Heart failure & cardiomyopathiesSecondary analysis

Semaglutide and Exercise Function in Obesity-Related Heart Failure with Preserved Ejection Fraction (HFpEF)

JACC Heart FailPublished

  • Prespecified secondary analysis of the STEP-HFpEF Program randomised trials (pooled)
  • placebo-controlled

Authors' conclusion

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.

Study context

Population
Patients with obesity-related HFpEF
Participants
1,145 patients
Comparison
Semaglutide vs placebo
Primary endpoint
Change in 6MWD
Follow-up
20 and 52 weeks

Primary result

As reported in the abstract

6MWD
Semaglutide vs PlaceboTreatment difference, m (95% CI)P value
20 weeks
14.6(8.6–20.7)
P < 0.0001
52 weeks
17.1(9.2–25.0)
P < 0.0001

Further findings

6MWD by subgroup

Increases in 6MWD similar across all relevant subgroups, no significant interactions

KCCQ-CSS, body weight, C-reactive protein, hierarchical composite, NT-proBNP by tertile of baseline 6MWD

Semaglutide improved all across the spectrum of baseline 6MWD
all Pinteraction = NS

6MWD per 1-unit BMI decrease on semaglutide

Increase in 6MWD per 1-unit BMI decrease
4.1 m (95% CI: 2.4-5.7 m; P < 0.0001)

Baseline associates of lower 6MWD

Lower 6MWD: older, lower KCCQ-CSS, higher BMI and waist circumference, higher C-reactive protein, higher NT-proBNP, more diuretic use

Original publication

Semaglutide and Exercise Function in Obesity-Related HFpEF. JACC Heart Fail. Published 3 October 2025. doi:10.1016/j.jchf.2025.102660

Summarised from the published abstract; every number is checked against it