Pharmacological management of heart failure

Heart failure (HF) is a clinical syndrome of increasing global prevalence, affecting over 64 million people worldwide and representing a leading cause of cardiovascular mortality and recurrent hospitalization. Pharmacological management of HF has undergone a radical transformation over recent decades, shifting from a symptom-driven approach to a disease-modifying paradigm targeting simultaneous inhibition of multiple neurohormonal and metabolic pathways. This narrative review synthesizes evidence from major randomized controlled trials and current international guidelines (ESC 2021/2023, ACC/AHA/HFSA 2022) on pharmacological therapy across the full spectrum of ejection fraction. Quadruple therapy, combining an ARNI or ACE inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor, represents the current standard of care in heart failure with reduced ejection fraction, with well-established benefits on all-cause mortality and hospitalizations. SGLT2 inhibitors have also extended therapeutic coverage to heart failure with preserved and mildly reduced ejection fraction. A distinct dimension of HF management concerns its bidirectional relationship with glucose metabolism: type 2 diabetes mellitus is present in 30-45% of HF patients and worsens prognosis through lipotoxicity, oxidative stress and diabetic cardiomyopathy, while chronic HF itself induces insulin resistance through sympathetic activation and tissue hypoperfusion. In patients affected by heart failure and diabetes mellitus, thiazolidinediones should be avoided, while SGLT2 inhibitors, which address both conditions simultaneously, are favored. The gap between guideline recommendations and real-world clinical practice remains a major challenge, and early initiation with intensive up-titration of guideline-directed medical therapy represents the most immediate clinical priority for reducing mortality and rehospitalization in this population.