Efficacy of Mitiglinide Combined with Dapagliflozin in Streptozotocin-nicotinamide-induced Type 2 Diabetic Rats and in Zucker Fatty Rats

Abstract

The efficacy of the combination of the rapid-acting insulin secretagogue mitiglinide and the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin was explored in streptozotocin-nicotinamide-induced type 2 diabetic (STZ-NA) rats and in Zucker fatty (ZF) rats. The STZ-NA rats were prepared at 8 weeks of age. At 9 weeks of age, the combination study was conducted by oral glucose tolerance test (OGTT). At 13 weeks of age, ZF rats were dosed orally with dapagliflozin once daily up to the 22(nd) day. At days 15 and 22, the combination study was conducted by OGTT. In 2 different animal models, plasma glucose levels were strongly suppressed by the combination of mitiglinide and dapagliflozin as compared with either drug alone. The urinary glucose excretion was drastically elevated in the dapagliflozin group, but the combination with mitiglinide suppressed it about 50%. In STZ-NA rats, the plasma insulin secretion by the combination of both drugs was about at the same level as in the mitiglinide group. In ZF rats, the plasma insulin secretion by the combination of both drugs was less than mitiglinide group. Thus, in 2 different animal models, the combination of mitiglinide and dapagliflozin showed stronger antihyperglycemic action accompanied by less insulin secretion than mitiglinide alone, and reduced the urinary glucose excretion as compared with dapagliflozin used alone. These results indicate that the combination of mitiglinide and dapagliflozin can be a promising combination for the treatment of diabetic patients.

Effects of combination of mitiglinide with various oral antidiabetic drugs in streptozotocin‐nicotinamide‐induced type 2 diabetic rats and Zucker fatty rats

“…Combining mitiglinide and canagliflozin induced stronger hypoglycaemic effects, and less insulin secretion than mitiglinide alone did. The hypoglycaemic effect was similar to that induced by dapagliflozin . These findings reflected both the rapid insulin secretion by mitiglinide and SGLT2 inhibition by canagliflozin.…”

“…We previously confirmed the additive hypoglycaemic effects of the mitiglinide and DPP‐IV or SGLT2 inhibitor combination. In contrast to the enhancement of activity alone, we showed that these combinations reduced side effects of each antidiabetic drug by decreasing their dose requirements while maintaining the hypoglycaemic effects . Mitiglinide showed an additive hypoglycaemic effect in combination with the four antidiabetic drugs used in this study.…”

“…Similarly, in combining mitiglinide and an α‐GI, mitiglinide exhibited an additive effect on the SGLT1 and SGLT2 inhibitory actions of canagliflozin. Additionally, the canagliflozin‐induced increase in urinary volume and glucose excretion was more significant than that induced by dapagliflozin . In contrast to dapagliflozin that exhibits high SGLT2 selectivity, the antidiabetic effects of canagliflozin have been attributed to its inhibition of SGLT1 and SGLT2 in the kidneys .…”

“…Additionally, we examined the usefulness of combining mitiglinide and voglibose using the OSTT in STZ‐NA rats because voglibose is an α‐GI. We previously investigated the combination effects of mitiglinide and dapagliflozin in STZ‐NA and ZF rats . Hypoglycaemic effects and urinary glucose excretion, the main pharmacological actions of SGLT2 inhibitors, were evident in the STZ‐NA rat model.…”

“…In a previous study, we evaluated the efficacy of the combination of mitiglinide and an SGLT2 inhibitor, dapagliflozin, in a type 2 diabetic rat model. We showed that this combination exhibited strong antihyperglycaemic effects, and the actions of both agents were complementary . In addition, we compared the individual effects of mitiglinide and glibenclamide administered in combination with the DPP‐IV inhibitor, sitagliptin.…”