Incretin combination therapy for the treatment of non-alcoholic steatohepatitis
Abstract
Aims: Agonists to the glucagon-like peptide 1 receptor (GLP1R) agonists and dual agonists targeting GLP1R 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: Advanced NASH was induced by pre-feeding C57BL/6J mice a diet rich in fat, sucrose and cholesterol for 36 weeks. This was followed by eight weeks of treatment with the receptor-specific agonists 1-GCG (20 µg/kg bid sc), 2-GLP1 (3 µg/kg bid sc) or 3-GIP (30 µg/kg bid sc), or the dual (1+2) or triple (1+2+3) combinations thereof. A dual GLP1R/GCGR agonistic peptide, 4-dual-GLP1/GCGR (30 µg/kg bid sc), and liraglutide (100 µg/kg bid sc) were included as references. Results: Whereas 1-GCG and 3-GIP alone, at the selected low dose, 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 NAFLD activity score (NAS). In addition, there was a trend to further reduction in markers of hepatic inflammation and fibrosis. Notably, compared to high-dose liraglutide, 4-dual-GLP1R/GCG as well as the dual and triple combinations of selective mono-agonists demonstrated stronger improvement in NAS at the same extent of body weight loss. Conclusions: GCGR and GIPR agonism provide additional, body weight-independent improvement in a murine model of advanced NASH with fibrosis on top of GLP1R agonism.
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