Current status and future of drug therapy for obesity-related heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) now constitutes over 50% of global heart failure (HF) burden, with obesity recognized as a central pathogenic driver. Recent advances in anti-obesity medication (AOM) have redefined management strategies. This review summarizes landmark developments: sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as the first agents with robust prognostic benefit; Glucagon like peptide-1 receptor agonists (GLP-1RA) and Glucose dependent insulin peptide (GIP) and GLP-1 dual receptor agonists (e.g., Tirzepatide) demonstrate disease-modifying effects through weight loss and direct cardiac remodeling reversal; and the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone shows enhanced efficacy in obese subgroups. We also critically analyze the “obesity paradox”, propose biomarker-guided phenotyping, and address translational challenges including cost accessibility and long-term efficacy sustainability. The latest adipokine hypothesis also elucidates the pathogenesis of HFpEF, and based on this hypothesis, some new pharmacological treatment strategies have been proposed. This article will also discuss this and differentiate the deposition of visceral fat and epicardial fat.