Dennis P. Scanlon, PhD: Let’s transition and talk about reducing cardiovascular risk in the broad population of patients with diabetes. Dr Bloomgarden, can you talk about the relationship between diabetes and heart failure?
Zachary Bloomgarden, MD: Sure. Diabetes is associated with increased likelihood of atherosclerotic cardiovascular disease. Period, we know that. And certainly, individuals who have myocardial damage have decreased heart function and are at risk of heart failure. In addition, we know about insulin resistance and the hypercoagulable state of diabetes. But it’s not as widely appreciated that there are many pro-fibrotic factors which are expressed in persons with diabetes. And so, the myocardium actually undergoes fibrosis and this could be found, and then there’s a whole entity of microvascular heart disease which is not quite as well characterized but certainly has been well shown in animal studies and in man.
And so, for a variety of reasons, persons with diabetes have evidence of decreased heart function, and endocrinologists are now aware of 2 different types of heart failure—heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. These are extremely important causes of morbidity and mortality. People with heart failure feel tired. They have less energy and then, eventually, they progress to peripheral edema, dyspnea, and all of the classic things that we learned. Every day I see someone who comes in, who I may have known for many years, and now they’re saying, “I don’t feel so good.” And I know this is someone who has had documented coronary disease in the past (or whatever), and it becomes very attractive to say (in this population which is so common), we may have a specific drug that could be useful.
Dennis P. Scanlon, PhD: Dr Inzucchi, what have we learned since the initial findings about the effect of empagliflozin and the rates of hospitalization for patients with heart failure?
Silvio Inzucchi, MD: This was a secondary endpoint in the EMPA-REG OUTCOME trial, and the effect was quite strong. It was about a 35% risk reduction and a very common scenario—which is a patient with type 2 diabetes with known coronary artery disease who gets admitted with edema, pulmonary edema, or other signs of either heart failure with preserved or reduced ejection fraction (a real epidemic). I think cardiology colleagues are getting so good at saving people during their acute coronary syndromes that many patients are now living with somewhat damaged ventricles. So, the 35% risk reduction—we saw that and we wondered whether this was something that occurred in patients with established heart failure or whether it was preventing heart failure episodes. And I think the answer is both.
Unfortunately, we did not have good baseline left ventricular studies in our patients, so we can’t tell you who in the study had so-called HFpEF (with preserved ejection fraction), or HFrEF (with reduced ejection fraction). But what we do know is that of the 10% of patients who did have heart failure at baseline, at least by history, they experienced a reduction in their heart failure hospitalization rates that was statistically indistinguishable from the reduction in heart failure hospitalization rates in patients that never had heart failure before. So, this may be pushing the envelope a little bit because the study should state very clearly that it was not powered for heart failure, but it suggests that the drug could not only prevent clinical deterioration in patients with overt heart failure but could somehow prevent the development of new heart failure, which I think is a very important potential finding. Obviously, these are hypothesis generating. It’s attractive because it kind of makes sense. The cardiovascular mortality was surprising. The heart failure hospitalization was not. In fact, many of us have been encouraging heart failure trials with this class of drug for many years.
We will know, I think, in a few years. These studies are, now, just getting under way. There’s an empagliflozin study known as EMPEROR HF. Here, they will be looking at both HFpEF and HFrEF patients. I think it may be 2 studies, but they may be pooled in their analysis. And dapagliflozin is also undergoing a study known as DAPA-HF, and that is strictly a HFrEF study (a reduced, classic heart failure population). I believe those studies, which are just getting underway, will have some results in perhaps 3 or 4 years. Until then, we won’t know for sure, but it’s very important data, I think.
Dennis P. Scanlon, PhD: But those studies, unlike the others, are being powered to be able to answer those questions.
Silvio Inzucchi, MD: Absolutely. These are heart failure trials being driven by heart failure experts. Interestingly, they’re both recruiting both patients with and without diabetes. The heart failure community is very interested in this class because of the EMPA-REG signal, but the question is, will the benefits be seen again in the diabetic population? We hope so. But will they be extended to patients without diabetes? There is a glucosuric effect of these medications even in patients with normal glucose tolerance.
Zachary Bloomgarden, MD: Or in prediabetes. It would be fascinating if perfectly normal glucose tolerance didn’t benefit, prediabetes benefitted, and diabetes benefitted as a total hypothesis concept.