Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes-what hepatologists need to know.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic lipid accumulation, cell injury, inflammation and fibrosis. Insulin resistance, a hallmark of type 2 diabetes (T2D) and obesity, is a key pathogenic driver of NASH. Other than difficult-to-maintain lifestyle changes, there are no approved treatments for NASH. Due to their effects on multiple pathophysiological processes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been tested in disorders related to insulin resistance and metabolic defects. AIMS: To summarise studies of GLP-1RAs relevant to the treatment of NASH. METHODS: PubMed searches were performed and results were compiled. RESULTS: Large trials with GLP-1RAs in T2D demonstrate highly effective glucose lowering, with body weight loss, and in some cases, reduced cardiovascular events and improved liver transaminases. The GLP-1RAs, liraglutide and semaglutide, were associated with clinically relevant, sustained body weight reduction in individuals with overweight or obesity and without T2D. In a phase II trial in NASH, liraglutide reduced metabolic dysfunction, insulin resistance and lipotoxicity in key organs associated with NASH pathogenesis. Furthermore, liraglutide and semaglutide led to histological resolution of NASH in ~40% to 60% of patients, although a statistically significant effect on fibrosis has not been confirmed. Regarding safety, GLP-1RAs are associated with gastrointestinal and gallbladder-related adverse events, with the latter perhaps related to weight loss. Meta-analyses do not indicate increased risk of acute pancreatitis, pancreatic cancer or other malignancies with GLP-1RAs. CONCLUSIONS: These studies support the use of GLP-1RAs for the improvement of underlying metabolic dysfunction observed in NASH and suggest further long-term phase III trials are warranted.