GLP-1 receptor agonists and risk of hepatocellular carcinoma and all-cause mortality in patients with MASLD and type 2 diabetes: a propensity score-matched population-based cohort study.
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BACKGROUND: Hepatocellular carcinoma (HCC) is increasingly driven by non-viral causes, particularly metabolic dysfunction-associated steatotic liver disease (MASLD), which commonly coexists with type 2 diabetes mellitus (T2DM). Given the strong link between T2DM and HCC and the lack of approved pharmacologic preventive strategies, agents with dual metabolic and oncologic benefits are urgently needed. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated anti-inflammatory, anti-fibrotic, and potential anti-tumor effects. METHODS: We conducted a multinational retrospective cohort study using the TriNetX global network to evaluate associations between GLP-1RA use and incident HCC in patients with MASLD and T2DM. Adults aged 18-90 years with both conditions were identified between 2005 and 2025. Primary outcome was incident HCC; secondary was all-cause mortality. Adjusted hazard ratios (aHRs) were estimated using Cox models. RESULTS: After matching, 152,329 patients were included in each group. GLP-1RA use was associated with lower risks of HCC (aHR, 0.64; 95% CI, 0.42-0.98) and all-cause mortality (aHR, 0.37; 95% CI, 0.36-0.38). Subgroup, sensitivity, and control analyses supported the robustness of findings. CONCLUSIONS: GLP-1RA use was associated with significantly reduced risks of HCC and death in patients with MASLD and T2DM, supporting its potential for HCC chemoprevention.