Semaglutide for the Silent Phenotype: A Translational Signal in Obesity-Driven HFpEF

Obesity-related heart failure with preserved ejection fraction (HFpEF) represents an increasingly prevalent clinical phenotype characterized by exercise intolerance, systemic inflammation, and limited therapeutic options. Semaglutide, a glucagon-like peptide-1 receptor agonist approved for obesity management, has shown favorable effects on symptoms and cardiometabolic markers in patients with HFpEF and obesity, but the overall clinical profile of semaglutide across randomized trials and its relevance within the broader HFpEF therapeutic landscape remain incompletely defined. We conducted a systematic review and meta-analysis of randomized controlled trials evaluating semaglutide versus placebo in adults with HFpEF and obesity. MEDLINE, Embase, and CENTRAL were searched through February 2025. Six randomized trials (n = 4,216 participants) met inclusion criteria. Primary outcomes included changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and heart-failure hospitalization. Random-effects models were used for pooled analyses. Semaglutide significantly reduced NT-proBNP levels (mean difference -119.7 pg/ml; 95% CI -144.4 to -95.1; p <0.001) and improved KCCQ scores in trials enrolling HFpEF populations (mean difference +8.27 points; 95% CI 6.04 to 10.50; p <0.001). Semaglutide was also associated with a lower risk of heart-failure hospitalization (odds ratio 0.81; 95% CI 0.75 to 0.88; p <0.001). Between-study heterogeneity was low for primary outcomes, and sensitivity analyses confirmed the robustness of the pooled estimates, while meta-regression analyses did not identify significant modification of treatment effects by baseline C-reactive protein levels. In conclusion, semaglutide therapy in obesity-related HFpEF was associated with improvements in biomarkers, symptoms, and heart-failure hospitalization across randomized trials, providing a quantitative synthesis of emerging evidence supporting metabolic-targeted strategies in this increasingly recognized HFpEF phenotype.