Summary: In a prespecified pooled analysis of the two double-blind STEP-HFpEF program trials (n=1,145), once-weekly semaglutide 2.4 mg was associated with a higher proportion of patients improving in NYHA functional class at 52 weeks than placebo (32.6% vs 21.5%; OR 2.20, 95% CI 1.62-2.99; P<0.001) and fewer deteriorating (2.09% vs 5.24%; OR 0.36, 95% CI 0.19-0.70; P=0.003) in obesity-related heart failure with preserved ejection fraction.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 participants with obesity-related HFpEF (LVEF >=45%, BMI >=30) pooled from two international, double-blind randomised trials (STEP-HFpEF and STEP-HFpEF DM); multinational. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks (pooled active arm of both trials). |
| Comparison | Matching placebo for 52 weeks (pooled placebo arm), with outcomes analysed across baseline NYHA functional class categories. |
| Outcome | Improvement in NYHA functional class at 52 weeks: 32.6% vs 21.5% (OR 2.20, 95% CI 1.62-2.99; P<0.001). Deterioration: 2.09% vs 5.24% (OR 0.36, 95% CI 0.19-0.70; P=0.003). KCCQ-CCS improved across classes, numerically larger in NYHA III/IV (+10.5 points, 95% CI 6.6-14.4) than NYHA II (+6.0 points, 95% CI 3.4-8.6), interaction P=0.06 (not significant). Weight reduction was similar by class (about -8.4% vs -8.3%; interaction P=0.96). ARR/NNT not reported. |
STEP-HFpEF: Semaglutide and NYHA Class
Pooled RCT analysis · obesity-related HFpEF · 52 weeks
More patients on semaglutide 2.4 mg improved an NYHA class and fewer worsened versus placebo. The benefit is symptomatic and functional; hard outcomes such as hospitalisation and mortality were not tested.
Expert Commentary
This prespecified pooled analysis of the STEP-HFpEF program is best read as a functional-status companion to the two parent randomised trials rather than as standalone proof of a hard-outcome benefit. The signal is internally consistent: more semaglutide-treated patients moved up an NYHA class and fewer moved down, alongside gains in the KCCQ-CCS, six-minute walk distance, and reductions in C-reactive protein and NT-proBNP across baseline classes. The headline numbers are credible because they sit on top of two adequately powered double-blind trials, and the direction of effect aligns with the established weight and symptom benefits of high-dose semaglutide. The chief caveat is that NYHA functional class is a coarse, subjective ordinal measure prone to assessor variability, and the apparently larger benefit in NYHA III/IV came with an interaction P value of 0.06, which is not statistically significant and should be treated as hypothesis-generating, not as confirmed effect modification. The analysis is also a secondary look at a manufacturer-sponsored programme, with Novo Nordisk authors involved, so independent replication of the functional-class endpoint is welcome. Can I use this with my patients? Yes, for a patient with obesity-related HFpEF and limiting symptoms, this strengthens the case that semaglutide 2.4 mg can improve how they feel and function, though it does not yet establish reductions in hospitalisation or mortality. Clinicians should frame the benefit as symptomatic and functional and continue to track hard endpoints.
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