Sodium-glucose cotransporter 1&2 inhibitors in heart failure and diabetes mellitus: From foundational therapy to emerging frontiers

Abstract

Sodium-glucose cotransporter (SGLT) inhibitors have transformed cardiovascular therapeutics beyond glycemic control. Both selective SGLT2 and dual SGLT1/2 inhibitors demonstrate robust reductions in heart failure hospitalization (∼30%), cardiovascular mortality (13%-15%), and all-cause mortality across ejection fraction spectra, independent of diabetes status. Landmark trials including DAPA-HF, EMPEROR, and DELIVER established SGLT2 inhibitors as foundational therapy alongside RAAS inhibition, β-blockers, and mineralocorticoid receptor antagonists. Dual SGLT1/2 inhibition shows comparable heart failure benefits with potential stroke reduction (∼25%). Mechanisms involve natriuresis, improved myocardial energetics via NHE1 inhibition and ketone utilization, endothelial function improvement, and anti-inflammatory effects, transcending glucose lowering. Common adverse effects include genitourinary infections, mild hypovolemia, and rarely euglycemic ketoacidosis. Current guidelines provide Class I recommendations for SGLT2 inhibitors across heart failure phenotypes. However, despite robust evidence, implementation remains suboptimal and <50% prescription rates remain a challenge. We performed a systematic appraisal of landmark trials, real-world studies, and clinical guidelines to provide a comprehensive review of SGLT inhibitors in heart failure and diabetes.

Keywords: Diabetes mellitus; Heart failure; SGLT-1/2 inhibitors; SGLT-2 inhibitors.