2856-LB: Synergistic Effects of Vanoglipel and Metformin on Glycemic Control and Body Weight Reduction in a Diet-Induced Obese Mouse Model

Introduction and Objective: Vanoglipel (DA-1241), a G protein-coupled receptor 119 (GPR119) agonist, demonstrated efficacy in a Phase 1b study in patients with T2D. This study evaluated the effects of vanoglipel in combination with metformin, the standard-of-care therapy for T2D, on glycemic control and body weight in a diet-induced obese mouse model with mild hyperglycemia. Methods: Male C57BL/6J mice were fed a 60% kcal high-fat diet for 17 weeks and randomized by body weight and fat mass. Mice received vehicle, vanoglipel (100 mg/kg/day), metformin (300 mg/kg/day), or the combination for approximately 3 weeks. Data were analyzed by one-way ANOVA with multiple-comparison tests. Results: Compared with control, non-fasting blood glucose decreased in all treatment groups (vanoglipel: 17.3%, metformin: 14.9%, combination: 28.7%; p<0.05). After 6-hour fasting, the combination reduced glucose by 22.7% (p<0.05) and showed greater improvement than either monotherapy. Greater reductions in body weight and fat mass were also observed in the combination group. While each monotherapy reduced body weight by approximately 4%, the combination achieved a 16.3% reduction versus control (p<0.05). Fat mass increased by 0.4-1.4 g from baseline in the control and monotherapy groups but decreased by 3.6 g in the combination group (p<0.05). Combination treatment increased total GLP-1 and peptide YY (PYY) levels by 6.4-fold and 1.5-fold, respectively, and was accompanied by reduced food intake. These results suggest that multiple mechanisms, including enhanced gut peptide signaling, appetite suppression, and other potential pathways, may have contributed to the improved glycemic control and body weight reduction observed with the combination treatment. Conclusion: Vanoglipel combined with metformin improved glycemic control and reduced body weight to a greater extent than either monotherapy, suggesting its potential as a therapeutic combination strategy for additional metabolic benefit in T2D and obesity.