Summary: In a prespecified secondary analysis of the pooled STEP-HFpEF and STEP-HFpEF DM trials (n=1,145), once-weekly semaglutide 2.4 mg reduced NT-proBNP at 52 weeks versus placebo (estimated treatment ratio 0.82; 95% CI 0.74 to 0.91; P=0.0002). Improvements in health status were largest in participants with the highest baseline NT-proBNP, while weight loss was consistent across NT-proBNP levels.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related HFpEF (LVEF 45% or higher, BMI 30 kg/m2 or higher, KCCQ-CSS below 90); pooled, prespecified secondary analysis of two double-blind, placebo-controlled, randomised trials (STEP-HFpEF and STEP-HFpEF DM), international/multicentre. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks. |
| Comparison | Matching placebo for 52 weeks (1:1 randomisation across the pooled programme). |
| Outcome | NT-proBNP at 52 weeks reduced with semaglutide: estimated treatment ratio 0.82 (95% CI 0.74 to 0.91; P=0.0002). KCCQ-CSS improvement was greater with higher baseline NT-proBNP (tertile 1: +4.5 points, 95% CI 0.8 to 8.2; tertile 2: +6.2, 95% CI 2.4 to 10.0; tertile 3: +11.9, 95% CI 8.1 to 15.7; P interaction=0.02). Weight loss was consistent across baseline NT-proBNP (P interaction=0.21). NT-proBNP was an exploratory endpoint; the tertile findings are associational. No NNT/ARR reported for this surrogate analysis. |
Semaglutide and NT-proBNP in obesity-related HFpEF
Pooled RCT secondary analysis · HFpEF · 52 weeks
Once-weekly semaglutide 2.4 mg lowered NT-proBNP by 18% versus placebo at 52 weeks in obesity-related HFpEF, with the largest symptom gains in patients with the highest baseline natriuretic peptides. NT-proBNP was an exploratory surrogate endpoint, so this is hypothesis-supporting rather than an outcome trial.
Expert Commentary
This prespecified secondary analysis adds mechanistic weight to the STEP-HFpEF programme: the 18% relative reduction in NT-proBNP suggests that the symptomatic gains seen with semaglutide in obesity-related HFpEF are not explained by mechanical unloading from weight loss alone, since weight loss was similar across NT-proBNP strata yet symptom benefit tracked with higher baseline NT-proBNP. The verdict is that semaglutide plausibly modifies heart-failure pathobiology in this phenotype, though the conclusion should be read as hypothesis-supporting rather than definitive. The principal limitation is that NT-proBNP was an exploratory, surrogate endpoint and the tertile interaction is associational, not a randomised comparison of hard outcomes; reductions in a biomarker do not guarantee fewer hospitalisations or deaths. The trials were sponsored by the manufacturer (Novo Nordisk) and several authors are company employees, which warrants the usual caution even within a rigorously randomised, double-blind design. Can I use this with my patients? Yes, for a patient with obesity-related HFpEF and elevated natriuretic peptides who is being considered for semaglutide on the basis of the parent trials, this analysis is reassuring that the benefit is biologically coherent; it does not by itself create a new indication. Future event-driven trials should confirm whether biomarker improvement translates into reduced heart-failure events.
References
Petrie MC, Borlaug BA, Butler J, et al. Semaglutide and NT-proBNP in obesity-related HFpEF: insights from the STEP-HFpEF program. J Am Coll Cardiol. 2024;84(1):27-40. doi:10.1016/j.jacc.2024.04.022