Skip to content
2000
Volume 20, Issue 3
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970

Abstract

Background

Hepatocellular Carcinoma (HCC) is a public health problem around the world. Several studies have investigated the association between statin use and the risk of HCC, however, more studies are needed in this field.

Objectives

This systematic review and meta-analysis aimed to investigate the relationship between statin use and HCC risk.

Methods

Systematic searches of Web of Science, Scopus, PubMed, Cochrane Library, Science Direct, and Embase were conducted for studies published between 1980 and September 2023. Meta-analyses were performed using Stata 15 with a significance level of 0.05.

Results

The search retrieved 8,125 articles, of which 40 were included in the meta-analysis after applying eligibility criteria. The total sample was 5,732,948 participants, including 68,698 HCC cases. Statin use was associated with a 44% lower risk of HCC compared to non-use (RR 0.56, 95% CI 0.50–0.63, < 0.001). The RR was 0.54 (0.42-0.69) in American countries, 0.52 (0.44-0.62) in Asian countries, and 0.63 (0.48-0.84) in European countries. The RR was 0.50 (0.42-0.60) in studies with a mean age <50 years and 0.61 (0.53-0.70) in studies with a mean age ≥50 years. No evidence of publication bias was found (Begg’s test = 0.718).

Conclusion

This meta-analysis found statin use is associated with a significantly lower HCC risk. Statins may be a promising preventive intervention against HCC.

Loading

Article metrics loading...

/content/journals/pra/10.2174/0115748928282686231221070441
2024-01-26
2025-09-20
Loading full text...

Full text loading...

References

  1. Nattagh-EshtivaniE. BarghchiH. PahlavaniN. Biological and pharmacological effects and nutritional impact of phytosterols: A comprehensive review.Phytother. Res.202236129932210.1002/ptr.731234729825
    [Google Scholar]
  2. MovahedS. Varshoee TabriziF. PahlavaniN. Comprehensive assessment of nutritional status and nutritional-related complications in newly diagnosed esophageal cancer patients: A cross-sectional study.Clin. Nutr.20214064449445510.1016/j.clnu.2021.01.00333509666
    [Google Scholar]
  3. VillanuevaA. Hepatocellular Carcinoma.N. Engl. J. Med.2019380151450146210.1056/NEJMra171326330970190
    [Google Scholar]
  4. BruixJ. ReigM. ShermanM. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma.Gastroenterology2016150483585310.1053/j.gastro.2015.12.04126795574
    [Google Scholar]
  5. RafiemaneshH. Mohammadian-HafshejaniA. GhonchehM. Incidence and mortality of colorectal cancer and relationships with the human development index across the world.Asian Pac. J. Cancer Prev.20161752465247327268615
    [Google Scholar]
  6. SalehiniyaH. Ghobadi DashdebiS. RafiemaneshH. Mohammadian-HafshejaniA. EnayatradM. Time trend analysis of cancer‏ incidence in caspian sea, 2004 - 2009: A population-based cancer registries study (northern Iran).Caspian J. Intern. Med.201671253026958329
    [Google Scholar]
  7. RafiemaneshH. MehtarpoorM. Mohammadian-HafshejaniA. SalehiniyaH. EnayatradM. KhazaeiS. Cancer epidemiology and trends in Sistan and Baluchestan province, Iran.Med. J. Islam. Repub. Iran20152925426793645
    [Google Scholar]
  8. ShabgahA.G. NorouziF. Hedayati-MoghadamM. SoleimaniD. PahlavaniN. NavashenaqJ.G. A comprehensive review of long non-coding RNAs in the pathogenesis and development of non-alcoholic fatty liver disease.Nutr. Metab.20211812210.1186/s12986‑021‑00552‑533622377
    [Google Scholar]
  9. MansouriM. PahlavaniN. SharifiF. Dairy consumption in relation to hypertension among a large population of university students: The MEPHASOUS study.Diabetes Metab. Syndr. Obes.2020131633164210.2147/DMSO.S24859232523363
    [Google Scholar]
  10. ChenK. ManK. MetselaarH.J. JanssenH.L.A. PeppelenboschM.P. PanQ. Rationale of personalized immunosuppressive medication for hepatocellular carcinoma patients after liver transplantation.Liver Transpl.201420326126910.1002/lt.2380624376158
    [Google Scholar]
  11. DuBrayB.J.Jr ChapmanW.C. AndersonC.D. Hepatocellular carcinoma: A review of the surgical approaches to management.Mo. Med.2011108319519821736080
    [Google Scholar]
  12. LiaoX. BuY. JiaQ. Traditional chinese medicine as supportive care for the management of liver cancer: Past, present, and future.Genes Dis.20207337037910.1016/j.gendis.2019.10.01632884991
    [Google Scholar]
  13. XiS.Y. MinukG.Y. Role of traditional Chinese medicine in the management of patients with hepatocellular carcinoma.World J. Hepatol.2018101179980610.4254/wjh.v10.i11.79930533181
    [Google Scholar]
  14. RuizJ. MazzoliniG. SangroB. QianC. PrietoJ. Gene therapy of hepatocellular carcinoma.Dig. Dis.200119432433210.1159/00005069911935092
    [Google Scholar]
  15. ReghupatyS.C. SarkarD. Current status of gene therapy in hepatocellular carcinoma.Cancers2019119126510.3390/cancers1109126531466358
    [Google Scholar]
  16. DoychevaI. IssaD. WattK.D. LopezR. RifaiG. AlkhouriN. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in young adults in the United States.J. Clin. Gastroenterol.201852433934610.1097/MCG.000000000000092528961576
    [Google Scholar]
  17. MohammadianM. SoroushA. Mohammadian-HafshejaniA. TowhidiF. HadadianF. SalehiniyaH. The incidence and mortality of liver cancer and its relationship with development in asia.Asian Pac. J. Cancer Prev.20161742041204710.7314/APJCP.2016.17.4.204127221893
    [Google Scholar]
  18. VoorneveldP.W. ReimersM.S. BastiaannetE. Statin use after diagnosis of colon cancer and patient survival.Gastroenterology20171532470479.e410.1053/j.gastro.2017.05.01128512021
    [Google Scholar]
  19. ZhangY. LiangM. SunC. Statin use and risk of pancreatic cancer.Pancreas201948214215010.1097/MPA.000000000000122630640225
    [Google Scholar]
  20. Mohammadian-HafshejaniA. SherwinC.M.T. Heidari-SoureshjaniS. Do statins play any role in reducing the incidence and mortality of ovarian cancer? A systematic review and meta-analysis.J. Prev. Med. Hyg.2020613E331E33933150223
    [Google Scholar]
  21. ZhaoG. JiY. YeQ. Effect of statins use on risk and prognosis of breast cancer: A meta-analysis.Anticancer Drugs2022331e507e51810.1097/CAD.000000000000115134407042
    [Google Scholar]
  22. XuT. WangY. YuanJ. ChenY. The effect of statin treatment on outcomes of cardioembolic stroke: A systematic review and meta-analysis of real-world studies.CNS Drugs202135771772610.1007/s40263‑021‑00829‑634019256
    [Google Scholar]
  23. VallianouN. KostantinouA. KougiasM. KazazisC. Statins and cancer.Anticancer. Agents Med. Chem.201414570671210.2174/187152061366613112910503524295174
    [Google Scholar]
  24. VaklavasC. ChatzizisisY.S. TsimberidouA.M. Common cardiovascular medications in cancer therapeutics.Pharmacol. Ther.2011130217719010.1016/j.pharmthera.2011.01.00921277894
    [Google Scholar]
  25. Freed-PastorW.A. MizunoH. ZhaoX. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway.Cell20121481-224425810.1016/j.cell.2011.12.01722265415
    [Google Scholar]
  26. KanwalF. KramerJ.R. MapakshiS. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.Gastroenterology201815561828183710.1053/j.gastro.2018.08.024
    [Google Scholar]
  27. JanickoM. DrazilovaS. PellaD. FedackoJ. JarcuskaP. Pleiotropic effects of statins in the diseases of the liver.World J. Gastroenterol.201622276201621310.3748/wjg.v22.i27.620127468210
    [Google Scholar]
  28. PoseE. TrebickaJ. MookerjeeR.P. AngeliP. GinèsP. Statins: Old drugs as new therapy for liver diseases?J. Hepatol.201970119420210.1016/j.jhep.2018.07.01930075229
    [Google Scholar]
  29. JeonC.Y. GoodmanM.T. Cook-WiensG. SundaramV. Statin use and survival with early-stage hepatocellular carcinoma.Cancer Epidemiol. Biomarkers Prev.201625468669210.1158/1055‑9965.EPI‑15‑104026908429
    [Google Scholar]
  30. FriedmanG.D. FlickE.D. UdaltsovaN. Chan Pharm D J, Quesenberry CP Jr, Habel LA. Screening statins for possible carcinogenic risk: Up to 9 years of follow‐up of 361 859 recipients.Pharmacoepidemiol. Drug Saf.2008171273610.1002/pds.150717944002
    [Google Scholar]
  31. El-SeragH.B. JohnsonM.L. HachemC. MorganaR.O. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes.Gastroenterology200913651601160810.1053/j.gastro.2009.01.05319208359
    [Google Scholar]
  32. ChiuH.F. HoS.C. ChenC.C. YangC.Y. Statin use and the risk of liver cancer: A population-based case–control study.Am. J. Gastroenterol.2011106589489810.1038/ajg.2010.47521157439
    [Google Scholar]
  33. MarelliC. GunnarssonC. RossS. Statins and risk of cancer: A retrospective cohort analysis of 45,857 matched pairs from an electronic medical records database of 11 million adult Americans.J. Am. Coll. Cardiol.201158553053710.1016/j.jacc.2011.04.01521777752
    [Google Scholar]
  34. Björkhem-BergmanL. BackhedenM. Söderberg LöfdalK. Statin treatment reduces the risk of hepatocellular carcinoma but not colon cancer-results from a nationwide case-control study in Sweden.Pharmacoepidemiol. Drug Saf.201423101101110610.1002/pds.368525074765
    [Google Scholar]
  35. McGlynnK.A. HagbergK. ChenJ. Statin use and risk of primary liver cancer in the Clinical Practice Research Datalink.J. Natl. Cancer Inst.20151074djv00910.1093/jnci/djv00925722350
    [Google Scholar]
  36. KaplanD.E. SerperM.A. MehtaR. Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis.Gastroenterology201915661693170610.1053/j.gastro.2019.01.026
    [Google Scholar]
  37. TranK.T. McMenaminÚ.C. ColemanH.G. Statin use and risk of liver cancer: Evidence from two population‐based studies.Int. J. Cancer202014651250126010.1002/ijc.3242631112291
    [Google Scholar]
  38. PetersonJ. WelchV. LososM. TugwellP. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.OttawaOttawa Hospital Research Institute2011112
    [Google Scholar]
  39. KjaergardL.L. VillumsenJ. GluudC. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.Ann. Intern. Med.20011351198298910.7326/0003‑4819‑135‑11‑200112040‑0001011730399
    [Google Scholar]
  40. JadadA.R. MooreR.A. CarrollD. Assessing the quality of reports of randomized clinical trials: Is blinding necessary?Control. Clin. Trials199617111210.1016/0197‑2456(95)00134‑48721797
    [Google Scholar]
  41. FriisS. PoulsenA.H. JohnsenS.P. Cancer risk among statin users: A population‐based cohort study.Int. J. Cancer2005114464364710.1002/ijc.2075815578694
    [Google Scholar]
  42. KhuranaV. SalujaA. CalditoG. FortC. SchiffE. Statins are protective against hepatocellular cancer in patients with hepatitis C virus infection: half a million US veterans' study. Gastroenterology. Philadelphia : WB saunders co independence square west curtis center, STE 3002005
    [Google Scholar]
  43. SatoS. AjikiW. KobayashiT. AwataN. Pravastatin use and the five-year incidence of cancer in coronary heart disease patients: From the prevention of coronary sclerosis study.J. Epidemiol.200616520120610.2188/jea.16.>20116951539
    [Google Scholar]
  44. MatsushitaY. SugiharaM. KaburagiJ. Pravastatin use and cancer risk: A meta‐analysis of individual patient data from long‐term prospective controlled trials in Japan.Pharmacoepidemiol. Drug Saf.201019219620210.1002/pds.187019856484
    [Google Scholar]
  45. Emberson JR, Kearney PM, Blackwell L, et al. Lack of effect of lowering LDL cholesterol on cancer: Meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. In: Kronenberg F, Ed. PLoS One 2012; 7(1): e29849.10.1371/journal.pone.002984922276132
    [Google Scholar]
  46. TsanY.T. LeeC.H. WangJ.D. ChenP.C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.J. Clin. Oncol.201230662363010.1200/JCO.2011.36.091722271485
    [Google Scholar]
  47. KumarS. GraceN.D. QamarA.A. Statin use in patients with cirrhosis: A retrospective cohort study.Dig. Dis. Sci.20145981958196510.1007/s10620‑014‑3179‑224838495
    [Google Scholar]
  48. LeungH.W.C. ChanA.L.F. LoD. LeungJ.H. ChenH.L. Common cancer risk and statins: A population-based case–control study in a Chinese population.Expert Opin. Drug Saf.2013121192710.1517/14740338.2013.74439223199231
    [Google Scholar]
  49. LaiS.W. LiaoK.F. LaiH.C. MuoC.H. SungF.C. ChenP.C. Statin use and risk of hepatocellular carcinoma.Eur. J. Epidemiol.201328648549210.1007/s10654‑013‑9806‑y23681775
    [Google Scholar]
  50. McGlynnK.A. DivineG.W. SahasrabuddheV.V. Statin use and risk of hepatocellular carcinoma in a U.S. population.Cancer Epidemiol.201438552352710.1016/j.canep.2014.06.00925113938
    [Google Scholar]
  51. GalliL. SpagnuoloV. PoliA. Use of statins and risk of AIDS-defining and non-AIDS-defining malignancies among HIV-1 infected patients on antiretroviral therapy.AIDS201428162407241510.1097/QAD.000000000000044325160933
    [Google Scholar]
  52. ButtA.A. YanP. BonillaH. Effect of addition of statins to antiviral therapy in hepatitis C virus–infected persons: Results from ERCHIVES.Hepatology201562236537410.1002/hep.2783525847403
    [Google Scholar]
  53. HsiangJ.C. WongG.L.H. TseY.K. WongV.W.S. YipT.C.F. ChanH.L.Y. Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: A propensity score landmark analysis.J. Hepatol.20156351190119710.1016/j.jhep.2015.07.00926208777
    [Google Scholar]
  54. ChenC.I. KuanC.F. FangY.A. Cancer risk in HBV patients with statin and metformin use: A population-based cohort study.Medicine2015946e46210.1097/MD.000000000000046225674734
    [Google Scholar]
  55. ChenH.H. LinM.C. MuoC.H. YehS.Y. SungF.C. KaoC.H. Combination therapy of metformin and statin may decrease hepatocellular carcinoma among diabetic patients in asia.Medicine20159424e101310.1097/MD.000000000000101326091447
    [Google Scholar]
  56. SimonT.G. BonillaH. YanP. ChungR.T. ButtA.A. Atorvastatin and fluvastatin are associated with dose‐dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES.Hepatology2016641475710.1002/hep.2850626891205
    [Google Scholar]
  57. MohantyA. TateJ.P. Garcia-TsaoG. Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis C–related compensated cirrhosis.Gastroenterology20161502430440.e110.1053/j.gastro.2015.10.00726484707
    [Google Scholar]
  58. FriedmanG.D. AchacosoN. FiremanB. HabelL.A. Statins and reduced risk of liver cancer: Evidence for confounding.J. Natl. Cancer Inst.201610810djw10910.1093/jnci/djw>10927381455
    [Google Scholar]
  59. McGlynnK.A. HagbergK. ChenJ. Menopausal hormone therapy use and risk of primary liver cancer in the clinical practice research datalink.Int. J. Cancer201613892146215310.1002/ijc.2996026662112
    [Google Scholar]
  60. KimG. JangS.Y. HanE. Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case‐control study.Int. J. Cancer2017140479880610.1002/ijc.3050627861855
    [Google Scholar]
  61. KimG. JangS.Y. NamC.M. KangE.S. Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study.J. Hepatol.201868347648410.1016/j.jhep.2017.10.01829107150
    [Google Scholar]
  62. ChangF.M. WangY.P. LangH.C. Statins decrease the risk of decompensation in hepatitis B virus– and hepatitis C virus–related cirrhosis: A population‐based study.Hepatology201766389690710.1002/hep.2917228318053
    [Google Scholar]
  63. YiS.W. KimS.H. HanK.J. YiJ.J. OhrrH. Higher cholesterol levels, not statin use, are associated with a lower risk of hepatocellular carcinoma.Br. J. Cancer2020122563063310.1038/s41416‑019‑0691‑331857717
    [Google Scholar]
  64. GohM.J. SinnD.H. KimS. Statin use and the risk of hepatocellular carcinoma in patients with chronic hepatitis B.Hepatology20207162023203210.1002/hep.3097331556128
    [Google Scholar]
  65. KimG.A. ShimJ.J. LeeJ.S. Effect of statin use on liver cancer mortality considering hypercholesterolemia and obesity in patients with non-cirrhotic chronic hepatitis B.Yonsei Med. J.201960121203120810.3349/ymj.2019.60.12.120331769252
    [Google Scholar]
  66. SimonT.G. DubergA.S. AlemanS. Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: Results from a nationwide swedish population.Ann. Intern. Med.2019171531832710.7326/M18‑275331426090
    [Google Scholar]
  67. GermanM.N. LutzM.K. PickhardtP.J. BruceR.J. SaidA. Statin use is protective against hepatocellular carcinoma in patients with nonalcoholic fatty liver disease.J. Clin. Gastroenterol.202054873374010.1097/MCG.000000000000126031567625
    [Google Scholar]
  68. SungF.C. YehY.T. MuoC.H. HsuC.C. TsaiW.C. HsuY.H. Statins reduce hepatocellular carcinoma risk in patients with chronic kidney disease and end-stage renal disease: A 17-year longitudinal study.Cancers202214382510.3390/cancers1403082535159093
    [Google Scholar]
  69. KimH.W. JooY.S. KangS.C. Association of statin treatment with hepatocellular carcinoma risk in end-stage kidney disease patients with chronic viral hepatitis.Sci. Rep.20221211080710.1038/s41598‑022‑14713‑w35752695
    [Google Scholar]
  70. ZouB. OddenM.C. NguyenM.H. Statin use and reduced hepatocellular carcinoma risk in patients with nonalcoholic fatty liver disease.Clin. Gastroenterol. Hepatol.202321243544410.1016/j.cgh.2022.01.057
    [Google Scholar]
  71. VellM.S. LoombaR. KrishnanA. Association of statin use with risk of liver disease, hepatocellular carcinoma, and liver-related mortality.JAMA Netw. Open202366e232022210.1001/jamanetworkopen.2023.2022237358849
    [Google Scholar]
  72. ThurnherM. NussbaumerO. GruenbacherG. Novel aspects of mevalonate pathway inhibitors as antitumor agents.Clin. Cancer Res.201218133524353110.1158/1078‑0432.CCR‑12‑048922529099
    [Google Scholar]
  73. GazzerroP. ProtoM.C. GangemiG. Pharmacological actions of statins: A critical appraisal in the management of cancer.Pharmacol. Rev.201264110214610.1124/pr.111.00499422106090
    [Google Scholar]
  74. IslamM.M. PolyT.N. WaltherB.A. YangH.C. LiY-C.J. Statin use and the risk of hepatocellular carcinoma: A meta-analysis of observational studies.Cancers202012367110.3390/cancers1203067132183029
    [Google Scholar]
  75. KhazaalehS. SarminiM.T. AlomariM. Statin use reduces the risk of hepatocellular carcinoma: an updated meta-analysis and systematic review.Cureus2022147e2703210.7759/cureus.2703235989795
    [Google Scholar]
  76. HigginsJ.P.T. ThompsonS.G. DeeksJ.J. AltmanD.G. Measuring inconsistency in meta-analyses.BMJ2003327741455756010.1136/bmj.327.7414.55712958120
    [Google Scholar]
  77. BeckwittC.H. ShirahaK. WellsA. Lipophilic statins limit cancer cell growth and survival, via involvement of Akt signaling.PLoS One2018135e019742210.1371/journal.pone.019742229763460
    [Google Scholar]
  78. FengJ. DaiW. MaoY. Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis.J. Exp. Clin. Cancer Res.20203912410.1186/s13046‑020‑1528‑x32000827
    [Google Scholar]
  79. SinghS. SinghP.P. SinghA.G. MuradM.H. SanchezW. Statins are associated with a reduced risk of hepatocellular cancer: A systematic review and meta-analysis.Gastroenterology2013144232333210.1053/j.gastro.2012.10.00523063971
    [Google Scholar]
  80. WangY. WangW. WangM. ShiJ. JiaX. DangS. A meta-analysis of statin use and risk of hepatocellular carcinoma.Can. J. Gastroenterol. Hepatol.2022202211510.1155/2022/538904435356132
    [Google Scholar]
  81. SackettD.L. Bias in analytic research The case-control study consensus and controversy.Elsevier1979516310.1016/B978‑0‑08‑024907‑0.50013‑4
    [Google Scholar]
  82. PageM.J. SterneJ.A.C. HigginsJ.P.T. EggerM. Investigating and dealing with publication bias and other reporting biases in meta‐analyses of health research: A review.Res. Synth. Methods202112224825910.1002/jrsm.146833166064
    [Google Scholar]
  83. MorrowR.L. MintzesB. GrayG. LawM.R. GarrisonS. DormuthC.R. Factors relating to nonpublication and publication bias in clinical trials in Canada: A qualitative interview study.Br. J. Clin. Pharmacol.20238931198120610.1111/bcp.1557436268743
    [Google Scholar]
  84. SizarO. KhareS. JamilR.T. Statin Medications. StatPearls. Treasure Island, FL: StatPearls Publishing.2023Updated 2023 Feb 5 Internet Available from: https://www.ncbi.nlm.nih.gov/books/NBK430940/#
    [Google Scholar]
  85. GrabarekB.O. BorońD. MorawiecE. Crosstalk between statins and cancer prevention and therapy: An update.Pharmaceuticals20211412122010.3390/ph1412122034959621
    [Google Scholar]
  86. LiuC. ChenH. HuB. ShiJ. ChenY. HuangK. New insights into the therapeutic potentials of statins in cancer.Front. Pharmacol.202314118892610.3389/fphar.2023.118892637484027
    [Google Scholar]
  87. NewmanC.B. PreissD. TobertJ.A. Statin safety and associated adverse events: A scientific statement from the american heart association.Arterioscler. Thromb. Vasc. Biol.2019392e38e8110.1161/ATV.000000000000007330580575
    [Google Scholar]
/content/journals/pra/10.2174/0115748928282686231221070441
Loading
/content/journals/pra/10.2174/0115748928282686231221070441
Loading

Data & Media loading...

Supplements

PRISMA checklist is available as supplementary material on the publisher’s website along with the published article.


  • Article Type:
    Research Article
Keyword(s): chi-square tests; hepatocellular carcinoma; heterogeneity; meta-analysis; odd ratio; Statins
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test