J Gastrointestin Liver Dis, December 2020 Vol. 29 No 4: 629-635 1) Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, Jacksonville, Florida; 2) Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, Minnesota; 3) Department of Medicine, Division of Nephrology, University of Mississippi Medical Center, Jackson, Mississippi; 4) Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, Ohio, United States. Address for correspondence: Karn Wijarnpreecha, MD 4500 San Pablo Rd S, Jacksonville, Florida, USA, 32224 dr.karn.wi@gmail.com Received: 03.09.2020 Accepted: 16.10.2020 Statins and Risk of Cholangiocarcinoma: A Systematic Review and Meta-analysis Karn Wijarnpreecha 1 , Elizabeth S. Aby 2 , Hassan Ghoz 1 , Wisit Cheungpasitporn 3 , Frank J. Lukens 1 , Denise M. Harnois 1 , Patompong Ungprasert 4 INTRODUCTION Cholangiocarcinoma (CCA) are a heterogeneous group of biliary epithelial tumors, which are classified anatomically as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangio- carcinoma (ECC) [1]. Data suggests that ICC and ECC are biologically different cancers, with diferences in incidence, risk factors, and mortality [2]. Te incidence of ICC is increasing in the United States and around the world [3-5]. Te incidence of ECC, on the other hand, has remained stable [6]. Te overall SYSTEMATIC REVIEW AND META-ANALYSIS DOI: http://dx.doi.org/10.15403/jgld-2990 ABSTRACT Background & Aims: The use of statins has been shown to be associated with a decreased risk of cholangiocarcinoma (CCA) in many studies although the results have been inconsistent. We conducted this systematic review and meta-analysis to further investigate this possible association by identifying all relevant studies and combining their results together. Methods: A comprehensive literature review was conducted utilizing the MEDLINE and EMBASE databases through March 2020 to identify all studies that compared the risk of CCA among individuals who use statins with individuals who do not use statins. Efect estimates from each study were extracted and combined using the random-efect, generic inverse variance method of DerSimonian and Laird. Results: A total of seven studies with 6,251,187 participants fulflled the eligibility criteria and were included in this meta-analysis. Te pooled analysis found a signifcantly decreased risk of CCA among individuals who use statins compared with individuals who do not use statins with the pooled odds ratio of 0.68 (95% CI: 0.52-0.89; I 2 96%). Conclusions: Te current systematic review and meta-analysis found a signifcant association between the use of statins and a decreased risk of CCA. Key words: statins – bile duct cancer – biliary tract cancer – cholangiocarcinoma – meta-analysis. Abbreviations: CCA: cholangiocarcinoma; CI: confdence interval; ECC: extrahepatic cholangiocarcinoma; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; ICC: intrahepatic cholangiocarcinoma; OR: odds ratio; Rac1: Ras-related C3 botulinum toxin substrate 1; RR: relative risk. mortality associated with CCA in the United States has increased by 36% between 1999 and 2014 [6]. Te survival rate for CCA is low as patients are ofen diagnosed at a later stage and thus, efective treatments are lacking [7-9]. Given the poor prognosis associated with the diagnosis of CCA, preventative strategies are of paramount signifcance. The determinants of CCA risk are largely undefined but recently more attention is being paid to the role of lipid metabolism and metabolic syndrome on the risk of CCA. Some studies have shown a link between disorders of lipid regulation and metabolic syndrome and an increased risk of biliary tract cancers [10-12]. Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been theorized to exert benefcial anti-cancer efects in CCA, but the presumed chemopreventive efect of statins remains controversial [13- 19]. Te aim of this systematic review and meta-analysis was to assess whether statin use is associated with a reduced risk of CCA.