Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent condition, particularly among the aging population in the United States, and is associated with significant challenges due to its complex pathophysiology and limited therapeutic options. Historically, few pharmacological therapies have successfully mitigated HFpEF, making the emergence of effective treatments particularly significant. This review evaluates recent evidence on the therapeutic potential of semaglutide for managing HFpEF, especially in the obese population. Results from the STEP-HFpEF and STEP-HFpEF DM trials demonstrate that semaglutide, a glucagon-like peptide-1 receptor agonist originally developed for type 2 diabetes but now also approved for obesity treatment, significantly improves clinical outcomes such as symptom scores, body weight, exercise capacity, and inflammation markers in the obese population suffering from HFpEF. These improvements are attributed to both the weight loss induced by semaglutide and its direct effects on the congestive pathophysiology of HFpEF. The efficacy of semaglutide offers new hope for addressing a condition that has long lacked effective pharmacological interventions.
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