Sodium-Glucose Cotransporter-2 Inhibitors in Diabetes and Beyond: Mechanisms, Pleiotropic Benefits, and Clinical Use—Reviewing Protective Effects Exceeding Glycemic Control

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, also known as gliflozins, are a class of antidiabetic agents that act independently of insulin by promoting renal glucose excretion. They modulate glucose reabsorption in proximal renal tubules. Initially, they were used for the treatment of type 2 diabetes mellitus (T2DM); however, numerous pleiotropic benefits beyond glycemic control were observed. Large clinical trials confirmed their efficacy in reducing cardiovascular mortality, heart failure hospitalizations, and progression of chronic kidney disease. SGLT2 inhibitors reduce oxidative stress and inflammation and induce favorable metabolic adaptations, including lowering ketosis and upregulation of erythropoiesis. They also exert protective effects on hepatic and cognitive function. Additionally, SGLT2 inhibitors lower serum uric acid and reduce adipose tissue mass, which usually results in weight loss. Although generally well-tolerated, they are associated with increased risk of urogenital infections, euglycemic ketoacidosis, and a potentially enlarged amputation risk. Current guidelines worldwide recommend their use not only for T2DM but also for heart failure and chronic kidney disease, marking a paradigm shift toward organ-protective therapies. This review provides a comprehensive synthesis of current evidence on the mechanisms, clinical benefits, and safety profile of SGLT2 inhibitors, highlighting their expanding role in cardiometabolic and multisystem disease management.