879-P: The Effects of the Combination of Dorzagliatin and Canagliflozin on Glucose Homeostasis in Mice

Dorzagliatin is a newly approved glucokinase activator for treatment of type 2 diabetes. The mechanisms include improved GLP-1 secretion, restoration of islet function and increased insulin sensitivity in the liver. Canagliflozin is an SGLT2 inhibitor. To establish basis for clinical combination therapy, this study aims to assess the effects of combining these two drugs on the regulation of glucose homeostasis in mice. In single dose studies, wild-type mice were given either dorzagliatin (30 mg/Kg), canagliflozin (30 mg/Kg) or a combination of both. Then each group followed by a glucose challenge. Mice were also daily given either dorzagliatin (15 mg/Kg), canagliflozin (30 mg/Kg) or a combination for 5 days. Glucose and hormone levels were measured at random time, after overnight fasting, and 3 hours refeeding. Canagliflozin reduced glucose levels and enhanced glucose tolerance without affecting hormone secretion. In contrast, dorzagliatin exhibited comparable glucose-lowering effects by elevating insulin and GLP-1 secretion, with unaltered glucagon secretion. The combined medications enhanced glucose tolerance by augmenting the secretion of insulin, glucagon, and GLP-1. Canagliflozin, when used in combination with dorzagliatin, resulted in an amplification of glucagon secretion following a glucose challenge. Following 5 days of treatments, dorzagliatin demonstrated superior results in reducing glucose levels at random and 3 hours refeeding time points by increasing insulin and GLP-1 release. On the other hand, canagliflozin was more effective in lowering fasting glucose levels. When the two medicines were combined, glucose levels reduced at all time points, while the stimulatory effects of dorzagliatin on insulin and GLP-1 were maintained. This study has verified that GKA and SGLT2i reduce glucose levels through distinct mechanisms. GKA achieves this by enhancing the secretion of insulin and GLP-1. Both mechanisms of action are preserved when two drugs are combined.