Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.

PURPOSE Statins have potential protective effects against cancers, but no studies have focused on patients with chronic hepatitis B virus (HBV) infection. The purpose of this study was to investigate the association between the use of statins in HBV-infected patients and the risk of hepatocellular carcinoma (HCC). PATIENTS AND METHODS We conducted a population-based cohort study from the Taiwan National Health Insurance Research Database. A total of 33,413 HBV-infected patients were included as the study cohort. Each patient was individually tracked from 1997 to 2008 to identify incident cases of HCC since 1999. Subsequent use of statin, other lipid-lowering agents, aspirin, and angiotensin-converting enzyme inhibitors was identified. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) and 95% CIs for the association between the use of statins and the occurrence of HCC in the HBV-infected cohort. RESULTS There were 1,021 HCCs in the HBV cohort during the follow-up period of 328,946 person-years; the overall incidence rate was 310.4 HCCs per 100,000 person-years. There was a dose-response relationship between statin use and the risk of HCC in the HBV cohort. The adjusted HRs were 0.66 (95% CI, 0.44 to 0.99), 0.41 (95% CI, 0.27 to 0.61), and 0.34 (95% CI, 0.18 to 0.67) for statin use of 28 to 90, 91 to 365, and more than 365 cumulative defined daily doses (cDDDs), respectively, relative to no statin use (< 28 cDDDs). CONCLUSION Statin use may reduce the risk for HCC in HBV-infected patients in a dose-dependent manner. Further mechanistic research is needed.

[1]  Michael L. Johnson,et al.  Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. , 2009, Gastroenterology.

[2]  Lu-Yu Hwang,et al.  HEPATOCELLULAR CARCINOMA AND HEPATITIS B VIRUS A Prospective Study of 22 707 Men in Taiwan , 1981, The Lancet.

[3]  A. Jánosi,et al.  Rosuvastatin in older patients with systolic heart failure. , 2007, The New England journal of medicine.

[4]  Richard M. Martin,et al.  Statins and risk of cancer: A systematic review and metaanalysis , 2007, International journal of cancer.

[5]  Hermann Brenner,et al.  Individual and joint use of statins and low‐dose aspirin and risk of colorectal cancer: A population‐based case–control study , 2007, International journal of cancer.

[6]  R. Collins,et al.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins , 2005, The Lancet.

[7]  P. Nguyen,et al.  Comparative effects of lovastatin on mammary and prostate oncogenesis in transgenic mouse models. , 2003, Carcinogenesis.

[8]  M. Gale,et al.  Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[9]  M. Minden,et al.  HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis , 2002, Leukemia.

[10]  J. Kench,et al.  Genotype‐specific mechanisms for hepatic steatosis in chronic hepatitis C infection , 2002, Journal of gastroenterology and hepatology.

[11]  G. Targher,et al.  Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. , 2007, Journal of hepatology.

[12]  H. Behlouli,et al.  Statins and cancer risk. , 2008, The American journal of medicine.

[13]  M. Lai,et al.  Cancer trends in Taiwan. , 2010, Japanese journal of clinical oncology.

[14]  S. Hulley,et al.  Carcinogenicity of lipid-lowering drugs. , 1996, JAMA.

[15]  A. Peterson,et al.  Statins and Liver Toxicity: A Meta‐Analysis , 2004, Pharmacotherapy.

[16]  C. Hennekens,et al.  Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. , 1997, JAMA.

[17]  C. Heeschen,et al.  Statins Have Biphasic Effects on Angiogenesis , 2002, Circulation.

[18]  Ming-Shiang Wu,et al.  Early Helicobacter pylori eradication decreases risk of gastric cancer in patients with peptic ulcer disease. , 2009, Gastroenterology.

[19]  L. Penn,et al.  Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas. , 2002, Neoplasia.

[20]  H. Tsukuma,et al.  Risk factors for hepatocellular carcinoma among patients with chronic liver disease. , 1993, The New England journal of medicine.

[21]  D. Schuppan,et al.  Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells. , 2001, Journal of hepatology.

[22]  Carol Coupland,et al.  Individualising the risks of statins in men and women in England and Wales: population-based cohort study , 2010, Heart.

[23]  R. Karas,et al.  Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. , 2007, Journal of the American College of Cardiology.

[24]  J. Rodés,et al.  Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. , 2004, Gastroenterology.

[25]  Harlan M Krumholz,et al.  Withdrawn: P68 , 2006 .

[26]  D. Dhumeaux,et al.  Effect of simvastatin, an inhibitor of hydroxy‐methylglutaryl coenzyme a reductase, on the growth of human ito cells , 1994, Hepatology.

[27]  Chien-Jen Chen,et al.  Hepatitis B e antigen and the risk of hepatocellular carcinoma. , 2002, The New England journal of medicine.

[28]  P. Hebert.  Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. , 1997 .

[29]  R. Ozaki,et al.  Low triglyceride and nonuse of statins is associated with cancer in type 2 diabetes mellitus , 2011, Cancer.

[30]  KyungMann Kim.  Statin and cancer risks: from tasseomancy of epidemiologic studies to meta-analyses. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Pau-Chung Chen,et al.  Population-Based Case–Control Study of Chinese Herbal Products Containing Aristolochic Acid and Urinary Tract Cancer Risk , 2010, Journal of the National Cancer Institute.

[32]  Á. Pascual,et al.  3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation. , 2002, Atherosclerosis.

[33]  M. Tatsuta,et al.  3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis. , 2002, Gastroenterology.

[34]  J. Liao,et al.  Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[35]  Ching-Lan Cheng,et al.  Validation of the national health insurance research database with ischemic stroke cases in Taiwan , 2011, Pharmacoepidemiology and drug safety.

[36]  M. Hennerici,et al.  High-dose atorvastatin after stroke or transient ischemic attack. , 2006, The New England journal of medicine.

[37]  C. J. Chen,et al.  Hepatitis B and C viruses in the development of hepatocellular carcinoma. , 1994, Critical reviews in oncology/hematology.

[38]  D. Clain,et al.  Correlation between beta‐lipoprotein levels and outcome of hepatitis C treatment , 2006, Hepatology.

[39]  Chun-Yuh Yang,et al.  Statin Use and the Risk of Liver Cancer: A Population-Based Case–Control Study , 2011, The American Journal of Gastroenterology.

[40]  L. Platanias,et al.  Statins in tumor suppression. , 2008, Cancer letters.

[41]  C Michael White,et al.  Statins and Cancer Risk: A Meta-analysis , 2007 .

[42]  V. Steele,et al.  Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 rats. , 2006, Cancer research.

[43]  G. Feldmann,et al.  Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation. , 1997, Journal of hepatology.

[44]  Chien-Jen Chen,et al.  Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. , 2010, Gastroenterology.

[45]  James H. Lewis,et al.  Efficacy and safety of high‐dose pravastatin in hypercholesterolemic patients with well‐compensated chronic liver disease: Results of a prospective, randomized, double‐blind, placebo‐controlled, multicenter trial , 2007, Hepatology.

[46]  K. Keyomarsi,et al.  Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. , 1991, Cancer research.

[47]  J. Goldstein,et al.  Regulation of the mevalonate pathway , 1990, Nature.

[48]  Y. Matsuzawa,et al.  Hepatocellular Carcinoma (hcc) Causes Death in Patients with Cirrhosis and Is One of the Most Prevalent Malignant Tumours Effect of Pravastatin on Survival in Patients with Advanced Hepatocellular Carcinoma. a Randomized Controlled Trial , 2022 .

[49]  J. Olsen,et al.  Cancer risk among statin users: A population‐based cohort study , 2005, International journal of cancer.

[50]  J. Klenk,et al.  Serum triglyceride concentrations and cancer risk in a large cohort study in Austria , 2009, British Journal of Cancer.

[51]  M. Sadeghi,et al.  3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Thun,et al.  Long-term use of cholesterol-lowering drugs and cancer incidence in a large United States cohort. , 2010, Cancer research.

[53]  K. Naka,et al.  Different anti‐HCV profiles of statins and their potential for combination therapy with interferon , 2006, Hepatology.

[54]  Chien-Jen Chen,et al.  Hepatitis C Virus Infection and Increased Risk of Cerebrovascular Disease , 2010, Stroke.

[55]  J. Bruix,et al.  Management of hepatocellular carcinoma , 2005, Hepatology.

[56]  K. Keyomarsi,et al.  Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[57]  Ronit Almog,et al.  Statins and the risk of colorectal cancer. , 2005, The New England journal of medicine.

[58]  F. Nevens,et al.  Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho‐kinase and activation of endothelial nitric oxide synthase , 2007, Hepatology.

[59]  C. Fong,et al.  Statins, stem cells, and cancer , 2009, Journal of cellular biochemistry.

[60]  Carol Coupland,et al.  Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database , 2010, BMJ : British Medical Journal.

[61]  J. Owczarek,et al.  Statins: a new insight into their mechanisms of action and consequent pleiotropic effects. , 2007, Pharmacological reports : PR.

[62]  Kelvin K. W. Chan,et al.  The statins as anticancer agents. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.