Molecular metabolismNov 7, 2017

Greater liver fat and scarring reduction in mice with combined treatment of a diabetes hormone mimic and obeticholic acid

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 3, 2026

Abstract

Combination therapy with GLP-1R agonist IP118 and FXR agonist obeticholic acid (OCA) significantly reduced liver weight by 29% in mice with nonalcoholic steatohepatitis (NASH).

OCA alone reduced liver weight and lipid in NASH mice by 17%, but did not affect plasma ALT or AST levels.
IP118 alone significantly decreased liver weight by 21%, liver lipid by 15%, ALT by 29%, and AST by 27%.
The combination of OCA and IP118 resulted in greater reductions in liver weight, liver lipid, ALT, and AST compared to either drug alone.
Therapeutic effects of OCA + IP118 were linked to reductions in body weight of 4.3% and improved glycemic control.
In diet-induced obese mice, OCA + IP118 decreased body weight by 25.3%, outperforming the 12.5% reduction seen with IP118 alone.

Simplified

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice.

METHODS: OCA and IP118 alone and in combination were sub-chronically administered to Lep/Lepmice with diet-induced NASH or diet-induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lep/Lepmice was graded using a customized integrated scoring system. ob ob ob ob

RESULTS: OCA reduced liver weight and lipid in NASH mice (both by -17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (-21%), liver lipid (-15%), ALT (-29%), and AST (-27%). The combination of OCA + IP118 further reduced liver weight (-29%), liver lipid (-22%), ALT (-39%), and AST (-36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (-4.3% and -3.5% respectively) and improved glycemic control in OCA + IP118-treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight (-25.3%) to a greater degree than IP118 alone (-12.5%) and further improved glucose tolerance and reduced hepatic lipid.

CONCLUSION: Our data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH.

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Greater liver fat and scarring reduction in mice with combined treatment of a diabetes hormone mimic and obeticholic acid

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