2226 Cholesterol-Lowering Drugs and Prostate Cancer Risk: A Population-based Case-Control Study Teemu J. Murtola,1 Teuvo L.J. Tammela,2 Jorma Lahtela,3 and Anssi Auvinen4 1School of Public Health, 2Department of Urology, Tampere University Hospital and Medical School, University of Tampere, and 3Department of Internal Medicine, Tampere University Hospital, Tampere, Finland and 4The Finnish Cancer Institute, Helsinki, Finland Abstract Background: Previous studies have shown that statin ginally elevated overall prostate cancer risk [odds ratio use may reduce prostate cancer risk. In the current (OR), 1.07; 95% confidence interval (95% CI), 1.00-1.16]. study, we evaluated the association between serum However, none of the statins was associated with cholesterol–lowering medication use and prostate the overall prostate cancer risk when analyzed sepa- cancer risk at the population level. rately. On the other hand, the risk of advanced prostate Materials and Methods: All newly diagnosed prostate cancer was decreased among users of atorvastatin, cancer cases in Finland during 1995 to 2002 and matched lovastatin, and simvastatin (OR 0.61, 95% CI0.37-0.98; controls (24,723 case control pairs) were identified from OR 0.61, 95% CI0.43-0.85; and OR 0.78, 95% CI0.61-1.01, the Finnish Cancer Registry and the Population Register respectively). The risk was not affected among users of Center, respectively. Detailed information on cholester- other cholesterol drug groups. ol-lowering drug purchases during the study period was Conclusions: Our large population-based study showed obtained from the prescription database of the Social no evidence for reduced overall prostate cancer risk among Insurance Institution of Finland. users of cholesterol-lowering drugs, whereas the risk Results: After adjustment for potential confounders, of advanced cancer was decreased among statin users. having ever-use of any statin was associated with mar- (Cancer Epidemiol Biomarkers Prev 2007;16(11):2226–32) Introduction Prostate cancer is the most common malignancy among Asia, the incidence of prostate cancer is rising partly due men in most countries (1). It is also among the three most to the Westernization of life-styles (4). common causes of cancer death in most Western A group of cholesterol-lowering drugs, 3-hydroxy-3- countries (1). Nevertheless, prostate cancer is usually a methylglutaryl CoA reductase inhibitors (statins), have slowly growing cancer with a long latency period. shown promise in chemoprevention of prostate cancer. Autopsy studies show that a quarter of men in their Multiple statins have been reported to inhibit prostate 40s and up to 40% of men ages 80 years or older harbor cancer cell proliferation in vitro by induction of cell cycle indolent local malignant lesions of the prostate (2, 3). The arrest and apoptosis (5, 6). Recently, a large prospective slow growth rate of prostate cancer provides a window cohort study reported decreased risk of advanced of opportunity to influence different stages of carcino- prostate cancer among statin users, whereas the overall genesis, making prostate cancer an attractive target for prostate cancer risk was unaffected (7). Other observa- chemoprevention. Environmental factors strongly influ- tional studies have suggested reduced risk for also over- ence prostate cancer risk as shown by the Asian all prostate cancer in statin users (8, 9). However, recent immigrants in North America. Asian men traditionally meta-analyses of randomized trials of statins (10-12), have a low prostate cancer risk, although the prevalence along with other observational studies (13-16), have of latent prostate cancer precursors is comparable with revealed no association with the cancer of the prostate that of the population in the Western countries (4). or of any other site. However, among Asian immigrants in North America, Of the other types of cholesterol-lowering drugs, the risk of clinical cancer increases toward that of the fibrate use has not been found to affect cancer risk (8), Western population with years of residence, and also in although they are reported to cause neoplasia in rodents (17). The only study, to our knowledge, estimating cancer incidence in resin users concluded that statin users are Received 7/1/07; revised 8/24/07; accepted 9/19/07. 28% less likely to be diagnosed with any type of cancer Grant support: Academy of Finland grant 205 862, Sigrid Juselius Foundation, and Finnish Cancer Society. Teemu Murtola’s work was supported by grants from than the users of resins (13). No reports of acipimox effect Pirkanmaa Regional Fund of the Finnish Cultural Foundation, Medical Research Fund on cancer risk have been published. of Tampere and University Hospital, Irja Karvonen cancer trust and nonrestricted grants from Astellas, Lilly Foundation, Schering Foundation, and research foundation This study was undertaken to evaluate prostate cancer of Orion Pharma. risk among the users of cholesterol-lowering drugs at the The costs of publication of this article were defrayed in part by the payment of page population level. charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Teemu Murtola, University of Tampere, School of Public Health, University of Tampere, Tampere, FIN-33014, Finland. Phone: 358-3-3551-6168; Materials and Methods Fax: 358-3-3551-6057. E-mail: [email protected]. Copyright D 2007 American Association for Cancer Research. Study Design. All newly diagnosed prostate cancer doi:10.1158/1055-9965.EPI-07-0599 cases in Finland during 1995 to 2002 (25,029 men) were Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2007 American Association for Cancer Research. Cancer Epidemiology,Biomarkers & Prevention 2227 identified through the Finnish Cancer Registry. Data in Table 2. Prevalence of medication usage among the the Finnish Cancer Registry are collected through man- study population of all newly diagnosed prostate datory notifications of all the cancer diagnoses made by cancer cases in Finland in 1995 to 2002 and their all the Finnish health care units. Thus, it is a population- individually matched controls based, nationwide register with coverage of >99% of all Cholesterol drug use Cases Controls prostate cancer patients in Finland (18). The register information includes the primary site of cancer, histo- n % of total n % of total logy, date, and method of diagnosis. Information on the stage of prostate cancer was available in 55% of the cases Total number 24,723 100 24,723 100 Statin use (13,616 patients). Of these, 73% were localized. There Yes 2,622 10.6 2,439 9.9 were no substantial differences in median age between No 22,101 89.4 22,284 90.1 cases with or without information on stage (Table 1). Fibrate use However, the majority of cases without information on Yes 220 0.9 211 0.9 stage were diagnosed during the latter half of the study No 24,503 99.1 24,512 99.1 Usage of other cholesterol drugs* period, whereas the distribution of years of diagnosis Yes 61 0.2 52 0.2 was more even among the cases with stage (Table 1). The No 24,662 99.8 24,671 99.8 registry does not record differentiation, such as Gleason Antidiabetic medication use score, nor serum prostate-specific antigen (PSA) values. Yes 2,201 8.9 2,406 9.7 Practically all the cases were histologically confirmed No 22,522 91.1 22,317 90.3 (99.3 %). Also, cases with the diagnosis based solely on Antihypertensive drug use Yes 12,648 51.2 11,866 48.0 clinical (0.4 %), radiological (0.3 %), or specific labora- No 12,075 48.8 12,857 52.0 tory findings (0.02% of cases) were included. A total of 185 cases (0.7 %) with an unknown method of diagnosis *Includes users of resins and acipimox. were excluded. The controls were individually matched on the age and geographic area of the cases at the time of the The information on cholesterol-lowering medication diagnosis. The Population Register Center of Finland prescribed to the study population and reimbursed by selected 24,723 male controls, of whom a total of 963 the Social Insurance Institution of Finland (SII) during were subsequently diagnosed with prostate cancer dur- 1995 to 2002 was obtained from the comprehensive ing the study period. Thus, these men appeared twice nationwide prescription database of the SII. All choles- in the analysis, first as a control and later as a case in terol-lowering drugs in use in Finland during the study another matched case control pair. The population size period, with the exception of nicotinic acid, were reim- in Finnish municipalities ranges from <200 to 560,000 bursable and available through a physician’s prescription (19). Thus, matched controls could not be found from only, thus comprehensively documented by the data- the same municipality for 121 cases in the oldest age base. The database provided detailed information on group, resulting in their exclusion from the analyses. the quantity and time of the medication purchases for A total of 24,723 case control pairs were included in the each person in the study population for a maximum of analyses. 8 years. The drugs in clinical use in Finland during the After approval from the ethics committee of the study period were statins (atorvastatin since 1998, Pirkanmaa health care district, Finland (ETL R03290), cerivastatin from 1999 to 2001, fluvastatin since 1996, obtaining informed consent from the study population lovastatin, pravastatin, and simvastatin), fibrates (beza- was not required due to the large size of the population fibrate, clofibrate until 1998, fenofibrate since 2002, and and to the part of the population that is unattainable gemfibrozil), resins (cholestyramin and cholestipol), (deceased or emigrated) by the time of the study.