STEP-HFpEF trial deep-dive: semaglutide 2.4 mg in HFpEF + obesity (Kosiborod 2023 NEJM)
Last verified 2026-05-28 · Phase 3 · Completed (results published Sep 2023) · NCT04788511 ↗
STEP-HFpEF (NCT04788511) is the pivotal phase-3 trial that established semaglutide 2.4 mg as a disease-modifying therapy for heart failure with preserved ejection fraction (HFpEF) in adults with obesity. Novo Nordisk randomized 529 participants with HFpEF (left ventricular ejection fraction ≥45%), a body-mass index of at least 30, and New York Heart Association class II-IV symptoms 1:1 to once-weekly subcutaneous semaglutide 2.4 mg or matching placebo for 52 weeks. Type 2 diabetes was excluded; the sister trial STEP-HFpEF DM later replicated the analysis in HFpEF participants with diabetes. Results published by Kosiborod and colleagues in the New England Journal of Medicine on August 25, 2023 and presented at the European Society of Cardiology Congress showed that both co-primary endpoints — KCCQ-CSS change and body-weight change — favored semaglutide with margins large enough to clear every multiplicity-adjusted secondary endpoint as well.
- Enrollment
- 529
- Duration
- 52 weeks of treatment plus a 5-week off-drug follow-up period
- Drug
- Semaglutide 2.4 mg (Wegovy)
- Population
- Adults aged 18 or older with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%), New York Heart Association functional class II-IV symptoms, a body-mass index of 30 kg/m² or higher, a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score below 90 (substantial symptom burden), and a 6-minute walk distance of at least 100 meters. Type 2 diabetes was an exclusion. Median baseline body weight 105.1 kg, median BMI 37.0 kg/m², 56% female, median age 69, median NT-proBNP 451 pg/mL. Background therapy reflected real-world HFpEF practice, with diuretics in roughly 80% and SGLT2 inhibitors in fewer than 5% at enrollment.
Primary endpoint
Change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks (coprimary)
Treatment arm
+16.6 points
Comparator
+8.7 points
Treatment difference: Estimated treatment difference +7.8 points (95% CI 4.8 to 10.9; P<0.001)
Magnitude roughly twice the conventional 5-point threshold for a clinically meaningful within-patient KCCQ improvement; the largest KCCQ effect ever reported in a randomized HFpEF pharmacotherapy trial at the time of publication.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Percentage change in body weight at 52 weeks (coprimary) Weight loss magnitude consistent with semaglutide 2.4 mg in non-HFpEF obesity trials such as STEP-1, despite older, sicker, more diuretic-treated population. | −13.3% | −2.6% | Estimated treatment difference −10.7 percentage points (95% CI −11.9 to −9.4; P<0.001) |
| Change in 6-minute walk distance at 52 weeks (confirmatory secondary) Objective exercise-capacity gain that complements the patient-reported KCCQ improvement; magnitude comparable to cardiac-rehabilitation effect sizes. | +21.5 meters | +1.2 meters | Estimated treatment difference +20.3 meters (95% CI 8.6 to 32.1; P<0.001) |
| Hierarchical composite endpoint at 52 weeks (death, heart-failure events, KCCQ ≥15-point change, 6MWD ≥30-meter change) Hierarchical analysis ranks clinical events above symptom and function outcomes; the result indicates wins were driven primarily by KCCQ and 6MWD changes rather than mortality. | Win ratio 1.72 favoring semaglutide | Reference | Win ratio 1.72 (95% CI 1.37 to 2.15; P<0.001) |
| Change in C-reactive protein (hs-CRP) at 52 weeks (confirmatory secondary) A 39% relative reduction in systemic inflammation, supporting the hypothesis that obesity-driven inflammation contributes to HFpEF pathophysiology. | Ratio to baseline 0.57 | Ratio to baseline 0.92 | Estimated treatment ratio 0.61 (95% CI 0.51 to 0.72; P<0.001) |
| KCCQ-CSS responder analysis (≥5-point improvement at 52 weeks) Threshold corresponds to the conventional within-patient clinically important difference for KCCQ. | 76.7% | 61.4% | Odds ratio favored semaglutide; nominal P<0.001 per the publication |
| Body-weight reduction ≥10% at 52 weeks | 63.2% | 8.0% | Odds ratio favored semaglutide; nominal P<0.001 per the publication |
| NYHA functional class improvement at 52 weeks Roughly two of every five semaglutide participants moved up a functional class, generally from NYHA III to II or II to I. | Class improvement in 41.8% of participants | Class improvement in 27.6% of participants | Odds ratio 2.17 (95% CI 1.50 to 3.16); nominal P<0.001 |
| Change in NT-proBNP at 52 weeks (exploratory) Modest reduction; smaller in absolute terms than SGLT2-inhibitor HFpEF trials, consistent with a non-diuretic mechanism. | Ratio to baseline 0.85 | Ratio to baseline 1.01 | Estimated treatment ratio 0.84 (95% CI 0.74 to 0.95); nominal P=0.006 per the publication |
| Change in systolic blood pressure at 52 weeks | −3.0 mmHg | +0.2 mmHg | Estimated treatment difference −3.2 mmHg (95% CI −5.5 to −1.0) |
| Change in body-mass index at 52 weeks (kg/m²) | −4.7 kg/m² | −0.9 kg/m² | Estimated treatment difference −3.8 kg/m² (95% CI −4.2 to −3.3) |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Any serious adverse event Serious AEs were lower on semaglutide, driven largely by fewer cardiac-disorder serious events. | 13.3% (35/263) | 26.7% (71/266) |
| Adverse events leading to discontinuation Higher with semaglutide, predominantly because of gastrointestinal events during dose-escalation. | 13.3% (35/263) | 5.3% (14/266) |
| Gastrointestinal disorders (any) Pattern and time course mirror STEP-1; most events were mild to moderate and clustered during the 16-week escalation. | Higher with semaglutide; nausea and diarrhea were the most common individual events | Lower |
| Cardiac-disorder serious adverse events Sharp reduction in cardiac SAEs on semaglutide; the publication highlights this as a hypothesis-generating signal that requires confirmation in event-driven trials. | 2.7% (7/263) | 10.9% (29/266) |
| Adverse events leading to permanent treatment discontinuation due to GI events Consistent with the GI-tolerability profile from the broader STEP program. | Reported as the leading category of discontinuations | Lower |
Clinical significance
STEP-HFpEF was the first trial to establish a GLP-1 receptor agonist as a disease-modifying therapy in heart failure with preserved ejection fraction, a syndrome where almost no pharmacologic class had previously delivered a positive primary endpoint on patient-reported symptoms. The +7.8-point placebo-adjusted KCCQ-CSS improvement is roughly twice the conventional clinically meaningful threshold and exceeds the symptom effect of SGLT2 inhibitors reported in EMPEROR-Preserved and DELIVER. Combined with a 20.3-meter 6-minute-walk-distance gain, a 39% relative reduction in hs-CRP, and a 10.7-percentage-point weight-loss advantage, the trial reframed obesity-phenotype HFpEF as a cardiometabolic disease responsive to weight-loss biology. The findings, together with the STEP-HFpEF DM follow-up in patients with diabetes, supported the Wegovy heart-failure indication expansion for HFpEF with obesity.
Frequently Asked Questions
References
- 1.Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al.; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023. PMID: 37622681.
- 2.U.S. National Library of Medicine. Research Study on How Well Semaglutide Works in People Living With Heart Failure and Obesity (STEP-HFpEF) — Study Results. ClinicalTrials.gov, NCT04788511. 2023. https://clinicaltrials.gov/study/NCT04788511
- 3.Kosiborod MN, Petrie MC, Borlaug BA, et al.; STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes. N Engl J Med. 2024. PMID: 38587233.
- 4.Butler J, Shah SJ, Petrie MC, et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet. 2024. PMID: 38599221.
- 5.Novo Nordisk Inc. WEGOVY (semaglutide) injection — Prescribing Information. DailyMed (NIH/NLM). 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee06186f-2aa3-4990-a760-757579d8f77b
- 6.Packer M, Zile MR, Kramer CM, et al.; SUMMIT Trial Study Group. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025. PMID: 39555826.