The GLP-1 Agonist Semaglutide in HFpEF Cleared a Low Bar

John M. Mandrola, MD


August 26, 2023

On the big stage at the European Society of Cardiology (ESC) 2023 Congress, we heard the results of the STEP-HFpEF trial of semaglutide in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. You could feel the excitement in the packed auditorium. The trial discussant was ebullient in his praise.

This trial delivered a clearly positive result. But I worry that all the enthusiasm may blunt our science brains. Perhaps the bar for success of this drug class was set a bit too low.

The study of glucagon-like peptide 1 receptor (GLP-1) agonists as therapeutic agents in any chronic condition associated with obesity creates challenges for medical scientists.

Two facts: Obesity worsens any chronic condition. And this drug class consistently induces serious weight loss.

Patients who have both obesity and a chronic condition, such as HFpEF, will surely "feel better" with any method of weight loss.

One only needs to think about walking up a flight of stairs with and without a heavy backpack. In the matter of HFpEF, a condition that has dyspnea with exertion as one of its core symptoms, inducing weight loss will surely improve quality of life. If you breathe better, everything is better.

The STEP-HFpEF Trial

As heart failure trials go, STEP-HFpEF enrolled a small sample size of just over 500 patients with well-documented HFpEF and obesity (median body mass index [BMI], 37 kg/m2) and randomly assigned them to semaglutide or placebo.

The median age was 70 years, most patients were female, and the median left ventricular ejection fraction was 57%. Follow-up was 1 year.

The choice of dual primary endpoint requires attention. This was a change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score and the change in body weight. Secondary endpoints included changes in 6-minute walk distance, a hierarchical composite of many endpoints (using a win-ratio), and changes in biomarkers.

Every endpoint was positive. For the dual primary endpoints, the authors observed statistically and clinically significant improvements in the KCCQ score; weight loss, too, was substantial. The estimated difference in percentage body weight loss was 10.7% with semaglutide vs placebo.

Secondary endpoints favored semaglutide. Statistically significant improvements were seen in the 6-minute walk distance, win-ratio of multiple outcomes, and levels of C-reactive protein and N-terminal pro–B-type natriuretic peptide levels.


Patients approaching their seventh decade who struggle with obesity and HFpEF clearly felt better with their weight loss. They were able to walk longer distances and had favorable changes in biomarkers. STEP-HFpEF was clearly a positive trial.

We also worry a lot less about giving a new medication over the long term to older patients with a serious chronic condition than we would about giving this drug to adolescents or young adults with obesity who may have to take it for decades.

STEP-HFpEF also deserves praise for measuring endpoints that are important to patients. Cardiology has long focused on doctor-centric endpoints, such as hospitalizations for heart failure, which is reasonable but incomplete. A core tenet of doctoring is to improve quality of life. The KCCQ is a well-validated way to do that.

The median BMI in patients enrolled in STEP-HFpEF was 37 kg/m2, meaning half of these participants weighed more. In a patient who weighs 300 lb, a body weight loss of about 13.3% translates to nearly 40 lb. That's going to improve quality of life for any condition.

And that leads me to my main criticism: this trial was designed to win. Semaglutide cleared a low bar.

At ESC, there was much discussion about mechanism of benefit—was it simply the weight loss, or were there pleiotropic effects, such as reduction of inflammation? Proponents emphasized the favorable biomarkers. I would not. When you look to the primary endpoint of quality of life, that much weight loss explains nearly everything. Think of living life without that heavy backpack.

I also worry a lot about loss of blinding—which is no fault of the investigators. Patients enrolled in this trial surely had knowledge of what these drugs do. When those in the active arm stopped eating because of satiety, and then saw their weight drop, it seems likely that they would know their treatment assignment. That severely biases a patient-derived endpoint such as the KCCQ—and I think partially explains the remarkable effect size in the questionnaire.

Another worry I have with this class of drugs is cost. This, too, is not a criticism of the trial or investigators. HFpEF plus obesity is a common condition. If semaglutide gains a guideline recommendation for HFpEF, healthcare systems will be strained by costs. What will the threshold BMI be? Will it be the actual median BMI of 37 kg/m2, or will the entry criterion of 30 kg/m2? A BMI of 30 kg/m2 is almost the norm in much of the southern United States.

If I were a regulator, I would require the company to do an outcomes trial: a three-way trial where semaglutide is compared to placebo in one arm and an intensive lifestyle intervention in the other. How does this drug class compare to weight loss and fitness gained through changes in diet and activity?

In sum, STEP-HFpEF is a good start. But semaglutide has cleared a low bar.

Now show us how it performs in a clinical outcomes trial. This is where we will be able to measure its true value.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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