Semaglutide Provides Consistent Benefit Across Ejection Fraction in HFpEF


Prespecified analysis of STEP-HFpEF trial shows semaglutide benefits consistent across ejection fraction spectrum, offering potential HFpEF management.

Javed Butler, MD, MPH, MBA | Credit: BAIM Institute

Javed Butler, MD, MPH, MBA
Credit: BAIM Institute

A prespecified analysis of data from the STEP-HFpEF trial suggests the benefits of semaglutide observed in the trial were consistent across the spectrum of ejection fraction.

A landmark trial assessing the effects of semaglutide in patients with obesity and heart failure with preserved ejection fraction (HFpEF), the prespecified analysis, which was presented at the Heart Failure Society of America (HFSA) 2023 Annual Scientific Meeting, suggests semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary score (KCCQ-CSS) and body weight to a similar extent across left ventricular ejection fraction (LVEF) categories.1

“In this pre-specified analysis of the STEP-HFpEF trial, semaglutide was shown to improve symptoms, physical limitations, and exercise capacity, and reduced inflammation and body weight, to a similar extent across the EF spectrum, supporting the potential for use of semaglutide in patients with the obesity phenotype of HFpEF regardless of EF,” wrote investigators.1

As the medical community awaits the full results of the SELECT trial, the STEP-HFpEF captivated audiences when it was presented at the European Society of Cardiology 2023 Congress. Patients included in the trial underwent randomization in a 1:1 ratio to either semaglutide 2.4 mg or placebo therapy for 52 weeks. In addition to the dual primary endpoints, the trial also included multiple secondary endpoints such as change in the 6-minute walk distance, change in the C-reactive protein (CRP) level, and a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance.2

Overall, 529 patients underwent randomization. Of these, 263 were randomized to semaglutide and 266 were randomized to placebo, with 256 participants in the semaglutide arm and 254 patients in the placebo arm completing the trial.2

Results presented at ESC Congress 2023 suggested 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; < .001). For weight change, 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; < .001). The change in 6-minute walk distance 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 meters; 95% CI, 8.6 to 32.1; < .001).2

The HFSA 2023 analysis stratified patients into LVEF categories defined as: 45-49%, 50-59%, and 60% or greater. Of the 529 patients who underwent randomization, 85 had an LVEF of 45-40%, 215 had an LVEF of 50-59%, and 229 had an LVEF of 60% or greater.

Upon analysis, the following ETDs were observed for KCCQ-CSS (P=.56):1

45-49%: ETD, 5.0; 95% CI -2.7 to 12.8
  • 50-59%: ETD, 9.8; 95% CI, 5.0 to 14.6
  • 60% or more: ETD, 7.4 95% CI, 2.8 to 12.0

For weight change, the following ETDs were observed (P=.08):1

  • 45-49%: ETD, -7.6; 95% CI -10.7 to -4.4
  • 50-59%: ETD, -10.6; 95% CI, -12.6 to -8.6
  • 60% or more: ETD, -11.9; 95% CI, -13.8 to -9.9

Analysis of secondary endpoints of interest revealed LVEF did not influence 6-minute walk distance (P for interaction=.19), hierarchal composite endpoint (P for interaction=.43), and C-reactive protein (P for interaction= 0.26). Investigators also pointed out there was no influence on NT-proBNP, which was an exploratory endpoint (P for interaction= 0.96).1

In an editorial comment, Muthiah Vaduganathan, MD, MPH, and John Ostrominski, MD, both of Brigham and Women’s Hospital, commended study investigators for carrying out this prespecified analysis and also expressed excitement surrounding the potential of another agent for management of HFpEF.3

“The authors should be congratulated for an important analysis of this landmark trial, which unlike prior analyses of several major HF pharmacotherapeutic classes (beta-blockers, renin-angiotensin system inhibitors, angiotensin receptor-neprilysin inhibitors, and mineralocorticoid receptor antagonists) does not suggest attenuated benefits of semaglutide with higher LVEF,” wrote Vaduganthan and Ostrominski.3 “Rather, like SGLT2i, treatment effects were consistent across an LVEF range ≥45%. Given semaglutide 2.4 mg is currently available, these findings provide vital reassurance regarding the safety and efficacy of semaglutide when the LVEF is below normal.”


  1. Butler J, Abildstrøm SZ, Borlaug BA. Semaglutide Effects According to Ejection Fraction in Heart Failure with Preserved Ejection Fraction and Obesity. Journal of the American College of Cardiology. Published online October 8, 2023. doi:10.1016/j.jacc.2023.09.811
  2. Campbell P. Semaglutide 2.4 mg shows benefit as treatment for heart failure with obesity. HCP Live. August 24, 2023. Accessed October 8, 2023.
  3. Vaduganathan M, Ostrominski J. Glucagon-like Peptide-1 Receptor Agonists in Heart Failure: STEPping Across the Ejection Fraction Divide. Journal of the American College of Cardiology. Published online October 8, 2023. doi:10.1016/j.jacc.2023.09.812
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