Metformin reduces hepatocellular carcinoma risk in chronic hepatitis C with advanced fibrosis after SVR

Metformin may protect against hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients with advanced fibrosis after sustained virologic response (SVR) by enhancing immune response and altering tumour metabolism. Aim: To assess HCC incidence based on FIB-4 levels and evaluate metformin’s protective effect in CHC patients post-SVR.

Methods

A retrospective analysis of prospectively collected data was conducted in a multicentre cohort of 1,556 CHC patients with SVR after direct-acting antivirals (DAAs). Patients were followed for a median of 74 months. HCC incidence was stratified by FIB-4, type 2 diabetes mellitus (T2DM), clinically significant portal hypertension (CSPH), and metformin use.

A multivariate Cox model assessed the association between metformin use and HCC risk, adjusted for confounders, and validated via Random Survival Forest (RSF) and SHapley Additive exPlanations (SHAP). Results: HCC incidence increased with higher FIB-4, reaching 1.8 per 100 patient-years in the FIB-4 >3.25 group. Within this group, CSPH and T2DM were associated with higher HCC incidence, while metformin use was associated with a reduction to levels comparable to those in the intermediate FIB-4 group.

In multivariate analysis, FIB-4, cirrhosis, CSPH, smoking, and older age were independently associated with higher HCC risk, whereas metformin use was consistently associated with HCC hazard reduction. These findings were confirmed by RSF and SHAP analyses, which particularly highlighted the potential benefit of metformin in patients with advanced fibrosis and CSPH. Conclusions: FIB-4 effectively stratifies HCC risk post-SVR.

Metformin significantly lowers HCC risk, particularly in high-risk CHC patients with CSPH, T2DM, cirrhosis or smoking habit supporting its role in HCC prevention strategies.