May 3-7, 2017; Austin, TX; Full Report – Draft

Executive Highlights

Hello from the Live Music Capital of the World, where this week the music was accompanied by live presentations from AACE 2017! Diabetes tech sessions featured several heavy hitters, including two major pieces of Medtronic closed loop news: First, Dr. Moshe Phillip broadcasted that Medtronic's Advanced Hybrid Closed Loop (with automatic correction boluses) will “hopefully launch toward the end of next year (the first timing we have heard!), and second, Dr. Bruce Bode shared real-world 670G data from the priority access phase (n=~560). On the therapy side, a joint Amgen and Sanofi/Regeneron-sponsored town hall on PCSK9 inhibitors highlighted how more detailed, standardized guidelines are helping push for greater reimbursement of these agents. We also heard from the great Drs. Ralph DeFronzo and Ken Fujioka on comorbid chronic kidney disease and type 2 diabetes and precision medicine in obesity, respectively. When we weren’t in sessions with some incredible thought leaders (Drs. Anne Peters, George Grunberger, William Tamborlane, Judith Fradkin, and the list goes on…), we visited the spectacular AACE exhibit hall. This document includes our coverage of 16 booths from A-to-V, Abbott to Valeritas, and everything (alphabetically) in between. See below for updates from Tandem and TypeZero, Dr. Alan Garber on the level of evidence for the cardioprotective benefit of GLP-1 agonists vs. SGLT-2 inhibitors, Dr. Timothy Garvey on AACE’s new name for obesity (adiposity-based chronic disease, or ABCD) – plus much, much more. 

Detailed Discussion and Commentary

Meet-the-Experts

SGLT2 Inhibitors Town Hall: Renal Microscope - Benefits and Concerns

Ralph DeFronzo, MD (University of Texas Health Science Center, San Antonio, TX), Matthew Weir, MD (University of Maryland School of Medicine, Baltimore, MD)

In a deep-dive session on the renal effects of SGLT-2 inhibitors, both Drs. Ralph DeFronzo and Matthew Weir were extremely positive about the renal benefit of these agents and expressed strong confidence that the benefits extend to all members of the class. While acknowledging the mechanistic pathway in which SGLT-2 inhibitors can increase risk of diabetic ketoacidosis (DKA), both thought leaders emphasized that this is a rare and manageable adverse event in type 2 diabetes. As Dr. Weir put it, “The risk is vanishingly small relative to the cardiorenal protection.” Though renal outcomes were only a secondary endpoint in the EMPA-REG OUTCOME CVOT for Lilly/BI’s Jardiace (empagliflozin), both Drs. DeFronzo and Weir were impressed and excited by the data suggesting a renal-protective benefit for the agent. Both speakers acknowledged that the CREDENCE renal outcomes trial for J&J’s Invokana (canagliflozin, expected completion January 2020) will provide more definitive evidence (and potentially support a renal indication), but and Dr. DeFronzo passionately stated, “I will drop dead if these drugs don’t give us renal protection.” Indeed, Dr. Weir pointed out that SGLT-2 inhibitors have impressive benefits on blood pressure and albuminuria and “if renal outcomes don’t point in the right direction, it raises questions about everything we’ve learned about RAAS inhibitors in the treatment of diabetic nephropathy.” Further, Dr. Weir suggested that there’s no reason to believe that there are within-class differences between the agents, though he acknowledged that it’s difficult to say with 100% certainty without a head-to-head study,  (which manufacturers are unlikely to conduct (though presumably we could learn something from big data on this eventually). Overall, Dr. Weir emphasized that the upside to SGLT-2 inhibitors – both from a cardiovascular and a renal standpoint – is “substantial.” Dr. DeFronzo characterized EMPA-REG OUTCOME, along with positive GLP-1 agonist and TZD pioglitazone CVOTs, as heralding a new era of diabetes care in which we are going beyond glucose control to impact CV and renal outcomes. He suggested that it would be great to see outcomes studies of some of these agents in combination, in order to better understand if, say, empagliflozin and liraglutide have additive or synergistic effects on long-term outcomes. We would love to see this as well. Since , though such a study would likely be quite lengthy and costly,  – we’re curious if real-world data might be able to shed some light on this topic in lieu of a long-term randomized, controlled trial. The cost of this trial is, of course, extremely low compared to the billions of dollars spent each year on CV and kidney disease in people with diabetes. While a well-designed ambitious outcomes trial would cost in the hundreds of millions, tens of billions are spent annually on these presumably avoidable complications.

Interpreting Lipid Guidelines: How Low Should You Go?

Paul Jellinger, MD (Memorial Healthcare System, Fort Lauderdale, FL)

An Amgen- and Sanofi/Regeneron-sponsored town hall on PCSK9 inhibitors provided offered some hope for for a future of better reimbursement in the future. (i) For one, the 2017 AACE guidelines on dyslipidemia, published in February,  have established , for the first time, an extreme risk group that should be treated to a target of LDL <55 mg/dl – l, and  PCSK9 inhibitors are the most effective agents to get there. Dr. Paul Jellinger (Memorial Healthcare System, Fort Lauderdale, FL), who chaired this guideline-writing committee, discussed the group’s reasoning for this new risk category. He presented a large meta-analysis (n=169,138) which found that every 39 mg/dl reduction in LDL is associated with a 37% further reduction in major vascular events (p=0.004), even for people with baseline LDL already <70 mg/dl (the lowest lipid target in professional guidelines, previously). The IMPROVE-IT trial showed that LDL down to 53 mg/dl confers significant CV benefits. Notably, this finding was powered driven by the diabetes subgroup, and without this subset of participants Dr. Jellinger showed hownoted the effect almost doesn’t reach statistical significancet anymore. From this, he suggested that endocrinologists should be especially incentivized to drive LDL cholesterol even lower. The FOURIER trial for Amgen’s Repatha (evolocumab), which reported full results at ACC 2017, provided compelling evidence in support of the idea that “lower (LDL) for longer is better,” and reiterated that PCSK9 inhibitors are the best option to help patients achieve this goal. Indeed, one of our fondest wishes in the wake of FOURIER is for payers to recognize the undeniable cost-savingsvalue of PCSK9 inhibitors now that a product in the class has demonstrated a significant and meaningful impact on CV outcomes. The AACE lipid guidelines encouraging even lower LDL targets for certain patients will hopefully add to this momentum, since treatment recommendations from professional societies can go a long way in informing best practice and in affecting what payers reimburse. (ii) In another step toward to hopefully simplifying the reimbursement process for PCSK9 inhibitorsSecond, a consensus paper published in March has established more consistent definitions of “maximally-tolerated statin therapy,” “familial hypercholesterolemia,” “atherosclerotic cardiovascular disease,” and other terms used by payers for prior authorizations of PCSK9 inhibitors. With less ambiguity, the hope is that negotiations for prior authorizations will be smoother – at the very least, providers and payers will be on the same page – and that coverage overall will increase. Unfortunately, we don’t anticipate any quick fix to the challenging reimbursement landscape of PCSK9 inhibitors, but we’re glad to see AACE taking action and we commend Amgen and Sanofi/Regeneron for co-working together to sponsoring this session on a keyn all-important topic (Sanofi/Regeneron manufacture the second PCSK9 inhibitor on the market, Praluent [alirocumab]). The issue of poor reimbursement must be addressed for the sake of patients who stand to benefit from a more effective lipid-lowering medicine and for the sake of providers who spend valuable time trying to obtain prior authorizations. A survey by the National Lipid Association reported at ACC 2017 that prior authorizations for PCSK9 inhibitors are denied 96% of the time, and that even after time-consuming follow-up by providers, only 36% of requests are ultimately granted. Moreover, improving reimbursement prospects is a necessary step in order for this class of therapy as a whole to grow (including both Repatha and Praluent sales), and we imagine it’ll take all hands on deck to devise a suitable solution. Pooled 1Q17 revenue for the PCSK9 inhibitor class declined 12% sequentially to $85 million (from $97 million in 4Q16), sales nearly tripled year-over-year (YOY) from $29 million in 1Q16. Nearly two years after their mid-2015 launch, the class has fallen somewhat short of its blockbuster expectations thus far, due in no small part to ongoing reimbursement challenges.

Decision Support System for the Treatment of Diabetes

Moshe Phillip, MD (DreaMed, Petah Tikva, Israel)

In an aptly-titled “Meet the Experts” session, DreaMed’s Dr. Moshe Phillip shared that the clinician-facing Advisor Pro decision support system will enter a pivotal study “toward the end of July/early August.” The trial will be supported by the Helmsley Charitable Trust. The clinical decision support software will be integrated with Glooko’s platform, allowing clinicians to get advice on therapeutic adjustments for patients using CGM and pumps, though SMBG and MDI are also in development. Further, Dr. Phillip expressed that the software will be limited to provider-facing use at first, but once it gains their trust, he sees no reason why it can’t be tailored for patients at some point. In initial data relating to the Advisor shown at ATTD, the hypothesis of non-inferiority to real physicians has been validated: For six weeks, patients at Schneider Hospital assigned to either the Advisor (n=7) or the control group (expert physician-guided decisions; n=8) have spent similar time in range (52% in control vs. 50% with the Advisor), though the Advisor group spent slightly more time in hyperglycemia >180 mg/dl (42% control vs. 49% Advisor), and much less time in hypoglycemia <70 mg/dl (7% control vs. 2% Advisor). We are very excited about this software and others like it – the scalability and mathematically-driven titration are very exciting and should hopefully save providers a lot of time, while improving patient outcomes. The bigger key will be the go-to-market approach and design of these systems: What’s the business model (who pays and how much)? How much burden will these systems be to prescribe and use? How much confirmation will providers need to give for updated doses vs. letting systems run on their own and give recommendations straight to patients (once pre-configured)? Dr. Phillip also offered his thoughts on a litany of topics, ranging from the benefit of factory calibration, to Fiasp, and beyond – see below.

• “With Libre, which is factory calibrated, people don’t doubt the reading, because they’re not checking SMBG and seeing that the sensor is 10 mg/dl off. It’s like Waze [a navigation app] – it gets you to work in 40 min and you think it’s good, the best possible route but you have no control group. If you did, perhaps you’d trust Waze a little less.”
  
  • Editor’s Note: We wanted to address this comment on several fronts. A sensor running within 10 mg/dl is actually very accurate, and BGMs can regularly vary by 20 mg/dl or far more from test to test – and with hand-washing interference, BGMs can vary by 100+ mg/dl from test to test. A major upside of factory calibration is far less patient burden (a greater benefit-hassle ratio), and therefore, greater likelihood of wearing the device and benefitting from it. Last, the most dangerous outcome with glucose monitoring is the false high – a measured glucose that exceeds true glucose. This dangerous use case is eliminated with a factory calibrated sensor.
• “We’re currently running a study of Fiasp in pediatrics and adults. I’m afraid to share results because it’s confidential, but tailor your expectations to reality. It’s better, but not really immediate action.” This seems to be the consensus, both anecdotally and clinically: Phase 3 data have led some to suggest that Fiasp does not represent quite as significant of a leap forward as next-generation basal insulins, though we know many patients could still stand to benefit from Fiasp’s potential for tighter postprandial control, less hypoglycemia, and perhaps more flexible dosing. On the other hand, we have seen patients on social media exclaiming that Fiasp is a gamechanger. Hmmm ... the notion from our view that incremental benefit should be criticized is anathema to thinking about benefit overall.
• “As diabetologists, we are like advisors in a bank – we tell patients how to invest, but eventually they go home and treat themselves. All we do is diabetes psychology.” We thought this was a brilliant point, since it really underscores the value of technology and the changing role of HCPs – as algorithms analyze more data and give recommendation, HCPs should have more time to actually talk to patients.
• “I gave the same lecture a few days ago in Greece, and very few people could download data in their clinics, and very few type 2s had pumps. It’s obviously different here. I like this country.”

Advanced Diabetes Technology Concepts

Insulin Pumps: Current Landscape

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

In the course of his pump landscape overview, Emory’s Dr. Bruce Bode reported that he had seen some preliminary CareLink data from the 670G limited launch (n=~560 patients): Average blood glucose of 151 mg/dl, standard deviation of 52 mg/dl, percent of time <70 mg/dl of just 2.2%, and 0.3% time <50 mg/dl. Dr. Bode concluded that “this thing clearly works in real hands and is a gamechanger.” That “gamechanger” designation probably won’t apply to everyone, considering that those on the device right now are likely to be current pump+CGM users – we’ll be interested to see early feedback once the product is more widely available, especially to those not used to technology. The term may apply to those new to pumping and/or CGM. We’ve said for a long time that pumps need a killer app, and certainly movement toward the closed loop may well provide that for some. These data points are strikingly similar to those seen in the three-month pivotal trial, where standard deviation was 47 mg/dl, percent of time <70 mg/dl was 3.3%, percent of time <50 mg/dl was 0.6%. (Purists, like Kelly, point out that 2.2% of the time is actually 50% lower than 3.3%, or 16 fewer minutes in hypoglycemia per day, which she would happily take.) The 151 mg/dl mean glucose and minimal time in hypoglycemia suggests that the 670G has worked quite well, at least in this initial Customer Training Phase. We confirmed with Medtronic via email that it is targeting 650-750 patients in the 670G customer training phase, meaning the ~560 in this CareLink data set covers most of the patients.

• Dr. Bode soberingly commented on J&J’s and Roche’s diabetes businesses: “It’s a very difficult environment to make money, and if you can’t do that, you can’t keep letting your company lose money.” He noted that Animas’ artificial pancreas project with JDRF has been “delayed every three months for the last three years, and I don’t know if it’ll ever happen.” We haven’t heard an update on this front since late November, when the company told via email us it is still working with FDA to design a pivotal (see our automated insulin delivery competitive landscape). He was also uncertain about the status of the OneTouch via bolus-only patch deliver device, which, as of December, was expected to undergo a “focused” US launch in 1H17. On Roche, he noted that the pumps have “totally disappeared” in his clinic, and so have all of the Roche reps, even for BGM – we’re surprised by the last comment since Roche is currently launching the next-gen Accu Chek Guide BGM system in the US. As a reminder, J&J revealed in January that it will “explore strategic options” for its Diabetes Care segment (including sale); A week later, Roche had to dispel rumors that it will do the same, but it has halted sales of pumps in the US US (Dr. Bode has since called Roche and informed us that they will be supplying his office with a new rep for the Guide launch). Both companies were notably absent from the hands-on session that followed the talk, while Tandem, Medtronic, Insulet, Glooko, Dexcom, and Abbott were present.
• Alluding to Insulet’s pipeline, Dr. Bode mentioned that the current OmniPod reservoir only holds 200 units, but that’s going to change with potential use of concentrated insulin, and that the company is working on integrating CGM into their Personal Diabetes Manager. On the former, he is presumably referring to the U500 and U200 OmniPods with Lilly, and not an expanded reservoir – the U500 launch is expected in 1H19, and the U200 in late 2019-early 2020 (per November’s Investor Day presentation). On the CGM front, we assume Dr. Bode was referring to the Horizon OmniPod automated insulin delivery project with Dexcom, which will embed Bluetooth in the pod and talk directly to a Dexcom CGM (patients will remain in closed loop, even if the handheld is out of range). Insulet previously had its own internal project to build a CGM sensor into the pod, though this has been shelved (as far as we can tell) under the new management team. 

Questions and Answers

Dr. Robert Vigersky (Medtronic, Northridge, CA): We’re talking about the dawn phenomenon. The data is now evolving – we looked at consecutive nights in the same patient, and it’s really amazing that basal rates are different every single night. No two nights are the same, which explains why it’s so difficult to have a fixed basal rate.

A: We don’t see much dawn phenomenon, but everyone’s basal overnight depends on what happens during the day. If they’re active during the day, they’ll need less insulin at night, and if they eat pizza at night, they’ll be more insulin resistant that night. You’re right that a single basal rate is not a simple solution anymore. In type 2 diabetes, however, I think you can do reasonably well, but in type 1, there are issues with glucagon and we don’t have hepatic-specific insulin or faster acting insulins, but hopefully those will come in the future.

CGM: Moving Beyond SMBG

George Grunberger, MD (Grunberger Diabetes Institute, Bloomfield Hills, MI)

Dr. George Grunberger delivered an impassioned speech calling for improved coverage and use of CGM. He picked up where he left off at last year's AACE (where he expressed frustration in dealing with the challenges of working with Medicare to establish coverage of therapeutic CGM); but now that coverage has finally been established (“thank god”), he wished providers “good luck in the trenches” as they try to actually prescribe Dexcom’s G5 for Medicare beneficiaries. We had heard similar sentiments from patients and providers in recent weeks, and Dexcom finally brought the issue to light on this morning’s 1Q17 call: Patients on Medicare cannot get claims processed/reimbursed for Dexcom’s G5 until “final” “local coverage decisions” come through. Management hopes this will wrap up before the end of 2Q17, though it seems hard to call. According to Dr. Grunberger, CGM is ready for the prime time – he pointed to REPLACE-BG data (from ATTD), showing that non-adjunctive use of Dexcom G4 is equivalent to adjunctive use, to illustrate his point. In his opinion, accuracy is not the biggest concern– “give me a break – the allowable accuracy is 15%, 20% for SMBG and you’re telling me a MARD of a 10%-15% is a piece of garbage?” While we would point out that the comparison is not apples to oranges (e.g. a JDST publication estimates that a MARD of 3.25% to 5.25% would be required to meet ISO 15197:2013 accuracy requirements, which have since been updated to be more stringent), but his point is well taken. Simulation studies out of UVA have shown that MARD approaching 10%, along with trend information, is sufficient to dictate safe therapeutic decisions. But Dr. Grunberger doesn’t just walk the walk – he has actually prohibited fingersticks in some of his patients who still have the tendency to perform 10-15 SMBGs per day despite having been on CGM for a number of years.

Questions and Answers

Q: I try to be aggressive getting patients on CGM, but some patients just don’t understand how long rapid-acting insulin is in your system, so they stack. I finally got a patient on Dexcom, and then he turned off alarm, said he was having too many. But it’s not an alarm problem, it’s a stacking and education problem.

A: That’s very important. Some people are obsessed with confirming every number, and some don’t understand that we don’t have truly rapid-acting insulin. Thanks for bringing that up – sometimes knowing too much is not good. Education is important.

Applications of Technology to Your Patients

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

In a highly-entertaining talk, Dr. Irl Hirsch elucidated what he believes to be the four most common patient mistakes with respect to glucose monitoring (at least in his clinic): (i) over- or under-calibrating CGM – he recommended three times per day; (ii) not looking at the sensor often enough/only reacting to alarms – he recommended looking at least hourly to avoid getting to the point of alarm; (iii) overreacting to alarms and not taking into account lag times, resulting in insulin stacking; and (iv) not using enough SMBG to make decisions – even with the non-adjunctive ruling for the Dexcom G5, it is still mandated that patients verify CGM readings if they seem inaccurate for whatever reason. Dr. Hirsch also gave his thoughts on the biggest gap in diabetes technology, outcomes beyond A1c, and the prospect of putting type 2 patients on SAP.

• Dr. Hirsch echoed previous enthusiasm for smart insulin pens, calling them the greatest gap in diabetes technology. “It is such a disadvantage that we can see insulin information from pump patients but not MDIs. For me to be able to see what a patient is doing with insulin would be such a great advantage compared to what we have now.” Luckily, the pen dose capture competitive landscape is growing, with Companion Medical expected to launch this year – the company’s exhibit hall debut at ENDO last month may be an indication that it is close to commercializing.
• Dr. Hirsch continued on his quest to end A1c-centrism in favor of glucose-centrism: “14%-25% of A1c measurements are misleading in a typical diabetes practice. The whole thing about grading us, paying us, and deciding if we’re good doctors based on A1c – that’s garbage. It should be glucose. Ok, enough of my ranting.” We could actually listen to him go on for a lot longer…
• While presenting a case study, Dr. Hirsch briefly opined that we underutilize sensor-augmented pumps in the type 2 population. (we’d note that utilization is often driven by reimbursement, of which there is little to date for pump+CGM in type 2 diabetes.) Earlier in the morning, Dr. Bruce Bode suggested that pump penetration in US type 2s is <1% - not surprising considering the cost of devices, the lacking reimbursement, and the lack of design specific for type 2s. A meta-analysis from Dr. John Pickup’s group suggests that pumps are best-suited in type 2 for patients with with elevated A1c and insulin doses even after insulin optimization.

Moving Toward Artificial Pancreas

Moshe Phillip, MD (DreaMed, Petah Tikva, Israel)

Dr. Moshe Phillip suggested that Medtronic will hopefully be in a position to launch an advanced hybrid closed loop system “toward the end of next year” (meaning it will likely be ready to become a clinical product following the pivotal study, which will begin toward the end of this year). Though not from Medtronic itself, this is the first indication of a possible launch timeline we’ve ever heard for this product (formerly called the MiniMed 690G), which incorporates DreaMed’s Fuzzy Logic algorithm and will issue automatic correction boluses. If met, this timeline would put the US launch in the neighborhood of Tandem/TypeZero’s plans for Hypoglycemia-Hyperglycemia minimizer (also delivering automated correction boluses), Bigfoot Biomedical, and Beta Bionics’ insulin-only bionic pancreas (see our automated insulin delivery competitive landscape). At that point, Medtronic will have accrued substantial real-world data on the 670G and learned a lot about training and education and user experience. We’ll be interested to see how other companies’ first-gen products stack up? Dr. Phillip said that the bridging study is currently underway, and the NIH-funded pivotal study will probably be conducted toward the end of this year. According to Clinicaltrials.gov, the study is slated to begin in early December 2017 and wrap up in late June of 2020 – we assume the latter is very conservative, since each participant will only need six months to get through the study and based on Dr. Phillip’s projected launch timing. We saw preliminary  feasibility data with this next-gen algorithm (n=7) at ATTD, where Dr. Thomas Danne showed that the Advanced Hybrid Closed Loop improves post-meal control vs. the 670G.

Symposia

Precision Medicine for Diabetes: Where Are We?

Judith Fradkin, MD (NIDDK, Bethesda, MD)

NIDDK’s legendary Dr. Judith Fradkin discussed progress toward the holy grail of precision medicine in diabetes, from insights already gleaned from clinical trials to ongoing and upcoming efforts from the NIDDK to better identify, characterize, and optimally treat subgroups of patients with diabetes. Several NIDDK-sponsored trials are ongoing that will hopefully not only shed more light on different kinds of diabetes therapies, but also on the kinds of patients that might benefit most from these therapies. The GRADE comparative effectiveness study hopes to both comparatively assess the efficacy and safety of a sulfonylurea, a DPP-4 inhibitor, a GLP-1 agonist, and insulin (SGLT-2 inhibitors were not yet approved when this study was conceived – the lack of SGLT-2 inhibitor arm is truly unfortunate and a major shortcoming of this trial and its eventual results in our view). Further, the study seeks to determine the patient characteristics that might be associated with different responses to these drugs and the molecular pathways that might be involved in this differential response – to that end, the study is collecting genetic samples and stool samples (for microbiome screening) from participants. Dr. Fradkin also hopes that the long-term DPP Outcome Study (DPPOS) will be able to help predict which patient populations may benefit from long-term metformin therapy from an outcomes perspective. The trial is an extension of the DPP trial, in which participants with prediabetes originally randomized to metformin continued therapy while those not originally taking metformin only began the medication if prescribed by their doctor following development of type 2 diabetes. As such, Dr. Fradkin highlighted that this trial offers the largest randomized exposure to metformin ever. The trial hopes to assess the impact of metformin on cardiovascular disease, cancer, cognitive function, quality of life, and cost. Dr. Fradkin suggested that it will be especially useful to determine which subgroups are likely to benefit from metformin’s impact on cardiovascular disease and cancer.

• Overall, Dr. Fradkin highlighted two main strategies through which NIDDK hopes to advance precision medicine: (i) the examination of rare and extreme diabetes phenotypes to gain insight into pathology; and (ii) the application of “omics” approaches in clinical studies. She emphasized that NIDDK is very interested in partnering with AACE on the first approach, as AACE member endocrinologists are more likely to come across unique and complex diabetes cases that can provide valuable information. Additionally, if the NIDDK is alerted to this difficult cases, it can help the physician characterize the patient and determine the best course of treatment as well – a win-win situation. On the omics front, Dr. Fradkin highlighted the Accelerating Medicines Partnership, an NIH/industry collaboration to create an open-access portal of genetic and clinical data from over 100,000 patients with type 2 diabetes. The portal is available for anyone to analyze its data and could be used to identify novel therapeutic targets for type 2 diabetes.
• While in some ways, “precision medicine” on the level regularly practiced in oncology seems a thing of the future for diabetes and prediabetes, Dr. Fradkin pointed out that we’ve already learned valuable information from large, long-term trials of diabetes prevention. For instance, in the landmark Diabetes Prevention Program, in the overall cohort, intensive lifestyle therapy was found to be the most effective diabetes preventive intervention, followed by metformin, and then placebo. However, a subgroup analysis revealed that metformin was especially effective as a preventive therapy in younger patients (aged 25-44) – in fact, in this age group, metformin was about as effective as lifestyle therapy. On the other hand, metformin was much less effective as a prevention (nearly placebo rates of “efficacy”) in those aged 60 and older, while lifestyle in this group was even more effective than in the youngest age group. Similarly, in DPP, metformin was much more effective in women with a history of gestational diabetes than those without. Another trial, the TODAY study of children with type 2 diabetes, found that black participants specifically benefited from the addition of rosiglitazone or lifestyle therapy to metformin. Also Dr. Fradkin pointed to data from that study population as a whole showing that A1c achieved after treatment with metformin during the run in prior to randomization correlated strongly with subsequent loss of glycemic control.  This information suggests that more aggressive treatment may be required when youth with T2D fail to achieve near normalization of A1c in response to metformin. 
• In diabetic retinopathy, too, Dr. Fradkin explored how existing data can help individualize treatment decisions for this complication. Three VEGF inhibitors are currently commonly used to treat retinopathy: Roche/Novartis’ Lucentis (ranibizumab), Genetech’s Avastin (bevacizumab), and Bayer/Regeneron’s Eylea (aflibercept). In a comparative study of all three agents, Eylea was found to be substantially more effective at restoring visual acuity in patients with baseline acuity of 20/50 or worse. On the other hand, all three agents were comparably effective in patients with acuity better than 20/50. Dr. Fradkin pointed out that, importantly, Avastin is now generic and thus much more inexpensive than the other two agents. As a result, Dr. Fradkin suggested that these findings lend themselves to the recommendation for costly Eylea therapy in patients with visual acuity of 20/50 or worse and cheaper Avastin therapy for patients with better vision.

Diabetes Management: Applications of High Tech Innovations

William Tamborlane, MD (Yale University, New Haven, CT)

In front of a packed plenary audience, Dr. William Tamborlane reminded us how far we’ve come from the “bad old days” of diabetes care, and how there’s more hope to be had on the horizon. To Dr. Tamborlane, any day pre-1980 is considered the “bad old days” – patients were limited to beef and pork insulin, then regular insulin, all of which was often impure. There was no good way to monitor blood glucose – he recalled how physicians at Yale used to “torture youngsters” by asking them to test their urine glucose, and clinic visits were predicated on a single fasting glucose measurement (“that really helped a lot…not”). Aggressive therapy was unsafe and had unknown benefits, the typical adolescent A1c was between 11% and 12%, and it was common for young adults to develop microvascular complications. For Dr. Tamborlane, the “era of intensive treatment” began in the 1980s. He reminisced back to the Reflectance meter, one of the first dinosaurs of a glucose monitor: “Those of us who were around for it, we get a kick out of all the kvetching over the accuracy of CGM. It was this or nothing, so accuracy didn’t matter. The difference of blood glucose could be 150 mg/dl on the Clark Error Grid and it’d still be ok.” In 1979, a strapping young Dr. Tamborlane was first author on NEJM publication demonstrating for the first time that CSII can be used to treat patients with type 1 diabetes. Throughout this whole portion of the talk, we couldn’t help but recall the quote (usually attributed to Bill Gates) about how we overestimate the change that will occur in two years and underestimate the change that will happen in ten years. We really have come a long way, with treatment advances such as insulin analogs, smart insulin pumps, improved BGM accuracy, and CGM, yet the Inconvenient Truth is that the majority of people with diabetes are still not at their target A1c – the average A1c of adolescents in the DCCT was 9.5%, and according to 2015 T1D Exchange data, it is still over 9%. Dr. Tamborlane sees light at the end of the tunnel in the form of closed loop systems, new adjunctive therapies for type 1, and biologic solutions (transplant, stem cell therapy), but his group knows better than most that current options aren’t perfect. On the MiniMed 670G in particular, he said that patients would love to be able to: (i) adjust target glucose levels; (ii) manually set temp basals; (iii) manually give correction doses that correct to glucose levels <150 mg/dl; and (iv) track glucose and insulin delivery remotely on smartphone apps. Considering the magnitude of progress since the DCCT, we can’t wait to see what diabetes management looks like in another 25 years.

Creating the Ecosystem to Support Effective Technology for Patients with Diabetes

Robert Califf, MD (FDA, Silver Spring, MD)

Former FDA Commissioner Dr. Robert Califf delivered a plenary in front of a packed house on Saturday in which he explained why the FDA is so overburdened, elaborated on the “information revolution” in healthcare, and gave new details on Verily’s Project Baseline study. It is widely held that FDA is under-staffed, and the former Commissioner has seen it first hand: “Sometimes FDA appears to be slow because our people are doing so many other things that you may not realize.” Tobacco, food supply safety and security, cosmetics, veterinarian medicine, and even counterterrorism (of the biological and chemical varieties) all fall under FDA’s domain, in addition to medical therapies and devices. On a much more positive note, Dr. Califf has seen a revolution in healthcare during his career – a halving of CV death risk, plus a number of exciting drugs and devices – and the next revolution, in his opinion, will result from the transformation of information, something he has championed tirelessly. Currently, there exists tons of data, and hoards of information go into computers, but so little insight comes out – Dr. Califf pointed to the facts that the average doctor spends 2.5 hours in front of the computer for every hour with patients, and that <15% of major clinical decisions are supported by solid evidence. The former stat is even more harrowing than one from a February JAMA Viewpoint on physician burnout, which estimates that physicians spend approximately 33% of their work hours performing direct clinical work vs. 49% completing clerical tasks and interfacing with the EHR. Dr. Califf referenced many of the positive information aggregation and integration efforts currently ongoing: NEST (National Evaluation System for Health Technologies; aims to track medical device data and patient-reported outcomes through the use of real-world evidence); PCORnet (“we’re about to launch a very active phase of this”); and the NIH Collaboratory (“brings the cost of conducting trials from $150 million to $5-$15 million).  At the end of the day, data collection infrastructure is imperative, but with the quantity of information increasing exponentially, the key is to detect signals amongst the noise and generate insight whenever possible. In Dr. Califf’s wise words, “the best technology is good information. If we don’t figure out how to deal with it, it could be overwhelming and do more harm than good.”

• According to Dr. Califf, the Verily Project Baseline study population (a deep dive into human physiology and behavior that kicked off recently), will be enriched for those at risk of breast cancer, ovarian cancer, lung cancer, and cardiovascular disease, and will generate six terabytes(!) of data per visit. While the latter statement generated an audible “Oh my god” from the audience, we were more psyched to hear that cardiovascular disease will be a major focus of the study, considering the degree of comorbidity between CV risk and diabetes.
  
  • “Up until now, because of the limits of computation data storage and analysis, we’ve all been like the blind people and the elephant. We’ve all seen the part of human we’re interested in, not the whole picture.” The hope is that Project Baseline will help zoom out and bring a more holistic picture.
• “Activated patients are critical for diabetes, cardiovascular disease, pulmonary disease. There is already good patient advocacy, but it doesn’t have the same impact as advocacy for rare diseases or cancer. I don’t want to diminish the advocacy for those diseases, but as a society with fixed resources, you would be well served to help patients organize better when it comes to which therapies are developed and paid for.”
• “It would be good if every part of medicine could be like Google search, connected to every other thing so we know everything about that patient. Also, whenever we do a Google search, we’re participating in on average 10 clinical trials [A/B testing]. They wouldn’t think about changing anything without testing it rigorously first, yet in medicine, it’s special to randomize.” While clinical trials are still the standard, we’re hopeful that registries and large health systems will be able to provide settings for pseudo-randomized trials, where patients are “randomized” to different therapies and use them in the real-world.
• “We are faced with an exciting set of opportunities in science and medicine, but there are probably a lot of problems we aren’t prepared for yet.” Dr. Califf specifically referenced the Precision Medicine Initiative (PMI), complex regenerative medicine, and CRISPR/Cas9 gene editing.
  
  • On the PMI, he polled the audience “how many of you are ready to deal with whole genomes in your EMRs?” So little is known about the significance of genetic variations, and with whole-genome sequencing dropping in cost rapidly and no limit to EMR storage, physicians could be faced with human genomes and metagenomes (resident bacteria included!) in the near future.
  • Dr. Califf recalled that all in one day, the plant side of FDA, animal side, and human side of FDA briefed him on the potential of CRISPR/Cas9 gene editing. The plant side told him it could fix global hunger, the animal side said that animal models of human disease could do wonders for research (he also claimed that bacon grown in a dish tastes pretty good), and the human side said that there are 5,000 diseases with no treatment, and gene editing could hold the key.

Questions and Answers

Dr. R. Mack Harrell (Memorial Healthcare System, Hollywood, FL): We’ve gone through a 20-year phase of registry development, and the era seems to have come, so maybe it’s possible for small organizations like ours to enter it. What opportunities do you see for us to get on the board early?

Dr. Califf: It would be a big mistake to try to copy the strategies of decades ago. The organizing principle will be the integrated health system. Specialty societies should own the use of broader information capabilities to answer questions pertinent to patients, not create data.

Dr. Harrell: Hoards are still doing private practice, and they’re nervous about how they can survive and use information in the future.

Dr. Califf: [Venrock’s] Dr. Bob Kocher would be worth googling if you’re in that situation. He was part of the ACA, and has recently taken the position that small practitioners should band together into federations that share information. Learning increasingly will be done though machine learning, you can’t do that as an individual. In imaging especially, machines outperform radiologists hands down for static images. You still need the radiologist, but they now need to decide what to do with the computer’s diagnosis.

Dr. Harrell: What are your thoughts on IBM Watson?

Dr. Califf: Like most of this stuff, the hype greatly outdid the performance at the start. But all of Silicon Valley has failed in healthcare almost 100% of the time. We’re complicated, the current president found that out. I’m not giving up on Watson, it can do some things really well, but coming back to curation of information. One thing systems should be good at is serving up good information – one of the problems with Watson is if you put garbage in, you get garbage out. The most valued person in Silicon Valley is the data janitor who curates data.

The Aging Patient: Endocrinology for the Ages

Diabetes in Older Adults

Sue Kirkman, MD (UNC Diabetes Care Center, Chapel Hill, NC)

Dr. Sue Kirkman discussed the treatment of type 2 diabetes in older adults, ultimately emphasizing her view that the strategy to treat diabetes is more important than the actual A1c target in these patients. She underscored that there is great heterogeneity in the health status of older adults, with a wide range in functional ability and frailty in those 50 and older. What’s more, functional status is only loosely correlated with age and age by itself is not a good predictor of how frail an individual patient is. Thus, it’s important to assess the functional status, cognitive abilities, etc. of these patients and individualize treatment based on this assessment rather than rely on age thresholds to determine therapeutic goals. Like other thought leaders on the treatment of older adults, Dr. Kirkman emphasized the importance of minimizing hypoglycemia risk in this population that is especially vulnerable and acknowledged that the 5-10 year benefits of glycemic control may not be felt by a patient with a less than five year life expectancy. (How a PCP or other doctor would establish whether someone 50 or over would have less than five years’ life expectancy wasn’t established.) On the other hand, while some have advocated for A1c targets up to 9% for older, more frail adults, Dr. Kirkman argued, “Some of this focus on A1c is a bit misguided and it’s more important how we’re lowering A1c.” She expressed dissatisfaction with the American Geriatrics Society Choosing Wisely campaign, which in her view essentially imply that treating to a target A1c<7.5% using any agents besides metformin is bad clinical care. Rather than focus on recommendations for higher A1c targets in older adults, Dr. Kirkman advocated for carefully choosing appropriate medications based on a thorough consideration of their risk/benefit profile as it applies to a particular patient. We applaud this approach and have felt that the focus on “relaxing” A1c guidelines for some older adults can have unintended consequences if busy providers (especially in primary care) interpret them too broadly or too casually. Further, a recent study led by Joslin Clinic’s highly-regarded Drs. Katie Weinger and Medha Munshi showed that higher A1c targets don’t necessarily reduce hypoglycemia rates in older patients, suggesting that the choice of therapy and the use of CGM and other technological tools may be more helpful in reducing hypoglycemia than higher targets in and of itself. 

• Dr. Kirkman discussed the pros and cons of all the major diabetes drug classes for the treatment of older adults. She underscored the substantial hypoglycemia concerns associated with sulfonylureas and shared that she tends to avoid their use as much as she can. She was particularly positive about the benign benefit/risk profile of DPP-4 inhibitors – indeed, we feel that have learned from many KOLs that the older adult population is particularly suited to this easy-to-take, low-risk oral medication, particularly early in their disease (DPP-4 inhibitors do not have the potency of other classes like GLP-1, SGLT-2s, or insulin). Dr. Kirkman also felt that once-weekly GLP-1 agonists could be a good option for patients requiring greater potency and the ability for a greater impact on higher A1c efficacy, especially due to their low risk of hypoglycemia associated with the GLP-1 class. Interestingly, she suggested that the once-weekly formulations could be a good option for patients with cognitive impairments, as a family member could come by once a week to administer the drug. On the other hand, the weight loss effect of GLP-1 agonists (a boon for many patients with type 2 diabetes) may be a concern in some underweight older patients, she said. Dr. Kirkman also touched on the positive evidence for SGLT-2 inhibitors, from low risk of hypoglycemia and weight loss to potential reduction of CV events and death, though she does keep an eye out for hypotension in her older patients on these agents. Despite their overall favorable clinical profiles, Dr. Kirkman lamented the high cost of these newer medications, a particular concern for her patients on Medicare Part D who may be nearing the “donut hole” for coverage. Overall, she emphasized that there is no perfect drug for all older patients and all of these considerations, including cost, must be taken into account when individualizing therapy. We are glad that the medications were developed and point out the broad societal benefits that Big Pharma is enabling longer-term when these drugs can be made available to tens of millions more patients when they are in generic form.
• Dr. Kirkman suggested that, while she likes the clinical profile of DPP-4 inhibitors, their cost must be weighed against their impact on glycemic control and hypoglycemia. She pointed to Dr. Kasia Lipska’s findings that increased usage of newer diabetes drugs and decreased usage of SUs between 2006 and 2013 did not improve glycemic control or reduce hypoglycemia rates in the overall population. Dr. Lipska’s paper certainly lends itself to broad brush conclusions in the mainstream media that “newer diabetes drugs aren’t worth the money” – importantly though, Dr. Kirkman was not making this point herself and was largely pointing out that cost is an important consideration when weighting the benefits (or lack thereof) of a therapy against its downsides. That said, we’ve written extensively about this paper and we think it’s extremely important for those who write or speak about this paper to present a more nuanced view of its implications. First, while DPP-4 inhibitor and GLP-1 agonist usage significantly increased and SU usage decreased in the study population, the usage of SUs in 2013 (31%, down from 39% in 2006) still eclipsed that of the other two classes (15% usage of DPP-4 inhibitors in 2013, up from 0.5% and 5% usage of GLP-1 agonists, up from 3%). Furthermore, none of the patients in this paper were on SGLT-2 inhibitors – and overall usage of “new drugs” was only 20% at the end of the study period. Additionally, this study looked at the general population of people with type 2 diabetes, not just older adults who are at higher risk of hypoglycemia, so it’s possible that the relatively low rate of hypoglycemia in the general type 2 diabetes population masked the benefits of newer therapies in those more vulnerable to hypoglycemia, such as older adults. Overall, in our view, it would take much greater usage of DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors to sway hypoglycemia rates at the population level. We would have loved to see several subgroup analyses of this data: How did glycemic control and hypoglycemia rates change in older adults specifically? What were hypoglycemia rates specifically for those starting DPP-4 inhibitors and GLP-1 agonists during this time period? Since the publication of this study, we’ve been concerned about the broad brush takeaways and headlines these findings and the study authors’ (in our view, misguided) conclusions about the cost-effectiveness of new diabetes drugs can prompt. Indeed, this is the second time in a month that we’ve heard a high-profile leader in the diabetes field cite Dr. Lipska’s data – Dr. David Nathan also pointed to this data in his highly controversial debate with Dr. Daniel Drucker at ENDO 2017. That said, Dr. Kirkman’s citation of Dr. Lipska’s paper was a relatively small part of her overall wide-ranging and thoughtful discussion of diabetes treatment in older adults and she emphasized to us that she was in no way advocating for the use of all older drugs or suggesting that newer drugs are uniformly not cost-effective. We appreciated Dr. Kirkman’s clarification and hope that other leaders cite Dr. Lipska’s work with similar care and thoughtfulness; we also hope that Dr. Lipska will take on the requested sub-group analysis to see how hypoglcyemia in GLP-1 and DPP-4 inhibitors compared to hypoglycemia in SFUs, as that’s the real question, not just how hypoglcyemia changed wholesale in a population over the long-term..

Metabolic Bone Disease: What's New in 2017?

Diabetes and Bone

Clifford Rosen, MD (Maine Medical Center Research Institute, Scarborough, ME)

Dr. Clifford Rosen (Maine Medical Center Research Institute, Scarborough, ME) discussed the impact of different diabetes drug classes on bone in Through a comprehensive overview of the research connecting type 1 and type 2 diabetes to bone fracture risk Dr. Clifford Rosen (Maine Medical Center Research Institute, Scarborough, ME) wove in some commentary on how different diabetes drug classes impact bone. He suggested that DPP-4 inhibitors may improve fracture healing, since the enzyme DPP-4 slows down bone formation. In rodent models, osteoblasts (the cells that secrete the matrix for bone formation) recruit DPP-4 inhibitors, and when administered a drug from this class, mice show better osteoblast number. Dr. Rosen established early on in his talk that people with diabetes experience greater difficulty healing post-fracture, and he thus positioned DPP-4 inhibitors as “worthy of significant clinical attention” to address this complication. In our view, this evidence further reinforces the position of DPP-4 inhibitors as an ideal choice for older patients (many of whom are vulnerable to elevated fracture risk) based on their benign safety/tolerability profile. Turning away from these incretin-based agentsOn the other hand, Dr. Rosen presented insulin as most likely having neutral effects on the skeleton, while he emphasized that insulin-sensitizers like TZDs require more evaluation. TZDs have long been associated with heightened fracture risk, but important differences have surfaced in recent years distinguishing rosiglitazone from pioglitazone. Given the CV benefits linked to low-dose pioglitazone in the IRIS trial (on top of the drug’s generic status/low cost), many thought leaders have been returning to this agent for diabetes care – we were encouraged to hear a similar beat from Dr. Rosen, though he cautioned that more research might perhaps confirm the bone-related safety risks that have previously been identified for this therapy class. Then he turned to SGLT-2 inhibitors…

• Although tempted, Dr. Rosen refrained from sharing any specific details on SGLT-2 inhibitor Invokana (canagliflozin) and its association with bone fractures – “I can’t tell you about it. You’ll have to wait until CANVAS presents at ADA.” He underscored that fractures are not a class effect in this case. Back in September 2015, the FDA strengthened the label warning for bone fracture risk associated with J&J’s Invokana, but neither AZ’s Farxiga (dapagliflozin) nor Lilly/BI’s Jardiance (empagliflozin) have such label warnings. From our perspective, it seems like this safety warning (alongside concerns over DKA, lower limb amputation, and acute kidney injury) has negatively impacted J&J’s SGLT-2 inhibitor business – Invokana has been losing market share to Jardiance in the wake of positive EMPA-REG OUTCOME results, while Farxiga has mostly maintained its share of the market by value and by volume. All should do well commercially since this class is growing, though it is difficult to EMPA-REG OUTCOME found no significant difference in the incidence of bone fractures between participants treated with various doses of empagliflozin vs. placebo. Canagliflozin may tell the same or a different story, according to Dr. Rosen, but and we’ll have to wait (impatiently) until ADA 2017 in San Diego for the full CANVAS results to weigh in on this safety sagastory. We’re itching for this data, not only because we’re hoping for more evidence in support of a cardioprotective class effect, but because any reassuring safety results on Invokana wcould likely also boost the whole SGLT-2 inhibitor market – these agents show profound glucose-lowering and weight loss efficacy, and we’d love for more patients to benefit from them, provided they are safe and tolerable.

Sustaining Your Endocrine Practice

How the Trump Presidency will Affect Health Care

Jill Rathbun (Galileo Consulting Group, La Crosse, WI)

Less than 24 hours after the US House of Representatives passage of the American Health Care Act (AHCA), Ms. Jill Rathbun, a managing partner at Galileo Consulting Group, offered her take on what the next few months of the Trump Presidency might mean for healthcare. Overall, she framed the Trump Administration’s healthcare efforts with one concept: Less. “This administration is really about ‘less,’” as she put it, “Sometimes less is more and sometimes less is just less.” While there are cases of the former in the Trump Administration’s efforts (such as reducing the burden of EHR reporting for providers), the AHCA is unquestionably a case of the latter, in which patients will very likely have less insurance coverage. Ms. Rathbun emphasized the importance of understanding the proposed law and its potential impact, so that providers and the rest of the diabetes and healthcare community can effectively advocate for changes. She emphasized that the current proposed law is likely to undergo significant change, and it’s crucial that those in the healthcare field are ready to provide specific policy advice during this process that will hopefully minimize the negative impact to patients. Overall, Ms. Rathbun concluded, “Their less is more – more room for our ideas, and we need to be prepared to offer them.” Given the enormous complexity of healthcare in the US, we greatly appreciated Ms. Rathbun’s detailed discussion of the implications of the AHCA and echo her thoughts on the crucial importance of patient and provider advocacy during this process. Within the diabetes field, we were pleased to see the ADA, JDRF, and the Endocrine Society take a stand against this bill on behalf of people living with diabetes and those who care for them.

• Ms. Rathbun provided an overview of the litany of changes in the law that will very likely translate into reduced health coverage overall, including repeal of ACA health coverage mandates, removal of actuarial standards for health plans that required a certain percentage of premiums to go toward health benefits (rather than marketing, etc. for insurers), and elimination of subsidies to purchase health coverage and pay for deductibles/copays. Instead, the AHCA will offer tax credits to replace the premium and cost-sharing subsidies – these tax credits will be based on age, which led Ms. Rathbun to worry that the low level of financial help in purchasing coverage will lead too many healthy young people to opt-out of the insurance market, which would drive up the cost of insurance and make it possible that even the max $4,000 credit would not be enough to cover the costs of health coverage for older and more sick adults. The responsibility for these older and more sick indiviuduals would also largely shift to the states – the AHCA would create a “stability fund” of ~$138 billion (an additional $8 billion from the previous iteration of the AHCA, included to woo moderate Republicans) for states to help cover deductibles and premium costs for people with pre-existing conditions in a “high-risk pool.” That doesn’t sound good to us to have more variability introduced, though the devil will be in the details. That said, Ms. Rathbun noted that estimates have suggested that even this large pool of money will not be enough to adequately meet the needs to Americans currently living with pre-existing conditions – in fact, she pointed to estimates suggesting that this number is about $60 billion short of what’s needed. On top of all of these nationwide changes, the AHCA also offers individual states to waive the requirement of coverage for essential benefits, allow consideration of pre-existing conditions in determining plan cost in some circumstances, and remove age-banding,  (in which the cost of premiums for older members compared to younger members is capped).
• Despite the bleak outlook on healthcare as the AHCA is written, Ms. Rathbun offered some hope by emphasizing the long road and challenges the bill must navigate before it is signed into law. She suggested that the proposed law could change substantially in the Senate and it’s important to remember that this debate could go on until as late as December. First in the process moving forward, the Congressional Budget Office (CBO) must score the bill before it can pass forward to the Senate (in a rare move, the House had voted on the bill ahead of CBO scoring). Next, since the bill is being passed under the Reconciliation Process (in order to avoid a filibuster to potentially block an eventual vote on the bill), it is subject to a complex set of rules (including the “Byrd Rule”) which could force substantial changes in the bill, including to the major changes in the second version of the AHCA that swayed the more conservative members of the House to vote for it. Finally, Ms. Rathbun pointed out that Republican majority in the Senate is much more tenuous – the Republicans can only afford to lose two votes and still pass the bill and Ms. Rathbun estimates that they’re already eight to ten votes down with the current version of the bill.

The Practice of Obesity Medicine in 2017

The Latest and Greatest on Weight Loss Diets and Bariatric Surgery

Ken Fujioka, MD (Scripps, La Jolla, CA)

Dr. Ken Fujioka, a well-respected voice on best practice obesity management, discussed the role of genetics in the future of personalized nutrition and the role that genetics will play. Addressing young clinicians in the room, he forecasted that someday soon “you’ll be getting these genetic tests as your patient walks in the door for the first time” – what may seem futuristic is actually closer than we think. As an example, Dr. Fujioka presented a study correlating the C allele (a single genetic factor) with varying responses to dietary interventions. Individuals with the C allele present lost 4% body fat on a high carb diet vs. only 1% body fat on a low carb diet; they also experienced a mean 5.5 cm reduction in waist circumference on a high carb diet vs. 3 cm on a low carb diet. These are clinically-meaningful differences, Dr. Fujioka emphasized, and these findings are unique. He remarked that this is the first data to his knowledge following one allele prospectively to see how people respond to different diets. He also reminded everyone of the research showing that there’s no one “best” diet that works for everyone across the board – the macronutrient ratio of fat to protein to carb that works for one person won’t necessarily work for the next. Genetic tools that allow us to predict responses to diet and to truly personalize nutrition could thus revolutionize obesity as a therapeutic area. Genetic markers could reduce the trial-and-error that’s such a prominent part of current approaches to obesity management – this is a tremendously exciting notion to us, since so many patients experience frustration and burnout in chronic weight management, when ideally we’d like to promote self-efficacy and to motivate patients to stay engaged with their own health.

• Dr. Fujioka also touched upon FGF21 (fibroblast growth factor 21), which has been the target of many new drug candidates of-late: Roche added an FGF21 analog to its pipeline in 1Q17, and will conduct a phase 1b study of the agent in participants with type 2 diabetes and obesity (it’s unclear at this point whether the company will seek an indication for type 2 diabetes, obesity, or both). Novo Nordisk is investigating a phase 1 FGF21 analog for obesity, and BMS recently presented phase 2 data for a pegylated FGF21 analog in NASH. Dr. Fujioka underscored the potential of FGF21 analogs for people with obesity and type 2 diabetes, although we note that data in type 2 diabetes so far has been mixed – Lilly and Pfizer both had FGF21 candidates for type 2 diabetes in their pipelines, but both candidates were discontinued due to lackluster glucose-lowering results. Perhaps some of these other early-stage therapies will show more promise through clinical development. Dr. Fujioka pointed to elevated FGF21 levels found in people with high BMI, increased waist circumference, increased fat mass, and increased visceral adiposity. This correlation suggests that obesity may be an FGF21-resistant state, which means analogs of this hormone could bolster physiological supply in people trying to lose weight, and Dr. Fujioka thus endorsed this novel approach to obesity pharmacotherapy. Overall, we’re more optimistic for FGF21 as an obesity treatment (or even a NASH treatment) than we are about its potential for type 2 diabetes, given the increasingly high bar for new diabetes drugs. That said, given its modest glucose-lowering efficacy, we can envision a role for FGF21 in the treatment with people with obesity and prediabetes especially.

Different Approach to Obesity in T1D vs. T2DM

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

Dr. Richard Pratley (Florida Hospital Diabetes Institute, Orlando, FL) provided a fascinating overview of the management of comorbid diabetes and obesity, noting a recent “paradigm shift” such that obesity now frequently complicates the management of type 1 diabetes in addition to type 2 diabetes. As a testament to the importance of obesity management in diabetes care, this session was standing room only. Despite an increasing body of evidence surrounding the pharmacological and surgical management of obesity in people with type 2 diabetes, Dr. Pratley characterized the landscape of obesity management in type 1 diabetes as an “evidence-free zone.” On the pharmacotherapy front, virtually no studies exist investigating the efficacy of obesity medications in people with type 1 diabetes. However, some limited data exists on the efficacy of various type 2 diabetes medications with weight loss effects (namely GLP-1 agonists and SGLT-2 inhibitors) in people with type 1 diabetes and obesity. Novo Nordisk’s Victoza (liraglutide) is perhaps the most investigated therapy option for weight loss in type 1 diabetes: in the Lira-1 trial and the ADJUNCT ONE and ADJUNCT TWO trials, patients experienced modest ~4-5 kg (8.8-11 lbs) weight loss and ~0.2% A1c reduction with Victoza added to insulin therapy. Novo Nordisk declined to pursue an expanded indication for Victoza in type 1 diabetes after these underwhelming results due in part to worrisome safety signals for DKA and hypoglycemia. On a different note, safety and efficacy studies for the SGLT-2 inhibitor empagliflozin (Lilly/BI’s Jardiance) and SGLT-1/2 dual inhibitor sotagliflozin (Sanofi/Lexicon’s phase 3 candidate) in type 1 diabetes have shown modest weight loss benefits, though the high-profile DKA controversy associated with this class has some wary (we continue to believe that the risk can be managed through concerted patient and provider education efforts). A similar lack of evidence exists for bariatric surgery in type 1 diabetes, though a case review meta-analysis encompassing 107 patients with type 1 diabetes and obesity concluded that surgery, in addition to decreasing BMI, can decrease patients’ insulin requirements and modestly lower A1c, though at the risk of increased ketoacidosis. This is an area in which we’d love to see more work. As the obesity epidemic persists, the proportion of people with comorbid obesity and type 1 diabetes will only rise and we look forward to a future where clinicians better understand how to help patients manage the two synergistically.

State-of-the-Art Treatment of Obesity in Your Practice

Culinary Medicine in the Treatment of Obesity

Tim Harlan, MD (Tulane University, New Orleans, LA)

In a highly-entertaining talk, Dr. Tim Harlan (Tulane University, New Orleans, LA), a chef and restaurateur- turned- physician, provided a fascinating overview of his “culinary medicine” approach to obesity. He compellingly posited that traditional medicine sets people with obesity up for failure with its overemphasis on the number of pounds lost and argued that physicians should focus more on the “other half of the equation – the quality of the calories we put in our mouths.” To this end, he recently established the Goldring Center for Culinary Medicine, a first-of-its kind teaching kitchen owned and operated by Tulane University that, in addition to educating the community about health eating via free family cooking classes, educates medical students on how to teach their patients about nutrition. Dr. Harlan’s curriculum focuses on the Mediterranean diet given its extensively researched status, but he was careful to emphasize that “it’s not about recipes” and the principles of the Mediterranean diet can be applied to any cuisine by simply promoting nine key points: vegetables, legumes, fruits, nuts, whole grains, fish, monounsaturated fat, alcohol in moderation, and red meat in moderation. Literature suggests that improving one’s Mediterranean diet score by as little as two of these points has a marked impact on all-cause mortality – and, Dr. Harlan pointed out, it’s free. For this reason, he advised physicians to make use of this short, simple message of “two points” and begin the conversation about nutrition by asking patients for a diet recall (in which patients list everything they have eaten in the last 24 hours) – he emphasized that asking about this is just as important as asking about family medical history and surgical history., a tool he places on equal footing with family history and surgical history.

The Therapeutic Toolbox: Medications, Endoscopic Devices and Surgery

Lee Kaplan, MD (Harvard Medical School and Massachusetts General Hospital, Boston, MA)

In a very actionable talk, the always-engaging Dr. Lee Kaplan (Harvard Medical School and Massachusetts General Hospital, Boston, MA) overviewed presented an overview of his core principles forof obesity treatment. He began by defending the stance that the physiological regulation of energy balance drives eating behavior (and not the other way around), and the implication that the body has a defended set point weight that it vigorously defends, making weight loss is far more complicated than a simple equation of calories consumed and calories burned. Against this backdrop, Dr. Kaplan pointed out that we live in an environment that creates the “perfect storm” for abnormal metabolic physiology – from unhealthy dietary constituents, low muscle mass, sleep deprivation, disrupted circadian rhythmicity, and high prevalence of weight gain- inducing medications. Lifestyle interventions should focus on cCounteracting these forces with healthy diet, regular physical activity, more and better sleep, stress reduction, and stable eating patterns should be the guide to advised lifestyle modifications, he argued, and if this isn’t effective, anti-obesity medications followed by bariatric surgery can provide an extra push (though it is difficult to predict who will respond best to which therapy). Of course, the dream is to be able to replicate the effects of bariatric surgery via less invasive endoscopic or next-generation pharmaceutical techniques, and Dr. Kaplan expressed optimism that further research into the mechanism of action behind the metabolic effects of bariatric surgery can help make this a reality. Above all, Dr. Kaplan advised physicians to “treat obesity as you would treat any other disease” by approaching patients in a supportive and non-judgmental way, matching therapeutic invasiveness to obesity severity, and using combination therapies when possible to enhance benefit and minimize risk. Though obesity rates are rising at an epidemic level, this increasingly prevalent disease continues to be an area of unmet need.; we appreciate Dr. Kaplan’s cogent advice in a challenging disease state that continues to be so misunderstood.

Implementing the AACE Obesity Algorithm

Timothy Garvey, MD (University of Alabama, Birmingham, AL)

Dr. Timothy Garvey (University of Alabama, Birmingham, AL) reviewed highlighted the recent AACE position statement on obesity, which proposes a new name for the medical condition – adiposity-based chronic disease (ABCD). The suggested term is fitting, although we’re not sure patients (or some doctors) would be able to rattle off what it stands for: that said, obesity is indeed a chronic disease that requires lifelong management, is associated with complications that confer morbidity and mortality, and aligns with the classic primary, secondary, and tertiary prevention phases of a chronic condition. Dr. Garvey argued that “obesity” was severely lacking as a label because it’s not actionable, it’s not informative for overall health and wellness, nor is it sufficiently specific. “Obesity” doesn’t tell you anything about adipose tissue mass or the long-term complications an individual patient will encounter. The term is also clouded with stigma by now, and research shows that even well-trained healthcare providers display an unconscious bias toward patients with high BMI. Transitioning language in this therapeutic area to talk about “adiposity-based chronic disease” could circumvent this stigma and bias. Dr. Garvey explained that how ABCD medicalizes the condition and encourages people to think about it in the same category as any other disease, with symptoms and adverse health effects. Indeed, promoting thea conception of obesity as a biological disease is a crucial first step in promoting great acceptance of chronic medical management of obesity among convincing patients, providers, and payers that it can be treated with medical management. Uptake of obesity drugs, for example, remains low despite the demonstrated safety and efficacy of some of these newer agents (especially Novo Nordisk’s Saxenda) – providers/patients may be more likely to consider Saxenda as a therapy for adiposity-based chronic disease vs. obesity, and payers may be more likely to reimburse the drug for ABCD as well. We’re thrilled to see AACE stepping up with clear obesity treatment guidelines as well as this effort to medicalize the term. We see great potential for ABCD to combat stigma and unconscious provider bias, which is an absolutely essential goal, given that the vast majority of people with obesity aren’t currently receiving any medical treatment. AACE has been a trailblazer in the obesity healthcare field for some time now – the organization was one of the first to recognize obesity as a disease in 2011 (preceding even the American Medical Association’s recognition by two years) and to create complications-based treatment guidelines for the condition in 2016. We’re glad to see their continued leadership in this field!

Posters

Insights and Perceptions of Obesity Management in Older People with Obesity

M Look, A Golden, T Kyle, NV Dhurandhar, B Stevenin, Madhuri Mehta, and K Tomaszewski

In a poster, A Novo Nordisk aposter detailed a sub-analysis of people over 65 in the Novo Nordisk-sponsored ACTION study , described the surprising landscapeexperience of obesity in older Americans: they are diagnosed with obesity less frequently despite having more complications, and seek less support from physicians and yet succeed at weight loss more often. These findings were also shared in a press release from the company. Novo Nordisk’s ACTION study made waves at Obesity Week 2016 as the first ever large-scale investigation exploring the factors underlying the barriers to weigh management from the differing perspectives of stakeholders ranging from healthcare professionals (n=606), employers (n=153), and, most crucially, people with obesity themselves (n=3,008). Although older people with obesity (who comprised 31% of the people with obesity enrolled in the ACTION study) report considering obesity a disease at a similar frequency as their younger counterparts (66% vs. 64%), this group showed important differences in how they perceive and manage their obesity. Perhaps most crucially, though unsurprisingly, older people with obesity report greater comorbidity prevalence than younger people with obesity – 73% have high blood pressure (versus 43% for those under 65), 62% have high cholesterol (versus 34%), 31% have sleep apnea (versus 22%), and 31% have type 2 diabetes (versus 18%). Despite these trends suggestive of greater disease severity in older people, fewer older people with obesity (50%) report having received a formal obesity diagnosis than their younger counterparts (56%; p<0.05). That said, a greater number of older people with obesity reported weight loss success (defined as at least 10% body weight loss) in the past year compared to younger counterparts (13% versus 9%, p<0.05) even though a greater proportion of older people with obesity reported that they “do not seek support” from their physician for weight loss (44% vs. 35%, p<0.05). These counterintuitive findings may can perhaps be explained by different motivations for obesity management among older versus younger people: a greater proportion of older people with obesity reported that a specific medical event (heart attack, stroke, etc.) had a profound influence on their desire to manage weight (16% vs 12%, p<0.05) and cited improving existing health conditions as an overall goal to achieve as part of weight management (67% vs. 62%, p<0.05). This sub-analysis has immediate implications for obesity clinical practice. According to the study authors, clinicians should be especially attentive to the barriers and challenges toward obesity management in older people with obesity should be addressed by clinicians at least well as their younger counterparts are, given their higher success at obesity management. Furthermore, given that previous health events are especially motivating forces for weight loss in older people, clinicians should change the conversation so that patients receive counseling about weight management before and not after such an event takes place. This study reinforces that older patients have significantly different motivations and concerns from younger patients, and these considerations are important to keep in mind when individualizing therapy for older adults.

Product Theaters

670G Auto Pilot at Night, Co-Pilot during Day (Sponsored by Medtronic)

Scott Lee, MD (Medtronic, Minneapolis, MN)

Medtronic Global Medical Director Dr. Scott Lee shared how he explains the 670G value proposition to patients, excellent safety data from the continued access phase, and some of the positive feedback he’s heard from patients. The importance of effectively communicating the role of the 670G to patients can’t be understated, and to ensure the average person gets it, Dr. Lee resorts to metaphors. He compares the PID algorithm to cruise control, and tells patients that the system works like an auto pilot at night, while it is more of a co-pilot during the day. We love like this idea, as it gets across the pointemphasizes that the patient still has to drive – give insulin with a meal, respond to hyperglycemia,  and check blood glucose, etc. – but the 670G will accommodate provide some daytime guardrailsthem in the background, forgiving carb-counting inaccuracies, normal physiology, stress, and exercisehigh-fat meals, etc. In the continued access phase, Dr. Lee emphasized that there have been zero episodes of DKA and only two (!) episodes of severe hypoglycemia, both unrelated to closed loop (i.e., large boluses while in open loop). The safety profile of this device is definitely solid (especially compared to nothing), and on AACE Day #1, Dr. Bruce Bode shared encouragingqually impressive efficacy data from ~560 patients via CareLink (average glucose=151 mg/dl; standard dev=52 mg/dl – a standard deviation less than 50% of the “average” is typically seen as very good so a standard deviation less than 35% of the average is quite notable). Notably, Dr. Lee also commented that speaking to a nocturnal hypo-prone patient in the pivotal study about the overnight benefits of the 670G was “remarkable” and “one of the most moving experiences in [his] 20 years of practicing diabetes.” We were very moved by this - we’d love to see more moments of success for providers. Dr. Lee’s then said that tTraditional pump therapy , he added, seems “pretty crude and rudimentary” next to the automatic microni-boluses doses the 670G provides every 20 five minutes. “Theis most common clinical conundrum we see is patients doing the same thing every day and having very different day-to-day outcomes, and this helps address that problem for the first time.” The most important aspect of the 670G for patients he’s spoken to? It accommodates around imperfections, human-ness, allowing them to not feel guilty if they misestimate a bolus. This early feedback was very illuminating and reinforces our view that eventually, anyone on mealtime insulin should have the help of a computer – bolusing “in the wild” unaided by technology will thankfully become less and less common.

• Texas Diabetes and Endocrinology’s Dr. Thomas Blevins gave his account of the 670G training process in his clinic;  (see image below for protocol, which is the same that Yale’s Dr. Jennifer Sherr spoke about at CDTM). The 630->670G on-boarding paradigm is not very labor intensive and is well worth the investment, as the 670G could prevent future visits. Dr. Blevins has only had patients on the system for three to four weeks, but he characterized training as straightforward, and his patients, who come into the office two at a time, picked it up well, he said. On the whole, he called 670G “one of the nicest developments in diabetes that [he’s] seen in [his] 30 years practicing. We’d noteNotably, one of the  the slides characterized use of “close follow-up,” as a the key to success, and it will be interesting to see how scalable this device is for the average diabetologists. How easy will it be to prescribe and train once it is more broadly available?

Toward a Closed Loop System (Sponsored by Tandem)

Daniel Cherñavsky, MD (University of Virginia, Charlottesville, VA)

Tandem management shared that the t:slim X2-Dexcom G5 integration could be approved by FDA “very shortly”/“any day now.” Per the 1Q17 call, approval was expected by this summer and Tandem planned to launch this product within 30 days of approval. Subject to approval, current t:slim X2 users (10,000+ patients) will be able to update their pump’s software for free to add G5 integration (via the Tandem Device Updater). We think patients and providers will be thrilled by this capability. EVP Mr. Brian Hansen reiterated that this update will be free, but the company is unsure if the same will be said about the PLGS (launch expected early 2018) and hypo-hyper minimizer (launch expected by the end of 2018) systems. However, if they are not free, they will likely be “in the $199-$299 range, not in the thousands.” We’re glad to hear this, since many t:slim X2 customer would be frustrated to hear of a significant upgrade fee. That said, it’s a far cry from the costs of old to upgrade with many other systems.

• Tandem is “working on embedding advanced algorithms” in the t:sport patch-like durable pump, which is still in development. This is the first allusion to the pump (~50% smaller t:slim, worn on the body, short infusion set, no screen or buttons, wireless controller) since 2Q16, when management pushed PMA submission timing back to 2018 due to upcoming R&D work on the t:slim X2 with Dexcom CGM integration and automated insulin delivery. We were surprised to hear this mentioned, given the pressure Tandem has to execute on its current pipeline; perhaps we’ll hear an update on the next call. While the t:sport doesn’t match Insulet’s truly tubeless OmniPod, it would certainly bring a more competitive product for Tandem to court MDIs and differentiate from standard durable pumps.

New Perspectives on Existing Concepts of Cardiovascular Risk

Harold Bays, MD (Louisville Metabolic and Atherosclerosis, Louisville, KY)

In an Amgen-sponsored but unbranded product theater, Louisville’s Dr. Harold Bays discussed modifiable vs. unmodifiable CV risk factors, arguing that there’s a lot more we could be doing to reduce modifiable risk factors, particularly diet/exercise and obesity. While there’s little medicine can do to affect unmodifiable variables like age and race, Dr. Bays urged providers in the room to capitalize on opportunities to implement lifestyle interventions. That said, he acknowledged a glaring limitation to nutrition and exercise research: “We don’t do a very good job – as scientists, as clinicians, as researchers – sending clear messages on what is healthy vs. unhealthy diet and exercise.” The first step, then, is establishing clinically-grounded and easy-to-follow algorithms for dietary interventions and physical activity regimens. Suitable and standard guidelines for diet and exercise are still lacking in medicine. Dr. Bays shared his opinion that the “best” diet or exercise regimen are whichever ones a patient can stick to, as this promotes self-efficacy and health engagement. Even if the “best” a patient can commit to is light walking, Dr. Bays underscored that a small increase in exercise can still influence CV risk. He presented obesity as another modifiable risk factor for CV events, and made a compelling point on how to tackle stigma: The practice of obesity management needs to borrow language from the diabetes field, and providers should refer to “patients with overweight or obesity” rather than “obese patients,” just as endocrinologists have reached a consensus more or less on addressing “patients with diabetes” rather than “diabetics.” Dr. Bays explained how this choice vocabulary reflects a priority to treat the whole person, not just their disease. We couldn’t agree more on the value of terminology, and we see profound effects of vocabulary in the practice of treating obesity, where stigma abounds and where providers show an unconscious bias against people with overweight or obesity. An important first step to improve chronic weight management is promoting the concept of obesity as a chronic, biological disease, and vocabulary could go a long way in counteracting stigma and correcting biases.

• Dr. Bays listed “prior history of CV events” as an unmodifiable risk factor for future CV events but suggested that we may soon be able to move this variable into the modifiable category. Advanced therapies for diabetes, including Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) and Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), have shown CV benefit in long-term outcomes studies – the LEADER and EMPA-REG OUTCOME trials, respectively, demonstrated how these agents significantly reduce CV risk in people with a prior history of CV disease. It’s tremendously exciting that diabetes providers are now able to prescribe medicine to modify this risk factor though we think it’s very early days – we’re certainly eager to see “prior history of CV events” transitioned into a category of modifiable variables in CV prevention.

Corporate Symposia

Standardized Glucose Reporting: The New EKG for Diabetes (Sponsored by AbbotT)

George Grunberger, MD (Grunberger Diabetes Institute, Bloomfield Hills, MI)

Former AACE President Dr. George Grunberger highlighted the hot off the press Endocrine Practice Letter to the Editor in which he and Tulane’s Dr. Vivian Fonseca provide a follow-up to last year’s AACE CGM consensus conference with two recommended standard reports, as well as a third exhibit with additional suggested (non-standardized) CGM reports. The reports are essentially modified Ambulatory Glucose Profiles, with the first designed for CGM, and the second for BGM. Both have a top line containing information about usage/frequency of testing, with a dashboard below containing average glucose, eA1c, time in range, coefficient of variation, and standard deviation. Below the dashboard is the IDC-developed AGP, with the median glucose trace surrounded by clouds indicating 10-90 percentiles and 25-75 percentiles. The recommendations in the third figure were derived from last year’s AACE/ACE Consensus Conference on CGM, where CGM thought leaders convened to discuss data reporting, among other hot topics. Included in the list of recommendations for non-standardized reports, which are intended to be tailored to the individual clinic, are: (i) Individual daily tracings; (ii) pattern identification for hypoglycemia, hyperglycemia, and glycemic variability; (iii) glucose tracing that integrates logbook information; (iv) detailed information on the number of hypoglycemia events, duration and timing; (v) hypoglycemia reported <55 and <45 in addition to <70; (vi) risk indices – measures of frequency and extent of low and high blood glucose; (vii) post-meal glucose summaries; (viii) summaries of log book averages; and (ix) number and timing of calibrations (if applicable). We are delighted to see this guidance from AACE, and hope that companies manufacturers will continue to adopt the report as Abbott, Roche, Glooko/Diasend, Tidepool, and others have already done. As Dr. Grunberger always says, when cardiologists look at EKGs, they’re first question is never “which device did this come from?” – everything is immediately decipherable regardless of manufacturer, and glucose reports should be as universally understandable and “glance-able” as an EKG. This was the strongest call we’d heard yet for CGM data to be defined and measured consistently, and we believe patients would benefit profoundly from this approach – here’s to leadership from Drs. Grunberger and Fonseca.

• “Having FreeStyle Libre Pro in the office has truly, truly changed the way I and my patients think about diabetes. Isn’t it fun that this technology is finally hitting the market?” Dr. Grunberger isn’t the first to express the “how did we get along without this?” sentiment, but it is so impactful coming from a physician who has been caring for people with diabetes for multiple decades.
•  “The plea has been expressed by many patients, even regulators – just get away from this A1c-centric culture. Practitioners get graded on A1c. I can get all patient’s’ A1c lower than 6%, and probably half would survive. And it’s the whole stupidity of relying on A1c to dictate care.” Following the highly successful FDA Workshop on Outcomes Beyond A1c in August, we look forward to the nextfuture gatherings that  in the future (no date set yet) to discuss ways to move the needle away from sole focus on A1c and toward metrics such as time in range, hypoglycemia, and patient-reported outcomes that also incorporate A1c but contextualize it. We know a session at ADA will address this topic, as will other efforts ongoing in the community (e.g., JDRF’s T1D Outcomes program). 
• “We need better codes, how we get paid for expertise. We can figure out what’s going on in a fraction of a minute, but I’m not sure anyone understands the effort that goes in [to the entire process]. It’s incredibly labor-intensive. If you did in-depth analysis every day, maybe you’d see one patient a day.” We second this – there are so much better payments for analysis of heart disease and we hope this can be extended to CGM. Our sense is also that the codes that do exist aren’t well understood enough or optimally used and we hope to see improvement on this front. ?

Using Insulin When, Where, and How It's Needed: T2D Treatment in the Modern Age (Sponsored by Sanofi)

Guillermo Umpierrez, MD (Emory University, Atlanta, GA), Vivian Fonseca, MD (Tulane University, New Orleans, LA), Yehuda Handelsman, MD (Metabolic Institute of America, Tarzana, CA), Janet McGill, MD (Washington University School of Medicine, St. Louis, MO)

At a Sanofi-sponsored educational symposium, moderator Dr. Guillermo Umpierrez (Emory University, Atlanta, GA), suggested that the FDA was overly conservative in indicating Xultophy and Soliqua only for patients who have previously failed to reach goal with a basal insulin or the component GLP-1 agonist, excluding those who have yet to intensify their first-line diabetes therapy. Indeed, this was a major discussion point at the FDA Advisory Committee Hearings for both Xultophy and Soliqua, and we certainly agree that these combinations, which boast both a reduced side effect profile and enhanced clinical efficacy compared to either component monotherapy, are in many ways an ideal choice for insulin-naïve patients who are not at goal. Further, as a GLP-1 agonist intensification option, both products are currently only indicated for insulin-naïve patients who are already on the component GLP-1 agonist, excluding patients who may be on, say, Trulicity. This is especially a disadvantage for Soliqua, as very, very few patients are on standalone lixisenatide (hence the laser-focus on positioning Soliqua as a basal intensification option, we assume). Dr. Vivian Fonseca noted that the FDA could indicate these combinations for a wider patient population in the future, but not without more data. He pointed out that although the benefit of initiating injectable therapy with combinations over basal insulin or a GLP-1 agonist alone is obvious to clinicians, as a regulatory body the FDA must take a slower and more conservative stance, although it is being perhaps “overly cautious” in this case. To this end, past AACE president Dr. Yehuda Handelsman (Metabolic Institute of America, Tarzana, CA) provocatively argued that Novo Nordisk and Sanofi “didn’t do their job” at their respective Advisory Committee meetings for Xultophy and Soliqua in failing to secure an indication for a wider patient population. All we can hope is that with more time and more familiarity the convenience, patient friendliness, and high efficacy of these newly-launched combinations becomes more widely appreciated, and that these drugs will become accessible – both in terms of cost and in terms of label indication – for a wider array of people who could greatly benefit from them.

• Dr. Janet McGill (Washington University School of Medicine, St. Louis, MO) discussed the benefits of new basal insulin/GLP-1 agonist fixed-ratio combinations as a diabetes therapy intensification option. So great are the clinical benefits of these combinations that Dr. McGill framed them as a distinct milestone in the now 95-year history of insulin therapy development, comparable to the improvement that came from long-acting analogs over human insulin – wow! She took a deep dive into the impressive clinical data for Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s Soliqua (insulin glargine/lixisenatide), noting common themes of reduced weight gain (even weight loss), reduced hypoglycemia, and improved A1c, FPG, and PPG for combinations over each of their component monotherapies. Dr. McGill convincingly pointed out that the major limitations to reaching glycemic goals with insulin therapy are hypoglycemia, weight gain, and the complexity of an insulin regimen for the patient, so combinations like Xultophy and Soliqua – with their reduced side effect profile and greater ease of use – are in many ways an ideal alternative, not to mention their improved A1c efficacy over traditional insulin or GLP-1 agonist therapy alone.
• Tulane University’s Dr. Vivian Fonseca outlined reasons for and strategies to address clinical inertia in basal insulin initiation in type 2 diabetes patients. As Dr. Fonseca put it, insulin is tricky drug, one that requires complicated dosing and titration. Providers worry about patients missing dosing or not being able to titrate properly, and they shy away from prescribing a therapy that may cause hypoglycemia or induce weight gain. Fear of hypoglycemia and a desire to avoid weight gain affect patient perceptions of insulin therapy as well, and surveys show that between 17% and 28% of type 2 patients are unwilling to try a basal insulin product. Additionally, Dr. Fonseca pointed out that all-too-often, providers use insulin as a threat for their patients with type 2 diabetes, and the natural patient response is to view initiation of basal insulin as a failure on their part. Above all, there’s also the issue that busy healthcare providers don’t feel they have the time to thoroughly educate patients on insulin titration for optimal outcomes. Dr. Fonseca positioned education as step no. 1 in overcoming this clinical inertia, and he expressed some optimism that it will become more feasible as we move away from fee-for-service toward value-based healthcare. Currently, there’s no good system in place to reimburse providers for extra time spent on education, but given how critical this educational support can be for patient outcomes, it will naturally become more central in a value-based model – boy would we love to see this change! Dr. Fonseca also encouraged more reliance on diabetes educators and a broader diabetes care team to supply patient education alongside insulin therapy. He highlighted group-based education as another time-saving possibility. Dr. Fonseca emphasized that starting insulin should be a shared decision between patient and provider, and that HCPs should create an insulin regimen that fits into a patient’s everyday life. All of this rung incredibly true to us, and we appreciated Dr. Fonseca’s clear tips and tricks to beat inertia.
  
  • Dr. Fonseca proposed practical solutions for other barriers to initiation as well:
    • Patients sometimes forget insulin doses, which reduces the drug’s A1c-lowering efficacy, but we can now offer alerts, alarms, or reminders with fairly simple technology.
    • Some patients list injection pain as an obstacle, but this is becoming less of a problem with newer insulin pens and pumps.
    • Combining insulin with an SGLT-2 inhibitor can address concerns of weight gain (since SGLT-2 inhibitors have been associated with weight loss).
    • Providers shouldn’t be positioning insulin as a last resort or sign of treatment failure, and should consider CGM for their type 2 diabetes patients who are particularly prone to or afraid of hypoglycemia (or, individuals with hypoglycemia unawareness).
  • Dr. Fonseca also established, early on in his talk, why earlier intervention with insulin is beneficial in diabetes care. Data shows that insulin therapy not only improves glycemic control, but empowers patients and enhances quality of life. As we push for greater consideration of outcomes beyond A1c, we’re particularly excited to see data linking insulin to time in zone and quality of life metrics. While he said the diabetes community is not yet sure why insulin improves patient quality of life, Dr. Fonseca suggested a few possible explanations – tighter glycemic control, a greater sense of self-efficacy, or sharpened cognitive function (also associated with blood glucose-lowering).

Burning Questions About New and Emerging Injectable Therapies for Type 2 Diabetes (Sponsored by Novo Nordisk)

Daniel Einhorn, MD (Scripps Whittier Diabetes Institute, La Jolla, CA), Michelle Magee, MD (George Washington University, Washington, DC), Jorge Plutzky, MD (Brigham and Women’s Hospital, Boston, MA), and Ralph DeFronzo, MD (University of Texas Health Science Center, San Antonio, TX)

At a Novo Nordisk-sponsored educational symposium, Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX) provided a fascinating practical deep dive into the management of chronic kidney disease (CKD) comorbid with type 2 diabetes. He set the stage by underscoring the importance of preventing or minimizing progressive renal disease: beyond the risk of dialysis, CKD is associated with a 30%-40% increase in the risk of cardiovascular disease (independent of the effect of traditional cardiovascular risk factors that may also be present) and furthermore can lead to insulin resistance and decreased insulin secretion, exacerbating the progression of diabetes and thereby worsening CKD in a vicious cycle. Dr. DeFronzo issued the caveat that although traditional glycemic targets are the same for patients with CKD as those without, it is important to individualize pharmacotherapy choice with CKD in mind. For instance, though metformin is standard first-line therapy for type 2 diabetes, it is only appropriate for CKD patients with an eGFR >30-45 ml/min/1.73m² since metformin is largely cleared from the body via the kidneys. Furthermore, insulin and DPP-4 inhibitors require reduced dosing in patients with CKD, as impaired renal function can increase the risk of these agents producing hypoglycemia. Dr. DeFronzo also warned against the use of short-acting GLP-1 agonists (namely twice-daily exenatide and lixisenatide) in people with CKD as short-acting GLP-1 is eliminated through the kidneys via GFR and tubular degradation. Long-acting GLP-1, by contrast, do not use the kidney as the site of elimination so GLP-1 agonists such as liraglutide and dulaglutide are likely suitable for people with CKD, although this has not yet been rigorously investigated in clinical studies. All this said, Dr. DeFronzo concluded with a discussion of the SGLT-2 inhibitor class as the optimal choice for diabetes management in people with CKD given these agents’ potential preventative effect on renal outcomes. Indeed, in the EMPA-REG OUTCOME trial, empagliflozin produced impressive relative risk reductions in doubling of creatinine (44%), macro albuminuria (38%), renal replacement therapy (55%), all contributing to a 39% relative risk reduction in a composite renal endpoint. This is encouraging and reassuring (though, notably, a renal indication is unlikely to make it onto the empagliflozin label without a dedicated renal trial). SGLT-2 inhibitor manufacturers clearly have confidence in the renal benefit of the class – both J&J and AZ have initiated renal outcomes trials for their products. While diabetes treatment guidelines are beginning to take into account cardioprotective benefit data, we’re love to see clearer , and we look forward to a future where trials take a dedicated look at renal outcomes to make treatment guidelines more clear for the many people with diabetes with CKD or at risk of developing it.

Latest and Greatest in Practical Application of Cardiovascular Outcomes for Diabetes Drugs (Sponsored by AstraZeneca)

Daniel Einhorn, MD (Scripps Whittier Diabetes Institute, La Jolla, CA), Lawrence Blonde, MD (Ochsner Medical Center, New Orleans, LA), Mikhail Kosiborod, MD (Mount Sinai, New York, NY), Zach Bloomgarden, MD (Mount Sinai, New York, NY)

In an AZ-sponsored corporate symposium on the connection between diabetes, diabetes therapies, and CV risk, moderator Dr. Daniel Einhorn implied that EMPA-REG OUTCOME and LEADER have been incorporated into the next iteration of the AACE/ACE diabetes treatment algorithm in some fashion. He shared that the AACE/ACE guidelines writing committee had met that very afternoon and one of the chief questions on the agenda was what kind of recommendation these groundbreaking trials could support for empagliflozin and liraglutide, respectively. In particular, when asked in Q&A if empagliflozin and/or liraglutide could be positioned as first-line therapy (at least in those with cardiovascular disease), either replacing or alongside metformin, Dr. Einhorn responded, “That’s exactly the question AACE grappled with.” He emphasized that guidelines must follow clinical evidence as best as possible and strive to present the material in a coherent, easy-to-understand algorithm graphic. He teased, “I can’t tell you what we came up with, but you’ll see it soon and I think we resolved it in an elegant way.” As a reminder, the recently-updated ADA Standards of Care recommend empagliflozin and/or liraglutide in the treatment of patients with type 2 diabetes and existing cardiovascular disease, but does not go so far as to position these agents as first-line therapies. It would be a paradigm shift indeed to dethrone metformin as THE first-line therapy, though the AACE/ACE algorithm has historically been somewhat less conservative than the ADA/EASD guidelines so it’s fitting that they may be the first set of guidelines to take this monumental step.

• In a panel discussion, both Drs. Lawrence Blonde and Mikhail Kosiborod expressed their belief that EMPA-REG OUTCOME is a class effect. The question of whether the impressive cardioprotective (and renal) benefits demonstrated for Lilly/BI’s Jardiance in EMPA-REG OUTCOME apply to other SGLT-2 inhibitors has set the field abuzz in the last 1.5 years since the results were presented at EASD 2015 – and we’ve all been waiting with bated breath for results from the second SGLT-2 inhibitor CVOT to (hopefully) confirm the results. The CANVAS trial for J&J’s Invokana will report in just over a month at ADA 2017, but the conspicuous silence on topline results from J&J management has us wary that the results may not replicate the large benefit seen in EMPA-REG OUTCOME. Oveall, however, it’s too early to tell. Indeed, Dr. Blonde hedged today that it would not “shock” him if upcoming SGLT-2 inhibitor CVOTs do not demonstrate a cardiovascular benefit, based on the differences in their study design and participant population compared to EMPA-REG OUTCOME. We also heard a similar hint that CANVAS may not be a positive as hoped for from Dr. David Nathan at ENDO 2017… whatever the outcome, we shall learn it soon. Overall though, Dr. Blonde clearly feels that the lack of demonstrated benefit in CANVAS would not necessarily rule out a “real” class effect. Similarly, Dr. Kosiborod suggested that the determination of class effect will come from two key kinds of evidence: (i) additional CVOTS and (ii) largescale, real-world observational studies like CVD-REAL. Presented the ACC 2017, the study found that patients taking any SGLT-2 inhibitor experienced risk reductions for CV events comparable to the risk reductions observed in EMPA-REG OUTCOME, despite the fact that the vast majority of participants were taking Invokana or Farxiga rather than Jardiance. Furthermore, these risk reductions remained significant regardless of type of SGLT-2 inhibitor, leading Dr. Kosiborod to suggest that the data thus far all points to a class effect.
• Mount Sinai’s highly regarded Dr. Zach Bloomgarden provided a compelling overview of the challenges of extrapolating data from diabetes cardiovascular outcome trials (CVOTs) to the general population of patients with diabetes. Overall, he suggested that the design and participant inclusion/exclusion criteria for modern CVOTs limits their applicability to the “average” type 2 diabetes patient in clinic. In terms of design, he argued that “practical” durations for trials (on the order of years) may not be sufficient to tease out a cardioprotective benefit (which can take decades to manifest). As he put it, “We’re dealing with a disease that lasts decades and we want to base our clinical recommendations on relatively short trials that may not be applicable.” In addition to the length of the trial, the enrollment criteria can exclude a substantial proportion of the general population with type 2 diabetes. Dr. Bloomgarden pointed to a 2013 literature review that applied the enrollment criteria of five largescale outcomes studies (ACCORD, ADVANCE, PROactive, RECORD, and VADT) to members of a Scottish diabetes registry and found that, at most, only about a third of participants in the registry would have been eligible for enrollment (36% eligible by ADVANCE enrollment criteria, compared to 18% by VADT criteria, 11% by ACCORD criteria, 9% by RECORD criteria, and just 4% by PROactive criteria). Beyond the enrollment parameters included in the trial design, Dr. Bloomgarden also pointed out that participation in a clinical trial is self-selecting and thus these volunteers may not represent the general population either. In our view, these very valid concerns further underscore the need for long-term, real-world studies to complement randomized clinical trial data to help answer some of these questions. Dr. Bloomgarden acknowledged that innovative trial designs that retain randomization while addressing these issues would be extremely helpful, but he suggested that the exact design of such trials and how they would work is not clear at this point. In lieu of disruptive randomized trial design, Dr. Bloomgarden suggested that epidemiological observational data may shed some light on the generalizability of clinical trial results.

Continuous Glucose Monitoring as the Standard of Care: Clinical Outcomes, Improved Access and Non-Adjunctive Use

George Grunberger, MD (Grunberger Diabetes Institute, Bloomfield Hills, MI), Anne Peters, MD (USC Keck School of Medicine, Los Angeles, CA) and Kathleen Wyne (Ohio State University, Columbus, OH)

A 5am Dexcom-sponsored symposium featured countless pearls on CGM education and the psychology of reacting to trends, reimbursement, outcomes beyond A1c, and more from Drs. George Grunberger, Anne Peters, and Kathleen Wyne. Dr. Peters was happy about Medicare’s ruling to cover therapeutic CGM (just Dexcom G5 at this point), but reiterated what we have have been hearing from patients for weeks and Dexcom earlier this week – the devil is in the details. For example, local coverage determinations are still pending, meaning Dexcom’s 10,000+ interested Medicare patients are waiting to be shipped sensors; see our Dexcom 1Q17 report for more on this, including Liberty’s decision to stop processing for the time being. Dr. Peters told the audience (and Dexcom later confirmed in hallway chatter) that Medicare beneficiaries should directly contact Dexcom for now, and they will triage and help patients on a case-by-case basis. Some of the most valuable quotes (see below) touched on the psychology of wearing CGM, including non-adjunctive use and addressing feelings of failure. As always, we were also reminded of the insanity of reimbursement for CGM interpretation and the hoops these providers and patients must jump through. Earlier in the morning, Dr. Wyne offered practical tactics for helping patients get the most out of CGM: issues to consider when looking at CGM; insulin adjustment strategies (basal testing, post-meal monitoring); considering how yesterday affected today; and what questions to ask patients during a CGM review (What did you learn? What did you change, did it work? Did you consider looking at the evening prior to asses a morning glucose trend? What do you think we could work on changing for the future? These questions also reminded us of Margaret Anderson’s brilliant health citizenship panel at the Milken Global Conference - many patients’ mindset could be shifted quite dramatically). She also advocated for a CGM-first framework (giving a sensor to an MDI user at least one to four weeks before a pump), since (i) CGM-based glucose patterns can inform pump setup; and (ii) CGM has proven very effective in MDI. See the myriad quotable quotes from the symposium below.

• “I want everyone to get CGM-based education, whether or not I do it. There are people that I know won’t want to just take it out of the box and wear it – and there are educational materials, and YouTube, and neighbors, but I’d love to teach them some. I’m worried that some patients will overreact to data. I like using this time – a new tool, new teaching, a new approach – to help them benefit. The last thing you want is for failure to come into anyone’s brain. Tell patients that for the first two weeks we’re just getting a sense of who they are. Especially people running high, just be gentle because otherwise they’ll feel like a loser diabetic. I hate it when that happens.” – Dr. Peters
• “Reimbursement is one of the most frustrating aspects of our lives – imagine how much brain-power goes into what we do. Very few people appreciate the value we add. We’re stuck with ancient codes, one for download, one for interpretations. If patients get addicted to technology, you can help them, but you won’t get paid. Very frustrating. I have patients who will hold onto their Dexcom receiver in my office, won’t let my MA download, and I don’t get to see their data because their plan only covers interpretations twice per year. AACE is trying hard to make sure there are new codes to better reflect what we do in the 21^st century. Not only wish us luck, but support us.” – Dr. Grunberger
• “It seems really stupid, taking CGM away from old, hypo-prone people who need it most. We won this battle. A few hiccups. A few things we have to document, but Liberty has ceased for the moment shipping out CGM for seniors – waiting to figure out the details of reimbursement. If a patient was on CGM and is older than 65, they need to contact Dexcom directly. We’re just in a transition period, figuring out payment -- it will be reimbursed, but they should contact Dexcom at the moment. I’ve been told it won’t be long, but there’s a huge demand. We need to make sure we don’t make wrong expectations at the moment.” – Dr. Peters
• “Imagine that someone in the 21^st century is managing a patient on intensive insulin therapy not using CGM – it’s almost unconscionable.” – Dr. Grunberger
•  “Therapeutic CGM requires new thinking –people have been dosing straight off a number for so many years. It does make sense, but how can you find the time in practice to describe it? It’s labor intensive. To teach people to think differently, it’s not really the number you’re treating. Can people add, subtract, divide? It requires practice, and if you don’t then it’s useless.” – Dr. Grunberger
• “We don’t have any studies showing the effect of CGM on depression and anxiety – that’d be a great study and should be run.” – Dr. Wyne
• “Unfortunately, the primary outcome of the GOLD trial was A1c, but anyone who takes care of patients with diabetes knows that A1c is not the key outcome.” – Dr. Grunberger
• “We’ve been so A1c-centric, and it’s not really our fault; regulators at FDA said if you want to get to the market for diabetes, you have to lower A1c. … But with tech, based on glucose management, some patients will be obsessed with having an A1c of 5.1%, but for most, A1c is not the key metric. FDA had a public workshop in August about going beyond a1c. We were very vocal about things like time in range, hypoglycemia, and quality of life measures. A little soft, but gaining currency.” – Dr. Grunberger
• “A disadvantage of CGM is that, since you can see data all the time, you may want to keep bolusing. It’s good at end of the day if they can see hypoglycemia because it allows me to walk it back and show them how not to stack insulin.” – Dr. Grunberger
• “I finally talked a 22-year-old male into wearing CGM. He was in tears – he had been told for years that he’d been doing great, and didn’t expect the results he got. He had no idea that he was going low most nights and going high after meals. He’s worked hard to change variability, and needs to take insulin before meals.” – Dr. Wyne
• “My brain likes simplicity. The beauty of Tidepool is I have it on my dashboard. I don’t even have to plug in my password, I can just go through five different patients’ traces very quickly. Even 30 seconds of additional work drives me crazy. I, like many of you, look at data in my free time at night, which is free, volunteer work.” – Dr. Peters

Treatment Advances for Challenging Patients with Type 2 Diabetes: The Role of Emerging Insulin Combinations (Sponsored by Sanofi)

Lawrence Blonde, MD (Ochsner Medical Center, New Orleans, LA), Alan Garber, MD, PhD (Harvard University, Boston, MA), and Martin Abrahamson, MD (Harvard University, Boston, MA)

In a slight tangent during a Sanofi-sponsored corporate symposium, Dr. Alan Garber expressed his view that the evidence for cardioprotective benefit is stronger in GLP-1 agonists than in SGLT-2 inhibitors. In response to a question on when the AACE/ACE diabetes treatment guidelines might incorporate the data from EMPA-REG OUTCOME and LEADER trials demonstrating a cardioprotective benefit for SGLT-2 inhibitor empagliflozin and GLP-1 agonist liraglutide, Dr. Garber suggested that more evidence is needed. He emphasized that the EMPA-REG OUTCOME findings in particular were very surprising, without a demonstrated benefit on more traditional atherosclerotic endpoints (MI and stroke) despite strong results on reduction of death. As such, he stated, “Additional studies will be necessary before we can go out whole hog for a single drug or even a single class of agents.” On the other hand, he expressed somewhat more confidence in the cardiovascular benefit of GLP-1 agonists, given that results from two trials indicate a strong benefit: LEADER and SUSTAIN 6 (though he acknowledged that SUSTAIN 6 was designed as a safety study). Overall, however, Dr. Garber suggested that more trials and data may be necessary before a substantial change to the guidelines. Clearly, between his comments and those of Dr. Daniel Einhorn the day before, there is quite a bit lot to think about and consider in terms of potential changes to guidelines – this is likely true of discussion among thefor the AACE/ACE guidelines as well as others. We look forward to seeing what the leadership decides writing committee oon the positioning of empagliflozin and liraglutide in the next iteration of the algorithm – and our sense is that there may be some lack of consensus within the committeeit will be very interesting to see where consensus comes out on the committee. While we certainly agree that replicating CV findings in additional studies lend further confidence to the validity of the benefit, we’re not sure this is ahow realistic standard this will be given the extremely high cost of outcomes trials to say nothing of the length of time required – there is not much upside forwe don’t imagine Novo Nordisk to would repeat the LEADER trial, for instance. Additionally, while trials for additional agents in the class can certainly provide more information and confidence in findings if also positive, differences in trial design and participant population – not to mention potential differences in the molecular agent – can lead towill certainly make it hard to compare the results apples to apples (there’s lots of heterogeneity differences in the trial resultsdesigns). We’ve already seen this even amongst the GLP-1 agonist class – the ELIXA trial of lixisenatide, after all, was neutral and it’s unclear if that’s due to the even higher-risk patient population, the relatively short duration of the trial, the short-acting nature of lixisenatide, or the fact that lixisenatide is less homologous to human GLP-1 than liraglutide or semaglutide – or a combination of all three. While we see the logic of a more cautious, “wait-and-see” approach, we think that thehave also heard that the inclusion of these data in guidelines is enormously important for busy providers (particularly in primary care) who rely on these guidelines to learn about the unprecedented CV impact of these drugs. We also have begun to think more about patients and their reaction to cardio-protective data. At present, we think far more patients think day to day about the importance of glucose rather than cardiovascular risk – we certainly don’t think most patients are used to thinking about daily or weekly medicines from a cardio-protection perspective. And, yet, CV events prompt some of the highest costs in the system, practically speaking, to say nothing of reductions in quality of life that come from CV events (or dialysis, etc.) We look forward to the field doing more thinking about how to motivate patients in terms of CV risk reduction as this could be a way that some patients begin to feel more motivated (the notion of reducing the risk of a heart attack or stroke).

TypeZero inControl Advice/Remote Care Platform Trial Timing, Planned Studies, and Closed Loop Future Directions (Sponsored by Tandem)

Daniel Cherñavvsky, MD (CMO, TypeZero, Charlottesville, VA) & Patrick Keith-Hynes, MD (CSO, TypeZero, Charlottesville, VA)

At a Tandem-sponsored dinner, TypeZero CMO Dr. Daniel Cherñavvsky provided an encouraging look at the startup’s pipeline, including the first trial timing we’ve heard for the inControl Advice advisor to inform open-loop insulin dosing (type 1 trial, n=142, open for enrollment; type 2 trial to begin in 1Q-2Q18) and population risk analysis remote care platform (trial to begin in 2Q18). Dr. Cherñavvsky, who also holds an appointment as an assistant professor of the Center for diabetes technology at the University of Virginia,  spoke about a truly impressive breadth of ongoing or planned closed loop clinical trials:, adjunctive inhaled insulin (Afrezza) with closed loop (starting soon, collaboration between Yale University and the University of Virginia), fixed dose insulin/pramlintide mixture in closed loop (collaboration between Mayo Clinic’s Dr. Ananda Basu and UVA), physical activity informed closed loop (in collaboration with Dr. Marc Breton at UVA, and surely many more. Of course, there’s also the NIH-funded iDCL study, which is in the training phase and doubling as Tandem’s pivotal study, Project Nightlight (n=84, 11 months of closed loop vs. SAP), and Safety at Home (n=22, five months of use). Notably, the iDCL is designed for patients ages 14+, but the University of Virginia Center for diabetes technology has also submitted a grant application with NIH for adding pediatric patients ages 6-13, which (if funded) would also be in collaboration with TypeZero. Thanks to its UVA ties, this company is extremely prolific when it comes to generating clinical data – on top of the aforementioned studies, the TypeZero system has been tested in more than 42 trials since 2006, amounting to ~300,000 collective hours (>30 years) of closed loop! Read on for a list of TypeZero’s closed loop future directions, t:sport, inControl Advice and Remote Care Platform, and more!

• No avenues are off-limits in terms of future directions for TypeZero’s algorithms, devices, cloud usage, and hormones. Dr. Cherñavvsky displayed slides depicting the following potential future directions – since TypeZero now has a partnership with Cellnovo as well, these could apply to Cellnovo and/or Tandem:
  
  • Algorithms: Activity/exercise/sleep detection based on accelerometer or heart rate monitor; goal-oriented algorithms (user-selectable targets and thresholds, turning modules off and on); tunable algorithms that can be more or less aggressive; real-time estimation of insulin-sensitivity; and personalized algorithms that adapt to a patient’s individual, evolving physiology.
  • Devices: New sensors (Senseonics’ Eversense and Abbott’s FreeStyle Libre specifically called out); occlusion detection (JDRF grant proposal already submitted with Dr. Claudio Cobelli, as principal investigator in collaboration with UVA and TypeZero) modularity (swap pumps/sensors as needed); and integrated or standalone accelerometers.
  • The cloud: Semi-automated therapy optimization under the guidance of a physician; machine learning and AI tools to support personalization; and improved meal input through natural language processing and text input (in example working with Amazon Echo and Google so meals can be literally announced).
  • Hormones: Basal and bolus insulin; amylin for post-prandial control; glucagon for hypoglycemia rescue.
• TypeZero CSO Dr. Patrick Keith-Hynes introduced the inControl projects at DTM 2016 (including screenshots): InControl Advice is a smartphone app that provides open-loop insulin dosing advice and pattern recognition for those on MDI or pumps and CGM (including smart bolus calculator physical activity advice, interactive risk monitoring, and clinician messaging via a chat-based interface), and inControl Remote Care Platform is a tool for clinicians to optimize insulin pump or MDI therapy. The platform conducts risk-based therapy optimization using 2-4 weeks of CGM, BGM, and meal data to propose changes in insulin therapy, including basal, carb ratio, and correction factor. These tools could be tremendously useful for saving physician time while improving patient outcomes in a scalable way, especially for those who can’t afford or are not interested in closed loop systems.

Exhibit Hall

Abbott

The Abbott booth was essentially identical to that at ENDO 2017 – entirely dedicated to the FreeStyle Libre Pro (retrospective, blinded) professional CGM, with a tiny sliver calling attention to AGP with the tagline “the more you see, the more you can do.” The product launched in the US last fall, meaning this was the second time Libre Pro was not under glass in the US. The only difference we spotted since a month ago is that more providers have experience of how Libre Pro convinced someone to change behavior or picked up previously unidentified nighttime hypoglycemia – HCPs love it here, and some have even said they don’t know how they got along without it. We asked reps how the real-time consumer Libre FDA review is going, to which they responded that they’re not sure, but they are excited to sell it. One told us that whenever his team asks him about timing, he responds with the same five words CEO Miles White used on the 1Q17 quarterly earnings call: “Submitted. Waiting. Excited. Anticipating. Impatient.” The consumer version was submitted to FDA for both an adjunctive claim and a non-adjunctive (replacement) claim back in 3Q16, and management last guided for a 2H17 approval – we last heard that on the 4Q16 call, but of course FDA is very hard to predict.

Amgen

Amgen occupied a mid-sized booth decked out in the company’s classic royal blue and white color scheme at the front of the exhibit hall. The booth was almost entirely dedicated to the company’s PCSK9 inhibitor Repatha (evolocumab), featuring touchscreen displays animating the drug’s mechanism of action and large wall displays highlighting the drug’s efficacy data and ability to “maximize LDL reduction in one move.” A particularly prominent sign on a pedestal in the middle of the booth read “91% of adults covered” – a response, we imagine, to widespread concerns over affordability and accessibility of the PCSK9 inhibitor class. There were no hints of Repatha’s recently-demonstrated risk reduction for cardiovascular death – certainly a differentiating factor for the drug – likely due to the fact that the FOURIER CVOT reported only just over one month ago, and this data is not yet included on the label for Repatha (meaning Amgen is not allowed to discuss the data in its promotional materials).

AstraZeneca

AstraZeneca’s AACE 2017 presence featured a smaller, pared-down booth compared to what we’ve seen in past exhibit halls. Rather than highlight the full range of AZ diabetes products, the booth only featured signage and information for three therapies: SGLT-2 inhibitor Farxiga (dapagliflozin), combination Xigduo (dapagliflozin/metformin), and GLP-1 agonist Bydureon (exenatide once-weekly). We’re not surprised AZ is especially emphasizing these products, especially after its 1Q17 update in which management made clear that Farxiga especially is a cornerstone of the company’s growth strategy for its newly-formed Cardiovascular and Metabolic Disease unit. AZ is also undoubtedly looking ahead to CV outcomes for Farxiga and Bydureon – indeed, AZ representatives at the booth shared with us that many attendees were asking about the CVOTs for Farxiga (DECLARE) and Bydureon (EXSCEL). As we wait for results, AZ representatives highlighted the non-glucose-lowering benefits of Farxiga, especially the weight loss and blood pressure reductions observed in trials. Not even the logos for DPP-4 inhibitor Onglyza (saxagliptin), combination Kombiglyze (saxagliptin/metformin), or first-generation GLP-1 agonist Byetta (exenatide twice-daily) could be found anywhere on the AZ booth – a departure from the usual style. We were particularly disappointed by the lack of any sort of combination Qtern (saxagliptin/dapagliflozin) promotion as well – the product was approved in the US in March 2017 and we’ve been looking to AZ to grow the SGLT-2 inhibitor/DPP-4 inhibitor combination class. We think the combined efficacy profile of these combinations are particularly promising and we’ve been disappointed with their sluggish sales since the launch of Lilly’s Glyxambi (empagliflozin/linagliptin) in 2015.

BD

The BD booth didn’t showcase the MiniMed Pro infusion set with FlowSmart technology, a reminder that the set is on hold right now – good news from our view that it was tested and the companies are learning. Reps indicated that BD and Medtronic are working on optimizing the training protocol together (beginning a trial to validate updated training), and will probably perform another limited launch before opening it up to the broad market. We’re very glad to see careful rollout to ensure an optimal experience and while some may say it’s taking too long, we think they are exactly right to take the time needed. While shipments were temporarily halted following an initial limited launch (~500 customers) due to higher than expected number of reported complaints related to kinked cannulas and elevated blood glucose levels, management and patients frequently maintain that feedback has been positive overall. One NP AACE attendee claimed that the Pro set was the most comfortable set he’d ever worn – he exclusively inserted manually without incident (kinking, occlusion), and he can’t wait until it’s back on the market. We expect the re-launch will focus more on the inserter device since this seems a key to success.

Dexcom

The Dexcom booth was similar to that seen at ENDO, with materials related to the web-based Clarity data platform, the efficacy of CGM in MDI, and Medicare reimbursement. On the 1Q17 call earlier this week, we learned that 10,000+ Medicare patients are awaiting G5 shipment, as final local coverage determinations have not been established (hopefully expected in 2Q17). Dexcom told us that Medicare beneficiaries looking for CGM should get in touch with the company, and they will triage and handle each individual on a case-by-case basis. Dexcom said that the few claims it has submitted have been “pretty much” denied across the board, so we think things are pretty much at a standstill until the coverage decisions come through.

Glooko

A Glooko data scientist was present in the company’s booth in order to recruit providers for a study to optimize the “Best Day” pattern recognition feature of the platform – “who’s to say what the best day is?” He was looking to attract >30 clinicians to complete a survey that would get at what they consider to be a “good day” – more time in range? Minimal time in hypoglycemia? Hyperglycemia? (We vote all of the above, but with a focus on time-in-range and minimal variability.) He could then measure the agreement between physicians and compare the modal response to the algorithm, and eventually adjust the algorithm to reflect the values of the providers. This is a neat idea that could help patients figure out the behavioral and treatment decisions that lead to the best day-in day-out diabetes experience, and we wonder how patients and physicians might have different views. (We suspect patients care more about time-in-range, while physicians might talk more about average/A1c with hypoglycemia.)

J&J – Janssen

Half of J&J’s rather spacious booth was dedicated to the SGLT-2 inhibitor Invokana (canagliflozin) franchise, while half was devoted to LifeScan/Animas (see below). Invokamet XR (canagliflozin/metformin extended-release), FDA-approved last September, was highlighted front-and-center – an eye-catching overhead sign emphasized in red text that the combination product comes with once-daily dosing. Indeed, the added convenience of a single tablet rather than having to schedule two daily doses is a major selling point for Invokamet XR over its predecessor, Invokamet. From a commercial standpoint, it makes sense that J&J is most-heavily promoting the newest combination product within its SGLT-2 inhibitor business to spark additional uptake. Tall posters throughout the exhibit also displayed safety/efficacy data on standalone Invokana, with one banner announcing >11 million prescriptions written to-date. Despite plummeting sales in 1Q17, Invokana continues to lead the SGLT-2 inhibitor class in sales, while AZ’s Farxiga (dapagliflozin) leads the class in prescription volume.

J&J – LifeScan/Animas

On the OneTouch side, the bolus-only patch delivery device, OneTouch Via (formerly Calibra Finesse), is expected to roll out in a focused US launch in the coming months, beginning on the east coast and migrating west. We were glad to see WellDoc represented at the LifeScan booth, marketing the BlueStar/OneTouch Verio Flex BGM integration allowing passive blood glucose data integration in to the type 2 diabetes management software – nice! The WellDoc rep took us through a lengthy demo of the app, including the recently-added BlueStarU – a function of the AADE partnership. The beautifully-designed educational module consists of 91 lessons in 21 courses in eight topics – the rep said a patient could complete all of the lessons in about 12 weeks, minimum. WellDoc also has a partnership with Human API in the works to passively upload lab values (e.g., lipids, A1c) into the app. Animas showed the Vibe and Ping pumps, though didn’t have a timing update for the OneTouch Vibe Plus pump with Dexcom G5 integration. We were glad to see that J&J, in the midst of “seeking strategic options” for LifeScan/Animas/Calibra, was present in the hall.

Lilly

Lilly’s AACE 2017 booth was nearly a carbon-copy of its ENDO 2017 presence, right down to the delicious, high-traffic espresso bar centered in front of the enormous Lilly logo. Flanking each side of the espresso station were standalone panels each highlighting a major product in Lilly’s robust diabetes portfolio: on one side, SGLT-2 inhibitor Jardiance (empagliflozin), DPP-4 inhibitor Tradjenta (linagliptin), combination Glyxambi (empagliflozin/linagliptin), and Basaglar (biosimilar insulin glargine); and on the other side, GLP-1 agonist Trulicity (dulaglutide), the Humulin U500 KwikPen, and the Humalog U200 KwikPen. Additionally, in a prominent space between the insulins and the coffee, Lilly’s booth-within-a-booth on patient affordability and access made a return. We’ve been impressed by the dual-pronged, concrete steps the company is taking to address rising out-of-pocket costs for insulin and relieve financial burden at the patient level. First, Lilly launched a direct-to-patient discount insulin program in partnership with Blink Health this January. Taking it one step further, we recently learned that Lilly has begun engaging payers and employers directly to consider including insulin as a separate, copay-free benefit category within their health plans – we’re especially impressed by this effort to try and effect systems-level change on behalf of patients. The Lilly representative manning this section of the booth at AACE shared that these conversations continue, though no concrete progress has yet been made with any plans signing on to take this novel step.

MannKind

MannKind occupied a small but colorful booth on the edge of the AACE exhibit hall. The backdrop featured a playful message – INsulin, 12-15 minutes; OUTsulin, three hours – and sales reps positioned inhaled insulin Afrezza as an ideal option for bolusing because it’s quick in, quick out. Reps described the high incidence of hypoglycemia that stems from prandial insulins with slower offset, which is a story we hear all too often. This emphasis matches MannKind’s overarching commercial strategy to promote Afrezza’s rapid-acting nature rather than its inhaled nature – we think this was a very smart move, considering the previous emphasis on the inhaled administration brought to mind lingering concerns among some patients and providers of the long-term safety of inhaling a growth hormone daily. The company filed with the FDA for an ultra-rapid-acting designation in 3Q16 based on data presented at ADA 2016, and a regulatory decision is expected by September 30 – this label claim would allow for even more direct advertising on the faster onset/offset of Afrezza vs. existing options for mealtime insulin. A blown-up model of the inhalation device was mounted on the back wall of the booth. Visitors could also view the small, patient-friendly device up close, while a video on loop showed how to insert 4-, 8-, or 12-unit cartridges into the inhaler. This, too, matches MannKind’s greater commercial strategy in that it distinguishes Afrezza from Exubera – this previous inhaled insulin product by Pfizer failed commercially, and it involved a notoriously clunky, burdensome, indiscrete inhalation device. Patient feedback on Afrezza has been extremely positive (or occasionally neutral) except for complaints about reimbursement, and we love the idea of a more rapid-acting mealtime insulin option out there to reduce hypoglycemia risk and improve quality of life for people with diabetes. While sales of Afrezza have been hurt by competitive dynamics (some recent stories we’ve heard about formularies have been incredibly troubling and we’re going to write some open letters on these in an effort to get more insulin to more people), we do hold out hope for increased uptake of the product, and we look forward to MannKind’s 1Q17 update on May 10.

Merck

Merck put up its standard booth in the exhibit hall, complete with a rotating overhead sign highlighting DPP-4 inhibitor Januvia (sitagliptin), posters showing how Januvia as an add-on to metformin achieves lower A1c, lower fasting plasma glucose, and greater postprandial glucose control, interactive monitors with patient case studies, and of course, a froyo stand. We can’t wait to see additional measures when they have an SGLT-2 and an insulin on the market – it’s not that long! Wow, what’ll things look like when they can offer smart insulin?

Novo Nordisk

Novo Nordisk’s bustling main booth was positioned in the very center of the exhibit hall. Featuring plush white carpet and sleek wooden tables surrounding a (very popular) coffee bar, the floorspace was divided equally between three of the company’s most successful products: next-generation basal insulin Tresiba (insulin degludec), GLP-1 agonist Victoza (liraglutide), and the combination product Xultophy – launched in the US pharmacies just two days ago! Tresiba materials featured the product’s signature skydiving/parachute motif with the slogan “a proven A1c descent.” Data featured in the booth focused especially on the flexible dosing indication on Tresiba’s label and the fact that it is the only basal insulin pen with a max injection dose up to 160 units – this latter point is clearly part of Novo Nordisk’s efforts to position Tresiba for patients with type 2 diabetes and higher insulin requirements. Victoza materials highlighted the drug’s “3-for-1 benefits” – A1c efficacy, weight loss, and low rate of minor hypoglycemia – and emphasized that it is the #1 prescribed GLP-1 agonist globally. The messaging around Xultophy emphasized the combination product’s ability to “take glycemic control a step further” with the clinical benefits of both Tresiba and Victoza. Given Xultophy’s newly launched status (and indeed the existence of an earlier-to-market competitor in the US within this highly-anticipated new drug class, Sanofi’s Soliqua [insulin glargine/lixisenatide]) we were surprised that it wasn’t emphasized more prominently in Novo Nordisk’s booth. That said, management has noted that the company will prioritize Tresiba and Victoza individually for now, holding off on full-scale promotion efforts for Xultophy until there is more established familiarity around both of its component monotherapies. A separate, smaller booth toward the rear of the exhibit hall was devoted entirely to obesity medication Saxenda (liraglutide 3.0 mg), beckoning providers to “help your patients with obesity get the weight reductions they need.” The booth featured a photo of a women holding a larger pair of jeans – the classic “before and after” weight loss pose – with the phrases “excess weight,” “high cholesterol,” “large waistline,” and “high blood pressure,” emblazoned on the pants. Notably, the promotional materials referred to Saxenda as “the first and only GLP-1 agonist for chronic weight management” – emphasizing that obesity, like diabetes, is a disease that requires constant management.

Sanofi

Sanofi occupied a commanding booth at the very entrance of the packed exhibit hall, recognizable by its usual sleek white banner and overhead signs for its varied insulin analog offerings. In contrast to Novo Nordisk’s booth, which positioned its newly-launched basal insulin/GLP-1 agonist product Xultophy on equal footing with its more established products, Sanofi’s booth dedicated a majority of its square footage to Soliqua (insulin glargine/lixisenatide), as demarcated by the drug’s signature dark blue, purple, and gold color scheme. Launched in early January, Soliqua was the first basal insulin/GLP-1 agonist fixed-ratio combination to hit US pharmacies (Novo Nordisk’s Xultophy [insulin degludec/liraglutide] was FDA approved on the same day as Soliqua and launched just two days ago). The front walls of the booth displayed the clinical data for Soliqua and representatives were on hand to guide attendees through touchscreen displays of detailing Soliqua’s dosing and titration information. This messaging was largely centered on how to initiate for people hoping to intensify existing Lantus therapy – a smart move on Sanofi’s part given falling sales of flagship Lantus in the aftermath of its patent expiration and exclusion from formularies in favor of biosimilar insulin glargine Basaglar. The remainder of the booth was dedicated to Sanofi’s next-generation basal insulin Toujeo (U300 insulin glargine), with more touchscreen displays pointing to information on Toujeo’s efficacy in clinical studies and ease of use, touting Toujeo as providing “all day stability with an insulin of today.”

SANOFI/REGENERON

The Sanofi/Regeneron booth was positioned directly adjacent to Sanofi’s main booth, and PCSK9 inhibitor Praluent (alirocumab) took center stage. Throughout the booth was a motif of blue and green arrows, pointed down toward the ground to parallel Praluent’s LDL cholesterol-lowering action. Signage surrounding the booth’s perimeter emphasized Praluent’s efficacy and ease of use, posting large statistics boasting the drug’s “more than 60% LDL reduction” and the fact that “up to 80% of patients achieved their goal” when taking Praluent. With an eye toward personalization, Regeneron’s advertisements also emphasized the fact that Praluent comes in two different pens, a 75 mg/dl dose and a 150 mg/dl dose for “more power if you need it.”

Tandem

Tandem’s simple booth showcased the remote-upgradable t:slim X2, and reps suggested that feasibility data for the predictive low glucose suspend (PLGS) device will be presented at ADA. Commented one: “It’s looking good.” (No surprise here; it uses a very proven algorithm based on the academic literature.) He also highlighted that the G5 integration is under FDA review and expected to launch this summer, and that working with FDA has been “amazing.” We’re looking forward to a dinner symposium entitled “The Journey to Closed Loop Control” with TypeZero CMO Dr. Daniel Cherñavvsky tomorrow night, where we’ll hopefully hear about the latest in Tandem/TypeZero’s clinical data and/or pipeline.

Valeritas

While the Valeritas booth was business as usual, showing the mechanical basal-bolus V-Go patch delivery device, the company has two impressive posters at this year’s AACE. This is yet another company that doesn’t get enough credit, in our view, for making it easier to get the right therapy into patients. Both posters show that V-Go use results in A1c reductions in people with long-standing uncontrolled type 2 diabetes: In the first retrospective analysis (n=103), type 2 patients who switched to V-Go experienced significant and sustained A1c reductions as well as reductions in the total daily dose of insulin. In the second (n=89), 70% of type 2 patients with A1c >8% achieved an A1c <8% and/or a reduction in A1c ≥1% after switching from usual care to V-Go. Again, mean total daily insulin dose was significantly reduced from baseline. These studies add to the growing data collection supporting the clinical efficacy of V-Go. Valeritas successfully went public on the NASDAQ earlier this year (market cap currently ~$44 million), and a rep told us that the IPO successfully raised $55-$60 million – we have yet to see a confirmatory press release, but the stock is indeed trading on the NASDAQ.

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