August 31—September 4, 2019; Paris, France; Day #5 Highlights – Draft

Hello from Paris, where ESC 2019 just wrapped up this morning! What a meeting it’s been – we think the ramifications of this conference will be enormous for cardiology and endocrinology and for cardiometabolic protection in general. As always, it’s been a pleasure to work on translating these important findings for the broader diabetes community. See below for our top four highlights!

Top Four Highlights

1. SGLT-2 Inhibitors in Clinical Cardiology: “The Future is Heart Failure” + Could SGLT-2s Soon Become a Prediabetes Medication As Well?

We gained incredible insight into how clinical cardiologists perceive the future of SGLT-2 inhibitors in their practices at this Lilly/BI-sponsored symposium. It’s certainly a transformative time for the class, following Farxiga’s landmark positive HFrEF outcomes (both with and without diabetes) in DAPA-HF, along with a string of positive CVOT results over the last half-decade. Cardiologist Dr. Nikolaus Marx stated at the end of his presentation, “cardiologists are well positioned to initiate SGLT-2 inhibitors in appropriate patients, but we need to consult the endocrinologists and work together” – we certainly loved this spirit of collaboration and couldn’t agree more (and we would add PCPs and nephrologists to the list too). It’s astonishing how quickly these drugs are being taken up into different sectors of medicine (EMPA-REG results only came out in 2015), and we hope that diabetes continues to be viewed holistically as a cardiometabolic renal condition. The question on our minds? How will these practitioners work together to best provide comprehensive care for patients?

• Dr. Stefan Anker emphatically claimed, “the future is heart failure” (i.e., cardiology) to begin his talk on SGLT-2 inhibitors (empagliflozin). According to Dr. Anker, glucose medications will become CV medications for not only those with diabetes, but also those with pre-diabetes and no diabetes at all in the future. The results from DAPA-HF support his prediction—he said that this study is truly going to be paradigm-shifting for the field. People with prediabetes were 37% of its study population and had positive results were consistent with the overall study. In the EMPA-REG outcome trial reduced risk of CV death and hospitalization for heart failure occurred early and was sustained throughout the trial, consistent at both the 10 mg and 25 mg dose. Notably, the effect of empagliflozin on these outcomes was largely independent of A1c – between A1c of 7% to 10%, there was no significant difference in results, leading Dr. Anker to speculate if A1c could go even lower and if the drug could be used in prediabetes and people without diabetes. Empagliflozin was associated with both lower risk of heart failure rehospitalization and all-cause mortality in comparison to placebo from as early as 30 days, hinting at the speed of its benefit.

Dr. Anker then presented empagliflozin statistics of particular interest to cardiologists.

• Acknowledging that heart failure in the trial was only a “checkbox question” (“have you had HF?”), heart failure outcomes improved regardless of baseline HF status. Similarly, risk of CV death, all-cause mortality, and three point-MACE benefits were consistent across patients both with and without left ventricular hypertrophy (LVH) at baseline.

• EMPA-HEART also demonstrated a meaningful reduction in left ventricular mass index (LVMi) from baseline with empagliflozin 10 mg/day vs. placebo (-3.4 g/m², 95%: -5.9 to -0.8, p=0.01).

• Dr. Anker also noted that SGLT-2 inhibitors may selectively regulate interstitial volume with minimal change in blood volume, while loop diuretics may cause a reduction in both interstitial and intravascular volumes. Larger reductions in interstitial fluid volume could more effectively (i) relieve signs and symptoms of interstitial congestion; (ii) provide partial relief to elevated cardiac filling pressures; (iii) and prevent harmful effects of excessive blood volume depletion. No lasting increase in sodium excretion was observed with empagliflozin in patients without diabetes and in those with type 2 diabetes and preserved kidney function.

• Dr. Anker closed out his session noting the upcoming HF trials for Lilly/BI’s empagliflozin: (i) EMPEROR PRESERVED and (ii) EMPEROR REDUCED testing CV mortality and hospitalization for heart failure for HFpEF and HFrEF, respectively; functional capacity studies (iii) EMPERIAL PRESERVED and (iv) EMPERIAL REDUCED; and (v) EMPA-VISION, a mechanist study. Quite the HF portfolio – we note that type 1 patients are included in some of these trials.

• The new ESC guidelines served as the foundation for Dr. Nikolaus Marx’s engaging talk on two cardiology case studies which featured SGLT-2 inhibitors. To begin, Dr. Marx re-emphasized that according to the new guidelines, if a patient has ASCVD or high/very high CV risk, they should receive an SGLT-2 inhibitor or GLP-1, irrespective of A1c, as a class 1 recommendation. When prescribing between the drugs, two points should be considered (i) SGLT-2 inhibitors are taken orally, while GLP-1s are subcutaneously administered; and (ii) the patient should have an eGFR >60 ml/min/1.73 m² to take an SGLT-2 inhibitor.

  • In the first case study, a 63-year-old white male, who is an active smoker with hypertension and type 2 diabetes, was admitted for recurrent chest pain on exercise. His LDL-C was 135 mg/dl, A1c 8.5%, and eGFR 85 ml/min/1.73 m². A coronary angiography showed two-vessel disease, as well as PCI with DES implantation LAD. His current medications were rampril 5 mg bid and metformin 850 mg bid. After a diagnosis of CAD, aspirin 100 mg/day, clopidogrel 75 mg/day for 6 months after PCI, and atorvastatin 40 mg/day were added. The question Dr. Marx posed was: “how to optimize CV risk management?” Based on the patient’s preference for an oral medication, as well as an eGFR of 85, 10 mg/day of empagliflozin was prescribed.

  • Patient two was a 70-year-old white female with hypertension and type 2 diabetes who presented with worsening symptoms of shortness of breath and fatigue upon mild exercise. Her LDL-C was 65 mg/dl, A1c 8.1%, and eGFR 71 ml/min/1.73 m². In terms of CV history, the patient had ischemic cardiomyopathy, an LV of 38%, 3-vessel CAD, CABG 10 years ago, and NHYA class II. Her current medications were 100 mg/day aspirin, 5 mg bid rampiril, 850 mg bid metformin, 100 mg/day sitagliptin, and 20 mg/day rosuvastatin. Again, how to optimize CV risk management? To answer this, Dr. Marx pointed out that SGLT-2 inhibitors may further reduce CV endpoints through a reduction of heart failure-related events. In comparison, DPP-4 inhibitors like sitagliptin have had mixed results on this front (though results are exploratory across all drugs, excluding dapagliflozin). Beta-blockers (since LVEF <40%) and an SGLT-2 inhibitor with proven CV benefit for CV protection and a reduced risk of hospitalization for heart failure were prescribed.

  • Dr. Marx underscored that in patients with type 2 diabetes and heart failure, signs of volume depletion should be monitored, and a diuretic dose adjustment should be considered. In addition, he added that an initial dip in eGFR may occur upon treatment with an SGLT-2 inhibitor with subsequent stabilization.

  • Notably, in Dr. Marx’s own practice in Aachen, Germany, all patients hospitalized in the cardiology department are screened for diabetes – presumably this is being done many other places as well. If A1c ≥6.5%, individuals are diagnosed with diabetes. If A1c is >5.5% and <6.5%, an OGTT is recommended.

Questions and Answers:

Q: What would you tell your patients who are starting an SGLT-2 inhibitor?

Dr. Marx: I would warn them of the genital infection risk and the sick day protocol for restarting SGLT-2 use.

Q: In the first case study, if the patient had ASCVD, would it be better to use a GLP-1? Based on what the ADA recommends.

Dr. Marx: I tried to refer to the most recent European guidelines which don’t make the distinction between GLP-1s and SLGT-2s. I think at this point, there’s not a difference. Both are recommended as class 1 agents.

2. Dr. Mikhail Kosiborod Highlights Low Prescription Rates of SGLT-2s and GLP-1s Amongst Cardiologists – Can DAPA-HF Help Turn the Tide?

Echoing relevant themes from his similar talk on “Belling the Cat” from AHA 2018, the renowned Dr. Mikhail Kosiborod lamented the fact that cardiologists continue to “sit on the sidelines” in regard to prescribing SGLT-2 inhibitors and GLP-1 agonists. Dr. Kosiborod briefly presented prescription data for both of these therapy classes (see below) broken down by specialty, highlighting how minimal prescription rates have been in cardiology. Understandably, the majority of prescriptions for both classes still come from endocrinologists, with major upticks in rates following the emergence of positive CVOT data. Nevertheless, we note that these CVOT data, along with CV indications for specific therapies in both classes, have not appeared to meaningfully budge prescription rates for cardiologists (Dr. Kosiborod explained how the cardiology community sits back and commends the positive data but has not yet fully acted upon these meaningful advances). Will positive results from DAPA-HF move the needle here where other trials have not? We’re a bit hopeful on this front, especially considering the immensely positive reaction to these results that we’ve experienced at ESC 2019 from the cardiology community. Moreover, DAPA-HF showed resoundingly consistent effects in patients with prediabetes and without diabetes, and we would think that this robust effect would speak to the cardiology community more deeply. On this front, Dr. Kosiborod attributed much of cardiologists’ hesitation in using these therapies because of their status as “glucose-lowering therapies” and potential encroachment on the turf of endocrinologists and PCPs. DAPA-HF should go a long way in addressing this first concern, seeing how robust Farxiga’s effect was in completely independent of diabetes status.

3. Harvard’s Dr. Mandeep Mehra’s Deep Dive on US Healthcare System: Points to “Third Party Mafia” of Insurers/PBMs and Growth of Administrative Workforce as Major Problems; Advocates for Primarily Single Payer System

In a broader session on health economics, Harvard’s high-powered Dr. Mandeep Mehra gave a tour-de-force presentation on the US healthcare landscape, pointing out several misconceptions with the system, identifying major sources of inefficiency, and putting forward his path to an improved system. We highly recommend viewing Dr. Mehra’s full presentation and perusing his slides here. It’s always interesting to see how the US healthcare system is described in front of a primarily European audience, and we thought Dr. Mehra fantastically explained the nuances of the US system to this audience.

• Dr. Mehra first attempted to debunk the myth that the US pays exorbitant amounts in healthcare costs only to receive subpar care for its population. He noted that perception of the US system often includes the fact that the US spends the most in the healthcare as a percentage of GDP while lagging behind in important health metrics including life expectancy, infant mortality, low birth weight, injuries and homicides, adolescent pregnancy, STDs and HIV/AIDS, drug-related deaths, obesity, diabetes, and heart disease, chronic lung disease, and disability rates. Moreover, many Americans under 65 (13% as of 2018) remain uninsured, and 45% are underinsured. Attempting to explain this paradox, Dr. Mehra asserted that it’s important to take into “national investment in health” instead of only looking at healthcare spending. Looking at this metric, which includes healthcare PLUS social care spending as a fraction of GDP, the US is squarely in the middle of the pack in relation to other developed countries (see slide below). We’re curious as to how a greater shift in spending in the US toward social care might help to improve outcomes.

• In the past two decades, the US has doubled the physician workforce but simultaneously increased the healthcare administrative workforce by 33-fold. This creates an “enormously bureaucratic system” that is both difficult for patients to engage with and responsible for driving inefficiency. Dr. Mehra pointed to the multi-payer system that the US has, with its fragmented landscape of numerous private and public insurers, that is at the core of this explosive growth of administrative workers and larger inefficiencies. On the whole, administrative costs in the US total ~8% of healthcare spending, compared to between 1%-3% in other countries.

• In what he deemed as the “elephant in the room,” Dr. Mehra noted the “terrible, terrible costs” that the US pays for pharmaceuticals. Per-capita spending in the US for pharmaceuticals is $1,443, compared to between $466-$939 in other countries. Why is this so? Dr. Mehra explained the in the US, government payers are barred from negotiating drug prices with pharma, unlike in other countries where the government can do so. As a result, drug costs vary widely amongst the different payers in the US, therefore creating what Dr. Mehra described as “five different healthcare models moving in parallel.”

  • As a sidenote, in our view, the answer is fairly more complex – few patients found price increases problematic when payers were shouldering such a high share. As employers have shifted more costs to patients, price sensitivity has increased; as well, single-payer systems have had considerably more power to resist price increases. Although more recently, the US payers like Medicare and Medicaid have been less interested in paying more than other governments, for some time, they did not resist high rebates. Meanwhile, NHS and other international government payers have not offered to take part in “global pricing,” where they pay more so that the US can pay less.

• Dr. Mehra argued that the key problem with the US healthcare landscape is the “third party mafia” of insurance companies and PBMs that drive up costs with profit-seeking motives. Dr. Mehra called these entities the “fundamental flaw’ in the US healthcare system and noted that much of the US system’s concentrated costs are funneled to these players. In his view, these third-party intermediaries that connect payers, providers, and patients should not be for-profit institutions. Of course, in most other countries with universal healthcare coverage, these services are primarily provided for by the government and are not-for-profit. We’re always curious to learn more about the function of PBMs and the value that they might be providing (or not providing) in our current system.

• What’s the proposed solution? Dr. Mehra called for a system that (i) primarily involves a single payer; (ii) has an individual mandate + higher subsidies to make premium products attractive to the younger healthy population; and (iii) the removal of perverse incentives in the form of third-party insurance companies and PBMs. Of course, we imagine that there could be significant political headwinds to this solution, if indeed it is a solution.

4. Improving CV Risk in Patients with Obesity: A Long-Term Investment

In one of his signature energetic presentations, Dr. Naveed Sattar confidently claimed that he would “bet his mortgage” on weight loss affecting cardiovascular disease risk. He noted, “as a community, we’ve been nihilistic to say, ‘we’ll give [patients] a diet, they won’t follow it, and nothing will change…we need to change the agenda on weight. We need to encourage people to try and fail and try and fail, until they have sustainable changes in their diet.” While he acknowledged that the range of treatments for obesity is growing, Dr. Sattar strongly backed dietary change as the cornerstone of weight loss.

• Dr. Sattar framed weight loss as a goal with both immediate quality of life benefits and long-term cardiovascular benefits. Evidence suggests that “big, intentional weight loss,” such as bariatric surgery or intensive lifestyle intervention, could lessen CVD over 5-10 years. For example, the Swedish Obesity Surgery intervention study showed a 19% remission of hypertension in patients treated with bariatric surgery vs. 11% for standard of care, as well as a 36% remission of type 2 diabetes vs. 13% for standard of care, over 10 years. The 13.3 year follow-up of the study also showed a hazard ratio of 0.56 for CVD events in patients with type 2 diabetes. Dr. Sattar contrasted this with to the Da Qing RCT study on type 2 diabetes which showed that for smaller weight loss by lifestyle intervention, a benefit in CVD (HR=0.74) was only seen after 20-30 years.

• The primary mechanisms by which weight loss affects CVD, include increased insulin, renal SGLT-2, glomerular hyperfiltration, and transforming growth factor TGF, all of which contribute to sodium and glucose retention, as well as intravascular volume increase. The subsequent elevation in volume status/hemodynamic and glomerular stress contribute to heart failure and kidney disease (these mechanisms act alongside the MI, CVD, and peripheral artery disease, which are caused by increased lipids, glucose, and blood pressure – the traditional focus of obesity and CVD).

• The importance of early prevention, especially in vulnerable pediatric populations, was certainly a focus across the entire session. Disturbingly, CV mortality increases 5-6x for adolescents who have a BMI ≥95% during adolescence.

• Dr. Erin Bohula surveyed the pharmacologic strategies to address obesity, focusing on the recent landscape of obesity CVOTs. To begin, Dr. Bohula gave some background on the current treatment options for obesity, including (i) lifestyle changes; (ii) bariatric surgery; and (iii) pharmacologic strategies. In terms of efficacy, lifestyle treatment and bariatric procedures exist at the extremes at 2.5-8% and 15-65% of net weight loss, respectively, while pharmacologic treatments currently stand at 3.5-14%.

  • Overall, drugs have struggled to demonstrate both safety and efficacy as well as tolerability. CRESCENDO (rimonabant) was discontinued due to serious psychiatric events, mainly suicide. SCOUT (sibutramine) showed a 16% increase in MACE, presumably due to increased HR and BP. The Light study (naltrexone-buproprion) was discontinued after interim data showed mixed results on MACE. Lorcaserin showed safety in CAMELLIA, as well as a net -2.8 kg of weight loss compared to placebo, on a background of standard of care and is sold as Belviq by Arena Pharmaceuticals. As to why CV benefits were not seen with lorcaserin, Dr. Bohula surmised that “it makes sense that biologically you need to accrue the benefits of better lipid control and A1c control over time,” just as the benefits of LDL-C lowering need the same extended duration. 

  • In the obesity pipeline, Dr. Bohula pointed to (i) Lilly’s dual GLP-1/GIP tirzepatide in patients with type 2 diabetes and obesity; and Novo Nordisk’s Ozempic in people with obesity and without diabetes. Currently, the higher 2.4 mg dose of semaglutide is being studied in this cohort in the SELECT CVOT.

--by Ursula Biba, Rhea Teng, Martin Kurian, and Kelly Close