Semaglutide for HFpEF? Breaking Down the STEP-HFpEF Trial, with Javed Butler, MD

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Javed Butler, MD, discusses the overall results of the STEP-HFpEF trial, how he interprets the reduction in adjudicated heart failure events, and how the community's recent experience with SGLT2 inhibitors might inform uptake strategies for semaglutide 2.4 mg.

The understanding and management of heart failure with preserved ejection fraction (HFpEF) has undergone a transformation in recent years and the STEP-HFpEF at the European Society of Cardiology (ESC) Congress 2023 provides the latest evidence this transformation is still ongoing.

A randomized, double-blind, placebo-controlled trial conducted at 96 sites in Asia, Europe, and North and South America, the STEP-HFpEF trial assessed the effects of semaglutide 2.4 mg (Wegovy) against placebo therapy on symptoms and functional status in adults with obesity and HFpEF. The trial enrolled 529 participants, with 266 and 263 randomized to the semaglutide 2.4 mg and placebo arms, respectively.1

The trial had dual primary endpoints defined as change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and change in body weight. At baseline, the overall study cohort had a median age of 69 years, a median body weight of 105.1 kg, and a median BMI of 37 kg/m2, with 66% having a BMI of 35 kg/m2 or greater. Additionally, the cohort had a baseline median KCCQ-CSS of 58.9, median 6-minute walk distance of 320.0 meters, median CRP level of 3.8 mg/L, median LVEF of 57.0%, and median NT-proBNP of 450.8 pg/mL.1

Upon analysis, the mean change in the KCCQ-CSS was 16.6 points with semaglutide 2.4 mg and 8.7 points with placebo (estimated treatment difference [ETD], 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P < .001). When assessing body weight reductions, results suggested the mean percentage change in body weight was −13.3% with semaglutide 2.4 mg and −2.6% with placebo (ETD, −10.7 percentage points; 95% CI, −11.9 to −9.4; P < .001). For 6-minute walk distance, the observed change also favored semaglutide 2.4 mg, with a mean change of 21.5 meters with semaglutide 2.4 mg compared to 1.2 meters with placebo (ETD, 20.3 m; 95% CI, 8.6 to 32.1; P < .001).1

An additional secondary endpoint of the trial was a hierarchal composite outcome including death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance. When assessing this endpoint, results suggested 1 such event occurred in the semaglutide 2.4 mg group compared to 12 in the placebo arm (Hazard Ratio, 0.08; 95% CI, 0.00 to 0.42).1

With these results coming less than a month after Novo Nordisk announced topline results from the SELECT trial, semaglutide 2.4 mg seems poised for an entry into treatment algorithms for cardiologists’ patients in the near future.2 Check out this interview with trial investigator Javed Butler, MD, president of the Baylor Scott and White Research Institute, for more insight into study results, a potential role for semaglutide in the cardiologist’s armamentarium, and how study investigators interpret the difference in adjudicated events.

Disclosures: Butler reports having received funding for consulting or research grants from Novo Nordisk, Bayer, Boehringer Ingelheim Pharmaceuticals, Inc, Merck & Co., Inc., Novartis, AstraZeneca Pharmaceuticals, and others.


  1. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. The New England Journal of Medicine. Published online August 25, 2023. doi:10.1056/NEJMoa2306963
  2. Campbell P. Select trial shows semaglutide 2.4 mg could reduce cardiovascular risk. HCP Live. August 8, 2023. Accessed August 24, 2023.