Summary: In a prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials (n=1,145 adults with obesity-related HFpEF), once-weekly semaglutide 2.4 mg improved New York Heart Association (NYHA) functional class over 52 weeks. More semaglutide-treated than placebo-treated patients improved (32.6% vs 21.5%; OR 2.20, 95% CI 1.62-2.99; P<0.001) and fewer deteriorated (2.09% vs 5.24%; OR 0.36, 95% CI 0.19-0.70; P=0.003).
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related HFpEF (LVEF ≥45%, BMI ≥30 kg/m², KCCQ-CSS <90); pooled data from two international, double-blind, randomised controlled trials (STEP-HFpEF and STEP-HFpEF DM); prespecified secondary analysis. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks (pooled semaglutide arm). |
| Comparison | Matching placebo for 52 weeks (pooled placebo arm). |
| Outcome | Improvement in NYHA functional class at 52 weeks: 32.6% (semaglutide) vs 21.5% (placebo); OR 2.20 (95% CI 1.62-2.99), P<0.001. Deterioration in NYHA class: 2.09% vs 5.24%; OR 0.36 (95% CI 0.19-0.70), P=0.003. KCCQ-CSS improvement was larger in NYHA class III/IV (10.5 points, 95% CI 6.6-14.4) than class II (6.0 points, 95% CI 3.4-8.6), P interaction=0.06. Bodyweight reduction was similar across baseline NYHA class (class II -8.4%; class III/IV -8.3%; P interaction=0.96). Absolute risk reduction and number needed to treat were not reported for these endpoints. |
Semaglutide and NYHA Class in Obesity-Related HFpEF
Pooled RCT analysis · obesity-related HFpEF · 52 weeks
Once-weekly semaglutide 2.4 mg more than doubled the odds of NYHA class improvement and cut the odds of deterioration roughly two-thirds versus placebo over 52 weeks in obesity-related HFpEF.
Expert Commentary
This prespecified pooled analysis of two adequately powered, double-blind randomised trials offers reasonably robust evidence that once-weekly semaglutide 2.4 mg improves NYHA functional class in obesity-related HFpEF, with roughly half again as many patients improving and substantially fewer deteriorating relative to placebo. The verdict is that the signal is real and clinically coherent, sitting alongside the parent trials’ documented gains in symptoms, physical limitation, and exercise capacity. The principal limitation is that NYHA functional class is a coarse, subjective, observer-assigned ordinal measure that is prone to misclassification and is not a hard clinical endpoint; improvement in functional class is not equivalent to a reduction in heart-failure hospitalisation or death, which these trials were not designed to capture. The analysis was funded by the manufacturer and several authors are company employees, so independent replication remains desirable. Can I use this with my patients? Yes, for the well-defined trial phenotype, namely an ambulant adult with obesity, an ejection fraction of at least 45 percent, and symptomatic heart failure, semaglutide is a reasonable option to improve functional status, provided weight-management and cardiometabolic goals are shared. It should not be extrapolated to non-obese HFpEF or to outcomes it did not measure. Clinicians should set expectations around symptom and functional benefit rather than promising mortality gains, and await event-driven trials.
References
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. 2024;84(3):247-257. doi:10.1016/j.jacc.2024.04.038