Glucagon-Like Peptide-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic disorders characterised by excessive fat accumulation in the liver in the absence of significant alcohol intake. Its progressive form, non-alcoholic steatohepatitis (NASH), combines steatosis with inflammation and fibrosis and represents a leading cause of chronic liver failure worldwide. There is a pressing need for targeted pharmacotherapies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for glycaemic control in type 2 diabetes, have demonstrated pleiotropic benefits including weight loss, improved insulin sensitivity and anti-inflammatory effects. Mechanistically, GLP-1 RAs reduce hepatic de novo lipogenesis, enhance fatty acid oxidation, mitigate endoplasmic reticulum stress and may promote autophagy. Clinically, these agents afford dual mitigation of obesity and dysglycaemia, making them attractive candidates for NAFLD management. Recent advances have explored both direct hepatic actions and systemic metabolic improvements, underscoring the global significance of GLP-1 RA therapy in curbing the burden of fatty liver disease.

Research from Nature Portfolio

A phase 2a randomised, double-blind, placebo-controlled trial of a novel tri-agonist targeting glucose-dependent insulinotropic polypeptide, GLP-1 and glucagon receptors reported profound reductions in liver fat content in participants with metabolic dysfunction-associated steatotic liver disease. After 24 weeks of once-weekly subcutaneous administration, mean relative liver fat reductions ranged from approximately 43 % at the lowest dose to over 82 % at higher doses, with a majority of treated individuals achieving normal hepatic fat levels. These decreases correlated closely with body-weight loss, abdominal fat reduction and improved indices of insulin sensitivity and lipid metabolism, illustrating the potential of multi-receptor agonism to deliver rapid and sustained amelioration of steatosis.

Glucagon-Like Peptide-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

GLP-1 receptor agonist: A class of drugs that mimic the incretin hormone GLP-1, enhancing insulin secretion, reducing appetite and exerting extra-pancreatic effects.

Non-alcoholic fatty liver disease (NAFLD): A condition characterised by excessive fat accumulation in hepatocytes without significant alcohol consumption.

Non-alcoholic steatohepatitis (NASH): An advanced form of NAFLD marked by hepatocellular inflammation, cell injury and varying degrees of fibrosis.

Hepatic steatosis: The pathological accumulation of triglycerides within liver cells.

Phase 2 clinical trial: A mid-stage study designed to evaluate efficacy, optimal dosing and safety in a target patient population.

References

1. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine (2024).
2. Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials. Metabolites (2021).
3. GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. International Journal of Molecular Sciences (2023).