PMID-39222642 — Kosiborod 4-Trial Pooled Analysis: Semaglutide in HFpEF/HFmrEF (Lancet 2024)

[DRAFT — authored 2026-04-19. Citation verified against PubMed/Lancet 2026-04-19.]

Citation

Kosiborod MN, Deanfield J, Pratley R, Borlaug BA, Butler J, Davies MJ, Emerson SS, Kahn SE, Kitzman DW, Lingvay I, Mahaffey KW, Patel MR, Petrie MC, Plutzky J, Rasmussen S, Ryan DH, Sattar N, Shah SJ, Verma S, Weeke PE, Lincoff AM; SELECT Trial Committees and Investigators. 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. PMID: 39222642.

External URL: PubMed

Study Design

• Design: Pooled individual-participant analysis of four large semaglutide randomized trials
• Trials: SELECT (CV outcomes in obesity without DM) + FLOW (CKD in T2D) + STEP-HFpEF + STEP-HFpEF DM
• Population: 3,743 participants with HF (HFpEF or HFmrEF, LVEF ≥40%)
  • Semaglutide group: 1,914
  • Placebo group: 1,829
• Primary outcomes: Composite of CV death or worsening HF events; individual components

Key Findings

• Combined CV death or worsening HF events: 103 (5.4%) semaglutide vs 138 (7.5%) placebo; HR 0.69 (95% CI 0.53-0.89), P=0.0045
• Worsening HF events alone: 54 (2.8%) sem vs 86 (4.7%) placebo; HR 0.59 (95% CI 0.41-0.82), P=0.0019
• Cardiovascular death alone: HR 0.82 (95% CI 0.57-1.16), P=0.25 (not significant — underpowered)
• Serious adverse events: 29.9% sem vs 38.7% placebo
• Consistency: Benefits preserved across demographic subgroups (age, sex, baseline BMI, baseline LVEF, baseline HF etiology)

Clinical Relevance

This pooled analysis is the largest and highest-quality evidence synthesis for semaglutide in HFpEF/HFmrEF. Core teaching points:

1. HR 0.69 for composite CV death or worsening HF — a clinically meaningful 31% relative risk reduction across 3,743 participants.
2. Worsening HF events reduced by 41% — a clean, direction-consistent safety-plus-efficacy signal.
3. Guideline-level evidence — this pooled analysis underpins the 2025-2026 ADA, AACE, and EASO recommendations for semaglutide in HFpEF + obesity.
4. Parallel findings in other metabolic phenotypes — SELECT established CV benefit in obesity + ASCVD without DM; FLOW established kidney benefit in T2D + CKD; now this pool extends to HF across both DM and non-DM populations.

Linked Peptides

• Semaglutide

Related Lessons

• Lesson 5.2 — Semaglutide Deep Dive (comprehensive HF evidence base)
• Lesson 5.4 — Class-level HF evidence across the GLP-1 class

Related Studies

• PMID-37622681 – STEP-HFpEF Kosiborod Semaglutide HFpEF Obesity
• PMID-38587233 – STEP-HFpEF DM Kosiborod Semaglutide HFpEF T2D
• PMID-38599221 – Butler Pooled STEP-HFpEF Lancet 2024
• PMID-37952131 – SELECT Cardiovascular Outcomes Trial (SELECT source)
• PMID-38785209 – FLOW Semaglutide Kidney Outcomes CKD T2DM (FLOW source)

Tags

#research #pooled-analysis #phase-3 #semaglutide #heart-failure #hfpef #hfmref #select #flow #step-hfpef