1842-P: Reduction in HbA1c and Adiposity in Obese Mice Treated with Celecoxib, Valsartan, and Metformin Compared with Metformin Monotherapy

Introduction and Objective: Adiposity is a major driver of insulin resistance and pancreatic β-cell dysfunction in Type 2 Diabetes Mellitus (T2D). Although multiple drug classes improve insulin resistance and/or β-cell function, they do not directly target adiposity, and durable HbA1c control remains sub-optimal. This study evaluated whether combined cyclooxygenase-2 (Cox-2) inhibition (celecoxib) and angiotensin II type 1 receptor blockade (valsartan) improves glycaemic and adiposity-related outcomes when administered in combination with metformin in a diet-induced obesity model of early T2D. Methods: Male C57Bl/6J mice were fed a high-fat diet (HFD) for 16 weeks and treated for 31 days with metformin (150 mg/kg), celecoxib (10 mg/kg), valsartan (2 mg/kg), or their combination. Body weight, visceral adiposity, and glycated hemoglobin (HbA1c) were assessed. Between-group comparisons were performed using one-way ANOVA. Results: Combination and metformin-treated mice showed no significant change in mean % body weight from baseline, whereas HFD controls gained 8.1% by day 29 (p = 0.005). Combination-treated mice showed a significant reduction in perirenal visceral adipose tissue relative to body weight compared with HFD controls and metformin-treated mice (both p < 0.01). Combination-treated mice also exhibited lower HbA1c%, with a 1.4% reduction versus HFD controls (p < 0.001) and a 1.1% reduction versus metformin monotherapy (p = 0.045), whereas metformin monotherapy produced a non-significant 0.3% reduction (p = 0.97) Conclusion: Targeting Cox-2-mediated inflammation and the renin-angiotensin system in addition to metformin provides superior glycaemic control compared with metformin monotherapy in an early T2D model, while also reducing visceral adiposity. This combination therapy represents a biologically distinct approach to addressing key pathogenic features of T2D beyond glucose lowering alone. Disclosure G. Tachas: Employee; Current; Myopharm Limited. A.S. Padhye: Employee; Current; Myopharm Limited. K. Phoenix: Employee; Current; Myopharm.