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In part 4, the conclusion of this Exclusive Interview, Javed Butler talks with Diabetes in Control Publisher Steve Freed about the use of SGLT2 to help prevent heart failure but not as a current treatment method.
Javed Butler, MD, MPH, MBA, is a cardiologist, professor, and chairman of medicine at the University of Mississippi Medical Center.
Transcript of this video segment:
Freed: And how do SGLT2 inhibitors impact heart failure outcomes?
Butler: So, what is very interesting is that, one, we have to differentiate prevention of heart failure from treatment of heart failure. Two completely different concepts. Today, we don’t have enough data to say that SGLT2 inhibitors are treatment for heart failure. We are not there yet. There’s another relevant level of granularity here. So, if a diabetic patient has heart failure and if you want to give them SGLT2 inhibitors to treat diabetes, go ahead, no problem. But don’t think that you are treating heart failure. However, there are plethora of data that in high risk patients by giving SGLT2 inhibitors to treat diabetes, you prevent heart failure. And unlike other cardiovascular outcomes either with GLP-1 agonists or with SGLT2 inhibitors but there is this heterogeneity in terms of cardiovascular risk and MI risk, stroke risk, and this that and the other. For heart failure, it’s consistent. With EMPA-REG trial, 35% or so reduction in heart failure risk. With CANVAS, 35% or so reduction in risk. And then the REAL evidence with CVD-REAL, six different countries, three different SGLT2 inhibitors, again 30%-plus risk there. So, prevention, very consistently we are seeing the same result over and over again, but there are about four outcomes trials going on right now. First, SGLT2 inhibitors in patients who already have heart failure. But there our prism is a little bit different through which we are looking at it; because we are trying to treat heart failure with SGLT2 inhibitors, those trials are including both patients with and without diabetes. Its idea is to treat heart failure irrespective of diabetes.
Freed: And are those studies blinded?
Butler: Yes. So, these are large, 5,000 to 7,000 patients, randomized control trials, multinational.
Freed: So, you’re asking some patients to take a placebo.
Butler: Correct.
Freed: You’re asking some patients to take an SGLT2 inhibitor that we know can prevent heart failure; we don’t know if it’s treating heart failure, but we know that it can prevent death.
Butler: Very, very, very good question. So, we have actually published on this issue of the ethics of blinded randomization in this era with SGLT2 inhibitors and heart failure. So, again, so, we have a whole vast amount of knowledge from the past experiences that what works in coronary artery disease does not necessarily work in heart failure. So, for instance there’s not a single person who would argue that statin therapy is good in coronary artery disease. But if you give a statin therapy to heart failure patients, it won’t impact heart outcomes at all. So, that’s one issue. The second issue is that the cumulative impact that was assessed in heart failure patients in EMPA-REG trial was about 700 patients. This is like a robust phase 2 study, so we really don’t know the outcomes. And three, what works in heart failure with reduced ejection fraction does not work in heart failure with preserved ejection fraction. So, if you look at the broad landscape, I think it is not only ethical, it’s actually imperative to study these agents before we incur the cost and the potential for side-effects and whatnot in heart failure patients whether there is incremental benefit in heart failure per se. But if you are a person with a history of coronary disease or stroke but no heart failure, by all means the data are pretty clear for prevention of heart failure.
Freed: So, we know how SGLT2s work when it comes to reducing blood sugars. It increases the excretion in the urine of glucose. How does it work as far as the heart goes?
Butler: So, I can give a long answer and the short answer is I don’t know because there are so many pharmacodynamic effects of these agents that could be hypothesized for improvement in outcome. But of these 10 different things that these drugs do which one is actually clicking, we don’t know. So, obviously you have better control of glucose, you have preservation of GFR, you have a decrease in visceral adiposity and associated reduction in oxidative stress and inflammation, you have decreased arterial stiffness, you have low level of ketogenesis which is a preferred fuel in the failing heart. So, one can go on and on with the potential list of mechanisms that might benefit. But I don’t know today where I can draw that causal link of one on one of why the improvement is happening. On the other hand however, the prevention of heart failure is not seen in some 200 patients small study. We have seen it in hundreds of thousands of patients across different countries and different trials. It’s a pretty robust impact of about 30%. So, the chances of these data being chance finding are incredibly small.
Freed: And would you give credit to the ruckus about Avandia with heart failure, that it’s because of that particular situation that the FDA now requires diabetes drugs to go through heart evaluation studies. And because of that we now have products that we can say can prevent heart disease by a certain percent.
Butler: So, the answer is absolutely yes. There are things that we discover in medicine and there are things that we stumble upon, either way learning more is good. But to me, the question this raises is actually very different, and the question is that, for diseases that are not very common; primary pulmonary hypertension, congenital heart disease — and when we approve therapies on smaller studies because they make patients feel better, is really you’d start scratching your head that you actually don’t know what you’re doing to the patient in the long run. Are you improving outcome, worsening outcome, or you’re outcome neutral.
Freed: So, what are the ongoing trials of the SGLT2 inhibitors because it seems like it’s an important discovery and we’re finding that it can do so many things?
Butler: So, the CBOTs that have come out thus far were all focused right in the middle of the spectrum of diabetes which is high risk patients with diabetes either with known cardiovascular disease or a high risk for cardiovascular disease. So, now the data which are anxiously awaited are going to the two extremes beyond that middle. So, either the primary prevention less sick patients, so DECLARE has a very sizable proportion of those patients who do not have known cardiovascular disease. They are still higher risk. They’re not like a 20-year old without risk, still high risk, but at least not known cardiovascular disease on one hand. And on the other end of the spectrum are people who are much more sick, which is the heart failure population, and there are four ongoing trials there.