Dr Javed Butler: How STEP-HFpEF Findings on Semaglutide Translate to Clinical Practice

In the STEP-HFpEF trial, the 3 confirmatory secondary end points observed were higher Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), higher 6-minute walk distance, and more reduced C-reactive protein (CRP) levels in the semaglutide group compared with placebo.

Javed Butler, MD, MPH, MBA, professor of medicine at University of Mississippi, president of the Baylor Scott & White Research Institute, explains how each of these findings translate into clinical care and whether they indicate semaglutide as a potential treatment for patients with obesity-related heart failure with preserved ejection fraction (HFpEF).

Transcript

How do each of the findings in STEP-HFpEF translate into clinical care?

There are a lot of theories out there about pathophysiology of HFpEF. We focused on this specific population of obese HFpEF, and in this particular trial, those without type 2 diabetes—there is a sister trial going on right now with type 2 diabetes. Part of that pathophysiology is inflammation, and hsCRP [high-sensitivity CRP] is a marker of inflammation, so it gives some validity that if the patients feel better and their CRP level goes down, you feel some comfort that it's the pathophysiology that you're impacting. Because one of the things people will say [is], "Well, if you have weight loss in a person who's obese, how do you know that you're affecting the pathophysiology of heart failure favorably?" What we found in that trial was not only improvement in quality of life and functional capacity, but a reduction in CRP. In other words, you're impacting the basic pathophysiology of HFpEF.

The other thing I want to highlight is that the degree of improvement in functional capacity or quality of life is really impressive. I mean, most of the other pharmacotherapies, we had about a 3-point improvement in KCCQ here, it was in excess of 7.5 points, so these are really, really impressive results. I think today, if a clinician wants to now start thinking about in obese patients the use of semaglutide to improve symptoms and quality of life, they should feel pretty comfortable.

But then the next question comes up. It's tough to have this much improvement in quality of life or functional capacity without improving the underlying pathophysiology of the disease. But if you're improving underlying pathophysiology, then technically that raises the question, "Are the people going to live longer and not get hospitalized?" This trial was not designed to look at that question, but surely the data would suggest that that's the next direction we need to go to.

With no approved therapies for obesity-related HFpEF, how do the results of STEP-HFpEF suggest semaglutide as a potential treatment for patients with obesity-related HFpEF?

The last few years have been really good for patients with HFpEF. We had this sort of mindset over a long time that nothing improves HFpEF outcomes. We have 2 positive trials with SGLT2 [sodium-glucose cotransporter-2] inhibitors—in obesity, and no obesity—across the spectrum of EF now, so that's great news. And now, we have this trial [that is] positive. Let's see what we find with the STEP-HFpEF in patients with diabetes, we'll put the data together. But I think in HFpEF patients with obesity, we should feel pretty comfortable that giving these therapies will improve patient's functional capacity and quality of life.

Now, this was a small trial [with] short-term follow-up, but whatever few clinical events we had, they were literally almost uniformly in patients who are in standard of care and we saw significant benefit with semaglutide. I don't think that this is confirmatory data, but this is strong enough that we feel that the next best step is to now look at the clinical outcomes of these therapies.

I think we should feel pretty comfortable—let's see what the guidelines say when they get some time to digest these data—but I think we should feel pretty comfortable that this is yet another therapy to improve quality of life and functional capacity. But, boy, I really hope that we now move on to large outcomes trials.

This transcript has been lightly edited for clarity.