Summary: In a post-hoc, participant-level pooled analysis of four randomised trials (SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM) including 3743 patients with a history of heart failure with mildly reduced or preserved ejection fraction (HFpEF), once-weekly semaglutide was associated with a lower risk of the composite of cardiovascular death or worsening heart failure (HR 0.69; 95% CI 0.53-0.89; p=0.0045). Worsening heart failure events alone were reduced (HR 0.59; 0.41-0.82; p=0.0019), whereas cardiovascular death alone was not significantly lower (HR 0.82; 0.57-1.16; p=0.25).
PICO Summary
| Element | Detail |
|---|---|
| Population | 3743 participants with an investigator-reported history of HFpEF (mildly reduced or preserved ejection fraction), drawn from 22,282 participants across four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM); post-hoc pooled, participant-level analysis. Multinational. |
| Intervention | Once-weekly subcutaneous semaglutide (2.4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1.0 mg in FLOW); n=1914. |
| Comparison | Matching placebo injections on the same schedule; n=1829. |
| Outcome | Composite of cardiovascular death or worsening heart failure event: 103/1914 (5.4%) vs 138/1829 (7.5%); HR 0.69 (95% CI 0.53-0.89); p=0.0045; absolute risk reduction approximately 2.1 percentage points (NNT approximately 48). Worsening heart failure events: 54 (2.8%) vs 86 (4.7%); HR 0.59 (0.41-0.82); p=0.0019. Cardiovascular death alone: 59 (3.1%) vs 67 (3.7%); HR 0.82 (0.57-1.16); p=0.25 (not significant). Serious adverse events: 572 (29.9%) vs 708 (38.7%). |
Semaglutide in HFpEF: pooled analysis of four trials
Pooled RCT analysis · HFpEF · 4 trials
Once-weekly semaglutide lowered the composite of CV death or worsening heart failure in HFpEF, driven by fewer worsening-HF events; CV death alone was not significantly reduced. Hypothesis-generating, post-hoc pooled data.
Expert Commentary
The signal here is encouraging but should be read with the design firmly in mind. This is a post-hoc, participant-level pooling of four trials that were not individually designed or powered to test clinical heart failure events in HFpEF, so the findings are best treated as hypothesis-generating rather than as confirmatory proof of an outcome benefit. The composite was driven by worsening heart failure events, which were reduced, while cardiovascular death alone was not significantly affected; the headline therefore reflects a morbidity benefit more than a demonstrated mortality benefit. The principal limitation worth weighing is selection of the HFpEF subgroup by investigator-reported history rather than by a prospectively adjudicated, uniform diagnostic standard, which introduces heterogeneity across the contributing cohorts. The analysis was funded by the manufacturer (Novo Nordisk), the parent trials were open-label for injection burden in places, and effect sizes, while plausible, warrant the usual caution applied to pooled sponsor-led work. Can I use this with my patients? Reasonably yes for a defined group: the patient with obesity-related or diabetes-associated HFpEF who already has a metabolic indication for semaglutide, where symptom and event data now align. It should not yet be positioned as a standalone HFpEF event-prevention therapy on this evidence. A dedicated, prospectively powered outcomes trial in HFpEF would settle the question.
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