A Meta-Analysis of Statin Use and Risk of Hepatocellular Carcinoma

Abstract

Background. The use of statins is a potential protective factor against the development of hepatocellular carcinoma. Therefore, we conducted a meta-analysis to evaluate the contribution of statins to the risk of hepatocellular carcinoma. Methods. We searched for PubMed and EMBASE through January 2021. Results. Thirty-two studies (eighteen cohort, eleven case-control, and three randomized controlled trials) reporting 56,838 cases of hepatocellular carcinoma in 4,963,518 persons were included. Statin users were less likely to develop hepatocellular carcinoma than nonusers (adjusted odds ratio, 0.58; 95% CI: 0.51–0.67). Stratified analysis showed that statins reduced the risk of hepatocellular carcinoma in Asian and Western populations (odds ratio, 0.54 vs. 0.60). Besides, statins have protective effects against hepatocellular carcinoma after hepatitis B virus (odds ratio, 0.44; 95% CI: 0.22–0.85) and hepatitis C virus infections (odds ratio, 0.53; 95% CI: 0.49–0.57). Statins have protective effects on people with chronic liver disease (odds ratio, 0.52; 95% CI: 0.40–0.68) and on the general population (odds ratio, 0.60; 95% CI: 0.50–0.72). Lipophilic statins can prevent hepatocellular carcinoma (odds ratio, 0.51, 95% CI: 0.46–0.57), while hydrophilic statins cannot (odds ratio, 0.77, 95% CI: 0.58–1.02). The single-drug analyses showed that simvastatin (odds ratio, 0.53, 95% CI: 0.48–0.59), atorvastatin (odds ratio, 0.54, 95% CI: 0.45–0.64), rosuvastatin (odds ratio, 0.55, 95% CI: 0.37–0.83), lovastatin (odds ratio, 0.30, 95% CI: 0.15–0.62), and pitavastatin (odds ratio, 0.36, 95% CI: 0.17–0.75) had significant benefits. Further studies have shown that those in the high-dose group experienced better effects in preventing hepatocellular carcinoma (adjusted hazard ratio, 0.38 vs. 0.55). Further research found that the combined use of aspirin did not increase the chemoprevention effect of liver cancer (odds ratio, 0.57; 95% CI: 0.40–0.81). In addition, the preventive effect of statins improved with the extension of follow-up time (odds ratio, 0.54 vs. 0.65). Conclusion. Our meta-analysis shows that the use of statins is associated with a lower risk of liver cancer.

Effect of Pravastatin and Simvastatin on the Reduction of Cytochrome C

“…Hydrophilic statins on the other hand cannot. This association can mostly be seen in patients with the highest accumulative dose of statins compared to the patients with the lowest accumulative dose [ 22 , 23 ]. The antitumor effect of statins has been observed by others as well.…”

“…Fluvastatin (lipophilic statin) can induce the mitochondrial pathway of apoptosis in hepatocellular carcinoma cell lines [ 22 ]. During this process, the expression of anti-apoptotic Bcl2 diminishes, while the expression of pro-apoptotic Bax increases.…”

Statin use and risk of progression to liver cirrhosis in chronic hepatitis B independent of conventional risk factors: A nationwide study

“…Third, primarily owing to the limited availability of detailed information in the NHIS database, we cannot assess the different effect of lipophilic versus hydrophilic statins on progression to LC. Although several studies have suggested that lipophilic statins should have a more favorable effect on preventing HCC development than hydrophilic statins, [ 36 , 37 ] there has been no study comparing its different effect regarding the progression to LC among the HBV‐infected population. It can be conjectured that lipophilic statins have stronger chemoprotective effects than hydrophilic statins owing to better fat solubility and membrane permeability as well as increasing nitric oxide availability.…”

Hepatocellular Carcinoma Chemoprevention with Generic Agents

“…45 No enhanced HCC risk reduction was observed by addition of aspirin in a recent meta-analysis. 46 Atorvastatin, a lipophilic statin, inhibits oncogenic YAP, Akt, and retinoid X receptor pathways and suppresses high-risk pattern of a clinical HCC risk–predictive signature, PLS, in cell culture model of HCV infection and NAFLD. 36…”

“…45 No enhanced HCC risk reduction was observed by addition of aspirin in a recent meta-analysis. 46 Atorvastatin, a lipophilic statin, inhibits oncogenic YAP, Akt, and retinoid X receptor pathways and suppresses high-risk pattern of a clinical HCC risk-predictive signature, PLS, in cell culture model of HCV infection and NAFLD. 36 Based on these encouraging findings, lipophilic statins have been evaluated in currently ongoing prospective clinical trials to confirm their association with reduced HCC incidence and/or surrogate end points (►Table 1).…”