Supaglutide alleviates hepatic steatosis in monkeys with spontaneous MASH

Abstract

Background: Glucagon-like peptide 1 (GLP-1) is an incretin hormone and plays an important role in regulating glucose homeostasis. GLP-1 has a short half-life due to degrading enzyme dipeptidyl peptidase-IV and rapid kidney clearance, which limits its clinical application as a therapeutic agent. We demonstrated previously that supaglutide, a novel long-acting GLP-1 analog, exerted hypoglycemic, hypolipidemic, and weight loss effects in type 2 diabetic db/db mice, DIO mice, and diabetic monkeys. In the present study, we investigated supaglutide's therapeutic efficacy in rhesus monkeys with spontaneous metabolic dysfunction-associated steatohepatitis (MASH).

Methods: 15 rhesus monkeys with biopsy-confirmed MASH were divided into three groups, receiving supaglutide 50 µg/kg, supaglutide 150 µg/kg, and placebo, respectively, by weekly subcutaneous injection for 3 months. Liver fat content quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), liver pathology, and metabolic parameters were assessed.

Results: We found that once-weekly subcutaneous injections of supaglutide for 3 months significantly reduced hepatic fat accumulation, with a 40% percentage decrease in MRI-PDFF from baseline (P < 0.001 vs. Placebo). Treatment with supaglutide alleviated hepatic histological steatosis (nonalcoholic fatty liver disease activity score P < 0.001 vs. Placebo) without worsening of fibrosis, as assessed by ultrasound-guided liver biopsy. Supaglutide concomitantly ameliorated liver injury exemplified by a lowering tendency of hepatic alanine aminotransferase levels. Supaglutide also decreased body weight in a dose-dependent fashion accompanied by decreased food intake, improved lipid profile and glycemic control.

Conclusions: Supaglutide exerts beneficial effects on hepatic and metabolic outcomes in spontaneous MASH monkeys.

Keywords: Glucagon-like peptide 1; Liver biopsy; Liver fat content; Metabolic dysfunction-associated steatohepatitis; Supaglutide.

Fig. 1

Study design. The experiment consists of two periods: adaptation (4 weeks) and observation (13 weeks). The black dots indicate time points of physical examination and blood sampling for laboratory testing as indicated. The red dots indicate time points of MRI-PDFF as indicated. The triangles indicate the time points for the liver biopsy. The arrow indicates the time point for the titration of Supa from 100 µg/kg to 150 µg/kg. Abbreviations: MRI-PDFF, magnetic resonance imaging-proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; MASH, metabolic dysfunction-associated steatohepatitis; QW, once weekly; SC, Subcutaneous; Supa, supaglutide

Fig. 2

Supaglutide decreases liver fat content as assessed by MRI-PDFF. A Representative liver MRI-PDFF images with supaglutide treatment. B Pre- and post-treatment liver fat content levels, and C Percentage change of liver fat content from baseline as assessed by MRI-PDFF. Data were expressed as Mean ± SEM. **, p < 0.01 compared to the baseline. ###, p < 0.001 compared to the placebo. Abbreviations: MRI-PDFF, magnetic resonance imaging-proton density fat fraction; Supa, supaglutide

Fig. 3

Supaglutide alleviated MASH progression without worsening of fibrosis. A Change of NAFLD activity score from baseline. B Pre- and post-treatment fibrosis area fraction. Data were expressed as Mean ± SEM. ##, p < 0.01 compared to the placebo. Abbreviations: MAFLD, metabolic dysfunction-associated steatotic liver disease; Supa, supaglutide

Fig. 4

Supaglutide improves liver histopathology. Histological changes in hepatic steatosis, lobular inflammation, ballooning and fibrosis stage as assessed by A H&E, and B Masson staining in liver post- vs. pre-treatment biopsies. Blue arrows show inflammatory foci

Fig. 5

Supaglutide decreases liver injury biomarkers. Change of A ALT, B AST, and C GGT. All data were expressed as Mean ± SEM. #, ## p < 0.05 and 0.01 compared to the placebo. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyl transferase; Supa, supaglutide

Fig. 6

Supaglutide decreases food intake and bodyweight. Percentage change of A bodyweight, B BMI, and C food intake. Data were expressed as Mean ± SEM. #, ## p < 0.05 and 0.01 compared to the placebo. Abbreviations: BMI, body mass index; Supa, supaglutide

Fig. 7

Supaglutide improves lipid and glucose profiles. A-C Percentage change of lipids from baseline. D-E Pre- and post-treatment blood glucose levels. Data were expressed as Mean ± SEM. #, ## p < 0.05 and 0.01 compared to the placebo. Abbreviations: FPG, fasting plasma glucose; FRA, fructosamine; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride; Supa, supaglutide