Association of GLP-1 Receptor Agonists and Hepatocellular Carcinoma Incidence and Hepatic Decompensation in Patients With Type 2 Diabetes

Abstract

Background & aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer death. HCC is preventable with about 70% of HCC attributable to modifiable risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), Food and Drug Administration-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 and 95% confidence interval calculated.

Results: GLP-1RAs were associated with a lower risk of incident HCC with hazard ratio 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 6 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 with 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.

Keywords: Cancer Prevention; Glucagon-Like Peptide-1 Receptor Agonists; Hepatocellular Carcinoma; Real-World Evidence; Type 2 Diabetes Mellitus.

Figure 1.

Risk of incident (first-time diagnosis) HCC and hepatic decompensating events in patients with T2DM. (A) Comparison of the risk of incident HCC between propensity score–matched cohorts. (B) Comparison of the risk of hepatic decompensating events between propensity score–matched cohorts. Outcomes were followed for 5 years after the index event (prescription of GLP-1RA vs specific non-GLP-1RA anti-diabetes medication classes [but not both] in 1/2010–2/2019). Hazard rates were calculated using Kaplan-Meier analysis to estimate the probability of outcome at daily time intervals with censoring applied. Overall risk = number of patients with outcomes during the follow-up time window/number of patients in the cohort at the beginning of the time window. A plus sign (+) indicates that a patient was prescribed GLP-1RA or non-GLP-1RA anti-diabetes medication, while a minus sign (−) indicates that they were not. SU, sulfonylureas, TZD, thiazolidinediones.

Figure 2.

Risk of incident (first-time diagnosis) HCC and hepatic decompensating events in patients with T2DM, with and without obesity. (A) Comparison of the risk of incident HCC between propensity score–matched cohorts. (B) Comparison of the risk of hepatic decompensating events between propensity score–matched cohorts. Outcomes were followed for 5 years after the index event.

Figure 3.

Risk of the incident (first-time diagnosis) HCC and hepatic decompensating events in patients with T2DM, with and without MASLD, MASH, and liver fibrosis and cirrhosis. (A) Comparison of the risk of incident HCC between propensity score–matched cohorts. (B) Comparison of the risk of hepatic decompensating events between propensity score–matched cohorts. Outcomes were followed for 5 years after the index event.

Figure 4.

Risk of the incident (first-time diagnosis) HCC and hepatic decompensating events in patients with T2DM, with and without alcohol or tobacco use disorders. (A) Comparison of the risk of incident HCC between propensity score–matched cohorts. (B) Comparison of the risk of hepatic decompensating events between propensity score–matched cohorts. Outcomes were followed for 5 years after the index event.

Figure 5.

Comparing GLP-1RA combination therapies with monotherapies for the risk of the incident (first-time diagnosis) HCC and hepatic decompensating events in patients with T2DM. (A) Comparison of the risk of incident HCC between propensity score–matched cohorts. (B) Comparison of the risk of hepatic decompensating events between propensity score–matched cohorts. Outcomes were followed for 5 years after the index event (prescription of GLP-1RA for the GLP-RA combination therapies vs specific anti-diabetes medication classes for monotherapies from January 2010 to February 2019).