Sodium Glucose Cotransporter 2 Inhibitors as a New Treatment for Diabetes Mellitus

Context: Sodium-glucose cotransporter 2 (SGLT2) expressed in the proximal renal tubules accounts for about 90% of the reabsorption of glucose from tubular fluid. Genetic defects of SGLT2 result in a benign familial renal glucosuria. Pharmacological agents that block SGLT2 are being tested as potential treatment for type 2 diabetes mellitus. Evidence Acquisition: A Pubmed search was used to identify all relevant articles on the physiology of SGLTs as well as published preclinical and clinical experimental studies with SGLT2 inhibitors; a reference search of all retrieved articles was also undertaken. Evidence Synthesis: SGLT2 is almost exclusively expressed in the proximal renal tubules. Preclinical studies with selective SLGT2 inhibitors show dose-dependent glucosuria and lowering of blood glucose in models of type 2 diabetes. Preliminary clinical studies of up to 3-month duration show dose-dependent lowering of glycosylated hemoglobin up to 0.9% along with modest weight loss. Side effects include an increase in genital fungal infection compared to placebo, increased urine volume (300-400 ml/24 h), and evidence of volume depletion consistent with mild diuretic effect. Conclusion: SGLT2 inhibitors are showing promise as a useful addition to the current therapeutic options in type 2 diabetes mellitus. Results of ongoing phase III clinical trials are awaited and will determine whether the risk-benefit ratio will allow approval of this new class of drug for the management of type 2 diabetes mellitus. (J Clin Endocrinol Metab 95: 34-42, 2010)