Advances in the Pharmacological Treatment of Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) represents approximately half of all heart failure cases and poses a growing global health challenge driven by an ageing population and an increasing comorbidity burden. Once regarded as a condition without effective, evidence-based therapy, HFpEF has undergone a paradigm shift in recent years. Advances in the understanding of its complex pathophysiology have highlighted the multifactorial interplay between systemic inflammation, endothelial dysfunction, and metabolic derangements. The introduction of sodium-glucose cotransporter 2 inhibitors has transformed the HFpEF therapeutic landscape, following large-scale trials such as EMPEROR-Preserved and DELIVER demonstrating consistent reductions in mortality/morbidity in this patient population. More recently, the non-steroidal mineralocorticoid receptor antagonist finerenone, tested in the FINEARTS-HF trial, was also shown to improve mortality/morbidity in HFpEF, marking a further milestone in disease-modifying therapy. Further, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and a dual gastric inhibitory polypeptide analogue/GLP-1 RA (tirzepatide) have shown to reduce body weight and improve quality of life and mortality/morbidity in the obese-HFpEF phenotype, suggesting the need of additional tailoring of HFpEF therapy based on specific patient profiles. Despite these advances, HFpEF remains a frequently underdiagnosed syndrome, with diagnostic uncertainty often delaying therapy. Comprehensive management of comorbidities and systematic implementation of guideline-directed medical therapy remain crucial to improve patient outcomes. This narrative review provides an updated overview of the pathophysiological mechanisms, diagnostic approaches, and evolving pharmacological strategies shaping the modern management of HFpEF.