Simvastatin Treatment in Patients with Liver Cirrhosis: a Phase II Randomized Placebo Controlled Trial Shows Reduction in IL-6 Levels.

Hepatocellular carcinoma (HCC) is a lethal cancer with rising burden. Few clinical trials have evaluated preventive strategies for HCC in high-risk patients with liver cirrhosis. Observational studies show statins are associated with reduced HCC risk, although a causal link has yet to be established. This multicenter randomized double-blinded, placebo-controlled phase II trial of 40 mg/day oral simvastatin to reduce the likelihood of hepatocarcinogenesis was conducted at four sites in the United States. The primary outcome was change in serum AFP-L3% from baseline to 6 months. Secondary biomarker endpoints include changes in serum AFP, serum IL-6, serum deoxycholic acid, liver stiffness, MELD score, and FIB-4 score. Comparisons were made using paired t-tests or the Wilcoxon rank sum test. Forty-five participants completed the intervention and final study assessments (Mean age, 58 years; Female, 42%; Asian, 2.2%, Black or African American, 11%, White, 87%, Hispanic or Latino, 51%; Child Pugh [CP] A, 69%, CP B, 16%). 10/45 (22%) had detectable AFP-L3%, which did not differ between intervention arms. Serum IL-6 levels, detectable in all participants, decreased significantly in the simvastatin compared to the placebo group (p=0.02). The number and grade of adverse events did not differ between groups. In this randomized controlled trial, simvastatin was well-tolerated in patients with liver cirrhosis but did not result in a decrease in AFP-L3%, potentially owing to the low number of participants with detectable AFP/AFP-L3%. Simvastatin did result in a decrease in IL-6, offering one potential anti-cancer mechanism of simvastatin in the setting of cirrhosis.