Semaglutide and Exercise Function in Obesity-Related HFpEF

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Obesity-related heart failure with preserved ejection fraction (HFpEF) (n=1145). Intervention: Semaglutide vs. Matching placebo on top of standard of care. Primary outcome: Change in 6-minute walk distance (6MWD) from baseline to 52 weeks (MD 17.1 m, 95% CI 9.2-25.0, p=<0.0001).

Q: What does this research mean for the field?

Semaglutide significantly improves 6-minute walk distance by 17.1 m at 52 weeks compared with placebo in patients with obesity-related HFpEF, with benefits consistent across baseline exercise capacity and strongly correlated with magnitude of weight loss. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To assess baseline determinants of impaired exercise function and evaluate the effects of semaglutide on 6-minute walk distance and clinical endpoints across baseline exercise capacity in obesity-related HFpEF.

Barry A. Borlaug; Dalane W. Kitzman; Shachi Patel; Khaja Chinnakondepalli; Javed Butler; Melanie J. Davies; Mark C. Petrie; Sanjiv J. Shah; Subodh Verma; Julio Núñez; Mette Nygaard Einfeldt; Karoline Liisberg; Afshin Salsali; Mikhail Kosiborod

doi:10.1016/j.jchf.2025.102660

October 4, 2025JACC Heart FailureOpen Access

Semaglutide and Exercise Function in Obesity-Related HFpEF

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Key result

Semaglutide increases 6-minute walk distance by ~17 m vs placebo in obesity-related HFpEF.

MD +17.1 m
95% CI 9.2-25.0
P<0.0001
n=1,145

Graphical abstract published by JACC Heart Failure — Graphical abstract · Published by JACC Heart Failure · CC BY 4.0

Why the study?

Exercise function quantified by 6-minute walk distance is severely impaired in patients with HFpEF, motivating evaluation of semaglutide's effects on exercise function and key endpoints.

Does once-weekly subcutaneous semaglutide 2.4 mg improve exercise function (6MWD) and HF-related symptoms across the spectrum of baseline 6MWD in patients with obesity-related HFpEF?

Key Points

To assess baseline determinants of impaired exercise function and evaluate the effects of semaglutide on 6-minute walk distance and clinical endpoints across baseline exercise capacity in obesity-related HFpEF.
Prespecified pooled secondary analysis of 1,145 randomized participants from the STEP-HFpEF (N=529; NCT04788511) and STEP-HFpEF DM (N=616; NCT04916470) trials.
Participants received semaglutide or placebo and were evaluated for 6-minute walk distance (6MWD), KCCQ-CSS, body weight, CRP, and NT-proBNP at 20 and 52 weeks across baseline 6MWD tertiles.
Semaglutide significantly improved 6MWD versus placebo at 20 weeks (treatment difference: 14.6 m; 95% CI: 8.6–20.7 m; P < 0.0001) and at 52 weeks (treatment difference: 17.1 m; 95% CI: 9.2–25.0 m; P < 0.0001).
Mean percentage increases in 6MWD at 52 weeks were 9.6% (95% CI: 7.4%–11.7%) with semaglutide compared with 3.7% (95% CI: 1.6%–5.9%) with placebo, with consistent gains across baseline 6MWD tertiles.
Each 1-unit decrease in body mass index on semaglutide was associated with a 4.1 m (95% CI: 2.4–5.7 m) increase in 6MWD (P < 0.0001), and semaglutide was associated with fewer serious adverse events across all tertiles.

Study Design

Type

RCT (n=1,145)

Blinding

Double-blind

Randomization

1:1 randomization stratified by BMI <35 kg/m2 vs >=35 kg/m2

Multicenter

Yes

Structured PICO

Does once-weekly subcutaneous semaglutide 2.4 mg improve exercise function (6MWD) and HF-related symptoms across the spectrum of baseline 6MWD in patients with obesity-related HFpEF?

P

Population

1,145 adults with obesity-related HFpEF (LVEF >=45%, BMI >=30 kg/m2, NYHA class II-IV, KCCQ-CSS <90, baseline 6MWD >=100 m) across two pooled multinational trials (STEP-HFpEF and STEP-HFpEF DM) followed for 52 weeks.

I

Intervention

Semaglutide 2.4 mg subcutaneously once-weekly target dose on top of standard of care for 52 weeks

C

Comparator

Matching placebo subcutaneously once-weekly on top of standard of care for 52 weeks

O

Outcome

Dual primary endpoints: 1) change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) from baseline to 52 weeks; and 2) percent change in body weight from baseline to 52 weeks (this prespecified secondary analysis focused on change in 6-minute walk distance [6MWD] at 20 and 52 weeks and endpoints stratified by baseline 6MWD tertiles)patient reported

Main Result

Mean Difference: 17.1 (95% CI 9.2–25)

Absolute Event Rate: 9.6% vs 3.7%

p-value: p=<0.0001

In patients with obesity-related HFpEF, semaglutide significantly improves 6-minute walk distance as early as 20 weeks and sustains benefits through 52 weeks across the entire spectrum of baseline exercise impairment, with improvements strongly correlated with the magnitude of weight loss.

Limitations

Majority of participants were White, limiting generalizability
52-week duration of treatment was relatively short
Low background use of SGLT2 inhibitors
Direct assessments of body composition and muscle strength were not performed
The majority of participants in the STEP-HFpEF program were White, which may limit generalizability.
The 52-week duration of treatment was relatively short, and whether the observed effects might have persisted (or been amplified) with longer treatment is not known.
Use of SGLT2 inhibitors was low, because these agents were not yet approved for treatment of HFpEF at the time the trials were conducted.
Direct assessments of body composition and muscle strength were not performed in this multicenter trial.

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Implication

Semaglutide improves functional capacity in obesity-related HFpEF; extends STEP-HFpEF evidence by linking gains to weight-loss magnitude.

Abstract

BACKGROUND: Exercise function quantified by 6-minute walk distance (6MWD) is severely impaired in patients with heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: This prespecified secondary analysis of pooled data from the STEP-HFpEF Program (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) examined factors associated with impaired exercise function at baseline, detailed effects of semaglutide on 6MWD, and on other key trial endpoints according to baseline 6MWD in patients with HFpEF. METHODS: Associates of 6MWD were assessed at baseline, and effects of semaglutide on 6MWD were evaluated at early (20 weeks) and final (52 weeks) time points, across subgroups, and according to the magnitude of weight loss achieved. Effects of semaglutide on the dual primary (changes in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score [KCCQ-CSS] and body weight) and secondary/exploratory endpoints were contrasted by tertiles of baseline 6MWD. Each 1-unit decrease in body mass index on treatment with semaglutide was associated with a 4.1 m (95% CI: 2.4-5.7 m) increase in 6MWD (P < 0.0001). CONCLUSIONS: In patients with obesity-related HFpEF, impaired 6MWD is most strongly associated with excess adiposity, congestion, and inflammation. Semaglutide-mediated improvements in HF-related symptoms, physical limitations, and exercise function were consistent across the spectrum of baseline 6MWD, observed as early as 20 weeks after the initiation of treatment, preceding maximal weight loss. The effects were consistent across subgroups. There was strong correlation between greater magnitude of weight loss and greater improvements in 6MWD. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF], NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM], NCT04916470).

Discussion

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Cite This Study

Borlaug et al. (2025) conducted an RCT in Obesity-related heart failure with preserved ejection fraction (HFpEF) (n=1,145). Semaglutide vs. Matching placebo on top of standard of care was evaluated on Change in 6-minute walk distance (6MWD) from baseline to 52 weeks (MD 17.1 m, 95% CI 9.2-25.0, p=<0.0001).

synapsesocial.com/papers/6a064ca80924dc877016d8a9 https://doi.org/10.1016/j.jchf.2025.102660

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Semaglutide and Exercise Function in Obesity-Related HFpEF

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Semaglutide and Exercise Function in Obesity-Related HFpEF

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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