PMID-37622681 — STEP-HFpEF: Semaglutide in HFpEF + Obesity (no T2D)

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

Citation

Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, Hovingh GK, Kitzman DW, Lindegaard ML, Møller DV, Shah SJ, Treppendahl MB, Verma S, Abhayaratna W, Ahmed FZ, Chopra V, Ezekowitz J, Fu M, Ito H, Lelonek M, Melenovský V, Merkely B, Núñez J, Perna E, Schou M, Senni M, Sharma K, Van der Meer P, von Lewinski D, Wolf D, Petrie MC; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069-1084. doi: 10.1056/NEJMoa2306963. PMID: 37622681.

External URL: PubMed

Study Design

Design: Double-blind, randomized, placebo-controlled, multicenter Phase 3
Population: Adults with HFpEF (LVEF ≥45%) + obesity (BMI ≥30), without type 2 diabetes
N: 529 participants
Intervention: Semaglutide 2.4 mg weekly SC vs matching placebo; 52 weeks
Dual primary endpoints: (1) Change in Kansas City Cardiomyopathy Questionnaire — Clinical Summary Score (KCCQ-CSS); (2) Change in body weight from baseline to week 52

Key Findings

KCCQ-CSS change: Semaglutide +16.6 vs placebo +8.7 (estimated treatment difference +7.8 points, 95% CI 4.8-10.9, P<0.001)
Body weight change: Semaglutide −13.3% vs placebo −2.6% (estimated treatment difference −10.7 pp, 95% CI −11.9 to −9.4, P<0.001)
6-minute walk distance: Significant improvement with semaglutide (+21.5 m treatment difference)
C-reactive protein: Larger reduction with semaglutide (~44% reduction)
NT-proBNP: Significant reduction with semaglutide
Serious adverse events: Fewer with semaglutide (primarily reduced cardiac events)

Clinical Relevance

STEP-HFpEF is the landmark Phase 3 trial establishing that weight-loss pharmacotherapy (semaglutide 2.4 mg) improves HF-specific symptoms, physical function, and quality of life in patients with obesity-related HFpEF without T2D. Core points:

HFpEF is a disease of metabolic dysfunction + obesity — the trial demonstrates this mechanistically (weight, CRP, 6MWD all improve together).
KCCQ-CSS gain of 7.8 points exceeds the clinically meaningful difference threshold of ~5 points.
Positions semaglutide 2.4 mg as disease-modifying in the obesity-HFpEF phenotype, beyond glycemic or weight-only effects.

Linked Peptides

Semaglutide

Related Lessons

Lesson 5.2 — Semaglutide Deep Dive (HFpEF subsection)
Lesson 5.4 — HF evidence for class

PMID-37622681 – STEP-HFpEF Kosiborod Semaglutide HFpEF Obesity