Summary: In a post-hoc pooled, participant-level analysis of 3743 patients with mildly reduced or preserved ejection fraction heart failure (HFpEF) across four randomised trials, once-weekly subcutaneous semaglutide reduced the composite of cardiovascular death or worsening heart failure events (HR 0.69, 95% CI 0.53 to 0.89, p=0.0045) and worsening heart failure events alone (HR 0.59, 95% CI 0.41 to 0.82, p=0.0019). No significant effect on cardiovascular death alone was observed (HR 0.82, 95% CI 0.57 to 1.16, p=0.25).
PICO Summary
| Element | Detail |
|---|---|
| Population | 3743 adults with an investigator-reported history of HFpEF (16.8% of 22282 participants) pooled across four multinational, double-blind, randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM); post-hoc, participant-level analysis. Cohorts spanned obesity-related HFpEF, atherosclerotic cardiovascular disease with overweight or obesity, and type 2 diabetes with chronic kidney disease. |
| Intervention | Once-weekly subcutaneous semaglutide (2.4 mg in SELECT, STEP-HFpEF, STEP-HFpEF DM; 1.0 mg in FLOW); n=1914. |
| Comparison | Matching placebo under analogous trial conditions; n=1829. |
| Outcome | Composite of cardiovascular death or first worsening heart failure event: 103/1914 (5.4%) vs 138/1829 (7.5%); HR 0.69 (95% CI 0.53 to 0.89), p=0.0045. Worsening heart failure events alone: 54 (2.8%) vs 86 (4.7%); HR 0.59 (95% CI 0.41 to 0.82), p=0.0019. Cardiovascular death alone: 59 (3.1%) vs 67 (3.7%); HR 0.82 (95% CI 0.57 to 1.16), p=0.25 (not significant). Serious adverse events: 572 (29.9%) vs 708 (38.7%). |
Semaglutide in HFpEF
Pooled analysis · 4 RCTs · HFpEF
Semaglutide cut the composite of CV death or worsening heart failure by about 31% in HFpEF, driven by fewer worsening heart failure events; CV death alone was not significantly reduced.
Expert Commentary
The verdict is cautiously favourable but should be read as hypothesis-generating rather than confirmatory. A relative reduction of roughly 31% in the composite of cardiovascular death or worsening heart failure, mirrored by a clear signal for worsening heart failure events, is clinically meaningful in a population for whom disease-modifying options remain scarce. The honest counterweight is that this was a post-hoc, pooled analysis in which HFpEF was defined by an investigator-reported history rather than by prespecified, adjudicated entry criteria, so the cohort is heterogeneous and the composite was driven by heart failure events while cardiovascular death alone was not significantly reduced. The trials were funded by the manufacturer, Novo Nordisk, and although the parent studies were placebo-controlled and double-blind, weight loss can unblind participants and influence symptom-based outcomes. Can I use this with my patients? Provisionally yes for a patient with obesity-related HFpEF and an established indication for semaglutide, in whom a lower burden of worsening heart failure is a welcome secondary benefit, but it should not yet be prescribed as a dedicated heart failure therapy on this evidence alone. A prospective, event-driven outcomes trial in HFpEF is needed to convert this promising association into a firm treatment recommendation.
References
Kosiborod MN, Deanfield J, Pratley R, et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. Lancet. 2024;404(10456):949-961. doi:10.1016/S0140-6736(24)01643-X