Summary: In a prespecified echocardiography substudy of the double-blind STEP-HFpEF Program (n=491 of 1,145), once-weekly semaglutide 2.4 mg attenuated left atrial volume remodelling versus placebo over 52 weeks (estimated mean difference -6.13 mL; 95% CI -9.85 to -2.41; P=0.0013), with smaller right ventricular dimensions and modest diastolic improvements but no change in left ventricular systolic function.
PICO Summary
| Element | Detail |
|---|---|
| Population | 491 of 1,145 adults (43%) with obesity-related heart failure with preserved ejection fraction (LVEF >=45%, BMI >=30) who had paired echocardiograms at randomisation and 52 weeks, pooled from the international, multicentre, double-blind STEP-HFpEF and STEP-HFpEF DM randomised controlled trials. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks (n=253). |
| Comparison | Matching placebo for 52 weeks (n=238). |
| Outcome | Prespecified primary outcome, change in left atrial (LA) volume: estimated mean difference (EMD) -6.13 mL (95% CI -9.85 to -2.41; P=0.0013) favouring semaglutide. Secondary echocardiographic outcomes (not adjusted for multiplicity): RV end-diastolic area EMD -1.99 cm (95% CI -3.60 to -0.38; P=0.016); RV end-systolic area EMD -1.41 cm (95% CI -2.42 to -0.40; P=0.0064); 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). No significant effect on left ventricular dimensions, mass, or systolic function. Greater weight loss was associated with greater LA volume reduction (P=0.033). Effects were not modified by diabetes or atrial fibrillation status. No ARR or NNT applicable (continuous imaging endpoints). |
Semaglutide & Cardiac Remodelling in HFpEF
Echo substudy · RCT · obesity HFpEF · 52 weeks
Semaglutide attenuated left atrial remodelling versus placebo over 52 weeks, with smaller right ventricular dimensions and modest diastolic gains but no change in LV systolic function. Secondary echo signals are exploratory and hypothesis-generating.
Expert Commentary
This echocardiography substudy strengthens the mechanistic case that semaglutide is more than a symptom modifier in obesity-related HFpEF. The prespecified primary outcome was met: left atrial remodelling, a marker tightly linked to filling pressures and prognosis in this phenotype, was attenuated by roughly six millilitres against placebo within a double-blind randomised framework. Reductions in right ventricular dimensions and the diastolic indices point in a consistent direction, and the weight-loss correlation with left atrial volume offers a plausible pathway. The verdict is cautiously positive but qualified. The principal limitation is that only 43% of the parent cohort contributed paired imaging, and every secondary echocardiographic outcome was exploratory and unadjusted for multiple comparisons, so the diastolic and right ventricular signals should be read as hypothesis-generating rather than confirmed. The trial was funded by the manufacturer, with sponsor employees among the authors, and although the parent design was double-blind, imaging substudies remain vulnerable to differential follow-up. Effect sizes here are modest, not implausibly large. Can I use this with my patients? Yes, as supportive context when counselling a patient with obesity-related HFpEF who is already a candidate for semaglutide on symptom and weight grounds, but not as a standalone reason to start therapy. One would wish to see whether these structural changes translate into hard event reduction before treating reverse remodelling as the goal.
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