Glucagon-like Peptide-1-based and Emerging Cardiometabolic Therapies in Heart Failure with Preserved Ejection Fraction: Linking Molecular Mechanisms to Clinical Outcomes

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome driven by frequent coexistence of cardio-renal-metabolic comorbidities. It has growing epidemiological relevance as global populations age. At its pathophysiological core lies a state of chronic systemic inflammation, coronary microvascular dysfunction and myocardial remodelling, a cascade where epicardial adipose tissue plays a pivotal amplifying role. This complexity is driving a fundamental shift in HFpEF management towards integrated cardiometabolic targeting. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the dual GLP1/glucose-dependent insulinotropic polypeptide (GIP)-RA tirzepatide have emerged as compelling multi-system agents, simultaneously addressing several key pathophysiological drivers of the syndrome with consistent improvements in symptoms, functional capacity and clinical outcomes. Nevertheless, questions remain regarding the long-term impact on cardiovascular outcomes, consequences of discontinuing treatment and the potential loss of muscle mass. This review examines the pathophysiological basis of HFpEF within the cardio-renal-metabolic continuum, appraising the clinical evidence, benefits and limitations of GLP-1RAs in HFpEF and discussing future directions including phenotype-directed therapy, mechanism-based combination strategies and next-generation molecules.