Cumulative Metformin Use and Hepatocellular Carcinoma Risk After HCV SVR: A Multicentre Cohort Study.

Abstract

Although sustained virological response (SVR) after hepatitis C virus treatment reduces hepatocellular carcinoma (HCC) incidence, residual risk persists. Metformin has been associated with lower HCC risk, but whether cumulative metformin exposure (CME) lowers post-SVR risk remains unclear. We evaluated whether CME was associated with lower HCC risk after SVR. We analysed a multicentre cohort of 1531 patients who achieved SVR after direct-acting antiviral therapy (median follow-up, 75.5 months). Metformin exposure was modelled as a time-updated cumulative variable in start-stop Cox models to control for immortal-time bias. Stabilised inverse probability weighting addressed confounding by indication and censoring. The overall model was sex-stratified and adjusted for FIB-4, clinically significant portal hypertension (CSPH), type 2 diabetes mellitus (T2DM) and smoking. A prespecified T2DM-restricted analysis used T2DM-specific IPTW plus IPCW, sex stratification and CSPH adjustment. During follow-up, 50 patients developed HCC. Crude incidence was highest among patients with FIB-4 > 3.25, CSPH and T2DM without metformin exposure (4.84 cases per 100 person-years). In the overall weighted model, CME was associated with lower HCC risk (HR, 0.46 per year; 95% CI, 0.27-0.77; p = 0.004). CSPH, T2DM, smoking and FIB-4 > 3.25 independently increased risk. In the T2DM-restricted model, each additional year remained associated with lower HCC hazard (HR, 0.49; 95% CI, 0.29-0.84; p = 0.009), whereas CSPH was associated with higher risk (HR, 6.04; 95% CI, 2.12-17.19; p < 0.001). After SVR, CME was associated with lower HCC risk; this possible duration-dependent inverse association was clinically interpretable only among metformin-eligible patients with T2DM. People cured of hepatitis C can still develop liver cancer, especially with diabetes and advanced liver disease. Longer metformin use after cure was associated with lower liver cancer risk among people with diabetes. Metformin deserves further prevention studies, although regular surveillance remains essential.