Summary: In a pre-specified pooled analysis of the STEP-HFpEF and STEP-HFpEF-DM randomised trials (n = 1145), once-weekly semaglutide 2.4 mg improved heart failure symptoms and body weight versus placebo across all baseline diuretic strata over 52 weeks. Loop diuretic dose fell by 17% with semaglutide versus a 2.4% rise with placebo (P < .0001), and symptom benefit was most pronounced in patients already on loop diuretics.
PICO Summary
| Element | Detail |
|---|---|
| Population | n = 1145 adults with obesity-related HFpEF (BMI ≥ 30 kg/m²); pre-specified pooled, double-blind, multicentre analysis of two randomised trials (STEP-HFpEF and STEP-HFpEF-DM); international sites. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks, stratified by baseline diuretic use (no diuretic, non-loop only, and loop diuretic at <40, 40, and >40 mg/day furosemide equivalents). |
| Comparison | Matched placebo for 52 weeks on top of standard care, within the same diuretic strata. |
| Outcome | Weight: adjusted mean difference vs placebo ranged from −8.8% (95% CI −10.3, −6.3) to −6.9% (95% CI −9.1, −4.7) across strata; interaction P = .39. KCCQ clinical summary score: greater gain in patients on loop diuretics, +9.3 (95% CI 6.5, 12.1) vs +4.7 (95% CI 1.3, 8.2) in those not on loop diuretics; P = .042. Secondary endpoints including 6-minute walk distance consistent across strata (interaction P = .24–.92). Loop diuretic dose: −17% with semaglutide vs +2.4% with placebo (P < .0001); OR for dose reduction 2.67 (95% CI 1.70, 4.18) and for dose increase 0.35 (95% CI 0.23, 0.53). Safety favoured semaglutide across strata. No ARR/NNT reported. |
Semaglutide and diuretic use in obesity-related HFpEF
Pooled RCT analysis · obesity-related HFpEF · 52 weeks
Over 52 weeks, semaglutide cut loop diuretic dose (17% fall vs 2.4% rise) and reduced weight uniformly across diuretic strata, with the largest symptom gain in patients already on loop diuretics.
Expert Commentary
This pre-specified pooled analysis strengthens the case that semaglutide acts as more than a weight-loss agent in obesity-related HFpEF. Weight reduction was uniform across diuretic strata, while symptom improvement was actually larger in patients already on loop diuretics, and loop diuretic requirements fell rather than rose. The findings are internally consistent and the figures here were independently cross-checked against the published report. The central caveat is interpretive: this is a secondary subgroup analysis of two trials pooled together, so the diuretic strata are observational rather than randomised comparisons, and the symptom interaction (P = .042) should be read as hypothesis-generating, not as proof that loop diuretic users derive uniquely greater benefit. The trials were industry-funded with manufacturer co-authors, which warrants the usual scrutiny, though the double-blind randomised design and consistent direction of effect temper that concern. Can I use this with my patients? Reasonably yes, for the symptomatic patient with obesity-related HFpEF on a loop diuretic in whom semaglutide is already being considered; it offers a plausible signal that diuretic burden may ease rather than worsen. It does not establish hard-outcome (mortality or hospitalisation) benefit. Clinicians should monitor volume status and diuretic dose actively as weight falls, and look for dedicated outcome trials to confirm these symptom and deprescribing signals.
References
Shah SJ, Sharma K, Borlaug BA, Butler J, Davies M, Kitzman DW, et al. Semaglutide and diuretic use in obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF-DM trials. Eur Heart J. 2024;45(35):3254–3269. doi:10.1093/eurheartj/ehae322