In 1,145 obese HFpEF patients, semaglutide improved NYHA functional class in 33% vs 22% on placebo, with the greatest symptom improvements seen in patients with the most severe baseline limitations (NYHA III/IV).
OR 2.20 for NYHA improvementSemaglutide-treated patients were more than twice as likely to improve their heart failure functional class compared to placebo over 52 weeks
What the researchers found
Semaglutide improved NYHA class in 32.6% vs 21.5% placebo (OR 2.20, P<0.001). Deterioration occurred in only 2.1% vs 5.2% (OR 0.36, P=0.003). KCCQ-CSS improvement was especially pronounced in NYHA III/IV (10.5 points vs 6.0 in class II). Weight loss was consistent (~8.4%) regardless of baseline NYHA class. Consistent improvements in 6MWD, CRP, and NT-proBNP across all categories.
Why it matters
NYHA functional class is one of the most important clinical measures in heart failure — it directly reflects how heart failure limits daily life. Showing that semaglutide improves functional status, with the biggest gains in the most limited patients, demonstrates meaningful clinical benefit beyond just weight loss.
The numbers in context
Analysis from the STEP-HFpEF program. NYHA functional class ranges from I (no limitation) to IV (severe limitation).
How the study worked
Prespecified pooled analysis of STEP-HFpEF and STEP-HFpEF DM — two international, double-blind, placebo-controlled RCTs. 1,145 participants with obesity-related HFpEF randomized to semaglutide 2.4 mg weekly or placebo for 52 weeks. Primary outcome: change in NYHA functional class. Secondary: KCCQ-CSS, 6MWD, bodyweight, CRP, NT-proBNP by baseline NYHA class.
Who was studied
Patients with obesity-related HFpEF from the STEP-HFpEF program
What this study cannot tell us
Post-hoc pooled analysis — though prespecified, it combines two trials with slightly different populations (with and without T2D). NYHA classification is somewhat subjective. 52-week follow-up may not capture durability of functional improvement. The sickest patients (NYHA IV) were underrepresented.
How to read the evidence
Rated strong: prespecified pooled analysis of two rigorous, double-blind, placebo-controlled RCTs totaling 1,145 participants, published in JACC.
When this study was published
Published in 2024. Extends the evidence from the landmark STEP-HFpEF trials by demonstrating functional class improvement.
The bigger picture
This analysis strengthens the case for semaglutide as a true heart failure therapy — not just a weight loss drug that incidentally helps the heart. The finding that the sickest patients benefit most suggests semaglutide should be considered earlier and more aggressively in obese HFpEF, particularly for patients with significant functional limitations.
Questions still open
- Does the functional improvement persist beyond 52 weeks, or does it plateau or reverse?
- Should semaglutide be preferentially prescribed for NYHA III/IV patients given their greater symptom improvement?
- How does semaglutide's functional improvement compare to traditional heart failure medications in HFpEF?
Common questions
Does semaglutide help with heart failure symptoms?
Do sicker heart failure patients benefit more from semaglutide?
Read the original research
Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program.
Journal of the American College of Cardiology, 84(3), 247-257
Citation
Schou, Morten; Petrie, Mark C; Borlaug, Barry A; Butler, Javed; Davies, Melanie J; Kitzman, Dalane W; Shah, Sanjiv J; Verma, Subodh; Patel, Shachi; Chinnakondepalli, Khaja M; Harring, Signe; Abildstrøm, Steen Z; Liisberg, Karoline; Kosiborod, Mikhail N. (2024). Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program.. Journal of the American College of Cardiology, 84(3), 247-257. https://doi.org/10.1016/j.jacc.2024.04.038