1779-P: Significant Synergistic Hypoglycemic Effects in Type 2 Diabetes Mellitus by HDM1010

Introduction and Objective: Substantial research has demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT-2i) combination therapy plays an important role in the treatment of type 2 diabetes mellitus (T2DM). Here, we investigated the potential synergistic hypoglycemic effects of HDM1010, which is a combination product of HDM1002 and SGLT-2i in a T2DM mouse model. Methods: After the induction of T2DM with a high-fat diet followed with i.p. injection of streptozotocin, the humanized GLP-1R (C57BL/6J) transgenic mice were treated with daily oral gavage of HDM1002 (20 or 40 mg/kg), and SGLT-2i (1 or 5 mg/kg), or their combinations for 28 days. Random blood glucose (RBG) was monitored during the treatment period, then fasting blood glucose (FBG), HbA1c(%), homeostasis model assessment of insulin resistance (HOMA-IR) and liver function parameters were evaluated at the study endpoint. Results: All four combination groups of HDM1002 and SGLT-2i reduced RBG levels synergistically (RBG AUCTD1-TD27: p<0.0001 vs. monotherapy groups), and exerted a significant synergistic lowering effect on FBG and achieving normoglycemic levels. 40 mg/kg HDM1002+1 mg/kg SGLT2i (HOMA-IR: p<0.05 vs. monotherapy groups) exerted a synergistic effect in improving insulin resistance. Three combination groups (40 mg/kg HDM1002+1 mg/kg SGLT2i, 20/40 mg/kg HDM1002+5 mg/kg SGLT2i) showed a synergistic and significantly greater reduction in HbA1c levels (HbA1c%: p<0.05 vs. monotherapy groups). No hepatic burden was observed in combination therapy. Conclusion: Collectively, HDM1010 exhibits a faster, more optimal, and more stable effect on blood glucose control, which indicates its superiority. Investigational new drug application has been approved by FDA.