Beyond weight loss: the long-term effects of glucagon-like peptide-1 receptor agonists in metabolic dysfunction-associated steatohepatitis and fibrosis regression

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by hepatic steatosis, inflammation, and fibrosis. Although lifestyle modification is foundational, effective pharmacotherapy is needed, particularly for advanced fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show promise beyond weight loss, but their long-term effects on fibrosis and underlying mechanisms remain unclear. This systematic review evaluates their effects on MASH and fibrosis, mechanisms of action, clinical evidence, and knowledge gaps. A systematic search of PubMed, Embase, Medline, and Cochrane Library identified randomized controlled trials and observational studies evaluating GLP-1 RAs in MASLD, reporting histological or non-invasive markers of fibrosis and steatosis. Comparisons with pioglitazone and vitamin E, alongside cardiovascular and metabolic outcomes, were assessed. GLP-1 RAs improved hepatic steatosis and inflammation, although fibrosis regression varied across trials, some demonstrated MASH resolution without worsening fibrosis, while others reported modest effects. Additional benefits included improvements in weight, glycemic control, lipid profiles, and cardiovascular risk factors. The contribution of direct hepatic versus weight-mediated effects remains unclear, and long-term safety in cirrhosis, including sarcopenia and worsening portal hypertension, requires further investigation. GLP-1 RAs offer promising hepatic and extrahepatic benefits in MASLD, but their effects on fibrosis require confirmation through larger, longer-term trials with robust histological endpoints. Combination therapy, long-term safety, and individualized treatment remain priorities for defining their role as first-line therapy.