Vol. 7, Issue 2, Part A (2025)

Heart failure with reduced ejection fraction (HFrEF) remains a significant cause of morbidity and mortality worldwide, requiring optimal pharmacological strategies to improve patient outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNIs) represent two innovative therapeutic classes that have transformed HFrEF management through complementary mechanisms. SGLT2i reduce glucose and sodium reabsorption in the kidneys, leading to osmotic diuresis, natriuresis, improved myocardial energy efficiency, and renal protection. ARNIs combine neprilysin inhibition with angiotensin receptor blockade, enhancing natriuretic peptide activity while attenuating maladaptive neurohormonal responses. Large-scale randomized controlled trials, including DAPA-HF, EMPEROR-Reduced, and PARADIGM-HF, demonstrate that both drug classes significantly reduce cardiovascular mortality, hospitalizations, and improve quality of life. Their combined use offers synergistic benefits in cardiac remodeling, renal preservation, and metabolic regulation, with a favorable safety profile when monitored appropriately. Clinical pharmacists play a pivotal role in optimizing therapy initiation, titration, patient education, and adherence, ultimately bridging the gap between clinical evidence and real-world practice. This review highlights the pharmacology, clinical evidence, safety considerations, renal and metabolic benefits, and the pharmacist’s role in the integrated management of HFrEF using SGLT2i and ARNIs.