Mechanisms of GLP-1 Receptor Agonists in HFpEF: Exploring Weight-Dependent and Independent Drivers of Therapeutic Benefit

Heart failure with preserved ejection fraction is a complex and increasingly prevalent condition often associated with metabolic comorbidities such as obesity, diabetes, and hypertension. Although its burden is substantial, therapeutic progress has lagged compared with heart failure with reduced ejection fraction. GLP-1RAs (glucagon-like peptide-1 receptor agonists), initially developed for glycemic control in type 2 diabetes, have emerged as promising therapeutic agents for the obese/cardiometabolic heart failure with preserved ejection fraction phenotype. Recent trials, including STEP-HFpEF and SUMMIT, have demonstrated improvements in symptoms, quality of life, and reductions in heart failure events. Beyond inducing substantial weight loss, GLP-1RAs exert a range of metabolic, cardiovascular, and anti-inflammatory effects. In this review, we summarize weight-dependent and weight-independent actions of GLP-1RAs and outline how these mechanisms may influence cardiovascular physiology, myocardial remodeling, cardiac metabolism, renal sodium handling, and systemic inflammation in heart failure with preserved ejection fraction.