Introduction and Objective: The GLP-1: GIP receptor dual agonist Tirzepatide has demonstrated therapeutic efficacy on clinical endpoints in a recent phase 2 clinical trial in patients with metabolic-dysfunction associated steatohepatitis (MASH) and liver fibrosis. The present study aimed to evaluate therapeutic efficacy of tirzepatide on clinical endpoints and outcome in the GAN diet-induced obese (DIO) mouse model of MASH with advanced fibrosis and hepatocellular carcinoma (HCC).Methods: Male GAN DIO-MASH-HCC mice with liver biopsy-confirmed NAFLD Activity Score (NAS ≥5) and advanced fibrosis (stage F3) received (SC, QD) vehicle (n=15) or tirzepatide (10 nmol/kg, n=17) for 14 weeks. Tumor histopathological evaluation was performed by an expert pathologist. Histopathological scoring was performed. Additional endpoints included blood and liver biochemistry and quantitative liver histology.Results: GAN DIO-MASH-HCC mice demonstrated progressive tumor burden over the 14-week study period. Tirzepatide completely prevented progression in tumor burden and reduced histological marker for hepatocellular proliferation (Ki67). Concurrently, tirzepatide improved hallmarks of MASH, including hepatomegaly, transaminases (ALT/AST), plasma and liver lipids (TG/TC), in addition to histopathological ≥2 point improvement in NAS. In agreement, tirzepatide reduced quantitative histological markers of steatosis and inflammation (CD45, galectin-3). Tirzepatide did not improve fibrosis stage, albeit reduces clinical-derived plasma fibrosis markers (TIMP-1, PIIINP) and histological marker for hepatic stellate cell activation (α-SMA), indicating anti-fibrogenic action.Conclusion: This is the first study to demonstrate that tirzepatide reduces tumor burden and improves clinical biomarkers and histopathological endpoints for NAFLD Activity Score in a preclinical translational diet-induced obese mouse model of MASH-driven HCC with advanced fibrosis.
M. Feigh: None. N.O. Eskesen: Employee; Gubra. J. Nøhr-Meldgaard: None. S.E. Pors: None. H.H. Hansen: None.
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