'Big Win' for Anti-Obesity Medication in Heart Failure

In this video, Harlan Krumholz, MD, SM, of the Yale School of Medicine and Yale New Haven Hospital in Connecticut, discusses a randomized trial that showed semaglutide (Wegovy) led to improvements in symptoms and weight for heart failure patients with obesity. The study, presented last week at the European Society of Cardiology Congress and published in the New England Journal of Medicine, also suggested better outcomes with the GLP-1 receptor agonist when it came to hard cardiovascular endpoints.

Krumholz is the director of the Center for Outcomes Research and Evaluation, the Harold H. Hines Jr. Professor of Medicine, and a professor in the Institute for Social and Policy Studies, of Investigative Medicine and of Public Health.

The following is a transcript of his remarks:

It's another big win for the anti-obesity drugs. This time, not for just diabetes, not for just obesity, but in a new area, in a combined area: heart failure with preserved systolic function and obesity.

In a report that's coming out in the New England Journal of Medicine, a clinical trial focused on heart failure with preserved ejection fraction (HFpEF). The benefits of using semaglutide are shown to be quite impressive.

So, heart failure with preserved ejection fraction is quite a common condition. Among people who have heart failure, about half of them have this with normal ejection fraction. It's associated with a high symptom burden and functional impairment, and actually outcomes that aren't so different from people who have depressed systolic function. No therapies have been approved to target this obesity-related heart failure.

And why do I say obesity-related? Well, it turns out that a very high percentage of people with heart failure and preserved ejection fraction actually have obesity or are markedly overweight. And growing evidence suggests that obesity and excess adiposity are not simply coexisting with heart failure, but actually may be contributing to heart failure.

Today, Mikhail Kosiborod presented at the European Society of Cardiology meetings a trial that had been conducted where they randomized 529 patients with heart failure with preserved ejection fraction and a body mass index of 30 or higher to receive semaglutide once weekly at 2.4 mg for 52 weeks. Now, what they focused on in the endpoints was actually health status and quality of life. So they had this endpoint of the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), which ranges from zero to a hundred and captures how people feel. They also looked at the change in body weight.

And so what did it find? The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo. That leads to a difference of 7.8 points and was highly significant. Now, when we usually think about this score, even a change of just five points seems to be clinically important to patients. So this change of almost eight points is important and clinically significant.

Now, the mean percentage change in body weight was a loss of about 13.3% in the semaglutide group compared with 2.6% in the placebo group. Then they looked at a whole range of other outcomes. They looked at CRP [C-reactive protein] levels, which declined much more in the group that had been treated with semaglutide, and they looked at 6-minute walk tests. They actually looked at a combined endpoint that looked at heart failure hospitalization or urgent visit for heart failure in a time-to-event analysis -- and also, although it is secondary and exploratory, showed a very highly significant result. Only one person in the semaglutide group had this, whereas 12 people in the placebo group had this. And this was, as I said, highly significant.

Now, there are a couple things to know about this study. Most of the participants, about 56%, were women. But it was kind of a good balance, but it wasn't so balanced on diversity -- 96% were white. The median age was 69 years. At the outset, the median body weight was 105 kilograms and the median BMI was 37 -- about 66% (two-thirds) had a BMI of 35 or higher. The median KCCQ-CSS was about 59 points. What's important about this is that this is conveying that this is a group that was limited, symptomatic -- their health status wasn't great. And also, there was a lot of room for them to improve.

I mean, sometimes we do these studies and there's a ceiling effect. People are already feeling quite good; it's hard to show a big improvement. In this group of patients with heart failure with preserved ejection fraction, that Kansas City Cardiomyopathy Questionnaire [Clinical] Summary Score indicates that this is a group that was having trouble.

So overall in this randomized placebo-controlled trial in patients with heart failure with preserved systolic function and obesity, once-weekly semaglutide at a dose of 2.4 mg led to a much larger reduction in heart failure-related symptoms and physical limitations. It's a big win.

Now, some people have said to me, "Well, I want to wait until the FDA weighs in on this. It doesn't have an indication yet for heart failure." But look, these people all had an indication for semaglutide just based on their obesity. I believe these drugs are going to be shown to be beneficial in a wide range of situations. We just heard recently that the outcomes trial that is being run with semaglutide is positive. That information came out in a disclosure by the company that they have to make for regulatory reasons. We haven't seen any details about that study, but we're hearing hints.

Look, we already know the GLP-1 agonists -- these anti-obesity drugs -- are being used and, at least in diabetes, are associated with reduced risk. Now we've got this news that, in people with obesity, it reduces risk. Now we've got this new information for heart failure with preserved systolic function that it improves how people feel, that it improves their physical functioning, and there's a hint here -- although it wasn't a primary endpoint -- there's a hint that it may actually also improve outcomes. So, everything's kind of moving in this direction. Of course, I'm talking about anti-obesity drugs in this class in general, but this is about semaglutide in particular.

We're going to have to stay tuned. I'm not thinking about these drugs anymore for what they're doing for weight loss or how people look. I'm thinking that these are drugs that can help potentiate how people feel, they can help people live longer, they can reduce risk, and we're going to have to stay tuned on this.

But for one of the major conditions of our time, obesity -- for which we've made very little progress and are almost continually losing ground and it's associated with almost 200 different medical conditions -- we're now seeing that the treatment with this class of medications is making a difference.

This isn't going to be in the purview of the endocrinologist. We're not just thinking about diabetes anymore, but cardiology, cardiologists, primary care, anyone who's taking care of people with obesity are going to need to really be up-to-date on what's going on.

Then we're going to need to dig down and make sure that people get access to these medications, as they're proven to be beneficial on outcomes. We have to make sure that these barriers to access don't exacerbate disparities and we have to pay attention to equity issues within society.

But all this to just convey to you this good news today. It does seem like semaglutide is an effective agent for people who have heart failure with preserved ejection fraction and obesity. Stay tuned. There's going to be a lot more information on these classes of drugs as many more studies come to their ending point, and we'll be hearing about them at big meetings like this.

Comment