Glucagon-Like Peptide-1 Receptor Agonists and Hepatocellular Carcinoma Prevention: A Meta-Analysis and Clinical Decision Framework

Background & Aims: While glucagon-like peptide-1 receptor agonists (GLP-1RAs) show promise for hepatoprotection in type 2 diabetes mellitus (T2DM), the magnitude of hepatocellular carcinoma (HCC) risk reduction and optimal patient selection remain unclear. This is particularly relevant given that metabolic dysfunction-associated steatotic liver disease (MASLD) affects 70% of patients with T2DM and represents a major HCC risk factor. We conducted a comprehensive meta-analysis to quantify GLP-1RA efficacy in HCC prevention and inform clinical implementation strategies. Methods: We systematically searched PubMed, Embase, and Web of Science through June 2025 for cohort studies comparing HCC incidence between GLP-1RA users and nonusers with T2DM. Random-effects meta-analysis, network meta-analysis, and meta-regression were performed. Heterogeneity was explored through stratified analyses and quantitative bias assessment. Results: Nine studies encompassing 2,283,835 total patients (analyzed cohorts: 1,012,482) were included. GLP-1RA use was associated with a 42% reduced HCC risk (pooled HR 0.60, 95% CI: 0.41–0.88; I2 = 86.2%). Effect magnitude varied significantly by comparator: versus insulin (HR 0.29, 95% CI: 0.13–0.67), versus oral agents (HR 0.81, 95% CI: 0.63–1.05), versus no treatment (HR 0.77, 95% CI: 0.52–1.14). Meta-regression identified insulin as comparator as the primary driver of heterogeneity, explaining 55% of the between-study variance. Benefits were greatest in patients without cirrhosis (HR 0.41, 95% CI: 0.29–0.58). Network meta-analysis ranked GLP-1RAs highest for HCC prevention (SUCRA 0.89), with insulin ranking lowest (0.08). The number needed to treat ranged from 24 to 476. Conclusions: GLP-1RAs substantially reduce HCC risk in T2DM, with benefits partly attributable to avoiding insulin's potential hepatotoxicity. These findings support the preferential use of GLP-1RAs over insulin in patients at HCC risk.