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 0.74-0.91; P=0.0002). Health-status improvement was larger in patients with higher baseline NT-proBNP, while weight loss was similar across NT-proBNP levels.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related heart failure with preserved ejection fraction (LVEF ≥45%, BMI ≥30 kg/m², KCCQ-CSS <90); prespecified secondary analysis of two pooled double-blind, placebo-controlled, multicentre randomised trials (STEP-HFpEF and STEP-HFpEF DM). |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks. |
| Comparison | Matching placebo once weekly for 52 weeks (1:1 randomisation across the pooled programme). |
| Outcome | NT-proBNP fell with semaglutide versus placebo at 52 weeks (estimated treatment ratio 0.82; 95% CI 0.74-0.91; P=0.0002). KCCQ health-status gains were greater with higher baseline NT-proBNP (tertile 1 +4.5 points, 95% CI 0.8-8.2; tertile 2 +6.2, 95% CI 2.4-10.0; tertile 3 +11.9, 95% CI 8.1-15.7; P interaction=0.02). Weight loss was consistent across NT-proBNP levels (P interaction=0.21). No event-driven endpoint (death or heart-failure hospitalisation) was tested; absolute risk reduction and NNT are not applicable. |
Semaglutide and NT-proBNP in obesity-related HFpEF
RCT secondary analysis · obesity HFpEF · 52 weeks
Once-weekly semaglutide 2.4 mg lowered NT-proBNP by about 18% versus placebo at 52 weeks, with larger symptom gains in patients starting at higher NT-proBNP. The signal is hypothesis-generating; no hard event endpoint was tested.
Expert Commentary
This analysis adds mechanistic texture to the STEP-HFpEF programme by showing that semaglutide lowers NT-proBNP, a marker of cardiac wall stress, by roughly 18 percent relative to placebo. The finding suggests that the symptomatic benefit observed in the parent trials is not driven by weight loss alone, since reductions in this biomarker accompanied larger health-status gains in patients who started with higher NT-proBNP. The verdict is that the biological signal is supportive but should be read as hypothesis-generating rather than definitive, because this is a prespecified secondary, exploratory analysis of pooled data and NT-proBNP was an exploratory endpoint, not a hard clinical outcome. The chief limitation is that the programme was not powered or designed to test event-driven endpoints such as heart-failure hospitalisation or death, so a biomarker change cannot be equated with prognostic benefit. Manufacturer involvement also warrants caution, as the sponsor employed several co-authors and the data are from a single drug developer. Can I use this with my patients? For a patient with obesity-related HFpEF already considered for semaglutide on symptom grounds, these data reinforce that choice and hint at a cardiac mechanism, but they do not yet justify prescribing semaglutide specifically to lower NT-proBNP. Dedicated outcome trials should now confirm whether this biomarker shift translates into fewer 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