Retatrutide Shows Multiple Metabolic Benefits in Diet-Induced Obese MASH Mouse and Hamster Models.

OBJECTIVE/METHODS: Our aim was to evaluate the efficacy of the triple glucagon, GIP, and GLP-1 receptor agonist retatrutide in diet-induced obese MASH mouse and hamster models, two preclinical models that we routinely use for assessing new therapies targeting obesity. RESULTS: In mice, retatrutide strongly reduced body weight by 31% (p < 0.0001 vs. vehicle), both fat and lean mass, and food and water intake during the first days of treatment, while energy expenditure was not altered significantly. Retatrutide markedly reduced the HOMA-IR index of insulin resistance, hepatic steatosis score, fatty acids, triglycerides, and total cholesterol content. In hamsters, retatrutide altered food preference with increased chow diet intake and decreased high fat/cholesterol diet and 10% fructose water intake. The significant weight loss was associated with a reduction in fat and lean mass, but the lean mass was not different after 5 weeks of treatment with no change in mineral bone density. Retatrutide significantly reduced HOMA-IR, plasma triglycerides, and LDL-cholesterol levels. Although retatrutide did not reduce histopathological scoring, there was a 50% reduction in hepatic triglyceride content (p < 0.01). CONCLUSIONS: Retatrutide demonstrates multiple metabolic benefits in both mouse and hamster models. Our preclinical setting will help to assess the efficacy of novel therapies targeting obesity and MASH.