Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole, and we have two Northwestern Medicine physicians here for you today in a thought leader panel discussing and highlighting the connection between diabetes and heart disease and the use of semaglutide for prevention. Joining me is Dr. Robert Kushner. He's a Professor of Endocrinology and Medical Education; and Dr. Sanjeev Shah, Stone Endowed Professor, the Director of Research for the Bluhm Cardiovascular Institute and the Director of the Heart Failure with Preserved Ejection Fraction Program at Northwestern University Feinberg School of Medicine.

Doctors, thank you so much for joining us today. And Dr. Kushner, I'd like to start with you. Can you give us a little background on this topic? Some of the key factors that are contributing to the epidemic that we're seeing of obesity and diabetes in our society today? Kind of give us an overview of the scope of really what we're discussing here today.

Robert Kushner, MD: Sure. Thanks, Melanie. Thank you for having me as well. We are truly in an epidemic of both having obesity and diabetes. In fact, the term we use now is called diabesity in order to draw a link between the two conditions. Forty-two percent of Americans have obesity, and that is leading in large part to the increase in diabetes as well. It's due to genetics and changes in our environment, physical activity, diet, how we get around, how we move stress in our body and so forth. So, the endpoint is that the combination of obesity and diabetes is leading to multiple complications and comorbidities. One of which we're talking about today is cardiovascular disease.

Melanie Cole, MS: It certainly is a complex issue. And as you said, there are so many factors that we could not solve them on this podcast today, but we're seeing so much of it even in children, Dr. Kushner. We're really seeing diabetes and obesity coming together and now impending heart disease and blood pressure issues, as you said, those comorbid conditions. So, it really is an epidemic.

And Dr. Shah, you both helped lead two high-profile studies published in the New England Journal of Medicine. Can you please share what inspired your study designs? We'll start with you. And then Dr. Kushner, I'd like you to jump in after.

Sanjiv J Shah, MD: Sure. Thank you. And thanks for having me. I agree a lot with what Dr. Kushner said. I mean, you know, there's such an epidemic of diabesity. And the things that he mentioned that are risk factors for obesity and diabetes, like sedentary lifestyle, inactivity, the poor diet, some of the environmental stressors, those are all the same risk factors for heart failure, specifically heart failure with a preserved ejection fraction. And heart failure with preserved EF or HFpEF really wasn't the focus of heart failure for decades. Only in the last couple of decades has it really come to the fore. And we now know that HFpEF really constitutes more than 50% and possibly even 60% of all heart failure today, at least in the United States, and that's because of this diabesity epidemic.

And so, what really sort of got us to do these trials is that we were seeing in our patients with HFpEF that obesity was a major risk factor, as was diabetes, yet a lot of the scientific community was ignoring these. In fact, it was hard to get obese patients into these trials. They would get excluded from the trials. And so, we were really clamoring in the field, those of us who see a lot of these patients, that we really need to do something to prove that weight loss therapies can improve the lives, the outcomes of these patients with HFpEF. And we did that. We sort of went to multiple different companies to try to advocate for using weight loss drugs in this population and finally got Novo Nordisk to sponsor a pair of trials, the STEP-HFpEF and STEP-HFpEF DM trials, which were in patients with HFpEF with and without diabetes and a BMI, body mass index, of greater than 30. So, that's how it all came about. But it was an uphill battle for nearly 10 years to convince Big Pharma to do this and take it on.

Robert Kushner, MD: The trial that I was involved with also published in New England Journal was called SELECT, studying semaglutide, also produced by Novo Nordisk. And the study designed for SELECT was a little bit broader. And as we know, individuals with diabetes, of which many of them have obesity, have been shown to have improvement in cardiovascular outcome when using a drug like semaglutide as well as others.

What was never shown, however, is does a drug like semaglutide reduce the risk of cardiovascular disease in those that already have cardiovascular disease with overweight or obesity, but without diabetes. We never saw that before. So, the design of this trial, which was a randomized double blind, 804 clinical sites and so forth, is to take individuals who are overweight or with obesity with preexisting cardiovascular disease, but without diabetes and randomize them to a drug semaglutide or placebo and see for the very first time, does it reduce the risk of having a secondary event? And the outcome is positive, which we'll talk about momentarily.

Melanie Cole, MS: Well, thank you for both telling us about the two trials. And Dr. Shah, how do these findings of the two studies complement each other? As we're learning more and more about the interplay between obesity, diabetes, and cardiovascular disease, and Dr. Kushner was talking about SELECT trial, and you were talking about HFpEF, speak about why they complement each other so well as far as findings.

Sanjiv J Shah, MD: Sure. Well, in the STEP-HFpEF trial, so that was the first trial we published, that was in patients without diabetes who were obese, BMI greater than 30. In that trial, what we found was that semaglutide at the high dose, 2.4 milligrams, which really causes considerable weight loss, did in fact cause about 11-12% greater weight loss in those treated with semaglutide versus placebo. So, it did what we thought it would do. But in addition to that, it improved health status, so quality of life and symptoms. It improved it to a greater extent than any heart failure trial ever done using a drug. And it also improved their six-minute walk distance, so their exercise capacity. And it greatly reduced heart failure events, so heart failure hospitalizations. Now, it wasn't powered for the latter, but it really was striking at how good it was at doing that.

And the interesting thing about the trial was that this wasn't in patients with diabetes. And it also showed that there were improvements in biomarkers like NT-proBNP, which is a biomarker of congestion and inflammation, hs-CRP. And so, these improvements in these biomarkers were happening before all of the weight loss. So, we think it's having a primary decongestant effect, and there's still a lot to learn. And the diabetes trial, the sister trial, which we subsequently published, very similar results. You know, I think as we know, diabetes these drugs, is associated with a less degree of weight loss, but the improvements we saw were just as beneficial. So again, this decoupling from weight loss, these GLP-1 receptor agonists seem to be doing something that is above and beyond weight loss, possibly. And then, we combined these two in a paper in Lancet and definitively showed that it really does reduce heart failure events by 70%. And that really is remarkable because, for example, the only other drug that's approved in HFpEF broadly are SGLT2 inhibitors, and those lower the risk of heart failure events by about 18-20%. So, we're really seeing a much greater reduction.

And finally, SELECT, I think is really, really important because SELECT was a much bigger trial, and in fact, enrolled thousands of patients with heart failure, both with HFpEF and heart failure with reduced EF, and again, is showing a reduction in heart failure events and improvement in overall events in these patients with heart failure and obesity on these drugs. So, I think they complement each other quite well.

Robert Kushner, MD: Yeah. Thanks, Dr. Shah. You're absolutely right. SELECT had 17,000 individuals or patients who were enrolled, half of them the semaglutide and the other half the placebo. Of the 17,000 individuals, one-fourth of them had congestive heart failure, and half of those, or 13% of the whole population were categorized as HFpEFs. A fraction of the individuals had HFpEFs, which Dr. Shah just talked about, which his entire trial studied.

There was a composite heart failure score looked at in SELECT. And indeed, we found that the hazard ratio was 0.82, in other words, an 18% reduction in MACE or major adverse cardiac event in those individuals. So, that really crossed over very nicely. Whereas the trials that Dr. Shah was involved with really emphasized the importance of improvement in quality of life like the six-minute walk test and other outcome measures, shortness of breath and so forth, the SELECT added additional value in looking at reduction in major adverse cardiac events in those individuals.

Melanie Cole, MS: These are very significant findings. And as Dr. Kushner said, quality of life is such a part of the whole circle of this obesity, diabetes, cardiovascular disease. And as we said, all those risk factors that go with it, Dr. Shah, I'd like you to speak about some of the key insights from your research that physicians should consider for patient care. And in light of them, how should they reassess their approach to treating cardiovascular disease in patients with obesity and diabetes? Take us from bench to bedside. How will this really affect what goes on every day in offices like yours?

Sanjiv J Shah, MD: Well, from a practical standpoint, I think the biggest message I can give people is that don't ignore obese individuals. You know, don't write off their symptoms because they really have real disease that can be treated. So, in my realm with heart failure with preserved ejection fraction, obese patients are often short of breath, and it's often ascribed just to their obesity alone. But in fact, many of these patients have heart failure. And what's compounding the problem is that the most common test to diagnose heart failure, especially when the ejection fraction is normal, is a BNP or an NT-proBNP. And we know that in obese individuals, these biomarkers are falsely low. We know that adipocytes clear BNP. We know that patients with obesity make less BNP and NT-proBNP. And so, they don't get diagnosed. People are falsely thinking that they don't have heart failure because their BNP is low. And so for that reason, we clinicians really need to have a low threshold to look for the diagnosis and then treat it aggressively. And patients can feel so much better as we saw in the trial.

Both obesity and diabetes, I think, are major risk factors for cardiovascular disease because of their effects on the vasculature. We know that both obesity and diabetes are associated with microvascular dysfunction, systemic inflammation, which basically, I say, poisons, adversely affects the endothelium, the lining of blood vessels. We have coronary microvascular dysfunction a lot of times. Both conditions are associated with epicardial fat, and that epicardial fat is known and has been shown to be deleterious to the myocardium itself. And these changes coupled with large artery stiffening and atherosclerosis really combine to make these patients have those MACE events that Dr. Kushner was talking about.

So, we are really doing a disservice, I think, to many of our patients with obesity, unless we really probe into their complaints and say, "What exactly is going on?" And we do adequate screening, and listen to them, and actually treat their disease.

Robert Kushner, MD: Regarding the SELECT trial, I think the most significant point to make regarding clinical practice is it definitively showed that adding semaglutide 2.4 milligrams reduced the occurrence of cardiovascular events by 20% in individuals with overweight or obesity but without diabetes. And the important message is that this was on top of standard care. So, this is dealing with the residual risk that isn't being addressed by typical standard care.

The other thing I want to emphasize is that this was a secondary prevention cardiovascular outcome trial. Therefore, we should not be extrapolating these effects to primary prevention, such as an individual with overweight and obesity does not have cardiovascular disease. We don't know whether these same events would occur. We do know, however, that these individuals would lose weight. With that is a reduction in all of the cardiovascular risk factors. But if you have a patient with overweight, obesity, and pre-existing cardiovascular disease, then we now know that you can reduce the occurrence of a secondary event by dealing with that residual risk by adding a drug like semaglutide.

Sanjiv J Shah, MD: Dr. Kushner, you know, I agree with all those points. And one of the things that comes up is that these drugs, in addition to the fact that many of our patients with obesity without diabetes have no access to these drugs because insurance, the other thing that people talk about is that these drugs reduce intake. And so, you get not only a loss of fat mass, but of muscle mass. And we worry about that in our older patients with sarcopenic obesity or older patients that are frail with HFpEF. Do you see this loss of skeletal mass, which can be up to 30-40% of the total fat mass? Is that real? Is it muscle that these patients aren't even using? What should we do about that?

Robert Kushner, MD: That's a great question, Dr. Shah. Just being an obesity specialist, I never thought that I would be worrying that my patients would be losing too much weight by using an anti-obesity medication. That is the inflection point we find ourselves in now. These drugs are incredibly effective. We are concerned about individuals losing too much muscle mass, and I could throw in bone mass as well, in vulnerable individuals, certainly in elderly individuals.

Now, you're talking about patients who are more likely to really have complications and having other side effects from congestive heart failure in individuals in their 50s, 60s or so or older having excessive amount of muscle mass, just starting with less muscle mass. But that also goes for individuals even in their 30s or 40s. So as a clinician, we need to be monitoring these patients very carefully. How much weight loss they're losing, the rate of weight loss, and whether they're adding exercise, particularly resistance training in their treatment regimen and additional protein in their diet. So, these are the cutting-edge clinical research issues that we're now facing with these highly effective obesity medications.

Melanie Cole, MS: This is a fascinating conversation. As an exercise physiologist, I'm so happy and gratified to see experts such as yourselves really digging into this, because it is such an issue with our country. And I would really like to give you each a final thought here. Dr. Kushner, as we're talking about how the clinical outcomes detailed in these papers influence the current understanding of that progression from obesity and diabetes to cardiovascular disease from a research perspective, what's next? Will you have further studies? What are you going to do next?

Robert Kushner, MD: Well, currently, we're working under secondary papers and postdoc analyses of SELECT. It has really been a treasure trove of data generated from this study. For example, papers are now exploring the full safety profile of this drug. It was used up to four years in this study. We're looking at the effects of weight loss on the impact as well as baseline hemoglobin A1c on these outcomes and further exploring other outcomes such as heart failure or CKD.

One important point is that we don't fully know what mediated the reduction in MACE. Was it due to weight loss? Was it due to reduction in inflammation that Dr. Shah was talking about before? Also, BNP is a direct effects of the glp-1 receptor agonist on the heart, on the kidney, on other metabolic processes. So, we need to really untangle what is it about this drug and weight loss that's causing these positive effects and then apply that learning to new drugs that are on the horizon.

Melanie Cole, MS: Dr. Shah, last word to you. As we know, cardiovascular diabetes and obesity, they're very complicated diseases. They impact millions of patients around the country. Why is Northwestern Medicine really a destination for patients with complex health issues? I'd like you to wrap it up and summarize for us the studies and why these studies are just so important for patients at Northwestern Medicine.

Sanjiv J Shah, MD: That's a great question. I mean, I have been working here for 17 years. I know Dr. Kushner, longer. I mean, I think we really enjoy working here because of the collaborative nature and the true multidisciplinary holistic care of patients, and at the same time providing them with access to the latest in research advancements and development of new therapies and diagnostic tests.

We've shown here that in three trials, STEP-HFpEF, STEP-HFpEF DM, and the SELECT trial, that, overwhelmingly, semaglutide does improve symptoms and outcomes in patients with pre-existing cardiovascular disease, and in particular patients with heart failure with a preserved ejection fraction, which is becoming more and more prominent in our society. So, that, I think, is a major advance, but the advances don't stop there. To dovetail with what Dr. Kushner was saying, we are also looking at many of these secondary analyses of the STEP trials, but even more exciting is the new therapies that are in development.

We are studying in HFpEF a novel metabolic mitochondrial accelerator called HU6 that does not reduce total mass, but only visceral fat in HFpEF. So, it really just burns the visceral fat and doesn't alter intake. And so, it could be an adjunctive therapy without losing muscle mass.

There's another class of drugs that are called activin type 2 receptor blockade with antibodies. And those are really interesting drugs as well that are in development that reduce total body fat mass, but actually stimulate skeletal muscle growth. So, these are things that we're studying, that we're excited about, and I think make Northwestern really a destination for the most advanced and collaborative healthcare.

Melanie Cole, MS: Thank you both so much. This was a great conversation. You gave us a lot of insight and so much to think about. Thank you again for joining us. And to refer your patient or for more information, we have two websites to share with you today, breakthroughsforphysicians.nm.org/cardiovascular and breakthroughsforphysicians.nm.org/endocrinology. And you can find out more about both studies at those websites. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. Please always remember to subscribe, rate, and review Better Edge on Apple Podcasts, Spotify, iHeart, and Pandora. Until next time, I'm Melanie Cole.