GLP-1 receptor agonists at the crossroads of diabetes, hepatic steatosis, and hepatocellular carcinoma

Abstract The epidemiology of hepatocellular carcinoma (HCC) is increasingly shaped by the expanding burden of type 2 diabetes (T2D), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed as glucose-lowering agents, have emerged as systemic metabolic therapies with effects extending beyond glycemic control, including weight reduction, cardiovascular and renal protection, and improvement of steatotic liver disease. This review summarizes current evidence on the potential role of GLP-1RAs in modifying the natural history of MASLD and reducing HCC risk. Clinical trials consistently support beneficial effects on steatosis and metabolic dysfunction-associated steatohepatitis, particularly in non-cirrhotic patients, whereas effects in established cirrhosis appear less consistent. Real-world studies and target trial emulations suggest that GLP-1RA use may be associated with lower rates of hepatic decompensation, cirrhosis progression, and incident HCC, although the magnitude and robustness of these associations vary according to disease stage, comparator therapy, exposure definition, and outcome hierarchy. The strongest apparent benefit is generally observed against insulin or sulfonylureas, while differences are attenuated in comparisons with other metabolically favorable agents, such as SGLT2 inhibitors. Mechanistic data support indirect hepatoprotective actions mediated by reduced insulin resistance, lipotoxicity, inflammation, fibrogenesis, adipose–liver crosstalk, and tumor-promoting pathways. Overall, GLP-1RAs represent promising disease-modifying agents in metabolic liver disease, but dedicated prospective studies are required to establish causality and define their role in HCC prevention.