3068-LB: A Next-Generation GLP-1/GIP/GCG/Gastrin Quadruple Agonist with Potent Antiobesity and Glucose-Lowering Effects

Introduction and Objective: We developed a novel GLP-1/GIP/Glucagon/Gastrin quadruple agonist to address unmet needs in glycemic control and renal protection beyond current triple agonists. We hypothesized that incorporating Gastrin signaling provides additive benefits by enhancing pancreatic beta-cell function and downregulating renal SGLT2 expression. This study evaluates the pharmacological profile and therapeutic efficacy of this quadruple agonist in obesity animal model. Methods: In vitro receptor activation was measured in GLP-1R, GIPR, GCGR, and Gastrin overexpressed CHO-K1 cells using cAMP or p-ERK assays. To assess renal effects, SGLT2 protein expression was analyzed in HK-2 cells via Immunoblot. For in vivo study, Diet-Induced Obese C57BL/6J mice were administered the quadruple agonists for 21 days. Endpoints included body weight change, food intake, and fasting glucose levels. An Oral Glucose Tolerance Test was performed in normal mice. Results: The quadruple agonist #1 and #2 exhibited superior potency relative to native ligand response (set at 100%): GLP-1 31.9 and 15.0%, GIP 67.7 and 9.2%, Glucagon 33.4 and 31.9%, and Gastrin 27.3 and 37.7%. Immunoblot analysis in HK-2 cells confirmed a reduction in SGLT2 expression. In DIO mice, 21 days of treatment elicited a robust body weight reduction of 59.4 and 54.7% (vs. -0.7% for vehicle; p<0.001), accompanied by a 75.8 and 61.4% suppression in cumulative food intake. Fasting glucose levels decreased to 101.8 and 69.5 mg/dL, compared with 222.9 mg/dL in the vehicle group. In the OGTT, the quadruple agonist reduced glucose AUC by 50.1 and 48.7%. Conclusion: This novel quadruple agonist demonstrates potent weight-lowering efficacy and superior glycemic control. Gastrin signaling additional therapeutic benefit through enhanced pancreatic function and renal SGLT2 downregulation. These findings suggest that this quadruple agonist is a promising next-generation candidate for obesity and type 2 diabetes, surpassing current multi-agonist standards. Disclosure S. Lee: None.