Semaglutide Treatment Effect in People With Obesity and HFpEF - STEP-HFpEF

Contribution To Literature:

Highlighted text has been updated as of November 12, 2023.

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

Quality of life (QoL) assessments: KCCQ data were available for 91% at 52 weeks. The median KCCQ-CSS was 59 points. Treatment with semaglutide (vs. placebo) improved all three KCCQ summary domains (estimated treatment differences and 95% confidence intervals for KCCQ-CSS, Overall Summary Score (OSS), and Total Symptom Score (TSS): 7.8 [4.8, 10.9], 7.5 [4.4, 10.6], and 9.0 [5.4, 12.5]. Of patients treated with semaglutide, 37.9% experienced an increase in KCCQ-CSS of ≥20 points, compared with 26.6% treated with placebo. Conversely, 4.9% of patients treated with semaglutide experienced a decrease in KCCQ-CSS of ≥10 points, compared with 11% in the placebo group. There was a significant, linear relationship between greater weight loss and larger improvements in KCCQ-OSS (p < 0.001).


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 QoL outcomes including KCCQ-CSS and 6-minute walk distance at 52 weeks. Semaglutide produced improvements in HF-related symptoms, physical limitations, and exercise function, regardless of baseline health status. 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.


Kosiborod MN, Verma S, Borlaug BA, et al. Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial. Circulation 2023;Nov 12:[Epub ahead of print].

Presented by Dr. Mikhail Kosiborod at the American Heart Association Scientific Sessions, Philadelphia, PA, November 12, 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, Acute Heart Failure

Keywords: ACC23, Glucagon-Like Peptide-1 Receptor, Heart Failure, Obesity

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