Chemoprevention of Hepatocellular Carcinoma With Statins, Aspirin and Metformin

Rebecca W. Zeng; Jie Ning Yong; Darren J. H. Tan; Clarissa E. Fu; Wen Hui Lim; Jieling Xiao; Kai En Chan; Caitlyn Tan; Xin Lei Goh; Douglas Chee; Nicholas Syn; Eunice X. Tan; Mark D. Muthiah; Cheng Han Ng; Nobuharu Tamaki; Sung Won Lee; Beom Kyung Kim; Mindie H. Nguyen; Rohit Loomba; Daniel Q. Huang


Aliment Pharmacol Ther. 2023;57(6):600-609. 

In This Article

Abstract and Introduction


Background: Emerging data suggest that statins, aspirin and metformin may protect against hepatocellular carcinoma (HCC) development. However, prior meta-analyses were limited by heterogeneity and inclusion of studies without adequate adjustment for baseline risks.

Aim: To examine by an updated meta-analysis the association between these medications and HCC risk.

Methods: Medline and Embase databases were searched from inception to March 2022 for studies that balanced baseline risks between study groups via propensity score matching or inverse probability of treatment weighting, that reported the impact of statins, aspirin or metformin on HCC risk. Multivariable-adjusted hazard ratios (HRs) for HCC were pooled using a random effects model.

Results: Statin use was associated with reduced HCC risk overall (HR: 0.52; 95% CI: 0.37–0.72) (10 studies, 1,774,476), and in subgroup analyses for cirrhosis, hepatitis B/C, non-alcoholic fatty liver disease, studies accounting for concurrent aspirin and metformin consumption and lipophilic statins. Aspirin use was associated with reduced HCC risk overall (HR: 0.48; 95% CI: 0.27–0.87) (11 studies, 2,190,285 patients) but not in studies accounting for concurrent statin and metformin use. Metformin use was not associated with reduced HCC risk overall (HR: 0.57; 95% CI: 0.31–1.06) (3 studies, 125,458 patients). Most analyses had moderate/substantial heterogeneity, except in follow-up <60 months for aspirin (I 2 = 0%).

Conclusion: Although statin and aspirin use were associated with reduced HCC risk, only statin use was significant in subgroup analyses accounting for concurrent medications. Metformin use was not associated with reduced HCC risk. These data have implications for future clinical trial design.


Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide.[1,2] Patients with HCC have a 5-year survival of less than 20% overall.[3–7] The poor prognosis of HCC, in general, has led to increased interest in HCC prevention. Emerging data suggest that the use of statins, aspirin and metformin may be chemoprotective against HCC.[8–12] However, prior meta-analyses on this topic had some limitations such as pooling odds ratios that are not time-to-event measurements,[11,13–16] or pooling data that had not been adequately adjusted for background differences in treated versus untreated patients. There have also been several recent relevant large studies that were not included in previous meta-analyses.[17–20]

In light of these considerations, we performed an updated meta-analysis to determine the association between the risk of HCC and the use of statins, aspirin or metformin. We included cohort studies that balanced patient baseline characteristics between groups by propensity score matching (PSM) or inverse probability of treatment weighting (IPTW) to provide robust estimates of the comparative risk of HCC between study groups.[21–24] We performed a pooled analysis of co-variate-adjusted hazard ratios (HRs) to account for censoring of events and investigated heterogeneity by performing multiple subgroup analyses for relevant factors such as cirrhosis, sex, liver disease aetiology, method of HCC diagnosis, concurrent medication use, follow-up duration and the use of competing risks of death.