Semaglutides Big Step in HFpEF With Obesity Investigator Interview

The GLP-1 receptor agonist semaglutide led to weight loss and improved quality of life in patients with heart failure with preserved ejection fraction and obesity.
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Tricia Ward: Hi. I'm Tricia Ward from Medscape Cardiology, reporting from the 2023 European Society of Cardiology Congress in Amsterdam. I'm joined today by Dr Mikhail Kosiborod from Saint Luke's Mid America Heart Institute. Welcome.
Mikhail N. Kosiborod, MD: Thank you. Great to be with you.
Ward: You presented the STEP-HFpEF trial. Can you tell us the top-line findings of that trial?
STEP-HFpEF Key Findings
Kosiborod: Sure. It was a randomized, double-blind trial of semaglutide 2.4 mg once weekly vs placebo in patients with symptomatic heart failure with preserved ejection fraction and obesity as evidenced by body mass index of at least 30 kg/m2 or higher. These patients were treated for 52 weeks in total, and we had dual primary endpoints. These were change in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, which is the gold standard for assessing heart failure-related symptoms and physical limitations, and change in body weight. There were a number of secondary endpoints and exploratory endpoints as well.
The bottom line is that in these patients who are quite symptomatic and functionally impaired at baseline, treatment with semaglutide resulted in marked improvements in symptoms, physical limitations, and patients' quality of life. And it also, not surprisingly, produced substantial weight loss as compared with placebo.
As I mentioned, we had a number of other endpoints, what we call confirmatory secondary endpoints - meaning that they were tested in a hierarchical sequence with appropriate control for type I error, and these included change in 6-minute walking distance. That improved significantly, by more than 20 m with semaglutide compared with placebo. Inflammation went down, as measured by C-reactive protein. And we also had this direct composite endpoint, which included clinical events as well as changes in symptoms and physical limitations and walking distance. That was quite favorable for semaglutide compared with placebo. All of these were highly statistically significant. The improvements in symptoms and physical limitations were the largest that we've seen with any drug ever in this patient population, so, pretty substantial benefits.
Ward: The question now is, are the GLP-1 receptor agonists a weight loss drug - and because you affected the weight loss, you have this effect - or are they going to be a heart failure with preserved ejection fraction (HFpEF) drug?
Kosiborod: The whole point of the trial was really to demonstrate that in many patients, these two conditions are intricately linked. I mean, it's a little bit of an artificial distinction. People always want to put these things into buckets and say, "Well, what kind of drug is it? What kind of drug is the SGLT2 inhibitor?" I'm playing devil's advocate here. Is it a heart failure drug? Is it a kidney drug? Is it a diabetes drug? Well, it's all of the above.
And I think GLP-1 receptor agonists are a pluripotent class of medications. Why is that? Well, let's take obesity, for example. The concept and hypothesis of the STEP-HFpEF trial was that in a large number of patients who have HFpEF, obesity is not just a coexisting condition; it's a root cause and the key reason they developed heart failure, and the key driver of worsening heart failure progression. By targeting obesity and treating it, you're treating heart failure. So I think it's a bit of an artificial separation because the whole point is, if obesity is the root cause, then you have to address it to effectively treat heart failure. I think the reason we see such dramatic improvements in patient symptoms and physical limitations due to heart failure is because we are addressing the root cause of the problem.
Is the Weight Loss With Semaglutide Fat Loss?
Ward: One of the discussants noted that sometimes weight loss isn't necessarily fat loss. In this trial, you also measured waist circumference.
Kosiborod: We did measure waist circumference; it went down significantly and was one of the secondary endpoints. So that was clearly favorable to semaglutide and not surprising, given the extent of weight loss that we saw. We didn't do body composition analysis in this particular trial, but there have been other trials with semaglutide or other GLP-1 receptor agonist-based treatments that show that the vast majority of weight loss is due to loss of fat mass. It's not 100%. I mean, it's very difficult to lose weight with any intervention and purely lose fat; that really does not happen. But most of the weight loss is due to fat loss.
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