Semaglutide and Exercise Function in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program.

Borlaug BA, Kitzman DW, Patel S, Chinnakondepalli KM, Butler J, Davies MJ, Petrie MC, Shah SJ, Verma S, Núñez J, Einfeldt MN, Liisberg K, Salsali A, Kosiborod MN

JACC. Heart failure3 Oct 2025Cited by 9 (Europe PMC)

PMID41045908PMCIDPMC12688318DOI10.1016/j.jchf.2025.102660PepBankPUB-41045908

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Summary

BackgroundExercise function quantified by 6-minute walk distance (6MWD) is severely impaired in patients with heart failure with preserved ejection fraction (HFpEF).ObjectivesThis 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.MethodsAssociates 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.ResultsThe authors randomized 1,145 patients to semaglutide or placebo. Compared with patients who had obesity-related HFpEF and higher 6MWD, those with lower 6MWD were older and had lower KCCQ-CSS, higher body mass index and waist circumference, greater systemic inflammation (higher C-reactive protein), and more severe congestion (higher N-terminal pro-B-type natriuretic peptide, more diuretic use). Treatment with semaglutide increased 6MWD compared with placebo, an effect apparent at 20 weeks (treatment difference 14.6 m [95% CI: 8.6-20.7 m]; P < 0.0001) that was maintained at 52 weeks (treatment difference 17.1 m [95% CI: 9.2-25.0 m]; P < 0.0001). Increases in 6MWD with semaglutide (vs placebo) were similar across all relevant subgroups, with no significant interactions. Treatment with semaglutide increased KCCQ-CSS and reduced body weight, reduced C-reactive protein, improved the hierarchical composite (death, heart failure events, change in KCCQ-CSS and 6MWD), and reduced N-terminal pro-B-type natriuretic peptide across the spectrum of baseline 6MWD (all P_interaction = NS). 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).ConclusionsIn 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).

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study9

9 results from studies that gave the peptide. 9 results from people.

01HumanRandomized controlled trialEfficacy outcome
In patients with obesity-related HFpEF, semaglutide increased the KCCQ-CSS across the spectrum of baseline 6MWD, with no significant interaction.
In plain wordsIn people with obesity and heart failure, semaglutide improved a symptom score more than placebo, whatever their starting walking distance.
Peptide
Semaglutide
Outcome
IncreaseKCCQ-CSS across baseline 6MWD tertiles
Study
n = 1,145
Comparator
Placebo
Analysis
Primary
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Treatment with semaglutide increased KCCQ-CSS and reduced body weight, reduced C-reactive protein, improved the hierarchical composite (death, heart failure events, change in KCCQ-CSS and 6MWD), and reduced N-terminal pro-B-type natriuretic peptide across the spectrum of baseline 6MWD (all P_interaction = NS).
1 context sentence(design, population, supporting numbers)
Summary · context
The authors randomized 1,145 patients to semaglutide or placebo.
Show in the study text Report a problemFND-4104590804
02HumanRandomized controlled trialEfficacy outcome
In patients with obesity-related HFpEF, semaglutide reduced body weight across the spectrum of baseline 6MWD, with no significant interaction.
In plain wordsIn people with obesity and heart failure, semaglutide reduced body weight more than placebo, whatever their starting walking distance.
Peptide
Semaglutide
Outcome
DecreaseBody weight across baseline 6MWD tertiles
Study
n = 1,145
Comparator
Placebo
Analysis
Primary
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Treatment with semaglutide increased KCCQ-CSS and reduced body weight, reduced C-reactive protein, improved the hierarchical composite (death, heart failure events, change in KCCQ-CSS and 6MWD), and reduced N-terminal pro-B-type natriuretic peptide across the spectrum of baseline 6MWD (all P_interaction = NS).
1 context sentence(design, population, supporting numbers)
Summary · context
The authors randomized 1,145 patients to semaglutide or placebo.
Show in the study text Report a problemFND-4104590805
03HumanRandomized controlled trialEfficacy outcome
In patients with obesity-related HFpEF, semaglutide increased 6-minute walk distance versus placebo at 20 weeks (treatment difference 14.6 m).
In plain wordsIn people with obesity and heart failure, semaglutide increased walking distance more than placebo after 20 weeks.
Peptide
Semaglutide
Outcome
Increase6-minute walk distance at 20 weeks
Study
n = 1,145
Comparator
Placebo
Outcome group
Exercise and physical function · Cardiovascular
Studied dose
Dose not stated · 20 weeksAs given in this study (human).
Measurements
6MWD treatment difference
14.6 m
20 weeks
Source sentences
Summary
Treatment with semaglutide increased 6MWD compared with placebo, an effect apparent at 20 weeks (treatment difference 14.6 m [95% CI: 8.6-20.7 m]; P < 0.0001) that was maintained at 52 weeks (treatment difference 17.1 m [95% CI: 9.2-25.0 m]; P < 0.0001).
1 context sentence(design, population, supporting numbers)
Summary · context
The authors randomized 1,145 patients to semaglutide or placebo.
Show in the study text Report a problemFND-4104590801
04HumanRandomized controlled trialEfficacy outcome
In patients with obesity-related HFpEF, semaglutide increased 6-minute walk distance versus placebo at 52 weeks (treatment difference 17.1 m).
In plain wordsIn people with obesity and heart failure, semaglutide increased walking distance more than placebo after 52 weeks.
Peptide
Semaglutide
Outcome
Increase6-minute walk distance at 52 weeks
Study
n = 1,145
Comparator
Placebo
Outcome group
Exercise and physical function · Cardiovascular
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Measurements
6MWD treatment difference
17.1 m
52 weeks
Source sentences
Summary
Treatment with semaglutide increased 6MWD compared with placebo, an effect apparent at 20 weeks (treatment difference 14.6 m [95% CI: 8.6-20.7 m]; P < 0.0001) that was maintained at 52 weeks (treatment difference 17.1 m [95% CI: 9.2-25.0 m]; P < 0.0001).
1 context sentence(design, population, supporting numbers)
Summary · context
The authors randomized 1,145 patients to semaglutide or placebo.
Show in the study text Report a problemFND-4104590802
05HumanRandomized controlled trialEfficacy outcome
In patients with obesity-related HFpEF, the 6MWD increase with semaglutide versus placebo was similar across all relevant subgroups, with no significant interactions.
In plain wordsIn people with obesity and heart failure, the walking distance benefit of semaglutide over placebo was similar across subgroups.
Peptide
Semaglutide
Outcome
No significant change6MWD effect across subgroups
Study
n = 1,145
Comparator
Placebo
Outcome group
Exercise and physical function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Increases in 6MWD with semaglutide (vs placebo) were similar across all relevant subgroups, with no significant interactions.
1 context sentence(design, population, supporting numbers)
Summary · context
The authors randomized 1,145 patients to semaglutide or placebo.
Show in the study text Report a problemFND-4104590803
06HumanRandomized controlled trialEfficacy outcome
In patients with obesity-related HFpEF, semaglutide reduced C-reactive protein across the spectrum of baseline 6MWD, with no significant interaction.
In plain wordsIn people with obesity and heart failure, semaglutide lowered an inflammation marker more than placebo, whatever their starting walking distance.
Peptide
Semaglutide
Outcome
DecreaseC-reactive protein across baseline 6MWD tertiles
Study
n = 1,145
Comparator
Placebo
Outcome group
Inflammation markers · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Treatment with semaglutide increased KCCQ-CSS and reduced body weight, reduced C-reactive protein, improved the hierarchical composite (death, heart failure events, change in KCCQ-CSS and 6MWD), and reduced N-terminal pro-B-type natriuretic peptide across the spectrum of baseline 6MWD (all P_interaction = NS).
1 context sentence(design, population, supporting numbers)
Summary · context
The authors randomized 1,145 patients to semaglutide or placebo.
Show in the study text Report a problemFND-4104590806
07HumanRandomized controlled trialEfficacy outcome
In patients with obesity-related HFpEF, semaglutide improved the hierarchical composite of death, heart failure events, KCCQ-CSS change and 6MWD change across the spectrum of baseline 6MWD.
In plain wordsIn people with obesity and heart failure, semaglutide improved a combined measure of death, heart failure events, symptoms and walking distance versus placebo.
Peptide
Semaglutide
Outcome
IncreaseHierarchical composite endpoint across baseline 6MWD tertiles
Study
n = 1,145
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Treatment with semaglutide increased KCCQ-CSS and reduced body weight, reduced C-reactive protein, improved the hierarchical composite (death, heart failure events, change in KCCQ-CSS and 6MWD), and reduced N-terminal pro-B-type natriuretic peptide across the spectrum of baseline 6MWD (all P_interaction = NS).
1 context sentence(design, population, supporting numbers)
Summary · context
The authors randomized 1,145 patients to semaglutide or placebo.
Show in the study text Report a problemFND-4104590807
08HumanRandomized controlled trialEfficacy outcome
In patients with obesity-related HFpEF, semaglutide reduced N-terminal pro-B-type natriuretic peptide across the spectrum of baseline 6MWD, with no significant interaction.
In plain wordsIn people with obesity and heart failure, semaglutide lowered a heart strain marker more than placebo, whatever their starting walking distance.
Peptide
Semaglutide
Outcome
DecreaseNT-proBNP across baseline 6MWD tertiles
Study
n = 1,145
Comparator
Placebo
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Treatment with semaglutide increased KCCQ-CSS and reduced body weight, reduced C-reactive protein, improved the hierarchical composite (death, heart failure events, change in KCCQ-CSS and 6MWD), and reduced N-terminal pro-B-type natriuretic peptide across the spectrum of baseline 6MWD (all P_interaction = NS).
1 context sentence(design, population, supporting numbers)
Summary · context
The authors randomized 1,145 patients to semaglutide or placebo.
Show in the study text Report a problemFND-4104590808
09HumanRandomized controlled trialOther
In semaglutide-treated patients with obesity-related HFpEF, each 1-unit decrease in body mass index was associated with a 4.1 m increase in 6MWD.
In plain wordsIn people with obesity and heart failure treated with semaglutide, more BMI loss was linked to a longer walking distance.
Peptide
Semaglutide
Outcome
Not applicableAssociation of BMI decrease with 6MWD change
Study
n = 1,145
Outcome group
Exercise and physical function · Cardiovascular
Studied dose
Dose not stated
Measurements
6MWD increase per 1-unit BMI decrease
4.1 m
semaglutide
Source sentences
Summary
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).
1 context sentence(design, population, supporting numbers)
Summary · context
The authors randomized 1,145 patients to semaglutide or placebo.
Show in the study text Report a problemFND-4104590809

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 completed · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3NCT04916470

Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes

Novo Nordisk A/Sn = 61715 Jun 2021 to 11 Oct 2023

Heart Failure With Preserved Ejection Fraction (HFpEF) and Diabetes Mellitus, Type 2

Trial page ClinicalTrials.govUpdated 26 Nov 2025

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
11 Oct 2026, 00:04 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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