Incretin combination therapy for the treatment of non-alcoholic steatohepatitis

Area of Science:

• Metabolic diseases
• Hepatology
• Pharmacology

Background:

• Non-alcoholic steatohepatitis (NASH) is a progressive liver disease with limited treatment options.
• Targeting incretin receptors, including GLP-1R, GCGR, and GIPR, shows promise for metabolic and liver diseases.
• Understanding the combinatorial effects of these receptor agonists is crucial for developing effective therapies.

Purpose of the Study:

• To evaluate the efficacy of individual and combined agonists for GLP-1R, GCGR, and GIPR.
• To assess the impact on systemic and hepatic metabolism in a diet-induced NASH mouse model.
• To determine the contribution and additive effects of targeting these receptors simultaneously.

Main Methods:

• Diet-induced NASH was established in C57BL/6J mice over 36 weeks.
• Mice were treated with selective mono-agonists (GCG, GLP1, GIP), dual combinations, or a triple combination.
• A dual GLP-1R/GCGR agonist and liraglutide were used as reference treatments.

Main Results:

• Combination therapy with GLP-1R agonists and GCG or GIP agonists led to weight loss and reduced liver lipids.
• The triple combination and a dual GLP-1R/GCGR agonist significantly improved NASH histological scores.
• These improvements were more pronounced than high-dose liraglutide, even with similar weight loss.

Conclusions:

• GCGR and GIPR agonism provide significant benefits beyond GLP-1R agonism in a murine NASH model.
• Combinatorial targeting of these receptors offers additive effects, improving liver disease independently of body weight loss.
• These findings support the development of multi-agonist therapies for NASH and related metabolic disorders.