Semaglutide Can Preserve, Possibly Improve, NYHA Functional Class in Obesity-Related HFpEF

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A STEP-HFpEF analysis suggests semaglutide 2.4 mg (Wegovy) confers benefit across the spectrum of NYHA functional class among patients with obesity-related HFpEF.

An analysis of the STEP-HFpEF program suggests use of semaglutide 2.4 mg (Wegovy) could help prevent deterioration, and possibly improve, NYHA functional class status among patients with obesity-related heart failure with preserved ejection fraction (HFpEF).

Leveraging data from the STEP-HFpEF and STEP-HFpEF DM trials, investigators found offered consistent benefits on heart failure-related symptoms, physical limitations, exercise function, bodyweight and biomarkers of inflammation and congestion across all NYHA functional class categories.1

“In patients with obesity-related HFpEF, fewer semaglutide-treated than placebo-treated patients experienced a deterioration, and more experienced an improvement, in NYHA functional class at 52 weeks," wrote investigators. "Semaglutide, compared with placebo, consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced bodyweight and biomarkers of inflammation and congestion in all NYHA functional class categories.”

Presented at ESC Congress 2023 and ACC.24, respectively, the STEP-HFpEF and STEP-HFpEF DM trials offered further clarity into the cardioprotective benefits of semaglutide use and detailed the benefits on obesity-related HFpEF among patients with and without diabetes mellitus. Both trials had dual primary endpoints of change from baseline in the KCCQ-CSS and the change in body weight at 52 weeks.1

In STEP-HFpEF, 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). Assessments of body weight change indicated the mean percentage change from baseline 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).2

In STEP-HFpEF DM, the mean change from baseline KCCQ-CSS was 13.7 points with semaglutide 2.4 mg and 6.4 points with placebo (ETD, 7.3 points; 95% CI, 4.1 to 10.4; < .001). Assessments of body weight change indicated the mean percentage change from baseline in body weight was −9.8% with semaglutide and −3.4% with placebo therapy (ETD, −6.4 percentage points; 95% CI, −7.6 to −5.2; < .001).3

In the current study, a team of investigators from the STEP-HFpEF program led by Morten Schou, MD, PhD, director of Heart Failure Research at Herlev-Gentofte Hospital, sought to evaluate the effect of the GLP-1 receptor agonist on NYHA functional class as well as the effect across baseline function class on heart failure-related symptoms and other outcomes. Of the 1145 patients included within the program, 785 were classified in NYHA functional class II, 358 were classified in NYHA functional class III, and 2 were classified as NYHA functional class IV.1

Results indicated patients receiving semaglutide were more likely to experience an improvement (32.6% vs 21.5%; Odds Ratio [OR], 2.20; 95% CI, 1.62 to 2.99; P <.001) and less likely to experience a deterioration (2.09% vs 5.24%; OR, 0.36; 95% CI, 0.19 to 0.70; P = .003) in NYHA functional class relative to their counterparts receiving placebo therapy. Further analysis suggested semaglutide conferred a consistent benefit on KCCQ-CCS across NYHA functional class categories, with the greatest magnitude of benefit observed for those with more severe heart failure (P interaction = .06).1

The degree of body weight observed with semaglutide relative to placebo was similar regardless of baseline NYHA functional class category (P interaction = .96). Investigators noted semaglutide provided consistent, but nonsignificant reductions in C-reactive protein and NTproBNP relative placebo as well as improved 6-minute walking distance. Investigators highlighted a consistent, but nonsignificant reduction in a hierarchical composite endpoint death, heart failure events, differences in KCCQ-CSS, and 6-minute walking distance changes.1

“The mechanisms of the improvement in NYHA functional class in the STEP-HFpEF program are likely multifactorial. Weight loss itself can result in improved functional status, but our data suggest that weight-independent effects of semaglutide also contribute to the observed benefits,” investigators wrote.1 “Specifically, there appeared to be a larger improvement in HF-related symptoms and physical limitations among patients in NYHA functional classes III/IV than those in NYHA functional class II, even though the degree of weight loss was similar across NYHA subgroups.”


  1. Schou M, Petrie MC, Borlaug BA, et al. Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program. J Am Coll Cardiol. Published online June 12, 2024. doi:10.1016/j.jacc.2024.04.038
  2. Campbell P. Semaglutide 2.4 mg shows benefit as treatment for heart failure with obesity. HCP Live. August 24, 2023. Accessed July 10, 2024.
  3. Campbell P. Step HFPEF DM: Semaglutide 2.4 mg improves functional status, symptoms in patients with diabetes, HFPEF. HCP Live. April 6, 2024. Accessed July 10, 2024.