November 29-December 1, 2018; Los Angeles, CA; Full Report – Draft

Greetings from Los Angeles, where our team recently attended the World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease (WCIRDC) 2018. Below, we have our top six highlights. Key coverage includes a fascinating debate on the use of GLP-1 agonists or SGLT-2 inhibitors for established ASCVD, new-age diabetes and CV risk models from renowned Drs. Vivian Fonseca and Tim Garvey, a call-to-action on obesity and CV prevention in type 1 diabetes from Dr. Richard Pratley, and a 10,000-foot NASH overview from Dr. Bart Staels. Read on!

Top Six Highlights

1. Drs. Husain and Mudaliar Debate GLP-1s vs. SGLT-2s for Established ASCVD; SGLT-2 HF and Renal Benefit, GLP-1 MACE and Weight Reductions Highlighted

A fascinating debate between University of Toronto’s Dr. Mansoor Husain and UCSD’s Dr. Sunder Mudaliar pitted GLP-1 agonists vs. SGLT-2 inhibitors for people with established CV disease and diabetes. For reference, the recent ADA/EASD Consensus Statement recommends GLP-1 agonists if established atherosclerotic CV disease (ASCVD) predominates and SGLT-2 inhibitors if heart failure or chronic kidney disease (CKD) predominates. By comparison, the first-ever ACC Consensus Statement on novel therapies for type 2 diabetes recommends SGLT-2s for heart failure and GLP-1s for established ASCVD and CKD (eGFR<45 mL/min/1.73 m²) – the CKD recommendation being in place due to a known decrease in glycemic efficacy of SGLT-2 inhibitors at lower eGFRs, with acknowledgment that nephroprotection of SGLT-2 inhibitors is currently under investigation (and going quite well).

• Arguing on behalf of GLP-1 agonists, Dr. Husain broke down the issues and myths of the class’ use:

  • GLP-1 CVOTs show inconsistent reductions in MACE: ISSUE, but due to different structures. All GLP-1s with homology ≥90% (liraglutide, semaglutide, dulaglutide, albiglutide) to native GLP-1 have demonstrated CV benefit in their respective CVOTs, while exendin-based molecules (exenatide and lixisenatide) have not.

  • GLP-1 agonists may be unsafe in HF patients: MYTH. No increase in hospitalization for heart failure was found in ELIXA, LEADER, SUSTAIN-6, EXSCEL, or HARMONY.

  • GLP-1s increase heart rate, which is a concern in people with cardiovascular disease: MYTH. LEADER results for participants who experienced a heart rate increase ≥ 10 bpm still trended in favor of liraglutide on the 3-point MACE and hospitalization for heart failure endpoints, though significance was not reached.

  • Weight loss with SGLT-2 inhibitors is as good as with GLP-1 agonists: DEPENDS ON THE AGENT. For GLP-1s, relative weight loss to placebo was 2.3 kg in LEADER, 4.35 kg in SUSTAIN-6, 0.86 kg in HARMONY, 1.27 kg in EXSCEL, and 0.7 kg in ELIXA compared to 1.98 kg in EMPA-REG, 1.60 kg in CANVAS, and 1.8 in DECLARE for SGLT-2s.

  • Adherence with SGLT-2 inhibitors is better than with GLP-1 agonists: MYTH (based on CVOT discontinuation rates). The highest discontinuation rate of any GLP-1 agonist CVOT was 43% (EXSCEL) – nearly the same as the highest for an SGLT-2 inhibitor: 43.7% (CANVAS). All others (for both classes) ranged between 17% (LEADER) and 27.5% (ELIXA).

  • Costs of using SGLT-2 inhibitors are less than GLP-1 agonists: ISSUE (for list prices). Dr. Husain pegged SGLT-2 inhibitors at $484/month in the US (not broken down by product), compared to $755/month for Lilly’s Trulicity (dulaglutide), $833/month for Novo Nordisk’s Victoza (liraglutide), $684/month for AZ’s Bydureon (exenatide ER), and $702/month for Novo Nordisk’s Ozempic (semaglutide). Of course, these are list prices, and the price paid out-of-pocket by the patient could be much less depending on coverage.

• Dr. Husain reminded the audience that oral semaglutide is on its way. Following strong results from the phase 3 PIONEER program, including a 51% reduction in CV death (HR=0.49, p=0.03) in the short PIONEER 6 CVOT, Novo Nordisk plans to file the powerful agent in 1H19.

• Despite being assigned the GLP-1 side of this debate, Dr. Husain asserted that combined SGLT-2 and GLP-1 use could provide additive benefit (see below). For context, according to the recent ACC guidelines, concomitant usage of a GLP-1 agonist and SGLT-2 inhibitor is reasonable if clinically indicated according to ADA’s 2018 Standards of Care, though authors warn of high out-of-pocket costs and possible drug interactions due to opposite effects on glucagon.

• As expected, Dr. Mudaliar pointed heavily toward the heart failure and renal benefits of SGLT-2 inhibitors in his case for their use over GLP-1 agonists. Importantly, he noted that effective medications for mitigating MI and atherosclerotic CV disease already exist, whereas no Class 1A recommended therapies for HFpEF (heart failure with preserved ejection fraction) exist, while five exist for HFrEF (heart failure with reduced ejection fraction). While this could change in 2019 should results from PARAGON-HF for Novartis’ Entresto be positive, the need for better treatment strategies remains, especially since HFpEF is common and serious for people with diabetes. To this end, we were reminded of a quote from Dr. Kosiborod at EASD 2018, “What is becoming pretty obvious to us in the CV field is that heart failure is not only the most common comorbidity of diabetes but also the one that is associated with the worst prognosis […] SGLT-2s are the first class of drugs for diabetes with a very promising signal in prevention of heart failure.” Indeed, following very positive heart failure results from DECLARE (for AZ’s Farxiga) at AHA 2018, the evidence suppports a beneficial class effect of SGLT-2 inhibitors on heart failure (tangentially related to one of our favorite quotes from ESC 2016 – “cardiologists want to look at empagliflozin as a CV drug with a glucose-lowering effect”). Away from heart failure, the “icing on the cake” for SGLT-2 inhibitors according to Dr. Mudaliar is their renal benefit – most overtly demonstrated by CREDENCE being stopped one year early due to efficacy. He reminded the audience that Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) had no effect on hard renal outcomes (doubling of creatinine, renal replacement therapy, renal death) in LEADER. However, Dr. Mudaliar did not stop there, referencing Dr. Marc Sabatine et al.’s recent comment piece in the Lancet emphasizing that cardio-renal benefit from SGLT-2 inhibitors appear to vary across the diabetes continuum. From the authors’ perspective, risk reduction for MACE events with an SGLT-2 seems to be limited to secondary prevention populations with established CVD, while the effect of SGLT-2 inhibitors in preventing heart failure hospitalizations and protecting renal function appears to apply to both secondary and primary prevention populations. Compiling all of this together – HF benefit, renal benefit, and secondary prevention MACE benefit – Dr. Mudaliar concluded that SGLT-2 inhibitors should “of course” be used before GLP-1 agonists, briefly acknowledging potential benefit of concomitant administration.

2. Dr. Fonseca Breaks Down Powerful BRAVO Risk Engine – a Major Step Toward Personalized Medicine?; Predicts Cost-effectiveness, Mortality, Individual CV and Microvascular Outcomes, and More with High External Validity

Dr. Vivian Fonseca broke down the construction, purpose, and application of the Building, Relating, Assessing, Validating Outcomes (BRAVO) of Diabetes Model – a supercharged risk engine based on the landmark ACCORD trial which can be used to predict outcomes and risk of complications. Current diabetes models either heavily rely on outdated data (e.g., the UKPDS risk engine based on data from the 1970s) or an insufficient number of variables to predict much beyond general short-term CV risk (e.g., the Framingham equation). By comparison, BRAVO draws on the full gamut of risk factors (A1c, LDL, severe hypoglycemia, body weight), demographics, geography, and behavioral factors (adherence, access to care, lifestyle) to provide risk for individual CV and microvascular outcomes as well as life expectancy (see below). Moreover, BRAVO has the potential to predict biomarker progression (e.g., A1c, LDL) over time and provide QALY/cost estimations of various treatments. To this end, Dr. Fonseca painted a picture for shared decision-making using BRAVO in which a patient walks into a clinic, and based on that individual’s characteristics and history, BRAVO simulates potential future outcomes (complications, mortality, hypoglycemia risk, etc.) to guide clinicians and patients toward individualized therapies most suited for preventing specific risk – talk about personalized medicine! And that’s not all. Dr. Fonseca posited that BRAVO’s utility extends beyond the clinic as well, potentially answering important questions for healthcare systems (risk stratification for resource allocation), policy makers (cost-effectiveness analysis), and hospitals (QI evaluation).

• BRAVO has been validated against 18 other large clinical trials with a high degree of accuracy, tempering concerns over generalizability given that it was built only from one study’s population (albeit a massive one). The most recent CVOTs are well represented among those tested – including CANVAS, EMPA-REG ELIXA, LEADER, and the TIMI-56 study group – as well as studies of lower-risk populations such as the VADT and ADVANCE trials. The model has predicted MI, stroke, congestive heart failure, angina, revascularization, and mortality incidence from all 18 trials with a strong r² value of 0.91.

3. Personalized Diabetes Prevention Via Cardiometabolic Disease Staging: “We Have the Tools to Prevent Up to 80% of Incident Type 2 Diabetes from Overweight/Obesity,” Says Dr. Tim Garvey

In a tantalizingly titled talk, “We Can Stem the Diabetes Epidemic and Do it Adroitly: Here’s How,” University of Alabama’s Dr. Tim Garvey outlined an improved risk stratification system for progression of overweight/obesity to type 2 diabetes, positing that we have the tools to prevent up to 80% of incident diabetes. In new data currently under review for publication, Dr. Garvey applied the Cardiometabolic Disease Staging (CMDS) system – a gender-race specific scoring system for incident diabetes risk based on CV, glycemic, and demographic factors – to the REGARDS (REasons for Geographic and Racial Differences in Stroke, n=22,733) and ARIC (Atherosclerosis Risk in Communities, n=~1,200) study populations.  The previously published CMDS uses bivariate inputs and Garvey has been subsequently studying a Bayesian hierarchical model using continuous covariates to try to better predict CVD and type 2 diabetes which apparently has an ROC AUC of about 0.8, which was better than the original CMDS model (unpublished data). Seeing as the at-risk pool for diabetes encompasses 40% of the adult population, this degree of specificity and sensitivity is integral to reducing social costs and patient suffering in the US. Specifically, being able to target high risk individuals with more aggressive weight loss interventions (pharmacotherapy or bariatric surgery) improves effectiveness, the benefit/risk ratio, and presumably cost effectiveness (according to Dr. Garvey), with lower numbers-needed-to treat (NNT). For example, in a recent analysis of the pooled phase 3 results of Vivus’ Qsymia (phentermine/topiramate ER), Dr. Garvey found that those with a CMDS >60 have an NNT of only 18 compared to 258 for those with a CMDS <29, suggesting that HCP’s could have a much greater impact prescribing Qsymia to those with higher CMDS scores (notably, CMDS is independent of BMI). We also imagine that the specific components of the CMDS could spur hypotheses on strong responders to treatments, and we’d love to see a similar CMDS component analysis done on Qsymia/other pharmacotherapies with this goal in mind. Ultimately, Dr. Garvey believes this patient-centric approach for individualization of therapy is a model that could be rationally adopted by health care systems with integration into overall portfolios of care – a system which would certainly reduce burden on both HCPs and patients.

4. “We Can’t Forget About Type 1 Diabetes!” Dr. Pratley in Call-to-Action for Bolstered Knowledge Bases on Obesity, CV Prevention

Florida Hospital Diabetes Institute’s Dr. Richard Pratley called for attendees to not “forget about type 1 diabetes,” promoting bolstered evidence bases on preventing CV disease in type 1 and the efficacy of diet, pharmacotherapy, and surgery on comorbid obesity. By his calculations, aggressive treatment of uncontrolled diabetes can cause a net 400-600 calorie/day positive energy balance, driving weight gain through intensive insulin treatment, aging, and environmental changes. To this end, obesity is a growing problem in type 1 diabetes, especially for those older than 25, for whom comorbid overweight/obesity prevalence in the US is greater than 50% according to the Type 1 Diabetes Exchange (see below). Moreover, although intensive glucose control has been shown to significantly reduce long-term CV risk (per DCCT/EDIC), weight gain is associated with a whole host of CV risk factors, contributing to ~10-fold increased risk of CV disease in those with type 1 compared to those without diabetes (and 10-15 year earlier occurrence). With this as motivation, Dr. Pratley asserted that even modest weight loss (5-10%) can have considerable medical benefits, including improvements in A1c, blood pressure, total cholesterol, and HDL cholesterol at the least, and additional reduction in triglyceride levels at best. However, there is a paucity of knowledge on both obesity/overweight interventions and CV safety of novel therapies for those with type 1 diabetes, as patients with type 1 are often excluded from weight loss trials and CVOTs. As such, Dr. Pratley has teamed up with Dr. Elizabeth Mayer-Davis at UNC Chapel Hill, Dr. David Maahs at Stanford, Dr. Kimberly Driscoll at the University of Colorado Denver, and Drs. Karen Corbin and Anna Casu at his home institution to form the Advancing Care for Type 1 Diabetes and Obesity Network (ACT1ON) – a consortium of clinical, behavioral, and basic scientists with expertise in endocrinology, epidemiology, nutrition, exercise physiology, clinical psychology, and biostatistics aimed at elucidating the drivers of overweight and obesity in type 1 and developing evidence-based guidelines for weight management and loss – nice! So far, the consortium has published reviews on the pathophysiology, clinical impact, of overweight/obesity in type 1 as well as the biopsychosocial aspects of weight management; in the future, the group plans to investigate the influence of glycemic control and obesity on energy balance, dietary responses to hypoglycemia, and conduct an initial pilot/feasibility study of three diets in type 1 diabetes (details were not given). He implored his fellow attendees to also contribute, reiterating the need to build an evidence base for preventing CV disease in type 1 with diet/weight loss, obesity drugs, statins and BP drugs, glycemic control, and novel agents (SGLT-2 inhibitors and GLP-1 agonists). In rationalizing the need to investigate these newer therapies, he pointed to the LIRA-1 study protocol (Novo Nordisk’s GLP-1 agonist Victoza [liraglutide] in type 1 diabetes), which produced ~15 lbs placebo-adjusted weight loss as an adjunct to insulin over 26 weeks, as well as older data from investigations of sotagliflozin (Sanofi/Lexicon’s SGLT-1/2 dual inhibitor), which conferred ~12 lbs placebo-adjusted weight loss over 52 weeks from a baseline of ~192 lbs. Notably, both of these studies achieved the necessary >5% weight loss which Dr. Pratley previously deemed the threshold for considerable CV risk reduction. Unfortunately, modest results from the subsequent ADJUNCT ONE and ADJUNCT TWO trials for liraglutide in type 1 caused Novo Nordisk to stop pursuing the indication further. However, multiple manufacturers have continued to pursue SGLT-2 inhibitors for type 1 (regulatory submissions from Sanofi/Lexicon and AZ in 2018, phase 3 results EASE from Lilly/BI), with primary headwinds stemming from DKA concern. That said, the discussion of the risk/benefit profile of this class in type 1 continues, as FDA will be hosting an Advisory Committee for sotagliflozin on January 17, 2019. Should the drug subsequently be approved, there will come the question of whether a post-market CVOT would be mandated; if not, we wonder whether manufacturers would ever consider taking one on themselves. Doubtless, the data would be incredibly valuable for patients and the diabetes field (Dr. Julio Rosenstock called a type 1 CVOT an “opportunity” following presentation of EASE results for Lilly/BI’s empagliflozin at EASD 2018), though we recognize that recruiting the necessary population to power the CVOT could be prohibitively expensive and time-consuming. As we understand it, BI/Lilly may have data on this front after the EMPEROR program (set to read out in 2020), since the sub-group element has a high number of both type 1 and type 2 patients - we are eager to hear more on this front.

5. Dr. Bart Staels Gives 10,000-foot NASH Overview

In a sweeping overview of the NAFLD/NASH competitive landscape (see below), University of Lille’s Dr. Bart Staels detailed the wide variety of therapeutic targets for the disease. To our understanding, the biology of NASH is still poorly understood, hence the wide variety of mechanisms and targets being investigated, which Dr. Staels broke down into five categories: (i) Nuclear receptors (PPARs, FXR); (ii) fibroblast growth factors (FGF19, FGF21); (iii) FA and TG synthesis inhibitors (ACCi, DGAT2i); (iv) incretins (GLP-1, GLP-1/glucagon); and (v) SGLT-1/2 inhibitors (see below). Excitingly, four candidates have entered active phase 3 development (see the NAFLD/NASH competitive landscape): Gilead’s selonsertib (ASK1 inhibitor), Genfit’s elafibranor (PPAR alpha/gamma agonist), Intercept’s obeticholic acid (FXR agonist), and Allergan’s cenicriviroc (CCR2/5 inhibitor). Data for all four of these compounds could be available in 2019 (Gilead’s and Intercept’s trials are scheduled to complete in the first half of the year; Allergan’s and Genfit’s in the fourth quarter), making the prospect for a landmark approval submission in late 2019 or early 2020 high. As suggested by the range of drug classes present in the diagram below, 2019 and early 2020 data are much more than evaluations of specific drugs – they could hint as to which classes and mechanisms will be most effective in future drug development. Moreover, given the multifactorial nature of NAFLD/NASH pathogenesis (characterized by lipotoxicity, fibrogenesis, and inflammation), there naturally comes the question of whether a multi-target approach will maximize the effectiveness of NASH treatment (some experts certainly believe so).

• Dr. Staels presented recent data for canagliflozin’s potential in NAFLD/NASH. Promisingly, the SGLT-2 inhibitor conferred reductions in absolute and relative hepatic fat content compared to placebo in this phase 1 study, though the difference was only significant for absolute fat in participants with NAFLD (see below). Very notably, Novartis is conducting a phase 2 clinical trial for an SGLT-1/SGLT-2 dual inhibitor which may be complete by the fourth quarter of 2019.

6. Dr. Knowles Reviews Diabetogenic Effect of Statins, Introduces Enrolling Mechanistic Study

Stanford’s Dr. Joshua Knowles introduced a new clinical study to investigate how statins increase the risk of diabetes. The relationship between lower LDL-C levels and increased risk of type 2 diabetes is well-established, supported by both clinical trial and genetic evidence. Moreover, data from the TNT and SPARCL trials (n=~11,000 total; ~5 years follow-up), suggests that statins particularly increase the relative risk of type 2 diabetes in those with prediabetes (see below). However, many questions remain, including: Is the development of dysglycemia incremental in all patients taking statins or accentuated in insulin resistant individuals (those with high triglycerides)? To answer this, enrollment has opened for a three-month study comparing the use of statins in those in need of LDL-C lowering (≥130 mg/dl) with low triglycerides (<150 mg/dl; the “insulin sensitive group”) vs. high triglycerides (>150 mg/dl; the “insulin resistant group”). After three months, an insulin suppression test and graded glucose infusion test will be compared across groups to determine insulin sensitivity and secretion; the trial is expected to wrap up in February 2019.

• Of course, we shouldn’t stop giving statins, because the benefits are compelling for those people with cardiovascular risk factors, but this work raises important questions. For example, what happens if we give a statin to someone who already has diabetes – we don’t know if it changes glycemia. Is there a dose effect? Does the risk go away if statins are discontinued? Is the risk canceled out by ACE inhibitors? Does new-onset diabetes caused by statins have the same risk of complications?

• An interesting study design pearl from Dr. Knowles was the use of neighborhood social network NextDoor for recruitment. He did not comment further, though we were intrigued by this new-age approach.

--by Charlie Alexander, Peter Rentzepis and Kelly Close