Effectiveness in the inhibition of dapagliflozin and canagliflozin on M-type K+ current and α-methylglucoside-induced current in pituitary tumor (GH3) and pheochromocytoma PC12 cells

Inhibiting sodium-glucose co-transporters (SGLTs), which have a key role in the reabsorption of glucose in the kidney, has been proposed as a novel therapeutic strategy for diabetes. Genetic mutations in the kidney-specific SGLT2 isoform that result in benign renal glycosuria, as well as preclinical and clinical studies with SGLT2 inhibitors in type 2 diabetes, support the potential of this approach. These investigations indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. Although data from ongoing Phase III trials of these agents are needed to more fully assess safety, results suggest that the beneficial effects of SGLT2 inhibition might be achieved without exerting significant side effects--an advantage over many current diabetes medications. This article discusses the role of SGLT2 in glucose homeostasis and the evidence available so far on the therapeutic potential of blocking these transporters in the treatment of diabetes.

Dapagliflozin, administered to patients in once-daily oral doses, is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that blocks the reabsorption of glucose from urine into the blood. This 14-day study randomized patients with type 2 diabetes mellitus (T2DM) to four treatment groups receiving daily oral doses of 5-, 25-, or 100-mg doses of dapagliflozin or placebo, in order to evaluate glucosuria and glycemic parameters. Significant reductions in fasting serum glucose (FSG) were observed on day 2 with 100 mg dapagliflozin (-9.3%, P < 0.001), and dose-dependent reductions were observed on day 13 with the 5-mg (-11.7%; P < 0.05), 25-mg (-13.3%; P < 0.05), and 100-mg (-21.8%; P < 0.0001) doses as compared with placebo. Significant improvements in oral glucose tolerance test (OGTT) were observed with all doses on days 2 and 13 (P < 0.001 as compared with placebo). On day 14, urine glucose values were 36.6, 70.1, and 69.9 g/day for the 5-, 25-, and 100-mg doses (as compared with no change for placebo), which were slightly lower than those on day 1. This was attributed to the decrease in filtered glucose load following improved glycemic control. Dapagliflozin produced dose-dependent increases in glucosuria and clinically meaningful changes in glycemic parameters in T2DM patients.

The inhibition of gut and renal sodium-glucose cotransporters (SGLTs) has been proposed as a novel therapeutic approach to the treatment of diabetes. We have identified dapagliflozin as a potent and selective inhibitor of the renal sodium-glucose cotransporter SGLT2 in vitro and characterized its in vitro and in vivo pharmacology. Cell-based assays measuring glucose analog uptake were used to assess dapagliflozin's ability to inhibit sodium-dependent and facilitative glucose transport activity. Acute and multi-dose studies in normal and diabetic rats were performed to assess the ability of dapagliflozin to improve fed and fasting plasma glucose levels. A hyperinsulinemic-euglycemic clamp study was performed to assess the ability of dapagliflozin to improve glucose utilization after multi-dose treatment. Dapagliflozin potently and selectively inhibited human SGLT2 versus human SGLT1, the major cotransporter of glucose in the gut, and did not significantly inhibit facilitative glucose transport in human adipocytes. In vivo, dapagliflozin acutely induced renal glucose excretion in normal and diabetic rats, improved glucose tolerance in normal rats, and reduced hyperglycemia in Zucker diabetic fatty (ZDF) rats after single oral doses ranging from 0.1 to 1.0 mg/kg. Once-daily dapagliflozin treatment over 2 weeks significantly lowered fasting and fed glucose levels at doses ranging from 0.1 to 1.0 mg/kg and resulted in a significant increase in glucose utilization rate accompanied by a significant reduction in glucose production. These data suggest that dapagliflozin has the potential to be an efficacious treatment for type 2 diabetes.