Incretin combination therapy for the treatment of non‐alcoholic steatohepatitis

Aims To test specific mono‐agonists to the glucagon‐like peptide‐1 receptor (GLP‐1R), glucagon receptor (GCGR) and glucose‐dependent insulinotropic peptide receptor (GIPR), individually and in combination, in a mouse model of diet‐induced non‐alcoholic steatohepatitis (NASH) and fibrosis in order to decipher the contribution of their activities and potential additive effects to improving systemic and hepatic metabolism. Materials and methods We induced NASH by pre‐feeding C57BL/6J mice a diet rich in fat, fructose and cholesterol for 36 weeks. This was followed by 8 weeks of treatment with the receptor‐specific agonists 1‐GCG (20 μg/kg twice daily), 2‐GLP1 (3 μg/kg twice daily) or 3‐GIP (30 μg/kg twice daily), or the dual (1 + 2) or triple (1 + 2 + 3) combinations thereof. A dual GLP‐1R/GCGR agonistic peptide, 4‐dual‐GLP1/GCGR (30 μg/kg twice daily), and liraglutide (100 μg/kg twice daily) were included as references. Results Whereas low‐dose 1‐GCG or 3‐GIP alone did not influence body weight, liver lipids and histology, their combination with 2‐GLP1 provided additional weight loss, reduction in liver triglycerides and improvement in histological disease activity score. Notably, 4‐dual‐GLP‐1R/GCGR and the triple combination of selective mono‐agonists led to a significantly stronger reduction in the histological non‐alcoholic fatty liver disease activity score compared to high‐dose liraglutide, at the same extent of body weight loss. Conclusions GCGR and GIPR agonism provide additional, body weight‐independent improvements on top of GLP‐1R agonism in a murine model of manifest NASH with fibrosis.