Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide, with increased prevalence in individuals with chronic liver conditions and type 2 diabetes mellitus (T2DM). Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) have shown promise in diabetes management and may influence liver disease progression. This systematic review and meta-analysis aimed to assess the efficacy of GLP-1 RAs in reducing the risk of HCC in patients with T2DM.

We conducted a literature search of PubMed, EMBASE, and Web of Science up to August 1, 2024. Studies that evaluated the incidence of HCC in T2DM patients treated with GLP-1 RAs compared to other therapies were included. Meta-analyses were performed using a random-effects model to compute pooled hazard ratios (HRs) and 95% confidence intervals (CIs), and heterogeneity was assessed using the I² statistic. All statistical analyses were performed in R software version 4.3.

Eight studies met the inclusion criteria. The pooled analysis demonstrated that GLP-1 RA treatment was associated with a significant reduction in HCC risk compared to insulin or no GLP-1 RA treatment (pooled HR = 0.41, 95% CI: 0.28 to 0.55), with considerable heterogeneity (I² = 74%). Compared to metformin and DPP-4 inhibitors, GLP-1 RAs did not significantly alter HCC risk (HR = 0.99, 95% CI: 0.79 to 1.27 for metformin; HR = 1.05, 95% CI: 0.80 to 1.39 for DPP-4 inhibitors). However, GLP-1 RAs were associated with a reduced risk compared to sulfonylureas (HR = 0.78, 95% CI: 0.65 to 0.93).

GLP-1 RAs may offer protective benefits against HCC in T2DM patients compared to insulin or no GLP-1 RAs, but not significantly over other antidiabetic medications. This review indicates the need for further randomized controlled trials to clarify the role of GLP-1 RAs in HCC risk mitigation and to explore their mechanistic pathways in liver disease management.