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Hot Line: Once-weekly semaglutide in people with HFpEF and obesity

26 Aug 2023

ESC Congress 2023’s Hot Line sessions got off to a stimulating start with the presentation of results from the STEP-HFpEF trial by Professor Mikhail Kosiborod (Saint Luke's Mid America Heart Institute - Kansas City, USA).


Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have an especially high burden of debilitating symptoms and physical limitations, which collectively result in a poor quality of life.1,2 Few treatment options are available and no pharmacotherapies that specifically target obesity as a treatment for HFpEF have been tested in randomised controlled trials.

The double-blind STEP-HFpEF trial was conducted across 13 countries in Asia, Europe, North America and South America. In total, 529 patients with HFpEF (LVEF 45%) were included if they also had body mass index (BMI) 30 kg/m2, NYHA functional class II–IV and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90 points. Participants were randomised to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 52 weeks. The trial had two primary endpoints: change from baseline to week 52 in KCCQ-CSS and in body weight.

Just over half of the participants were women (56%); median values were 69 years for age and 37.0 kg/m2 for BMI. Patients had a substantial degree of HF-related symptoms, physical limitations and poor exercise tolerance: 33.8% were NYHA class III–IV, median KCCQ-CSS was 58.9 points and median 6-minute walk distance (6MWD) was 320 m.

The trial met both primary endpoints.

The mean change in KCCQ-CSS from baseline to week 52 was 16.6 points with semaglutide versus 8.7 points with placebo (estimated treatment difference [ETD] 7.8 points; 95% CI 4.8 to 10.9; p<0.001). The mean change in body weight from baseline to week 52 was -13.3% with semaglutide versus -2.6% with placebo (ETD -10.7%; 95% CI -11.9% to -9.4%; p<0.001).

The trial also met all confirmatory secondary endpoints. The mean change in 6MWD was 21.5 m for semaglutide versus 1.2 m for placebo (p<0.001). When the hierarchical composite endpoint of death, HF events and change in KCCQ-CSS and 6MWD was studied, semaglutide produced more wins than placebo (win ratio 1.72; 95% CI 1.37 to 2.15; p<0.001). The mean change in C-reactive protein was -43.5% and -7.3% with semaglutide and placebo, respectively (p<0.001).

In terms of exploratory endpoints, the change in NT-proBNP at 52 weeks was -20.9% and -5.3% for semaglutide versus placebo. One patient in the semaglutide group and 12 in the placebo group experienced an adjudicated event of HF hospitalisation or urgent visit. Serious adverse events were reported in 13.3% and 26.7% participants with semaglutide and placebo, respectively.

Prof. Kosiborod concludes, “To our knowledge, this is the first trial of a pharmacologic agent to specifically target obesity as a treatment strategy for HFpEF, and the magnitude of the benefits we observed is the largest seen with any agent in HFpEF. This will likely have a significant impact on clinical practice, especially since there is a dearth of efficacious therapies in this vulnerable patient group. We believe that these findings should also change the nature of the conversation about the role of obesity in HFpEF, as the STEP-HFpEF results clearly indicate that obesity is not simply a comorbidity in patients with HFpEF but a root cause and a target for therapeutic intervention.”


  1. Reddy YNV, et al. Mayo Clin Proc. 2019;94:1199–1209.
  2. Reddy YNV, et al. Eur J Heart Fail. 2020;22:1009–1018.