Sodium glucose co-transporter 2 inhibitors and their mechanism for improving glycemia in patients with type 2 diabetes

Jaime A Davidson, Louis Kuritzky
Postgraduate Medicine 2014, 126 (6): 33-48
Most antihyperglycemic agents available for the treatment of type 2 diabetes mellitus (T2DM) have insulin-dependent mechanisms of action; that is, they either stimulate insulin production (sulfonylureas, glinides, incretin mimetics, dipeptidyl peptidase-4 inhibitors), improve insulin sensitivity (thiazolidinediones, biguanides), or directly augment endogenous insulin (basal and prandial insulins). As β-cell function deteriorates, combination therapy is usually needed to effectively control glycemia. Moreover, some antihyperglycemic agents are associated with adverse effects, such as weight gain and hypoglycemia. A novel approach for treating T2DM is to inhibit renal glucose reabsorption through inhibition of sodium glucose co-transporter 2 (SGLT2), which is responsible for the majority of glucose reabsorption in the renal proximal tubule. By reducing the renal capacity to reabsorb filtered glucose, SGLT2 inhibitors increase excretion of excess glucose in urine, thereby decreasing plasma glucose concentration. Thus, although glucosuria is often viewed as an indicator of systemic hyperglycemia, this perception needs to be modified in patients treated with SGLT2 inhibitors where glucosuria is an indicator of the desired treatment effect. Currently, 2 SGLT2 inhibitors, canagliflozin and dapagliflozin, are approved in the United States for the treatment of patients with T2DM; other SGLT2 inhibitors are in various stages of clinical development. Clinical studies in patients with T2DM on a variety of background diabetes treatments have demonstrated the efficacy of canagliflozin and dapagliflozin in improving glycemic control and reducing body weight and blood pressure. Canagliflozin and dapagliflozin are generally well tolerated, with a low risk of hypoglycemia when not used in combination with insulin and/or sulfonylurea. Higher incidences of genital mycotic infections and adverse events related to osmotic diuresis and volume depletion were observed with both agents; they were generally mild or moderate and infrequently led to study discontinuation. Based on current evidence, SGLT2 inhibitors provide an important new treatment option for patients with T2DM.

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