Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice

Hani Jouihan, Sarah Will, Silvia Guionaud, Michelle L. Boland, Stephanie Oldham, Peter Ravn, Anthony Celeste, James L. Trevaskis

The current standard of care for nonalcoholic steatohepatitis (NASH) is limited to ameliorating components of the associated metabolic syndrome. Unfortunately, the long-term effectiveness of these interventions is questionable. Therefore, developing new pharmacological therapies is vital to combating the complex nature of NASH. Jouihan and colleagues investigated the use of long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist IP118 and the farnesoid-X receptor (FXR) agonist obeticholic acid (OCA). They found that their combination is more effective than using either compounds separately in slowing or reversing NASH-associated defects including hepatic steatosis and fibrosis.

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 Lepob/Lepob mice 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 Lepob/Lepob mice was graded using a customized integrated scoring system.

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.

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