Effects of the combination of SGLT2 selective inhibitor ipragliflozin and various antidiabetic drugs in type 2 diabetic mice

The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the combinatory effects of SGLT2 selective inhibitor ipragliflozin and various antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice were investigated. Ipragliflozin dose-dependently increased urinary glucose excretion and improved glucose tolerance. In addition, each antidiabetic drug (mitiglinide, glibenclamide, sitagliptin, insulin, metformin, voglibose, or rosiglitazone) also significantly improved glucose tolerance without affecting urinary glucose excretion. Combination treatment of ipragliflozin with each antidiabetic drug additively improved glucose tolerance. In these experiments, ipragliflozin-induced increases in urinary glucose excretion were not influenced by combination treatment with antidiabetic drugs. Further, ipragliflozin did not affect antidiabetic drug-induced insulinotropic action (mitiglinide and glibenclamide), increases in plasma glucagon-like peptide-1 and insulin levels via inhibition of dipeptidyl peptidase 4 activity (sitagliptin), increases in plasma insulin level (insulin), decreases in hepatic phosphoenolpyruvate carboxykinase activity (metformin), inhibition of small intestinal disaccharidase activity (voglibose), or improvement of impaired insulin secretion (rosiglitazone). These results suggest that combination treatment of ipragliflozin with various antidiabetic drugs additively enhances the improvement in glucose tolerance without affecting each drug's unique pharmacological effects. Ipragliflozin may therefore be expected to be effective when administered as part of a combination regimen in the treatment of type 2 diabetes.