Heart failure with preserved ejection fraction therapeutics: in search of the pillars

Heart failure (HF) affects nearly 8 million individuals in the USA, with approximately half diagnosed with heart failure with preserved ejection fraction (HFpEF). HFpEF is associated with high morbidity and mortality, with fewer than 25% of patients surviving beyond 5 years after diagnosis. Historically, poor outcomes have been largely attributed to a lack of effective disease-modifying therapies. However, the past 5 years have marked a transformative era in HFpEF management, with multiple landmark clinical trials demonstrating benefits for novel therapeutic classes. These include sodium-glucose cotransporter 2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (Ns-MRAs), and glucagon-like peptide-1 (GLP-1) receptor agonists, particularly for the obesity-related HFpEF phenotype. In this review, we summarize the evolution of HFpEF therapeutics, from traditional heart failure treatments with limited efficacy to emerging targeted therapies, highlighting the latest evidence shaping a modern, comprehensive approach to HFpEF management.