Incretin-Based Therapies in Adiposity-Driven HFpEF: Mechanisms, Clinical Evidence and Therapeutic Implications

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a common and clinically significant form of heart failure. Recent evidence suggests that central, visceral, and epicardial adiposity are associated with obesity-related HFpEF. This review evaluates how adiposity distribution alters HFpEF pathophysiology and examines the mechanistic, preclinical, and clinical evidence supporting semaglutide and related incretin-based therapies in adiposity-associated HFpEF. Visceral adipose tissue has been associated with elevated cardiac filling pressures, while epicardial adipose tissue is located directly beside the myocardium and may contribute to inflammation and myocardial stiffness. Central adiposity has also been associated with greater HFpEF severity, along with metabolic dysfunction, collagen remodeling, and reduced natriuretic peptide levels. Preclinical studies suggest that semaglutide may influence cardiac structure and inflammatory signaling through mechanisms beyond weight loss. Human trial evidence from the STEP-HFpEF program, pooled semaglutide analyses, and the SUMMIT trial has demonstrated improvements in symptoms, functional capacity, cardiac stress markers, and worsening heart failure events with semaglutide and tirzepatide. However, cardiovascular mortality alone was not significantly reduced in pooled semaglutide analyses, and treatment discontinuation and gastrointestinal adverse effects remain relevant considerations. Glucagon-like peptide-1 (GLP-1) receptor agonists and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) therapies may address adiposity-associated mechanisms underlying HFpEF in addition to improving downstream symptoms and functional outcomes.