Effect of Semaglutide 2.4 mg Once Weekly on Function and Symptoms in Subjects With Obesity-Related Heart Failure With Preserved Ejection Fraction - STEP-HFpEF

Contribution To Literature:

The STEP-HFpEF trial showed that, among obese patients with HFpEF, once weekly subcutaneous semaglutide was superior to placebo in improving body weight and patient-oriented QoL outcomes at 52 weeks.


The goal of the trial was to compare the safety and efficacy of semaglutide among patients with heart failure with preserved ejection fraction (HFpEF) and obesity.

Study Design

Patients were randomized in a 1:1 fashion to once weekly subcutaneous semaglutide (n = 263) or matching placebo (n = 266) for 52 weeks. Randomization was stratified according to baseline body mass index (BMI) <35 vs. ≥35 kg/m2). Semaglutide treatment was initiated at a dose of 0.25 mg once weekly for the first 4 weeks, and the dose was escalated every 4 weeks with the aim of reaching the maintenance dose of 2.4 mg by week 16.

  • Total randomized participants: 529
  • Median duration of follow-up: 52 weeks
  • Median patient age: 69 years
  • Percentage female: 56.1%

Inclusion criteria:

  • Age ≥18 years
  • Left ventricular ejection fraction (LVEF) of ≥45%
  • A BMI of ≥30 kg/m2
  • New York Heart Association functional class II, III, or IV symptoms
  • Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) <90 points
  • Six-minute walk distance of ≥100 m
  • At least one of the following findings: elevated LV filling pressures, elevated natriuretic peptide levels plus echocardiographic abnormalities, or hospitalization for HF in the 12 months before screening plus ongoing treatment with diuretics or echocardiographic abnormalities

Exclusion criteria:

  • Patient-reported change in body weight of >5 kg within 90 days before screening
  • History of diabetes

Other salient features/characteristics:

  • White race: 96%
  • Median body weight: 105.1 kg
  • Median BMI: 37 kg/m2
  • Median baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP): 450.8 pg/mL
  • Hospitalization for HF within 1 year: 15.3%
  • Baseline medications: Diuretic: 80.7%, mineralocorticoid receptor antagonist: 34.8%, sodium–glucose cotransporter-2 (SGLT2) inhibitor: 3.6%

Principal Findings:

The co-primary endpoints for semaglutide vs. placebo from baseline to week 52:

  • Change in KCCQ-CSS: 16.6 vs. 8.7 (p < 0.001)
  • Percentage change in body weight: -13.3 vs. -2.6 (p < 0.001)

Key secondary outcomes for semaglutide vs. placebo:

  • Change in 6-minute walk distance from baseline to week 52: 21.5 vs. 1.2 m (p < 0.001)
  • Percentage reduction from baseline to week 52 in NT-proBNP: -20.9 vs. -5.3 (p < 0.05)
  • Hospitalization or urgent visit for HF: 1 vs. 12 events (p < 0.05)
  • Adverse events were similar


The results of this trial show that among obese patients with HFpEF, once weekly subcutaneous semaglutide was superior to placebo in improving body weight (~11% greater weight loss) and patient-oriented quality of life (QoL) outcomes including KCCQ-CSS and 6-minute walk distance at 52 weeks. The trial was underpowered for clinical events, although reductions in HF were noted. These are landmark findings and support a larger outcomes trial to study the effect of glucagon-like peptide-1 (GLP-1) receptor agonists among patients with HFpEF and obesity.

One limitation of this trial is that very few patients were on SGLT2 inhibitors at baseline. It is also unclear if the improvements in HF-related QoL measures were driven by weight loss (suggesting that other weight loss measures could be considered and potentially beneficial) or independent of this.


Highlighted text has been updated as of September 21, 2023.

Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al., on behalf of the STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients With Heart Failure With Preserved Ejection Fraction and Obesity. N Engl J Med 2023;389:1069-84.

Editorial: Pinto YM. Heart Failure With Preserved Ejection Fraction — A Metabolic Disease? N Engl J Med 2023;389:1145-6.

Presented by Dr. Mikhail Kosiborod at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 25, 2023.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Chronic Heart Failure

Keywords: ESC23, ESC Congress, Glucagon-Like Peptide-1 Receptor, Heart Failure, Heart Failure, Diastolic, Metabolic Diseases, Obesity, Secondary Prevention, Stroke Volume

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