Incretin combination therapy for the treatment of non‐alcoholic steatohepatitis

Abstract

Aims Glucagon‐like peptide 1 receptor (GLP‐1R) agonists and dual agonists targeting GLP‐1R and the glucagon receptor (GCGR) or the glucose‐dependent insulinotropic peptide receptor (GIPR) are currently being developed for the treatment of non‐alcoholic steatohepatitis (NASH). We have tested specific mono‐agonists to these three receptors individually and in combination in a mouse model of diet‐induced NASH and fibrosis, to decipher the contribution of their activities and potential additive effects on improving systemic and hepatic metabolism. Materials and methods NASH was induced by pre‐feeding C57BL/6J mice a diet rich in fat, fructose and cholesterol for 36 weeks. This was followed by eight weeks of treatment with the receptor‐specific agonists 1‐GCG (20 μg/kg b.i.d.), 2‐GLP1 (3 μg/kg b.i.d.) or 3‐GIP (30 μg/kg b.i.d.), 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 b.i.d.), and liraglutide (100 μg/kg b.i.d.) 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, compared to high‐dose liraglutide, 4‐dual‐GLP‐1R/GCG and the triple combination of selective mono‐agonists demonstrated stronger reduction in NAFLD activity score at the same extent of 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.