-180 mg/dl), 2% time <70 mg/dl, and 25% time >180 mg/dl. The change from manual mode was also similar to the other groups: a +1.9 hour improvement in time-in-range (73% vs. 65%), no change in hypoglycemia, and an 8 mg/dl improvement in mean glucose. Notably, the MDI users spent 82% of the time in Auto Mode, slightly higher than the real-world users (79%) and closer to the pivotal’s 87%. Ideally, Medtronic would’ve also presented outcomes from the patients’ pre-670G MDI days – the transition we’re really interested in – though that would’ve admittedly been a much more difficult analysis to conduct.

    • In the biggest outcomes-based deal in pumps/CGM to date, Medtronic launched a 670G outcomes guarantee for payers: if there is a diabetes-related hospitalization or ER visit for a patient on the 670G, Medtronic will reimburse it up to a cap of $25,000 over a four-year period. Wow! We admire this move – the third public value-based contract for Medtronic Diabetes after deals with Aetna and UHC. This 670G guarantee shows Medtronic standing by its devices’ outcomes by putting its own money on the line! Will it put pressure on the rest of the field to propose similar arrangements? Will it change coverage dynamics in the US market? Will such guarantees become table stakes for competing in the future? Though 670G is on the market, Medtronic’s pipeline for improvements is moving slower than we expected even a year ago. Using payers as an additional battle ground could insulate 670G against competitive system with more compelling feature sets (e.g., auto bolusing in Tandem’s Control-IQ, no-fingersticks with Dexcom’s G6 integrated systems, potential smartphone control from Bigfoot and Insulet, etc.). 

    • Medtronic also finally announced CE Mark for the MiniMed 670G hybrid closed loop, with a launch to commence this fall in 10 European countries: Belgium, Denmark, Finland, Ireland, Italy, Netherlands, Spain, Sweden, Switzerland, and the UK. As noted above, it will launch with pediatric approval (7+ years) from the start.

  • Diabeloop 12-week home data (n=67) from a randomized crossover trial of its AID system (Cellnovo patch pump + Dexcom CGM + algorithm on handset) were very positive, with time in 70-180 mg/dl increasing by over two hours/day vs. open loop. Efficacy in the overnight period was very similar to that seen in the 24-hour data. Diabeloop still intends to obtain CE Mark and launch in France, the Netherlands, and Sweden in late 2018. Assuming it hits this goal, it is likely to be second to market OUS with hybrid closed loop, following the 670G.

  • Tandem’s Basal-IQ (predictive low glucose suspend) with Dexcom’s G6 received FDA approval the day before ADA started in users 6+ years. A US launch is expected in August, including a free software update for in-warranty t:slim X2 users. This will be the second approved AID system to launch in the US, following the 670G. Basal-IQ was not a major focus at this ADA or in Tandem’s booth, but we expect it will have a big presence at AADE.

    • Tandem didn’t have new data on its Control-IQ closed loop system (t:slim X2 + G6 + TypeZero) with auto correction boluses, but we learned that the pivotal opened enrollment as of June 21 - see the ClinicalTrials.gov post here. The plan is to enroll 168 participants, comparing six months of closed-loop to six months of sensor-augmented pump therapy (same devices, no automation). The study is expected to finish by “April 2019,” with a primary outcome of time-in-range and a remarkable number of secondary outcomes. As of two months ago, Tandem expected a rolling PMA submission in the second half of this year and a US launch in “1H19” – this is ambitious timing to be sure, though the precursor Basal-IQ has hit its timing with the added bonus of integrating with Dexcom’s G6 iCGM. Even if the timing slips, Tandem looks positioned to be second to market in the US with hybrid closed loop, and the first with a system that includes automatic bolusing.

• Brave moves from SOOIL Korea and Diabeloop to embrace and incorporate software from the OpenAPS community show how industry and the DIY movement don’t have to stand on opposite sides of the street. At DiabetesMine’s D-Data Exchange, SOOIL’s Mr. Justin Walker shared bold plans to submit the company’s smartphone-controlled Dana RS insulin pump to the FDA/CE Mark with an open communication protocol, and to also register a version of the open source OpenAPS algorithm. In other words, a pump tailored for the DIY community, which could radically change the innovation paradigm in the field. Meanwhile, Diabeloop will incorporate features inspired and at least partially designed by the OpenAPS community in its second-generation closed loop, expected to begin rolling out in early 2019. One of the modules, a fallback setting for when the patient is kicked out of closed loop, was “nearly copied and pasted” from OpenAPS, and the company would also like to include a variant of OpenAPS’ “eating soon” setting in the second-gen system. We will be keeping an eye on all of the regulatory questions that come with open protocol/DIY approaches: Will SOOIL actually do what it claims? Will it have to run a pivotal RCT with the OpenAPS algorithm running on its pump? Will the open protocol pump become a compelling feature that drives pump uptake? What if the OpenAPS algorithm is improved by a DIY developer on Github – could users of the SOOIL system adapt the updated algorithm? What kind of studies will needed to incorporate modes like “eating soon” into a commercial system (Diabeloop believes in silico simulation will be sufficient, at least in the EU)? Will other companies follow suit, leveraging and helping to scale the DIY community’s – presumably free – work?

• We also saw excellent academic research from the McGill (pramlintide + insulin), MGH/BU Bionic Pancreas (insulin-only vs. insulin/glucagon), Cambridge (inpatient fully closed loop in type 2s), and Harvard (MPC plus adaptive algorithms) groups. The work reflects an important academic community move to improve current hybrid closed loop with additional hormones, smarter algorithms, and new populations.

  • The JDRF-funded, 24-hour McGill study with the Class AP algorithm that Lilly has licensed, found bihormonal closed loop (insulin + pramlintide [amylin analog] infused in a fixed ratio) significantly boosted time-in-range to 86% vs. 74% with insulin alone (+3 hours/day). Notably, this improvement didn’t come at the expense of increased hypoglycemia or side effects, and was apparently driven by much-improved postprandial response. We thought this was among the most groundbreaking AID research at ADA – hopefully an amylin/insulin co-formulation will remain in the cards as a strong next-gen closed-loop addition!  

  • The Bionic Pancreas team presented head-to-head data comparing seven days of insulin-only closed loop to seven days of bihormonal (insulin/glucagon) closed loop to seven days of usual care. Bihormonal had a slight edge in the well-controlled study: mean glucose was 165 mg/dl on usual care, dropped to 148 mg/dl on insulin-only, and dropped further to 139 mg/dl on bihormonal. Similarly, time-in-range (70-180) was 60% on usual care, improving to 72% with insulin-only and up further to 79% with bihormonal. Median % time <54 mg/dl was very similar across the three arms and extremely low (<0.7% in all three arms). Overall, the Bionic Pancreas insulin-only outcomes look excellent and similar to other systems – with some potential user experience advantages around startup and meals – and the addition of glucagon seems to add a bit more efficacy and aggressiveness. (Of course, whether payers/patients will cover the cost of glucagon remains to be seen, but it is truly exciting to see the head-to-head research being done.)

  • The Cambridge closed loop group scored a major win at ADA, presenting positive fully automated inpatient type 2 closed loop data, which was simultaneously published in the NEJM. Overall, participants who received closed loop therapy (n=70) spent a significant 5.8 more hours in-range (100-180 mg/dl; 65.8% vs. 41.5%) and 6.2 fewer hours >180 mg/dl (23.6% vs. 49.5%) per day as compared to the control (n=66). Wow! We cannot wait to see closed loop make its way into the hospital.

  • Finally, a poster (Pinsker et al.) described the compelling results of Harvard’s eMPC (“enhanced MPC”) algorithm, set to be evaluated in protocol four of the IDCL as soon as 4Q18. The algorithm builds on a traditional MPC by adapting insulin response to the degree of confidence (“trust index”) it has in a certain action. With this additional software, n=15 participants saw time-in-range increase from ~75% on SAP to 88% on hybrid closed loop over a two-day study. Time <70 mg/dl was reduced five-fold, from 7.8% to 1.5%. Impressively, time-in-range was 88% both during the day and overnight, despite at least three meals per day with a minimum of 30 carbs/meal and one unannounced exercise session on the morning of day two. We look forward to the IDCL study to see if the trust index can maintain effectiveness over a longer time period, in the real-world, and in a bigger sample.

Moving from Beyond A1c Consensus to Validation, Headlined with TIR Data from DCCT

• The “Beyond A1c” movement has picked up tremendous momentum in just one year: from initial consensus on definitions at ADA 2017 to the start of validating CGM-based outcomes at this ADA! The headline presentation came from Jaeb’s masterful Dr. Roy Beck, who shared a never-before-seen time-in-range analysis of DCCT (seven-point fingerstick) data – it turns out that the correlation is very strong between time in 70-180 mg/dl and microvascular complications, a tremendous win in the fight to validate CGM metrics! Time in 70-180 mg/dl (>50%, 40%-50%, 30%-40%, <30%) had a stepwise correlation with retinopathy progression and development of microalbuminuria in the DCCT. Notably, each 10-percentage-point drop in time-in-range increased the hazard rate for retinopathy progression by 61% and for microalbuminuria by 53%. Side-by-side, the A1c and time-in-range graphs looked almost identical – wow! It is remarkable the correlation is this tight, given that seven-point daily fingersticks were only taken quarterly during DCCT (pre/post meals and pre-bedtime). If anything, Dr Beck pointed out, the correlation might be stronger with CGM, which would more accurately capture time-in-range after meals and overnight. We hope these data, once published (forthcoming), make a compelling case to regulators and payers that time-in-range endpoints are truly meaningful. And on a related note, that we do NOT need a modern-day DCCT to validate time-in-range.

• “Going Beyond A1c” mentions were the norm at ADA 2018, rather than an exception. About a year ago, we’d enthusiastically note any time a speaker referenced the importance of CGM endpoints, the limitations of A1c, the value of time-in-range and AGP, etc.; now, it is increasingly rare not to see such mentions, at least in device-related talks. (The diabetes therapy world is more A1c-centric, though drug presentations are increasingly sharing CGM data too – e.g., SGLT inhibitors in type 1 diabetes.) We saw Beyond-A1c talks from Dr. Rich Bergenstal (the new “GMI” calculator on Jaeb.org, replacing “estimated A1c” [eA1c]), Dr. Irl Hirsch’s group on misleading A1c’s (34% of patients in the study had discordant average glucoses not aligning with expected A1c), and even heard a mention from Dr. Helen Murphy on the limitations of A1c in pregnancy (while A1c levels vary predictably over the course of gestation in pregnant women with type 1 diabetes, mean blood glucose actually remains constant). Of course, all AID talks focused on time-in-range and related CGM endpoints, and several sub-analyses of CGM trials also highlighted A1c vs. CGM endpoints.

  • It’s not just researchers who have joined the beyond A1c movement – industry members are on board as well. For instance, Medtronic’s MiniMed 670G product theater emphasized the importance of time-in-range and the limitations of A1c, with Yale’s Dr. Jennifer Sherr and IDC’s Dr. Anders Carlson underscoring the value of time-in-range for both patients and providers. It’s a good sign to see industry promoting CGM-based outcomes – at the end of the day, a beyond-A1c climate would be more kind to their devices, systems, and apps (+ many drugs) than an A1c-centric one.

• It was highly encouraging to see the CGM consensus definitions widely used throughout ADA – 70-180 mg/dl for time-in-range, <70 and <54 for hypoglycemia, >180 and >250 for hyperglycemia, and coefficient of variation (SD divided by the mean). We also noticed emerging discussion of benchmarks, with many highlighting the MiniMed 670G pivotal trial’s >70% time-in-range as a goal to shoot for. Will benchmarking see more discussion in the next year, particularly as the validation movement expands? We think so, as it will be key for the field to define a clinically meaningful increase in time-in-range and reduction in hypoglycemia. Dr. Beck’s new DCCT/time-in-range data could certainly help on that front!

CGM as “Emerging Standard of Care,” and Not Just for Type 1s; Four CGMs Make ADA Debut; Convincing Professional CGM Outcomes as Use Cases Expand

• The absence of a major outcomes trial readout didn’t stop CGM from driving much of the technology advances (not to mention hallway buzz) at ADA – we wish we had counted how many times speakers framed CGM as the “standard of care” throughout the meeting. It was good timing too, as four – yes, four! – CGMs were making their ADA debuts: Dexcom G6, Abbott FreeStyle Libre real time, Senseonics Eversense, and Medtronic Guardian Connect. During the Q&A section of a Hypo-RESOLVE presentation, Sheffield’s Professor Simon Heller boldly forecasted that all type 1s will be on CGM in the next five years. (We think it will take longer, but doubling in the next five years certainly seems doable in the US and Europe.) Just three days earlier, Dr. Jim Chamberlain (St. Mark’s Diabetes Center) had predicted that CGM will replace BGM “completely” in the next five years, especially for those on intensive insulin therapy. Dr. Chamberlain’s comments were especially telling, given that they were directed towards primary care providers – as other thought leaders have continued to emphasize, integration of diabetes technology into primary care will be essential in truly expanding CGM penetration. Importantly, these sentiments were not exclusive to just those with type 1 diabetes – we heard stronger evidence on the value of CGM in pregnancy, in low-resource settings, and for type 2s, including those not on insulin. UW’s Dr. Irl Hirsch also described CGM as the “emerging standard of care” and underscored its relevance in type 1 diabetes, type 2 diabetes, and atypical diabetes. At a pre-conference event, he emphasized that his biggest surprise has been the value of CGM as a behavior change tool in type 2. We can’t wait to see this studied in a bigger way!

  • Of course, it’s also critical to remember that only ~0.5% of the world’s diagnosed diabetes population (by our estimate) currently wears CGM, and cost/reimbursement and integration into clinical practice will have to continue to improve in order for that number to increase drastically.

• We were very impressed by data demonstrating the value of professional CGM, especially in low-resource settings – we can’t recall ever seeing this much focus on outcomes and cost-effectiveness for clinic-owned CGM at a meeting! In particular, we were struck by an oral presentation detailing the successful implementation of an interim intervention technique (IIT) using Abbott’s FreeStyle Libre Pro in India. One HCP visit in the middle of a single 14-day blinded professional CGM session drove remarkable improvements in daily average glucose (from 191 to 137 mg/dl), time-in-range (+9 hours/day), time <70 mg/dl (-1 hour/day), and time >180 mg/dl (-8 hours/day) in 105 type 2 adults. These results show the incredible potential of “low-cost” intermittent CGM to change the lives of people with diabetes. (One FreeStyle Libre Pro costs ~$40, which is a non-trivial amount to many people around the world, but an amazing investment in long-term health if these intermittent-wear outcomes can be sustained.) On the opposite side of the spectrum, Dr. Rich Bergenstal et al. analyzed sequential FreeStyle Libre Pro use in the US, examining results from a first FreeStyle Libre Pro, and then a second, when the first and second were separated by ~five months. Results were encouraging, showing the intervention drove strong time-in-range improvements in high A1c users. Both studies reiterate what many in the field are beginning to accept: When used in a smart, intentional manner, CGM can be applied effectively for a variety of individuals in a variety of settings.

  • Henry Ford Health System’s highly-respected Ms. Davida Kruger described the profitability of professional CGM in her clinic. Reimbursement has long been a pain point for providers, so we are delighted to hear from multiple high-profile providers now that implementing CGM isn’t a money-losing proposition. Ms. Kruger’s clinic grossed ~$750,000 in annual revenue from >1,400 patients on professional and personal CGM – that in addition to how much more comfortable she felt treating her patients every day since she knew what exactly she should be treating. Similarly, at diaTribe/TCOYD’s Forum, we also heard from Dr. Carol Wysham, who will not see a new patient until they wear CGM at baseline – she wants the data available before the first visit. Wow! Of course, such integration requires some serious workflow modifications – how can other clinics learn from these successes to expand CGM access while keeping the bottom line in the black?

• We were very pleased to hear from numerous speakers that CGM is not just for adults with type 1 diabetes: Commentary held and outcomes showed that people with type 2 diabetes, adolescents/young-adults with diabetes, and pregnant type 1s can all benefit (and often in a cost-effective manner). Our very own Ms. Kelly Close echoed this sentiment Abbott-sponsored corporate symposium by asking what it would take to make CGM “the aspirin of diabetes.” Aspirin is widely-used in a very broad population, and it’s used in many different ways (for pain, CV protection, fever, swelling, etc.). Like with Aspirin, she argued, everyone with diabetes (and even prediabetes) could benefit from continuous glucose data at some point and in some form, it’s just about figuring out the right technology (e.g., type of sensor, level of automation), behavioral support (e.g., human coaching), and frequency/duration of use for each individual to maximize health and economic benefit.

  • The inimitable Drs. Anne Peters and Irl Hirsch shared fascinating CGM case studies during a pre-conference CGM workshop, emphasizing the benefits of CGM in type 2 diabetes. We were interested to hear from Dr. Peters that CGM benefits are “harder to show in trials,” especially in type 2s with less risks of lows. She also mentioned that there is little data on use of CGM in type 2s overall – how can we incentivize such studies so as to drive more robust clinical guidelines and recommendations?

  • Although adolescents and young adults are a traditionally tough-to-reach population, we saw encouraging RCT sub-analyses making a strong case for the efficacy of FreeStyle Libre in adolescents (13-17 year-olds; SELFY) and young adults (18-24 year-olds; IMPACT). Both populations achieved improvements in time-in-range, while teens also improved time >180 mg/dl and young adults also reduced time <70 mg/dl. FreeStyle Libre is still not yet approved for people under 18-years-old in the US, though management noted during the 1Q18 call’s Q&A that a pediatric claim was expected to be  filed with FDA before the end of the year.

  • If the compelling CONCEPTT RCT (CGM in type 1 pregnancy) data shared at EASD last summer weren’t convincing enough, Norwich Medical School’s Dr. Helen Murphy showed unpublished data denoting ~4.5 hours/day during which the CGM group had significantly lower glucose than the SMBG group. Even if the A1c advantage in the CGM group at 34 weeks (-0.2%) didn’t blow attendees away, 4.5 hours/day means a lot less fetal exposure to hyperglycemia! Moreover, she posited that use of CGM in pregnancy is likely to be cost-effective due to reduced neonatal hospital stay and fewer NICU admissions. If there’s anything we learned from the debate between Dr. Denice Feig and Dr. Elisabeth Mathiesen on CGM use in type 1 women during pregnancy, it’s that cost effectiveness may very well be the deciding factor for many providers and clinics. Dr. Feig noted that her team is currently investigating the cost effectiveness of CGM in pregnancy, but she believes that as more advanced, factory-calibrated CGMs come to market, CGM costs will only decline.

• Real-world data flooded ADA, continuing to demonstrate substantial improvements in glycemia with CGM use. Abbott’s FreeStyle Libre real-world data set has now reached an incredible 470,643 readers, amounting to 4.8 billion glucose readings, and the strong correlation between increased scanning frequency and decreased hypoglycemia continues to hold – a new analysis from ~238,000 of those readers showed that increased scanning also correlates with decreased glycemic variability. We also saw the first real-world data for Libre users in the US (n=7,979), suggesting that the consistently observed correlations in the EU between higher scanning frequency, lower mean glucose, and lower hypoglycemia, have safely arrived on American soil. Unpublished T1D Exchange data also demonstrated the A1c benefits of CGM in type 1 diabetes – we were especially impressed by the improvements achieved in children <13 years-old (0.9% lower A1c in CGM users than in non-CGM users). Importantly, this trend holds regardless of insulin delivery method. While all these improvements are undoubtedly heartening, we’re hoping penetration rises – T1D Exchange data shared last fall suggests CGM penetration in the US is at just 24%. We’re hopeful for expansion given that there are now four user-friendly, accurate CGMs are on the market, but there’s clearly much more work that needs to be done.

T2D Insulin Delivery Device RCTs (J&J One Touch Via, Insulet/Lilly U500 Omnipod) Positive Overall – A Good Omen for Market Adoption and Sustainable Businesses in T2D?

• ADA saw report-outs of two of the most highly-anticipated RCTs of novel insulin delivery devices for type 2 diabetes: J&J’s One Touch Via bolus-only insulin delivery device (formerly the Calibra Finesse) and Insulet/Lilly’s U500 Omnipod. We were shocked that One Touch Via didn’t drive greater A1c reductions than pens for type 2s starting on basal-bolus insulin therapy (-1.6% vs. -1.7%), but we believe the similar glycemic outcomes were in part due to the study’s design (more below), and there were highly encouraging preferences for One Touch Via expressed by both patients and providers. Plus, in real-world use, A1c reductions on that level with a device are quite rare to see! The U500 Omnipod did drive a greater A1c reduction than U500 MDI group (-1.27% vs. -0.85%), and with a much lower total daily dose (constant, whereas the MDI group went up by a concerning 50 units/day). This came at the expense of a slight increase in nocturnal hypoglycemia, though the absolute differences in events per year (~2-5) were tiny, and therefore not likely to be clinically significant. At the end of the day, the type 2 insulin delivery device/pump market is severely underpenetrated and high potential, though novel devices like Valeritas’s V-Go, Cequr’s PAQ, and One Touch Via have been slow to scale or even launch (V-Go is the only one on the market). We’d like to see many more type 2s with tubeless devices that make insulin more convenient and easier to use. Fully-featured pumps developed specifically for the type 2 population like Insulet/Lilly’s U500 and U200 Omnipods as well as BD’s “Swatch” patch pump should also help make a dent in outcomes and costs while retaining benefits like connectivity. The U500 Omnipod is expected to launch next year; we’ll wait for Insulet’s 2Q18 call for more specifics on FDA submission. One Touch Via’s future is still unclear in J&J’s hands – it is not part of the Platinum acquisition of LifeScan, and we believe this asset could fit in with many companies (e.g., BD, Insulet, Medtronic, Abbott, or even an insulin company who could prefill it). Given Via’s study outcomes and patient/HCP preferences, we think the real-world performance might be stronger than the RCT; we hope the device finds a future somewhere!

  • Though One Touch Via didn’t drive greater A1c reductions than the Novo Nordisk FlexPen, we are still very positive on the results for two reasons: (i) All enrollees used a pattern-based logbook, which combined SMBG values with a simple insulin adjustment algorithm, which may have confounded the study – the FlexPen group did far better than would be expected in real-world use; and (ii) Subjective reports from the full study population were almost invariably in favor of the OneTouch Via over the FlexPen, from both patients and providers – notably, 91% of providers preferred the One Touch Via over pens to advance type 2 patients from basal to basal-bolus insulin. That both patients and providers expressed such strong preference for Via is a likely sign that the device is less cumbersome, easier to use, more discrete, and easier to train than injections; even if it didn’t confer better glycemic outcomes, we suspect it would drive greater adherence (and by proxy, outcomes) in a real-world setting.

• The Cambridge closed loop group led by Dr. Roman Hovorka also presented compelling data from inpatient fully automated closed loop in type 2s. See the automated insulin delivery theme above for details.

New Era of Diabetes Apps? Decision Support, Decoding Data, Driving Glucose Prediction, Radically Convenient Coaching and Education

• Diabetes apps had a stronger presence at this ADA (in both orals and the exhibit hall), reflecting a shift to mobile software that will drive automatic data upload/analysis, remote monitoring, glucose prediction, decision support, and in-the-moment education. Our own Adam Brown summarized the state of the field in his presentation, Can Diabetes Apps Make Our Lives Easier? His slides, posted at diaTribe.org/Apps2018, have already been viewed nearly 500 times, reflecting plenty of interest in this still-young area – go download them if you are even vaguely interested in this area as he changed lots of minds on the arena. Adam highlighted two key bars for apps to cross – radically convenient tools and decision support aids – sharing more than 40 examples of diabetes apps that meet one or both bars. One of those, Medtronic/IBM Watson’s Sugar.IQ, had its formal launch at ADA, receiving the lion’s share of the Guardian Connect mobile CGM product theater. An oral on Sugar.IQ showed encouraging early launch data – +36 minutes/day in-range = 220 hours a year! – and we’ll be fascinated to see how much it can drive adoption of Medtronic’s standalone CGM. Medtronic plans to quickly follow (within the next year) with four-hour forward-looking hypoglycemia prediction, a widely anticipated feature. At Diabetes Mine’s D-Data Exchange, One Drop also announced plans to launch up to 12-hour forward-looking glucose prediction for type 2 non-insulin users (3Q18), a step into decision support for a population with very little data. Diabetes devices with companion apps are also becoming far more commonplace: Dexcom’s G6, Senseonics’ Eversense, and Insulet’s Omnipod Dash all launched at ADA, showcasing mobile apps that replace physical objects (CGM receivers) and/or capture data that previously required clunky desktop software and custom cables. While some providers remain overwhelmed at the thought of remote monitoring diabetes data, many seemed relieved at having any data to make decisions during appointments. On the diabetes education front, we were glad to see BD formally launch Briight, its AI chat and diabetes education app – see our complete review here. Plenty of coaching and remote care efforts – leveraging apps and connected devices – also shared new data at ADA, including Livongo, Onduo (Sanofi/Verily), Omada, One Drop, and Virta. None were huge outcomes studies of apps, but we were glad to see encouraging efficacy, engagement, and/or cost savings potential. Work is also refreshingly expanding on the food education front: (i) Ascensia’s diabetes challenge winner, Whisk, is an AI-driven food platform that will recommend foods and recipes based on blood glucose levels; and (ii) Medtronic launched an expanded partnership with Nutrino to link meal photos with professional iPro2 CGM responses in a one-page report.

Smart Pens/Pen Caps Inch Forward, Opening Up New Avenues of Research, and Informing Decision Support

• At ADA 2017, there was an impactful poster from Common Sensing, but no commercial movement from the smart pen landscape to speak of. This year, Companion Medical had its first ADA booth following US launch, Novo Nordisk showed off its NFC-enabled, reusable Novo Pen 6 in the exhibit hall, and we heard about lots of in-progress research. The field is still moving slower than we had hoped – arguably where CGM was about 3-4 years ago – but as the hardware and research gains momentum, we hope things show acceleration at future ADAs. Leaders in the field clearly recognize that pumps are not going to be a solution for everyone on insulin, and providers still have a significant gap in injection data that could be filled with smart pens. Though we only saw two possible dose capture form factors at ADA – durable pen and durable pen cap – we appreciate that numerous players are generating a wide variety of MDI dose capture options that will meet the needs of a variety of patient lifestyles. See our smart pen/cap competitive landscape.

  • Companion’s InPen (iOS only) has now been available in limited capacity in the US for ~six months, and the company celebrated the milestone with its first ADA booth. The booth showed off the new “Insights by InPen” reports, which we believe to be the first page in the US to show providers data from a smart pen in conjunction with an AGP-like glucose profile. We also learned that Companion has closed a Series C, and though it won’t comment on the size or investors yet, an SEC Form D filed on May 3^rd suggests that the total offering amount was ~$18.5 million.

  • At Novo Nordisk’s booth, tucked in a corner on the international side, we found the smart Novo Pen 6, which is currently piloting ~10 Swedish clinics (~1,000 patients) but now expected to expand “soon.” In its current form, the pen enables providers to upload insulin usage data to their Glooko/Diasend NFC pad within seconds, though we’d guess that Bluetooth communication is on the roadmap too. The pen’s dial also has a low-tech display on it, giving the size of the last dose and the time since the last dose.

  • Common Sensing’s smart Gocap pen cap is now being used by Good Measures’ diabetes management/coaching program, alongside a US beta launch and a pilot with One Drop and Innovation Health.

• There were just two exclusively smart pen/dose capture abstracts at ADA – both from the UVA, Stanford, Mt. Sinai group using NFC-enabled Novo Nordisk pens – but both give insight into the injection behavior of a well-managed group of type 1s. In one poster, over one in four meals had either a late or missed meal bolus, with 13% of total meals accompanied by a late bolus, and 14% of meals with no bolus whatsoever. Baseline A1c was provided, but there was a significant positive correlation between the number of missed meal boluses and A1c (there was no such correlation between late boluses and A1c). In the second poster, we were actually surprised to learn that the overall percent of pen injections that were primed was 80%. Percentage of missed prime doses did not correlate with A1c, but seemed to be more common with male gender and younger age. While these studies don’t necessarily give insight into the behavior of an entire population, they do show the power of injection dose capture, especially in tandem with CGM, as an educational tool. A provider will be able to assess patient’s dosing habits, and educate accordingly. As insulin companies assess their pipelines, we hope to see more investment in dose capture, data, and decision support – the outcomes potential could be just as big as improved new insulin formulations! 

• On day #1, we also saw a session dedicated to decision support, including new data and studies for type 1s on MDI. Through a ~four-week study of UVA’s decision support platform (with Dexcom CGM and Novo Nordisk connected pens), which included clinic-based meals and exercise, the system significantly improved a number of glucose parameters relative to standard of care: Primarily, coefficient of variation fell from 36% at baseline to 33% (34% -> 30% at mealtime), largely from less hypoglycemia, as time ≤70 mg/dl decreased by ~33 minutes per day (from 3.2% to 0.88%). In the study, the system recommended changes in therapy based on retrospective risk zones, adjusted boluses based on ratio of real-time insulin sensitivity to historical insulin sensitivity, and provided advice on how to handle exercise. OHSU’s Dr. Jessica Castle introduced the Helmsley Charitable Trust-funded, Jaeb-coordinated T1-DEXI pilot study. The pilot will enroll 60 individuals between ages 15-70 with type 1 diabetes, and collect one month of insulin, CGM, food, and physical activity data using Dexcom G5, DiabNext’s Clipsulin dose capture device (an unconventional choice), a Garmin activity tracker, and a custom app developed at OHSU for food photos and exercise logging. It will eventually inform a larger study of 300-500 subjects with a goal of building better exercise and food models for automated MDI titration. It is still early days for decision support for MDIs using dose capture, with no commercial products (apart from Companion’s bolus calculator). That said, this academic work, and especially pipeline systems from the likes of Lilly and Bigfoot, give us hope that many pen users will be able to benefit from closed loop-esque algorithms in the not-so-distant future.

Strong Remote Care Results for Prevention and Treatment of Type 2 Diabetes – Big Focus on Cost-Effectiveness

• ADA showcased a host of impressive data on remote care interventions, headlined by very strong results from Virta in prediabetes and Hygieia in a high-A1c type 2 insulin users. For the first time, we saw one-year data from Virta’s very-low-carb diet plus remote coaching in the prediabetes population: Of the 95 completers (82% retention), a staggering 61% moved from prediabetes to normoglycemia (A1c <5.7%) and not a single person progressed to type 2 diabetes. Moreover, body weight dropped an average of 29 lbs (11.5%) from baseline 111 kg (~245 lbs). These findings go along nicely with evidence from Virta’s controlled study in type 2 diabetes, which has demonstrated ~60% diabetes reversal (defined as an A1c <6.5% and elimination of all medications except metformin) at one year. Equally impressive was a Hygieia poster from its pilot with Blue Cross Blue Shield of Michigan (n=160 completers), demonstrating a remarkable 2.3% A1c drop at nine months from its insulin guidance service (specialty clinics + insulin titration + remote care + BGM). For individuals taking one or more expensive medication (GLP-1 agonists, DPP-4 inhibitors, SGLT- 2 inhibitors) at baseline, average prescription savings were $6,172 per patient-year. Across the entire population, prescription savings were $1,736 per patient-year – this notably doesn’t include savings from medical utilization.

• We also noted outcomes/cost-effectiveness posters from Omada, Livongo, and a 19-year telemedicine study from India! A Humana/Omada poster analyzed Medicare Advantage per member per month (PMPM) costs, finding that Omada’s 12-month digital diabetes program surprisingly didn’t impact total costs with statistical significance, though still drove cumulative savings of $1,298 per member (~$54 saved per member per month).  The authors note that pharmacy cost reductions typically precede medical cost reduction in this population, and propose that a longer-term follow-up may show more marked cost reductions. A separate poster showed that Omada’s intervention in a population of 107 employees greatly reduced prediabetes/diabetes prevalence. Meanwhile, a Livongo poster directly examining medical spending for Livongo users vs. matched non-Livongo users over 12 months. Intriguingly, the study found that a 10% increase in monthly Livongo usage rate was linked to a 2.1% decrease in medical spending, driven by a 2.9% reduction in spending on office-based services. Finally, the 19-year telemedicine intervention (n=414 type 2s) from Jothydev’s Diabetes and Research Centers – ~14.5 virtual consultations for education and medication titration plus ~two physical consultations per year – led to a 0.7% drop in A1c (baseline: 8.3%) and the prevention of vascular complications in a remarkable 94% of participants. There was no control or typical population data shared, but the results strike us as very positive, and more scalable than high-touch clinic-based care. 

• We expect to see digital diabetes care companies continue to take on more responsibility for patient outcomes, and payers/employers to gladly bring them on board to do so. In such an economy, companies will continue to compete on cost-effectiveness as much as they do on health and wellbeing outcomes. There was no data on the Diabeter approach– where a clinic takes on all aspects of and financial responsibility for a patient’s care – at ADA, though Medtronic has said it will look to expand the model into US type 2 clinics. How will this approach compare to that in which (i) payers contract with providers for narrow outcomes; and/or (ii) payers contract with exclusively-digital providers, but in-person care is delivered separately (e.g., Virta for diabetes reversal, Omada for weight loss, mySugr, Onduo, One Drop, etc.)?Will digital and in-person providers eventually have to merge, or at least collaborate, to optimally align incentives of care delivery?

GLP-1 Agonists

Oral Presentations: Updates from Type 2 Diabetes Trials

Superior Efficacy of Insulin Degludec/Liraglutide (IDegLira) vs. Insulin Glargine (IGlar U100) as Add-On to SGLT-2 Inhibitor ± Oral Antidiabetic Drug (OAD) Therapy in Patients with Type 2 Diabetes – DUAL IX Trial

Athena Philis-Tsimikas, MD (Scripps Diabetes Institute, San Diego, CA)

Novo Nordisk’s fixed-ratio basal insulin/GLP-1 agonist Xultophy (insulin degludec/liraglutide) offered superior glucose-lowering vs. insulin glargine (Sanofi’s Lantus) in insulin-naïve patients already on an SGLT-2 inhibitor, providing an additional 1.9% drop in A1c vs. 1.7% with Lantus (p<0.0001). This data from DUAL IX (24 weeks, n=420) was the subject of an oral presentation by Dr. Athena Philis-Tsimikas, and Novo Nordisk also published an announcement of these results on Saturday morning. Our obvious takeaway is that a 1.9% drop is better than a 1.7% drop but a 1.7% drop is just far better than nothing – we are surprised that the dual GLP-1/basal combo didn’t do better than Lantus alone though of course this is not “real life” but a randomized controlled trial. Mean A1c fell from a baseline 8.2% to 6.3% with Xultophy (-1.9%) and from 8.4% to 6.7% with Lantus (-1.7%). Both results are obviously very strong and we aren’t sure that the strongest case could be made not just to add Lantus given the difference in cost. While 85% of the Xultophy group achieved an A1c <7%, fully 71% of the Lantus group (OR=1.98, 95% CI: 1.17-3.34) did as well – again, both are very strong. Very notably, however, hypoglycemia and weight was where the rubber met the road - Xultophy was associated with a 58% lower rate of severe or confirmed symptomatic hypoglycemia vs. Lantus (0.37 events/patient-year vs. 0.90, 38 vs. 95 total events, p=0.0035), and the average total daily insulin dose was lower with Xultophy (36 units/day) compared to Lantus (54 units/day, p<0.0001 for comparison) – these differences seem bigger from our view, particularly the insulin dose in terms of cost alone! While mean body weight increased by ~4.4 lbs in the Lantus group (baseline ~191 lbs), it remained unchanged with Xultophy around baseline ~196 lbs (p<0.0001), reinforcing that the GLP-1 component of the combo balances out the undesirable effects of insulin. We point out that some studies in the DUAL program have shown Xultophy to reduce body weight (e.g. DUAL VII), but without a doubt, a weight neutral therapy is far preferable to a drug that causes weight gain. Dr. Philis-Tsimikas also presented a composite outcome, which she says gives a clearer picture of the overall benefit to patients: The proportion of participants achieving A1c <7% without hypoglycemia or weight gain was 42% in the Xultophy group and 17% in the Lantus group (OR=3.36, 95% CI: 2.09-5.41). A 9-point SMBG analysis showed that Xultophy lowers postprandial glucose more so than fasting plasma glucose in relation to Lantus. We find the overall package of DUAL IX data impressive. Insulin, despite its unwanted side-effects of weight gain and hypoglycemia, is a powerful glucose-lowering agent, and it’s noteworthy to see Xultophy match and surpass that glycemic efficacy with much milder side-effects. The background of SGLT-2 inhibitors also implies that these patients are already taking one potent anti-hyperglycemic drug, and makes the benefits of Xultophy all the more remarkable. At baseline, ~40% of patients were on AZ’s Farxiga, ~35% on Lilly/BI’s Jardiance, and ~30% on J&J’s Invokana.

• With these results, we gain valuable evidence that Xultophy can be safely added to an SGLT-2 inhibitor. Indeed, we’ve long been keen on GLP-1/SGLT-2 combination therapy, and the triple combination resulting from SGLT-2 + Xultophy could be a compelling choice for many patients seeking compounded glucose-lowering and even cardioprotection. Moreover, this study adds to the growing body of evidence supporting the efficacy and safety of SGLT-2/GLP-1 combinations, joining DURATION-8 and AWARD-10.

• In our opinion, Xultophy and Sanofi’s Soliqua (insulin glargine/lixisenatide) remain tragically underutilized. Many providers continue to view Xultophy and Soliqua as therapies reserved for those with more progressive diabetes, not considering them until patients are failing on oral therapies. So many patients are not meeting glucose targets and could seriously benefit from the impressive glucose-lowering efficacy and mild side-effect profile that Xultophy and Soliqua offer, and we think it’s an absolute shame that so few patients are on these – indeed, Dr. John Buse once called Xultophy “the most effective anti-hyperglycemic agent on the planet.” That said, we also understand that these products come with significant limitations in that patients and providers can’t choose which insulin and GLP-1 to combine or which ratio to dose them in, and the indications are fairly narrow and require patients to fail on a component therapy first. Moreover, Professor Philip Home has asserted that many diabetologists consider GLP-1 agonists a pre-insulin therapy, making their combination with insulin seem illogical. All this said, it does seem as if the tide could be turning: Xultophy sales rose 26% sequentially in 1Q18, and Novo Nordisk is asking FDA to add DEVOTE and LEADER data to the US label, which would be a big win. We’ll continue to keep a close eye on this groundbreaking class.

• DUAL IX underscores Xultophy’s value as a safer, more effective alternative to standard of care insulin therapy. DUAL V (n=557), presented at ADA 2015, compared Xultophy vs. Lantus in patients already on Lantus and metformin; in that trial, patients were either switched to Xultophy or intensified on Lantus. At 26 weeks, Xultophy gave a 1.8% drop in A1c vs. a 1.1% drop with intensified Lantus (p<0.001), also offering ~7 lbs of weight benefit vs. Lantus, a 57% drop in hypoglycemia, and an 83% reduction in nocturnal hypoglycemia. Also very notably, DUAL VII found that Xultophy was non-inferior to basal-bolus therapy with Lantus + NovoLog. Each regimen gave a mean 1.5% drop in A1c from a baseline of 8.2%, and Xultophy was associated with a significant 89% reduction in hypoglycemia vs. basal-bolus. With the convenience of a once-daily injection and a less severe side-effect profile vs. insulin, Xultophy is a very compelling therapeutic option, though we acknowledge that reimbursement for the fixed-ratio combination isn’t ideal.

Efficacy and Safety of an Expanded Dulaglutide Dose Range – A Phase 2, Placebo-Controlled Trial in T2D Patients on Metformin

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

Lilly recently initiated a phase 3 study (AWARD-11) of high-dose dulaglutide, and Dr. Juan Frias showed us why: He shared very positive phase 2 results on 3.0 mg and 4.5 mg doses of the GLP-1 agonist, which is currently formulated in 0.75 mg or 1.5 mg doses (branded Trulicity). Patients with type 2 diabetes and overweight/obesity (n=318) were randomized to placebo, 1.5 mg dulaglutide, 3.0 mg dulaglutide, or 4.5 mg dulaglutide once-weekly for 18 weeks. Dr. Frias emphasized the on-treatment analysis, which excluded data from individuals who required rescue therapy (n=263, i.e. 55 patients dropped out from the study or needed rescue medication). Within this cohort, A1c dropped by a mean 1.5% in both high-dose dulaglutide groups vs. 0.4% with placebo, giving an estimated treatment difference of ~1.0% (p<0.001). Baseline A1c was 8.1% across the board, and fell 1.2% in the 1.5 mg Trulicity arm – this is still meaningful glycemic efficacy, though it was smaller in magnitude than that of the higher doses. At week 18, 58% of participants in the 4.5 mg group achieved the ADA target of A1c <7% vs. 70% of the 3.0 mg group, 67% of the 1.5 mg group, and only 17% of the placebo group (all p<0.001 vs. placebo). We might expect the highest dose group to feature the greatest proportion of patients meeting A1c goal, but Dr. Frias explained that more people from this arm discontinued treatment, leading to the smaller percentage. There were 18 people who prematurely stopped treatment of 4.5 mg dulaglutide (24%), 10 who prematurely stopped 3.0 mg dulaglutide (13%), nine who stopped 1.5 mg dulaglutide (11%), and 11 who stopped placebo (13%). Dr. Frias added that the higher discontinuation rate isn’t a major cause for concern given the small sample size of a phase 2 trial. Nonetheless, this piqued our interest, and we’ll be keeping an eye out for any such trend in AWARD-11 data. Dr. Frias showed that adverse events were generally well-balanced across the four study arms, with some exceptions that he also attributed to small sample size. For example, 84% of participants on 3.0 mg dulaglutide experienced a treatment-emergent adverse event vs. 67% of the 1.5 mg cohort and 70% of the 4.5 mg cohort. GI symptoms occurred at similar frequency across dulaglutide groups (as expected, all higher rates vs. placebo). Nausea was slightly more common in the 4.5 mg arm (30%) vs. the 3.0 mg arm (24%) or 1.5 mg arm (22%), while diarrhea was most common in the 3.0 mg arm (23%) vs. 20% with 4.5 mg and 11% with 1.5 mg. Again, we’ll have to wait for phase 3 results for a clearer picture on safety, but nothing from phase 2 leads us to believe that higher doses of Lilly’s GLP-1 wouldn’t be worth the tradeoff of slightly more GI side-effects (which are typically mild, and subside over time) for greater glucose-lowering and weight loss efficacy. On this last point, Dr. Frias noted ~10 lbs weight loss with 4.5 mg dulaglutide, ~9 lbs with 3.0 mg, ~6 lbs with 1.5 mg, and ~4 lbs with placebo (baseline body weight ~202 lbs, all p<0.001 vs. placebo). In our view, the weight loss with GLP-1 agonists is just as if not more exciting as the glycemic efficacy, and we’d love to see this class of agents investigated and applied more in obesity.

• According to Dr. Frias, Lilly investigated dulaglutide doses of up to 12 mg/week before deciding that 1.5 mg/week would be optimal for Trulicity. The dose-finding study AWARD-5 was the determining factor. Researchers now believe that higher doses could provide additional benefit – on both glucose control and body weight – with an acceptable safety/tolerability profile. When Lilly management first added these investigational dulaglutide doses to the R&D pipeline, we suspected that they might be branded as a new product, much like Novo Nordisk markets high-dose liraglutide as Saxenda (for obesity) instead of Victoza (for type 2 diabetes). Based on Dr. Frias’ talk, we wonder if the higher doses could become new doses of Trulicity (especially because the company is still focused on type 2 diabetes rather than a distinct indication), and how the regulatory pathways would differ.

• Lilly issued a press release covering this new data on Saturday morning. The phase 3 AWARD-11 study is expected to complete in October 2019, per ClinicalTrials.gov.

• Dr. Jeff Emmick, VP of Product Development for Lilly Diabetes, expressed excitement about these phase 2 results. As he put it, “type 2 diabetes is progressive, and we are looking to offer choice to people who need additional blood sugar control beyond the two effective Trulicity doses already approved.” These comments make it seem more likely that Lilly plans to commercialize 3.0 mg and 4.5 mg dulaglutide as new doses of Trulicity, rather than as a distinct diabetes product (though this is still our speculation). Dr. Emmick continued, “the investigational Trulicity doses could offer adults with type 2 diabetes the option to advance treatment without having to change medication.” We imagine this continuity of care would be a meaningful win for patients.

Efficacy of Semaglutide vs. Dulaglutide across Baseline HbA1c in SUSTAIN 7

Richard Pratley, MD (Florida Hospital, Orlando, FL)

Dr. Richard Pratley discussed a new analysis of SUSTAIN 7 across baseline A1c subgroups, highlighting the consistent superiority of Novo Nordisk’s Ozempic (semaglutide) over Lilly’s Trulicity (dulaglutide). This head-to-head trial, sponsored by Novo Nordisk, was published earlier this year in the Lancet Diabetes & Endocrinology. The study (n=1,201) evaluated 0.5 mg semaglutide vs. 0.75 mg dulaglutide (the lower available doses) and compared 1.0 mg semaglutide vs. 1.5 mg dulaglutide (the higher available doses). Overall, there was a ~0.4% A1c treatment difference between the two weekly GLP-1s, and semaglutide offered ~double the weight loss in both comparisons. Dr. Pratley showed how semaglutide’s weight loss benefit was maintained regardless of a patient’s starting A1c, whether ≤7.5%, >7.5%-8.0%, >8.0%-8.5%, >8.5%-9.0%, or >9.0%. The p-value for interaction was >0.05, suggesting that Ozempic’s weight benefit was not driven by any particular baseline A1c subgroup. The p-value for interaction with A1c reduction was statistically significant (p=0.0179 for the low dose comparison, p=0.0257 for the high dose comparison), with Ozempic demonstrating a greater glycemic benefit at higher baseline A1c. In the subgroup with starting A1c >9.0%, A1c dropped 2.3% with 0.5 mg semaglutide vs. 1.5% with 0.75 mg dulaglutide (estimated treatment difference 0.8%), and 2.8% with 1.0 mg semaglutide vs. 2.1% with 1.5 mg dulaglutide (estimated treatment difference 0.7%). Meanwhile, among participants with starting A1c ≤7.5%, mean A1c decline was 1.0% with 0.5 mg Ozempic vs. 0.8% with 0.75 mg Trulicity (estimated treatment difference 0.2%), and 1.2% with 1.0 mg Ozempic vs. 0.9% with 1.5 mg Trulicity (estimated treatment difference 0.3%). Note the smaller estimated treatment differences in this latter example, and also that higher doses of GLP-1 were consistently stronger in A1c-lowering, as we’d expect. It makes sense to us that those with higher baseline A1c drove this particular result for semaglutide vs. dulaglutide (more room for A1c to fall, and for a more potent molecule to show its strength), and indeed, these are the patients who have the most to gain from a best-in-class GLP-1 agonist in the real world. Dr. Pratley’s presentation on the whole confirmed the robustness of evidence in SUSTAIN 7, and gave us even more reason to believe that Ozempic is an incredible addition to our diabetes treatment toolkit (this second-gen GLP-1 from Novo Nordisk was FDA-approved last December, launched in February). We’re particularly interested on the weight loss that comes with GLP-1 therapy as we know this is very important for patients, and we were struck by the fact that low-dose semaglutide stimulated more weight loss than high-dose dulaglutide across all baseline A1c cohorts.

• Dr. Pratley shared findings on the proportion of patients with baseline A1c >9.0% achieving target A1c <7.0% at the end of 40 weeks. As shown in the image below, 44% of those in this cohort given low-dose semaglutide reached A1c below 7.0% vs. 18% of those given low-dose dulaglutide (OR=3.50, 95% CI: 1.48-8.27); 55% of those taking high-dose semaglutide reached the recommended ADA target vs. 34% of those taking high-dose dulaglutide (OR=2.66, 95% CI: 1.15-6.19). Dr. Pratley further described how 41% of patients in this cohort taking 1.0 mg Ozempic achieved the AACE goal of A1c ≤6.5% vs. 20% of those taking 1.5 mg Trulicity (OR=2.85, 95% CI: 1.17-6.95). These confidence intervals are wide because of the small number of participants in each baseline A1c bracket, but we still found this data quite valuable in showing how Ozempic could help real-world patients improve outcomes with better hyperglycemia management. To be clear, we also see tremendous advantages to Trulicity, which is a highly-effective diabetes drug that comes in a very patient-friendly (and popular) autoinjector. We celebrate this expanded patient choice within the GLP-1 agonist class, this opportunity for more personalization of diabetes care.

• Turning to safety, Dr. Pratley assured that there was no significant difference in adverse event rates across subgroups, and he presented a table to support this claim. We noticed the absence of any information specific to retinopathy, and we’re curious whether this risk was exacerbated among patients with higher A1c to start. Thought leaders have attributed the retinopathy risk signal from SUSTAIN 6 (HR=1.76; 95% CI: 1.11-2.78; p=0.02) to “early worsening phenomenon,” wherein rapid A1c decline from a high baseline leads to a transient increase in retinopathy events. After all, semaglutide is an extremely potent glucose-lowering drug, and people experienced a steeper A1c decline with Ozempic in SUSTAIN 7 if they were in the >9.0% subgroup. There was no signal for retinopathy in the overall SUSTAIN 7 dataset (four events across two semaglutide arms vs. five events across two dulaglutide arms). Again, this is merely our curiosity, not a product of concern – we’re very positive on the risk/benefit profile of semaglutide and believe the retinopathy risk (if it exists at all) is manageable. Novo Nordisk has agreed to conduct a long-term retinopathy outcomes trial as part of European approval of Ozempic, and we’re hopeful that this study could put any lingering concerns to bed.

Select Questions and Answers

Q: Can you comment on the greater weight reduction seen with semaglutide and the proposed mechanisms for this?

A: This difference has been consistent across trials of semaglutide; it’s not limited to this particular trial. The general thinking is that it’s related to greater efficacy at the GLP-1 receptor, and perhaps differences seen here have to do with the size of the molecule. Semaglutide is smaller, and perhaps has more access to the nervous system than the larger dulaglutide.

More Subjects Achieved Composite Reductions ³1% A1c, ³5% Body Weight, and ³5 mmHg SBP with Semaglutide vs. Comparators (SUSTAIN 1-5, 7)

Kathleen Dungan, MD (Ohio State University, Columbus, OH)

Dr. Kathleen Dungan presented results from a post-hoc analysis of the SUSTAIN 1-5 and 7 trials demonstrating that participants treated with semaglutide were more likely to achieve a composite endpoint of (i) reduction in A1c ³1%; (ii) weight loss ³5%; (iii) and systolic blood pressure reduction ³5 mmHg. Across the studies included in the analysis, semaglutide was compared to placebo, a DPP-4 inhibitor (sitagliptin), two GLP-1 agonists (once-weekly dulaglutide and exenatide), and insulin glargine. SUSTAIN study features and baseline patient characteristics are summarized in the table below. In every SUSTAIN 1-5 and 7 study and across all comparators, significantly more patients in the semaglutide treatment arm(s) achieved the composite endpoint than in the comparator arm (p<0.001 for all comparisons). The percentage of semaglutide-treated patients who were able to achieve the composite endpoint range from 14% with the low dose of semaglutide in SUSTAIN 4 to 37% with the high dose of semaglutide as an add-on to basal insulin in SUSTAIN 5. For comparison, between 1%-12% of participants in active comparator groups were able to achieve the composite endpoint and only 2% of patients in the placebo arms were able to achieve the endpoint. These results offer further evidence that, in addition to potent A1c reduction, semaglutide offers improvements in outcomes beyond A1c, including body weight and CV risk factors. As a reminder, Novo Nordisk launched semaglutide as Ozempic to US pharmacies in February 2018.

	Comparator	N	Baseline A1c	Baseline Body Weight	Baseline Systolic Blood Pressure
SUSTAIN 1	Placebo	388	8.1%	91.9 kg (203 lbs)	129 mmHg
SUSTAIN 2	Januvia (sitagliptin)	1,231	8.1%	89.5 kg (197 lbs)	133 mmHg
SUSTAIN 3	Bydureon (exenatide once-weekly)	813	8.3%	95.8 kg (211 lbs)	134 mmHg
SUSTAIN 4	Lantus (insulin glargine)	1,089	8.2%	93.5 kg (206 lbs)	132 mmHg
SUSTAIN 5	Vs. placebo as an add-on to basal insulin	397	8.4%	91.7 kg (202 lbs)	135 mmHg
SUSTAIN 7	Trulicity (dulaglutide)	1,201	8.2%	95.2 kg (210 lbs)	133 mmHg

Durable HbA1c Reduction with Initial Combination Therapy with Metformin/Pioglitazone/Exenatide in Subjects with New-Onset Diabetes – Six-Year Follow-Up of the EDICT Study

Muhammad Abdul-Ghani, MD (University of Texas Health Science Center, San Antonio, TX)

EDICT investigators found continued efficacy of triple combination therapy (metformin + TZD pioglitazone + GLP-1 exenatide) out to six years, as we learned in Dr. Muhammad Abdul-Ghani’s oral presentation. Mean A1c remained astondingly low around 5.8% in the triple therapy group, but increased slightly in the conventional therapy arm to ~6.7% (p<0.0001). At three years, participants had reached A1c ~5.8% with triple therapy and ~6.5% with conventional treatment (p<0.0001), after starting with baseline A1c of 8.7%-8.8%. Recall that EDICT enrolled newly-diagnosed patients, so mean diabetes duration at baseline was only ~five months; baseline BMI was~36 kg/m² and participants were 46 years-old, on average. Dr. Abdul-Ghani reported a ~10-fold difference in hypoglycemia between the two treatment groups over six years, favoring the combination regimen (p<0.0001). He noted that at least 80% of participants in the triple therapy arm maintained A1c below the 6.5% target at the six-year mark vs. fewer than 50% of people receiving standard of care. This is a stark difference, pointing to early triple therapy as the more favorable approach to diabetes management, although we should mention that sample size had dwindled somewhat by year six. Dr. Abdul-Ghani estimated that between 30%-40% of the original participant pool (n=271) made it into the six-year analysis, and this detracts from the robustness of results. That’s not to say that we aren’t convinced of the advantages to early combination therapy, and in fact, we’d love to see more of this treatment approach in real clinical settings (related, we hope that payers make early combination regimens an affordable/accessible option). We do wonder whether metformin + pioglitazone + exenatide is the right combination, although answering that question will surely require much more research. At ENDO 2018, Yale’s Dr. Silvio Inzucchi referred to the EDICT trial as “so 1980s” because we now have more advanced diabetes drugs at our disposal, such as SGLT-2 inhibitors. Given limited real-world access to SGLT-2s, we still consider this analysis of metformin/TZD/GLP-1 very valuable (though as we understand it, the GLP-1 class is also plagued by poor reimbursement). Similarly, the criticism arose during Q&A that EDICT’s conventional treatment arm used ADA standards that are no longer relevant today (metformin, SUs, and insulin, whereas the ADA has recommended newer, safer therapies in its 2018 Standards of Care). We’d argue back that so many patients today are still only accessing metformin, sulfonylureas (with their associated weight gain and hypoglycemia risk and beta cell burnout), and insulin (and not necessarily insulin analogs). As we see it, EDICT contributes to the case for combination therapy in type 2 diabetes, and the insights won’t stop here. Dr. Abdul-Ghani shared that the EDICT group will next washout medications and observe response, and will conduct a baseline analysis to probe for factors that predict a particular response to a particular treatment.

Comparing Treatment Strategies for Patients with Very Elevated HbA1c – A Randomized Trial

Marconi Abreu, MD (UT Southwestern Medical Center, Dallas, TX)

Dr. Marconi Abreu presented a first-of-its-kind study that only included type 2 diabetes patients with very elevated A1c (>10%). Results showed that treatment with basal insulin + a GLP-1 agonist was superior to basal-bolus insulin in terms of A1c reduction, weight loss, hypoglycemia frequency, and quality of life. This is unsurprising to us and we’re surprised there is not more use of GLP-1 like this in the real world. The SIMPLE study (n=120) enrolled type 2s on background metformin with a mean baseline A1c of 12.1%. Participants were randomized to basal insulin + GLP-1 (Novo Nordisk’s Levemir + Victoza) or to a basal-bolus regimen (Levemir + NovoLog) for six months, at which point 62% of the former group had reached A1c <8% compared to only 41% of the latter group (p<0.05). The estimated treatment difference for A1c was 1% in favor of the GLP-1-containing approach (p=0.03). Dr. Abreu highlighted significantly greater weight loss with basal + GLP-1 as opposed to basal-bolus (estimated treatment difference ~8 lbs, p=0.001) and noted a lower proportion of patients on GLP-1 experiencing any hypoglycemia (35% vs. 66%, p<0.05). He also shared findings from the study’s quality of life assessments, and unsurprisingly, basal insulin + GLP-1 was superior to basal-bolus therapy on general health perception, treatment satisfaction, and fear of hypoglycemia – multiple important patient reported outcomes (PROs). We hear often that weight gain and hypoglycemia are hugely detrimental to patient quality of life, and it follows that a GLP-1 agonist like Victoza (liraglutide) would be associated with improved quality of life, given that it stimulates meaningful weight loss and doesn’t introduce excess hypo risk. Turning to adverse events, Dr. Abreu pointed to increased rates nausea and vomiting that occurred with GLP-1 treatment vs. without, but this was also expected; we note that most GLP-1 agonists are associated with mild to moderate GI discomfort that subsides over time. It’s encouraging to see clinical research like this being done with patient populations that have been understudied in the past, and we certainly see key potential for GLP-1 agonists to help those with very elevated A1c. Notably, AACE recommends starting patients on basal insulin right away if they have A1c above 9% with symptoms, and suggests prescribing a GLP-1 agonist or an SGLT-2 inhibitor alongside – it is of course shocking that the trial coordinators could even find 120 people with A1cs over 10 only on metformin. According to ADA’s 2018 Standards of Care, patients with an entry A1c >10% should immediately be put on a combination injectable – a fixed-ratio basal insulin/GLP-1 agonist (like Novo Nordisk’s Xultophy or Sanofi’s Soliqua). We’ll be keeping an eye on treatment guidelines to see if the recommendations for people with very high A1c evolve with additional clinical trial data, though it seems to us like the recommendations are already pretty solid and the challenge is getting access to GLP-1s or fixed-ratio combinations for these patients most in-need.

Oral Presentations: Hypoglycemia – Reducing the Risk

Effect of Combination Therapy with Liraglutide Plus Canagliflozin on HGP and A1c vs. Each Therapy Alone in T2D

Muhammad Abdul-Ghani, MD (University of Texas Health Science Center, San Antonio, TX)

Dr. Muhammad Abdul-Ghani discussed a small study (n=45) investigating one of our favorite potential combination therapies: GLP-1 + SGLT-2. Patients with type 2 diabetes were randomized to the higher dose of Novo Nordisk’s Victoza (liraglutide 1.8 mg), to the higher dose of J&J’s Invokana (canagliflozin 300 mg), or to a combination of both. After four months of treatment, combo therapy conferred more than additive weight loss – this was remarkable to see and makes us wonder ever the more why we even think about using monotherapy in diabetes. Body weight fell ~8 lbs from a baseline ~216 lbs in the canagliflozin group, fell ~4 lbs from a baseline ~213 lbs in the liraglutide group, and fell ~14 lbs (!) from a baseline ~217 lbs with both GLP-1 and SGLT-2 together. (If weight loss was exactly additive, we’d expect to see a ~12 lbs reduction in the combo group.) A1c reductions were less than additive, but were still greater with the combination (-1.9%) vs. either monotherapy (-1.1% with canagliflozin, -1.6% with liraglutide). Baseline A1c was pretty low at ~8.2%. Notably, these weight loss and A1c results match findings from DURATION-8 (n=695), AZ’s larger clinical trial evaluating Bydureon (exenatide) + Farxiga (dapagliflozin) co-administration. After seven months in DURATION-8, weight loss in the combination therapy arm (~8 lbs) was the sum of mean weight loss with standalone GLP-1 (~3 lbs) + standalone SGLT-2 (~5 lbs). Meanwhile, the effect on A1c was less than additive but was still statistically superior. Mean A1c drop was 2% in the combo arm, 1.6% in the exenatide arm, and 1.4% in the dapagliflozin arm, all from a baseline of 9.3%. So it seems that co-administration of a GLP-1 agonist and an SGLT-2 inhibitor could be a very effective intervention for patients in need of additional weight loss (and of course, the majority of patients with type 2 diabetes are looking to lose weight), even if the extra glycemic improvement is more marginal. We can see how the synergy of these agents confers at least additive weight loss, with the GLP-1 suppressing appetite and slowing gastric emptying while the SGLT-2 dramatically increases glycosuria. We’re curious about the potential for additive CV benefit as well, because by the same mechanistic logic, GLP-1 therapy could address atherosclerosis while SGLT-2 treatment protects against heart failure. The CV efficacy of GLP-1 + SGLT-2 co-administration has yet to be investigated in a rigorous RCT, but we’re certainly keen to see that study, and in the meantime, it’s reassuring to know that combination therapy across these drug classes is safe. ADA/EASD’s new draft consensus statement recommends prescribing GLP-1 alongside an SGLT-2 for certain patients who can access/afford it, and we’d love to see these advanced products reach more patient hands, as real-world use is eggregiosly low right now. According to a Diabetes Care article published last Fall, only 7% and 4% of US adults with type 2 diabetes have ever been prescribed a GLP-1 agonist or an SGLT-2 inhibitor, respectively – truly shameful in our view.

• Dr. Abdul-Ghani also spoke to the differential effects of GLP-1 and SGLT-2 on glucagon response. More specifically, GLP-1 agonists are known to inhibit glucagon secretion, while SGLT-2 inhibitors raise plasma glucagon concentration – Dr. John Buse has shared a word of caution around these opposing effects, although he co-chaired the ADA/EASD consensus writing committee that recommends this particular combination for patients above A1c target at high CV risk. In Dr. Abdul-Ghani’s 45-person trial, canagliflozin monotherapy increased hepatic glucagon production and thereby increased glucagon levels in the blood, as expected. Liraglutide monotherapy caused a small decrease in hepatic glucagon production and in plasma glucagon concentration. The glucagon response with canagliflozin + liraglutide together was somewhat surprising: Hepatic glucagon production rose ~15%, but there was no corresponding rise in plasma glucagon levels. Dr. Abdul-Ghani explained that there must be other mechanisms at play; our interest is piqued, and we hope to learn much more about glucagon response with GLP-1 vs. SGLT-2 vs. their combination going forward.

Select Questions and Answers

Professor Kamlesh Khunti (Leicester Diabetes Center, UK): In clinical practice, we wouldn’t usually use these two simultaneously, so can you comment on what you expect the benefits to be when GLP-1 and SGLT-2 are prescribed sequentially, in either order?

Dr. Abdul-Ghani: I’d be surprised if there were any major differences with sequential prescription. As you see here, this combination might be disappointing in terms of A1c reduction, however in terms of weight loss, it’s a very attractive combination especially for people with obesity. As for the glucagon response when you prescribe these sequentially, it’s difficult to speculate, because we have no data. I expect that giving an SGLT-2 on top of a GLP-1 would result in a small increase in glucagon. From this data, it seems that the decrease in glucagon is not that much of an important player.

Symposium: Exploring the Next Frontier in Diabetes Pharmacology

The Dual/Triple Peptides – Premise, Technologies, and Clinical Promise

Richard DiMarchi, PhD (Indiana University, Bloomington, IN)

GLP-1 agonists are a tremendous therapy class, offering profound glucose-lowering and weight loss, targeting multiple physiological defects that give rise to type 2 diabetes. But is this the finish line? Or, as the renowned and highly-respected Dr. Richard DiMarchi asked, “are we there yet?” Dr. DiMarchi discussed the promise of dual and triple agonists incorporating GLP-1 – including GLP-1/glucagon, GLP-1/GIP, and GLP-1/glucagon/GIP – which he positioned as the next generation of type 2 diabetes drugs. He also reviewed positive early research on the efficacy of FGF21 and leptin analogs. Dr. DiMarchi showed how GLP-1/glucagon dual agonism has consistently yielded superior results to GLP-1 agonism alone in preclinical models. He pointed out that this competitive landscape has grown rather robust in recent years, with Sanofi, Janssen, Merck, AZ/MedImmune, Zealand, Novo Nordisk, and many others all developing candidates. Several of these companies are targeting an obesity indication instead of type 2 diabetes, and we’re certainly excited about this potential to address the vast unmet need in obesity therapy. Dr. DiMarchi highlighted Sanofi’s SAR425899 for its “impressive weight loss results” in phase 2 (this data has yet to be peer-reviewed and published, so the most we’ve heard publicly came in CEO Mr. Olivier Brandicourt’s JPM remarks), although on the company’s 1Q18 earnings call management alluded to some tolerability issues related to a higher-than-expected GLP-1 effect. In our view, this doesn’t undercut the promise of this emerging therapy class, but it does underscore the need for a compelling safety/tolerability profile, because the next wave of diabetes treatment should make life easier for patients, reducing the daily burden of this chronic disease – that said, getting there may be more work, which is not a problem. Dr. DiMarchi also mentioned two positive phase 2 readouts on MedImmune’s GLP-1/glucagon dual agonist, which were presented earlier that morning at ADA; this candidate is also being investigated for NAFLD/NASH, another area of high unmet need and no approved therapeutic candidates to date. Turning to GLP-1/GIP dual agonists (click for the relatively less robust competitive landscape), Dr. DiMarchi launched into a description of synergistic mechanisms. If you give GIP as monotherapy, you run the risk of stimulating adipocytes, he explained, but in combination with GLP-1 this molecule drives greater glycemic improvements. Moreover, GIP is an endogenous incretin hormone, and restoring the response in type 2 diabetes can help “normalize” insulin production. Dr. DiMarchi concluded on a distinctly optimistic note, suggesting that “there are multiple ways to get to poly-agonism,” and that poly-agonism is going to offer “greater efficacy and hopefully greater safety” to patients.

• Notably, Dr. DiMarchi referred to the SCALE program for obesity drug Saxenda (liraglutide 3.0 mg) as “the end of the beginning,” and he applauded Novo Nordisk for its commitment to obesity as a therapeutic indication before anyone else was showing interest (presumably this excludes the smaller companies – Vivus, Orexigen, and Arena). We echo these kudos, and we’re hopeful that Novo Nordisk’s leading role in the obesity market will bring more attention and awareness to obesity as a chronic disease – we haven’t seen too much to date yet on this front. That said, the company is involved in multiple efforts to reduce stigma around obesity, as outlined at Capital Markets Day last year (changing people’s mindset with the ACTION study, increasing HCP engagement with the Rethink Obesity platform, and expanding patient access to care by supporting the Treat and Reduce Obesity Act). Saxenda captured ~73% of pooled obesity drug sales in 1Q18, and Novo Nordisk also has a robust obesity pipeline with semaglutide advancing into phase 3 this year and six phase 1/2 candidates.

Stretching It Out – Very-Long-Acting Agents and Implantable Technologies for Drug Delivery in Diabetes

Carlos Alvarez, PharmD (Texas Tech University, Lubbock, TX)

Dr. Carlos Alvarez shared his take on promising, long-acting drug delivery systems that he hopes will increase adherence – specifically, he touched on Intarcia’s ITCA 650 (implantable exenatide mini pump, providing GLP-1 therapy for three-six months continuously) and a new GLP-1 receptor antibody, Glutazumab. As background, Intarcia received a Complete Response Letter (CRL) for ITCA 650 in September 2017, and the company is now preparing to re-file the candidate with FDA (no timing for resubmission has been announced). While this was disappointing news, Dr. Alvarez was optimistic that ITCA 650 may reach the market in “the next year or so.” Presumably, this would mean FDA resubmission is right around the corner; we can’t be sure what the status is, but our sense is that it’s taking more work to put together a re-filing package than we originally anticipated. Nonetheless, we echo Dr. Alvarez’s enthusiasm for this candidate, which could make GLP-1 agonist treatment much easier and more adherence-friendly for people with diabetes. Intarcia CEO Mr. Kurt Graves has highlighted this adherence piece in conversations with our team. We’ve also heard that ITCA 650 won’t be distributed through PBMs, which could result in more attractive pricing for patients, more access.

• Dr. Alvarez also seemed excited about Glutazumab, a GLP-1 receptor monoclonal antibody being developed by Gmax Biopharm. The agent is in phase 2 studies in Australia and New Zealand. According to Gmax’s website, Glutazumab (or GMA 102) could overcome shortcomings of currently available GLP-1 agonists, namely that there’s some on-target toxicity. The humanized monoclonal antibody has a GLP-1 fragment attached, which could lessen on-target toxicity. According to Dr. Alvarez, Glutazumab showed comparable glucose control to dulaglutide (Lilly’s once-weekly GLP-1 agonist Trulicity) for slightly longer duration in a mouse model of diabetes. This is only preclinical data, but our interest is piqued for another approach to longer-lasting GLP-1 therapy.

• Dr. Alvarez mentioned microneedle patches, islet cell implantation, and thermally sensitive biopolymers as exciting drug delivery systems as well. He suggested that microneedle patches could (eventually) replace insulin injections, but noted that they are currently in early-stage clinical trials for a wide range of therapies. With respect to islet cell implantation, Dr. Alvarez focused primarily on ViaCyte’s PEC-Encap, a semipermeable encapsulation device that can house beta cells and prevent the need for chronic immunosuppression. He remarked that ViaCyte is working to downsize the PEC-Encap device to about the size of a quarter. Lastly, Dr. Alvarez stressed that thermally sensitive biopolymers and elastin-like polypeptides, which can be attached to small, short-acting peptides such as GLP-1s, have the potential to extend the dosing of these drugs for up to 6-12 months. Again, he acknowledged that these candidates are in the very early stages of clinical development.

Symposium: Prioritizing Injectable Therapies in Type 2 Diabetes

When Should Fixed-Ratio Basal Insulin/GLP-1 Agonist Combination Products be Considered?

Vivian Fonseca, MD (Tulane University, New Orleans, LA)

Tulane’s Dr. Vivian Fonseca suggested that fixed-ratio combination therapy with basal insulin/GLP-1 should be the first injectable drug used in type 2 diabetes – and he argued that FDA should update the Xultophy and Soliqua product labels to allow for this. Music to our ears – from his lips …!

Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s Soliqua (insulin glargine/lixisenatide) were both approved for the US market on the same day in November 2016. Here we are a year and a half later, and commercial uptake of these products has been disappointingly, remarkably low. Dr. Fonseca attributed this in part to the restrictive indications on both drugs: FDA stipulated that Xultophy can only be used after basal insulin or liraglutide (Victoza) in any given patient (very surprising), while Soliqua can only be used after basal insulin or lixisenatide (Adlyxin). This precludes fixed-ratio combination therapy from being used as a first injectable, it unnecessarily delays treatment intensification and exposes patients to more hyperglycemia (and possibly hypoglycemia), and it’s been especially challenging for the Soliqua franchise since standalone Adlyxin is prescribed so infrequently. Dr. Fonseca characterized this as a “limitation in the packet insert that creates issues in patient access” to fixed-ratio combination products, and he noted that there are already enough barriers to optimal diabetes care without this one. We’ll keep an eye out for the label updates Dr. Fonseca proposed, and in the meantime, we hope to see continued efforts from Novo Nordisk and Sanofi to educate providers about this new therapy class. Our sense is that many HCPs (and especially PCPs) aren’t entirely comfortable (read: many, at all) with the concept of a fixed-ratio combination, and we owe it to patients (and providers themselves!) to spread more awareness of medicines that profoundly lower A1c without weight gain or excess hypoglycemia risk. For more on basal insulin/GLP-1, see our coverage of DUAL IX results (Xultophy vs. Lantus) from earlier at ADA.

Symposium: Update on Diabetic Retinopathy Clinical Trials

Update on Retinopathy Outcomes in GLP-1 Trials

Wiley Chambers, MD (FDA, Silver Springs, MD)

FDA Deputy Director Dr. Wiley Chambers (Department of Transplant and Ophthalmology Products) argued that the retinopathy signal observed in SUSTAIN 6 for Novo Nordisk’s Ozempic (semaglutide) was based on poorly chosen and poorly defined endpoints. This signal is not necessarily cause for alarm, he asserted. An ophthalmologist by training, Dr. Chambers echoed and expanded upon the conclusions drawn by the independent group of ophthalmologists consulted by the FDA prior to the Advisory Committee meeting for semaglutide. SUSTAIN 6 examined three endpoints related to retinopathy: (i) need for retinal photocoagulation or treatment with intravitreal agents; (ii) vitreous hemorrhage; and (iii) onset of diabetes-related blindness (defined as Snellen visual acuity of 20/200 or less or visual field <20 degrees in the better eye with best correction possible). Dr. Chambers systematically described why each of these were inappropriate endpoints to evaluate retinopathy risk in the trial – this would be a big deal to come from any endocrinologist and especially one that works for the FDA!

• Regarding the first endpoint – need for retinal photocoagulation or treatment with intravitreal agents – Dr. Chambers pointed out that the SUSTAIN 6 protocol did not clearly define at which point these therapies would be considered necessary. Turning to the American Academy of Ophthalmology clinical guidelines, he noted that there’s some ambiguity in when these therapies are recommended for diabetic retinopathy. Further, the actual adjudication of this endpoint was based on whether or not participants received photocoagulation or intravitreal injection, not actually whether they needed it. Dr. Chambers emphasized that the clinical decision to actually provide therapy is influenced by a number of factors, including (i) expected decreased visual function associated with photocoagulation; (ii) risk of endophthalmitis associated with injection; (iii) economic cost to patient; and (iv) economic benefit to physician performing photocoagulation or delivering the injection. He further emphasized that the effect of these factors on whether or not someone who needs therapy actually receives it is magnified with the clinical practice guidelines are ambiguous, as they are in this case. We were reminded of Dr. Andrew Boulton’s commentary in reaction to the CANVAS amputation signal; he stressed that amputation is a “soft endpoint,” requiring active decision-making from patient and provider, and this parallels the “need” for retinal photocoagulation or intravitreal agents in SUSTAIN 6.

• Regarding the second retinopathy endpoint of vitreous hemorrhage, Dr. Chambers acknowledged that it’s an uncommon endpoint that can be bad, but that there’s a range of severity of the hemorrhage and the SUSTAIN 6 protocol did not clearly define a threshold for significance. He noted that vitreous hemorrhage can both clear on its own or persist, and the clinical significance of the two is not equal. Further, he pointed out that there was an imbalance in past history of vitreous hemorrhage at baseline in SUSTAIN 6, which may have confounded the results.

• Finally, and notably, Dr. Chambers asserted that the third retinopathy endpoint in SUSTAIN 6 – regarding diabetes-related blindness – was poorly chosen and defined. As it was written, the endpoint only evaluated visual acuity in the better eye, so a participant could be completely blind in one eye and not meet the endpoint. He further underscored that diabetes-related blindness is a rare event and that diabetes increases the rate of cataract progression that independently can cause a 20/200 visual acuity.

• Dr. Chambers emphasized that even if SUSTAIN 6 demonstrated an increased risk of retinopathy with more appropriate endpoints, he would not be unduly concerned about the safety of semaglutide. He stated that it’s well-known that rapid A1c reductions can cause an increase in events related to retinopathy in the first year. He highlighted the DCCT trial as the best example of this, in which retinopathy rates were higher in the intensive treatment group initially. Over seven-nine years, intensive A1c control was clearly better for microvascular outcomes including retinopathy. This came up at the semaglutide Advisory Committee meeting, and panelists referred to the transient increase in retinopathy events with dramatic A1c reduction as “early worsening phenomenon. “As ophthalmologists, we don’t get particularly concerned if we see a few more events early on because in the long term we know it’s in the patient’s best interest,” Dr. Chambers emphasized. Indeed, the independent group of ophthalmologists consulted by the FDA prior to the Advisory Committee meeting found no reason to restrict patient population or dose titration of semaglutide at all. While we were very reassured by this, we also think it’s too bad that the original drama and trauma had to appear.

• We’re reassured by Dr. Chambers remarks on the SUSTAIN 6 retinopathy results and by the ophthalmologist’s perspective he brings to this issue. While the signal should not be ignored, it certainly appears that semaglutide’s substantial benefits outweigh this possible risk. Moreover, any retinopathy risk can be managed with appropriate patient selection and screening strategies. While the retinopathy signal caused murmurs of discomfort in the audience when SUSTAIN 6 was presented at EASD 2016, most thought leaders have not seem particularly worried since then though at the time it did take some attention away from the notable results. Nonetheless, we appreciated Dr. Chambers’ clear, systemic, and reasoned approach to reassuring the diabetes providers in the room on this front, and it’s undoubtedly beyond valuable to hear this endorsement of semaglutide’s safety from an FDA employee.

• Dr. Chambers argued for a more rigorous approach to evaluating retinopathy in future trials using the Early Treatment Diabetic Retinopathy Scale (ETDRS). Going forward, he suggested that clinical trial protocols can call for photographs to be taken of both retinas – interestingly, Dr. Chambers noted that dilation would not even be required for this. The photographs can then be graded by an ophthalmologist or a reading center using the ETDRS scale and the retinopathy endpoint would be defined as a three-step change on the ETDRS.

Questions and Answers

Q: I’m not so comforted by your explanation of the GLP-1 data. If I look at the data carefully, I wonder about the decrease in A1c which you seem to suggest is the mechanism behind the retinopathy. The SGLT-2 inhibitors didn’t have that finding, unless they just didn’t look at retinopathy. Those also I think similarly decreased A1c levels. Also, DCCT actually came back after two to three years and your data was 100-some weeks and the curves were still parallel.

A: The first point I want to make from that trial is that those were not the right endpoints. That trial did not take photos so there was no way to grade retinopathy to get an accurate view of what the retinopathy actually was. We can’t base any conclusions on the endpoints measured. I would’ve expected more events and for the data to behave more like DCCT if they had chosen the right endpoints. I don’t know that for sure, but that’s my guess based on previous info.

Q: You haven’t addressed my question about SGLT-2 inhibitors.

A: It’s a matter of whether enough people had enough retinopathy in the trial to see a sufficient change. In some of the SGLT-2 inhibitor data I’ve looked at, I have seen similar large drops in A1c and similar increases in retinopathy. The data is not public, but I have seen consistent results.

Q: For GLP-1 agonists, are there any retina-specific effects that are known, such as receptors on the retina?

A: I don’t know. That doesn’t mean there aren’t any, but I’m not aware of it.

Symposium: The Intestine in the Regulation of Metabolism, Immunity, and Insulin Sensitivity

Enteroendocrine Functions of the Intestine

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

The highly-respected Dr. Daniel Drucker discussed some of GLP-1’s hidden talents beyond glucose regulation during this Saturday afternoon symposium. He explained that while the field has primarily focused for the past 20 years on GLP-1’s ability to stimulate insulin secretion, the peptide has a wide range of effects outside of the beta cells. For example, evidence shows that GLP-1 increases protein biosynthesis in the pancreas, markedly increases proliferation in the gut, and is a crucial part of the intestinal immune response. It essentially acts as a pathogen sensor that alerts the body when the barrier function of the intestine has broken down and the innate immune system needs to be activated. Unlike many other pathways, this response is highly conserved from mice to humans. There is also evidence to suggest that GLP-1 plays a role in regulating the gut microbiome, as mice missing a GLP-1 receptor have abnormal composition of their gut flora. Dr. Drucker also spent some time reviewing data on GLP-2’s role in regulating the microbiome and inhibiting gallbladder emptying. GLP-1 agonists are some of the most advanced therapies available for type 2 diabetes, but the drug class also stimulates profound weight loss (and is thus important for obesity care as well) and boasts potential in diabetes-adjacent indications like NASH (e.g., Novo Nordisk is investigating semaglutide in NASH). At this ADA, we even heard renewed promise for GLP-1 agonist liraglutide in type 1 diabetes (though Novo Nordisk management has no plans to pursue a type 1 indication for Victoza – it has said that it may do this for oral semaglutide and we could see a strong possibility that the type 1 results came out the way they did due to dosing decisions rather than anything else). Some researchers are interested in applying GLP-1 in Alzheimer’s. All this is to say that there could be untapped potential in GLP-1 agonists, and Dr. Drucker’s talk was inspiring to this end.

Questions and Answers

Q: Have you done a double knockout of GLP-1 and GLP-2?

A: You would think that if they have overlapping actions on gut barrier function that a double knockout would have profound phenotypes. We made that mouse about six years ago. It’s not published because our 379 experiments were amazingly normal. It baffles us why the individual knockouts have interesting phenotypes but the double knockout clearly has tremendous compensation.

Q: You mentioned all the key intestinal organs, but these compounds are secreted into the portal system. Are there effects on the liver?

A: We never see GLP-1 receptors in hepatocytes. If you download every RNA seq of hepatocytes, I don’t believe you ever detect the GLP-1 receptor in hepatocytes. It may come in through immune infiltration but I think it’s very rare. There are GLP-2 receptors in the liver but not in hepatocytes. We’re doing a lot of cell sorting and looking for it; it’s not very abundant but it is there. Any actions on the liver are almost certainly indirect.

Q: There’s a growing body of literature about the GLP-1 receptor on macrophages and endothelial cells in the context of atherosclerosis. Is there evidence of the receptor on resident macrophages of the intestine?

A: No, there is a growing body of evidence that there may be actions of these peptides on those cell types. We never find the receptor on macrophages or on the majority of endothelial cells. It is on some; the mouse lung is loaded with GLP-1 receptors, but the human lung is not. We have taken out almost every major blood vessel in the mouse and most endothelial cells and macrophages don’t express the receptor, so I would question the mechanism being reported.

Q: You said the GLP-1 receptor is expressed on intestinal lymphocytes. Is it also on other lymphocytes? What about in the adipose tissue where lymphocytes play a big role?

A: I can never exclude the possibility that somewhere the receptor pops up. We never see it outside the gut in lymphocytes. Every week when someone publishes another RNA seq, we just never see it outside the gut. Someone probably has data to refute that, but so far we don’t see it.

Product Theaters

Developments in GLP-1 Treatment Options for Adults with Type 2 Diabetes (Sponsored by Novo Nordisk)

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

Speaking to an absolutely packed room, Dr. James Gavin made the case that Novo Nordisk’s Ozempic (semaglutide) “consistently outperforms” comparators including placebo, DPP-4 inhibitors, and other GLP-1 agonists in terms of both A1c reduction and outcomes beyond A1c. Briefly reviewing the comprehensive SUSTAIN phase 3 clinical trial program, Dr. Gavin underscored that “it doesn’t matter which trial we look at, there is outperformance by both doses of Ozempic compared to comparators” in terms of glycemic reduction, achievement of A1c goal <7%, and weight loss. Dr. Gavin especially emphasized comparisons of Ozempic to other GLP-1 agonists and to DPP-4 inhibitors. He spent substantial time drilling down into the results of SUSTAIN 7, the head-to-head trial of Ozempic vs. Lilly’s once-weekly GLP-1 Trulicity (dulaglutide). While acknowledging that the study was not designed for this comparison, he pointed out that the low dose of Ozempic achieved comparable A1c-lowering to the high dose of Trulicity (we noticed something similar on weight loss as well). Next, Dr. Gavin gave the audience the option of voting to examine the SUSTAIN 2 (head-to-head comparison with Merck’s DPP-4 inhibitor Januvia) or the SUSTAIN 3 (head-to-head comparison with AZ’s GLP-1 agonist Bydureon) in more detail. The audience overwhelmingly voted for SUSTAIN 3, which speaks to the hunger amongst diabetes providers to learn more about the advanced GLP-1 agonist class in general. It’s clear that Novo Nordisk is trying to differentiate Ozempic as a potential best-in-class GLP-1 option, and all the SUSTAIN data certainly points in this direction. That said, we’re reminded of Dr. Ralph DeFronzo’s remarks at AACE just a couple months ago: “All of these drugs are fantastic, and all you need to do is make sure your patient is on one of them.” Despite findings from SUSTAIN 7, Trulicity is a phenomenal diabetes therapy that could help so many patients in the real world, and we shouldn’t lose sight of the class-wide benefits to GLP-1s as we interpret head-to-head data. Dr. DeFronzo suggested that which GLP-1 agonist to prescribe will most likely come down to a patient’s insurance rather than comparative efficacy. And being on any GLP-1 agonist is better than being on none of them.

• Regarding the safety warnings on the Ozempic label, Dr. Gavin repeatedly suggested that much of the risk can be mitigated by clinicians screening patients regularly and “doing more vigilantly those things that we should be doing anyway in routine follow-up.” On retinopathy, he argued that HCPs should be screening patients regularly for eye complications anyway and that being more cautious about using Ozempic in patients with a history of retinopathy can largely mitigate the risk. Similarly, regarding the acute kidney injury warning, Dr. Gavin emphasized that clinicians should be assessing patients’ renal function regularly anyway.

• Dr. Gavin also highlighted the surprising and highly intriguing SUSTAIN 6 results, which demonstrated an impressive statistically significant 26% reduction in three-point MACE (MI, stroke, and CV death) for Ozempic. That said, Dr. Gavin was careful to note that these results represent a “substantial demonstration of CV safety and no increased risk of MACE,” but did not make any claims toward a cardioprotective effect for the drug. Given the product theater setting, Dr. Gavin was prohibited from making any off-label comments, but it’s clear that SUSTAIN 6 is a highlight of the clinical trial program for Ozempic and to a certain extent, the data can compellingly speak for itself. Still, the value of having an indication for cardioprotection is indisputable in terms of spreading awareness to busy HCPs/patients, and we have our eyes and ears peeled for Novo Nordisk’s next moves on this front.

The Role of GLP-1 Receptor Agonist Therapy in Type 2 Diabetes Management (Sponsored by AZ)

Robert Busch, MD (Albany Medical College, NY)

Dr. Robert Busch presented a comprehensive overview of GLP-1 agonists, then focused specifically on AZ’s once-weekly Bydureon (exenatide) and on the new BCise autoinjector. He opened with the ominous octet and described how GLP-1 agonists target multiple pathophysiological defects in type 2 diabetes at low hypoglycemia risk. Dr. Busch emphasized the class’ efficacy in patients with dysfunctional beta cells and thus its utility late in the disease course. He walked attendees through the evolution of the once-weekly exenatide experience and recent microsphere technology: AZ’s Byetta, Bydureon single-dose tray, Bydureon dual chamber pen, and Bydureon BCise autoinjector. BCise was also a main focus of AZ’s exhibit hall booth at ADA, and we can’t emphasize enough how much easier it is for patients to use an autoinjector rather than a single-dose reconstitution kit or even the dual chamber pen (which still required a lengthy tapping and mixing process). We’re thus very excited about the new BCise offering, and we hope it stimulates Bydureon sales as the IDEO-designed Trulicity autoinjector did for Lilly’s GLP-1 franchise. Dr. Busch showed Bydureon’s safety and efficacy by summarizing DURATION trials. In addition, he displayed DURATION-NEO-1 data to highlight the advantages of Bydureon BCise in particular. He also demonstrated the “mix, unlock, and inject” steps of the product. In summary, Dr. Busch underscored Bydureon BCise’ efficacy and safety profile, noted its continuous-release microsphere technology as well as its additional weight loss benefit, and highlighted the product’s convenient design. Bydureon BCise recently received a positive CHMP opinion, and final EMA marketing authorization is expected in 2H18.

Posters

Effect and Safety of Oral Semaglutide Monotherapy in Type 2 Diabetes – PIONEER 1 Trial

VR Aroda, J Rosenstock, Y Terauchi, O Jeppesen, E Christiansen, CL Hertz, M Haluzik

Building on the topline results released in February, Novo Nordisk presented full data from PIONEER 1 (oral semaglutide vs. placebo) on a late-breaking poster. Adults with type 2 diabetes (n=703) started on either 3 mg oral semaglutide, were up-titrated to 7 mg or 14 mg over eight weeks, or were randomized to placebo. The total treatment duration was 26 weeks. In the on-treatment analysis, A1c declined by 0.8% in the 3 mg group, -1.3% in the 7 mg group, -1.5% in the 14 mg group, and only -0.1% in the placebo group, leading to estimated treatment differences of 0.7%, 1.2%, and 1.4%, respectively (all p<0.001). Baseline A1c was 7.9% (3 mg, placebo) or 8.0% (7 mg, 14 mg). Oral semaglutide stimulated very meaningful weight loss – ~4 lbs with the 3 mg dose, ~6 lbs with the 7 mg dose, and ~9 lbs with the 14 mg dose after just 26 weeks. Mean weight loss was ~3 lbs in the placebo group, leading to estimated treatment differences of 1 lb (non-significant p-value), ~3 lbs (p<0.05), and ~6 lbs (p<0.001). The decline in body weight started immediately and continued steadily over these 6+ months, without major plateauing, and we’ll be curious to see if the oral GLP-1 agonist confers even more weight loss with longer exposure time. Novo Nordisk is also exploring injectable semaglutide as an obesity drug, and we’re cautiously optimistic that an oral formulation could ultimately help many people with type 2 diabetes/obesity. Baseline body weight was ~194 lbs across PIONEER 1, which means patients on 14 mg oral semaglutide lost ~5% body weight on average (experts say 5%-10% weight loss is needed for metabolic benefits, though the obesity field is now striving to break through this threshold with drugs that offer 15%-20% weight loss). In addition, the poster mentions that 44% of people on 14 mg semaglutide experienced at least 5% weight loss vs. 16% of individuals taking placebo (p<0.001). The composite outcome of A1c <7% without weight gain or hypoglycemia was achieved by 73% of participants on high-dose semaglutide vs. 27% of those on placebo (p<0.001), and the composite of at least 1% A1c decline + at least 3% weight loss was seen in 54% and 11%, respectively (p<0.001). Fasting plasma glucose fell 12 mg/dl with the lowest dose of oral semaglutide, -27 mg/dl with the medium dose, and -37 mg/dl with the highest dose vs. +4 mg/dl with placebo (all p<0.001). Baseline fasting glucose was ~159 mg/dl. Lastly from the on-treatment principle, 59%, 72%, and 80% of semaglutide-treated patients (3 mg, 7 mg, and 14 mg, respectively) achieved A1c <7% after 26 weeks, while only 34% of placebo-treated patients reached this ADA-recommended target (all p<0.001 vs. placebo).

• Novo Nordisk management explained to us recently that FDA requires an intention-to-treat analysis wherein all patients are considered, even those who discontinued from the study or who used rescue medication. Participants in the placebo group are more likely to need rescue therapy, and including them thus mutes the apparent efficacy of the study drug. Presumably, excluding dropouts in the on-treatment analysis would have the opposite effect, amplifying the apparent efficacy of oral semaglutide, but the discontinuation rate in PIONEER 1 was about what’s expected for any GLP-1 agonist. Four people (2%), seven people (4%), and 13 people (7%) prematurely discontinued 3 mg, 7 mg, and 14 mg semaglutide, respectively, vs. four people (2%) from the placebo group. In PIONEER 4, 11% of individuals taking 14 mg semaglutide dropped out (this was a longer, 52-week study) vs. 9% of those taking injectable GLP-1 Victoza (liraglutide). Rates of GI side-effects, including nausea, vomiting, and diarrhea, were also as expected for a GLP-1 agonist (18%-31% of oral semaglutide patients vs. 17% of placebo patients). In any case, Novo Nordisk’s first-in-class oral GLP-1 met its primary endpoint within the intention-to-treat principle, in that all three doses showed superior A1c-lowering vs. placebo. We’ll be keeping our ear to the ground for more on these two different statistical approaches (intention-to-treat vs. on-treatment), listening for any clues as to which analysis non-FDA regulators will use.

• We’ve heard some speculation that the fasting requirements around oral semaglutide will impose undue burden on patients. As stated on the poster, PIONEER 1 participants were instructed to take their dose in a fasting state every morning and to refrain from eating for another 30 minutes thereafter. While this could be perceived as a nuisance by some patients, we think that many others will decide the glucose-lowering and weight loss are well worth it; plus, oral semaglutide is an appetite-suppressant, which could ease the post-dose fasting. Non-adherence to this protocol would undercut the efficacy of oral semaglutide. Based on the compelling efficacy data from PIONEER 1, we suspect adherence was fairly strong, but we’d love specific details on this. Moreover, since adherence is always lower outside the context of an RCT, we’ll be curious to see if Novo Nordisk invests in any support tools – digital or otherwise – to aid real-world engagement.

• Which dose(s) will Novo Nordisk choose for commercialization? Management has previously shared plans to submit an NDA for oral semaglutide in 2019. Apparently, the company used mathematical modeling to find an optimal dose of the oral GLP-1, settling on 14 mg once-daily. Given the higher rates of nausea and dropout associated with the higher dose, will Novo Nordisk opt for 7 mg instead, or for both? On the other hand, it’s important to note that glycemic improvements and weight loss were also greater in the higher dose group, and nausea is usually mild to moderate and tends to subside over time.

• The phase 3 PIONEER program for oral semaglutide features 10 trials in total. Four of these have reported topline data (1, 2, 4, and 7), and this late-breaker offered the first full PIONEER dataset. We look forward to many more readouts on oral semaglutide in the remainder of 2018 – it’s shaping up to be “the year of oral GLP-1.” We spoke to Dr. Todd Hobbs (Novo Nordisk's CMO in North America) about the PIONEER program, and he shared that he's most excited for the PIONEER 6 CVOT results, which will be informative for our clinical understanding of oral semaglutide as well as the company's commercialization efforts. To be sure, it's becoming increasingly difficult for a new diabetes drug to gain traction on the market without CV benefit, now that multiple GLP-1s and SGLT-2s have shown cardioprotection, and now that patients/providers are looking for more than A1c reduction from their pharmacotherapy.

• Dr. Hobbs affirmed that Novo Nordisk is committed to providing high-quality educational materials to help real-world patients adhere to the oral semaglutide fasting requirements. He acknowledged that participants in a clinical trial typically have more support in their diabetes management and overall health engagement vs. patients in the real world; to keep adherence rates strong so that oral semaglutide's efficacy is preserved outside of RCTs, he alluded to replicating support materials from the PIONEER program for the real world. He also emphasized that adherence to oral semaglutide in PIONEER 1 was as high as you'd expect for a GLP-1 agonist. And, he pointed to the longer duration of follow-up in PIONEER 3 (78 weeks), describing how participants were able to stick to their oral semaglutide regimen (dose timing/fasting) for a lengthy period of time.

Phase 3 PIONEER Program

Trial	Estimated Enrollment	Comparator/Design	Timeline
PIONEER 1	704	Placebo	Completed December 2017; Topline results announced February 2018; Full results coming on ADA poster (2-LB)
PIONEER 2	816	Lilly/BI’s Jardiance (empagliflozin)	Completed March 2018; Topline results announced May 2018
PIONEER 3	1,860	Merck’s Januvia (sitagliptin)	Completed March 2018, Topline results expected by June 30, 2018
PIONEER 4	711	Novo Nordisk’s Victoza (liraglutide)	Completed March 2018; Topline results announced June 2018
PIONEER 5	324	Moderate renal impairment	Expected to complete May 2018
PIONEER 6	3,176	CVOT	Expected to complete September 2018
PIONEER 7	504	Flexible dose escalation	Completed March 2019; Topline results announced June 2018
PIONEER 8	720	Insulin add-on	Expected to complete August 2018
PIONEER 9	230	Placebo and liraglutide in Japan	Expected to complete August 2018
PIONEER 10	336	Lilly’s Trulicity (dulaglutide) as an add-on to oral agents in Japan	Expected to complete July 2018

Patients with Type 2 Diabetes on the Maximum Dose of Insulin Degludec/Liraglutide (IDegLira) Achieve Glycemic Target: Analyses from the DUAL Program

L Meneghini, S Linjawi, P Serusclat, T Vilsbøll, B Agner, T Hansen, and L Leiter

According to this post-hoc analysis of Novo Nordisk’s DUAL program (I-V and VII), the subgroup of “sicker” patients who required titration to the maximum dose of Xultophy (50 units insulin degludec/1.8 mg liraglutide) still experienced better outcomes than healthier participants on placebo or comparator therapies. With the exception of DUAL VII (Xultophy vs. basal-bolus), all studies found that high-dose Xultophy led to a higher proportion of patients achieving an A1c <7% vs. placebo or an active comparator. In DUAL I, 74% of participants on max-dose Xultophy achieved an A1c <7% vs. 65% of patients taking Tresiba (insulin degludec) monotherapy and 61% taking Victoza (liraglutide) monotherapy; 87% of those taking a lower dose of Xultophy achieved A1c <7%. DUAL III-V tell a similar story, with participants on max-dose Xultophy achieving better outcomes than the comparator, but underperforming relative to their counterparts on a lower Xultophy dose. In DUAL III, 73% of participants on max-dose Xultophy achieved an A1c of <7% vs. 36% on Victoza monotherapy and 78% on low-dose Xultophy. In DUAL IV, 61% of participants on max-dose Xultophy reached target A1c vs. 29% on placebo and 82% on low-dose Xultophy. In DUAL V, 68% of people on max-dose Xultophy achieved target A1c vs. 47% on Lantus (insulin glargine) and 74% on low-dose Xultophy. Notably, in DUAL II, 63% of patients on max-dose Xultophy achieved target A1c – more than Tresiba monotherapy (23%) and even lower-dose Xultophy (55%). By contrast, 57% of max-dose Xultophy patients in DUAL VII achieved target A1c vs. 67% of patients randomized to basal-bolus therapy with Lantus and NovoLog and 71% of low-dose Xultophy patients. Despite the break from pattern with DUAL VII, this analysis as a whole speaks to Xultophy’s incredible potency as an anti-hyperglycemic agent. It’s heartening to see that people who require more aggressive diabetes therapy at baseline can still go on to see excellent outcomes. This poster illustrates the importance of abolishing the treat-to-fail paradigm in diabetes care so that more patients are put on a drug like Xultophy earlier in the course of disease progression. In fact, in a separate ADA talk, Dr. Vivian Fonseca argued that FDA should change the Xultophy and Soliqua (insulin glargine/lixisenatide) labels so that these fixed-ratio combinations can be used as a first injectable therapy instead of only as an intensification from basal insulin or GLP-1 monotherapy.

Renal Outcomes in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL)

MA Bethel, RJ Mentz, P Merrill, JB Buse, JC Chan, SG Goodman, N Iqbal, N Jakuboniene, BG Katona, Y Lokhnygina, RD Lopes, AP Maggioni, PK Ohman, NR Poulter, A Ramachandran, T Tankova, B Zinman, AF Hernandez, RR Holman

Following the presentation of primary EXSCEL results at EASD 2017, AZ followed up with an ADA poster displaying renal outcomes from the CVOT. The once-weekly GLP-1 agonist Bydureon (exenatide) showed compelling renal safety and hinted at efficacy, much like the drug showed compelling CV safety and possible CV benefit … more on this below. Patients on Bydureon saw a smaller margin of eGFR decline (~0.2 ml/min/1.73m² from a baseline ~78 ml/min/1.73m²) over the course of the trial compared to their counterparts on placebo, though this did not reach statistical significance (p=0.39). New-onset macroalbuminuria occurred in 2.2% of exenatide-treated patients vs. 2.5% of placebo patients (HR=0.84, 95% CI: 0.67-1.04, p=0.11). The composite endpoint of 40% reduction in eGFR, renal replacement therapy, or renal death occurred in 3.8% and 4.2% of participants, respectively, again trending in favor of Bydureon but not reaching statistical significance (HR=0.87, 95% CI: 0.73-1.04, p=0.13) in the population studied. Investigators did find a significant benefit to Bydureon on a second renal composite endpoint, comprised of 40% decline in eGFR, renal replacement therapy, renal death, or new-onset macroalbuminuria (relative risk reduction 15%, HR=0.85, 95% CI: 0.74-0.98, p=0.03).

• This renal data parallels CV data from EXSCEL, in that Bydureon has missed thresholds for statistical significance but shows some potential for efficacy. As a reminder, once-weekly exenatide was a razor-thin margin away from demonstrating CV efficacy in EXSCEL: The hazard ratio for three-point MACE (non-fatal MI, non-fatal stroke, CV death) was 0.93 (95% CI: 0.85-1.00, p<0.001 for non-inferiority, p=0.06 for superiority). Cardioprotection was evident in participants older than 65 (HR=0.80, 95% CI: 0.71-0.91), and we’d be curious to see renal outcomes in different EXSCEL subgroups as well. Several thought leaders have attributed EXSCEL’s neutral CV findings to its pragmatic trial design, and we think it’s likely that the large primary prevention cohort (“less sick” patients), lower adherence/higher dropout rate, and wide range of concomitant medications used in the placebo group all muted the appearance of CV benefit. Could the same be true for renal protective effects? This is a question at least worth asking, in our opinion, as the field continues to discuss class effects of GLP-1s (that said, we sense much more enthusiasm from thought leaders for the CV benefits of GLP-1 agonists rather than the renal benefits). For context, Novo Nordisk’s Victoza (liraglutide) reduced risk for adverse renal outcomes by 22% vs. placebo (HR=0.78, 95% CI: 0.67-0.92, p=0.003) in LEADER. In SUSTAIN 6, semaglutide (now branded as Ozempic) reduced nephropathy risk by 36% vs. placebo (HR=0.64, 95% CI: 0.46-0.88, p=0.005).

Patient-Reported Outcomes (PROs) for Insulin Degludec/Liraglutide (IDegLira) vs. Insulin Glargine (IGlar U100) as Add-On to Sodium-Glucose Co-Transporter-2 Inhibitor (SGLT2i) ± Oral Antidiabetic Drug (OAD) Therapy in Patients with Type 2 Diabetes (T2D) – DUAL IX Trial

M Brod, L Billings, R Busch, S Harris, C Portillo, R Sahay, A Busk, S Eggert, N Halladin, A Philis-Tsimikas

Dr. Athena Philis-Tsimikas announced safety/efficacy results from DUAL IX in an oral presentation, and this late-breaking poster provided more color on the study with patient-reported outcomes. Investigators measured PROs twice, once at baseline and again after 26 weeks of treatment, using the TRIM-D questionnaire (Treatment Related Impact Measure for Diabetes). Five domains were evaluated: (i) treatment burden; (ii) daily life; (iii) diabetes management; (iv) compliance (though we hate that word); and (v) psychological health. By the end of the study, participants randomized to Novo Nordisk’s Xultophy (insulin degludec/liraglutide fixed-ratio combination) reported a significantly greater improvement in treatment burden compared to their counterparts randomized to Sanofi’s Lantus (insulin glargine) – the estimated treatment difference was a score of 3.18 (95% CI: 0.12-6.24, p=0.0414). Xultophy was also associated with a greater jump in the diabetes management domain, with an estimated treatment difference of 7.27 (95% CI: 3.98-10.54, p<0.0001). TRIM-D score overall improved more so with Xultophy than with Lantus (ETD 2.78, 95% CI: 0.83-4.73, p=0.0052), although there was no significant between-group difference in the other domains. It makes sense to us that Xultophy would perform well on PROs, because it’s a much more convenient product to use compared to Lantus (or any basal insulin monotherapy), offering lower injection burden and milder side-effects and probably just more glee overall. For instance, there was no change in body weight in the DUAL IX Xultophy group whereas weight increased ~4.4 lbs in the Lantus group, and we know that weight effects have a profound influence on patients’ treatment satisfaction and quality of life. Notably, in other clinical trials such as DUAL VII, Xultophy has actually stimulated some weight loss (although a weight neutral therapy is still an important step above a drug that promotes weight gain). This poster concluded that Xultophy improves clinical outcomes as well as treatment management outcomes when compared to Lantus. We’re pleased but not particularly surprised to see these results, and we only wish that more real-world patients were accessing this product, because to-date commercial uptake of fixed-ratio basal/GLP-1 combos (also Sanofi’s Soliqua) has been disappointingly low.

Use of Big-Data Algorithms to Characterize Patients with T2D on Basal Insulin (BI) Who Add a Glucagon-Like Peptide-1 Receptor Agonist (GLP-1 RA) and Predict Their A1C Response

E Zimmermann, A Lenart, J Diogo, Da Rocha Fernandes, S Eggert, and M Ranthe

The authors of this fascinating Novo Nordisk poster mined large datasets of type 2 patients on basal insulin in the US, and found that the number one predictor of benefit from adding a GLP-1 agonist – defined as a ≥1% decrease in A1c – was baseline A1c. Of the 8,731 patients examined in the US IBM Explorys database, only 2,592 (~30%) “responded” to the addition of a GLP-1 agonist. The authors performed a logistic regression with 23 pre-specified variables followed by a hypothesis-free machine-learning model, finding A1c to be “the only important variable at baseline for predicting a ≥1% decline in A1c.” The first thing we’d say – a 1% A1c drop is a pretty high bar. Comorbidities, age, BMI, heart failure, co-medications, and “other cardiac disease” were not significant. Individuals with baseline A1c ≥10% had an ~83% chance of seeing a ≥1% A1c drop (OR: 4.98, 95% CI: 4.16-5.95); those with baseline A1c 9%-<10% had a ~71% chance of seeing a ≥1% A1c drop (OR: 2.48, 95% CI: 2.08-2.96); individuals with baseline A1c 8.5%-<9% had a ~62% chance of seeing a ≥1% A1c drop (OR: 1.61, 95% CI: 1.33-1.95); and lastly, those with baseline A1cs <7%-<8% all had <33% chance of response. In light of other GLP-1 data, these results are not entirely unexpected, because higher baseline A1c implies more room for A1c to fall – and GLP-1 agonists are incredibly potent anti-hyperglycemic agents. Importantly, the definition of “response” in this study was extremely narrow in our view, discounting other clinical benefits of GLP-1 agonism. Most notably, GLP-1s offer CV benefit completely independent of glucose-lowering. Even if chances of a large A1c response are low in individuals with A1c <8%, (i) the CV-protective effects of these drugs are well-documented; (ii) since they are glycemic-dependent, they could cut back on hypoglycemia while boosting time-in-range (understandably, CGM was not used in this analysis), and (iii) they induce very meaningful weight loss (high-dose liraglutide is even indicated for obesity, branded as Saxenda). With these other benefits factored in, we’re willing to bet that more than 30% of those taking GLP-1s on top of basal insulin could be classified as responders. Further, these results are from real-world use, and thus do not come without confounds – that is, what are the characteristics of individuals who are on basal insulin and have high A1cs? Do they have to ration doses due to coverage/economic concerns? Do they have providers who are hesitant to increase doses? Are they less likely to use CGM? Are they more likely to face food insecurity and have less access to safe areas (and time!) for exercise? All of these factors may also play into the prediction of who will be a responder (when using A1c as a criterion) to the addition of a GLP-1 agonist.

• The authors also looked into the people who were most likely to receive GLP-1 agonists on top of basal insulin in the real-world setting (n=80,019 type 2s on basal insulin who did or did not initiate GLP-1 therapy): length of time on basal insulin (>180 days), taking co-medications, private insurance, age (<75 years), and BMI (>30 kg/m²) were the top factors. In the real world, baseline A1c does not appear to be an input in the decision-making process for providers (8.2% in non-initiators, 8.7% in initiators). Ultimately, in appreciation of outcomes beyond A1c, we are glad to see that providers are not taking a very A1c-centric view – and while this poster is interesting and an impressive demonstration of big dataset analysis, we hope “response” continues to be defined more broadly than “sizable A1c reduction” by both payers and providers.

Treatment Effects of Once-Weekly Dulaglutide vs. Insulin Glargine in Patients with Different Baseline Glycemic Patterns (Based on High/Low Fasting or High/Low Prandial Glucose): A Post-Hoc Analysis of the AWARD-2 Clinical Trial

F Giorgino, M Yu, A Haupt, Z Milicevic, and LE Garcia-Perez

Dr. Francesco Giorgino led this post-hoc analysis of Lilly’s AWARD-2 trial (GLP-1 agonist Trulicity vs. basal insulin Lantus in type 2s), which found that dulaglutide’s benefits on glucose and body weight hold across subsets of patients with different glycemic patterns. Trulicity 1.5 mg (the higher of two available doses) produced statistically significant reductions in A1c vs. Lantus at one year for each glycemic subgroup: Low fasting glucose/low postprandial glucose (-0.6% vs. -0.2%, n=183); low fasting glucose/high postprandial glucose (-0.9% vs. -0.5%, n=57); high fasting glucose/low postprandial glucose (-1.0% vs. 0.5%, n=63); and high fasting glucose/high postprandial glucose (-1.4% vs. -0.9%, n=201). The poster displayed similar results for weight loss, always favoring Trulicity, as is to be expected from a potent GLP-1 agonist: Across all four subgroups, weight loss at one year ranged from ~3.5 lbs to 4 lbs with 1.5 mg Trulicity vs. ~1.5 lbs to 6 lbs gained with Lantus. We appreciated this additional insight into Trulicity’s clinical profile for different kinds of patients.

DURATION-8 Randomized Controlled Trial 104-Week Results – Once-Weekly Exenatide (ExQW) plus Once-Daily Dapagliflozin (DAPA) vs. ExQW or DAPA Alone

S Jabbour, C Guja, E Hardy, S Bhattacharya, P Ohman, J Frias

Two-year DURATION-8 results confirmed findings from 28 weeks and 52 weeks, showing stable benefits to GLP-1 + SGLT-2 co-administration vs. either treatment alone. According to this poster, 62% of participants initially enrolled in DURATION-8 (n=695) continued through two years (n=431). The trial randomized patients with type 2 diabetes and relatively high A1c (baseline 9.3%) to AZ’s GLP-1 agonist Bydureon (exenatide once-weekly), to AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin once-daily), or to a combination regimen of both. A1c declined by a mean 1.7% in the combination arm after 104 weeks vs. -1.3% in the exenatide only arm (p<0.01) and -1% in the dapagliflozin only arm (p<0.001). It’s quite notable from our view that GLP-1 + SGLT-2 co-administration maintained A1c >1.5% below baseline over two years. The weight loss results from this 104-week follow-up were interesting: from a baseline ~200 lbs, body weight dropped ~5.5 lbs with Bydureon + Farxiga therapy, falling only ~1.7 lbs with Bydureon alone (p<0.001) and actually falling numerically more (-6.6 lbs) with Farxiga alone, though this difference was not statistically significant. If anything, this speaks to the profound weight loss potential of SGLT-2 therapy, though we remain very excited about the promise of additive weight loss with GLP-1 + SGLT-2 combinations. As a reminder, in the initial 28-week readout from DURATION-8, weight loss was almost additive in the combo arm (~8 lbs weight loss with Bydureon + Farxiga vs. ~3.5 lbs with exenatide monotherapy and ~4.8 lbs with dapa monotherapy).

EXSCEL: Once-Weekly Exenatide Reduces Medical Resource Utilization in Patients with Type 2 Diabetes

SD Reed, Y Li, H Dakin, F Becker, J Leal, SM Gustavson, B Kartman, E Wittbrodt, RJ Mentz, N Pagidipati, MA Bethel, AM Gray, RR Holman, AF Hernandez

A new healthcare utilization analysis of EXSCEL found that treatment with AZ’s GLP-1 agonist Bydureon (exenatide once-weekly) led to a small but significant reduction in inpatient hospital stays: 7.05 days with Bydureon vs. 7.46 days with placebo (p=0.048). While the amount of time spent in the hospital was higher for placebo-treated vs. Bydureon-treated patients, overall rates of hospitalization were nearly equivalent between the two groups. The mean number of hospitalizations per patient over the course of the EXSCEL trial was also balanced across groups (0.83 with exenatide vs. 0.84 with placebo). Annual rates of hospitalization ranged from 0.24 to 0.29 hospitalizations per person-year from year #1 to year #5, and again there was no significant difference seen between groups. Bydureon-treated patients did have fewer outpatient visits to their usual diabetes care provider over the course of the study (mean 8.88 visits vs. 9.14 visits with placebo, p=0.048), though overall outpatient visits to other HCPs were balanced (12.19 visits vs. 11.78 visits, p=0.804). We would be interested to know how these small reductions in inpatient hospital stays and diabetes-related outpatient visits translate to potential cost-savings for the healthcare system (or even for the individual patient). Beyond monetary savings, we imagine there’s increased quality of life associated with even a small mean decrease in time spent in the hospital. Our curiosity is also piqued as to what is driving these reductions in medical resource utilization with Bydureon: Given the near-significant reduction in risk for three-point MACE (HR=0.91, 95% CI: 0.83-1.00, p=0.061 for superiority) with Bydureon in EXSCEL, we’d venture a guess that the lion’s share is attributable to a reduction in CV events, though this wasn’t specified in the analysis. Notably, renal outcomes data from EXSCEL was also presented on an ADA poster, and Bydureon narrowly missed statistical significance for renal protection. Our sense is that like other GLP-1 agonists, weekly exenatide is a powerful drug that could improve outcomes and quality of life for many people with diabetes, though the change in medical resource utilization was perhaps underwhelming in this one particular analysis.

Comparative Glycemic Effectiveness of Dulaglutide vs. Liraglutide and Exenatide QW in a US Real-World Setting

R Mody, Q Huang, M Yu, H Patel, R Zhao, M Grabner, L Lando

This poster displayed real-world data on 2,014 patients initiating one of three GLP-1 agonists, either Lilly’s Trulicity (dulaglutide once-weekly), Novo Nordisk’s Victoza (liraglutide once-daily), or AZ’s Bydureon (exenatide once-weekly). After one year, dulaglutide gave a significantly greater A1c drop (-1% from a baseline 8.8%) vs. liraglutide (-0.8% from a baseline 8.7%) when looking at matched pairs of participants (p<0.05). Glucose-lowering was also significantly better with dulaglutide vs. exenatide (-0.8% from a baseline 8.9%, p<0.05). Notably, all patients in this study on Bydureon were using the dual-chamber pen, and we wonder how the results might differ with AZ’s new autoinjector called Bydureon BCise. Patient feedback has been very positive for the IDEO-designed Trulicity autoinjector, and presumably, a more patient-friendly device will improve adherence and outcomes with Bydureon as well – though this remains to be seen in future data, whether real-world or from an RCT. This study also examined the effect of patient adherence to their GLP-1 treatments. Unsurprisingly, adherence was associated with significantly greater A1c decline after 12 months: In the dulaglutide vs. liraglutide cohort, A1c fell by a mean 1.3% among adherent patients (n=315) and by only 0.7% among non-adherent patients (n=270, p<0.001). Our minds immediately jumped to – which of these products was easiest for patients to adhere to? – but it appears that the proportion of adherent patients was about constant across all three GLP-1s. Data was gathered from the Healthcare Integrated Research Database.

Lixisenatide and Renal Outcomes in Patients with Type 2 Diabetes: A Post-Hoc Analysis of the ELIXA Trial

M Muskiet, L Tonneijck, Y Huang, M Liu, A Saremi, H Lambers Heerspink, D Van Rallte

A post-hoc analysis of Sanofi’s ELIXA CVOT revealed renal benefits to GLP-1 agonist Adlyxin (lixisenatide). Of the 6,068 participants enrolled (all with type 2 diabetes and a recent acute coronary event), 1,056 had microalbuminuria and 389 had macroalbuminuria. In these cohorts with baseline renal impairment, treatment with lixisenatide attenuated further changes in UACR (p=0.0505 for microalbuminuria and p=0.0084 for macroalbuminuria). The poster emphasized that these results were independent of changes in A1c. Lixisenatide had no significant renal effects for patients with normoalbuminuria at baseline. Our interest is piqued when it comes to GLP-1 agonists and renal protection, though we think it’s unlikely that Sanofi will take this on for standalone Adlyxin (at WCPD 2018, we heard a hint that Novo Nordisk might pursue a dedicated kidney outcomes study with semaglutide). After all, the company’s main priority for lixisenatide seems to be the fixed-ratio combination with insulin glargine (Soliqua). Nonetheless, CKD remains an area of astronomical unmet need, and it would be a major win for patients and providers if the field discovered independent renal protection with GLP-1 agonists (i.e. renal benefit unrelated to A1c-lowering).

Comparative Cardiovascular Effectiveness of SGLT-2 Inhibitors vs. Liraglutide in Routine Care

E Patorno, B Everett, S Schneeweiss, R Glynn, J Liu, and S Kim

Now that two classes of diabetes therapy are considered cardioprotective (GLP-1s and SGLT-2s), people are understandably curious to know how their CV effects differ. This retrospective cohort study found no significant difference in CV morbidity overall in type 2s treated with Novo Nordisk’s Victoza (liraglutide) vs. SGLT-2 inhibitors, though there was a significantly lower risk of hospitalization for heart failure in the SGLT-2 group. Following the results from LEADER, EMPA-REG OUTCOME, and CANVAS demonstrating CV benefits with these agents in an RCT setting, this analysis aimed to compare their effects on CV outcomes in real-world practice. The researchers followed a cohort of patients with type 2 diabetes from a US commercial healthcare dataset who initiated treatment with either Victoza (n=22,066) or an SGLT-2 (n=35,272) between April 2013 and September 2015. They used propensity score matching to create 17,203 pairs of patients with balanced baseline risk factors. After 30 months, there was no significant difference between the two groups in the incidence of the primary composite endpoint of MI, stroke, or hospitalization for heart failure (HR = 1.01, 95% CI: 0.76-1.34), nor was there a significant difference for the expanded composite endpoint (hospitalization for acute MI, unstable angina, ischemic or hemorrhagic stroke, or coronary revascularization) or for MI or stroke hospitalization individually. Notably, patients taking SGLT-2 inhibitors did face 32% lower risk for heart failure hospitalization compared to their counterparts on Victoza (HR = 0.68, 95% CI: 0.52-0.88), which falls in line with major CVOT findings – SGLT-2s have shown a distinct and profound heart failure benefit (enough to spark new outcomes trials investigating their use in chronic heart failure, outside the context of diabetes) while GLP-1s seem to exert their cardioprotection via anti-atherosclerotic effects. Results from this analysis were similar among patients with and without a history of CV disease (that is, secondary and primary prevention populations). This data suggests that there is no clinically meaningful difference in most of the CV benefits of Victoza vs. SGLT-2 inhibitors, but that the oral agents might be the preferred option for patients at risk of heart failure, specifically. Of note, we’ve heard from several thought leaders that they’d recommend GLP-1s for attacking atherosclerosis and SGLT-2s for addressing heart failure risk, if it comes down to this choice: Dr. Naveed Sattar endorsed this view at ESC 2017, Dr. Steven Marso suggested the same at this ADA, and the new ADA/EASD consensus statement for 2018 even makes this distinction between ischemic events and heart failure for choosing cardioprotective diabetes therapy. All this said, it’s worth pausing to note how wonderful it is that we’re even having this discussion – because we have not one, but two diabetes drug classes that help protect patients from adverse CV outcomes, and nobody would have dreamed of this even five years ago (before EMPA-REG was the first positive diabetes CVOT to read out).

Real-World Comparative Effectiveness, Treatment Patterns, and Costs in Type 2 Diabetes Mellitus (T2DM) Patients Initiated on Canagliflozin 300 mg (CANA) or a Glucagon-Like Peptide-1 Receptor Agonist (GLP-1)

M Singhal, H Tan, C Coleman, WH Herman, J Cai, M Han, M Ingham

This study found that type 2 diabetes patients initiated on J&J’s SGLT-2 inhibitor Invokana (canagliflozin) had similar A1c values, greater adherence, less discontinuation, and lower treatment costs compared to patients started on a GLP-1 agonist. This was a retrospective observational study based on administrative claims and laboratory data from the HealthCore Integrated Research Database, and it compared patients starting on Invokana (n=755) or a GLP-1 agonist (n=2,146) between April 1, 2013 and February 28, 2016. After 12 months follow-up, there was no significant difference in A1c change between these two groups, implying similar glucose-lowering efficacy from Invokana and GLP-1s. Patients on Invokana were less likely to achieve A1c <7% (27.1% vs. 30.4%), were equally likely to achieve A1c <8% (51.9% vs. 49.7%), and were more likely to achieve A1c <9% (69.4% vs. 61.9%). A greater proportion of patients were adherent to index medication over 12 months with Invokana vs. GLP-1s (47.5% vs. 37.5%, p<0.001). In addition, patients showed a lower likelihood of discontinuing Invokana therapy vs. GLP-1 therapy (49.6% vs. 57.4%, HR=0.78, 95% CI: 0.70-0.99). Regarding medication-related costs, continuous 12-month pharmacy expenses were $1,421 lower with Invokana vs. GLP-1s. Notably, this follows a similar real-world analysis published in March, which found that Invokana treatment would save $3,326 per patient per year compared to GLP-1 treatment; adherence was also markedly better with Invokana vs. GLP-1s in this previous study. What we take from this set of findings is that adherence is easier with SGLT-2 inhibitors (oral agents) vs. GLP-1 agonists (injectable agents) – not a surprising conclusion in and of itself, though it’s interesting to see how adherence translates into cost-savings for the patient and for the health system. Without a doubt, both of these therapy classes offer incredible benefits to patients, and both are vastly under-utilized today. We’ll be curious to see how cost and adherence differences might influence future guideline considerations; of note, the latest ADA/EASD consensus statement draft recommends both GLP-1s and SGLT-2s for cardioprotection, and differentiates between a class that’s more effective in counteracting atherosclerosis (GLP-1) and one that’s more effective in lowering heart failure risk (SGLT-2).

Corporate Symposium: Multi-Mechanistic, Insulin-Based Approaches for Achieving A1c/PPG Targets and Optimizing Safety in Challenging Patients with Type 2 Diabetes (Sponsored by Sanofi)

Physiologic Basis and Practical Rationale for Fixed-Ratio Insulin/GLP-1 Agonist Combinations

Vivian Fonseca, MD (Tulane University, New Orleans, LA)

Dr. Vivian Fonseca reviewed the rationale for fixed-ratio basal insulin/GLP-1 agonist combinations based on their complementary mechanisms of action and the inadequacy of the current sequential treatment approach to type 2 diabetes. He criticized the culture of clinical inertia that leads HCPs to fail to increase insulin doses and/or add new medications as the disease progresses. He argued that combination therapy with drugs that target multiple contributors to hyperglycemia is the most effective approach. Basal insulin/GLP-1 agonist combinations are an attractive option because they target both fasting and postprandial glucose without increasing the risk of hypoglycemia or causing weight gain, and the availability of fixed-ratio combinations simplifies medication regimen and decreases injection burden. Dr. Fonseca spoke multiple times about the merits of the basal/GLP-1 class at ADA 2018, even advocating that FDA change the product labels for Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s Soliqua (insulin glargine/lixisenatide) so that they can be prescribed as the first injectable in type 2 diabetes care, before insulin or GLP-1 monotherapy.

Advanced Basal Insulin Options and Improving Outcomes in T2D

Lawrence Blonde, MD (Ochsner Medical Center, New Orleans, LA)

Dr. Lawrence Blonde focused on the benefits of newer basal insulins, specifically Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (insulin glargine U300). He reviewed the BEGIN and SWITCH trials showing less hypoglycemia with Tresiba vs. Sanofi’s first-gen Lantus (insulin glargine) and the EDITION trials showing less hypoglycemia and weight gain with Toujeo compared to Lantus. He also discussed DELIVER D+ (presented as poster 1056-P), a retrospective cohort study of EMR data that found a significant reduction in overall hypoglycemia and hypoglycemia related to inpatient or ED encounters with Toujeo and a numerical but not significant reduction with Tresiba. Tying this back to the main theme of the corporate symposium, Dr. Blonde noted that despite improved options in basal insulin, many patients cannot reach their target A1c with basal insulin alone. He explained that adding a GLP-1 agonist can be a good option when additional basal titration is not working.

Questions and Answers

Dr. Vivian Fonseca: Both fixed-ratio combinations use U100 insulin. We have U200 degludec and U300 glargine. Do you think we will see combinations with these in the future? Should we be pushing for that?

Dr. Juan Frias: For IDegLira, degludec U100 and U200 have the same PK/PD profile, so it’s a non-issue. The question is about U300 glargine because it does have a different profile. My understanding is that with this clinical development, the timing wasn’t right. To my knowledge it’s not in development. I honestly don’t know, but the data looks very good with glargine U100, so it is what it is.

Dr. Blonde: The data shows that the biggest difference between U300 and U100 glargine is a modest reduction in hypoglycemia. Here we’re adding a GLP-1 agonist to U100 insulin and it mitigates hypoglycemia and shows significant improvements in A1c vs. U100 alone.

Dr. Pablo Mora: Real-world studies can’t control for everything completely. They can only attribute hypoglycemia to basal insulin, but you have to account for other risk factors like being elderly or having sulfonylureas on board.

Q: Would this patient Emmanuel [one of the case studies] be sent for a medical nutrition therapy consult?

Dr. Frias: Yes.

Dr. Fonseca: I send everyone to a nutritionist because I know so little about diet.

Q: What is the upper age limit for GLP-1 agonists?

Dr. Blonde: To me, age is less important than its accompaniments. I think age itself is not particularly serious; it’s whether you have comorbidities that might be an issue. I don’t have a specific age limit.

Dr. Mora: For example, liraglutide has been studied in people 65, 75 and older and been found to be safe.

Dr. Fonseca: I’ve developed a dislike for studies that call 65 elderly. It’s frailty, ability to inject, and renal insufficiency that are important.

Q: Do you use GLP-1 agonists in patients already on basal-bolus insulin?

Dr. Mora: Yes, there are even guidelines saying that it’s a far better choice to add a GLP-1 agonist to basal insulin than to add prandial insulin. We do add it for patients on basal-bolus therapy. That’s one way we “rescue” accumulated insulin. Very commonly, patients tend to be able to reduce their prandial and basal insulin.

Dr. Blonde: I’ve taken people on basal-bolus insulin and added a GLP-1 agonist and they were able to reduce their insulin.

Dr. Fonseca: I do a lot of this at the VA. For patients on basal-bolus who are poorly controlled, I add a weekly GLP-1 agonist. They’re already doing 28 injections a week, so I don’t want to add a fifth every day. I cut down their dose of prandial insulin. They lose lots of weight and many come off the prandial insulin; some remain on it.

Dr. Blonde: We may be able to do some switching to the co-formulation.

Dr. Fonseca: Some people may be on too high of an insulin dose

Dr. Frias: 28 shots a week is pretty bad.

Q: Do you add GLP-1 agonists to U500 insulin?

Dr. Fonseca: I don’t have many patients on U500 insulin. There’s no reason not to.

Dr. Mora: Five years ago I used to have far more patients who appeared to require U500 insulin. Maybe it’s just a perception, but the introduction of GLP-1 agonists and SGLT-2 inhibitors kind of forced us not to require concentrated insulin as often.

Q: Would you use Soliqua twice a day because of its short half-life?

Dr. Mora: There was always a concern that if you were to give lixisenatide alone, you would need to give it more than once a day. Based on the LixiLan-O trial, there was as much effect with the fixed-ratio combination given in the morning.

Dr. Frias: With lixisenatide, it didn’t make much difference to give it twice a day and there were more side-effects.

Q: How do you predict responders to this combination?

Dr. Fonseca: Not everyone responds to GLP-1 agonists. Everyone responds here because you have insulin.

Dr. Frias: With any medication, when you look at a clinical trial the results are the average values. That means half do worse and half do better. At the end of the day, there are probably some characteristics that predict response, but in my practice it’s hard to predict. Try something and monitor the patient. If it’s not working, change it.

Dr. Fonseca: They’re looking at glycated albumin as a biomarker for glucose control. That should be approved by the end of the year. Otherwise you’re waiting for the A1c in three months; here we’ll get an answer in two weeks.

Dr. Mora: My observation is that patients on GLP-1 agonists tend to fall into three categories. There are some people who are extremely sensitive, who start gagging when you put the pen in front of them. There’s another group that’s mildly sensitive that tends to do well. There’s also a group that’s very resistant, that need higher doses. There is some concept of resistance to GLP-1 agonists.

Q: I had a patient on Lantus on Humalog, 150 U/day, who switched to Xultophy 50 U once a day. Their A1c dropped from 9% to 7.2% and they had a fair amount of weight loss. How did that happen?

Dr. Blonde: They switched to a much simpler regimen.

Dr. Fonseca: It’s the simplicity. The patient probably wasn’t taking all four injections. I’ve had patients on those doses switch and have great responses. It spares lots of insulin.

Q: Why does insurance approve Xultophy and Victoza but not Saxenda?

Dr. Fonseca: Getting approval for weight loss is much more challenging. The maximum dose of liraglutide for glucose lowering is 1.8 mg. With Saxenda you get more weight loss but you don’t get more glycemic response.

Dr. Mora: They’re looking into whether there’s the same progression with semaglutide and dulaglutide.

Q: When would you choose semaglutide instead of a fixed-ratio combination? When you need to lose lots of weight?

Dr. Frias: That’s a good question. That could be a nice study to do, looking at the free combination with semaglutide vs. a fixed-ratio combination. Lots of the time it’s a matter of insurance coverage and convenience.

Dr. Blonde: It’s classic shared decision-making – here are the options, do you have a preference? (Editor’s note – assuming that their payer is flexible)

Dr. Frias: There were patients in both trials who reached the maximum dose. Most achieved their goal but some did not. There are situations where you start one of the combinations and reach the maximum dose and the patient is not under control. Then you can split the difference: keep titrating the insulin and use a GLP-1 agonist separately.

Dr. Mora: In terms of weight loss, there hasn’t been a head-to-head study. Once you achieve glycemic control, you have increased weight reduction at the full dose of semaglutide.

Q: Are these combinations safe in patients with CKD?

Dr. Frias: They haven’t been studied much in patients with a GFR <30. GLP-1 agonists don’t have a negative effect on the kidney, but if you have dysfunction you can get dehydrated and prerenal and have a problem.

Dr. Fonseca: There were a fair number of people on liraglutide in LEADER with CKD and they actually did very well.

Dr. Frias: I would be cautious with it, especially with a GFR <30.

Q: How does the price stack up?

Dr. Frias: I’m not sure. I would talk to a rep. There are usually good programs companies have for patient assistance. If the patient has insurance, there’s the advantage of having one copay instead of two. Right now there are programs to assist with copays. I don’t know what the exact price is.

Q: How come insulin levels go down with short-acting GLP-1 agonists and up with long-acting ones?

Dr. Mora: Since you decrease gastric emptying, you don’t need as much insulin secretion. It’s not necessarily an effect of decreased insulin action, there’s just less needed.

Q: Are oral GLP-1 agonists coming? Will anyone use injectables after that?

Dr. Frias: We’ll see the data. It’s looking good for oral semaglutide.

Dr. Blonde: No single medication is perfect for everyone. This is a great thing compared to when I started, when we were lucky to get two or three blood sugars a year and only had animal insulins and sulfonylureas. Now we have a plethora of agents that provide lots of options.

Dr. Fonseca: Until then, we have this and it’s very effective.

Corporate Symposium: Pointed Discussions – Clinical Conversations about Reducing CV Risks in Patients with Type 2 Diabetes Using Newer Options in Injectable Anti-Hyperglycemic Therapy (Sponsored by Novo Nordisk)

Treating Patients with T2D and High CV Risk with New and Existing Options in Injectable Anti-Hyperglycemic Therapy

Steven Marso, MD (HCA Midwest Health, Kansas City, KS)

Dr. Steven Marso advocated for GLP-1 agonists to address CV risk in patients with diabetes, and as this was an unbranded corporate symposium, he spoke to the benefits of all products in the class (not just Novo Nordisk’s Ozempic or Victoza). In fact, Dr. Marso suggested that he believes in a cardioprotective class effect for GLP-1s. As he put it, “EXSCEL was neutral if you’re a purist, but if you’re a pragmatist, it was more similar than different to LEADER.” We’ve heard similar commentary from several thought leaders (e.g. at WCTC 2017, Dr. Ralph DeFronzo called EXSCEL “probably positive,” and many have attributed the near-miss for statistically significant superiority to pragmatic trial design). A meta-analysis of GLP-1 CVOTs presented at IDF found class effects on three-point MACE, CV death, and all-cause death – see these results published online in the Lancet Diabetes & Endocrinology. Continuing his talk, Dr. Marso addressed the criticism that diabetes CVOTs have been enriched with a high-risk patient population, limiting their generalizability. Indeed, the study population in EXSCEL was “less sick” at baseline compared to the population in LEADER (for Victoza) or SUSTAIN 6 (for Ozempic), and this is one possible reason for diverging results (neutral in the case of EXSCEL vs. positive for LEADER and SUSTAIN 6). According to Dr. Marso, 47% of real-world type 2 diabetes patients in the US would qualify for participation in EXSCEL, 13% would qualify for LEADER, 12% for SUSTAIN 6, and 6% for ELIXA (for Sanofi’s Adlyxin). He underscored that >60% of real-world type 2s would be eligible for at least one of these trials. “Is this relevant to people you see in your clinic? The short answer is yes.”

• Dr. Marso also briefly touched on the correlation between hypoglycemia and MACE events. He pointed to one paper published last month in Diabetes Care which outlined the relationship between hypoglycemia and CV events in LEADER; Dr. Bernard Zinman presented these findings at ADA 2017, highlighting a six-fold increased risk for MACE in the seven days following an episode of severe hypoglycemia (HR=7.3, 95% CI: 1.8-29, p<0.05). This LEADER post-hoc illustrated that hypoglycemia is an independent CV risk factor (it did not interfere with liraglutide’s demonstrated CV benefits). We also saw post-hoc analyses of DEVOTE (for Novo Nordisk’s basal insulin Tresiba) at EASD 2017 linking glycemic variability and CV risk.

SGLT Inhibitors

Oral Presentations: SGLT2 Inhibitors – From Mechanisms to Clinical Trials

Canagliflozin and Cardiovascular (CV) Outcomes in Patients with Chronic Kidney Disease

Dick de Zeeuw, MD (University of Groningen, Netherlands)

A positive CANVAS post-hoc indicated that J&J’s SGLT-2 Invokana (canagliflozin) has similar CV and renal benefits regardless of a patient’s renal function at baseline, despite a smaller mean A1c reduction at lower eGFR. Dr. Dick de Zeeuw presented this analysis (n=10,142), which was simultaneously published in Circulation. He highlighted a lack of heterogeneity on CANVAS’ primary three-point MACE outcome (p=0.33) across four groups divided by baseline eGFR: <45 ml/min/1.73 m² (n=554, 6% of participants), 45-<60 ml/min/1.73 m² (n=1,485, 15%), 60-<90 ml/min/1.73 m² (n=5,625, 56%), and ≥90 ml/min/1.73 m² (n=2,476, 24%); ~21% of the CANVAS population had stage 3a or 3b CKD at baseline. In a primary endpoint analysis split at an eGFR of 60 ml/min/1.73 m² (i.e. CKD vs. no CKD), the interaction with three-point MACE was also non-significant (p=0.08). Interestingly, hazard ratios trended more positively in favor canagliflozin at lower eGFR, though CANVAS was not powered to detect differences within or between these groups. That said, we wouldn’t be surprised if patients who are “more sick” overall garner slightly more benefit from the cardioprotection associated with SGLT-2 inhibitors, simply because there’s more room for risk reduction. And, we’re seeing increasing emphasis in the diabetes field on how renal function is an independent risk factor for CV morbidity.

• Looking at components of the primary endpoint, no heterogeneity based on renal function was found for CV death (p=0.53 for both analyses) or MI (p=0.04 by CKD/no CKD and p=0.08 by CKD stage). The interaction with stroke was significant (p=0.01 for both), but (i) we know stroke events are relatively uncommon, reducing the power of this analysis and (ii) Dr. de Zeeuw noted that patients with worse renal function still trended toward benefitting more; he called this “possible heterogeneity.” There was no interaction on hospitalization for heart failure (p=0.20 for CKD/no CKD and p=0.62 by CKD stage) or the composite renal endpoint (p=0.28 for CKD/no CKD and p=0.59 by CKD stage). All of these results support that the benefits of Invokana on CV/renal outcomes are not blunted by reductions in renal function, nor are they driven by a particular subgroup of renal function. Furthermore, interaction p-values suggested no imbalance on key safety endpoints by CKD stage, including amputations (p=0.51), fractures (p=0.87), overall serious adverse events (p=0.30), adverse events leading to discontinuation (p=0.44), serious acute kidney injury (p=0.74), serious hyperkalemia (p=0.24), and serious renal-related adverse events (p=0.85). Results were consistent despite notable differences in baseline characteristics across CKD stages, including on baseline CV disease (73% in lowest eGFR group vs. 62% in highest eGFR group), albuminuria (56% vs. 25%), duration of diabetes (17 vs. 12 years), and age (69 vs. 59 years).

• These results highlighted the attenuation of glucose-lowering efficacy from Invokana in people with reduced renal function. From a 0.76% placebo-adjusted A1c drop in the ≥90 ml/min/1.73 m² group over the course of CANVAS, A1c-lowering efficacy was more than halved in the <45 ml/min/1.73 m² group to -0.35% (p<0.0001 for comparison). Placebo-adjusted A1c reductions were 0.45% and 0.57% in the middle two eGFR groups, indicating a direct and progressive relationship between eGFR and A1c reduction. This finding is more or less in line with what’d we expect: Given the mechanism of action of SGLT-2 inhibitors, glucose-lowering is less substantial in people with kidney dysfunction. Since Invokana is a partial SGLT-1 inhibitor, we wonder if glycemic efficacy is preserved more at lower eGFR compared to Jardiance (empagliflozin), Farxiga (dapagliflozin), or Steglatro (ertugliflozin). In any case, it’s positive that canagliflozin continues to protect against adverse CV outcomes despite less glucose-lowering – this reaffirms that the CV benefit in CANVAS was not driven by changes in A1c (but rather, is inherent to the molecule), and it raises exciting possibilities about SGLT-2 as CV or renal medicine independent of diabetes.

  • FDA currently recommends against using Invokana in patients with an eGFR below 45 ml/min/1.73 m² (only the lower 100 mg dose is recommended below 60 ml/min/1.73 m²). Farxiga and Steglatro are not recommended in those with eGFR <60 ml/min/1.73 m², nor is Jardiance below 45 ml/min/1.73 m². Importantly, these recommendations have everything to do with declining glycemic efficacy, rather than a particular safety signal, but thought leaders have expressed hope that SGLT-2 inhibitors could still be used below these thresholds specifically for CV/renal protection (again, thinking about hard outcomes independent of A1c). At ESC 2017, for instance, Dr. David Fitchett postulated 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.

• These results bode well for J&J’s CREDENCE trial, which has a composite primary endpoint of end-stage renal disease, doubling of serum creatinine, and renal or CV death and has enrolled patients with type 2 diabetes and an eGFR ≥30 to <90 ml/min/1.73 m² (expected to complete in June 2019). In CANVAS, canagliflozin was associated with an impressive 40% relative risk reduction (HR=0.60, 95% CI: 0.47-0.77) for the renal composite endpoint of 40% reduction in eGFR, end-stage renal disease, or renal death; combined with other positive renal results, this effect pointed to the possibility of significant renal protection with Invokana. It’s hard to overstate the potential implications here: Kidney disease (particularly end-stage) remains a tremendous area of unmet need in diabetes, and there’s an enormously high cost to both patients and the health system associated with dialysis. HCPs lack any tools beyond intensive glycemic and blood pressure control to stem progression of kidney disease, making SGLT-2s and also GLP-1s all the more exciting. CANVAS even saw a 70% increase in regression of albuminuria with canagliflozin vs. placebo (HR=1.70, 95% CI: 1.51-1.91), indicating that the drug might even improve renal function. To this end, Lilly/BI are also investigating Jardiance (empagliflozin) in the upcoming EMPA-KIDNEY trial and AZ has initiated the Dapa-CKD trial for Farxiga (dapagliflozin), expected to complete in November 2020.

  • For reference, CANVAS enrolled patients with an eGFR ≥30 ml/min/1.73 m² (i.e. through stage 3 CKD); ~25% of participants had an eGFR too high to qualify for CREDENCE. Thus, CREDENCE’s population will, overall, be less healthy from a renal function perspective. The aim of CREDENCE is to show an impact on renal outcomes; a key secondary endpoint includes CV death and hospitalization for heart failure which, J&J has previously explained to us, is the company’s reason for not initiating a second heart failure trial (as Lilly/BI and AZ have done).

• Directly following Dr. de Zeeuw, Dr. Priscilla Hollander reviewed a safety analysis comparing the CANVAS program (n=10,142) to the pooled phase 3/4 program (n=8,114) for Invokana. She emphasized that canagliflozin’s amputation signal was only seen in the CANVAS program (HR=1.97, 95% CI: 1.42-2.75), with similar signals in CANVAS (HR=2.12, 95% CI: 1.34-3.38) and CANVAS-R (HR=1.80, 95% CI: 1.10-2.93). There were far fewer events in the pooled program, and canagliflozin was associated with a 77% reduction in amputations with a wide confidence interval (HR=0.23, 95% CI: 0.06-0.89). These results reinforce our understanding that baseline factors have a very strong effect on amputation risk in general and with canagliflozin – that is, the signal is predominantly seen in patients who are high-risk for amputations to begin with (see our ADA coverage of the real-world OBSERVE-4D analysis for more on this dynamic). To be clear, the sum of data suggests that Invokana itself also heightens risk for lower limb amputations, but this might not be concerning in real-world practice unless a patient exhibits other risk factors as well. Notable baseline differences in CANVAS vs. phase 3/4 trials include prevalence of hypertension (90% vs. 65%), history of heart failure (14% vs. 3%), history of CV disease (66% vs. 7%), and history of amputation (2% vs. 0.1%), as well as duration of diabetes (14 vs. 8 years) – indeed, a sicker group overall.

Dapagliflozin + Saxagliptin Shows Non-Inferior A1C Reduction vs. Insulin Glargine in Patients with Type 2 Diabetes Inadequately Controlled by Metformin With or Without Sulfonylurea

Serge Jabbour, MD (Thomas Jefferson University, Philadelphia, PA)

Two back-to-back oral presentations highlighted Qtern’s (dapagliflozin/saxagliptin) efficacy vs. two powerful glucose-lowering agents – insulin glargine and SU glimepiride. Dr. Serge Jabbour presented the insulin glargine study and Dr. Juan Frias presented the glimepiride one, both talks centering around a common theme: While insulin and sulfonylureas offer relatively quick/steep A1c reductions, they also confer significant risk for hypoglycemia and weight gain. As such, a goal in diabetes drug development has been creating products that can match this glycemic efficacy with a much stronger safety profile, and it seems like AZ’s Qtern (among other fixed-dose SGLT-2/DPP-4 combos) might be one such drug. Dr. Jabbour took the stage first: This study randomized 650 patients with type 2 diabetes to the 10 mg dapa/5 mg saxa combination or to insulin glargine (Sanofi’s Lantus) for 24 weeks. The trial met its primary endpoint by showing non-inferior A1c reductions with Qtern (-1.7% from baseline 9.0%) vs. insulin glargine (-1.5% from baseline 9.1%, p=0.118). Body weight fell by a mean ~3 lbs (baseline ~198 lbs) among patients taking the combination and rose ~5 lbs in the insulin glargine arm, leading to an estimated treatment difference of ~8 lbs (p<0.001). Hypoglycemia was significantly less common in the Qtern arm vs. the glargine arm (p<0.001), with 21% and 38% of patients respectively having a confirmed hypo event. There were zero episodes of severe hypoglycemia in the Qtern arm vs. three in the glargine arm.

• Dr. Jabbour especially emphasized data on the composite endpoint of A1c <7% without weight gain or hypoglycemia, which fit with the theme of these oral presentations – achieving similar glucose control without the undesirable effects of insulin therapy (or sulfonylureas). He reported that 17% of people taking saxa/dapa achieved this composite outcome vs. only 3% of patients on insulin glargine (p<0.001). A similar proportion of each group reached A1c <7% (33% vs. 34%), but arguably the most notable finding from this study was Qtern’s substantial and significant benefit on hypoglycemia and weight loss.

• Professional CGM was used to assess changes in 24-hour glucose and time-in-range. After two weeks of treatment, mean 24-hour glucose had dropped 49 mg/dl in the Qtern arm vs. -29 mg/dl in the Lantus arm (p<0.0001). This difference lost statistical significance at week 24 (-49 mg/dl vs. -44 mg/dl, p=0.1984), primarily because of continued decline in the basal insulin arm. This makes sense, given that more patients were titrated to their optimal basal insulin dose by the end of the study vs. two weeks in. Dr. Jabbour framed the two-week CGM results by highlighting a real-world misconception among patients/HCPs: that insulin is the most efficient in lowering blood glucose. On the contrary, 24-hour glucose was more swiftly decreased with fixed-dose saxa/dapa, which is easy to prescribe and easy to take (no titration needed!). Dr. Jabbour continued by discussing time-in-range, which improved 34% in the Qtern group and improved 29% in the insulin glargine group from baseline to study end (p=0.0327). He concluded by once again underscoring Qtern’s glycemic efficacy and very mild side-effects, and he shared that a trial extension (another 28 weeks) is ongoing.

• During Q&A, Dr. Priscilla Hollander raised an interesting point about guidelines. ADA currently recommends insulin or an injectable combination therapy for patients with A1c >10%, but could oral SGLT-2/DPP-4 combos have a role to play here? Dr. Jabbour explained how this study enrolled patients with an A1c up to 12%, suggesting that Qtern would be a safe option in type 2s with very high A1c. Whether it would be better than insulin or a fixed-ratio basal insulin/GLP-1 combination for this patient population is still an open question. And of course, the average baseline A1c in this trial was below 10% (~9%).

Dapagliflozin + Saxagliptin Add-On vs. Glimepiride Add-On to Metformin in Patients with Poorly Controlled Type 2 Diabetes

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

Next, Dr. Frias presented findings from a 52-week trial (n=443) of Qtern vs. glimepiride added onto metformin. From a baseline 8.4%, A1c fell 1.4% with the combination therapy, and from a baseline 8.5%, A1c fell 1% with the sulfonylurea (p=0.001). Dr. Frias showed on a graph how A1c was similar in both groups through week 16, but then rose slightly in the glimepiride arm, which points to the attenuated efficacy seen with sulfonylureas over time (due to beta cell burnout). Weight dropped ~7 lbs with Qtern and climbed ~2 lbs with glimepiride after one year (baseline body weight ~196 lbs, p=0.001). Again, weight gain is a known side-effect of sulfonylurea treatment, while weight loss has been well-documented for SGLT-2 inhibitors and their combinations. Systolic blood pressure decreased slightly in the Qtern arm (-3 mmHg) and increased slightly in the glimepiride arm (+1 mmHg) from a baseline of ~131 mmHg (p=0.007). Hypoglycemia was observed in 19% of people taking Qtern and in 42% of people taking glimepiride; severe hypoglycemia was observed in no Qtern patients and in two glimepiride patients (1%). Hypoglycemia is the third major side-effect of sulfonylureas, alongside weight gain and beta cell burnout, and we also note some uncertainty around CV harm. In our view, this drug class is truly subpar and we wish SUs weren’t the most common second-line prescription for type 2 diabetes around the world, but we also understand that their generic status/low cost makes them the only affordable option for many patients. We sincerely hope that payers heed the results showing superior safety/efficacy to other diabetes therapies, including SGLT-2/DPP-4, and that they improve reimbursement for treatments that will be cost-saving in the long run.

• Like Dr. Jabbour, Dr. Frias also paused on data showing Qtern’s superiority on the composite endpoint of A1c <7% without weight gain or hypoglycemia: 30% of participants in the saxa/dapa arm achieved this outcome vs. only 7% of participants on glimepiride (p<0.001). Moreover, 35% of people taking Qtern reached A1c <7% without hypoglycemia after one year, compared to 15% of people taking glimepiride (p<0.001). Dr. Frias stressed the clinical relevance of these composite outcomes, and these findings left us all the more convinced that Qtern should be better utilized in diabetes care.

• Treatment-related adverse events were more common with Qtern vs. glimepiride, and Dr. Frias attributed this mostly to urinary and genital infections.

• We were fortunate to speak with AZ’s Mr. Rod Wooten (VP of CV and Metabolic Disease) and Dr. Jim McDermott (VP of US Medical Affairs for Diabetes) earlier at ADA, and they expressed excitement about this Qtern data. Uptake of this fixed-dose combination product has been sluggish so far, since FDA approval in 1Q17, which matches sales trends of this SGLT-2/DPP-4 class overall (also featuring Lilly/BI’s Glyxambi and Merck/Pfizer’s Steglujan). It was thus reassuring to hear directly from AZ management that the company remains very committed to Qtern and to getting this therapy into more patient hands. To be sure, combination therapy is clearly under-prescribed by diabetes care providers in relation to the vast numbers of patients who could benefit from it, and Mr. Wooten described how HCPs in the US still prefer single agents to fixed-dose (or fixed-ratio) combinations. But there are distinct advantages to a fixed-dose product; beyond clinical benefits, this single pill can improve adherence vs. two separate pills, and in general it introduces more convenience and simplicity to a patient’s diabetes management. We’re keeping our fingers crossed that Qtern can gain more traction on the market in the near-future.

ADA Presidents' Select Abstract: Mechanism by Which Dapagliflozin Induces Euglycemic Ketoacidosis in Rats

Rachel Perry, PhD (Yale University, New Haven, CT)

Yale’s Dr. Rachel Perry presented this select abstract suggesting that SGLT-2 inhibitor induced DKA requires the confluence of two events – reduced insulin level + volume depletion. Dr. Perry’s work investigates the mechanism of increased DKA risk due to SGLT-2 inhibitor treatment, and her team has found that dapagliflozin (AZ’s Farxiga) causes plasma volume depletion and induces a cascade of increases in glucocorticoids and catecholamines that stimulate lipolysis, ketogeneis, and eventually euglycemic ketoacidosis. Treatment of Sprague-Dawley rats with dapagliflozin increased the rate of hepatic ketogenesis vs. treatment with placebo (35 μmol/kg-min vs. 136 μmol/kg-min, p<0.0001). This led to volume depletion which sparked a rise in plasma catecholamine (epinephrine 0.5 nM vs. 7.3 nM, p<0.001; norepinephrine 2.5 nM vs. 19.8 nM, p<0.01) and elevated corticosterone (115 ng/ml vs. 233 ng/ml, p<0.01) relative to placebo. Dr. Perry described how these effects occurred simultaneously with a dapagliflozin-mediated reduction in insulin levels (p=0.004), culminating in DKA. We are intrigued by this insight into DKA physiology, as this safety issue remains a significant concern when it comes to the otherwise extremely promising class of SGLT inhibitors for type 1 diabetes. We wonder if increased emphasis on sustaining fluid levels can help to reduce DKA events related to SGLT therapy. To be sure, hydration was repeatedly recommended by thought leaders at the ATTD consensus conference on DKA risk management for type 1s taking an SGLT inhibitor.

• Dr. Perry emphasized that volume depletion is necessary but not sufficient in order for a DKA episode to occur. In her investigations, rodents treated with dapagliflozin show significant (p<0.01) increases in corticosterone, epinephrine, and norepinephrine levels along with significant (p<0.001) increases in fatty acid turnover, hepatic acetyl coA levels, and endogenous glucose production. However, these increases in markers of steroid production, lipolysis, and gluceoneogenesis were dependent on the volume depletion effect of dapagliflozin. When rodents were treated with both dapagliflozin and saline injections, these levels decreased to those of the control group. Thus, Dr. Perry concluded that volume depletion is necessary for DKA to occur, but she went on to explain why volume depletion on its own is not sufficient to provoke ketosis. When treated with the diuretic furosemide, plasma beta-hydroxybutyrate concentrations and turnover rates did not significantly change from control, indicating the failure to induce ketosis with this intervention. Conversely, these measures were significantly different upon treatment with dapagliflozin. Drawing on these observations, Dr. Perry underscored that an insulin-lowering effect is needed in conjunction with volume depletion to cause a DKA event. In line with this, thought leaders have stressed that treating DKA requires both glucose and insulin (as counterintuitive as this may feel for patients, caregivers, ER staff, etc.).

• Could the volume depletion effects of SGLT inhibitors be a target for the prevention of SGLT-related DKA? Dr. Perry raised this intriguing possibility. Seeing as volume depletion was necessary to cause DKA, she proposed this as a potential action point to minimize DKA risk. Although she didn’t go into specifics, we’re definitely interested in this idea, and we’d note that any intervention would ideally preserve all the benefits to SGLT therapy while mitigating DKA risk.

Oral Presentations: Hypoglycemia – Reducing the Risk

Effect of Combination Therapy with Liraglutide Plus Canagliflozin on HGP and A1c vs. Each Therapy Alone in T2D

Muhammad Abdul-Ghani, MD (University of Texas Health Science Center, San Antonio, TX)

Dr. Muhammad Abdul-Ghani discussed a small study (n=45) investigating one of our favorite potential combination therapies: GLP-1 + SGLT-2. Patients with type 2 diabetes were randomized to the higher dose of Novo Nordisk’s Victoza (liraglutide 1.8 mg), to the higher dose of J&J’s Invokana (canagliflozin 300 mg), or to a combination of both. After four months of treatment, combo therapy conferred more than additive weight loss – this was remarkable to see. Body weight fell ~8 lbs from a baseline ~216 lbs in the canagliflozin group, fell ~4 lbs from a baseline ~213 lbs in the liraglutide group, and fell ~14 lbs (!) from a baseline ~217 lbs with both GLP-1 and SGLT-2 together. (If weight loss was exactly additive, we’d expect to see a ~12 lbs reduction in the combo group.) A1c reductions were less than additive, but were still greater with the combination (-1.9%) vs. either monotherapy (-1.1% with canagliflozin, -1.6% with liraglutide). Baseline A1c was ~8.2%. Notably, these weight loss and A1c results match findings from DURATION-8 (n=695), AZ’s larger clinical trial evaluating Bydureon (exenatide) + Farxiga (dapagliflozin) co-administration. After seven months in DURATION-8, weight loss in the combination therapy arm (~8 lbs) was the sum of mean weight loss with standalone GLP-1 (~3 lbs) + standalone SGLT-2 (~5 lbs). Meanwhile, the effect on A1c was less than additive but was still statistically superior. Mean A1c drop was 2% in the combo arm, 1.6% in the exenatide arm, and 1.4% in the dapagliflozin arm, all from a baseline of 9.3%. So, it seems that co-administration of a GLP-1 agonist and an SGLT-2 inhibitor could be a very effective intervention for patients in need of additional weight loss (and of course, the majority of patients with type 2 diabetes are looking to lose weight), even if the extra glycemic improvement is more marginal. We can see how the synergy of these agents confers at least additive weight loss, with the GLP-1 suppressing appetite and slowing gastric emptying while the SGLT-2 dramatically increases glycosuria. We’re curious about the potential for additive CV benefit as well, because by the same mechanistic logic, GLP-1 therapy could address atherosclerosis while SGLT-2 treatment protects against heart failure. The CV efficacy of GLP-1 + SGLT-2 co-administration has yet to be investigated in a rigorous RCT, but we’re certainly keen to see that study, and in the meantime, it’s reassuring to know that combination therapy across these drug classes is safe. ADA/EASD’s new draft consensus statement recommends prescribing GLP-1 alongside an SGLT-2 for certain patients who can access/afford it, and we’d love to see these advanced products reach more patient hands, as real-world use is upsettingly low right now. According to a Diabetes Care article published last Fall, only 7% and 4% of US adults with type 2 diabetes have ever been prescribed a GLP-1 agonist or an SGLT-2 inhibitor, respectively.

• Dr. Abdul-Ghani also spoke to the differential effects of GLP-1 and SGLT-2 on glucagon response. More specifically, GLP-1 agonists are known to inhibit glucagon secretion, while SGLT-2 inhibitors raise plasma glucagon concentration – Dr. John Buse has shared a word of caution around these opposing effects, although he co-chaired the ADA/EASD consensus writing committee that recommends this particular combination for patients above A1c target at high CV risk. In Dr. Abdul-Ghani’s 45-person trial, canagliflozin monotherapy increased hepatic glucagon production and thereby increased glucagon levels in the blood, as expected. Liraglutide monotherapy caused a small decrease in hepatic glucagon production and in plasma glucagon concentration. The glucagon response with canagliflozin + liraglutide together was somewhat surprising: Hepatic glucagon production rose ~15%, but there was no corresponding rise in plasma glucagon levels. Dr. Abdul-Ghani explained that there must be other mechanisms at play; our interest is piqued, and we hope to learn much more about glucagon response with GLP-1 vs. SGLT-2 vs. their combination going forward.

Select Questions and Answers

Professor Kamlesh Khunti (Leicester Diabetes Center, UK): In clinical practice, we wouldn’t usually use these two simultaneously, so can you comment on what you expect the benefits to be when GLP-1 and SGLT-2 are prescribed sequentially, in either order?

Dr. Abdul-Ghani: I’d be surprised if there were any major differences with sequential prescription. As you see here, this combination might be disappointing in terms of A1c reduction, however in terms of weight loss, it’s a very attractive combination especially for people with obesity. As for the glucagon response when you prescribe these sequentially, it’s difficult to speculate, because we have no data. I expect that giving an SGLT-2 on top of a GLP-1 would result in a small increase in glucagon. From this data, it seems that the decrease in glucagon is not that much of an important player.

Oral Presentations: Prediction and Prevention of Cardiovascular Risk

SGLT-2 Inhibitors and Stroke Risk in Patients with Type 2 Diabetes – A Systematic Review and Meta-Analysis

Man Guo, MD (Southwest Medical University, Luzhou, China)

SGLT-2 inhibitors as a class do not increase the risk of stroke, according to this meta-analysis from China’s Southwest Medical University. Researchers mined data from 32 SGLT-2 inhibitor trials encompassing 75,540 participants and the three leading SGLT-2 products: canagliflozin (J&J’s Invokana), dapagliflozin (AZ’s Farxiga), and empagliflozin (Lilly/BI’s Jardiance).  Compared to placebo, there was no significant increase in the incidence of stroke for participants on an SGLT-2 inhibitor as monotherapy (RR=1.01, 95%: CI 0.93-1.10, p=0.972) or as a component of combination therapy (RR=1.0, 95% CI: 0.92-1.09, p=0.846). Furthermore, there was no increase in stroke risk for any of the individual SGLT-2 inhibitor therapies, canagliflozin (RR=0.91), dapagliflozin (RR=0.99), or empagliflozin (RR=1.03). Subgroup analyses confirmed that this holds true regardless of age, sex, diabetes duration, BMI, and A1c. This is reassuring news, given some concern over possible effects of SGLT-2 inhibitor on stroke following a hazard ratio to the left of unity for the individual stroke outcome in the EMPA-REG CVOT for empagliflozin (HR=1.24, 95% CI=0.92-1.67, p=0.16), though this concern had already been mostly mitigated with a resoundingly neutral stroke signal in the subsequent CANVAS trial for canagliflozin (HR=0.90, 95% CI: 0.71-1.15).

Oral Presentations: Regulation of Islet Function in Health and Disease

Dapagliflozin Treatment Impacts ß, but Not α Cell Function in Normal Human Islets

Chunhua Dai, MD (Vanderbilt University, Nashville, TN)

Dr. Chunhua Dai discussed several nonclinical studies demonstrating that clinically-relevant levels of the SGLT-2 inhibitor dapagliflozin (AZ’s Farxiga) reduced glucose-stimulated insulin secretion but did not affect glucagon levels or islet survival/growth. Human islet cells from three donors were transplanted into mice. After four weeks of dapagliflozin treatment, there was no significant change in fasting plasma glucose, glucagon, or human insulin levels. When these mice were given a glucose challenge, dapagliflozin caused lower blood glucose (287 mg/dl vs. 375 mg/dl, p=0.003) and lower human insulin levels (0.96 ng/ml vs. 2.05 ng/ml, p<0.0001), while glucagon was unchanged (75 pg/ml vs. 86 pg/ml, p=0.4883). Since there was no observed change in glucagon response, Dr. Dai suggested that dapagliflozin doesn’t affect alpha cell function. That said, when his group repeated this procedure in an in vitro culture of human islets, there was no significant change in insulin or glucagon response after glucose challenge. So it seems that much more remains to be discovered about dapagliflozin’s precise action on healthy human beta cells.

Symposium: Cardio-Renal Effects of Glucose-Lowering Therapies

Heart Failure Management in the Era of EMPA-REG OUTCOME and the CANVAS Program

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

Noted cardiologist Dr. Mikhail Kosiborod provided a crash course on heart failure and its intersection with diabetes. He framed these as “conjoined epidemics,” outlining that elevated A1c is a major risk factor for developing heart failure (starting even in the prediabetes range) and heart failure is likewise a major risk factor for diabetes (the counter-regulatory hormone response in heart failure can exacerbate insulin resistance). Consistent with this, heart failure is quickly becoming the most common CV complication of diabetes and it already holds the designation of most morbid CV event for people with diabetes with a “dismal” <25% five-year survival rate following hospitalization for heart failure. Dr. Kosiborod mentioned that heart failure itself is still under-recognized in the cardiology community, and this is particularly true for HFpEF, or heart failure with preserved ejection fraction. In contrast to HFrEF (heart failure with reduced ejection fraction), which involves a decrease in cardiac output following an insult to the myocardium, HFpEF is a systemic disease associated with excess adiposity and insulin resistance – the “cardiac manifestation” of obesity (alongside NAFLD as the hepatic manifestation of obesity, hypertension as the vascular manifestation, and so on). In step with the rising obesity epidemic, an increasing proportion of heart failure hospitalizations are now due to HFpEF as opposed to HFrEF – a troubling situation since most disease-modifying therapies for heart failure (beta blockers, ACE/ARB inhibitors, aldosterone blockers, nitrates, etc.) are only effective in the HFrEF subtype. The only treatment options for HFpEF are diuretics and digoxin to improve symptoms, but these do nothing to improve survival or reduce the risk of hospitalization.

• Against this backdrop, Dr. Kosiborod framed obesity and metabolic syndrome as the most impactful targets for HFpEF prevention and treatment. A 2016 JAMA study found that HFpEF is responsive to intensive lifestyle modification: Over 20 weeks, aerobic training and caloric restriction each produced a significant ~6% improvement in cardiac oxygen consumption, and the combination of both aerobic training and caloric restriction boosted this to ~14%. “It’s shocking,” Dr. Kosiborod said, that no studies to-date have evaluated the effect of bariatric surgery on heart failure given its resolution of other obesity-related sequelae including NAFLD and diabetes.

• Of course, no heart failure talk would be complete without discussing the promise of SGLT-2 inhibitors for this indication. Both Lilly/BI’s Jardiance (empagliflozin) and J&J’s Invokana (canagliflozin) demonstrated compelling risk reduction for heart failure hospitalization in the EMPA-REG OUTCOME and CANVAS trials, respectively. These findings are complemented by real-world evidence from AZ’s CVD-REAL study, for which Dr. Kosiborod is a primary investigator. These results have inspired dedicated investigations of SGLT-2s for the treatment of heart failure (rather than the prevention of heart failure in people with diabetes), namely the EMPEROR HF program for Jardiance and the Dapa-HF study  for AZ’s Farxiga (dapagliflozin).

Product Theaters

Jardiance (Empagliflozin) Tablets – Evolving Clinical Development

Pam Taub, MD (UCSD, San Diego, CA); Leigh Perreault, MD (University of Colorado, Denver, CO)

Drs. Pam Taub and Leigh Perreault presented a full-throated endorsement of SGLT-2 inhibitor Lilly/BI’s Jardiance (empagliflozin) from a CV perspective, drawing on EMPA-REG OUTCOME data. Dr. Taub emphasized that A1c is only the tip of the iceberg when it comes to managing diabetes; as a cardiologist, she thinks of diabetes mostly in terms of the resulting hypercoagulable state and endothelial dysfunction that make treating CV conditions more difficult. Both speakers portrayed Jardiance as comparable to statins in terms of how compelling the mortality data is; they expressed hope that it will be just as widely prescribed in the near future (this was amazing to hear). Dr. Taub questioned some of her cardiology colleagues’ assumption that Jardiance is primarily a diabetes drug, arguing that death is “the ultimate outcome” and therefore “everyone should be prescribing it” for the relevant patients. In terms of adverse events, the speakers explained the importance of educating patients about the possibility of urinary tract infections and genital mycotic infections given the drug’s mechanism. They presented reassuring data from EMPA-REG OUTCOME showing no difference in rates of more serious adverse events between the treatment and control groups.

Questions and Answers

Q: What is the mechanism of action?

A: Currently the mechanism of CV benefit is unknown. It is an area of very active research.

Q: Can you review the A1c subgroup data?

A: There were sensitivity analyses looking at whether this is only beneficial in people with very high A1cs, very low A1cs, or some sweet spot. The answer was no. They looked at different subgroups and the CV benefits were seen across all of them.

Q: In post-marketing settings, have you seen more amputations?

A: You always see more of everything post-marketing. A patient could’ve taken the drug once or every day for 10 years and they can report an event to the FDA that will be put down as potentially related. It’s hard to know the denominator of drug exposure. Post-marketing surveillance can be helpful to pick up things we didn’t see in clinical trials, which involved thousands of patients rather than the millions taking the drug. There’s some indication that there might be signals not seen in the trials, but it’s hard to prove causation. All of the companies are collecting amputation data and posting it.

Q: Can we prescribe Jardiance with the claim of CV death in the absence of background metformin?

A: In the trials, most patients were on metformin and about 20% were not. I don’t think there was enough power to delineate whether the people not on metformin had a benefit. Right now, the standards still say metformin is the initial drug therapy for type 2 diabetes and you can add Jardiance after. There was a small subgroup analysis from UKPDS suggesting that metformin might have CV benefit, but it was very small and not powered like this. Right now, it is still the recommendation to initiate metformin first. Clinically, I have a lot of patients who have initiated metformin and had GI side-effects such that they can’t tolerate it. They sometimes end up on Jardiance alone.

Q: Do we know the cause of the genital infections?

A: The drug’s mechanism of action for glucose-lowering is that it blocks maladaptive overexpression of SGLT-2 in the proximal tubule. This leads to wasting of glucose in the urine and makes the urine highly glucose filled. I had a nurse practitioner running down the hall saying “you put this patient on one of those fancy new drugs and now her urine is full of glucose” and I said “yes! That means it’s working.” Bugs like glucose, so if you’re peeing it out, bugs can use it as fuel. That’s probably the cause, but I’m not an infectious disease expert. Patients with diabetes also have slightly impaired immunity.

Q: What was the significance of the MI and stroke results?

A: There was no difference between groups. All of the benefit was driven by CV death. There was no effect on MI and stroke. There was a numerical increase in stroke in the active group. The question is whether that’s meaningful. It was not statistically significant. The patients in the intention to treat analysis weren’t all still taking the drug when this data was included, and they have done analyses about stroke and found that the majority of events happened after discontinuation of active drug. When you look at the composite endpoint, the trial was not powered to look at one part. So yes, there was a numerical increase, it was potentially related to people stopping the drug, and it was not significant.

Q: How low can eGFR drop before you should stop treatment?

A: I don’t check immediately. I wait 6-8 weeks. Initially there are lots of mechanisms leading to a transient decrease in eGFR. After 6-8 weeks, if it’s below 45 ml/min/1.73m², I will stop the drug.

The renal changes are really fascinating. When you waste glucose in the proximal tubule, the macula densa cells can really see the sodium in the distal tubule because it’s not so diluted from glucose. That tells the afferent arteriole to constrict and protects the kidney from glomerular hyperfiltration, which is probably a good thing. Don’t continue the drug if the GFR is persistently below 45. You can initiate it if it’s above 45, if it dips below you can watch it, and if it doesn’t recover, the recommendation is to not continue.

Q: Do you need to achieve a target dose or can you keep people at 10 mg? Does the 10 mg dose offer the same benefit as the 25 mg dose?

A: You don’t need to increase the dose. The trial looked at the two doses and found comparable CV benefit. In the analysis, they pooled the groups together. If someone is on 10 mg and doing well, you don’t need to increase it.

Posters

Canagliflozin vs. Other Anti-Hyperglycemic Agents on the Risk of Below-Knee Amputation (BKA) for Patients with T2DM – A Real-World Analysis of >700,000 US Patients

P Ryan, JB Buse, M Schuemie, F Defalco, Z Yuan, P Stang, JA Berlin, N Rosenthal

J&J’s OBSERVE-4D study was featured on a late-breaking poster: >700,000 real-world US patients were analyzed, and SGLT-2 inhibitor Invokana (canagliflozin) was not associated with an increased risk of below-knee amputations vs. non-SGLT-2 inhibitor diabetes therapies, except metformin (intent-to-treat HR=1.01, 95% CI: 0.93-1.10, p=0.71; on-treatment HR=0.75, 95% CI: 0.40-1.41, p=0.25). Amputations were also balanced between Invokana and other SGLT-2s (intent-to-treat HR=1.13, 95% CI: 0.99-1.29, p=0.06; on-treatment HR=1.14, 95% CI: 0.67-1.93, p=0.48). See the full paper here. These are reassuring results for Invokana, since one year ago at ADA 2017, CANVAS showed a nearly two-fold risk for lower limb amputations with canagliflozin vs. placebo (HR=1.97, 95% CI: 1.41-2.75, p<0.001). Questions remain about the safety of canagliflozin (especially since a black box warning for amputations is on the product label), although some also believe that depending on how the trials were constructed (there’s little standardization sought among CVOTs) that design could’ve and some thought leaders have endorsed switching patients onto another SGLT-2 inhibitor for the highest-risk patients (who will have to go off the therapy in time). Dr. John Buse explained in a press gathering that while he was very reassured by the results, given a choice of SGLT-2 inhibitors he would not prescribe Invokana to patients with risk factors for amputation (prior amputation, severe neuropathy, peripheral vascular disease, and very high A1c). Notably, OBSERVE-4D found similar results in the subset of patients with established CV disease vs. the total study population (on-treatment HR=0.72, 95% CI: 0.34-1.51), suggesting that CV disease did not confer additional amputation risk in this real-world sample. We’ve heard some speculation that the high-risk patient population in CANVAS may have contributed to the amputation finding. For reference, in CANVAS, baseline CV disease independently conferred a 50% increased risk of amputation in a multivariate analysis of risk factors (HR=1.50, 95% CI: 1.0-2.3), though this did not explain away the correlation between cana and lower-extremity amputations (i.e. in cohorts with and without baseline CV disease, amputations were more common with Invokana vs. placebo). In an interview with Dr. Paul Burton (VP Scientific Affairs, Janssen), we learned that roughly 25% of people in OBSERVE-4D had established CV disease, coming in far below the 66% of participants in CANVAS who had prior CV events at randomization. It’s possible that evaluating a greater proportion of patients without baseline CV disease had a bearing on OBSERVE-4D’s positive safety results, although it’s reassuring that data from the highest-risk quartile matched overall data.

• Dr. Burton emphasized that sample size in OBSERVE-4D was much larger than a CVOT. That said, we also point to results from EASEL, another real-world study (n=25, 258) from J&J that linked SGLT-2 inhibitors with a ~doubled risk of lower limb amputations (HR=1.99, 95% CI: 1.12-3.51, p=0.018); 58% of observed patients in EASEL were on Invokana, 26% on Lilly/BI’s Jardiance (empagliflozin), and 16% on AZ’s Farxiga (dapagliflozin). We asked Dr. Buse how he views OBSERVE-4D and EASEL in relation to each other, and he too highlighted the order-of-magnitude difference in population exposed. While he did acknowledge that it’s difficult to pinpoint why the two trials reached different conclusions, he also pointed out that the trials’ confidence intervals readily overlap with one another (though on the wrong side of 1.0). Dr. Buse also mentioned that, when OBSERVE-4D is published, there will be a tool that allows any reader to do whatever they want with the dataset – this is now available here.

• Perhaps the most significant limitation of OBSERVE-4D was that median on-treatment exposure time was <six months, raising questions as to whether the study was long enough to detect an amputation signal. In CANVAS, the amputation curves continued to widen over the duration of the trial. Dr. Burton affirmed that J&J will continue to look at this real-world data over time, and he noted that in CANVAS, an amputation signal would have actually been detected even at six months. Moreover, he shared that OBSERVE-4D found no signal for amputations in patients with longer duration of exposure to canagliflozin, up to one-two years. Dr. Buse reiterated this finding, adding that there’s no hint of amputation rates changing over time and the six-month HR in CANVAS would have been 1.81.

• Ultimately, we don’t think that OBSERVE-4D will completely negate the amputation signal seen in CANVAS (even though it should given the experts to whom we’ve spoken), but it should serve as a reminder to HCPs that canagliflozin is a potent, efficacious drug (more on specific clinical benefits below), that base rate of amputations is very low even in diabetes, and that this risk is manageable with careful monitoring of the feet. Dr. Burton described how providers have come to understand that the absolute increase in amputations seen in CANVAS was quite low (0.2%-0.3%). Moreover, he underscored that HCPs can identify patients at-risk for amputations (e.g. those with prior amputations, those with peripheral arterial disease) and decide against prescribing Invokana (or prescribe it, but monitor extremely closely). We’re not totally sure about the first point, because our sense is that the average (busy) PCP sees the black box warning for amputations and pivots away from Invokana (to another SGLT-2, or to another therapy class altogether); in fact, Dr. Buse touched on the need to help PCPs understand the risk/benefit profile of Invokana. Invokana sales have been falling since the black box was added in May 2017, although J&J has always cited pricing pressure as the primary reason for this (and indeed, the company offers one of the best Patient Assistance Programs according to diaTribe’s analysis). We think there’s a major opportunity here for J&J to double down and really invest in the class but we don’t see J&J CEO Alex Gorsky doing this – too bad, and we hope we’re wrong.

• On a very exciting note, OBSERVE-4D also confirmed the heart failure benefit of the SGLT-2 inhibitor class. On-treatment analysis identified a 61% risk reduction in hospitalization for heart failure with Invokana vs. non-SGLT-2 therapies (HR=0.39, 95% CI: 0.26-0.60, p=0.01), and no difference on this heart failure endpoint with Invokana vs. other SGLT-2s (HR=0.90, 95% CI: 0.71-1.13, p=0.22). In the subgroup with established CV disease, the reduction was 56% (HR=0.44, 95% CI: 0.36-0.54). These findings corroborate the positive heart failure outcomes from both CANVAS and EMPA-REG (for Lilly/BI’s Jardiance), as well as findings from the real-world, AZ-sponsored CVD-REAL program. A 61% risk reduction strikes us as remarkably robust, though Dr. Burton attributed this to the nature of real-world evidence; he acknowledged that he would not expect this to actually be significantly greater than the risk reductions seen in CVD-REAL. Moreover, heart failure results were again similar in the overall cohort and the subgroup with established CV disease. In the future, we’d be interested to see results from the primary prevention cohort only. The role of SGLT-2s in primary vs. secondary CV prevention remains a key area of investigation, as CANVAS and EMPA-REG OUTCOME enrolled predominantly participants with baseline CV disease. DECLARE, AZ’s CVOT for Farxiga slated to read out later in 2018, has enrolled a 59% primary prevention cohort. On the whole, we’ve noticed tremendous thought leader enthusiasm for SGLT-2s, particularly from cardiologists, who are very focused on the heart failure benefit these agents offer; to this end, Lilly/BI and AZ have initiated the dedicated EMPEROR and Dapa-HF trials to investigate Jardiance and Farxiga, respectively, in patients with heart failure with or without diabetes. Dr. Burton shared that while J&J has considered conducting a dedicated heart failure trial, management feels that CREDENCE, the renal outcomes trial for Invokana, will be a good approach to the heart failure question, since that study is enrolling patients with stage 2-3 CKD who should experience a fair number of heart failure events. CREDENCE is expected to complete in June 2019.

  • It’s worth noting that the intent-to-treat analysis was not completed for Invokana vs. non-SGLT-2 therapies because of heterogeneity (I²=0.59) between the four databases used. Though these all trended in the right direction (HRs=0.63, 0.94, 0.83, 0.73), only two were statistically significant on their own. However, we understand this heterogeneity to be an issue of statistical power and we imagine that very few would argue against a class effect for SGLT-2s on reducing heart failure hospitalizations at this point. The intent-to-treat analysis of Invokana vs. other SGLT-2s revealed no difference (HR=1.07, 95% CI: 0.95-1.20, p=0.16).

• OBSERVE-4D pulled data from four US claims databases, evaluating new users to SGLT-2s and other glucose-lowering therapies with propensity score matching and other sensitivity analyses. In total, 142,000 new users of canagliflozin, 110,000 new users of other SGLT-2s, and 460,000 new users of other therapies were included in the study. For reference, the intent-to-treat period was defined as one day following exposure to the last day of observation in the database, while the on-treatment period was one day following exposure through the period of persistent exposure, allowing for ≤30-day gaps between exposure. If patients started a non-metformin diabetes drug (other than SGLT-2 inhibitors), they were censored from the sample. Databases included Truven’s Commercial Claims and Encounters, multi-state Medicaid and Medicare Supplemental Beneficiaries, and OptumInsight’s Clinformatics Datamart.

Lower Risk of CV Events and Death Associated with Initiation of SGLT-2 vs. DPP-4 Inhibitors – Analysis from the CVD-REAL 2 Study

S Kohsaka, C Lam, D Kim, A Karasik, N Tangri, S Goh, M Thuresson, H Chen, F Surmont, N Hammar, P Fenici, M Kosiborod

In CVD-REAL 2, AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) was associated with lower risk for heart failure hospitalization and all-cause mortality compared to DPP-4 inhibitors. Dapagliflozin reduced risk for heart failure by 13% vs. DPP-4s (HR=0.87, 95% CI: 0.79-0.95). The benefit on all-cause death was even more pronounced, with a 26% relative risk reduction favoring dapa (HR=0.74, 95% CI: 0.67-0.83). The SGLT-2 inhibitor also offered a significant 18% relative risk reduction for stroke compared to DPP-4 inhibitors (HR=0.82, 95% CI: 0.75-0.89), while the benefit on MI just barely met the threshold for statistical significance (HR=0.86, 95% CI: 0.74-0.99). Notably, there were relatively fewer MI events in the course of CVD-REAL 2 follow-up (721 MIs vs. 2,156 strokes, 1,825 hospitalizations for heart failure, and 1,366 strokes), so this sub-analysis may have been underpowered. Regardless, we’ve gathered from thought leaders that cardioprotection with SGLT-2s is most likely driven by a heart failure benefit, and this poster certainly contributes additional evidence to that line of thinking. Heart failure was added as a co-primary endpoint in AZ’s DECLARE trial for Farxiga, and you can bet we’ll be eager to see these results when the CVOT reports later this year.

• The majority (75%) of participants in CVD-REAL 2 had no history of CV disease at baseline. There’s been exciting talk in the diabetes field about the promise of SGLT-2 inhibitors in primary CV prevention, and very notably, the DECLARE trial also enrolls a majority primary prevention cohort. CVD-REAL and CVD-REAL 2 both bode well for DECLARE results, but data from the randomized controlled trial will certainly be more telling and more definitive. We wonder if Farxiga might be the first diabetes drug indicated for cardioprotection in diabetes patients without established CV disease (both Jardiance and Victoza have CV indications currently, but these only apply to patients with pre-existing CV morbidity).

• Dr. Mikhail Kosiborod presented overall CVD-REAL 2 results at the annual ACC meeting earlier this year. The findings were simultaneously published in JACC. SGLT-2 inhibitors were compared to other glucose-lowering drugs in general (as opposed to this analysis, which focused on DPP-4s specifically for the comparator arm), and showed significant benefit on all-cause death (HR=0.51, 95% CI: 0.37-0.70, p<0.001) as well as hospitalization for heart failure (HR=0.64, 95% CI: 0.50-0.82, p=0.001). Dr. Kosiborod announced the original CVD-REAL results at ACC 2017. This is an impressive endeavor in real-world evidence by AZ, one that has already brought so much learning on the SGLT-2 inhibitor class. At CODHy Asia Pacific this year, we heard abundant praise for CVD-REAL 2 because it focuses on countries that are often under-represented in research (South Korea, Japan, Australia, Israel, and Singapore).

DURATION-8 Randomized Controlled Trial 104-Week Results – Once-Weekly Exenatide (ExQW) plus Once-Daily Dapagliflozin (DAPA) vs. ExQW or DAPA Alone

S Jabbour, C Guja, E Hardy, S Bhattacharya, P Ohman, J Frias

Two-year DURATION-8 results confirmed findings from 28 weeks and 52 weeks, showing stable benefits to GLP-1 + SGLT-2 co-administration vs. either treatment alone. According to this poster, 62% of participants initially enrolled in DURATION-8 (n=695) continued through two years (n=431). The trial randomized patients with type 2 diabetes and relatively high A1c (baseline 9.3%) to AZ’s GLP-1 agonist Bydureon (exenatide once-weekly), to AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin once-daily), or to a combination regimen of both. A1c declined by a mean 1.7% in the combination arm after 104 weeks vs. -1.3% in the exenatide only arm (p<0.01) and -1% in the dapagliflozin only arm (p<0.001). Change in A1c from baseline is also captured in the image below. It’s quite notable from our view that GLP-1 + SGLT-2 co-administration maintained A1c >1.5% below baseline over two years. The weight loss results from this 104-week follow-up were interesting: From a baseline ~200 lbs, body weight dropped ~5.5 lbs with Bydureon + Farxiga therapy, falling only ~1.7 lbs with Bydureon alone (p<0.001) and actually falling numerically more (-6.6 lbs) with Farxiga alone, though this difference was not statistically significant. If anything, this speaks to the profound weight loss potential of SGLT-2 therapy, though we remain very excited about the promise of additive weight loss with GLP-1 + SGLT-2 combinations. As a reminder, in the initial 28-week readout from DURATION-8, weight loss was almost additive in the combo arm (~8 lbs weight loss with Bydureon + Farxiga vs. ~3.5 lbs with exenatide monotherapy and ~4.8 lbs with dapa monotherapy).

Long-Term Efficacy and Safety of Ertugliflozin in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin Monotherapy: 104-week VERTIS MET Trial

S Gallo, B Charbonne, A Goldman, H Shi, S Huyck, A Darekar, B Lauring, S Terra

This poster offered a long-term look at the efficacy of ertugliflozin (Merck/Pfizer’s newly-launched SGLT-2 inhibitor Steglatro). The VERTIS MET trial randomized 621 adults with type 2 diabetes to either 5 mg ertugliflozin (n=207), 15 mg ertugliflozin (n=205), or placebo (n=209), and 26-week results were presented on a poster at ADA 2017. Here, the investigators reported 52- and 104-week results, confirming Steglatro’s significant benefits on A1c and body weight. Importantly, in addition to background metformin, all participants started taking glimepiride (a sulfonylurea) from week 26 through week 104. At 52 weeks, mean A1c decline from a baseline 8% was -0.7% with low-dose ertugliflozin, -1.0% with high-dose ertugliflozin, and -0.7% with placebo/glimepiride. After 104 weeks, A1c reductions were -0.6%, -0.9%, and -0.6%, respectively. Given that sulfonylureas are known to be very effective blood glucose-lowering agents, it’s quite notable in our view that the higher Steglatro dose consistently gave ~0.2% more A1c drop. A head-to-head study of ertugliflozin vs. glimepiride was presented at EASD 2017, showing similar change in A1c with high-dose Steglatro and with the SU over 52 weeks. We’d certainly expect an SGLT-2 inhibitor to offer better glucose control than glimepiride over the long term, since sulfonylureas cause beta cell burnout that sooner or later attenuates their glycemic efficacy. SUs come with a host of other side-effects as well, including weight gain and hypoglycemia. In line with this, Steglatro’s weight benefit really shined in VERTIS MET at weeks 52 and 104. After one year, both ertugliflozin doses gave ~7 lbs weight loss while body weight was unchanged from baseline in the placebo/glimepiride group. Placebo-treated patients experienced some weight loss in the first 26 weeks of this study, but weight regain began as soon as glimepiride was initiated, and it quickly returned to baseline. After two years, mean weight loss was ~8 lbs in both ertugliflozin arms and was again near baseline in the placebo/glimepiride arm. It’s exciting that weight loss continued through two years with Steglatro; even though patients only lost an additional ~1 lb on average in the second year, we too-often see weight regain in obesity trials because of the body’s homeostatic response to any weight loss, so it’s good to observe the curve continue in the right direction in VERTIS MET. As expected, symptomatic hypoglycemia was more common in the placebo/glimepiride group vs. either Steglatro group over two years. There were 28 hypoglycemia events recorded for patients on placebo/glimepiride (13.4%), 12 for patients on 5 mg ertugliflozin (5.8%), and 12 for patients on 15 mg ertugliflozin (5.9%).

• The poster also shared the proportion of people in each treatment arm who required rescue medication during the course of VERTIS MET. At the one-year mark, 17% of patients randomized to placebo/glimepiride needed rescue therapy compared to only 4% of patients on low-dose Steglatro and 2% of patients on high-dose Steglatro. At the two-year mark, these numbers grew to 24%, 11%, and 11%, respectively, but the same general trend held true: Fewer type 2s given Steglatro needed additional therapy to move toward their glycemic target. At the end of 104-week follow-up, 25% of patients on 5 mg and 34% of patients on 15 mg Steglatro achieved A1c <7% vs. 19% of placebo patients. The stricter target of A1c <6.5% was met by 11%, 12%, and 7% of each group, respectively.

• This data confirmed two things for us: (i) Steglatro is a highly efficacious SGLT-2 inhibitor and could help many patients with glucose control and weight loss. (ii) Sulfonylureas do more harm than good, and it’s a shame that they’re still the most frequently prescribed second-line diabetes drug. We’re hopeful that as more advanced drugs go generic – including SGLT-2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists – they’ll replace SUs in major treatment algorithms so that these agents really fall out of favor. If sulfonylureas were submitted to FDA today, we’re skeptical that they’d even be approved. Meanwhile, the evidence supporting ertugliflozin’s safety/efficacy is strong (other posters at ADA confirmed the agent’s renal and bone safety as well, as you’ll see below). Commercial uptake of Steglatro is extremely low right now, which isn’t unexpected for a product that launched ~six months ago without meaningful reimbursement in the US. Merck/Pfizer are focused on building payer coverage throughout 2018 so that the Steglatro franchise (which also features fixed-dose combinations Segluromet and Steglujan) can take off in 2019. We’re excited about a four-product SGLT-2 inhibitor market (Steglatro, J&J’s Invokana, Lilly/BI’s Jardiance, & AZ’s Farxiga) and only hope that more patients in-need can access this incredible therapy class.

Assessment of Adverse Renal Effects in Patients with Type 2 Diabetes Mellitus Receiving Ertugliflozin

S Patel, A Hickman, R Frederich, B Lauring, S G. Terra, S. Johnson, S Huyck, and J Mancuso

To ensure the renal safety of Merck/Pfizer’s new SGLT-2 inhibitor Steglatro (ertugliflozin), investigators embarked on this post-hoc analysis of seven phase 3 VERTIS studies (n=4,859). Overall, there was no significant difference in adverse renal events (acute kidney injury, acute pre-renal failure, renal failure, or renal impairment) with ertugliflozin (n=3,315) vs. placebo (n=1,544; only three of the seven studies evaluated were placebo-controlled, hence the smaller placebo group in this analysis). In the subgroup of participants with eGFR <45 ml/min/1.73m² at baseline, there were numerically more renal adverse events with Steglatro (7, or 6.4%) vs. placebo (0, 0%), but the poster emphasized that “very few renal events were adjudicated as causally related to study medication.” In other words, it’s possible that this finding was due to chance. Steglatro was FDA-approved in December 2017 and notably, the product label recommends against use in patients with eGFR <60 ml/min/1.73m²; ertugliflozin is officially contraindicated when eGFR falls below 30 ml/min/1.73m². The agent showed strong renal safety in the subgroup with eGFR between 45-60 ml/min/1.73m² – 4 events with ertugliflozin (1.4%) vs. 2 with placebo (1.6%) – which makes us wonder whether there’s a case to change the label recommendation (starting the warning at <45 instead of <60 ml/min/1.73m²). Of course, there are likely other factors underlying this <60 ml/min/1.73m² cutoff as it’s stipulated on the drug label; we’ve heard from several thought leaders that these label recommendations are more so due to a presumed loss of efficacy at lower eGFR rather than any specific safety concerns. In fact, the conversation around SGLT-2 inhibitors and renal effects has been dominated by the possibility of renal protection rather than renal safety of late. Merck/Pfizer’s VERTIS CV trial, expected to complete in October 2019, will unveil any cardio/renal protection with Steglatro, and we look very forward to those results.

Evaluation of Fractures, Bone Mineral Density (BMD), and Bone Biomarkers in Patients with Type 2 Diabetes Mellitus (T2DM) Receiving Ertugliflozin

MA Hickman, R Frederich, S Patel, S Gallo, B Lauring, S Terra, S Johnson, U Masiukiewicz, S Huyck, J Mancuso

There was absolutely no difference in bone fractures with SGLT-2 inhibitor Steglatro (ertugliflozin) vs. placebo across the VERTIS clinical program, according to this poster by Dr. Mary Hickman and colleagues. Investigators looked at a broad pool of 4,859 type 2s across seven phase 3 studies of ertugliflozin. In total, there were nine patients on high-dose Steglatro (15 mg) who had a confirmed fracture while on treatment (0.5%), nine on low-dose Steglatro (5 mg, 0.5%), and nine on placebo (0.6%) – that’s quite a compelling balance across treatment arms. Steglatro was not associated with a significant change in bone mineral density (BMD) at the lumbar spine, femoral neck, or distal forearm. After 104 weeks of therapy, there was a larger decline in BMD at the hip with Steglatro vs. placebo or SU glimepiride (-1.7% with 5 mg, -2% with 15 mg, -1.2% with placebo/SU), but this was not deemed to be clinically-meaningful. The poster named weight loss as a contributing factor for BMD decline (and indeed, ertugliflozin stimulates profound weight loss – one of the key advantages to SGLT-2 therapy and one of the key disadvantages to SU therapy), attributing ~10% of the between-group BMD differences to changes in body weight. Additionally, the poster reported small increases in serum phosphate and serum magnesium with Steglatro vs. placebo/glimepiride, but the clinical significance of these marginal changes has yet to be determined.

• Bone health has been an especially hot topic in the context of SGLT-2 therapy ever since CANVAS (for J&J’s Invokana) reported at ADA last year. The CVOT found compelling CV and renal risk reduction with canagliflozin vs. placebo, but also revealed a nearly two-fold risk for lower limb amputations (HR=1.97, 95% CI: 1.41-2.75, p<0.001). Fractures were also more common with Invokana vs. placebo (HR=1.23, 95% CI: 0.99-1.52), though this relationship did not show statistical significance and appeared only in CANVAS (HR=1.55, 95% CI: 1.21-1.97), not in CANVAS-R (HR=0.86, 95% CI: 0.62-1.19). There was an imbalance in amputations across the VERTIS program (3 patients on 5 mg ertugliflozin, 8 patients on 15 mg ertugliflozin, only 1 patient on placebo), but this was not statistically significant and importantly, it’s not an official black box warning on the Steglatro label. FDA did add a black box warning to all canagliflozin-containing medicines in May 2017, after an interim analysis of the CANVAS dataset. This post-hoc analysis lends additional reassuring evidence about Steglatro’s safety when it comes to bone health, and we imagine this will be important as Merck/Pfizer work to penetrate the market with their new product (which is joining a class of Invokana, Lilly/BI’s Jardiance, and AZ’s Farxiga).

• To be clear, we haven’t heard from anyone in the diabetes field that amputation/bone-related concerns should deter HCPs from prescribing SGLT-2s, because the base rate of amputations is very low even in a diabetes patient population, and because the benefits to SGLT-2s far outweigh the possible risks – after all, these agents offer impressive reductions in glucose, body weight, blood pressure, and even CV/renal complications. Nonetheless, it’ll be valuable for real-world patients/providers to see compelling safety data on all of these products, including new-kid-on-the-block Steglatro, which just launched in the US in 1Q18.

Efficacy and Safety of Ertugliflozin Across Racial Groups in Patients with Type 2 Diabetes Mellitus

J Liu, L Tarasenko, A Pong, S Huyck, L Wu, J Mancuso, S Terra, B Lauring

This poster broke down major results from the VERTIS program by participant race, whether White (n=1,134), Black (n=102), Asian (n=233), or Other (n=75). Merck/Pfizer’s SGLT-2 inhibitor Steglatro (ertugliflozin) showed significant efficacy vs. placebo across groups, lowering A1c, stimulating weight loss, and reducing blood pressure. The data for A1c-lowering (over 26 weeks) is summarized in the table below, and results followed the same pattern for weight loss and blood pressure decline, with one exception – there was a larger drop in systolic blood pressure in Black participants compared to other racial groups, favoring Steglatro. This wasn’t discussed in-depth on the poster, but it seems that Black patients randomized to placebo saw a larger jump in systolic blood pressure vs. the placebo arm of any other racial group, which led to higher placebo-adjusted values. It’s important to acknowledge the difference in sample size across these four subgroups, for one because it explains the wider confidence intervals for Black, Asian, and Other, and also because it highlights the under-representation of minorities in clinical trials. In our view, it’s imperative that diabetes clinical trials start recruiting more diverse participants, as this disease disproportionately affects minorities. Of course, we understand that clinical trial recruitment is its own beast, with its own set of challenges, but we hope to see diversity become more of a priority in this process. Limitations aside (i.e. small sample size for minorities), this analysis is definitely positive for ertugliflozin, and we’d love to see this product widely used in the real-world type 2 diabetes population. Merck/Pfizer launched Steglatro to US pharmacies in 1Q18, so it’s fairly new to market. The ertugliflozin franchise also encompasses fixed-dose combinations Segluromet (ertugliflozin/metformin) and Steglujan (ertugliflozin/sitagliptin).

Placebo-Adjusted A1c Results, 26 Weeks

	Overall A1c change (95% CI)	White A1c change (95% CI)	Black A1c change (95% CI)	Asian A1c change (95% CI)	Other A1c change (95% CI)
5 mg ertugliflozin	-0.8% (-0.9%, -0.7%)	-0.8% (-1.0%, -0.7%)	-0.7% (-1.2%, -0.2%)	-0.8% (-1.1%, -0.5%)	-0.3% (-0.9%, +0.3%)
15 mg ertugliflozin	-0.9% (-1.0%, -0.8%)	-1.0% (-1.1%, -0.8%)	-0.8% (-1.3%, -0.3%)	-1.0% (-1.3%, -0.8%)	-0.9% (-1.5%, -0.3%)

Real-World Comparative Effectiveness, Treatment Patterns, and Costs in Type 2 Diabetes Mellitus (T2DM) Patients Initiated on Canagliflozin 300 mg (CANA) or a Glucagon-Like Peptide-1 Receptor Agonist (GLP-1)

M Singhal, H Tan, C Coleman, WH Herman, J Cai, M Han, M Ingham

This study found that type 2 diabetes patients initiated on J&J’s SGLT-2 inhibitor Invokana (canagliflozin) had similar A1c values, greater adherence, less discontinuation, and lower treatment costs compared to patients started on a GLP-1 agonist. This was a retrospective observational study based on administrative claims and laboratory data from the HealthCore Integrated Research Database, and it compared patients starting on Invokana (n=755) or a GLP-1 agonist (n=2,146) between April 1, 2013 and February 28, 2016. After 12 months follow-up, there was no significant difference in A1c change between these two groups, implying similar glucose-lowering efficacy from Invokana and GLP-1s. Patients on Invokana were less likely to achieve A1c <7% (27.1% vs. 30.4%), were equally likely to achieve A1c <8% (51.9% vs. 49.7%), and were more likely to achieve A1c <9% (69.4% vs. 61.9%). A greater proportion of patients were adherent to index medication over 12 months with Invokana vs. GLP-1s (47.5% vs. 37.5%, p<0.001). In addition, patients showed a lower likelihood of discontinuing Invokana therapy vs. GLP-1 therapy (49.6% vs. 57.4%, HR=0.78, 95% CI: 0.70-0.99). Regarding medication-related costs, continuous 12-month pharmacy expenses were $1,421 lower with Invokana vs. GLP-1s. Notably, this follows a similar real-world analysis published in March, which found that Invokana treatment would save $3,326 per patient per year compared to GLP-1 treatment; adherence was also markedly better with Invokana vs. GLP-1s in this previous study. What we take from this set of findings is that adherence is easier with SGLT-2 inhibitors (oral agents) vs. GLP-1 agonists (injectable agents) – not a surprising conclusion in and of itself, though it’s interesting to see how adherence translates into cost-savings for the patient and for the health system. Without a doubt, both of these therapy classes offer incredible benefits to patients, and both are vastly under-utilized today. We’ll be curious to see how cost and adherence differences might influence future guideline considerations; of note, the latest ADA/EASD consensus statement draft recommends both GLP-1s and SGLT-2s for cardioprotection, and differentiates between a class that’s more effective in counteracting atherosclerosis (GLP-1) and one that’s more effective in lowering heart failure risk (SGLT-2).

Cost-Effectiveness Analysis of Empagliflozin Compared to Canagliflozin or Standard of Care in Patients with T2DM and Established Cardiovascular Disease

A Kansal, O Reifsnider, J Lee, K Fahrbach, P Gandhi, E Pfarr, and A Ustyugova

This cost-effectiveness analysis found that Lilly/BI’s Jardiance (empagliflozin) achieved better health outcomes at lower costs compared to J&J’s Invokana (canagliflozin). The researchers generated a population of simulated patients and randomized them to either Jardiance + standard of care, Invokana + standard of care, or standard of care alone. They ran a model that included nine possible CV/renal events and select adverse events (genital mycotic infections, kidney injury, lower limb amputation, and bone fracture) based on the endpoints of the EMPA-REG OUTCOME and CANVAS trials. Inputs to the model included survival rates, treatment effect, and occurrence of adverse events based on data from these CVOTs; quality of life parameters; and costs (wholesale acquisition costs for the treatments and acute and long-term costs for each event). The model produced similar hazard ratios for Jardiance vs. standard of care alone as those found in the EMPA-REG OUTCOME trial, confirming its validity. It also found longer survival and fewer adverse effects (lower limb amputations, kidney injury, and bone fractures) with Jardiance compared to Invokana. These more favorable outcomes yielded savings of $1,967 per patient, which were offset by the higher cost of Jardiance (a difference of $1,577 per patient) but still led to net savings of $390 per patient. Based on this analysis, adding Jardiance to standard of care meets ICER’s threshold for cost-effectiveness, with a cost of $24,604 per quality-adjusted life year. These results provide another argument to support the choice of Jardiance as the first-line SGLT-2 inhibitor for patients at high CV risk, a trend we have already seen in clinical practice since FDA added a CV indication to the Jardiance product label. That said, we’ve gathered from thought leaders anecdotally that Invokana is more potent in lowering glucose and body weight compared to Jardiance, and ultimately, we still see a favorable benefit/risk profile for canagliflozin because base rate of amputations is so low. Cost-effectiveness comparisons will only become increasingly important as issues of access/affordability in diabetes persist (and as this epidemic continues to grow), but we suspect that between-class comparisons will be more valuable at the population level than within-class comparisons. That is to say, we imagine being on any SGLT-2 inhibitor is better than being on none of them, especially when the common alternatives for oral diabetes treatment are sulfonylureas (associated with hypoglycemia, weight gain, beta cell burnout, and possible harm) or DPP-4s (well-tolerated but not as potent as SGLT-2s, without weight or CV benefit).

Temporal Trends in the Use of SGLT-2 Inhibitors – The Global DISCOVER Study

M Kosiborod, H Chen, J Cid-Ruzafa, P Fenici, M Gomes, N Hammar, K Khunti, S Pocock, M Shestakova, I Shimomura, F Surmont, F Tang, L Ji

Since the landmark EMPA-REG OUTCOME trial reported positive results at EASD 2015, we’ve been somewhat underwhelmed by sales growth in the SGLT-2 inhibitor class. The SGLT-2 market grew 44% YOY in 2016 (nearing $3 billion) and grew 24% YOY to hit $3.5 billion in 2017 – while these margins are impressive, we might have expected an even steeper climb following EMPA-REG and Jardiance’s (empagliflozin) CV indication. After all, CV disease remains the leading cause of death for people with diabetes, and here’s a drug known to significantly reduce CV death. This poster presented an analysis of the global observational DISCOVER study (n=15,992) and confirmed our sense that SGLT-2 uptake has been “modest” in the wake of EMPA-REG OUTCOME. As background, DISCOVER enrolled nearly 16,000 adults with type 2 diabetes from 38 different countries at the time they were initiating second-line therapy. For this analysis, the authors focused on the 11,706 patients who were not on an SGLT-2 inhibitor at baseline, and who had data recorded at both six and 12 months. Around 10% of this cohort was prescribed an SGLT-2 during the course of follow-up (n=1,138), with only a modestly increased rate of prescription post-EMPA-REG (6% vs. 8%, p<0.001). The poster reported that 10% of SGLT-2 prescriptions pre-EMPA-REG went to someone with macrovascular disease vs. 14% of post-EMPA-REG prescriptions; even though Jardiance and other agents in the class are recommended for people with prior CV events (either officially by FDA, or by diabetes KOLs), that didn’t seem to be guiding prescriptions in the DISCOVER population. History of microvascular complications similarly had no effect on the likelihood of being prescribed an SGLT-2 inhibitor. The authors concluded that SGLT-2 inhibitor use remains low in the real world, and that uptake wasn’t all that stimulated by the readout of EMPA-REG OUTCOME. That said, we’re far from giving up on this therapy class, especially because there are now two positive CVOTs (CANVAS for J&J’s Invokana reported at ADA 2017) and there may be a third by year-end (DECLARE for AZ’s Farxiga), revealing a cardioprotective class effect of SGLT-2s and boosting volume/sales.

Comparative Cardiovascular Effectiveness of SGLT-2 Inhibitors vs. Liraglutide in Routine Care

E Patorno, B Everett, S Schneeweiss, R Glynn, J Liu, and S Kim

Now that two classes of diabetes therapy are considered cardioprotective (GLP-1s and SGLT-2s), people are understandably curious to know how their CV effects differ. This retrospective cohort study found no significant difference in CV morbidity overall in type 2s treated with Novo Nordisk’s Victoza (liraglutide) vs. SGLT-2 inhibitors, though there was a significantly lower risk of hospitalization for heart failure in the SGLT-2 group. Following the results from LEADER, EMPA-REG OUTCOME, and CANVAS demonstrating CV benefits with these agents in an RCT setting, this analysis aimed to compare their effects on CV outcomes in real-world practice. The researchers followed a cohort of patients with type 2 diabetes from a US commercial healthcare dataset who initiated treatment with either Victoza (n=22,066) or an SGLT-2 (n=35,272) between April 2013 and September 2015. They used propensity score matching to create 17,203 pairs of patients with balanced baseline risk factors. After 30 months, there was no significant difference between the two groups in the incidence of the primary composite endpoint of MI, stroke, or hospitalization for heart failure (HR = 1.01, 95% CI: 0.76-1.34), nor was there a significant difference for the expanded composite endpoint (hospitalization for acute MI, unstable angina, ischemic or hemorrhagic stroke, or coronary revascularization) or for MI or stroke hospitalization individually. Notably, patients taking SGLT-2 inhibitors did face 32% lower risk for heart failure hospitalization compared to their counterparts on Victoza (HR = 0.68, 95% CI: 0.52-0.88), which falls in line with major CVOT findings – SGLT-2s have shown a distinct and profound heart failure benefit (enough to spark new outcomes trials investigating their use in chronic heart failure, outside the context of diabetes) while GLP-1s seem to exert their cardioprotection via anti-atherosclerotic effects. Results from this analysis were similar among patients with and without a history of CV disease (that is, secondary and primary prevention populations). This data suggests that there is no clinically meaningful difference in most of the CV benefits of Victoza vs. SGLT-2 inhibitors, but that the oral agents might be the preferred option for patients at risk of heart failure, specifically. Of note, we’ve heard from several thought leaders that they’d recommend GLP-1s for attacking atherosclerosis and SGLT-2s for addressing heart failure risk, if it comes down to this choice: Dr. Naveed Sattar endorsed this view at ESC 2017, Dr. Steven Marso suggested the same at this ADA, and the new ADA/EASD consensus statement for 2018 even makes this distinction between ischemic events and heart failure for choosing cardioprotective diabetes therapy. All this said, it’s worth pausing to note how wonderful it is that we’re even having this discussion – because we have not one, but two diabetes drug classes that help protect patients from adverse CV outcomes, and nobody would have dreamed of this even five years ago (before EMPA-REG was the first positive diabetes CVOT to read out).

Corporate Symposium: Multifaceted Approaches to Treating Type 2 Diabetes (Sponsored by Merck)

Individualization is Key

Carol Wysham, MD (University of Washington, Seattle, WA); John E. Anderson, MD (Frist Clinic, Nashville, TN); Anne Peters, MD (Keck School of Medicine, Los Angeles, CA); Bernard Zinman, MD (Mount Sinai Hospital, Toronto, Canada)

Dr. Carol Wysham chaired this Merck-sponsored symposium focused on medication prescription beyond metformin. Four diabetes care providers shared their approaches to type 2 diabetes management, with an emphasis on second-line therapy choice after metformin. Dr. John Anderson encouraged HCPs to set personal blood glucose targets based on a patient’s hypoglycemia risk, diabetes duration, comorbidities, and CV conditions. As an example, he reminded everyone that a very intensive glucose-lowering regimen might not be ideal for a patient at high risk for hypoglycemia – we implore that HCPs consider advanced drugs (GLP-1s, SGLT-2s, and Novo Nordisk’s basal insulin Tresiba all offer lower hypoglycemia risk) and tools like CGM before switching these particular patients to a higher A1c target. Dr. Carol Wysham directed attention to NAFLD, which is highly associated with insulin resistance and which can progress to NASH. She described the difficultly of diagnosing NAFLD/NASH, which is one reason that this epidemic is on a steep climb. While no drugs are yet FDA-approved for NASH (see our competitive landscape of candidates in development), Dr. Wysham suggested that GLP-1s and SGLT-2s can help, mostly because weight loss is an effective treatment for hepatic conditions. We recently heard the same message from Dr. Tim Garvey at AACE, and we’ve noticed a push of late for endocrinologists to start treating NASH more seriously (because of the overlap with type 2 diabetes, and because of the weight loss component). Next, the esteemed Dr. Anne Peters clarified the difference between clinical depression and diabetes distress, which appears in 18%-35% of diabetes patients (both type 1 and type 2). Dr. Peters advised opening a conversation with patients to explain that diabetes distress is a natural and common response to coping with this chronic disease. She urged that in order to best provide diabetes care, HCPs need systematic reporting systems, sufficient time with patients, and appropriate work-life balance.

• Last but not least, Dr. Bernard Zinman took the stage and presented his paradigm for initial combination therapy. The current time taken to receive additional anti-hyperglycemic therapies after initial failure of metformin is over one year. Dr. Zinman stressed that early combination therapies must give low risk for hypoglycemia and must be weight neutral (if not weight loss-promoting); he noted that documentation in this area is lacking. In his view, Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Merck/Pfizer’s newly-launched Steglujan (ertugliflozin/sitagliptin) are particularly efficacious – it’s too bad in our view that US doctors (and others globally) seem to find combination therapy so challenging.

Adjunct Therapies for Type 1 Diabetes

International Consensus Meeting on DKA Mitigation for Adjunct SGLT-1 and SGLT-2 Inhibitor Treatment in Type 1 Diabetes

Summary of Discussion

Before official ADA programming began, 30 thought leaders gathered in a small Hyatt conference room to start drafting a consensus paper on managing DKA risk in type 1s taking an SGLT inhibitor. After four hours, the group was still far from consensus. Everyone wholeheartedly agreed that the benefits of this drug class in people with type 1 diabetes far exceed the risks; Drs. Satish Garg and Helena Rodbard described dramatic weight loss and how this makes patients want to continue their SGLT regimen, while Dr. John Buse and others emphasized the decreased glucose variability/increased time-in-range. Prof. Thomas Danne, who organized this meeting on behalf of ATTD, mentioned that every single person invited accepted his invitation. “I think that goes to show how people feel about these agents, and wanting to get them distributed to patients with type 1 diabetes safely,” he remarked. We were certainly overwhelmed by the passion in the room, as we’re acutely aware of the unmet need for adjunct type 1 diabetes therapies, and it’s inspiring to know that so many of the most highly-esteemed diabetes docs are committed to this, too. At this stage, there are more questions than answers when it comes to best practices for DKA risk mitigation, but we’re optimistic that this consensus group will help make the practice of SGLTs for type 1 safer in the real world. Sanofi/Lexicon have filed an NDA for SGLT-1/2 dual inhibitor sotagliflozin (intended brand name Zynquista), and AZ is targeting 2H18 for FDA submission of SGLT-2 inhibitor dapagliflozin for type 1. Both sota and dapa have been submitted to EMA for a type 1 diabetes indication, and Lilly/BI will present phase 3 data on empagliflozin in type 1 (the EASE program) on Tuesday. We’re anticipating an FDA Advisory Committee in January, and Prof. Danne set the goal of having a manuscript published by end of 2018, “to be looked at before regulatory meetings.”

There was some disagreement on where this paper should be submitted – Diabetes Care, or a journal more widely-read by PCPs, like JAMA? Dr. Jay Skyler pointed out that primary care providers and hospitalists are an important audience; DKA is less familiar within these healthcare communities, and ER staff might need the most education on how to treat an episode of DKA, since they’re the providers on the front lines. Dr. William Tamborlane captured a key theme of the consensus when he suggested an aim toward recommendations that “educate the uneducated HCPs without tying our hands.” That is to say, diabetologists well-versed in prescribing SGLTs to type 1s may be able to maximize benefit and maintain safety even in those at high-risk for DKA (e.g. more frequent intense exercise, higher starting A1c, etc.). To this end, the group settled on issuing clear and specific guidelines rather than mandatory requirements. Below, we summarize some of the major areas of agreement that emerged from this gathering, as well as some areas of continued debate. We follow that with future directions for research and quotable quotes. We look forward to reading this consensus paper once finalized.

Representatives from Sanofi, Lexicon, AZ, and Lilly/BI lined the back wall of the conference room, but were not active participants in the discussion. Similarly, two representatives from FDA’s Division of Metabolism and Endocrinology Products listened to the conversation but did not comment; they were Drs. Mahtab Niyyati and Mitra Rauschecker. Prof. Danne invited EMA to send representatives but did not hear back. Our two cents is that many people with type 1 diabetes are already taking SGLT-2 inhibitors off-label, and regulatory approval will make this practice much safer overall. The thought leaders acknowledged several times today that we have very limited evidence on SGLT-related DKA in type 1s, because across RCTs there have been <30 events – this group is in a unique position of writing a consensus document that is less data-driven, and is more so built from clinical expertise. Approval of these first oral adjunct treatments would also offer an opportunity for real-world evidence collection on safety as well as efficacy.

• To be sure, there was strong agreement in the room on some points, most notably that these therapies should be approved for type 1 diabetes given the immense clinical benefits of weight loss and increased time-in-range. Dr. Jeremy Pettus suggested starting the consensus manuscript with an explicit emphasis on these benefits, so that HCPs don’t shy away from SGLTs due to a small (but serious) risk of DKA. Others echoed this sentiment, underscoring that DKA risk should be manageable in the real world. The question remains how best to manage it.

  • To maximize efficacy and ensure safety, thought leaders agreed that education will be key. Dr. Anne Peter spoke from her experience prescribing canagliflozin (J&J’s SGLT-2 Invokana) to patients with type 1 diabetes in J&J’s phase 2 trial, when she saw three episodes of DKA. One year later, she was prescribing SGLT-2s to type 1s without running into any DKA. Dr. Peters emphasized the value of teaching providers how to teach their patients (“I learned how to teach DKA risk management,” she said).

  • There was consensus on how to treat DKA when it appears, via the STICH paradigm: STop the SGLT inhibitor + Insulin + Carbs + Hydrate. Thought leaders discussed eating 30g of carbs, injecting insulin, and re-checking ketones every three-four hours, then seeking emergency medical care if necessary. Prof. Danne acknowledged that it’s counterintuitive for a patient to both administer insulin and eat carbs when blood glucose is in-range (the room nodded in agreement); getting this message across to patients, HCPs, and ER staff is thus critical. There were also mentions of checking for pump failure. Importantly, there’s a distinction between ketosis and DKA, and Dr. Chantal Mathieu stressed that DKA is reversible if certain steps are taken swiftly.

  • Not all type 1s are ideal candidates for an SGLT inhibitor, and these drugs shouldn’t be taken in certain scenarios. The experts agreed that patients on a low carb diet probably shouldn’t add an SGLT to their medication regimen. Dr. Peters shared that she sometimes frames this as a choice for her patients: Do you want an SGLT inhibitor or do you want to stick to a low carb diet? She added that the risk/benefit ratio of SGLT inhibitors may be skewed toward risk in patients with lower engagement/adherence (i.e. skipping insulin doses) and in those with limited access to emergency care. In her experience, SGLTs are riskier in her East LA patients vs. her West LA/Beverley Hills patients, and the sad reality is that individuals of lower socioeconomic status, who are more vulnerable to diabetes and its complications, who stand to benefit immensely from an adjunct therapy that improves their time-in-range, body weight, and insulin regimen, these people also face the greatest DKA risk. Of course, access issues are inescapable for any diabetes drug class. Still, it’s upsetting to think that access to care is so closely linked to safety outcomes in the case of SGLT inhibitors as adjunct treatments in type 1. When should patients be told to hold their SGLT inhibitor? The group listed surgery, fasting, and intense physical activity (Dr. Helena Rodbard told the story of one of her patients climbing Machu Picchu in Peru, and leaving her SGLT-2 at home).

  • Wallet cards emerged as a promising safety strategy for anyone with type 1 diabetes taking an SGLT. Dr. Mathieu recommended dedicating one side of the card to risk minimization (e.g. be wary of high alcohol intake) and the other side to treatment (e.g. STICH). To us, this seems like a fairly simple, feasible, and impactful idea. Should these cards originate from the manufacturer and be dispensed at the pharmacy, or be given to patients by their prescribing clinician? How might FDA regulate the language on these cards?

• The morning featured more debate than agreement, however. There was continued discussion on ketone monitoring (how often, and with urine or blood?), insulin adjustments (reduction by how much, and should this come from basal or bolus?), and A1c cutoffs (what threshold, and should insulin optimization always come first?).

  • Ketone monitoring frequency/methodology: As Prof. Danne put it, “if we had a continuous ketone monitor, there wouldn’t be a controversy here.” But the question stands as to how often patients should check ketones. Daily (in the morning)? A few times per week (largely for education purposes)? Only when one feels ill? There was limited agreement on which of these options is best or safest for the majority of patients. Prof. Simon Heller asserted early in the discussion that he would preferably ask all patients for daily ketone checking, because it’s precautionary and because people are more likely to follow a daily routine. Dr. Peters’ personal protocol stipulates daily checking unless the patient feels “100%” (we wonder if that’s too subjective?), and Dr. Paresh Dandona endorsed checking once or twice each week, mostly so that the patient is informed about DKA. Dr. Peters also aptly pointed out that we ask people with diabetes to check their blood glucose every morning, so the concept isn’t unheard of. Notably, Dr. Mathieu was very opposed to the requirement that patients should check ketones every morning. She explained that all the cases of DKA she has witnessed have happened during the day, absent of morning ketones. Moreover, the burden of checking daily for an unlikely event isn’t sustainable; patients will do it for a while and then the practice will fade away (Drs. Mathieu, Pettus, and Tamborlane all agreed on this point). As such, perhaps patients should be taught to check ketones during illness or prolonged activity, and most importantly, when feeling unwell. There were audible murmurs of disagreement when the conversation veered toward “checking ketones only when ill is OK.” Increasingly, we wonder if this will differ drastically by individual patient, making it challenging to write one recommendation for the majority. We did very much appreciate Dr. Garg’s emphasis on the high cost of blood ketone monitoring. He suggested that this will frustrate patients if they aren’t actually detecting a problem. He further underscored that there isn’t concrete evidence that daily checking prevents episodes of DKA. This was not a protocol used in clinical trials.

  • Dr. Ele Ferrannini argued that assessing ketone trends is more important than a single measurement in time: “You can’t find a random occurrence with a random strategy.” If ketones rise in response to insulin limitation, that’s a signal for danger. He also described how DKA is always linked to a recognizable cause. There’s always a trigger, which means there’s always a way to prevent DK from occurring. Dr. George Grunberger echoed this view that DKA is distinctly preventable, referencing AACE’s consensus conference in asserting that DKA can always be traced back to a trigger.

  • Dr. Peters asks patients looking to start on an SGLT-2 off-label to check ketones daily for one-two weeks before initiating the drug. She uses this to understand adherence and to educate patients on how to monitor for ketones; it also allows her to establish a personal baseline for that particular patient, to confirm that he/she isn’t in ketosis on a daily basis without the drug. Dr. Pettus added that these one-two weeks of lead-up also help ensure that the patient has access to ketone testing supplies. Dr. Mathieu pointed out that it can indicate whether a patient is under-insulinized, with the caveat that high morning ketones can be a consequence of overnight hypoglycemia; Dr. Skyler made a plug for CGM to discern this.

  • At what precise ketone level should patients/providers be concerned? Suggested cutoffs were 0.5-1.0 mmol/L (risk of ketosis; repeat check in 30-60 minutes), 1-3 mmol/L (confirmed ketosis of varying severity; take fluids, eat carbs, and bolus insulin), and >3 mmol/L (high risk of DKA; consider going to ER if persistent vomiting and signs of dehydration). Many seemed concerned that the lower end of these recommendations was actually too conservative. Dr. Mathieu explained that the 0.6 mmol/L cutoff used in phase 3 trials was based on insulin pump studies; she described it as a level at which everything is not yet lost and where giving carbs and insulin can solve the problem. Dr. Pettus expressed worry that many patients would sporadically have levels around 0.6 mmol/L, causing undue stress; in his clinic, people with type 1 are taught that anything over 1.0 and certainly 1.5 mmol/L is cause for concern. Dr. Tamborlane stated that for anything <1.0 mmol/L, he’d tell patients to eat, take insulin, and check ketones again at lunch. Dr. Buse added that he doesn’t think the drug even needs to be held at 0.6 mmol/L, especially if the patient knows how to handle it. Once again, we’re moving toward this notion that DKA risk management will have to be personalized.

  • The issue of blood vs. urine ketone monitoring was another point of debate, though there did seem to be some agreement that “urine is fine, but blood is better” (in Prof. Danne’s words). Indeed, the only hurdle to absolute endorsement of blood testing seems to be the prohibitive cost, at ~$1-2 per strip plus another meter (not trivial, especially with daily checking). As Drs. Pettus and Mathieu emphasized, people hate peeing on strips for reasons of both convenience and perceived hygiene. Dr. Mathieu further suggested that checking via urine won’t catch DKA early enough. What’s more, blood checking is faster and far more precise – at ketone levels between ~0.5-0.6 mmol/L, it can be really hard to tell if there’s a problem from urine testing. Moreover, Dr. Ferrannini explained that ketones aren’t always filtered into the urine, depending on hydration level. All this said, urine is better than nothing, and it could make sense for patients to regularly monitor with urine strips and follow up with a blood meter if they sense a problem. We were glad to hear the room call on industry to work with payers and ketone meter/strip manufacturers to make these supplies more affordable and more frequently reimbursed. Dr. Jake Kushner even positioned this as a “business opportunity” for SGLT manufacturers. The idea that ketone strips could be included in the box with an SGLT inhibitor was met with great enthusiasm.

  • Insulin dose reduction: Should basal or bolus insulin be reduced, and by how much? Should this differ based on the molecule used? Dr. Buse advocated that the group create a table of insulin adjustment recommendations by agent (he alluded to differences between sotagliflozin, dapagliflozin, canagliflozin, and empagliflozin). Dr. Garg argued fiercely that basal insulin should be changed minimally, because as he put it, DKA happens when basal insulin gets interrupted. This argument is in line with what Drs. Garg and Dandona discussed at AACE 2018, when they speculated that the lack of a large basal depot in pump users was responsible for the seemingly higher DKA risk in this patient population. This idea that basal insulin offers a baseline level of protection against ketogenesis makes sense to us. On the other hand, Dr. Peters – who has prescribed SGLT-2s off-label to >100 type 1s, with minimal DKA – recommended reducing basal insulin by 10% if the patient is at target A1c or has a history of nocturnal hypoglycemia. Dr. FJ Ampudia-Blasco was another proponent of reducing basal insulin, and he shared that in his practice, they reduce basal by 20% in those close to target and ≤10% in those with higher A1c. Dr. Pettus offered that, per this late-breaker to be presented on Sunday, ~70%-80% of the insulin reduction in inTandem1 and 2 came from bolus insulin doses; we aren’t aware of any data on this from DEPICT, but Dr. Mathieu seemed to suggest that basal was more commonly reduced in that program. As such, both the type and magnitude of recommended insulin reduction seems to remain a point of contention, and again there will be need for personalization of care. Dr. Pettus called for more data on this front, also raising the possibility that a higher SGLT dose might equal greater reduction in insulin dose. We agree that this issue warrants further investigation, and we wouldn’t be surprised if Dr. Peters’ protocol of reducing basal works so well because she’s only been able to use SGLT-2 inhibitors thus far: Is it possible that basal insulin reduction is better for SGLT-2 inhibitors, while bolus reduction is better for SGLT-1/2 inhibitors? This could be sorted out in Dr. Buse’s table. For reference, the inTandem protocol suggested a 30% reduction in first meal bolus, otherwise maximum tolerated standard of care insulin therapy as determined by the HCP. The DEPICT program capped insulin reductions at 20% of the total daily dose; in DEPICT 1, average reductions were 9% for 5 mg and 13% for 10 mg dapagliflozin vs. placebo.

  • Patient selection: Should there be an A1c cutoff or other recommended restrictions on SGLT inhibitor prescription – and if so, what? Much of the disagreement on patient selection centered around whether it’s safe to give an SGLT to a patient who has an A1c around or above 10%-11%. Some felt that the safest way to use these agents would be to help patients already in fairly good control, already highly engaged in their diabetes self-management. Dr. Skyler argued for insulin optimization before starting an SGLT therapy in any type 1 patient. “Even if you’re around 9%, you should be increasing insulin first, not just adding an SGLT-2 inhibitor. Get patients in good control and then smooth things out with the SGLT.” He explained that high A1c is often a sign of under-insulinization, and Dr. Pettus noted that there may be a tendency to prescribe a pill that’s seemingly “easier” without due consideration of how to maximize insulin benefits. At the same time, Dr. Skyler acknowledged that this practice isn’t always possible: “15% of the teenagers in my practice have an A1c >11%, and they’ve been ‘optimizing insulin’ for five years.” Dr. Helena Rodbard look a slightly more liberal view and was unwilling to outright exclude people with an A1c of ~9%-10%, explaining that she just wouldn’t cut back on insulin when adding an SGLT inhibitor in this population.

  • Dr. Ferrannini considered insulin optimization something to recommend but not mandate, and he also cautioned against thinking of SGLT inhibitors as a cure-all for poor glucose control. Others also shied away from the idea of putting hard and fast rules in place, evoking Dr. Tamborlane’s philosophy of “educating the uneducated HCPs without tying our hands.” Dr. Peters added an illuminating dimension when she recounted two sets of patients, the first being older people with type 1, some of whom have CV disease and want an SGLT inhibitor for the cardioprotection, and the second being women with slightly high A1cs who shy away from more insulin because of fear of weight gain. In her words, “I’m more nervous with a higher A1c, but if they aren’t ketotic and they’re willing to work with me, I’ll do it.” Dr. Buse put things aptly when he offered the example that being on a pump is objectively a higher-risk situation, but those patients aren’t going to be excluded. “All of these things are not an absolute…Why even name a number? It’s not like the risk starts at one point.” He described how a hard cutoff just hurts the people hovering around that cutoff.

  • Dr. Garg described another unfortunate reality that people with high A1c, most likely to benefit from an SGLT inhibitor (glucose-lowering, weight loss), might also face higher risk for DKA. That said, while it’s well-established through T1D Exchange data that risk for DKA is generally increased among patients with higher A1cs, it’s unclear how SGLT-related DKA occurs – and it may not be correct to assume that patients with a higher A1c automatically carry risk factors for DKA, or that these risk factors are actually relevant in terms of SGLT-related DKA. There simply isn’t enough data to determine whether patients with a higher A1c see more DKA with SGLT inhibitors – an industry member in the back of the room actually shared the limited evidence they have may even suggest the opposite. Ultimately, though, they and other members of industry sitting in the back of the room confirmed that the number of DKA events in trials conducted to-date is too small to discern real trends.

• The meeting concluded with a rundown of lingering questions and knowledge gaps. Most of this four-hour conversation identified uncertainties to explore further, but there were a few interesting questions that came up only toward the end:

  • Do the CV/renal protective effects of SGLT inhibitors carry over into type 1 diabetes? Dr. Peters noted that many of her older patients with type 1 who also have CV disease ask to start an SGLT-2 inhibitor off-label; they’ve heard of the CV benefits in type 2 diabetes and want to experience the same. JDRF’s Dr. Sanjoy Dutta shared that the organization has been surveying pharmaceutical industry reps as well as KOLs, and has found that there’s some interest in conducting a type 1 CVOT down the road (though the first priority is definitely investigating these agents for glucose control). Dr. Garg was skeptical about the feasibility of this trial, but Dr. Buse defended the plausibility as long as the CVOT enrolls type 1s with established CV disease. We’d certainly be keen to see this CVOT, and it’s good to hear early interest from JDRF. We’ll be curious to hear from Sanofi/Lexicon, AZ, and Lilly/BI on their interest in funding such a CVOT. Notably, a Lilly/BI representative brought everyone’s attention to EMPEROR HF and EMPA-KIDNEY, as both programs will enroll subgroups with type 1 diabetes. These studies of SGLT-2 inhibitor empagliflozin in heart failure and CKD will offer a glimpse at CV/renal protection in type 1. According to ClinicalTrials.gov, people with type 1 diabetes are excluded from AZ’s Dapa-HF and Dapa-CKD.

  • If we have relatively limited data on SGLT use in adult type 1s, use in pediatrics and geriatrics is really an “evidence-free zone.” We expect to see clinical trials enrolling adolescents in the mid-term future, provided sotagliflozin and dapagliflozin are approved for adults with type 1 diabetes. As for the older type 1 patient population, Japan’s Dr. Kotaro Yokote emphasized that it’s not about age, but about self-management capacity: If a patient has cognitive dysfunction, he will definitely face higher risk of DKA, but otherwise SGLTs could have tremendous benefits in the elderly (we loved this sentiment, and couldn’t agree more).

  • Dr. Ele Ferrannini pointed to SGLT inhibitors/physical activity as another “evidence-free zone,” highlighting the possibility for future research. His comments elicited nods from almost everyone around the table.

  • Prof. Simon Heller advised that after this consensus paper is finalized, a prospective study be conducted to rigorously evaluate the proposed protocols for DKA risk management. We don’t yet know what works, and like most things in clinical science, this question demands gold standard RCT evidence. Prof. Heller elaborated, “these opinions are not based on a huge amount of evidence, and to that end, I hope we’re going to actually study whether our protocol is effective. We owe it to patients.”

• There were so many incredible insights shared at this gathering, some too good to paraphrase, and so we bring you quotable quotes:

  • “I had two sisters both randomized in a sotagliflozin trial, one to the study drug, another to placebo. Soon after starting therapy, one loved me and the other hated me, and that speaks to the benefits of these adjunct treatments in type 1 diabetes.” – Dr. George Grunberger

  • “We’re writing this manuscript because we think this drug class is worth it.” – Dr. Jeremy Pettus

  • “I’d rather that some people just not get SGLT inhibitors based on our recommendations, rather than see an epidemic of DKA after these drugs are approved. I’d rather the 20% of patients who could really benefit get this drug.” – Dr. John Buse

  • “My patients have said to me, ‘doc, I’m melting away, I want to keep taking this drug.’ Patients really care about the weight loss with these agents.” – Dr. Satish Garg

  • “People like the weight loss, and what really makes them feel better is that their blood sugars are less variable.” – Dr. John Buse

  • “If we had a continuous ketone monitor (CKM), there wouldn’t be a controversy here.” – Prof. Thomas Danne

  • “AACE hosted a conference on this issue a few years ago, and we found that in every single case, DKA could have been prevented. It was never unexpected; you could always trace it back to a trigger. The conclusion of that conference was that this is a real risk, and let’s make sure that people are educated on safety strategies. You’d hate this class to be damned because people don’t know how to use it.” – Dr. George Grunberger

  • “Let’s scream it loud – DKA can happen at normal glycemia when you’re on SGLT inhibitor therapy.” – Prof. Moshe Phillip

  • “Let’s keep in mind that these recommendations are not for the Anne Peters of the world. We need consensus advice for the people who aren’t as experienced as everyone around this table, but who will encounter type 1 patients who want an SGLT inhibitor, and who may encounter SGLT-related DKA.” – Dr. Chantal Mathieu

Symposium: SGLT Inhibition for Type 1 Diabetes Mellitus Management – How Far Have We Gone?

Empagliflozin “Ease” Development Program to Support Regulatory Approval

Julio Rosenstock, MD (Dallas Diabetes Research Center, TX)

Dr. Julio Rosenstock shared the first phase 3 findings on Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) in type 1 diabetes; these were very high-level topline results (no specific numbers), and a full results presentation is expected at EASD (on October 4). The EASE program (n=1,680) randomized patients with type 1 diabetes to empagliflozin or to placebo. EASE-2 (n=720) and EASE-3 (n=960) both met their primary endpoint of superior A1c reductions with the SGLT-2 vs. placebo after 26 weeks, and very notably, the 2.5 mg empagliflozin dose used in EASE-3 demonstrated significant glycemic efficacy (and weight loss efficacy) without a significant spike in DKA. Jardiance for type 2 diabetes is available in 10 mg or 25 mg pills, and Dr. Rosenstock described the background to evaluating an even lower dose in type 1: 2.5 mg tablets were used in the phase 2 dose-ranging EASE-1 study, and showed remarkably similar effects to the 10 mg tablets. He speculated that 2.5 mg empagliflozin could have hit the “sweet spot” of adjunct oral treatment for type 1 diabetes. We can’t assess this hypothesis until we actually see the EASE data, and we look very forward to EASD for this. Recall that DEPICT-1 showed no imbalance in DKA between AZ’s Farxiga (dapagliflozin) and placebo at 24 weeks, but this serious safety risk appeared in follow-up out to one year. Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin has been linked to elevated DKA risk in all phase 3 inTandem trials so far. On the other hand, DKA does seem to be dose-dependent to some extent, based on our understanding of all DEPICT and inTandem results presented or published to-date. We’re more intrigued than anything else about how 2.5 mg empagliflozin performed in EASE-3, and it would of course be a big win for patients if this formulation uniquely did not show any DKA risk signal (this would seem unlikely but we have not heard KOLs discuss it at length). We’re in wait-and-see mode. Lilly/BI also issued a factual press release about this topline data, which you’ll find here.

EASE-2 + EASE-3 Summary of Results

• Dr. Rosenstock reviewed study design for both phase 3 EASE trials. EASE-2 started with six weeks of insulin optimization, followed by two weeks of placebo run-in. Type 1s were then randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo for 52 weeks total, though the primary endpoint was read at 26 weeks. EASE-3 was similar in design except that there was a fourth treatment arm – 2.5 mg empagliflozin – and there was no trial extension after week 26. It’s important to note that EASE-3 was a relatively shorter study, especially if the conclusion is that this lower dose doesn’t confer excess DKA risk (again, DKA risk did not appear in the first phase of DEPICT-1 but became apparent after a full year of follow-up). Both EASE studies collected three weeks of follow-up data after patients stopped their assigned therapy. Baseline A1c was a mean 8.1% in EASE-2 and 8.2% in EASE-3, while baseline BMI was 29 kg/m² and 28 kg/m², respectively. Mean duration of type 1 diabetes was 23 years in EASE-2 and 21 years in EASE-3; EASE-2 included 41% pump users (the rest MDI) and EASE-3 included 66% pump users (the rest MDI).

• Despite the potential promise of 2.5 mg empagliflozin for type 1, Dr. Rosenstock emphasized that DKA is a real and serious concern when giving therapy that is adjunct to insulin. He shared a conservative perspective on DKA risk management, arguing that all type 1 patients taking an SGLT inhibitor should regularly monitor blood ketones – urine strips are not enough, in Dr. Rosenstock’s view. “I don’t think people with type 1 should be using these drugs without having a blood ketone monitoring tool,” he established, also noting that DKA is preventable if it’s detected early (hence the push for more aggressive and diligent checking). We spent Friday morning in a room full of 30 thought leaders debating questions like this (how often type 1s on an oral adjunct should check ketones, which method they should use, whether basal or bolus insulin should be reduced, etc.), at a gathering organized by Professor Thomas Danne and ATTD. Some shared commentary in line with Dr. Rosenstock’s remarks, while others opt for a less stringent DKA risk management protocol in their clinical practice (currently, SGLTs are only prescribed off-label to type 1s). For example, Prof. Chantal Mathieu suggested that asking a patient to check ketones every morning imposes an undue burden and is unsustainable (meaning people will do it for a few weeks, and then will taper off or stop); she reinforced that in clinical studies, most DKA events occurred randomly during the day in the absence of elevated morning ketones. In Prof. Mathieu’s view, it’s more valuable for patients to learn to check ketones when they feel unwell. This area still has some ambiguity but we believe experts will reach consensus on this front. We’re leaning toward a more conservative approach to DKA risk management as well, because we want to make sure these products are approved for type 1 diabetes and are used safely in real-world patients, though we’re refining our thinking as we continue to absorb insights. As Dr. John Buse put it during the Friday consensus meeting, “I’d rather that some people just not get SGLT inhibitors based on our recommendations, rather than see an epidemic of DKA after these drugs are approved. I’d rather the 20% of patients who could really benefit get this drug.” From our view, there is incredible consensus already that “patient selection” is incredibly important – which patients specifically should be left out is also evolving.

• As for the competitive landscape, AZ has submitted SGLT-2 inhibitor Farxiga (dapagliflozin) for a type 1 indication in Europe and Japan. The company plans to follow-up with an FDA submission in the second half of this year. Sanofi/Lexicon have filed their SGLT-1/2 dual inhibitor sotagliflozin with both FDA and EMA, and recently announced the intended brand name “Zynquista.” In all likelihood, FDA will convene an Advisory Committee meeting to discuss DKA and the risk/benefit profile of SGLT inhibitors in type 1 diabetes. We suspect this will take place in DC around January, and perhaps FDA will consider having one meeting for both AZ’s and Sanofi/Lexicon’s molecules?

• During Q&A, Dr. Rosenstock pointed to the “opportunity” for a post-marketing CVOT in type 1 diabetes with one of these drugs. Given the high cost of running a CVOT, we wonder if manufacturers would ever consider taking this on themselves or whether it would have to be FDA-mandated. We agree it would be incredibly valuable for patients and for the diabetes field. See directly below for Dr. Rosenstock’s comments. As we understand it, BI/Lilly may have data on this front after the heart failure studies appear since the sub-group element has a high number of both type 1 and type 2 patients - we are eager to hear more on this front.

Select Questions and Answers:

Q: Dr. William Cefalu (ADA): Were there any particular CGM parameters you can share?

A: Dr. Rosenstock: There was a significant increase in time-in-range. And there was nice data on glucose variability.

Dr. Cefalu: I guess we’ll hear about it at EASD.

Comment: I would have thought that the renal protection of SGLT-2 inhibitors would be particularly relevant for the type 1 diabetes population, where mortality and reduced life expectancy is particularly seen in those with kidney disease.

Dr. Rosenstock: I totally agree. We’ve done a lot of CVOTs in type 2 diabetes, with more than 200,000 patients involved. I do think there’s an opportunity to do a post-marketing outcomes study in type 1 diabetes with established CV disease, and I hope it’s a requirement.

Should a Cardiovascular-Renal Prevention Outcome Trial with an SGLT Inhibitor Be Warranted in Type 1 Diabetes Mellitus?

David Cherney, PhD (University of Toronto, Canada)

Dr. David Cherney gave the final talk of ADA 2018, on a topic that’s been a major theme of this entire conference: SGLT inhibitors in type 1 diabetes. He outlined compelling reasons to believe that this therapy class could be CV/renal protective for patients with type 1, concluding that there’s an “urgent need” for cardio/renal outcomes trials in type 1 diabetes. While the mechanisms of SGLT inhibition should play out in type 1 diabetes much like they do in type 2 (Dr. Cherney highlighted natriuresis and hypoxia in particular), he acknowledged that we have no “hard evidence for end organ protection.” While Lilly/BI’s EMPA-KIDNEY outcomes trial of SGLT-2 inhibitor Jardiance (empagliflozin) in CKD will include a subpopulation with type 1 diabetes, Dr. Cherney speculated that this will be a small minority of patients, and that sub-analyses won’t be sufficiently powered. Lilly/BI representatives at Friday’s SGLT/DKA consensus meeting noted that the heart failure program around Jardiance (EMPEROR HF) will also enroll some participants with type 1 diabetes, and we imagine Dr. Cherney would have the same reservations about sub-analyses conducted here. In other words, we can’t rely on sub-analyses to yield insights on how SGLT inhibitors affect diabetes complications for people with type 1. (To our understanding, AZ’s parallel Dapa-CKD and Dapa-HF outcomes trials exclude patients with type 1 diabetes.) A recent paradigm shift in type 2 diabetes care has positioned CV risk reduction as a central goal of any treatment plan; the most noticeable change in type 1 diabetes care of late has been growing emphasis on glycemic outcomes beyond-A1c, but to be sure, CV and renal risk reduction are also of key interest for this patient population. Dr. Anne Peters has explained that many of her older patients with type 1 ask for an off-label SGLT-2 inhibitor because they’ve heard about the CV benefits in type 2 diabetes, and they want the same for themselves.

• Dr. Cherney listed several barriers to a type 1 diabetes CVOT as well, giving balance to his presentation. DKA is a small but significant risk associated with SGLT inhibitors, and he implied that investigators may not want to pass out this medicine to thousands of patients until better safety protocol are in place. As a reminder, Dr. Julio Rosenstock’s suggestion earlier in this same symposium was that AZ, Sanofi/Lexicon, or Lilly/BI conduct a post-market CVOT for their molecule in type 1 diabetes; presumably, safety procedures and risk management strategies will be more solid by the time these products reach the market (hopefully starting in mid-2019). We expect more counsel to be sought on this front. Dr. Cherney continued by mentioning the need for creative funding sources (perhaps a public-private partnership) and the need to enrich the patient population with established CV disease or DKD at baseline. He spoke to lessons learned from type 2 diabetes CVOTs in terms of enriching the study population to have an adequately powered trial. He also asked the question, “which outcomes?”, and we’d hope that such a trial would be very thoughtfully designed to measure the endpoints most meaningful in type 1 diabetes. We don’t think it’s too early to start talking about a type 1 CVOT, because we’re optimistic that SGLTs will eventually be approved for this indication, and regardless, we imagine patients will continue to take them off-label (so FDA may as well regulate safety, and research dollars should be invested in elucidating micro and macrovascular effects).

Oral Presentations: Clinical Trials in Type 1 Diabetes

Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type 1 Diabetes – DEPICT-2 Study

Chantal Mathieu, MD (UZ Leuven, Belgium)

Prof. Chantal Mathieu shared the first public results from DEPICT-2, investigating AZ’s SGLT-2 inhibitor dapagliflozin in patients with type 1 diabetes. ADA published a press release on this data simultaneous with the start of her oral presentation. DEPICT-2 (n=813) largely matched DEPICT-1 (n=833) in terms of major efficacy results, although there was an imbalance in DKA events which wasn’t seen in the first trial. After 24 weeks, patients randomized to 5 mg dapagliflozin as adjunct to insulin (n=271) saw placebo-adjusted A1c decline of 0.37%, while those randomized to 10 mg dapagliflozin (n=270) saw placebo-adjusted A1c decline of 0.42% (both p<0.0001). Baseline A1c was 8.4% across the trial. Weight loss was 3% greater in the 5 mg arm vs. placebo and 4% greater in the 10 mg arm vs. placebo (both p<0.0001). Baseline body weight was ~174 lbs (BMI 28 kg/m²). Total daily insulin dose fell 11% regardless of dose relative to placebo (p<0.0001), and at baseline, participants were taking 0.7 units/kg. Prof. Mathieu paused to emphasize the composite endpoint of ≥0.5% A1c reduction without severe hypoglycemia, achieved by 40% of the lower dose group and by 42% of the higher dose group vs. only 20% of the placebo group. DKA occurred in seven and six people from the 5 mg and 10 mg dapagliflozin arms, respectively, which corresponds to event rates of 2% and 3%. There were no instances of DKA reported in the placebo arm. Prof. Mathieu reviewed data on DKA events in pump users vs. MDI, episodes caused by pump failure vs. missed insulin dose, ultimately concluding that there was no clear pattern and DKA is a risk inherent to dapagliflozin and to adjunct type 1 diabetes therapies more generally. She continued, these events were sporadic throughout the 24 weeks of DEPICT-2; they weren’t concentrated toward the beginning of the study, when patients have just started their SGLT-2 prescription. These results and Prof. Mathieu’s comments confirm our sense that DKA is a class effect of adjunct therapies for type 1; even after DEPICT-1, DKA was still a concern for this molecule, and Prof. Mathieu clarified that events were balanced in that earlier study because of a higher rate in the placebo group – this is not surprising from our view, and our focus is still on how the field minimizes the chance of DKA. Now that AZ has submitted dapagliflozin for a type 1 indication to EMA (FDA filing planned for 2H18), and now that Sanofi/Lexicon have submitted sotagliflozin for type 1 to both FDA/EMA, the field needs to establish best practices for DKA risk management. There’s no question in our minds that the benefits far outweigh the risks, and we hope for more answers on DKA risk mitigation in the coming months: How often should patients taking an adjunct SGLT be asked to check ketones? By how much should their insulin dose be adjusted? Basal or bolus reduction? See our coverage of the ATTD Consensus meeting (hosted in conjunction with ADA 2018) for more.

• Prof. Mathieu gave a preview of the CGM data from DEPICT-2 – more granularity on these results came on a late-breaking poster (125-LB). Time-in-range (>70-180 mg/dl) increased 6% in six months with 5 mg dapagliflozin – that’s 1.5 hours per day that a patient spends feeling well, not working to correct hyper or hypoglycemia. In the 10 mg dapa arm, time-in-range grew 8% – that’s nearly two hours (both p<0.0001 vs. placebo). In the placebo group, time-in-range actually decreased 3% (this may not sound like a lot – it’s ~45 minutes/day, which is nearly five days a year!). We cannot emphasize enough the value of time-in-range as an outcome, because of how closely it’s correlated with quality of life (direct relationship) and with diabetes work (inverse relationship). Prof. Mathieu also reported a 10 mg/dl reduction in MAGE with 5 mg dapa (p<0.0001) and a 9 mg/dl reduction with 10 mg dapa (p=0.0001), highlighting the postprandial improvements with this adjunct treatment on top of insulin. There was no significant difference in hypoglycemia across groups.

• DEPICT-2 was a global study enrolling patients from 136 centers across 13 countries. Prof. Mathieu noted that the trial population was in pretty poor control at baseline: Inclusion criteria included A1c between 7.5%-10.5%, and one in five participants entered the study with an A1c >9%. Prof. Mathieu also highlighted the “remarkable retention” of DEPICT-2, explaining that 90% of patients starting on dapagliflozin continued through the six-month mark compared to 88% of placebo-treated patients – good patient selection, of course, and they love it as it fills a gap.

Select Questions and Answers

Q: Did you find that people with higher baseline A1c had more DKA? What was the effect of education?

A: In DEPICT-2, patients were educated to measure ketones when they felt sick. They were also instructed to eat carbs, give bolus, contact a medical team, etc. We looked at all 13 events but couldn’t find a pattern with higher A1c. Most events were random, not only happening at the beginning, but just throughout the six months.

Fifty-Two-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Adults with Type 1 Diabetes (inTandem1)

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

In an absolutely packed oral session, Dr. John Buse presented 52-week inTandem1 results (n=793), reinforcing the glycemic and weight loss benefits of sotagliflozin in adults with type 1 diabetes, while also confirming the DKA risk associated with all SGLT inhibitors in type 1. See the full results in Diabetes Care and the 24-weeks results here. At 52 weeks, sotagliflozin 200 mg gave a 0.25% drop in A1c vs. placebo (p<0.001) and 400 mg gave a 0.31% drop vs. placebo (p<0.001). This compares to placebo-adjusted A1c reductions of 0.36% and 0.41%, respectively, at 24 weeks. There was a noticeable rise in A1c during the trial’s extension period, but still a significant reduction overall. The net benefit endpoint of A1c <7% with no severe hypoglycemia or DKA was observed in 26% of sotagliflozin 200 mg participants vs. 19% of placebo participants, just missing significance (p=0.05). Sotagliflozin 400 mg gave net benefit in 32% of participants, and this was statistically significant compared to placebo (p<0.001). We remain very curious about the relative risk/benefit with respect to dose: Overall, higher doses have been associated with greater risk of DKA, but they also seem more effective on glucose and weight loss. Other endpoints also revealed dose effects of sotagliflozin: 200 mg was associated with a ~4 mg/dl drop in fasting plasma glucose (p=0.028 vs. placebo) vs. ~11 mg/dl with 400 mg (p<0.001 vs. placebo); this compared to a ~9 mg/dl rise in the placebo group. Dr. Buse also shared CGM data from inTandem1, noting a superior effect on 400 mg sotagliflozin vs. the 200 mg dose on pre-meal glucose in the context of overall increases in time-in-range with both doses. Notably, these results were presented alongside DEPICT-2 at the end of an oral presentations session otherwise dominated by tech trials, and Dr. Buse made a point to comment that the time-in-range benefits seen in inTandem1 were “on par with those discussed by speakers earlier in this session.” Exact numbers were not given but pooled CGM data from inTandem1 and 2 showed +1.3 hours and +2.8 hours more time-in-range with 200 mg and 400 mg sotagliflozin. Sanofi/Lexicon have filed sotagliflozin with FDA and EMA for a type 1 indication, and regulatory decisions are anticipated in 1Q19.

• On the all-important safety endpoint of DKA: 11 participants on 400 mg sotagliflozin experienced DKA (4.2% of the group), as did nine participants on 200 mg (3.4%) and one on placebo (0.4%). For a comprehensive take on DKA risk management, see our report on Friday’s SGLT/DKA consensus meeting. These DKA data include events adjudicated as (i) definite DKA and (ii) probable DKA. There were 22 events overall, in 21 patients. For 15 of 22 events, blood glucose at the time of DKA was >250 mg/dl; for the remaining seven, blood glucose was ≥150-250 mg/dl. As such, no truly euglycemic DKA occurred, and Dr. Buse himself has previously identified this as the real challenge, because blood sugar levels don’t alert a patient to anything being wrong. That said, blood glucose between 150-250 mg/dl wouldn’t necessarily cause alarm in most patients with type 1 diabetes. While exact data were not shared, Dr. Buse noted during Q&A that proportionally more DKA events occurred in patients on pumps. He also clarified that participants were instructed to check ketones when feeling unwell; in his practice, they were also told to check intermittently as general practice, though we understand that this was not part of the official inTandem1 protocol. Participants were given both blood and urine ketone testing supplies. Genital mycotic infections were also increased in the 200 mg (9%) and 400 mg (13%) groups vs. placebo (3%), as is to be expected for an SGLT inhibitor.

• Weight loss continued through 52 weeks, and there was a significant benefit with 400 mg over 200 mg sotagliflozin. From a baseline ~192 lbs, participants in the 200 mg group lost a mean ~7 lbs vs. placebo, while those on 400 mg of the drug lost a mean ~10 lbs vs. placebo. This represents a respective increase over ~5 lbs and ~8 lbs at week 24, driven by both weight loss in the sotagliflozin groups and ~2 lbs weight gain in the placebo group. Based on the graph in Dr. Buse’s presentation, it was clear that weight loss in the sotagliflozin groups did not level off over the 52 weeks, reflecting what Lexicon sees as one of the key benefits of the dual SGLT-1/2 inhibitor mechanism.

• Sotagliflozin was associated with a numerical but non-significant benefit on severe hypoglycemia. In the placebo group, 26 people (10%) experienced an episode of severe hypoglycemia, which was reduced to 17 (7%) in the 200 mg group and an identical 17 (7%) in the 400 mg group. In our view, this trend is quite clear (we’ll be interested to see full data from the rest of the inTandem program), and indeed, Lexicon has expressed its intention to make hypoglycemia data a key component of the overall sotagliflozin risk/benefit profile. While it may be tricky to do so without a significant result, we do think this could be a genuine benefit of the overall flatter glucose profile that sotagliflozin treatment offers.

• inTandem1 also found significant improvements in patient-reported outcomes with both sotagliflozin doses, maintained at 52 weeks. Participants completed the Diabetes Distress Scale, and both 200 mg (p=0.003) and 400 mg (p<0.001) were associated with significant drops in diabetes distress score vs. placebo. 

• Dr. Buse showed that bolus insulin was reduced more than basal insulin in participants on sotagliflozin. In inTandem1, basal dropped 2% and 6% (p<0.001 vs. placebo) while bolus rose 2% (p=0.23) and dropped 9% (p<0.001), with 200 mg and 400 mg respectively. In inTandem2, basal dropped 4% in both sotagliflozin groups (p=0.006), while bolus fell 4% (p=0.08) and -8% (p=0.06). Reduction of basal vs. bolus insulin is becoming an increasingly hot topic in terms of minimizing DKA risk (see an in-depth discussion of this issue here), and it seems like the best methods for reducing insulin might differ based on which SGLT is being used. For a deeper dive on insulin reduction in inTandem, see 5-LB from Dr. Jeremy Pettus, to be presented on Monday; this analysis shows that ~70%-80% of total insulin reduction in these two studies came from bolus insulin. For inTandem1, total daily insulin dose (TDD) fell by 4% with 200 mg and by 9% with 400 mg (both p<0.001 vs. placebo). For inTandem2, TDD fell by ~6% with 200 mg (p=0.002) and ~8% with 400 mg (p<0.001). TDD rose by 4% and 1% in respective placebo groups.

• Pooled CGM data from inTandem1 and 2 were presented in another poster, showing that sotagliflozin offers 1.3 to 2.8 more hours per day in-range (70-180 mg/dl) vs. placebo, according to a 278-person blinded CGM sub-study. On a primary endpoint of percent time-in-range at week 24, 200 mg sotagliflozin gave an additional 1.0 hr/day in range vs. baseline and 1.3 hrs/day vs. placebo (p=0.026), while 400 mg sotagliflozin gave an additional 2.5 hrs/day vs. baseline and 2.8 hrs/day vs. placebo (p<0.001). While time-in-range for the placebo group (n=93) remained constant at 52%, it rose from 52% to 58% with 200 mg (n=89) and from 51% to 64% with 400 mg (n=96). Mean daily glucose fell an average of 6 mg/dl in the 200 mg group (p=0.09 vs. placebo) and 17 mg/dl in the 400 mg group (p<0.001 vs. placebo), rising 2 mg/dl in the placebo group. Postprandial glucose also declined ~35 mg/dl and 50 mg/dl in the sotagliflozin groups compared to placebo (p<0.001 for both), a very compelling effect that the authors attribute to SGLT-1 inhibition in the proximal intestine. MAGE results followed a corresponding pattern, dropping 16 mg/dl (p=0.022) and 25 mg/dl (p<0.001), respectively, in the sotagliflozin groups and 3 mg/dl in the placebo group. Lexicon released topline data on this sub-study last September, and these data offer a fuller picture of the time-in-range and dose dependent benefits to sotagliflozin. Notably, time spent in hypoglycemia was not significantly affected, though small reductions were observed (i.e. the effect trended in the right direction); thus, the time-in-range benefit occurs almost entirely through reduced time spent >180 mg/dl. We remain convinced that time-in-range is perhaps the most important benefit type 1s get from SGLT inhibitors, and Lexicon has confirmed that this pooled CGM data is included in the regulatory submissions for Zynquista (the intended brand name, which we love!). Still, it’s unclear whether and how FDA/EMA might consider these data. We truly hope that FDA takes CGM findings into account when weighing the risk/benefit profile of these agents; spending an additional ~1-3 hours per day not worrying about or trying to correct hyperglycemia or hypoglycemia should translate to a serious quality of life benefit for patients.

Oral Presentations: From Progression to Management in Type 1 Diabetes – What Is New?

Metformin Improves Insulin Resistance (IR) and Vascular Health in Youth with Type 1 Diabetes (T1D)

Kristen Nadeau, MD (University of Colorado, Aurora, CO)

Dr. Kristen Nadeau presented new data from the EMERALD study revealing potential CV benefits of adjunct metformin therapy in youth with type 1 diabetes. Type 1s between age 12-21 (n=49) were randomized to metformin or placebo as adjunct to basal/bolus insulin for three months. Compared to those on placebo, participants on metformin experienced significant improvements in insulin resistance (p<0.01), aortic pulse wave velocity (-1.1 m/s vs. +4.1 m/s, p<0.04), aortic wall shear stress (-0.03 N/m² vs. +0.2 N/m², p=0.03), and carotid intima media thickness (cIMT), a common surrogate marker for CV risk (p=0.04). Additionally, metformin had marked effects on body composition, reducing body weight by ~1 lb vs. +3 lbs with placebo (p=0.004), BMI by 0.19 kg/m² vs. +0.44 kg/m² (p=0.005), and fat mass by ~1.5 lbs vs. +1.2 lbs (p=0.01). Metformin use was associated with no significant changes in A1c, blood pressure, LDL, HDL, triglycerides, or peripheral measures of arterial stiffness and function in this population. Dr. Nadeau hinted that the research team is still analyzing data on cardiac, renal, and mitochondrial function with metformin in type 1 diabetes, and we’re looking forward to learning the fuller picture.

• Dr. Nadeau suggested that these results bode well for the use of metformin as a cardioprotective intervention in youth with type 1, though we’d note that metformin has a rather mixed history when it comes to CV effects in this patient population. One year ago at ADA 2017, the JDRF-sponsored REMOVAL trial failed to show metformin’s CV efficacy on the primary endpoint of decreased mean cIMT over three years. While the tertiary outcome of maximal cIMT increased at a significantly slower pace in the metformin-treated group (0.012 mm/year) vs. the placebo group (0.25 mm/year, p=0.0093), our sense is that most thought leaders consider REMOVAL to be a resoundingly neutral study. REMOVAL comprised an adult patient population, and perhaps there are meaningful underlying differences of youth type 1 diabetes. In any case, the present findings add more data in favor of a beneficial CV effect for metformin in type 1 (albeit in a small study population). What we really need to reach conclusions on this question is a larger, longer study investigating hard CV outcomes with metformin (as opposed to these CV biomarkers), but the issue of funding remains (we’d love one of the three traditional funders – NIH, JDRF, or the Helmsley Charitable Trust). In the meantime, since many type 1s do take metformin off-label in the real world (for additional glucose-lowering, weight loss, etc.), it’s encouraging to see continued clinical research on this front and to get confirmation of safety with possible CV efficacy.

• Dr. Nadeau stressed that the primary rationale for adjunct therapy in type 1 diabetes is improvements in beyond-A1c outcomes, e.g. the vascular benefits observed in this study. These are especially important in light of the fact that people with type 1 diabetes, even youth, have elevated CV risk factors. In this study, participants with type 1 had greater vascular dysfunction (elevated aortic pulse wave velocity and aortic wall shear stress) compared to age- and BMI-matched controls without diabetes. In addition, the elevated insulin resistance seen in people with type 1 diabetes has a well-established relationship with CV morbidity.

Joint ADA/JDRF Symposium: Current Management of Type 1 Diabetes in Youth – What are the Options?

Beyond HbA1c – How Are We Managing Type 1 Diabetes Mellitus Comorbidities?

Peter Bjornstad, MD (Children’s Hospital Colorado, Aurora, CO)

Dr. Peter Bjornstad anchored a joint ADA/JDRF symposium with an emphasis on outcomes beyond A1c. He implored healthcare providers to move past glucose centricity and to place a more substantial focus on CV and renal risk reduction. Dr. Bjornstad began his talk with a summary of clinical trial data, showing that efficacy results of most cardioprotective drugs in type 1 diabetes are mixed at best. His overview covered statins (some positive CV effects in observational studies, but trials mostly negative), RAAS inhibitors (no reduction in albuminuria), metformin (some evidence of improved insulin sensitivity but data inconsistent, plus the REMOVAL trial found no cardioprotective benefit), and SGLT inhibitors (some blood pressure-lowering and attenuated hyperfiltration). Many of the studies he addressed found effects on some CV biomarkers but not others, which raises the question: Which biomarkers should we prioritize? (This is assuming that a full-fledged CV outcomes trial in type 1 diabetes is out of the question for the near-term future, but not forever.) Dr. Bjornstad implied that conventional biomarkers of CV and renal disease may not be completely trustworthy – in this category, he grouped albumin excretion, eGFR, and snGFR. He proposed a number of alternative CV/renal biomarkers, including eGFR measured by iohexol clearance or inulin clearance, kidney biopsies, measuring PWV or Alx, testing VO2 peak, or performing cardiac MRIs and myocardial perfusions. By optimizing our biomarkers, Dr. Bjornstad believes we can design enriched outcomes trials of high risk individuals displaying higher event rates, which increases the speed and sensitivity with which we can determine cardio/renal protective properties. In other words, Dr. Bjornstad sees biomarkers as a means to an end for a well-designed CVOT in type 1 diabetes – he didn’t suggest that studies of biomarkers could replace the insight offered through a full-fledged CVOT. In particular, he expressed his hope that a long-term outcomes study will reveal CV/benefits to SGLT inhibitor therapy in type 1 diabetes. We heard a similar sentiment from Dr. Anne Peters at the ATTD-sponsored consensus meeting on DKA with SGLT use in type 1 (she shared that many of her type 1 patients know about the CV benefits in type 2 diabetes and want the same cardioprotection for themselves). We’d also note that this was a major topic of discussion at ADA in general, and in fact, the very last talk of the meeting was Dr. David Cherney outlining the rationale for a type 1 diabetes CVOT (he called it an “urgent need”). Other thought leaders, including Dr. Satish Garg, have been skeptical about the feasibility of a CVOT conducted entirely in type 1 diabetes; securing funding could be a challenge, and Dr. Cherney suggested creative methods, perhaps a public-private partnership. We’d most certainly love to see a type 1 diabetes CVOT (after all, CV morbidity among type 1s remains a substantial unmet need), and we were intrigued by Dr. Bjornstad’s ideas on optimizing biomarkers.

Questions and Answers

Q: You didn’t talk much about genetics. What do you think about genetics, and really all the -omics of these people?

A: I think genetic risk factors are extremely important. They tie into loss of nephron numbers as well. If you are born with fewer nephrons then you are also more likely to lose them more quickly.

Q: I just wanted to note the apparent similarity between the heterogeneity of beta cell loss and nephron loss.

A: This is exactly right – there is not one type of diabetic kidney disease, or one type of nephron loss. It is a multifactorial process and is confounded by genetic factors.

Oral Presentations: SGLT-2 Inhibitors – From Mechanisms to Clinical Trials (With ADA Presidents' Select Abstract)

ADA Presidents' Select Abstract: Mechanism by Which Dapagliflozin Induces Euglycemic Ketoacidosis in Rats

Rachel Perry, PhD (Yale University, New Haven, CT)

Yale’s Dr. Rachel Perry presented this select abstract suggesting that SGLT-2 inhibitor induced DKA requires the confluence of two events – reduced insulin level + volume depletion. Dr. Perry’s work investigates the mechanism of increased DKA risk due to SGLT-2 inhibitor treatment, and her team has found that dapagliflozin (AZ’s Farxiga) causes plasma volume depletion and induces a cascade of increases in glucocorticoids and catecholamines that stimulate lipolysis, ketogeneis, and eventually euglycemic ketoacidosis. Treatment of Sprague-Dawley rats with dapagliflozin increased the rate of hepatic ketogenesis vs. treatment with placebo (35 μmol/kg-min vs. 136 μmol/kg-min, p<0.0001). This led to volume depletion which sparked a rise in plasma catecholamine (epinephrine 0.5 nM vs. 7.3 nM, p<0.001; norepinephrine 2.5 nM vs. 19.8 nM, p<0.01) and elevated corticosterone (115 ng/ml vs. 233 ng/ml, p<0.01) relative to placebo. Dr. Perry described how these effects occurred simultaneously with a dapagliflozin-mediated reduction in insulin levels (p=0.004), culminating in DKA. We are intrigued by this insight into DKA physiology, as this safety issue remains a significant concern when it comes to the otherwise extremely promising class of SGLT inhibitors for type 1 diabetes. We wonder if increased emphasis on sustaining fluid levels can help to reduce DKA events related to SGLT therapy. To be sure, hydration was repeatedly recommended by thought leaders at the ATTD consensus conference on DKA risk management for type 1s taking an SGLT inhibitor.

• Dr. Perry emphasized that volume depletion is necessary but not sufficient in order for a DKA episode to occur. In her investigations, rodents treated with dapagliflozin show significant (p<0.01) increases in corticosterone, epinephrine, and norepinephrine levels along with significant (p<0.001) increases in fatty acid turnover, hepatic acetyl coA levels, and endogenous glucose production. However, these increases in markers of steroid production, lipolysis, and gluceoneogenesis were dependent on the volume depletion effect of dapagliflozin. When rodents were treated with both dapagliflozin and saline injections, these levels decreased to those of the control group. Thus, Dr. Perry concluded that volume depletion is necessary for DKA to occur, but she went on to explain why volume depletion on its own is not sufficient to provoke ketosis. When treated with the diuretic furosemide, plasma beta-hydroxybutyrate concentrations and turnover rates did not significantly change from control, indicating the failure to induce ketosis with this intervention. Conversely, these measures were significantly different upon treatment with dapagliflozin. Drawing on these observations, Dr. Perry underscored that an insulin-lowering effect is needed in conjunction with volume depletion to cause a DKA event. In line with this, thought leaders have stressed that treating DKA requires both glucose and insulin (as counterintuitive as this may feel for patients, caregivers, ER staff, etc.).

• Could the volume depletion effects of SGLT inhibitors be a target for the prevention of SGLT-related DKA? Dr. Perry raised this intriguing possibility. Seeing as volume depletion was necessary to cause DKA, she proposed this as a potential action point to minimize DKA risk. Although she didn’t go into specifics, we’re definitely interested in this idea, and we’d note that any intervention would ideally preserve all the benefits to SGLT therapy while mitigating DKA risk.

Product Theaters

Improving Glycemic Control in Type 1 Diabetes – The Role of Insulin-Independent Pathways (Sponsored by Lexicon/Sanofi)

Yehuda Handelsman, MD (Metabolic Institute of America, Tarzana, CA)

In a packed lunchtime session, Dr. Yehuda Handelsman highlighted the unmet need for adjunct therapies in type 1 diabetes. As well, he advocated for a perspective shift to emphasize outcomes beyond A1c. Dr. Handelsman established hypoglycemia, hyperglycemia, and time-in-range as equally important metrics of successful type 1 diabetes management, citing one study in which a patient with A1c <7% was still spending nine hours a day out of range. Moreover, he showed that time-in-range is deeply important to patients: In another study, “blood glucose numbers in range all day” was far and away the number one factor for emotional well-being among type 1 patients (Runge et al., 2017). Dr. Handelsman professed hope that SGLT-1s, SGLT-2s, and even GLP-1s and glucagon could be effective adjunct therapies in type 1, and he stressed the importance of increasing research on their efficacy. To be sure, there’s plenty of published data pointing to the value of SGLT inhibitors in type 1 diabetes (this was a major theme of ADA 2018 overall), and two molecules have already been submitted to regulatory authorities for a type 1 indication (Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin and AZ’s SGLT-2 inhibitor dapagliflozin). Why do we need adjunct therapies? Dr. Handelsman discussed sobering numbers on current type 1 diabetes care with insulin alone, which include very high rates of hypoglycemia, weight gain and obesity concerns, and the emotional burden of day-to-day management. SGLT inhibitors could help address all of these current problems – according to Dr. Satish Garg, the weight loss associated with these agents keeps type 1s coming back for more of the drug, and Dr. John Buse has noted that greater time-in-range is the most apparent benefit for type 1s (currently using these drugs off-label). Dr. Handelsman mentioned 8-13 years lower life expectancy for type 1s vs. the background population, 75% of patients not reaching A1c <7% as recommended by ADA, patients averaging two episodes of symptomatic hypoglycemia per week, and 51% of patients reporting nocturnal hypoglycemia as their biggest worry. All of these concerns contribute to patients not taking insulin as prescribed and lead to worse clinical and quality of life outcomes. We are in complete agreement with Dr. Handelsman regarding the need for adjunct type 1 therapies and regarding the push toward time-in-range and other glycemic outcomes beyond A1c. We were particularly excited to see a large number of audience hands go up when asked “do you emphasize the importance of time-in-range to your patients?” and “do you try non-insulin methods for treating your T1D patients?”.

Posters

Liraglutide as an Additional Treatment to Insulin in Patients with Type 1 Diabetes Mellitus – A 52-Week Randomized Double-Blinded Placebo-Controlled Clinical Trial

P Dandona, H Ghanim, ND Kuhadiya, T Shah, JM Hejna, A Makdissi, M Batra, A Chaudhuri

Is there still hope for GLP-1s as adjunct therapy in type 1 diabetes? Novo Nordisk declined to move forward with liraglutide for type 1 after modest phase 3 results, but Dr. Paresh Dandona conducted another year-long trial in which the agent showed promise. We note that this was a much smaller study (n=46) than Novo Nordisk’s ADJUNCT ONE (n=1,398), but we were nonetheless struck by the 0.6% placebo-adjusted A1c decline with liraglutide (p=0.006), from a baseline 7.9%. For context, liraglutide gave a placebo-adjusted A1c reduction of only 0.2% in ADJUNCT ONE, and Dr. Dandona’s RCT found glycemic benefit on par with SGLT inhibitors in type 1 diabetes (e.g. 0.4% estimated treatment difference with dapagliflozin in DEPICT-2). Placebo-adjusted weight loss was ~6 lbs on average with adjunct liraglutide (baseline ~185 lbs, p=0.041). There was no significant difference in total daily insulin dose between the two treatment arms at the end of the trial. Moreover, hypoglycemia events and time spent <70 mg/dl were balanced across groups; however, CGM was only used for four weeks total, and we wonder what the time-in-range data would look like across all treatment exposure. Importantly, these findings all trend in liraglutide’s favor, whereas results in ADJUNCT ONE were more mixed. That liraglutide (branded as Victoza for type 2 diabetes) could offer type 1s additional glucose-lowering without additional hypoglycemia risk is an exciting prospect, and we wonder if there’s lingering interest in pursuing a type 1 indication for this drug. Victoza’s patent expiry is somewhat imminent (expected around 2022/2023). Perhaps generic liraglutide could be an effective and highly-affordable adjunct to insulin for people with type 1 diabetes, if further clinical trials corroborate what we saw on this late-breaking poster. ADA also issued a press release alongside. One thing’s for sure: There is so. much. enthusiasm. for adjunct type 1 diabetes therapy at this meeting.

• In a call with our team, Novo Nordisk's CMO in North America Dr. Todd Hobbs said it's unlikely the company will revive the type 1 program for Victoza. He elaborated on the ADJUNCT study results, explaining that investigators saw a lot of heterogeneity. Some people with type 1 diabetes experienced meaningful A1c-lowering and weight loss, while others didn't respond as positively, lead