The Role of Kidney in Glucose Homeostasis — SGLT2 Inhibitors, a New Approach in Diabetes Treatment

Vasileios Andrianesis; John Doupis


Expert Rev Clin Pharmacol. 2013;6(5):519-539. 

In This Article

Main Features of SGLT2 Inhibitors

Phlorizin opened the way for a new promising class of antidiabetic agents. The main action of SGLT2 inhibitors is the induction of glucosuria and osmotic diuresis. Further features, benefits and adverse effects of this class of agents are revealed from animal studies and clinical trials on the early drugs of this class.

SGLT2 inhibitors effectively reduce the HbA1c providing a hypoglycemia safe glucose control in patients with type 2 diabetes.[54,55] The mechanism of urinary excretion and not intracellular restoration of excess glucose leads to calories loss. This feature gives to SGLT2 inhibitors the additional advantage of body weight reduction, contrary to most of the other antidiabetic agents. The combination of weight loss and the mild diuretic effect of SGLT2 inhibitors, due to osmotic diuresis, may explain the reduction in blood pressure observed.[55–57] Treatment with SGLT2 inhibitors does not depend on insulin secretion or supplementation and consequently, the risk of hypoglycemia and decreased Insulin sensitivity is eliminated.[56] High oral bioavailability, which achieved by the latest agents, facilitates oral administration and ensures better patient compliance. The novel mechanism of action of SGLT2 inhibitors helps their concurrent administration with other anti-diabetic agents. Among the side effects observed in clinical trials, urinary tract infections and genital infections are the most common. Furthermore, mean changes from baseline in renal function tests (BUN and creatinine increase) during clinical trials on SGLT2 inhibitors place limits on the administration of SGLT2 inhibitors to patients with renal dysfunction.

The risk of hypoglycemia related to SGLTs inhibition was assessed in vivo by Nagata et al.[58] In this study was examined the inhibition of SGLT2 and SGLT1 in rats by tofogliflozin, a highly specific SGLT2 inhibitor and phorizin (SGLT1/2 inhibitor). It was demonstrated that in hypoglycemic conditions, the contribution of SGLT2 transporters in renal glucose reabsorption was smaller than under hyperglycemic condition and that SGLT2 selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.[58]

Finally, in the study of Yamaguhi et al. was exhibited that the in vivo selectivity of tofogliflozin and four other inhibitors toward SGLT2 transporter showed a good correlation with the in vitro data.[59]