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Semaglutide in Obesity-Related HFpEF: Pooled Analysis
Quick Takes
- Significant improvements in HF-related symptoms, physical limitations, and exercise function, and significant reductions in bodyweight were noted in the semaglutide group compared with the placebo group in obesity-related HFpEF.
- Whether concomitant administration of GLP-1 receptor agonists and SGLT2 inhibitors would result in additive effects on functional capacity and quality of life in people with obesity-related HFpEF or whether combined use may potentially diminish the individual benefits needs further study.
- Adequately powered randomized controlled trials are indicated to further validate whether these early beneficial effects of semaglutide translate into improvements in objective hard clinical endpoints in HFpEF.
Study Questions:
What are the effects of semaglutide across a broad range of outcomes in people with obesity-related heart failure with preserved ejection fraction (HFpEF) with and without diabetes, and consistency across key patient subgroups?
Methods:
The investigators conducted a prespecified pooled analysis of individual patient data from the STEP-HFpEF and STEP-HFpEF DM randomized, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged ≥18 years, had heart failure (HF) with a left ventricular ejection fraction (LVEF) of ≥45%, a body mass index (BMI) of ≥30 kg/m2, New York Heart Association class II–IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of HF-related symptoms and physical limitations) of <90 points. In STEP-HFpEF, people with diabetes or glycated hemoglobin (HbA1c) concentrations of ≥6.5% were excluded, whereas for inclusion in STEP-HFpEF DM, participants had to have been diagnosed with type 2 diabetes ≥90 days before screening and to have an HbA1c of ≤10%. In both trials, participants were randomly assigned to either 2.4 mg semaglutide once weekly or matched placebo for 52 weeks.
The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-minute walk distance (6MWD), a hierarchical composite endpoint (all-cause death, HF events, and differences in changes in KCCQ-CSS and 6MWD); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. They assessed safety in all participants who received ≥1 dose of the study drug.
Results:
Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and September 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1,145 were included in the pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS, 7.5 points [95% confidence interval, 5.3 to 9.8]; p < 0.0001; mean between-group difference in bodyweight at week 52, −8.4% [−9.2 to −7.5]; p < 0.0001).
For the confirmatory secondary endpoints, 6MWD (mean between-group difference at week 52, 17.1 m [9.2 to 25.0]) and the hierarchical composite endpoint (win ratio, 1.65 [1.42 to 1.91]) were significantly improved, and CRP concentrations (treatment ratio, 0.64 [0.56 to 0.72]) were significantly reduced, in the semaglutide group compared with the placebo group (p < 0.0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and LVEF. A total of 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group.
Conclusions:
The authors report that semaglutide was superior to placebo in improving HF-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related HFpEF.
Perspective:
This prespecified pooled assessment of individual patient-level data from STEP-HFpEF and STEP-HFpEF DM trials reports significant improvements in HF-related symptoms, physical limitations, and exercise function, and significant reductions in bodyweight in the semaglutide group compared with the placebo group. Furthermore, the beneficial effects of semaglutide were consistent across various participant subgroups. Of note, both the STEP-HFpEF and STEP-HFpEF DM trials were done before sodium-glucose cotransporter 2 (SGLT2) inhibitors were approved for HFpEF, Also, whether concomitant administration of glucagon-like peptide-1 (GLP-1) receptor agonists and SGLT2 inhibitors would result in additive effects on functional capacity and quality of life in people with obesity-related HFpEF or whether combined use may potentially diminish the individual benefits needs further study. Very importantly, adequately powered randomized controlled trials are needed to further validate whether these early beneficial effects of semaglutide translate into improvements in objective hard clinical endpoints in HFpEF.
Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention
Keywords: ACC24, ACC Annual Scientific Session, Heart Failure, Preserved Ejection Fraction, Obesity
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