October 4-7, 2017; Boston, MA; Full Report – Draft

Executive Highlights

In this report, we’ve compiled our full coverage of the 2017 Cardiometabolic Health Congress, held from October 4-7 in Boston, Massachusetts. This is always a fun, intimate meeting full of candid commentary – highlights include Drs. Jay Skyler and Robert Eckel on 2017’s biggest clinical trials, Dr. Anne Peters’ personal views on specific SGLT-2 inhibitors and GLP-1 agonists, and patient case consults with Drs. Skyler, Eckel, George Bakris, Christie Ballantyne, and Ms. Davida Kruger.

Detailed Discussion and Commentary

Session I: Dyslipidemia, Atherosclerosis and Cardiovascular Disease Risk Reduction

FDA Update and Late Breaking Clinical Trials

Jay Skyler, MD (University of Miami, FL)

Dr. Jay Skyler reviewed major diabetes clinical trials presented in the last year, since CMHC 2016, and shared how these studies have affected his clinical decision-making. CANVAS, J&J’s CVOT for SGLT-2 inhibitor Invokana (canagliflozin), found a 14% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, or CV death) vs. placebo, on par with the CV benefit seen in EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin). On the other hand, amputations were two-fold higher in the canagliflozin group vs. placebo group in CANVAS (HR=1.97, 95% CI: 1.41-2.75, p<0.001), but there was no greater amputation risk with empagliflozin vs. placebo in EMPA-REG OUTCOME. Dr. Skyler acknowledged that this bothers him, and explained that he’s switched all his patients on canagliflozin (there were only a few) to empagliflozin, because “why deal with this concern if you don’t have to?”. This was our initial impression after the CANVAS symposium at ADA as well although we imagine that patients were far sicker, on average, in this group, than many of Dr. Skyler’s patients may be (it goes without saying that patients who would’ve been admitted into that trial, probably a small percent of the total patient population, should not be prescribed canagliflozin). Since then, we’re heard from other thought leaders that they’re not overly concerned about canagliflozin/amputations, given that the background amputation rate is relatively low even in a diabetes population and especially compared to the CV event rate for this patient group. As one example, Dr. Anne Peters told us that some of her patients experience superior A1c-lowering and weight loss with canagliflozin vs. empagliflozin, and she underscored that amputation risk can be manageable with careful monitoring and strong patient education around foot care. Dr. Skyler spoke to this last point, advocating that diabetes care providers pay more attention to the feet – we would love to see this! After all, a majority of amputations in CANVAS were preceded by a known risk factor such as infection (the most common), gangrene, peripheral arterial disease, ulcers, acute limb ischemia, or neuropathy. We’re wary of over-comparison between CANVAS and EMPA-REG OUTCOME due to different protocols for how amputations were collected, different baseline study populations, etc. Moreover, even if providers feel strongly that empagliflozin is the better SGLT-2 choice, canagliflozin may be the only option for their patients on certain insurance plans – most notably, CVS Health has excluded Jardiance in favor of Invokana on its 2018 formulary.

• Dr. Skyler also summarized results from DEVOTE, ACE, TOSCA.IT, and EXSCEL, highlighting some of the “surprise” findings. DEVOTE was designed to evaluate CV outcomes with Novo Nordisk’s Tresiba (insulin degludec) vs. standard of care Lantus (Sanofi’s insulin glargine U100), but the real prize came in hypoglycemia data. Tresiba was associated with a 40% relative risk reduction for severe hypoglycemia (p<0.001) and with a 53% relative risk reduction for severe hypoglycemia overnight (p<0.001). During the ensuing panel discussion, Dr. Robert Eckel asked how much of this hypoglycemia benefit might be attributed to insulin degludec’s longer/flatter PK/PD profile, whereas insulin glargine U100 seems to tail-off. Dr. Skyler agreed, outlining that the mean duration of action for Lantus is 22 hours (not 24), with some patients experiencing even shorter-lasting effects. “We rely on endogenous insulin to take you over the gap,” he explained, “but it may not. 100% of the time that I use Lantus, I prescribe it twice-daily in my type 1 patients.” Dr. Skyler further suggested that Sanofi’s next-gen basal insulin Toujeo (insulin glargine U300) may confer similar hypoglycemia benefits to Tresiba, because it also boasts a longer/flatter PK/PD profile vs. lower-concentration Lantus. The “surprise” positive from ACE (a CVOT for alpha-glucosidase inhibitor acarbose conducted in China, presented at EASD) was the 18% risk reduction for new-onset type 2 diabetes (p=0.005), as Dr. Skyler mentioned in his talk.
• In discussing AZ’s EXSCEL trial, Dr. Skyler emphasized how exenatide just narrowly missed statistical significance for cardioprotection, with an upper bound of 95% confidence interval at 1.00 (HR=0.91, 95% CI: 0.83-1.00, p=0.06 for superiority). Picking up on themes from EASD, he underscored the pragmatic trial design and the use of single-dose Bydureon reconstitution kits, which likely contributed to poor adherence and high drop-out rates (43% in the exenatide arm, 40% in the placebo arm). We also find it interesting what Dr. Skyler didn’t say, with no mention of mechanistic differences between exendin-4-based molecules in the GLP-1 agonist class (exenatide, lixisenatide) vs. human GLP-1-based molecules (liraglutide, semaglutide) – he told is in a separate conversation after this talk that he doesn’t see substantial differences between GLP-1 therapies, because EXSCEL trends in the same direction as LEADER (for liraglutide) and SUSTAIN 6 (for semaglutide), missing superiority because of 43% known discontinuation (perhaps even higher with unreported non-persistence). Indeed, many thoughts leaders have recently voiced opposition to the molecular argument for within-class differences to GLP-1 products. As one example, Dr. Francesco Giorgino, who provided the discussant on EXSCEL, claimed that these molecular differences may lead to variations in signaling, but that this is unlikely to translate into meaningful differences on CV outcomes. In our view, EXSCEL does more to support the notion of a cardioprotective GLP-1 class effect than it does to refute it, given the pragmatic trial design, lower-risk population at baseline (27% primary prevention), compelling CV safety data, and extremely narrow miss on superiority (we heard it was about three patients – though have not been able to confirm this).

FDA Update and Late Breaking Clinical Trials

Robert Eckel, MD (University of Colorado, Aurora, CO)

“The field of obesity science is clearly maturing.” This very positive sentiment came from Dr. Robert Eckel as he launched into a rapid-fire overview of major obesity clinical trials from the past year. One study (n=160) found that combined aerobic/resistance exercise leads to greater improvements in functional status for people with obesity vs. either physical activity intervention on its own (provided the combination is successful in stimulating weight loss). Another trial (n=100, 69 complete the study in-full) compared alternate-day fasting vs. daily caloric restriction – both were equally effective in terms of adherence to regimen, weight loss, weight maintenance, and cardioprotection. A study (n=134 people with obesity) of bariatric surgery vs. medical management of diabetes found that the former was more successful in controlling type 2 diabetes and CV risk; surgery also resulted in less need for concomitant medications. A 12-year observational study on this topic highlighted much more weight loss with surgical treatment, but reflected on the ongoing uncertainty over which patients will benefit more from bariatric surgery vs. medical management. As Dr. Eckel put it, “I wish we could distinguish these patients upfront,” which would be a stride forward in personalized care, and would also lead to improved health outcomes and lower healthcare expenditures overall. Another paper attempted to answer Dr. Eckel’s wish, outlining factors associated with successful metabolic surgery for obesity (defined as BMI <30 kg/m² at one-year follow-up): Those who were younger, who had lower baseline body weight/BMI, who were male or white, who made >$75,000 in annual salary, and who had fewer background comorbidities were more likely to have a successful surgical intervention. Lastly, Dr. Eckel presented a meta-analysis on metabolically-healthy obesity (n=3.5 million!), which found that high body weight was still associated with greater CV morbidity over a mean 5.4-year follow-up, despite the absence of other risk factors like dyslipidemia, hypertension, or diabetes. The literature on metabolically-healthy obesity is mixed, but Dr. Eckel suggested that this paper makes a fairly convincing argument for the importance of weight loss regardless. We loved this summary of key science on obesity, and we’re glad that an expert like Dr. Eckel sees the needle moving toward better clinical understanding of this chronic condition. Obesity remains a massive public health problem, due in part to under-diagnosis and under-treatment, so it’s positive to see research identifying effective interventions though the translation to real world is slow. Indeed, implementing these strategies in the real world is a separate battle, one that must also take on stigma, poor reimbursement, a lack of investment in behavior and prevention and a host of other systems-related and commercial challenges.

Main Keynote: Gut Microbes as a Participant and Therapeutic Target in Cardiometabolic Diseases

Stanley Hazen, MD, PhD (Lerner Research Institute, Cleveland, OH)

Dr. Stanley Hazen delivered a compelling keynote address on the role of the microbiome in cardiometabolic disease, leading the audience through a deep dive into the potential role of the microbiome metabolite trimethylamine N-oxide (TMAO) in engendering risk for thrombosis, particularly MI and stroke. TMAO is a byproduct of gut microbes breaking down dietary choline, a nutrient found in the lipid phosphatidylcholine (also termed lecithin), which is found in many staples of the Western diet, including meat, high-fat dairy products, and egg yolk. In an initial examination of blood samples from >4,000 patients at the Cleveland Clinic, plasma TMAO levels were found to strongly predict risk for a thrombotic event. More recent meta-analyses looking at >26,000 individuals confirm that plasma or serum levels of TMAO are associated with incident CV morbidity/mortality risk, in both primary and secondary prevention patients. Dr. Hazen discussed animal studies from his own lab, which further underscore the relationship between TMAO and CV disease in a causal rather than correlational manner. In a recent microbial transplantation study, researchers harvested intestinal microbes from an inbred mouse strain that is thrombosis-prone and noted to have high TMAO producing microbes vs. intestinal microbes recovered from a low TMAO producing inbred strain of mice, and then transplanted these microbes into germ-free mice as recipients. Sure enough, the mice who received the transplant from the high-TMAO producing microbes were more prone to development of thrombosis, whereas the mice who received the transplant from the low-TMAO producing microbes showed reduced platelet reactivity and thrombosis potential during in vivo thrombosis model studies. Such studies thus show that gut microbes, via production of TMAO, impact platelet function and thrombosis potential. Dr. Hazen described how a similar effect was observed in a small in-human study earlier this year, in which just two months of choline supplementation (a 450 mg daily dose, equivalent to 3.5 eggs) in healthy volunteers produced >10-fold increases in plasma TMAO and a corresponding increase in blood platelet aggregation, perhaps foreshadowing greater risk of blood clotting and thrombosis. In terms of the clinical implications of this suggested connection between TMAO and thrombosis, dietary modification to reduce choline consumption is one obvious solution. Dr. Hazen reviewed results of studies showing vegetarians and vegans have lower TMAO than omnivores, and that adherence to a Mediterranean diet is associated with reduction in TMAO levels. He also alluded to a future of “personalized medicine for you and your gut microbes” involving the development of drugs that inhibit the bacterial enzymes responsible for creating TMAO (or any other metabolite for that matter) to reduce thrombosis, and consequently the risk of thrombotic events like MI or stroke. Dr. Hazen left the audience with reassurance that this example is just the tip of the iceberg when it comes to “drugging” the microbiome.

• Additional studies in Dr. Hazen’s lab suggest that the phosphatidylcholine to gut microbe to TMAO pathway has potential implications not only for thrombosis, but also heart failure, atherosclerosis, and CKD, and, of course TMAO is only one of many, many metabolites generated by gut microbes that influences everything from obesity to insulin resistance to blood pressure. Dr. Hazen asserted that soon we will begin to conceptualize the microbiome as a fully-fledged endocrine organ in its own right. The microbiome remains one of the hottest topics in obesity basic science, and we are excited to see this appreciation for the crucial role of the microbiome in health spilling over into cardiometabolic disease more broadly. These are certainly early days, but we feel lucky to have a front row seat to witness these exciting scientific developments, which, as Dr. Hazen pointed out, may very well become the basis of next-generation therapies for metabolic disease.

Corporate Symposium: Advancements in the Management of Patients with Type 2 Diabetes: Results from a Large Cardiovascular Outcomes Trial (Sponsored by Novo Nordisk)

Michael Davidson, MD (University of Chicago, IL)

Leading a Novo Nordisk-sponsored symposium, Dr. Michael Davidson outlined Victoza’s “transformative” cardioprotective benefits as demonstrated by the landmark LEADER trial. A LEADER investigator himself, Dr. Davidson reviewed the trial design and results, clearly enjoying himself when he unveiled the famed 13% risk reduction for the primary outcome of three-point MACE (non-fatal MI, non-fatal stroke, and CV death) with GLP-1 agonist liraglutide vs. placebo. He framed the value of these findings in the context of high residual CV risk in people with diabetes, who have an estimated eight-fold higher risk of acute MI and nearly seven-fold higher risk of stroke vs. a background population, based on 2010 data. As a specialist in preventative cardiology, Dr. Davidson underscored the need for aggressive CV risk management in diabetes with a discussion of life expectancy – we’d love to hear more about this from endocrinologists! On average, type 2 diabetes causes ~eight years of life lost, but this increases to approximately 15 years of life lost for diabetes and a history of stroke, and to a staggering 18 years of life lost for diabetes and a history of MI. As a benchmark, he pointed out that tobacco use, a health risk factor that HCPs aggressively warn against, is associated with a comparably low 10 years of life lost. His message was clear and compelling: CV risk in diabetes should be treated with the same urgency. In particular, Dr. Davidson called on his cardiology colleagues to help lead this charge and “take responsibility for the management of diabetes as a causal risk factor for CV disease.” He encouraged cardiologists in the audience to consider prescribing Victoza for their patients with diabetes, or to educate their patients’ PCPs about it (as the only GLP-1 agonist so far approved to reduce the risk of CV disease though the Bydureon data clearly showed a trend). This FDA approval of Victoza’s CV indication came through in August, following EMA approval of a similar label change in July. We appreciated Dr. Davidson’s closing words: “It’s time that these two diseases, diabetes and CV disease, are treated together as one.”

Corporate Symposium: Closing the Gap Created by Clinical Inertia: New Strategies for T2DM Treatment (Sponsored by Sanofi)

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

The esteemed Dr. Julio Rosenstock highlighted the multifaceted benefits to fixed-ratio basal insulin/GLP-1 agonist combinations, explaining the rationale behind their creation and the evidence supporting their efficacy. Basal insulin decreases hepatic glucose production and improves beta cell function, while GLP-1 agonists slow gastric emptying and increase glucose-mediated insulin release. These complementary mechanisms afford better control over nocturnal glycemia, fasting plasma glucose, and postprandial glucose. Moreover, and very importantly, GLP-1 agonists can counter the weight gain and hypoglycemia risk associated with insulin. If Dr. Rosenstock’s theoretical explanation wasn’t compelling enough, he also summarized key clinical trial data on Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s Soliqua (insulin glargine/lixisenatide). In LixiLan-O, treatment with Soliqua led to mean A1c decline from a baseline 8.1% to 6.5% after 30 weeks. In DUAL I, Xultophy led to mean A1c decline from 8.3% to 6.4% after 26 weeks. Both are incredible! This glycemic efficacy was consistent throughout the LixiLan and DUAL clinical programs, and occurred against a backdrop of small weight reductions (Xultophy has been associated with more significant weight loss to-date), no increase in hypoglycemia compared to placebo, and minimal GI side-effects vs. GLP-1 agonist monotherapy. Notably, these were not head-to-head trials, and thus shouldn’t be the basis for any efficacy comparisons between Xultophy and Soliqua. What’s truly exciting, in our view, is how much better this class is than agents that have come before it. We recently heard Dr. Rosenstock tout the favorable efficacy/milder side-effect profile of fixed-ratio combinations at EASD 2017 as well. His take-home message? Fixed-ratio combinations of basal insulin/GLP-1 agonists can give robust glycemic control, with a favorable safety profile, simplified regimen complexity, and ameliorated side-effects compared to each component alone. Moreover, he argued that we need more prescriptive guidelines so that advancement to fixed-ratio combinations actually happens. We would love to see this and believe it’s embarrassing for the diabetes field that this hasn’t already happened. We’ve been incredibly disappointed by the sluggish commercial uptake of Xultophy and Soliqua so far (despite the tremendous enthusiasm from thought leaders), and anything that gets these therapies into the hands of more patients would be a welcome change. For how fashionable it is to be “patient-centered” these days, this uptake is truly embarrassing for the field. (No one, by the way, has asked patient advocates for help that we know of.)

Corporate Symposium: Closing the Gap Created by Clinical Inertia: New Strategies for T2DM Treatment (Sponsored by Sanofi)

Athena Philis-Tsimikas, MD (Scripps Whittier Diabetes Institute, San Diego, CA); Yehuda Handelsman, MD (Los Angeles, CA)

According to Dr. Athena Philis-Tsimikas, barriers to treatment intensification (i.e. difficulty transitioning to injectable therapy) are what’s driving clinical inertia in the real world. In this Sanofi-sponsored breakfast symposium, she went on to describe technology and strategies to overcome said inertia. Data shows that PCPs are more likely to refer patients to specialists when initiating any insulin or GLP-1 agonist therapy. Barriers to insulin initiation itself are well-known: concerns over weight gain, hypoglycemia, proper titration, and lack of care team infrastructure to support all these challenges. Dr. Philis-Tsimikas argued that the way we currently ask people to start and self-titrate insulin is asking too much. In her eyes, even though we have impressive next-gen basal insulins with lower hypoglycemia risk and flatter PK/PD profiles, sending patients home with directions to self-monitor blood glucose, divide to find averages, and up-titrate to target is not easy for most (it’s actually exceptionally difficult). Dr. Philis-Tsimikas reviewed her ideas on best practice insulin initiation, emphasizing early preparation and discussion of insulin therapy (what are the patient’s concerns?), followed by initiation with effective explanation of titration, ongoing support through titration, and continual monitoring and adjusting of therapy. She pointed to titration as the most difficult aspect, and shared a number of insulin titration apps to help with this. Right now, there are ~125,000 healthcare apps available, and ~60,000 have some relevance to diabetes, with a few dozen performing titration calculations. While most of these are not FDA-approved, Voluntis’ Insulia, Amalgam Rx’s iSage Rx, Sanofi’s My Dose Coach, and Lilly’s Go Dose have all been cleared by regulators. Patients/providers alike should be wary of unapproved titration apps, but Dr. Philis-Tsimikas also presented a small study (n=61) of patients starting insulin glargine, which found that mobile communication in support of basal titration helped patients reach their optimal insulin dose (88% vs. 37% in usual care), demonstrating the distinct positive impact technology can have in this area.

• Dr. Yehuda Handelsman offered his own perspective on clinical inertia, emphasizing non-glycemic guidelines. In his words, you can’t say you’re a diabetologist and only care about glucose control. The 2017 AACE treatment algorithm has step-by-step models for evaluating and treating overweight/obesity, dyslipidemia, and hypertension, and Dr. Handelsman endorsed this comprehensive approach. Diving into the AACE glycemic control algorithm, he pointed out that insulin therapy is de-prioritized below GLP-1 agonists, SGLT-2 inhibitors, DPP-4 inhibitors, and TZDs in dual therapy, and is below all of these except DPP-4 inhibitors in triple therapy. Only for patients with entry A1c >9% who are showing symptoms should insulin be immediately considered. Dr. Handelsman attributed this tipping of the scale toward newer, non-insulin therapies to the fact that they come with no weight gain or sometimes spur weight loss, as well as mitigated hypoglycemia risk. We certainly appreciate that AACE has taken a more progressive/aggressive approach in its guidelines, particularly as the ADA algorithm does not clearly rank the efficacy and safety of different drug classes (though it does provide general information about efficacy, hypoglycemia, weight effects, side-effects, and cost).

Session II: Lifestyle Management of Cardiovascular Disease

Multidisciplinary Case Consults: Lifestyle and Obesity Management in the Cardiometabolic Patient

Jay Skyler, MD (University of Miami, FL); Robert Eckel, MD (University of Colorado, Aurora, CO)

In an interactive discussion of complex cardiometabolic patient cases, Drs. Jay Skyler and Robert Eckel endorsed TZD pioglitazone for NASH (but emphasized that this is not yet an FDA-approved indication for the generic drug). Reducing liver fat is a critical aspect to cardiometabolic disease management, according to Dr. Skyler. The cases presented involved some combination of type 2 diabetes, obesity, NASH, hypertension, dyslipidemia, etc., and liver fat was repeatedly mentioned as a core piece of cardiometabolic health. Here, pioglitazone could help. Dr. Eckel alluded to some of the safety concerns surrounding the TZD therapy class, which explain the drop-off in prescriptions seen in recent years, but underscored that most of this worry stemmed from rosiglitazone rather than pioglitazone. Low-dose pioglitazone (15 mg, no more than 30 mg) is less convincingly linked to bone disease, Dr. Eckel stated, and could prove incredibly beneficial in patients with more insulin resistance and NAFLD/NASH. Plus, he reminded the room that this agent is generic now, and therefore lower in cost. “We have some 30 treatments in development for NASH,” Dr. Skyler stated (see our competitive landscape for the list), “and none are approved yet, but we can turn to pioglitazone. I do.” NASH is an area of enormously high unmet need, and we hope to hear more about potential applications of pioglitazone for this condition at the European NASH summit next week.

Cardiometabolic Disorders: Diet Quality, Quantity, and Beyond

Jamy Ard, MD (Wake Forest University, WV); Janet de Jesus (NIH, Bethesda, MD); John Foreyt, PhD (Baylor University, Waco, TX)

A morning symposium on dietary recommendations to support cardiometabolic health featured wide-ranging commentary from experts on micronutrients, macronutrients, and the psychology of behavior change. On micronutrients, Wake Forest’s Dr. Jamy Ard discussed the emerging role of potassium in blood pressure management. Although there is not yet enough data on potassium to support an official dietary recommendation to increase potassium intake as a blood pressure control strategy, preliminary evidence suggests that this micronutrient can counteract the hypertension-inducing effects of excess sodium. A diet enriched with potassium could therefore be very strategic in the present food environment, where sodium is “baked into the food supply” at high levels. Dr. Ard noted that high-potassium foods (essentially all fruits and vegetables) have the added benefit of being low in sodium themselves. He added that potassium-rich food is an easier proposition for patients than consciously subtracting foods high in sodium.

• On macronutrients, NIH nutritionist Ms. Janet de Jesus came down hard on added sugar, and advised clinicians that one of the most important questions they can ask patients is “what are you drinking?” As much as half of all added sugar comes from beverages, and reducing consumption of soda and sugar sweetened beverages is her first recommendation for people who come to her for weight loss advice.
• On behavior change, Dr. John Foreyt, director of the Behavioral Medicine Research Center at Baylor College of Medicine, emphasized that patients are most successful at losing weight when their goals are framed in terms of functional aspirations rather than numbers on a scale. As an example, he suggested “I want to be able to play with my grandchildren without getting tired” instead of “I want to lose 10 pounds”. He also wisely pointed out that a patient’s support system, stress level, and psychological factors are as important to assess in developing a treatment plan as their BMI, A1c, and cholesterol levels.
• All three speakers endorsed a “small steps” approach toward incrementally making healthy lifestyle changes – a philosophy that Dr. Christie Ballantyne challenged during Q&A, noting that major progress requires major behavioral improvements: “If you smoke three packs a day and go down to two, that’s progress, but we really want you to stop smoking. And if you get 3,000 steps per day, 3,500 steps isn’t much better – we need you at 10,000.” We agree with the implication that incremental change will only be effective if there are ways of ensuring that it builds into substantial, clinically-meaningful change. Although there is still much more to be learned about precisely which behaviors are the most impactful to change, this pales in comparison to the issue of how to actually impart new behaviors. 

Featured Session: Novel Mechanisms for the Link Between Obesity and Type 2 Diabetes

Barbara Kahn, MD (Beth Israel Deaconess Medical Center, Needham, MA)

Dr. Barbara Kahn delivered an outstanding presentation connecting insulin resistance to both diabetes and obesity, focusing especially on the role of white adipose tissue is regulating whole body metabolism and inflammation. So this was pretty serious basic science. White adipose tissue is a storage depot, but also acts as an endocrine gland, secreting hormones, cytokines and proteins such as retinol binding protein 4 (RBP4). Dr. Kahn explained that RBP4 is made in the liver and in adipose tissue, is secreted, and is metabolized in cells to retinoic acid, which transduces expression of hundreds of genes. RBP4 has been heavily implicated in insulin resistance, as a mediator of adipose inflammation and insulin resistance. As Dr. Kahn pointed out, serum RBP4 is elevated in insulin resistant states in humans, before type 2 diabetes is apparent – the opportunity for prevention here is intriguing. Moreover, therapies that improve insulin sensitivity result in lower serum RBP4 levels, and studies in mouse models have shown that RBP4 is a cause, as well as a marker, of insulin resistance. Continuing on, Dr. Kahn demonstrated that higher RBP4 is correlated with dyslipidemia, hypertension, obesity, high waist:hip ratio, inflammation, and hepatic steatosis in human, underscoring its potential strong influence at the crux of metabolic health in general. Dr. Kahn and her colleagues have shown that RBP4 causes insulin resistance by eliciting white adipose tissue inflammation and this is independent of retinol. She outlined how RBP4 induces the production of inflammatory cytokines (TNFa, IL-6), leading to impaired insulin signaling and higher diabetes risk, and how injection of RBP4-activated antigen-presenting cells into normal mice is sufficient to cause inflammation and insulin resistance, indicating causality. This was a whirlwind of basic science, but Dr. Kahn made clear the possible applications to our understanding of diabetes/obesity development and treatment. Interest in white adipose tissue is certainly growing, and we’re excited for the next wave of findings.

• According to Dr. Kahn, RBP4 is just the tip of the iceberg: A gene set enrichment analysis revealed that fatty acid synthesis is one of the most highly-regulated GLUT4-mediated pathways. Interestingly, adipose-GLUT4 overexpressing mice have obesity but also enhanced glucose tolerance and enhanced fatty acid synthesis, disrupting the usual association between obesity and insulin resistance/glucose intolerance. This is where Carbohydrate Response Element Binding Protein (ChREBP), a transcription factor regulating glycolysis and lipogenesis, comes into play. Adipose ChREBP level is correlated with insulin sensitivity in humans, and ChREBP has been found to be critical for lipogenesis in adipose tissue. Further, Dr. Kahn described how ChREBP reduction in adipocytes, in otherwise normal mice, is sufficient to cause systemic and hepatic insulin resistance, affecting both the liver and muscle.
• Dr. Kahn’s team has identified a novel class of fatty acids, produced through lipogenesis, via lipidomic analysis. These were characterized as branched fatty acid esters of hydroxyl fatty acids (FAHFAs), and were found to be upregulated in the adipose tissue of adipose-GLUT4 overexpressing mice. When looking at these novel lipids in people with insulin resistance, higher serum levels were strongly correlated with higher insulin sensitivity, and levels were reduced in the adipose tissue of insulin-resistant humans. These lipids have also been shown to promote GLP-1 and insulin secretion and to reduce adipose tissue inflammation. This work has exciting applications and potential targets for restoring insulin sensitivity and possibly treating or preventing type 2 diabetes, although further research is needed to characterize the mechanistic role of these novel lipids in inflammation, GLP-1 and insulin secretion, and GLUT4 translocation.

Mini Session: Sleep Science: Effect of the Circadian Rhythm on Obesity and CVD

Frank Scheer, PhD (Harvard University, Cambridge, MA)

In a special interest session (we sure learned a lot), Harvard and Brigham and Women’s Hospital’s Dr. Frank Scheer discussed his research connecting circadian rhythms to metabolic health, including diabetes, prediabetes, obesity, and CV disease. Dr. Scheer described how many circulating cardiovascular risk factors fluctuate in concentration on a circadian basis, driven by our internal circadian clock. As one example, his lab demonstrated that pro-thrombotic protein PAI-1 accumulates throughout the night and falls throughout the day, peaking in concentration at ~6:30 am and hitting its lowest levels at ~2:30 pm, independent of behavioral and environmental influences  (the accompanying Editorial clarified that we’re having “PAI” for breakfast whether we like it or not). Furthermore, given that the regulation of metabolism also takes place on a tight circadian basis, it is perhaps unsurprising that circadian misalignment (as is typical with jetlag, shift work, etc.) has adverse consequences for glycemic control and CV health. Epidemiological studies show a correlation between shift work and the development of obesity, diabetes, and CV disease, and Dr. Scheer’s work corroborates that circadian misalignment is indeed causally related to these cardiometabolic conditions. In one in-laboratory study, individuals (n=10) subjected to circadian misalignment by living on 28-hour ‘days’ in a controlled laboratory setting in dim light conditions for 10 days showed increased mean arterial pressure and increased postprandial blood glucose, with three participants exhibiting a glucose response typical of prediabetes. Interestingly, Dr. Scheer explained that mis-timing between behaviors and circadian factors is not restricted to shift work and jet lag, but to some degree is also observed when eating closely to the intake of melatonin or closely to bedtime. Eating when circulating melatonin concentrations are elevated causes relative impairment of glucose tolerance. These adverse glycemic effects shows large interindividual differences that can be linked to genetic variants of a gene encoding the melatonin 1b receptor (MTNR1B). This risk variant rs10830963 is surprisingly common, present in ~50% of the population. According to a hot-off-the-press 2017 paper by de Luis et al., this particular polymorphism is also associated with lack of improvements in body weight and insulin resistance in response to a dietary intervention that improved these parameters in people without the high-risk genotype. As signaled by the recent announcement of the Nobel Prize in Physiology or Medicine – which was awarded to a group of scientists studying the biological clock – circadian rhythmicity is a fundamental and, until now, under-appreciated aspect of our biology. This fascinating work, though early-stage, adds one additional layer of complexity to our understanding of the multifactorial nature of cardiometabolic disease risk.

Lunch Symposium: CV Protection: Is it Achievable in Patients with T2DM?

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

Dr. Wendy Lane described historical type 2 diabetes treatment algorithms as a single bullseye targeting A1c – not even glucose profile or glycemic variation, but just an average. Fast forward to now, and her slide changed to display a multi-ring target, with CV risk reduction at the center. What’s powered this paradigm shift, she explained, is the emergence of positive CVOT data supporting the cardioprotective effects of approved diabetes drugs. Groundbreaking EMPA-REG OUTCOME results led the ADA to recommend empagliflozin (Lilly/BI’s SGLT-2 inhibitor Jardiance) for patients with type 2 diabetes and high CV risk in its 2017 Standards of Care, and the FDA approved a new CV indication for the product label. Similarly, LEADER data on Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) led to an ADA endorsement in its Standards of Care and an FDA-approved label update to reflect risk reduction for major adverse CV events. Dr. Lane described this more nuanced approach to diabetes care as a clear improvement. She encouraged HCPs in the room to aim for the heart of the target – “no pun intended,” she said. Given that CV disease remains the leading cause of death for people with type 2 diabetes, and given the enormous impact of CV events on quality of life and overall healthcare costs (due to hospitalizations, productivity loss, need for additional concomitant medications, etc.), we agree that this multi-ring target makes much more sense than the old way of doing things. With educational sessions like this, we’re glad to see HCPs being called-to-action around the paradigm shift in diabetes care, which is now also cardiology care. This symposium was jointly sponsored by Novo Nordisk and Lilly/BI, and we hope that manufacturers of cardioprotective diabetes drugs can work collaboratively exactly like this, going forward, to increase knowledge at the intersection of type 2 diabetes and CV disease.

• What about the other rings surrounding CV risk reduction at the heart of the target? Dr. Lane’s slides listed these as glycemic variability, A1c, weight, and hypoglycemia, and she reiterated that the glycemic and non-glycemic outcomes goals are equally important. She praised the most recent iteration of AACE guidelines for its 14 principles that closely match these priorities in diabetes care (and that push the outcomes beyond A1c movement forward). Specifically, Dr. Lane highlighted principle #5, the idea that choice of therapy should be individualized based on a patient’s medical history, characteristics, formulary restrictions (cost), and personal preference. She underscored principle #6, the idea that minimizing hypoglycemia should be a priority, and urged providers to use more advanced agents in place of sulfonylureas, which confer a known hypoglycemia risk – it is terrific to finally start to hear more about this and we believe it badly needs to continue to be said – SFUs would, of course, never be approved by the FDA today. She underlined principle #7, the idea that therapy needs to help patients with weight loss, or at least weight maintenance. And lastly, Dr. Lane called attention to principle #11, the idea that comprehensive diabetes management needs to control lipids, blood pressure, and related comorbidities. Circling back to her main point, she emphasized that “it ain’t just about glucose anymore,” because best practice diabetes care should really focus on health outcomes, not A1c. See our coverage on the recent consensus conference on glycemic outcomes beyond A1c for more on this important movement.

Lunch Symposium: CV Protection: Is It Achievable in Patients with T2DM?

Bejamin Scirica, MD (Brigham and Women’s Hospital, Boston, MA)

What should we expect next from CVOTs? Dr. Benjamin Scirica outlined several possibilities, including head-to-head studies, more data on microvascular outcomes, and more data on heart failure effects. As Dr. Scirica put it, each of these represents an outstanding question in diabetes research. In turn, the answers could improve best practice diabetes management and could help reduce micro and macrovascular complication rates in the real world. Few diabetes CVOTs to-date have compared outcomes between two active agents: The TOSCA.IT study of TZD pioglitazone vs. sulfonylureas, presented at EASD 2017, was one of the first, and Lilly/BI’s ongoing CAROLINA study is evaluating CV effects of DPP-4 inhibitor Tradjenta (linagliptin) vs. SU glimepiride (expected to complete March 2019). In real clinical settings, HCPs face tough decisions between drug classes, and sometimes between different agents in the same class, but never between a treatment and placebo – Dr. Scirica alluded to this irony as he advocated for head-to-head comparisons in the next wave of diabetes CVOTs. Importantly, he was very positive about this set of trials overall, explaining how the first wave of CVOTs largely confirmed safety (of DPP-4 inhibitors), while the second wave offered groundbreaking data showing CV efficacy (for SGLT-2 inhibitors and GLP-1 agonists). He expressed high hopes for the third wave of diabetes CVOTs to continue this momentum with more clinically useful findings. A head-to-head, for example, could identify a population of patients for whom metformin shouldn’t be first-line therapy, allowing providers to intervene more swiftly with more effective agents for cardio- and renal protection in those at highest risk (boy would we love to see this!).

• Dr. Scirica also warned against “a slavish focus just on macrovascular outcomes,” calling attention to renal outcomes and changes in eGFR with different diabetes therapies. To this end, we’re happy to note that all three SGLT-2 inhibitors on the market are being investigated in chronic kidney disease (CKD). J&J’s CREDENCE trial for Invokana (canagliflozin) is expected to complete in June 2019, AZ’s Dapa-CKD study for Farxiga (dapagliflozin) is expected to complete in November 2020, and Lilly/BI have announced plans for a clinical trial of Jardiance (empagliflozin) in CKD, though no timing has been disclosed.
• Dr. Scirica suggested that it will be important for future CVOTs to include heart failure as a primary endpoint, and he revealed that the DECLARE trial for AZ’s Farxiga (expected to complete in 2H18) will do just that. Knowing this, we’re even more eager to see full DECLARE results, given that both canagliflozin and empagliflozin demonstrated significant risk reduction for heart failure hospitalization in CANVAS and EMPA-REG OUTCOME, respectively. With heart failure as a primary endpoint in DECLARE, we wonder if relevant changes to the product label or to diabetes treatment algorithms might be implemented more swiftly for Farxiga. Moreover, AZ has launched a dedicated study of dapagliflozin in patients with chronic heart failure (Dapa-HF), and Lilly/BI have done the same with their EMPEROR clinical program for empagliflozin in chronic heart failure.

Session III: Diabetes Management

Reaching Glycemic Goals for Patients with T2DM: Insulin and Non-Insulin Therapies

Anne Peters, MD (University of Southern California, Los Angeles, CA)

Tasked with updating the CMHC community on therapies for glucose-lowering, Dr. Anne Peters drew from CVOT data and her own clinical experience to distinguish what works from what doesn’t. She put Novo Nordisk’s GLP-1 agonist candidate semaglutide on one end of the spectrum (“an amazing drug in terms of A1c reduction”), and put Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) on the other (“showed the least impressive glucose-lowering in these trials”). In reviewing SUSTAIN 6 results, Dr. Peters highlighted the marked drop in A1c from a baseline 8.7% to near 7% in the 1.0 mg semaglutide arm (for comparison, patients on 0.5 mg semaglutide experienced a mean A1c decline from 8.7% to 7.6%, while those on placebo experienced a mean decline to 8.3%). She added that it’s also impressive how this glucose-lowering effect was sustained throughout the two-year trial, with patients in the high-dose semaglutide arm maintaining A1cs between 7% and 7.5%, though she remarked that 104 weeks is relatively short for a CVOT. Dr. Peters established that this is a larger margin of A1c-lowering than has been seen in other large outcomes trials for a single therapy. Indeed, at ESC 2017, Dr. Esteban Jodar explained the larger A1c treatment difference in SUSTAIN 6 vs. other CVOTs by positioning semaglutide as a very potent molecule – this seems to be the consensus among thought leaders, as we approach the FDA Advisory Committee date (October 18) for this once-weekly product’s approval. Turning to EMPA-REG OUTCOME for empagliflozin, Dr. Peters showed a reduction in A1c with the SGLT-2 inhibitor that returns back to ~8% after 206 weeks (re-approaching baseline). Candidly, she stated that she doesn’t consider Jardiance to be a glucose-lowering drug. “I don’t see that much glucose-lowering in my patients, though I do see improvements in other CV risk factors.” That said, Dr. Peters did note that the baseline A1c in the EMPA-REG OUTCOME trial was lower than that of SUSTAIN 6, making A1c reduction more difficult to show (and, of course, it is difficult to compare glycemic responses across trials). While she didn’t call out J&J’s Invokana (canagliflozin) in this talk, we heard from Dr. Peters shortly after the CANVAS results presentation at ADA that she’s seen more success in her clinic with canagliflozin vs. empagliflozin, in terms of A1c reductions and weight loss. That said, A1c data was similar in CANVAS compared to EMPA-REG OUTCOME, with a large initial drop that was attenuated over time. Importantly, Dr. Peters did not undersell the profound CV benefits associated with Jardiance. She didn’t delve into cardioprotective effects at all, because the focus of these remarks was on treatments for glycemia, and to that end she underscored the need for combination approaches to achieve long-term glycemic control (given the rebound in A1c from empagliflozin therapy).

• Dr. Peters anchored her message on the importance of good glycemic control by describing how higher A1c increases risk for microvascular complications, which in turn deteriorate a person’s quality of life. “I like to think we’ve conquered the world. Retinopathy should be a thing of the past, and it is, in my Beverly Hills clinic. But I take care of patients in East Los Angeles every other day, where people struggle with access to healthcare, and do go blind all the time from diabetes complications. And it breaks my heart, because I know I can prevent this.”

Featured Session: New Insights into Insulin Resistance and How the Body Responds to It

Ronald Kahn, MD (Joslin Diabetes Center, Boston, MA)

Friday afternoon at CMHC was dedicated to diabetes management, and there was no better way to kick things off than with an expert lecture on insulin resistance by Dr. Ronald Kahn. He emphasized its role at the center of diabetes pathophysiology, obesity, central obesity, hypertension, dyslipidemia, hepatic steatosis, increased cancer risk, Alzheimer’s disease, accelerated atherosclerosis, and reproductive dysfunction… it was quite a list. Dr. Kahn outlined how insulin resistance can be characterized in one of two ways: (i) by decreased receptor sensitivity, which usually results from a defect in the protein and demands higher insulin concentration for a particular level of response, or (ii) by decreased responsiveness of the receptor, which usually results from a defect later on in the protein pathway. That insulin resistance can be subdivided like this is telling in itself, implying that we need more than one-size-fits-all approaches to treatment. Moreover, it’s fitting that the condition underlying a host of cardiometabolic disease states is nuanced in itself (making personalized medicine all the more important). Zooming in to the cellular level, Dr. Kahn described the mechanistic basis for insulin resistance: Upon reception of insulin, the insulin/IGF-1 receptors auto-phosphorylate, then phosphorylate insulin receptor substrates (IRS) that combine to drive forward either the PI 3-Kinase or MAP Kinase pathways. Downstream, the PI3K pathway promotes glucose transport through protein synthesis – in obesity, this pathway is not well-stimulated, and it behaves even worse in diabetes, resulting in insulin resistance. Particularly striking is that even in clinical prediabetes, patients have glucose uptake levels no better than those with fully-fledged type 2 diabetes – the difference being that those in prediabetes can still compensate with hyperinsulinemia. We also appreciated Dr. Kahn’s discussion of insulin resistance in the brain and its link to Alzheimer’s Disease (or, as some have called it, “type 3 diabetes”). Compelling evidence in knockout mice demonstrates that insulin signaling in the brain is important for cognitive function, mood, and behavior control. Knocking out the insulin receptor in the hippocampus (memory center) of mice results in learning deficits as well as short- and long-term memory deficits. Moreover, studies are starting to show how resistance manifests in the human brain. Small trials have begun to examine the use of diabetes drugs in Alzheimer’s disease (especially GLP-1 agonists like Novo Nordisk’s liraglutide), underscoring truly extensive impact of metabolic syndrome on the human body.

Managing Microvascular Complications of Diabetes for Improved Patient Outcomes

Roy Freeman (Harvard University, Cambridge, MA)

Harvard neurologist Dr. Roy Freeman called attention to the surprisingly high prevalence of peripheral diabetic neuropathy in the real world. He emphasized its association with pain (i.e. substantially reduced quality of life), heightened risk for amputation, and risk for sudden death, ultimately arguing that this diabetes complication “isn’t being taken seriously enough.” According to Dr. Freeman, diabetic neuropathy affects 66% of people with type 1 diabetes and 59% of people with type 2 diabetes in the US. Between 13%-34% of these cases present as painful neuropathy. Given the tens of millions of people with diabetes in America, these figures are not at all trivial. Dr. Freeman focused his discussion on two forms of neuropathy in particular: (i) neuropathy associated with impaired glucose tolerance and (ii) treatment-induced neuropathy. The first involves pain, abnormal skin sensation, and impaired touch sensation. Most notably, Dr. Freeman pointed out that unlike other microvascular complications of diabetes, which typically emerge after several years of disease, 10% of diabetes patients with this form of neuropathy present at the time of diagnosis. Treatment-induced neuropathy is rarer and involves acute, excruciating pain that even opioid therapy can’t relieve. Dr. Freeman explained that this latter form of neuropathy is usually precipitated by a rapid drop in A1c (at least 2%-3%). He urged HCPs in the audience to be aware of this risk in patients with high A1c about to undergo an intensification in their glycemic management. We were fascinated by this deep dive into neuropathy as a diabetes complication, and we appreciated the call-to-action. Dr. Freeman’s presentation reinforced our sense that with few available treatments and very little awareness, neuropathy remains an area of enormously high unmet need in diabetes care today. Moreover, the amputation signal seen in CANVAS for J&J’s SGLT-2 inhibitor Invokana (canagliflozin) came as a stark reminder of gaps in patient education around foot care and amputation risk more generally. The diabetes field needs greater awareness of all risk factors for amputation, including neuropathy, as Dr. Bruce Neal outlined at EASD last month, neuropathy was one of the common precipitating factors for amputations in CANVAS across both canagliflozin and placebo groups.

Session IV: Hypertension, Cardio-Renal, Heart Failure

Multidisciplinary Case Consults: Challenging Patient Cases in Hypertension, Cardio-Renal, and Heart Failure

Davida Kruger (Henry Ford Health System, Detroit, MI); Jay Skyler, MD (University of Miama, FL); Robert Eckel, MD (University of Colorado, Aurora, CO); George Bakris, MD (University of Chicago, IL); Christie Ballantyne, MD (Baylor University, Waco, TX)

Ms. Davida Kruger and Drs. Jay Skyler, Robert Eckel, George Bakris, and Christie Ballantyne participated in an interactive discussion of three audience-submitted patient cases. The experts urged HCPs to swiftly address the renal complications of diabetes, and expressed optimism for potential applications of SGLT-2 inhibitors in chronic kidney disease (CKD). To avoid hypoglycemia, Dr. Skyler advocated for a more advanced, next-generation basal insulin product like Novo Nordisk’s Tresiba (insulin degludec) or Sanofi’s Toujeo (insulin glargine U300). Dr. Eckel argued that basal insulin should never cause hypoglycemia – as he put it, it’s a matter of figuring out the appropriate basal rate, which is too-often overlooked in diabetes management (given how busy PCPs and endos can be). Ms. Kruger underscored the value of a nutritionist as a member of the diabetes care team. All five panelists agreed that psychosocial support is critical for people with diabetes (but still, is often missing), and there was no circumventing the ever-present issue of access/affordability for the safest, most effective diabetes drugs. This CMHC session featured some of the meeting’s greatest clinical pearls, and we summarize each patient case discussion in more detail below:

• Patient #1 was a 78 year-old white male with hypertension, hyperlipidemia, type 2 diabetes, coronary artery disease, and chronic kidney disease (CKD). For hyperglycemia, he was taking sitagliptin (Merck’s DPP-4 inhibitor Januvia) 100 mg daily. The panel discussed possible use of an SGLT-2 inhibitor, of linagliptin (Lilly/BI’s DPP-4 inhibitor Tradjenta) in place of sitagliptin, and of CGM. The patient was concerned with the additional expense of adding an SGLT-2 inhibitor to his medication regimen, even though this would promote CV and renal risk reduction (Dr. Bakris recommended Novo Nordisk’s GLP-1 agonist liraglutide, branded Victoza, for this dual risk reduction as well). These cost concerns should not be underemphasized, given that cost is the biggest driver of treatment decisions for real-world type 2 diabetes patients. The panelists also pointed out that SGLT-2 inhibitors are currently contraindicated for people with eGFR <30 ml/min/1.73m² (or a CKD diagnosis), though Dr. Ballantyne proposed that future studies evaluate SGLT-2 agents in patients like this. Indeed, all three SGLT-2 products currently on the market are being investigated for CKD: J&J’s CREDENCE trial for Invokana (canagliflozin) is furthest along, expected to complete in June 2019, while AZ’s Dapa-CKD study for Farxiga (dapagliflozin) is expected to complete in November 2020; Lilly/BI have announced plans for a trial of Jardiance (empagliflozin) in people with CKD with or without diabetes, but no timing details have yet been shared. We look very forward to results from all three trials, which could greatly expand the number of patients who can benefit from this advanced therapy class. Hopefully, additional evidence showing improved renal outcomes with SGLT-2 inhibitors will also sway payers to improve reimbursement. Interestingly, Dr. Bakris suggested that linagliptin should be substituted for sitagliptin if the patient has access. We heard from Dr. Per-Henrik Groop at EASD that Tradjenta is the only DPP-4 inhibitor that doesn’t have to be adjusted as eGFR falls, since linagliptin is excreted via the gut rather than the kidneys. This is certainly intriguing as we continue to realize the limitations of class effects – to this end, the upcoming CARMELINA CVOT for Tradjenta, expected to complete in December 2017, will reveal linagliptin’s impact on micro and macrovascular outcomes. Lastly, Ms. Kruger noted that using CGM would be helpful to get a better picture of this patient’s glycemia, because his A1c seemed so low. In general, the panelists had a hard time believing that this was an actual patient, considering the contrast between his comorbidities and his relatively good glycemic control.
• Patient #2 was a 79 year-old woman with two recent hospitalizations for hypoglycemia (once found unresponsive in her home) and an A1c near 10%. Panelists advocated for dietary intervention or a next-generation basal insulin to reduce her hypoglycemia risk. The patient was taking 16 units of insulin glargine (Sanofi’s Lantus) at night, plus two-eight units/day of insulin lispro (Lilly’s Humalog) dosed on a sliding scale. Ms. Kruger immediately suggested that inconsistent eating may be the culprit for this individual’s severe lows, and for this, she recommended referring the patient to a nutritionist. Dr. Eckel argued that basal insulin should never cause hypoglycemia, and stated that he’d hospitalize this woman for one or two days to figure out her appropriate basal rate. Dr. Skyler suggested Novo Nordisk’s next-gen Tresiba (insulin degludec) – which comes with a longer/flatter PK/PD profile and flexible dosing, not to mention lower hypoglycemia risk vs. Lantus as seen in the SWITCH and DEVOTE studies – or Sanofi’s next-gen Toujeo (insulin glargine U300). Unfortunately, panelists were unsure if Tresiba/Toujeo would be accessible for this patient, again underscoring the critical issue of affordability and reimbursement for the safest, most effective diabetes drugs.
• Patient #3 was a 52 year-old female, struggling to improve her glucose control and frustrated by 17 lbs of weight gain in the past 11 months (BMI 43 kg/m²). This individual felt too busy to exercise (she owned a struggling business with her husband), and was also experiencing depression and diabetes distress (alongside her retinopathy, polyneuropathy, nephropathy with microalbuminuria, obesity, hypertension, and dyslipidemia). The panelists launched into a discussion of psychological supports for this patient, and we were so glad to hear this theme come up at CMHC. Dr. Bakris advocated for visits with a nutritionist and psychologist, though Dr. Ballantyne reminded everyone that nutritionists and psychologists are poorly covered by insurance, as things stand. Ms. Kruger emphasized that this patient would benefit from nutrition education, while Dr. Eckel floated the idea of considering gastric bypass or a gastric sleeve (to quality, he noted that she has likely had diabetes for ~20 years and possibly would not do well with these surgical interventions). Overall, the panel agreed that this woman needs support from many different specialties, underscoring the importance of a diabetes care team/comprehensive approach to diabetes management.

Featured Session: Metabolomics and Kidney Disease

Kumar Sharma, MD (University of California, San Diego, CA)

Dr. Kumar Sharma kicked-off the final day of CMHC with a compelling talk on how metabolomics could improve drug development for diabetic kidney disease (DKD). A major theme of his remarks was the value of big data techniques to “de-convolute” complex conditions like kidney disease in order to generate new biological hypotheses. To this end, his research team has chemically analyzed urine samples from people without diabetes, people with diabetes, and people with diabetes and comorbid chronic kidney disease (CKD). They’ve found that levels of 13 different metabolites are significantly reduced in the diabetes/CKD condition relative to controls without diabetes. Twelve of these are significantly lowered relative to the diabetes/non-CKD condition, thus comprising a unique signature of DKD. Not only are these signatures helpful to identify DKD, but they can also be used to help predict an individual’s responsiveness to potential therapies. A good example of this comes from AbbVie’s phase 3 endothelin A antagonist atrasentan. The candidate showed a significant reduction in albuminuria in the phase 2 RADAR program, but a study by Dr. Sharma further revealed that 12 weeks of atrasentan treatment significantly increased the levels of four signature metabolites in the subset of participants with eGFR <60 ml/min/1.73m², suggesting that the drug may be particularly effective in this population. Dr. Sharma noted that we are approaching a paradigm shift toward more personalized diabetes care, where we can get much more detailed insight into the efficacy of a drug before prescribing it. In addition, Dr. Sharma’s metabolomic approach provides insight into the signaling pathways underlying the pathogenesis of DKD. The majority of the metabolites he found to be reduced in people with diabetes/kidney disease are produced in the mitochondria, leading to a series of studies probing mitochondrial function in DKD. Dr. Sharma’s current hypothesis is that DKD involves breakdown of the electron transport chain, leaving mitochondria in kidney cells to rely only on the less efficient process of glycolysis to generate energy from glucose. This hypothesis explains the ability of a preclinical NOX-1/4 inhibitor to improve DKD in mice in a study published by Dr. Sharma’s group last year: The agent prevents the breakdown of NADPH, an important component of the electron transport chain. This unexpected molecule could very well represent the next addition to the diabetic nephropathy competitive landscape thanks to these innovative techniques in metabolomics. We can only imagine what the future holds with this big data approach to drug development – not only for DKD, but also for metabolic disease more broadly. Undoubtedly, there are major challenges ahead for precision medicine in diabetes care, but we’re pleased to see researchers committed to this work, however early-stage.

Pre-Conference Business of Medicine Session

Expert Discussion: The Psychology Behind Patient Adherence

William Polonsky, PhD (Behavioral Diabetes Institute, San Diego, CA)

Dr. William Polonsky explained why most interventions to improve medication adherence have not been hugely effective to-date: They target “forgetfulness” (alerts, reminders, etc.) and ignore the major underlying problem – patients’ misconceptions about the safety, efficacy, and overall pro/con balance of taking diabetes drugs. While 60% of chronic disease patients report forgetfulness as a key reason for missed treatment doses or prescription refills, Dr. Polonsky argued that this is an oversimplification of the underlying psychology. In one study he presented, the survey participants who endorsed forgetfulness were also likely to question the efficacy of their prescribed medications and to feel burdened by high prescription drug cost (“it’s easy to forget doing something if you don’t like doing it”). Type 2 diabetes makes these beliefs more difficult to address, because hyperglycemia is a relatively invisible condition. Patients taking daily pills or injections for type 2 diabetes are unlikely to experience tangible benefits in the short term. What is more immediately apparent with these therapies is their side-effects, and often their high cost. It’s hard to motivate people to invest in their long-term health when the cons associated with a medication regimen are more tangible/hold greater mental weight, and Dr. Polonsky discussed how this issue is exacerbated when patients don’t trust their providers and thus may question their providers’ assurances that these pills/injections are really helping to prevent complications. Greater physician trust can lead to better medication adherence, according to Dr. Polonsky. Acknowledging that “trust” is a somewhat ambiguous term, he shared clinical evidence to support what works: People trust their HCP when they feel included in treatment decisions, and when they feel their needs are understood and prioritized. He briefly touched upon the inverse relationship between co-pays and adherence – when the former goes down, the latter goes up – again calling attention to the stark contrast between what is visible to patients (cost) and what is mostly invisible (hyperglycemia, maybe a complication down the line). Efforts to enhance adherence need to target these deeper causes (where “forgetfulness” is the superficial answer), and Dr. Polonsky suggested a few strategies to HCPs in the room. Notably, he advocated for more continuous contact between patient/provider, not only to remind, but to show the individual with diabetes that someone cares about their health and well-being – we so hope the powers that be listen to this! He made the astute point that one major difference between RCTs and the real world is this frequency of contact – study participants have a profound sense that someone is invested in their health outcomes, and we know all too well the gap between clinical trial results and what plays out in real-world clinical settings. Instead of asking whether or not a patient is adhering to their treatment regimen, Dr. Polonsky encouraged more subtle questions like “what’s one thing about taking your medications that’s been challenging?” or “aside from forgetting, what else is tough about taking your meds?”. It’s the provider’s responsibility to establish the expectation that chronic disease management is tough, says Dr. Polonsky, though we don’t think this really happens so much in the real world. Adhering to daily medication is understandably challenging for many, and people should feel comfortable admitting this to their HCP so that, together, patient/provider can devise strategies that may help. Above all, Dr. Polonsky emphasized that we need to address the commonly-held misconception that more medications signify diabetes failure. “If you can only focus on one thing, it’s this: spread the message that more medication doesn’t mean you are sicker; less medication doesn’t mean you are healthier.”

• For any doubters in the room, Dr. Polonsky established that poor medication adherence is indeed a major hurdle in diabetes care. After one year, <50% of patients are still taking at least 80% of their prescribed doses of a DPP-4 inhibitor, an SU, or a TZD (note that these are all orally-administered, and adherence is even more challenging for injectable therapies like GLP-1 agonists and insulin, particularly mealtime insulin). After two years, this drops to <40% for DPP-4 inhibitors and SUs, <30% for TZDs. Of course, this data only applies if people pick up their prescriptions from the pharmacy, and Dr. Polonsky emphasized that 31% of diabetes prescriptions are never filled in the first place. He went on to show how poor adherence increases hospitalization risk and overall medical costs. Patients with diabetes face a 39% greater risk for all-cause mortality with poor adherence to oral agents. Notably, says Dr. Polonsky, low adherence dissuades payers from covering advanced therapies, and leads to the persistent gap between RCTs and real-world evidence. As always, we were moved by Dr. Polonsky’s talk, reminded of this all-important issue in diabetes management that remains a problem despite efforts to correct it. We’d love to see Dr. Polonsky’s suggested strategies take root, reaching beyond forgetfulness to affect the core psychology of living with chronic disease.

Best Practices: Efficient and Cost Effective Management of the Authorization Process

Pamela Morris, MD (Medical University of South Carolina, Charleston, SC)

In a Sanofi/Regeneron-sponsored session, Dr. Pamela Morris was very critical of PBMs and formulary restrictions. She emphasized the substantial burden of prior authorizations (time-consuming for HCPs, access-limiting for patients), focusing especially on PCSK9 inhibitors. Advanced agents like PCSK9 inhibitors come with increased clinical development costs, which are passed on to payers and consumers, hence the very high price of Sanofi/Regeneron’s Praluent (alirocumab) and Amgen’s Repatha (evolocumab). This cost has hindered patient access, as both private and public payers typically require a prior authorization. Dr. Morris presented a 2014 MGH survey (n=1,774), which found that one in four hours of physician time is spent on administrative responsibilities. What nightmare systems problem! Prior authorizations in the survey were listed as the no. 1 most burdensome task. In a 2016 AMA survey (n=1,000), 75% of practicing physicians described the burden of prior authorizations as “high” or “extremely high,” and 90% reported that this process delays care, with the average HCP filling out >36 prior authorization forms per week. What makes these figures even more troubling is that after providers spend all this admin time, 96% of prior authorization requests for a PCSK9 inhibitor are initially denied by payers, according to a National Lipid Association survey; even after provider follow-up, which takes more time, only 36% are ultimately successful. Dr. Morris turned attention to PBMs to elucidate why the reimbursement system is broken. Formulary management is meant to (i) decrease costs; and (ii) improve patient outcomes by optimizing “appropriate and efficient utilization of medications.” According to Dr. Morris, PBMs actually do meet the first goal, mostly through cost-sharing and prior authorization requirements, but also by using stepped therapy and preferred drug lists (which greatly limit patient choice – a decidedly negative consequence, in our view). On the other hand, Dr. Morris argued that the PBM playbook does nothing to improve patient outcomes – more likely, it makes them worse. She showed how formulary restrictions are associated with reduced medication adherence. The effect of cost reduction strategies on patient outcomes is negative ~50% of the time and neutral ~36% of the time; 70% of the negative effect is on medication adherence. By nature, PBMs work to reduce healthcare expenditures on the most expensive drugs, but this means few patients can access these products, which are often the safest and most-effective options currently available. Overall, Dr. Morris’ talk reinforced our view that we need more transparency from PBMs to fully unravel the complicated pricing scheme for prescription drugs in the US. We’ve long been wary of the mysterious role PBMs play, and we thank Dr. Morris for adding this nuance to our understanding of these organizations.

• Dr. Kim Birtcher followed with a discussion of strategies and resources to support the prior authorization process, emphasizing that HCPs must prescribe only according to FDA-approved indications (for PCSK9 inhibitors, statin intolerance is not one of them). She advised paying attention to definitions of disease states in the FDA indications, and underscored that good documentation is key to prior authorization success. It’s important for HCPs to document disease state, previous medications, any intolerance, and responses to drugs – electronic health records can be used as support. Additionally, Dr. Birtcher suggested that a healthcare practice should have a clear protocol for handling prior authorizations to prevent delays or non-coverage. Having a single staff member dedicated to the process is incredibly helpful, according to Dr. Birtcher, as it cuts down on time to prepare/process forms, increases approval rate, and increases the number of patients who pick up their prescription. She added that patients should be warned of the possibility that a prior authorization is denied. Setting expectations is important, and patients should know upfront that there may be appeals involved, after which co-pay might still be high. We appreciated this practical advice, though it’s hard to get around the fact that reimbursement prospects for PCSK9 inhibitors are extremely poor. As Dr. Birtcher shared, even in a group of people with diagnosed familial hypercholesterolemia – for which PCSK9 inhibitors are indicated – 30% had some coverage denial in the last year, and 75% of those were for PCSK9 agents – this data is absolutely stunningly bad. Optimistically, she suggested that appeals are approved reasonably often in this setting. We hope the needle moves on PCSK9 coverage in the near-future, and our fingers are crossed that payers are swayed by compelling CV data from FOURIER (for Repatha) and upcoming results from ODYSSEY Outcomes (for Praluent).

Corporate Symposium: Awaken a Transformation in Type 2 Diabetes Management (Sponsored by Janssen)

Yehuda Handelsman, MD (Los Angeles, CA)

CANVAS was a primary focus of Dr. Yehuda Handelsman’s remarks during a Janssen-sponsored product theater, but rather than zeroing-in on cardioprotection, he emphasized weight loss and positive renal effects with SGLT-2 inhibitor Invokana (canagliflozin). Dr. Handelsman pointed out that weight loss with Invokana never plateaus, and that average weight change after 6.5 years was 3.5 lbs greater with canagliflozin vs. placebo. Invokana also gave a 0.58% greater drop in A1c over the same period, as well as a 3.9 mmHg greater decrease in systolic blood pressure. Perhaps most exciting, according to Dr. Handelsman, is that despite an initial drop in eGFR with Invokana, kidney function recovered and stabilized near baseline over the study period, while eGFR in the placebo group declined throughout. Moreover, renal outcomes data from CANVAS were positive: Canagliflozin gave a 40% risk reduction for the composite endpoint of renal death, renal replacement therapy, or 40% reduction in eGFR (HR=0.60, 95% CI: 0.47-0.77). On the amputation signal (a frequent topic when discussing CANVAS), Dr. Handelsman reiterated that patients should be screened for prior amputations, neuropathy, and peripheral vascular disease, and that they should be monitored throughout treatment for the development of neuropathy or foot problems – just like any other patient ought to be. When asked about off-label use of SGLT inhibitors in type 1 diabetes, Dr. Handelsman shared his perspective from involvement in AZ’s and Lexicon’s trials of dapagliflozin and sotagliflozin as adjunct treatments. He noted that one program advised reducing insulin dose by no more than 20% (we know this to be AZ’s guidance in DEPICT 1), while another (we would think the inTandem program) asked providers to reduce insulin by up to 30% due to concern over hypoglycemia – and, as Dr. Handelsman pointed out, this program saw more DKA. Dr. Handelsman seemed unconvinced of the need to reduce insulin at all with SGLT-1 or SGLT-2 inhibitors in type 1 diabetes (this echoes Dr. Chantal Mathieu’s commentary from EASD), and the explanation that too much insulin reduction can lead to DKA seems to hold true in the data. We certainly believe (and know personally) that this varies patient by patient but we believe that over 20% insulin drop isn’t typically needed according to AZ’s careful read of earlier-phase data.

Corporate Symposium: Jardiance (empagliflozin) Tablets: Evolving Clinical Development (Sponsored by Lilly/BI)

Rajat Deo, MD (University of Pennsylvania, Philadelphia, PA)

U Penn cardiologist Dr. Rajat Deo led a Lilly/BI-sponsored product theater on SGLT-2 inhibitor Jardiance (empagliflozin). In response to audience questions, he speculated on both (i) empagliflozin’s mechanism of CV benefit; and (ii) possible within-class differences for SGLT-2 inhibitors. Following Dr. Deo’s detailed overview of EMPA-REG OUTCOME results (14% relative risk reduction for three-point MACE, 38% for CV death, and 35% for heart failure hospitalization), HCPs in the audience wanted to know why and how this works. Dr. Deo provided two hypotheses: (i) The reduction in heart failure hospitalization in the empagliflozin vs. placebo arms could signal a reduction in pump failure that leads to less CV death; this theory is gaining support in the field, and Lilly/BI have even launched a dedicated clinical program for empagliflozin in chronic heart failure. (ii) Dr. Deo also suggested that empagliflozin might confer a benefit on arrhythmic mortality. Ongoing studies that rigorously adjudicate sudden cardiac death and arrhythmic events will evaluate this hypothesis more formally. This possibility could explain why Jardiance led to marked risk reduction for CV death without significantly affecting non-fatal MI or stroke. We expect the conversation on mechanism to continue for the foreseeable future, but in the meantime, we appreciate strong commentary in defense of empagliflozin’s cardioprotective effects – patients shouldn’t have to wait for mechanistic answers before starting a therapy that could extend their life and prevent major CV complications. CANVAS results for J&J’s Invokana (canagliflozin) corroborate the positive findings from EMPA-REG OUTCOME, lending additional support that the Jardiance results were not a fluke, and building a compelling case for a cardioprotective class effect. That said, CANVAS differed from EMPA-REG OUTCOME on safety findings, as canagliflozin was associated with a nearly two-fold risk for lower limb amputations (HR=1.97, 95% CI: 1.41-2.75, p<0.001), while empagliflozin has showed no such signal to date though the trials are difficult to compare given the different study populations. Dr. Deo acknowledged that amputations were adjudicated differently in these two trials – we think this is a very important point, and we caution against over-comparison – but he also spoke to molecular differences that could underlie the diverging amputation results. He pointed out that each SGLT-2 inhibitor on the market has a slightly different ratio of SGLT-1 vs. SGLT-2 inhibition. We heard similar remarks from Dr. Juris Meier at EASD 2017, who alluded to Invokana’s lower selectivity for the SGLT-2 receptor as one possible reason for increased amputation risk. Much more research is needed before we can connect this to amputation outcomes (and indeed, some thought leaders immediately criticized Dr. Meier’s speculation), and Dr. Deo agreed that additional investigations into the biological pathways affected by these therapies are necessary. We look very forward to future studies that elucidate the amputation signal in CANVAS, because this is definitely an important issue to sort out for patients who are at very high risk (presumably, for many patients, this risk won’t be a factor if they do not have other complications). Upcoming DECLARE results for AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin), expected in 2H18, may also shed light on this.

Corporate Symposium: Repatha (evolocumab): Take the Next Step (Sponsored by Amgen)

Yehuda Handelsman, MD (Los Angeles, CA)

Leading an Amgen-sponsored lunch session, past AACE president Dr. Yehuda Handelsman highlighted the LDL-lowering efficacy of PCSK9 inhibitor Repatha (evolocumab). He emphasized Repatha’s patient-friendly dosing options (a pen injection once every two weeks, or a once-monthly injection mediated by the hands-free Pushtronex on-body infuser device) and reviewed data from select clinical trials. In LAPLACE-2 (n=2,067), the addition of Repatha to statin therapy led to mean LDL reductions of 63%-75% vs. placebo. Impressively, more than 85% of patients randomized to Repatha achieved an LDL goal <70 mg/dl over the 12-week study duration. In the DESCARTES trial (n=901), patients randomized to evolocumab experienced a mean 57% reduction in LDL vs. placebo injection (-51.5% vs. +6.0%), and 82% of evolocumab-treated patients achieved an LDL goal <70 mg/dl at week 52 (compared to 6% of patients on placebo). Affordability has been a major concern with products in the PCSK9 class (also including Sanofi/Regeneron’s alirocumab, branded Praluent), and to this end, Dr. Handelsman noted that Repatha is covered under the majority of commercial and Medicare Part D plans. He further highlighted Amgen’s “Repatha Ready” patient assistance program, which offers $5 co-pay cards for commercially-insured patients. We view this as a good start, but note that there’s a long way to go in ensuring access for the many patients who could benefit from this drug’s potent LDL-lowering effects.

• In past earnings updates, Amgen management has expressed optimism regarding ongoing payer negotiations to improve reimbursement for Repatha, citing a proposed label update based on the FOURIER CVOT as a promising source of momentum on this front. With FOURIER, Repatha became the first PCSK9 inhibitor to report a cardioprotective effect (demonstrating a 15% risk reduction the composite primary endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization). A Supplemental Biologics License Application (sBLA) to have this positive CV outcomes data reflected on Repatha’s label is currently under priority review with the FDA – a decision is expected as soon as December 2, 2017.
• Although this wasn’t emphasized in Dr. Handelsman’s remarks, we note particular promise for this drug in people with diabetes, many of whom have hyperlipidemia and high residual CV risk. This was reinforced by a pre-specified sub-analysis of people with diabetes within the FOURIER trial, which revealed that Repatha reduced risk for the composite primary endpoint by 17% (HR=0.83, 95% CI: 0.75-0.93, p<0.0008) and for the key secondary endpoint of three-point MACE (CV death, non-fatal MI, or non-fatal stroke) by 18% (HR=0.82, 95% CI: 0.72-0.93, p<0.0021). This translates to a similar relative reduction for CV events with Repatha compared to the non-diabetes population, and, notably, for a larger absolute risk reduction given the higher baseline CV risk for people with diabetes. We hope this data, as well as the main FOURIER results, is compelling in the eyes of payers and providers alike, as we’d love to see greater uptake of Repatha among people with diabetes for the prevention of CV disease.

--by Ann Carracher, Abigail Dove, Payal Marathe, and Kelly Close