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
How does STEP-HFpEF compare to SUMMIT, the tirzepatide HFpEF trial?
STEP-HFpEF (semaglutide 2.4 mg, 529 participants, 52 weeks) and SUMMIT (tirzepatide titrated up to 15 mg, 731 participants, median 104 weeks of follow-up, NEJM 2025, PMID 39555826) are the two pivotal HFpEF-with-obesity trials and they used overlapping but not identical primary-endpoint structures. STEP-HFpEF reported a +7.8-point placebo-adjusted KCCQ-CSS improvement and a −10.7-percentage-point weight-loss difference. SUMMIT used a hierarchical composite of cardiovascular death plus worsening heart-failure events as one primary endpoint (positive — hazard ratio 0.62) and KCCQ-CSS change at one year as the other (positive — placebo-adjusted +6.9 points), and tirzepatide produced roughly 16% mean weight loss versus 2% on placebo. The trials are complementary rather than head-to-head: STEP-HFpEF established proof of concept on symptoms and function with a GLP-1 mono-agonist, and SUMMIT extended the framework to a GIP/GLP-1 dual agonist while adding event-based outcomes.
Does Wegovy work for HFpEF without obesity?
STEP-HFpEF enrolled only adults with a body-mass index of at least 30 kg/m², so the published efficacy and safety estimates do not generalize to HFpEF without obesity. The biological rationale for semaglutide in HFpEF rests heavily on the obesity-driven inflammation, plasma-volume expansion, and pericardial-fat-related ventricular constraint that characterize the obesity HFpEF phenotype, so investigators have explicitly framed STEP-HFpEF as a trial of the obesity-HFpEF phenotype rather than HFpEF in general. There is no randomized evidence that semaglutide improves KCCQ, 6-minute walk distance, or HFpEF outcomes in patients with HFpEF and a normal or low BMI, and current FDA labeling and clinical-society guidance reflect this restriction.
Does this trial apply to HFrEF (reduced-ejection-fraction heart failure)?
No. STEP-HFpEF required a left ventricular ejection fraction of at least 45 percent, so the results do not apply to heart failure with reduced ejection fraction. Anti-obesity GLP-1 receptor agonists have not yet completed a positive registrational outcome trial in HFrEF, and a 2025 individual-patient meta-analysis suggested GLP-1 RAs may even modestly increase heart-failure events in some HFrEF populations. SELECT (PMID 38086928) excluded most participants with NYHA class IV symptoms and showed cardiovascular benefit predominantly in atherosclerotic cardiovascular disease rather than HFrEF. The recommended posture is to use semaglutide 2.4 mg for HFpEF with obesity as supported by STEP-HFpEF and STEP-HFpEF DM, and to wait for dedicated HFrEF outcome data before extrapolating.
Is HFpEF with obesity an FDA-approved indication for Wegovy?
The Wegovy prescribing information includes language describing semaglutide 2.4 mg as indicated to reduce symptoms and physical-function limitations in adults with heart failure with preserved ejection fraction and obesity, supported by STEP-HFpEF and STEP-HFpEF DM. Wegovy was also approved for major adverse cardiovascular event reduction in adults with established cardiovascular disease and overweight or obesity based on SELECT. Coverage and step-therapy rules vary by payer and may require documentation of HFpEF (LVEF ≥45% on echocardiogram) plus BMI thresholds matching the label. Patients and prescribers should consult the current Wegovy prescribing information for the most up-to-date indication language, since cardiometabolic indications have been added incrementally.
How does Wegovy compare to SGLT2 inhibitors in HFpEF?
SGLT2 inhibitors (empagliflozin in EMPEROR-Preserved and dapagliflozin in DELIVER) reduced the composite of cardiovascular death or heart-failure hospitalization in broad HFpEF populations and produced KCCQ improvements of roughly 1.0 to 2.4 placebo-adjusted points at one year. Semaglutide 2.4 mg in STEP-HFpEF produced a +7.8-point KCCQ-CSS improvement, a 20.3-meter 6-minute-walk-distance gain, and a 10.7-percentage-point weight-loss advantage in the obesity HFpEF phenotype, but it was not powered for cardiovascular event endpoints. The two classes target different upstream biology (renal-handling/diuretic-like effects for SGLT2 inhibitors, weight loss and inflammation reduction for GLP-1 receptor agonists) and current expert commentary suggests they are likely complementary rather than substitutes. Combined use has not yet been studied in a randomized HFpEF outcome trial.
What happened in STEP-HFpEF DM, the follow-up in patients with diabetes?
STEP-HFpEF DM (PMID 38587233, NEJM April 2024) replicated the STEP-HFpEF design in 616 adults with HFpEF, obesity, and type 2 diabetes — the population excluded from the original trial. Co-primary endpoints were again KCCQ-CSS change and body-weight change at 52 weeks. Semaglutide 2.4 mg produced a +7.3-point placebo-adjusted KCCQ-CSS improvement and a −6.4-percentage-point weight-loss difference, both highly significant, despite the smaller weight loss typical of GLP-1 trials in diabetes. A 2024 Lancet pooled analysis (PMID 38599221) combined the two STEP-HFpEF trials and confirmed consistent symptom, function, and inflammatory benefits across the diabetes and non-diabetes strata.
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.