Attacking kidney's sodium glucose cotransporter may have advantages in type 2 diabetes

June 9, 2009

Inhibitors of sodium glucose cotransporter (SGLT)-2 offer the promise of reducing fasting glucose and hemoglobin A1c (HbA1c) levels, independent of acting on insulin, while reducing weight, says John P. Wilding, DM. Several SGLT-2 inhibitors are in development, and one, dapagliflozin, is in phase 3 clinical studies.

Inhibitors of sodium glucose cotransporter (SGLT)-2 offer the promise of reducing fasting glucose and hemoglobin A1c (HbA1c) levels, independent of acting on insulin, while reducing weight, says John P. Wilding, DM. Several SGLT-2 inhibitors are in development, and one, dapagliflozin, is in phase 3 clinical studies.

"The kidney plays a major often unrecognized vital role in glucose metabolism," he says. It filters and reabsorbs 180 g of insulin every day.

Evidence indicates that renal glucose reabsorption is increased in diabetes, and that increased renal glucose transporter expression and activity is associated with type 2 diabetes. SGLT-2 is responsible for about 90% of glucose reabsorption.

SLGT-2 inhibitors block the receptor in the proximal convoluted tubule in the kidney that is responsible for glucose reabsorption. Blocking this receptor increases urinary glucose excretion, thereby reducing fasting glucose levels and increasing urinary glucose secretion and urinary volume, leading to improvements in glucose levels and weight loss.

Dapagliflozin has been shown to reduce fasting glucose levels in a dose-dependent manner. At doses greater than 2.5 mg, its effect on fasting glucose is greater than that of 1,500 mg of metformin.

When added to insulin and oral insulin sensitizers in insulin-resistant patients with type 2 diabetes, dapagliflozin decreased HbA1c, fasting plasma glucose levels, and postprandial glucose levels and resulted in weight loss. "Reduced glucosuria largely explains weight gain during insulin therapy," says Dr. Wilding, reader in medicine, University of Liverpool and Aintree Hospital, UK. "If we can induce glucosuria, we can potentially prevent weight gain."

Typical weight loss with SGLT-2 inhibitors is 2.5 kg to 3.4 kg. Further, because SGLT-2 inhibitors act independently of insulin, the risk of hypoglycemia is low. These agents also may also have a diuretic effect to lower blood pressure.

Volume depletion in vulnerable patients is a potential concern with inhibition of SGLT-2 cotransporter, as is a possible increase in aldosterone levels.