Summary: In a prespecified echocardiography substudy of the STEP-HFpEF Program (n = 491 of 1,145; semaglutide n = 253, placebo n = 238), once-weekly semaglutide 2.4 mg attenuated progression of left atrial remodeling over 52 weeks, with an estimated mean difference in left atrial volume of -6.13 mL (95% CI: -9.85 to -2.41; P = 0.0013). Right ventricular size and several diastolic indices improved, while left ventricular mass and systolic function were unchanged. These are surrogate imaging endpoints, not clinical event outcomes.
PICO Summary
| Element | Detail |
|---|---|
| Population | Adults with obesity-related heart failure with preserved ejection fraction (HFpEF), with and without type 2 diabetes; echocardiography substudy of the pooled STEP-HFpEF and STEP-HFpEF DM randomised trials (n = 491 with paired echocardiograms at baseline and 52 weeks, of 1,145 enrolled; multinational, multicentre). |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks (n = 253). |
| Comparison | Matching placebo on a background of usual HFpEF care for 52 weeks (n = 238). |
| Outcome | Primary outcome (change in left atrial volume): EMD -6.13 mL (95% CI: -9.85 to -2.41; P = 0.0013). Right ventricular end-diastolic area: EMD -1.99 cm² (95% CI: -3.60 to -0.38; P = 0.016); RV end-systolic area: EMD -1.41 cm² (95% CI: -2.42 to -0.40; P = 0.0064). Diastolic indices: E-wave velocity EMD -5.63 cm/s (95% CI: -9.42 to -1.84; P = 0.0037); E/A ratio EMD -0.14 (95% CI: -0.24 to -0.04; P = 0.0075); E/e’ average EMD -0.79 (95% CI: -1.60 to 0.01; P = 0.05, borderline). No significant effect on left ventricular dimensions, mass, or systolic function. Effects not modified by diabetes or atrial fibrillation status. Absolute risk reduction and NNT are not applicable (continuous imaging endpoints; no clinical event outcomes reported). |
Semaglutide and Cardiac Remodeling in Obesity-Related HFpEF
RCT echo substudy · obesity HFpEF · 52 weeks
Over 52 weeks semaglutide attenuated adverse left atrial and right ventricular remodeling versus placebo, with the primary left atrial volume endpoint met. All endpoints are surrogate imaging markers, not clinical outcomes.
Expert Commentary
This prespecified echocardiography substudy provides mechanistic support for the symptomatic benefits already reported in the STEP-HFpEF Program. The verdict is that semaglutide was associated with statistically significant attenuation of adverse atrial and right ventricular remodeling and modest improvement in diastolic indices, with the primary left atrial volume endpoint clearly met. The findings are biologically coherent, and the consistency across diabetes and atrial fibrillation subgroups strengthens confidence. The single most important limitation is that every endpoint here is a surrogate imaging marker rather than a clinical outcome; reverse remodeling has not been shown to translate into fewer heart failure hospitalisations or deaths in this dataset, and the E/e’ signal was only borderline (P = 0.05). Only 43% of the parent cohort contributed paired echocardiograms, which introduces potential selection effects, and the trials were funded and partly authored by the manufacturer, Novo Nordisk, which warrants cautious interpretation despite the double-blind design. Can I use this with my patients? For a patient with obesity-related HFpEF already a candidate for semaglutide on symptom and weight grounds, these data are reassuring and consistent with disease modification, but they do not by themselves justify prescribing for a cardiac-remodeling indication. Confirmation against hard clinical endpoints in adequately powered outcome trials is needed before remodeling is treated as a therapeutic target.
References
Solomon SD, Ostrominski JW, Wang X, Shah SJ, Borlaug BA, Butler J, et al. Effect of semaglutide on cardiac structure and function in patients with obesity-related heart failure. J Am Coll Cardiol. 2024;84(17):1587-1602. doi:10.1016/j.jacc.2024.08.021