Summary: In a prespecified pooled analysis of 1,145 patients with obesity-related HFpEF across the two STEP-HFpEF trials, more patients given once-weekly semaglutide 2.4 mg than placebo improved by NYHA functional class at 52 weeks (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). Benefits across symptoms, function, and weight were consistent regardless of baseline NYHA class.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related heart failure with preserved ejection fraction; prespecified pooled analysis of two international, double-blind randomised trials (STEP-HFpEF and STEP-HFpEF DM). |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks. |
| Comparison | Matching placebo for 52 weeks. |
| 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, most in classes III/IV (10.5 points, 95% CI 6.6-14.4) vs class II (6.0 points, 95% CI 3.4-8.6; P interaction=0.06). Bodyweight reduction was similar by class (class II -8.4%, 95% CI -9.4 to -7.3; classes III/IV -8.3%, 95% CI -9.9 to -6.8; P interaction=0.96). Gains in 6-minute walk distance, the hierarchical composite, C-reactive protein, and NT-proBNP were consistent across classes. |
Semaglutide and NYHA class in obesity-related HFpEF
STEP-HFpEF pooled RCT analysis · type 2 diabetes & non-diabetes · 52 weeks
Once-weekly semaglutide 2.4 mg roughly doubled the odds of NYHA improvement and cut the odds of deterioration, with consistent symptom, function, and weight benefits across baseline NYHA classes.
Expert Commentary
This prespecified pooled analysis of the STEP-HFpEF program strengthens, but does not by itself establish, the case for semaglutide in obesity-related HFpEF. Because NYHA functional class change was a prespecified analysis outcome rather than a confirmatory primary endpoint, the verdict is best read as supportive and internally consistent: a roughly doubled odds of NYHA improvement and a markedly lower odds of deterioration align with the program’s established gains in symptoms, walking distance, and weight, with benefit seen across all baseline NYHA categories. The principal limitation is that NYHA class is a coarse, clinician-assigned ordinal measure prone to subjective drift, so its movement should be interpreted alongside the more granular KCCQ and 6-minute walk data rather than in isolation. The trials were industry-funded, with several authors employed by the manufacturer, which warrants the usual caution, although the double-blind randomised design and the consistency of effects across endpoints temper that concern. Can I use this with my patients? Yes, for the well-defined population studied here, namely adults with obesity-related HFpEF and meaningful symptom burden, for whom semaglutide is a reasonable symptom-directed option. Dedicated hard-outcome trials remain the priority, and clinicians should set expectations around symptom and functional gains rather than proven mortality benefit.
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