2540-P: Weight Loss with Tirzepatide and Retatrutide Is Associated with Changes in Food Preference and Multiple Metabolic Benefits in the Free Choice Diet–Induced Obese Hamster Model

Introduction and Objective: Tirzepatide (TIRZE), a GIP/GLP-1 receptors dual agonist, and retatrutide (RETA), a GIP/GLP-1/glucagon receptors triple agonist, have both demonstrated significant body weight loss and liver fat reduction in patients with obesity. To test whether this weight loss is associated with changes in food preference and improvements in metabolic disorders, we evaluated both drugs in the free choice diet-induced obese and dyslipidemic hamster, a model with a human-like lipoprotein metabolism used to assess new obesity therapies. Methods: Obesity was induced with a 20-week free choice diet, which presents hamsters with a choice between control chow diet or high fat/high cholesterol (HF/HC) diet, and normal water or 10% fructose water. Obese hamsters were then treated subcutaneously Q3D for 5 weeks with vehicle, TIRZE 15nmol/kg or RETA 15nmol/kg. Results: Both TIRZE and RETA significantly reduced body weight and altered food preference with greater chow diet intake and lower HF/HC diet and 10% fructose water intake. The weight lowering effect was associated with significant reduction in fat and lean mass, but the lean mass was not different after 5 weeks of treatment for both drugs. TIRZE and RETA significantly reduced glycemia and insulinemia, leading to lower HOMA-IR index of insulin resistance: -67% and -83%, respectively (both p<0.001 vs. vehicle). Both drugs significantly reduced plasma free fatty acids and triglycerides, lower VLDL- and LDL-cholesterol but unchanged HDL-cholesterol levels. Although histopathological scoring was unchanged, there was a 58% and 44% reduction in hepatic triglycerides content with TIRZE (p<0.01) and RETA (p<0.05), respectively. While TIRZE had no effect, RETA significantly reduced the hepatic expression of genes involved in inflammation and fibrosis. Conclusion: TIRZE and RETA demonstrate metabolic benefits in obese hamsters. Our preclinical setting will help to assess the efficacy of novel obesity therapies versus both drugs. Disclosure F. Briand: Employee; Current; PHYSIOGENEX. Stock/Shareholder; Current; PHYSIOGENEX. C. Bigot: Employee; Current; Physiogenex. E. Grasset: None. T. Sulpice: None.