Introduction and Objective: Substantial research shows that GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2i) exhibit complementary glucose-lowering mechanisms and are expected to have cardiorenal benefits. Here, we investigated the potential synergistic renoprotective effects of HDM1010, which is a combination product of HDM1002 and SGLT2i in a type 2 diabetes mellitus kidney disease (T2DKD) mouse model. Methods: After a 12-week induction of T2DKD with a high-fat diet followed with an i.p. injection of streptozotocin, mice were treated with daily oral gavage of HDM1002 (20 or 40 mg/kg), and SGLT2i (10 mg/kg), or their combinations for 10 weeks. Random blood glucose (RBG), urinary and blood parameters were monitored. Kidney tissues were harvested for histopathological evaluation. Results: HDM1010 reduced RBG levels synergistically (AUCTD1-TD70: 40 mg/kg HDM1002 was 1252 mmol/L·day vs. SGLT2i was 977.9 mmol/L·day vs. combination group was 707 mmol/L·day). The HDM1010 group also reduced urinary albumin-to-creatinine ratio (UACR) levels significantly and increased estimated glomerular filtration rate (eGFR). Moreover, the HDM1010 group significantly reduced glomerular score (Model was 1.67±0.33 vs. 40 mg/kg HDM1002 was 0.67±0.33 vs. SGLT2i was 0.50±0.22 vs. combination group was 0.00±0.00) and ameliorated renal inflammation score synergistically (Model was 2.50±0.22 vs. 40 mg/kg HDM1002 was 1.83±0.17 vs. SGLT2i was 1.83±0.48 vs. combination group was 0.67±0.21). Furthermore, HDM1010 also improved liver function in mice model. Conclusion: Collectively, HDM1010 exhibited more potent effect on blood glucose control, and demonstrated a synergistic improvement in renal function comparing with either monotherapy. Investigational new drug application has been prepared for further clinical development. Disclosure R. Zhu: None. Z. Li: None. H. Pan: None. C. Jiang: None. D. Liu: None.
ZHU et al. (Fri,) studied this question.