SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects

Type 2 diabetes mellitus is a chronic metabolic disease associated with high cardiovascular (CV) risk. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the latest class of antidiabetic medication that inhibit the absorption of glucose from the proximal tubule of the kidney and hence cause glycosuria. Four SGLT2i are currently commercially available in many countries: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. SGLT2i reduce glycated hemoglobin by 0.5%-1.0% and have shown favorable effects on body weight, blood pressure, lipid profile, arterial stiffness and endothelial function. More importantly, SGLT2i have demonstrated impressive cardioprotective and renoprotective effects. The main mechanisms underlying their cardioprotective effects have been attributed to improvement in cardiac cell metabolism, improvement in ventricular loading conditions, inhibition of the Na⁺/H⁺ exchange in the myocardial cells, alteration in adipokines and cytokines production, as well as reduction of cardiac cells necrosis and cardiac fibrosis. The main adverse events of SGLT2i include urinary tract and genital infections, as well as euglycemic diabetic ketoacidosis. Concerns have also been raised about the association of SGLT2i with lower limb amputations, Fournier gangrene, risk of bone fractures, female breast cancer, male bladder cancer, orthostatic hypotension, and acute kidney injury.