Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity (STEP-HFpEF)

Authors, Journal, Affiliations, Type, DOI

• 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, et al. for the STEP-HFpEF Trial Committees and Investigators
• New England Journal of Medicine 2023;389:1069-84 (published August 25, 2023)
• Affiliations: Saint Luke's Mid America Heart Institute/University of Missouri-Kansas City (lead); Novo Nordisk (sponsor); Mayo Clinic; multiple international sites
• Type: Randomized, double-blind, placebo-controlled trial; 96 sites in 13 countries
• DOI: 10.1056/NEJMoa2306963
• Funded by Novo Nordisk; ClinicalTrials.gov NCT04788511

Overview

STEP-HFpEF is the first pharmacologic trial to specifically target obesity as a therapeutic strategy in HFpEF. Among 529 patients with HFpEF (LVEF ≥45%) and obesity (BMI ≥30) without diabetes, once-weekly semaglutide 2.4mg for 52 weeks produced large improvements in HF symptoms, exercise function, and body weight compared to placebo. Both dual primary endpoints and all four confirmatory secondary endpoints were met with highly significant P values. Serious adverse events were significantly fewer with semaglutide, driven largely by fewer cardiac events, establishing semaglutide as a meaningful new therapeutic approach in this phenotype.

Keywords

Heart failure with preserved ejection fraction; obesity; semaglutide; GLP-1 receptor agonist; KCCQ; weight loss; exercise function; CRP; STEP-HFpEF

Key Takeaways

Background and Rationale

• HFpEF accounts for >50% of all HF in the United States and is increasing in prevalence; the majority of patients have overweight or obesity.
• Obesity is not simply a comorbidity in HFpEF — growing evidence suggests it actively drives disease development and progression through visceral adiposity, pericardial restraint, ventricular interdependence, systemic inflammation, and natriuretic peptide deficiency.
• Patients with obesity-HFpEF have more severe symptoms, worse functional capacity, and more impaired quality of life than non-obese HFpEF patients.
• Prior to this trial, no pharmacologic therapy specifically targeting obesity had been tested in HFpEF; lifestyle-mediated weight loss had shown benefit in small studies.
• Semaglutide 2.4mg once weekly is a potent GLP-1 receptor agonist approved for chronic weight management, with established effects on body weight and cardiometabolic risk factors.

Trial Design

• 529 patients randomized 1:1 to semaglutide 2.4mg SC once weekly vs placebo for 52 weeks; stratified by BMI (<35 vs ≥35)
• Dose escalation: 0.25mg weekly × 4 weeks → escalation every 4 weeks → target 2.4mg by week 16
• Eligibility: LVEF ≥45%; BMI ≥30; NYHA class II–IV; KCCQ-CSS <90; 6MWT ≥100m; plus ≥1 of: invasive elevated filling pressures, elevated NT-proBNP (BMI-stratified thresholds) + echo abnormalities, or HF hospitalisation within 12 months + diuretics or echo abnormalities
• Key exclusions: Diabetes (HbA1c ≥6.5% or known history); weight change >5kg within 90 days before screening
• Dual primary endpoints: Change in KCCQ-CSS and percentage change in body weight at week 52
• Confirmatory secondary endpoints: 6-minute walk distance; hierarchical composite (death + HF events + KCCQ-CSS differences + 6MWT difference); CRP level change
• Baseline characteristics: Median age 69 years; 56.1% women; 95.8% White; median weight 105.1kg; median BMI 37.0; 66% BMI ≥35; median KCCQ-CSS 58.9; median 6MWT 320m; median CRP 3.8 mg/L; 52% AF history; 15.3% hospitalised for HF in prior 12 months; only 3.6% on SGLT2 inhibitors

Dual Primary Endpoints (both met, P<0.001)

• KCCQ-CSS: Mean change +16.6 points (semaglutide) vs +8.7 points (placebo); estimated difference +7.8 points (95% CI 4.8–10.9; P<0.001)
  • For context: previous trials of SGLT2i, sacubitril-valsartan, and spironolactone in HFpEF showed only 0.5–2.3 point improvements
  • All responder analyses including ≥15-point improvements favored semaglutide (>2× the odds of large benefit)
• Body weight: Mean change −13.3% (semaglutide) vs −2.6% (placebo); estimated difference −10.7 percentage points (95% CI −11.9 to −9.4; P<0.001)

Confirmatory Secondary Endpoints (all met, P<0.001)

• 6-minute walk distance: +21.5m (semaglutide) vs +1.2m (placebo); estimated difference +20.3m (95% CI 8.6–32.1; P<0.001)
  • Greater than the improvement observed in HF-ACTION (exercise training in HFrEF) and comparable to exercise training trials in HFpEF
• Hierarchical composite (death + HF events + KCCQ + 6MWT): Stratified win ratio 1.72 (95% CI 1.37–2.15; P<0.001); the ≥15-point KCCQ-CSS difference component contributed most wins for semaglutide
• CRP: −43.5% (semaglutide) vs −7.3% (placebo); estimated treatment ratio 0.61 (95% CI 0.51–0.72; P<0.001) — suggesting significant anti-inflammatory effect

Exploratory and Supportive Findings

• HF hospitalizations or urgent visits: 1 (semaglutide) vs 12 (placebo); HR 0.08 (95% CI 0.00–0.42) — exploratory, not powered
• NT-proBNP: Greater reduction with semaglutide despite significant weight loss (counterintuitive given obesity-natriuretic peptide deficiency association); geometric mean ratio 0.78 vs 0.95 — suggests genuine hemodynamic benefit beyond weight loss
• Systolic blood pressure: Larger reduction in semaglutide group
• Atrial fibrillation/flutter events: Lower in semaglutide group (included in the lower serious adverse event count)

Safety

• Serious adverse events: 13.3% (semaglutide) vs 26.7% (placebo); P<0.001 — approximately half the rate
  • Difference primarily from lower cardiac disorder events: 2.7% vs 11.3% (P<0.001)
• Discontinuation due to any adverse event: 35 semaglutide vs 14 placebo — predominantly gastrointestinal (expected with GLP-1 RA)
• Discontinuation due to serious adverse events: 6 vs 6 — equal
• Deaths: 3 (semaglutide) vs 4 (placebo) — not powered to assess mortality

Mechanisms of Benefit

• Weight loss with reduction in visceral adipose tissue is likely an important contributor
• Hemodynamic effects suggested by NT-proBNP reduction despite weight loss (obesity reduces natriuretic peptide production — expected rise with weight loss was replaced by a fall)
• Anti-inflammatory effects demonstrated by CRP reduction
• Lower AF/flutter events suggest improved atrial hemodynamics and inflammation
• The authors conclude that benefits likely reflect both weight loss-mediated and direct drug-mediated mechanisms; the pathophysiology of obesity-HFpEF syndrome improved simultaneously with weight loss

Limitations of the Document

• Low non-White enrollment: Only 23.2% Black in US participants (in line with national HFpEF demographics, but limits generalizability to other populations)
• Underpowered for clinical events: Not designed to assess HF hospitalizations, CV death, or all-cause death as primary endpoints
• One-year follow-up only: Durability beyond 52 weeks unknown; however, no plateau effect observed at trial end suggests ongoing benefit potential
• No HbA1c data during follow-up: Excluded patients with diabetes; cannot assess whether glycemic changes contributed to benefit (though unlikely given baseline exclusions)
• Low SGLT2i use (3.6%): Reflects trial period and diabetes exclusion; separate ongoing STEP-HFpEF DM trial includes patients with T2DM and ≥32% SGLT2i use
• Sponsor involvement: Novo Nordisk funded; first draft by first author; sponsor responsible for data collection and analysis — potential for bias in a positive trial, though sponsor-independent validation of dual primary endpoints performed

Key Concepts Mentioned

• entities/HFpEF — primary disease target; obesity-HFpEF as distinct phenotype
• concepts/Obesity-Paradox — STEP-HFpEF directly contradicts the obesity paradox concept by demonstrating that intentional pharmacologic weight loss benefits HFpEF patients
• concepts/Visceral-Adiposity — visceral fat reduction proposed as key mechanism of semaglutide benefit in HFpEF

Key Entities Mentioned

• entities/Semaglutide — GLP-1 receptor agonist; 2.4mg SC weekly; primary intervention
• entities/Obesity — defining comorbidity; BMI ≥30 enrollment criterion
• entities/Kansas-City-Cardiomyopathy-Questionnaire — primary outcome instrument

Wiki Pages Updated

• Created: wiki/sources/semaglutide-stephfpef-nejm-2023.md
• Created: wiki/entities/Semaglutide.md
• Updated: wiki/entities/HFpEF.md
• Updated: wiki/concepts/Obesity-Paradox.md
• Updated: wiki/concepts/Visceral-Adiposity.md
• Updated: wiki/sourceindex.md
• Updated: wiki/wikiindex.md