Association of GLP-1 receptor agonists and hepatocellular carcinoma incidence and hepatic decompensation in patients with type 2 diabetes

Background & aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer death. HCC is preventable with about 70 percent of HCC attributable to modifiable risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), FDA-approved medications for treating type 2 diabetes mellitus (T2DM), have pleiotropic effects on counteracting risk factors for HCC. Here we evaluate the association of GLP-1RAs with incident HCC risk in a real-world population.

Methods: This retrospective cohort included 1,890,020 patients with a diagnosis of T2DM who were prescribed GLP-1RAs or other non-GLP-1RA anti-diabetes medications and had no prior diagnosis of HCC. Incident (first-time) diagnosis of HCC and hepatic decompensating events during a 5-year follow-up was compared between cohorts of patients prescribed GLP-1 RAs vs other anti-diabetes medications. Time-to-first-event analysis was performed using Kaplan-Meier survival analysis with hazard ratio (HR) and 95% confidence interval (CI) calculated.

Results: GLP-1RAs were associated with a lower risk of incident HCC with HR of 0.20 [0.14-0.31], 0.39 [0.21-0.69], 0.63 [0.26-1.50] compared with insulin, sulfonylureas, and metformin respectively. GLP-1RAs were associated with a significantly lower risk of hepatic decompensation compared with six other anti-diabetes medications. Reduced risks were observed in patients without and with different stages of fatty liver diseases, with more profound effects in patients without liver diseases. Similar findings were observed in patients with and without obesity and alcohol or tobacco use disorders. GLP-1RA combination therapies were associated with decreased risk for HCC and hepatic decompensations compared with monotherapies.

Conclusions: GLP-1RAs were associated with a reduced risk of incident HCC and hepatic decompensation compared to other anti-diabetes medications in patients with T2DM. These findings provide supporting evidence for future studies to investigate the underlying mechanisms and their clinical use.