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

Area of Science:

• Hepatology and oncology research
• Clinical pharmacology
• Viral hepatitis research

Background:

• Sustained virological response (SVR) post-hepatitis C virus (HCV) treatment reduces hepatocellular carcinoma (HCC) risk, but a residual risk remains.
• Metformin is linked to lower HCC risk, yet its impact on post-SVR risk based on cumulative exposure (CME) is not well-defined.

Purpose of the Study:

• To investigate the association between cumulative metformin exposure (CME) and the risk of developing hepatocellular carcinoma (HCC) in patients who have achieved sustained virological response (SVR) after direct-acting antiviral therapy.

Main Methods:

• A multicentre cohort of 1531 patients achieving SVR after direct-acting antiviral therapy was analyzed.
• Cumulative metformin exposure (CME) was modeled as a time-updated variable using start-stop Cox models, with stabilized inverse probability weighting to manage confounding.
• Analyses were sex-stratified and adjusted for FIB-4, clinically significant portal hypertension (CSPH), type 2 diabetes mellitus (T2DM), and smoking, with a prespecified T2DM-restricted analysis.

Main Results:

• Hepatocellular carcinoma (HCC) developed in 50 patients during a median follow-up of 75.5 months.
• Cumulative metformin exposure (CME) was associated with a significantly lower risk of HCC in the overall weighted model (HR, 0.46 per year; p=0.004).
• Factors independently increasing HCC risk included clinically significant portal hypertension (CSPH), type 2 diabetes mellitus (T2DM), smoking, and FIB-4 > 3.25. In T2DM patients, CME remained protective (HR, 0.49 per year; p=0.009), while CSPH increased risk (HR, 6.04; p<0.001).

Conclusions:

• Cumulative metformin exposure (CME) following sustained virological response (SVR) is associated with a reduced risk of hepatocellular carcinoma (HCC).
• This duration-dependent inverse association between CME and HCC risk is clinically significant and interpretable primarily in metformin-eligible patients with type 2 diabetes mellitus (T2DM).