Javed Butler 2018 Transcript

To see this interview in full, click here.

Freed:  This is Steve Freed and we’re here with Diabetes in Control, and we’re at the American Diabetes, 78th Scientific Sessions Meeting, and we have a very special guest. So we’re here today with Javed Butler, is that correct? MD, MPH, MBA. And maybe we can start off with, tell us a little bit about yourself and your practice.

Butler: So, I’m a cardiologist. My primary focus is heart failure transplant and my research focus is clinical trials and heart failure, mostly looking at Phase 2 clinical trials. I recently moved from New York to Jackson, Mississippi where I’m Chairman of Medicine at the University of Mississippi.

Freed: And I think the title of your presentation was Heart Failure Outcomes in Diabetes Cardiovascular Outcomes Trials and Evolving Landscape.

Butler:  Yes.

Freed: And maybe we can start out with, give us the luxury of the high points of your presentation. What you want medical professionals to walk away with? Because I once saw a presentation about what makes a good presenter, and that is when people walk away and take your information and use it in their practice.  And maybe you can give us some information that our readers and viewers will use in their practice.

Butler: Well, thank you very much first for the invitation to be with you today. If I were to summarize my entire presentation in two sentences, I would say, one, that while reduction in hemoglobin A1C is very important, and sort of the main goal of heart failure therapy, you’re not done improving patient’s long-term outcomes, and cardiovascular outcomes, which is the number one cause of morbidity-mortality in patients with diabetes is very, very important. So, our therapeutic approach to these patients should not be limited only to management of glucose but management of their cardiovascular risk. And the second sentence will be, that while for the longest time when we talk about cardiovascular risk, we have talked more about vascular risk which is myocardial infarction and stroke in subsequent cardiovascular mortality. But we are learning more and more how heart failure outcomes either through or alternate pathways from vascular disease may lead to adverse outcomes and then we have to think about heart failure outcomes as well and not only atherosclerotic outcomes.

Freed: Well, you must be excited about some of the new drug treatments that are out there, especially in diabetes when it comes to heart failure and death. Before I get into your questions, what is your thought process behind using the SGLT2s and the GLP-1s to lower the risk for people with diabetes as far as heart disease and even death?

Butler: Yeah. So, at least the high risk cardiovascular patients, we have enough data right now from the cardiovascular outcomes trial that, beyond glucose control, now we have therapies that modulate their cardiovascular risk also, but you don’t give anything up by doing so because microvascular risk reduction will occur nevertheless because of glucose control. So, now we have two classes of drugs, GLP-1 agonist, at least two of them, and SGLT2 inhibitors, two of them that have data which are out there to modulate cardiovascular risk. Now, there are a lot of sort of subtleties and nuances that some improved this kind of outcome, some improved that kind of outcome, but nevertheless at least we have some of the options. So, one issue is how do you preferentially give therapies in high risk patients that can improve outcomes? But also some of the classic therapies, at least putting the heart failure lens on, may have raised some concerns that they may actually worsen outcome as well.  So, it’s a pretty broad feel right now to think through what is the best way to treat your patients with diabetes.

Freed: And what are the goals when you’re treating a patient with diabetes? What do you try to accomplish?

Butler: Yeah. So, that’s an unbelievably important question about which we don’t think enough. So, generically speaking one can say that any disease that you treat, you basically have four goals. So, the number one goal for treating any disease is for making patients feel better because that’s why they come to the doctors or the nurses in the first place. While you have these diseases like high blood pressure, diabetes, which are largely asymptomatic, people don’t have symptoms. So, the symptom part is already taken care of. So then the second is to do things that will improve the underlying biology of the disease process. The third is that that treatment that is treating the underlying biology of the disease, that then should translate into improvement in secondary risk prevention, so stroke, myocardial infarction, chronic kidney disease, whatever the complications of that given disease is. And then lastly, all of this should hopefully translate into people living longer. So, it’s a spectrum, wherever we can modify things, we should modify, but we should try to reach all four aspects of the spectrum.

Freed: I think it’s curious that when we list the major causes of death in the United States we list heart disease way up there, even though that person had diabetes. So, do we list it as diabetes, heart failure due to diabetes? We don’t have that. We just basically say it’s cardiovascular.

Butler:  So, that’s a very, very complicated question. And the reason why that’s a complicated question is that the CDC reports that come out, they don’t want to double count things, so they don’t want to attribute causes of death to more than one thing. So then, the question is how far back do you go? So for instance, let me just give you one simple example. We all know that patients with heart failure have 10% to 20% risk of dying and only depending on how severe the heart failure is. But by the same token, we say that in the US about 50,000 people die of heart failure annually. If there are 5 million people with heart failure and 50,000 patients died that’s 1% mortality risk. That’s awesome. The problem is that, again, you have 250,000 deaths attributed to chronic ischemic heart disease. Well, what is that? There is, I don’t know, half a million deaths attributed to hypertension. Well, nobody dies of hypertension. They get stroke. They get heart failure. They get myocardial infarction. So, how far back do you go in diabetes, falls exactly in the same realm.

Freed: So, what are the cardiovascular risks in patients with diabetes? Because that’s usually — it’s usually about blood sugars, A1C, we’re not really talking about cardiovascular risk. If we can talk about, you have an increased risk in cardiovascular disease, maybe they’d go for a walk more often.

Butler:  Well, so, cardiovascular disease is all forms of cardiovascular disease. So, vascular part of it is myocardial infarction angina, coronary artery disease, stroke, TIA. And then, once you go sort of beyond that you can have heart failure which could be either related to coronary artery disease or could be primary myocardial dysfunction. And at least I myself think of chronic kidney disease as a form of vascular disease as well, so you can, in my mind, [lump chronic kidney disease as part of the spectrum of cardiovascular diseases as well.

Freed: Is there a high risk of developing heart failure with diabetes?

Butler:  Oh, absolutely. So, not only is there a particularly high risk of developing heart failure in those people who have diabetes, if you do develop heart failure they almost fall off the cliff, for lack of a better term. So, the risks are very high, so you are at a high risk of developing heart failure and you are at a much higher risk for a worse outcome once you have both diseases together. And it’s a bidirectional relationship because most likely both of these things are related to insulin resistance. So, the actual prevalence of diabetes in heart failure population is about 30% to 40% but another 30%-40% have pre-diabetes. So, this is a pretty tight link. So, if you have heart failure and you don’t have diabetes, you’re at a high risk of developing diabetes. If you have diabetes and you don’t have heart failure, you’re at a high risk of developing heart failure. And once you have both, your prognosis is considerably worse than if you were to have either of the two of them.

Freed: Are you saying that those people with heart disease or heart failure and diabetes are going to have worse outcomes?

Butler:  By far. By far.

Freed: And how do you explain that to a patient?

Butler:  So, the way I would sort of explain it to the patient is that we know quite a lot in terms of biology of how that risk occurs. Now, we are not only talking about theoretical risk in biology but we have therapies that improve outcomes. So, let me just rephrase it a different way. If you have a patient who comes to your clinic, is completely asymptomatic and is doing great and their blood pressure is 180 systolic, are we going to leave them alone? No, right? Because you’re trying to prevent future adverse outcomes. If their hemoglobin A1C is 12, will you leave them alone? No, because you treat glucose, because you’re trying to lower microvascular neuropathy, nephropathy, whatever, risk. So, I think we need to just broaden that horizon that in the very same spectrum we also now need to give therapies that can reduce the major cardiovascular events as well.

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.