Physicians' Academy for Cardiovascular Education

GLP-1RA effective in obesity phenotype of HFpEF, regardless of obesity class

Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial

Literature - Borlaug BA, Kitzman DW, Davies MJ, et al. - Nat Med. 2023 Sep;29(9):2358-2365. doi: 10.1038/s41591-023-02526-x

Introduction and methods


The obesity phenotype of HFpEF is a pathophysiologically distinct form of HFpEF that is characterized by more severe symptoms, poorer exercise capacity, more adverse hemodynamics, and greater risk of HF hospitalization compared with HFpEF patients without obesity [1-8]. Recently, the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial showed that semaglutide reduced symptoms, physical limitations, inflammation, and body weight and improved exercise function in patients with the obesity phenotype of HFpEF compared with placebo [9,10]. However, it is unclear whether these treatment effects vary by obesity class and whether they are related to the magnitude of body weight reduction.

Aim of the study

In a prespecified analysis of the STEP-HFpEF trial, the authors investigated the efficacy of semaglutide versus placebo in HFpEF patients across different obesity categories and whether the degree of body weight reduction achieved with semaglutide was related to the improvements in the key trial endpoints.


The STEP-HFpEF trial was an international, double-blind, placebo-controlled RCT in which 529 patients with the obesity phenotype of HFpEF (LVEF ≥45%; NYHA class II–IV HF symptoms; BMI ≥30 kg/m²) without diabetes were randomized to subcutaneous semaglutide 2.4 mg once weekly or placebo for 52 weeks, in addition to standard of care [10].


The dual primary endpoints of the STEP-HFpEF trial were change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and percent change in body weight from baseline to 52 weeks. Confirmatory secondary endpoints included change in 6-minute walk distance (6MWD), overall clinical benefit assessed using a hierarchical composite outcome (all-cause death, HF events, and several thresholds of change in KCCQ-CSS from baseline to 52 weeks and change in 6MWD ≥30 m), and change in CRP level from baseline to 52 weeks.

Safety and tolerability were assessed by reported serious adverse events and adverse events leading to premature treatment discontinuation.

Main results

Treatment effects by baseline obesity category

Association between semaglutide effects and weight change

Adverse events


In this prespecified analysis of the STEP-HFpEF trial among patients with the obesity phenotype of HFpEF, 52-week treatment with semaglutide versus placebo reduced body weight, HF-related symptoms, physical limitations, and systemic inflammation and improved exercise function, across all 3 obesity categories . In semaglutide-treated patients, the magnitude of benefit was associated with the degree of weight loss. According to the authors, “these data support semaglutide-mediated weight loss as a key treatment strategy in patients with the obesity phenotype of HFpEF” and “indicate that [those with only mild obesity] benefit just as much as patients with more severe obesity.”


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Find this article online at Nat Med.

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