Lowering plasma glucose concentration by inhibiting renal sodium-glucose cotransport

Abstract

Maintaining normoglycaemia not only reduces the risk of diabetic microvascular complications but also corrects the metabolic abnormalities that contribute to the development and progression of hyperglycaemia, that is insulin resistance and beta-cell dysfunction. Progressive beta-cell failure, in addition to side effects associated with many current antidiabetic agents, for example hypoglycaemia and weight gain, presents major obstacles to the achievement of the recommended goal of glycaemic control in patients with type 2 diabetes mellitus (T2DM). Thus, novel effective therapies are needed for optimal glucose control in subjects with T2DM. Most recently, specific inhibitors of the renal sodium-glucose cotransporter 2 (SGLT2) have been developed to produce glucosuria and lower the plasma glucose concentration. Because of the iR unique mechanism of action, which is independent of insulin secretion and insulin action, these agents are effective in lowering the plasma glucose concentration in all stages of the disease and can be combined with all other antidiabetic agents. In this review, we will summarize the available data concerning the mechanism of action, efficacy and safety of this novel class of antidiabetic agents.

Keywords: SGLT2 inhibition; kidney; sodium-glucose cotransport; type 2 diabetes.

Fig. 1

Sodium–glucose reuptake in renal proximal tubule epithelial cells.

Fig. 2

Kinetics of the renal handling of glucose.

Fig. 3

Impact of reduced renal function on the glucose-lowering efficiency of dapagliflozin. Adapted from Bristol Myers-Squibb NDA [27].