Combination approaches for the treatment of NASH are being actively pursued. We examined the effects of administration of a dual GLP-1 and glucagon receptor agonist (GLP-1:GCG, 0.015 mg/kg, s.c., q.d.) alone and combined with an FXR agonist (cilofexor, CILO; 30 mg/kg) and/or an acetyl-CoA carboxylase inhibitor (firsocostat analog, ACCi; 5 mg/kg, both p.o., q.d) on NASH endpoints in the AMLN diet-induced and biopsy-confirmed DIO-NASH mouse (n=15-16/group). After 12 weeks of treatment, GLP-1:GCG reduced body weight 15%, being slightly greater in the GLP-1:GCG + CILO group (22%). Liver triglyceride was reduced by GLP-1:GCG (by 76% vs. vehicle, p<0.001). Addition of CILO, ACCi or both to GLP-1:GCG further reduced liver lipid (by 82%, 88% and 91%, respectively). Histopathological pre-to-post NAFLD activity score (NAS) was reduced in 7/16 (44%) of vehicle controls and in all mice (100%) in the GLP-1:GCG-containing groups. In vehicle controls, 0/16 mice had a final NAS of 0-1 whereas this increased to 5/15 mice (33%) with GLP-1:GCG, and was not significantly improved by addition of CILO (7/15, 47%) or ACCi (6/16, 38%). Triple therapy increased number of mice with NAS of 0-1 to 11/16 (69%). GLP-1:GCG was associated with 1/15 mice (7%) improving pre-to-post fibrosis stage which was not altered by addition of CILO or ACCi, but increased to 7/16 (44%) with triple therapy. Collagen-1a and α-SMA immunoreactivity (% area) revealed no significant effect of GLP-1:GCG for collagen (5.7%), but reduction in α-SMA (1.4%, p<0.001) vs. vehicle (6.8% and 4.9%, respectively). Triple therapy reduced both collagen and α-SMA area (3.8% and 1.5%, respectively, both p<0.001 vs. vehicle).

In conclusion, GLP-1:GCG effectively reduced hepatic lipid and the addition of an FXR agonist and ACC inhibitor further improved pre-to-post NAS and fibrosis stage in DIO-NASH mice, supporting development of combination approaches for NASH.


J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. J. Norlin: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. D.A. Miranda: None. J.G. Bates: Employee; Self; Gilead Sciences, Inc. N.E. Zois: Employee; Self; Gubra. S. Veidal: None. M. Feigh: None. M. Latta: Employee; Self; Novo Nordisk A/S.

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