How Far beyond Diabetes Can the Benefits of Glucagon-like Peptide-1 Receptor Agonists Go? A Review of the Evidence on Their Effects on Hepatocellular Carcinoma

SIMPLE SUMMARY: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were drugs originally intended for the management of diabetes, while their role on the treatment of nonalcoholic steatohepatitis (NASH), and NASH-related hepatocellular carcinoma (HCC), has been at the forefront of medical investigation in recent years. This review presents a comprehensive compilation of extensive data on the putative role of GLP-1 RAs in the treatment of HCC, providing a solid foundation for further clarification of the molecular pathways involved. ABSTRACT: Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. Furthermore, they have demonstrated a wide range of extraglycemic effects that led to their evaluation as potential therapies for a variety of diseases beyond diabetes, such as obesity, neurogenerative disorders and nonalcoholic fatty liver disease. Given the presence of the GLP-1 receptor in hepatocytes, animal data suggest that GLP-1 RAs could regulate molecular pathways that are deeply involved in the genesis and progression of HCC, including inflammatory responses, tumor cell proliferation and oxidative stress, through direct and indirect effects on liver cells. However, future studies must assess several aspects of the benefit-to-risk ratio of the use of GLP-1 RAs in patients with HCC, including co-administration with approved systemic therapies, the incidence of gastrointestinal side effects in a high-risk population, and weight loss management in individuals with poor nutritional status and high rates of cancer cachexia. In this narrative review, we discuss the potential role of GLP-1 analogs in the treatment of HCC, focusing on the molecular mechanisms that could justify a possible benefit, but also referring to the potential clinical implications and areas for future research.