STEP-HFpEF: Semaglutide for Heart Failure With Preserved Ejection Fraction
Heart failure with preserved ejection fraction (HFpEF) is one of the most common and least treatable forms of heart failure. It disproportionately affects people with obesity, and for decades, no therapy has convincingly improved symptoms and function. STEP-HFpEF changed that.1
The trial randomized 529 participants with HFpEF, LVEF ≥45%, and BMI ≥30 to once-weekly semaglutide 2.4mg or placebo for 52 weeks. Published in the New England Journal of Medicine in August 2023, it demonstrated that semaglutide produced larger reductions in heart failure symptoms, greater improvements in exercise function, and meaningful weight loss compared to placebo.1,2
Dual Primary Endpoints
| Endpoint | Semaglutide | Placebo | Difference |
|---|---|---|---|
| KCCQ-CSS change (symptoms) | 16.6-point improvement | 8.7-point improvement | 7.8 points (P<0.001) |
| Body weight change | −13.3% | −1.8% | −11.5 percentage points (P<0.001) |
| 6-minute walk distance | Improved by 21.5m | Improved by 1.2m | +20.3m (P<0.001) |
| CRP reduction | −43.5% | −7.3% | Significant (P<0.001) |
Why KCCQ-CSS Matters
The Kansas City Cardiomyopathy Questionnaire (KCCQ) measures heart-failure-specific symptoms, physical limitations, and quality of life. A 5-point change is considered clinically meaningful. Semaglutide produced a 7.8-point improvement over placebo — a clearly meaningful benefit in a disease with few effective treatments.3
The improvement was consistent across age groups. A pre-specified pooled analysis of STEP-HFpEF and STEP-HFpEF DM (which included patients with diabetes) showed benefits in patients under 55, 55–64, 65–74, and 75+, with no treatment effect heterogeneity by age (P-interaction = 0.80 for KCCQ-CSS).5
The Diuretic Effect
A pooled analysis of 1,145 participants from both STEP-HFpEF trials revealed an unexpected finding: semaglutide reduced the need for loop diuretics. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group versus a 2.4% increase in the placebo group (P<0.0001). Patients on semaglutide were 2.67 times more likely to have their diuretic dose reduced and 0.35 times as likely to have it increased.4
This suggests semaglutide may reduce cardiac preload and fluid retention through weight loss and metabolic improvement — not just through appetite suppression but through genuine hemodynamic effects.
Clinical Implications
HFpEF accounts for roughly half of all heart failure cases and has been called the 'unmet need' of cardiology. SGLT2 inhibitors (empagliflozin) showed modest benefit. Semaglutide's effect on symptoms and function is larger and more clinically apparent. Whether this translates to reduced hospitalizations and mortality requires a dedicated outcomes trial — but the symptom improvement alone represents a meaningful clinical advance for millions of patients.
SOURCES
- Kosiborod MN, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. NEJM. 2023;389:1069-1084. DOI: 10.1056/NEJMoa2306963.
- ClinicalTrials.gov. NCT04788511 — STEP-HFpEF.
- Kosiborod MN, et al. Effects of semaglutide on symptoms, function, and quality of life. Circulation. 2024.
- Pandey A, et al. Semaglutide and diuretic use in HFpEF: pooled analysis. European Heart Journal. 2024.
- Borlaug BA, et al. Effects across the age spectrum: STEP-HFpEF programme. ESC Heart Failure. 2025.