1813-P: Coadministration of a GLP-1/Glucagon Receptor Agonist with an FXR Agonist and ACC Inhibitor Reverses Nonalcoholic Steatohepatitis (NASH) in Diet-Induced and Biopsy-Confirmed Mice

• DOI: 10.2337/db20-1813-p
• Publication Date: 2020-06-15T16:29:48Z
• Authors: JAMES L. TREVASKIS; JENNY NORLIN; DIEGO A. MIRANDA; JAMIE G. BATES; NORA E. ZOIS; SANNE VEIDAL; MICHAEL FEIGH; MARKUS LATTA
• Keywords: Nonalcoholic steatohepatitis; Steatohepatitis

Combination approaches for the treatment of NASH are being actively pursued. We examined effects administration a dual GLP-1 and glucagon receptor agonist (GLP-1:GCG, 0.015 mg/kg, s.c., q.d.) alone combined with an FXR (cilofexor, CILO; 30 mg/kg) and/or acetyl-CoA carboxylase inhibitor (firsocostat analog, ACCi; 5 both p.o., q.d) on endpoints in AMLN diet-induced biopsy-confirmed DIO-NASH mouse (n=15-16/group). After 12 weeks treatment, GLP-1:GCG reduced body weight 15%, slightly greater + CILO group (22%). Liver triglyceride was by (by 76% vs. vehicle, p<0.001). Addition CILO, ACCi or to further liver lipid 82%, 88% 91%, respectively). Histopathological pre-to-post NAFLD activity score (NAS) 7/16 (44%) vehicle controls all mice (100%) GLP-1:GCG-containing groups. In controls, 0/16 had final NAS 0-1 whereas this increased 5/15 (33%) GLP-1:GCG, not significantly improved addition (7/15, 47%) (6/16, 38%). Triple therapy number 11/16 (69%). associated 1/15 (7%) improving fibrosis stage which altered ACCi, but triple therapy. Collagen-1a α-SMA immunoreactivity (% area) revealed no significant effect collagen (5.7%), reduction (1.4%, p<0.001) (6.8% 4.9%, area (3.8% 1.5%, respectively, p<0.001 vehicle). conclusion, effectively hepatic ACC mice, supporting development combination NASH. Disclosure J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. J. Norlin: Novo Nordisk A/S. Stock/Shareholder; D.A. Miranda: None. J.G. Bates: N.E. Zois: Gubra. S. Veidal: M. Feigh: Latta: