Glucagon-like peptide-1 receptor agonist for primary prevention of hepatocellular carcinoma in high-risk patients: A real-world analysis across metabolic, viral, alcoholic, and hereditary liver disease.

10522 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. While antiviral and metabolic therapies have reduced incidence, scalable pharmacologic strategies for primary prevention (PP) remain a critical unmet need. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated preclinical antitumor activity and the potential to mitigate hepatic lipotoxicity while promoting metabolic reprogramming to stabilize cirrhosis. However, while chemoprevention signals are observed in metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes, the efficacy of GLP-1RAs for PP across diverse liver disease etiologies remains underexplored. To address this gap, we conducted a global, multicenter analysis on the efficacy and safety of GLP-1RAs for the PP of HCC in a pan-etiology high-risk cohort. Methods: A retrospective cohort study was conducted using the TriNetX database (150M patients across 108 health organizations). Adults 18–90 years at elevated HCC risk with ≥ 1 risk factor (chronic viral hepatitis, cirrhosis, MASLD, alcohol use disorder, or hereditary liver disorders) were identified. Cohort A (≥3 months of GLP-1RA) was propensity score-matched 1:1 with Cohort B (non-users) on demographics, HbA1c, BMI, and MELD-Na scores. The primary endpoint was incident HCC, and secondary endpoints were incidence of gastrointestinal (GI) side effects. We employed a 3-month lag period to mitigate immortal time bias. Time-to-event outcomes were assessed via Kaplan-Meier analysis and Cox proportional hazards models. Sensitivity & subgroup analyses were performed to confirm robustness across non-metabolic etiologies. Results: After matching, 592,718 patients were analyzed (296,359 per cohort). Median follow-up was 2,450 days for GLP-1RA users vs 2,114 days for non-users. GLP-1RA use was associated with a 73% reduction in incident HCC (140/296,345 events vs 432/296,198) HR 0.271 (0.224-0.328), (NNT=1,015). Notably, the protective effect was most pronounced in non-diabetics HR 0.179 (0.140-0.229) and lean patients (BMI < 29) HR 0.161 (0.103-0.252). Risk reductions were sustained across all etiologies, including alcohol liver disease (HR 0.379), cirrhosis (HR 0.456), chronic viral hepatitis (HR 0.477), and MASLD (HR 0.605). GLP-1RA use was associated with a significant increase in GI adverse events. Conclusions: GLP-1RA use was associated with a 73% reduction in incident HCC, consistent across subgroups. The enhanced benefit in non-diabetic and lean cohorts suggests a direct anti-neoplastic mechanism independent of weight loss or glycemic control. The NNT of 1,015 highlights the substantial public health impact of GLP-1RA therapy in preventing a high-mortality malignancy. These findings warrant prospective validation.