Brief Article Open Access
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Dec 21, 2011; 17(47): 5197-5202
Published online Dec 21, 2011. doi: 10.3748/wjg.v17.i47.5197
Statin use and the risk of colorectal cancer: A population-based case-control study
Meng-Hsuan Cheng, Division of Pulmonary and Critical Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan, China
Meng-Hsuan Cheng, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, China
Meng-Hsuan Cheng, Department of Internal Medicine, Ping-Tung Hospital, Department of Health, Executive Yuan, Ping-Tung 90054, Taiwan, China
Hui-Fen Chiu, Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, China
Shu-Chen Ho, Institute of Occupational Safety and Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, China
Shang-Shyue Tsai, Department of Healthcare Administration, I-Shou University, Kaohsiung 80708, Taiwan, China
Trong-Neng Wu, Department of Public Health, China Medical University, Taichung 40402, Taiwan, China
Trong-Neng Wu, Division of Environmental Health and Occupational Medicine, National Health Research Institute, Miaoli 10694, Taiwan, China
Chun-Yuh Yang, Faculty of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, China
Chun-Yuh Yang, Division of Environmental Health and Occupational Medicine, National Health Research Institute, Miaoli 10694, Taiwan, China
Author contributions: Cheng MH wrote the manuscript; Ho SC performed the statistical analysis; Chiu HF, Tsai SS and Wu TN provided essential insight into the interpretation of the results; Yang CY contributed to the study design and interpretation of the data and had full access to all the data in the study and took responsibility for the integrity of the data and accuracy of the data analysis.
Supported by A grant from the National Science Council, Executive Yuan, Taiwan, No. NSC97-2314-B-037-006-MY3
Correspondence to: Chun-Yuh Yang, PhD, MPH, Faculty of Public Health, Kaohsiung Medical University, 100 Shih-Chuan 1st RD, Kaohsiung 80708, Taiwan, China. chunyuh@kmu.edu.tw
Telephone: +886-7-3121101 Fax: +886-7-3110811
Received: February 1, 2011
Revised: March 28, 2011
Accepted: April 5, 2011
Published online: December 21, 2011

Abstract

AIM: To investigate whether the use of statins is associated with colorectal cancer risk.

METHODS: We conducted a population-based case-control study in Taiwan. Data were retrospectively collected from the Taiwan National Health Insurance Research Database. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of colorectal cancer between the period 2005 and 2008. The controls were matched to cases by age, sex, and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multiple logistic regression.

RESULTS: We examined 1156 colorectal cancer cases and 4624 controls. The unadjusted ORs for any statin prescription was 1.10 (95% CI = 0.94-1.30) and the adjusted OR was 1.09 (95% CI = 0.91-1.30). When statin use was categorized by cumulative dose, the adjusted ORs were 0.99 (95% CI = 0.78-1.27) for the group with cumulative statin use below 105 defined daily doses (DDDs); 1.07 (95% CI = 0.78-1.49) for the group with cumulative statin use between 106 and 298.66 DDDs; and 1.30 (95% CI = 0.96-1.75) for the group with cumulative statin use of 298.66 DDDs or more compared with nonusers.

CONCLUSION: This study does not provide support for a protective effect of statins against colorectal cancer.

Key Words: Case-control study; Colorectal cancer; Pharmacoepidemiology; Statins



INTRODUCTION

Statins are inhibitors of 3-hydroxy-3-methyl glutaryl co-enzyme A reductase which is a key enzyme in the rate-limiting step in cholesterol synthesis[1]. Statins are commonly used as cholesterol-lowering medications and have shown effectiveness in the primary and secondary prevention of heart attack and stroke[2,3]. The extensive evidence in this field has led to widespread use of these drugs.

Rodent studies indicate that statins are carcinogenic[4]. In contrast, several recent studies on human cancer cell lines and animal tumor models indicate that statins may have chemopreventive properties through the arrest of cell cycle progression[5], induction of apoptosis[1,6], suppression of angiogenesis[7,8], and inhibition of tumor growth and metastasis[9]. Results of a meta-analysis and observational studies revealed either no association[10-17] or a decrease in cancer incidence[18-26]. The reasons for the varying results are unclear but may be related to methodological issues, including small sample size and short follow-up periods[27].

Several epidemiologic studies have investigated the association between statin use and risk of colorectal cancer and the results have been inconsistent. Ten studies reported no statistically significant association between statin use and colorectal cancer risk[10,12,15,17,20-21,27-30]. However, three recent case-control studies reported that statin use is associated with a significant reduction in the risk of colorectal cancer[22,31-32].

Since large numbers of people utilize statins on a long-term basis, and because epidemiologic data linking statin use and risk of colorectal cancer are conflicting, we undertook the present study in Taiwan to evaluate the association between statin use and colorectal cancer risk.

MATERIALS AND METHODS
Data source

The National Health Insurance (NHI) program, which provides compulsory universal health insurance, was implemented in Taiwan on March 1, 1995. Under the NHI, 98% of the island’s population can receive all forms of health care services including outpatient services, inpatient care, Chinese medicine, dental care, childbirth, physical therapy, preventive health care, home care, and rehabilitation for chronic mental illness. In cooperation with the Bureau of NHI, the National Health Research Institute (NHRI) of Taiwan randomly sampled a representative database of 1  000  000 subjects from the entire NHI enrollees by means of a systematic sampling method for research purposes. There were no statistically significant differences in age, gender, and healthcare costs between the sample group and all enrollees, as reported by the NHRI. This dataset (from January 1996 to December 2008) includes all claim data for these 1  000  000 subjects, and offers a good opportunity to explore the relation between the use of statins and risk of colorectal cancer. These databases have previously been used for epidemiological research, and information on prescription use, diagnoses, and hospitalizations has been shown to be of high quality[33-35].

Because the identification numbers of all individuals in the NHRI databases were encrypted to protect the privacy of the individuals, this study was exempt from full review by the Institution Review Board.

Identification of cases and controls

Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of colorectal cancer (International Classification of Diseases, 9th revision, Clinical Modification Code 153-154) over a 4-year period, from January 1, 2005 to December 31, 2008, and who had no previous diagnosis of cancer.

Controls comprised patients who were admitted to hospital for diagnoses that were unrelated to statin use including orthopedic conditions, trauma (excluding wrist and hip fractures), and other conditions (acute infection, hernia, kidney stones, cholecystitis)[12,36]. Wrist and hip fractures were excluded because previous studies have reported a reduced risk of osteoporosis among statin users[37-40]. We identified four control patients per case patient. Control patients were matched to the cases by sex, year of birth, and index date and were without a previous cancer diagnosis. For controls, the index date (date of hospital admission) was within the same month of the index date (date of first-time diagnosis of colorectal cancer) of their matched case.

Exposure to statins

Information on all statin prescriptions was extracted from the NHRI prescription database. We collected the date of prescription, the daily dose, the number of days supplied. The defined daily doses (DDDs) recommended by the WHO[41] were used to quantify use of statins. Cumulative DDDs were estimated as the sum of dispensed DDD of any statins (lovastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, or atorvastatin) from January 1, 1996 to the index date.

Potential confounders

For all individuals in the study population, we identified variables which might confound the associations between statin use and colorectal cancer, including diabetes mellitus, cholecystectomy, liver disease, colorectal polyps, and inflammatory bowel disease, recorded between January 1, 1996, and the index date. In addition, we also obtained prescription data for other lipid-lowering drugs (including fibrate, niacin, bile-acid binding resins, and miscellaneous medications) and non-steroidal anti-inflammatory drugs (NSAIDs) that could potentially confound the association between statin use and the risk of colorectal cancer. We defined users of the above-mentioned medications as patients with at least one prescription over one year prior to the index date. Furthermore, colonoscopy, fecal occult blood testing (FOBT), and number of hospitalizations one year before the index date were treated as confounders.

Statistical analysis

For comparisons of proportions, chi-square statistics were used. A conditional logistic regression model was used to estimate the relative magnitude in relation to the use of statins. Exposure was defined as patients who received at least one prescription for a statin at any time between January 1, 1996 and the index date. In the analysis, the subjects were categorized into one of four statin exposure categories: nonusers (subjects with no prescription for any statins at any time between January 1, 1996 and the index date), low (the lowest 50th percentile; ≤ 105 DDDs); medium (50th-75th percentile; 106-298.66 DDDs); and high (above the 75th percentile; > 298.66 DDDs) based on the distribution of use among controls. Odd ratios (ORs) and their 95% confidence intervals (CIs) were calculated using patients with no exposure as the reference. Analyses were performed using the SAS statistical package (version 8.02, SAS Institute Inc). All statistical tests were two-sided. Values of P < 0.05 were considered statistically significant.

RESULTS

Records from 1156 colorectal cancer cases and 4624 selected matched controls were included in the analyses. Table 1 shows the distribution of demographic characteristics and selected medical conditions of the cancer cases and controls. The mean age was 68.34 years for cancer cases and 68.81 years for the controls. Case subjects were more likely to have had preventive services (screening colonoscopy and FOBT). The case group had a significantly higher rate of colorectal polyps than control patients. Use of other lipid-lowering drugs and NSAIDs were not significantly different between cases and controls.

Table 1 Demographic characteristics of colorectal cancer cases and controls.
VariableCases (n = 1156)Controls (n = 4624)Odds ratio (95% CI)
Age, yr (mean ± SD)68.34 ± 10.4069.29 ± 10.40-
Female (%)447 (38.67)1788 (38.67)-
No. of hospitalizations0.29 ± 0.930.26 ± 0.74P = 0.23
Diabetes (%)422 (36.51)1560 (33.74)1.13 (0.99-1.29)
Cholecystectomy (%)21 (1.82)105 (2.27)0.80 (0.50-1.28)
Liver disease (%)422 (36.51)1861 (40.25)0.85 (0.75-0.98)
Colorectal polyps (%)56 (4.84)76 (1.64)3.05 (2.14-4.33)
Inflammatory bowel disease (%)82 (7.09)315 (6.81)1.04 (0.81-1.34)
Colonoscopy (%)153 (13.24)42 (0.91)16.64 (11.75-23.57)
FOBT (%)152 (13.15)216 (4.67)3.09 (2.48-3.84)
NSAID (%)636 (55.02)2767 (59.84)0.82 (0.72-0.93)
Use of other lipid-lowering drugs (%)31 (2.68)180 (3.89)0.68 (0.46-1.00)

The observed associations between the use of statins and colorectal cancer are shown in Table 2. Ever-use of any statins was associated with a slight but not statistically significant increased colorectal cancer risk (adjusted OR = 1.09, 95% CI = 0.91-1.30). When statin use was categorized by cumulative dose, the adjusted ORs were 0.99 (95% CI = 0.78-1.27) for the group with cumulative statin use below 105 DDDs; 1.07 (95% CI = 0.78-1.49) for the group with cumulative statin use between 106 and 298.66 DDDs; and 1.30 (95% CI = 0.96-1.75) for the group with cumulative statin use of 298.66 DDDs or more compared with nonusers. Overall, we found no association between cumulative statin use and colorectal cancer risk. ORs for cancers of the colon and rectum considered separately were similar (data not shown).

Table 2 Associations between statin use and colorectal cancer risk in a population-based case-control study, Taiwan, 2005-2008.
Cases (n)/controls (n)Crude OR (95% CI)Adjusted OR (95% CI)1
Overall
No statin use914/37271.001.00
Any statin use242/8971.10 (0.94-1.30)1.09 (0.91-1.30)
Cumulative use
0914/37271.001.00
1-105 DDD112/4511.02 (0.82-1.27)0.99 (0.78-1.27)
106-298.66 DDD60/2211.11 (0.83-1.49)1.07 (0.78-1.49)
> 298.66 DDD70/2251.27 (0.96-1.68)1.30 (0.96-1.75)
DISCUSSION

In this population-based case-control study, we found that statin drug use was not associated with colorectal cancer risk. Our findings are consistent with ten recent studies which reported no associations between statin use and overall colorectal cancer risk[10,12,15,17,20-21,27-30].

Our results, however, conflict with three recent case-control studies. In a case-control study conducted in Israel, a reduced risk of colorectal cancer was found to be associated with the use of statins for at least 5 years, compared with less than 5 years of use (OR = 0.50, 95% CI = 0.40-0.63)[22]. Another population-based study from Germany showed that statin use was associated with a 35% (OR = 0.65, 95% CI = 0.43-0.99) colorectal risk reduction occurring within 1-4 years of statin use and no further risk reduction was seen after 5 years or more[31]. Neither study characterized the dose or duration of statins in detail and both studies defined statin use by recall. In a nested case-control study consisting solely of veterans with diabetes, using national databases of the Department of US Veterans Affairs and Medicare-linked files, Hachem et al[32] reported an odds ratio 0.91 (95% CI = 0.86-0.96) for colorectal cancer in relation to any statin use. However, there is no clear dose-response or duration-response relationship between filled statin prescriptions and colorectal cancer risk.

Duration of statin use may be important when investigating the chemopreventive effects of statins. We assessed exposure to statins measured as cumulative DDDs. Cumulative DDDs is a time-independent variable in which the daily supplies of each statin prescription dispensed were summed over time from January 1, 1996 to the index date. Because cumulative DDDs and statin duration are highly interrelated, it was not possible to model them together. Similar findings were noted when statin users were stratified by duration (data not shown).

There are at least two differences between our study and the study of Hachem et al[32]. First, their study population was limited to mostly male veterans with active access to health care and thus they were more likely to be prescribed a statin than the general population. Statin use was present in 51% of the study population. In our study this number was 19.4%. Second, the above-mentioned study was conducted among patients with diabetes who are known to have a higher likelihood of developing colorectal cancer[42]. Therefore, it is possible that it was easier to show benefit owing to the generally elevated risk in patients with diabetes[32]. Using an epidemiologic study which is restricted to patients with major risk factors means that the results of the restricted study may not necessarily apply to the portion of the population that was excluded. Whether a protective effect only occurs among patients who are already at higher risk of colorectal cancer requires further study. Other studies have reported a possible protective effect of statins in patients with diabetes on lung (adjusted OR = 0.43, 95% CI = 0.38-0.49)[24], pancreatic (adjusted OR = 0.32, 95% CI = 0.23-0.44)[25], and liver cancer (adjusted OR = 0.74, 95% CI = 0.64-0.87)[26].

One of the strengths of our study is the use of a computerized database, which is population-based and is highly representative. Because we included all patients newly diagnosed with colorectal cancer from 2005 to 2008, and because the control subjects in this study were selected from a simple random sampling of the insured general population, we can rule out the possibility of selection bias. Statins were available only on prescription. Because the data on statin use were obtained from an historical database which collects all prescription information before the date of colorectal cancer, recall bias for statin use was thus avoided.

Several limitations of the present study should be noted. First, although we adjusted for several potential confounders in the statistical analysis, a number of possible confounding variables, including family history of colorectal cancer, dietary habits or physical activity, and alcohol and tobacco use, which are associated with colorectal cancer were not included in our database. Second, we were unable to contact the patients directly about their use of statins because of anonymization of their identification number. Using pharmacy records representing dispensing data rather than usage data might have introduced an overestimation of statin use. However, there is no reason to assume that this would be different for cases and controls. Even if the patients did not take all of the statins prescribed, our findings would underestimate the effect of statin use. Third, lovastain and pravastatin (available in 1990), simvastatin (available in 1992), and fluvastatin (available in April, 1996) became available prior to patient enrollment in the database. Prescriptions for these drugs prior to 1996 would not be captured in our analysis. This could have underestimated the cumulative DDDs and may weaken the observed association. In addition, some exposure misclassification was likely caused by the fact that information on prescription was available only from 1996. Such misclassification, however, was likely to be non-differential, which would tend to underestimate rather than overestimate the association. Fourth, we were unable to analyze the risks for users of distinct statins separately due to the relatively small number of cases and the relatively small number of statin users. Fifth, data on the accuracy of discharge diagnoses are not available in Taiwan. Potential inaccurate data in the claims records could lead to possible misclassification. However, there is no reason to assume that this would be different for cases and controls. Lastly, as with any observational study, residual confounding by unmeasured factors which are different between cases and controls is also possible. However, the confounding effect of medical attention could be corrected for by introducing the number of hospitalizations into the conditional logistic regression model.

In summary, the results of this study do not provide support for an association between statin use and colorectal cancer risk. Given the widespread use of statins, it is prudent public health policy to continue monitoring cancer incidence among statin users, particularly as the duration of use is increasing[12].

ACKNOWLEDGMENTS

This study is based, in part, on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health or National Health Research Institutes.

COMMENTS
Background

Experimental studies have shown that statins have potential protective effects against cancer. Several epidemiologic studies have investigated the association between statin use and risk of colorectal cancer, and the results are inconsistent.

Research frontiers

This study was undertaken to examine the relationship between statin use and the risk of colorectal cancer.

Applications

Statins are widely used cholesterol-lowering drugs, and the duration of use is increasing. Further and larger studies are needed to determine the long-term effects of statin use on cancer development and to clarify whether statins are truly effective for cancer chemoprevention.

Peer review

This is a nice population-based study which strength is the fact that Taiwan National Health Insurance research program provides extensive data of one million patients. The methodology and statistical analysis is adequate and altogether the authors provide convincing evidence that statin use does not protect against the risk of colorectal cancer.

Footnotes

Peer reviewer: Pascal Gervaz, PhD, Department of Surgery, University Hospital Geneva, 4, Rue Gabrielle Perret Gentile, Geneva 1211, Switzerland

S- Editor Sun H L- Editor Webster JR E- Editor Zhang DN

References
1.  Wong WW, Dimitroulakos J, Minden MD, Penn LZ. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 2002;16:508-519.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 418]  [Cited by in F6Publishing: 443]  [Article Influence: 20.1]  [Reference Citation Analysis (0)]
2.  Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA. 1997;278:313-321.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 126]  [Cited by in F6Publishing: 136]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
3.  Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4794]  [Cited by in F6Publishing: 4766]  [Article Influence: 250.8]  [Reference Citation Analysis (0)]
4.  Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA. 1996;275:55-60.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 45]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
5.  Keyomarsi K, Sandoval L, Band V, Pardee AB. Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res. 1991;51:3602-3609.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Agarwal B, Rao CV, Bhendwal S, Ramey WR, Shirin H, Reddy BS, Holt PR. Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac. Gastroenterology. 1999;117:838-847.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 135]  [Cited by in F6Publishing: 141]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
7.  Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis. Circulation. 2002;105:739-745.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 462]  [Cited by in F6Publishing: 482]  [Article Influence: 21.9]  [Reference Citation Analysis (0)]
8.  Park HJ, Kong D, Iruela-Arispe L, Begley U, Tang D, Galper JB. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA. Circ Res. 2002;91:143-150.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 213]  [Cited by in F6Publishing: 203]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
9.  Mehta N, Hordines J, Sykes D, Doerr RJ, Cohen SA. Low density lipoproteins and Lovastatin modulate the organ-specific transendothelial migration of primary and metastatic human colon adenocarcinoma cell lines in vitro. Clin Exp Metastasis. 1998;16:587-594.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Kaye JA, Jick H. Statin use and cancer risk in the General Practice Research Database. Br J Cancer. 2004;90:635-637.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 201]  [Cited by in F6Publishing: 214]  [Article Influence: 10.7]  [Reference Citation Analysis (0)]
11.  Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: a meta-analysis. JAMA. 2006;295:74-80.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 441]  [Cited by in F6Publishing: 443]  [Article Influence: 24.6]  [Reference Citation Analysis (0)]
12.  Coogan PF, Rosenberg L, Strom BL. Statin use and the risk of 10 cancers. Epidemiology. 2007;18:213-219.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 123]  [Cited by in F6Publishing: 130]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
13.  Browning DR, Martin RM. Statins and risk of cancer: a systematic review and metaanalysis. Int J Cancer. 2007;120:833-843.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 171]  [Cited by in F6Publishing: 185]  [Article Influence: 10.9]  [Reference Citation Analysis (0)]
14.  Bonovas S, Filioussi K, Tsavaris N, Sitaras NM. Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials. J Clin Oncol. 2006;24:4808-4817.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 126]  [Cited by in F6Publishing: 136]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
15.  Setoguchi S, Glynn RJ, Avorn J, Mogun H, Schneeweiss S. Statins and the risk of lung, breast, and colorectal cancer in the elderly. Circulation. 2007;115:27-33.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 123]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
16.  Kuoppala J, Lamminpää A, Pukkala E. Statins and cancer: A systematic review and meta-analysis. Eur J Cancer. 2008;44:2122-2132.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 207]  [Cited by in F6Publishing: 221]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
17.  Haukka J, Sankila R, Klaukka T, Lonnqvist J, Niskanen L, Tanskanen A, Wahlbeck K, Tiihonen J. Incidence of cancer and statin usage--record linkage study. Int J Cancer. 2010;126:279-284.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 112]  [Cited by in F6Publishing: 129]  [Article Influence: 8.6]  [Reference Citation Analysis (0)]
18.  Cauley JA, Zmuda JM, Lui LY, Hillier TA, Ness RB, Stone KL, Cummings SR, Bauer DC. Lipid-lowering drug use and breast cancer in older women: a prospective study. J Womens Health (Larchmt). 2003;12:749-756.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 122]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
19.  Boudreau DM, Gardner JS, Malone KE, Heckbert SR, Blough DK, Daling JR. The association between 3-hydroxy-3-methylglutaryl conenzyme A inhibitor use and breast carcinoma risk among postmenopausal women: a case-control study. Cancer. 2004;100:2308-2316.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 100]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
20.  Graaf MR, Beiderbeck AB, Egberts AC, Richel DJ, Guchelaar HJ. The risk of cancer in users of statins. J Clin Oncol. 2004;22:2388-2394.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 396]  [Cited by in F6Publishing: 413]  [Article Influence: 20.7]  [Reference Citation Analysis (0)]
21.  Blais L, Desgagné A, LeLorier J. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study. Arch Intern Med. 2000;160:2363-2368.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 256]  [Cited by in F6Publishing: 275]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
22.  Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G. Statins and the risk of colorectal cancer. N Engl J Med. 2005;352:2184-2192.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 567]  [Cited by in F6Publishing: 583]  [Article Influence: 30.7]  [Reference Citation Analysis (0)]
23.  Shannon J, Tewoderos S, Garzotto M, Beer TM, Derenick R, Palma A, Farris PE. Statins and prostate cancer risk: a case-control study. Am J Epidemiol. 2005;162:318-325.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 183]  [Cited by in F6Publishing: 191]  [Article Influence: 10.1]  [Reference Citation Analysis (0)]
24.  Khurana V, Bejjanki HR, Caldito G, Owens MW. Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans. Chest. 2007;131:1282-1288.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 154]  [Cited by in F6Publishing: 158]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
25.  Khurana V, Sheth A, Caldito G, Barkin JS. Statins reduce the risk of pancreatic cancer in humans: a case-control study of half a million veterans. Pancreas. 2007;34:260-265.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 80]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
26.  El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology. 2009;136:1601-1608.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 205]  [Cited by in F6Publishing: 205]  [Article Influence: 13.7]  [Reference Citation Analysis (0)]
27.  Friis S, Poulsen AH, Johnsen SP, McLaughlin JK, Fryzek JP, Dalton SO, Sørensen HT, Olsen JH. Cancer risk among statin users: a population-based cohort study. Int J Cancer. 2005;114:643-647.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 218]  [Cited by in F6Publishing: 230]  [Article Influence: 12.1]  [Reference Citation Analysis (0)]
28.  Coogan PF, Smith J, Rosenberg L. Statin use and risk of colorectal cancer. J Natl Cancer Inst. 2007;99:32-40.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 101]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
29.  Jacobs EJ, Rodriguez C, Brady KA, Connell CJ, Thun MJ, Calle EE. Cholesterol-lowering drugs and colorectal cancer incidence in a large United States cohort. J Natl Cancer Inst. 2006;98:69-72.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 74]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
30.  Vinogradova Y, Hippisley-Cox J, Coupland C, Logan RF. Risk of colorectal cancer in patients prescribed statins, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors: nested case-control study. Gastroenterology. 2007;133:393-402.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 74]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
31.  Hoffmeister M, Chang-Claude J, Brenner H. Individual and joint use of statins and low-dose aspirin and risk of colorectal cancer: a population-based case-control study. Int J Cancer. 2007;121:1325-1330.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 66]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
32.  Hachem C, Morgan R, Johnson M, Kuebeler M, El-Serag H. Statins and the risk of colorectal carcinoma: a nested case-control study in veterans with diabetes. Am J Gastroenterol. 2009;104:1241-1248.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 40]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
33.  Kuo HW, Tsai SS, Tiao MM, Yang CY. Epidemiological features of CKD in Taiwan. Am J Kidney Dis. 2007;49:46-55.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 197]  [Cited by in F6Publishing: 209]  [Article Influence: 12.3]  [Reference Citation Analysis (0)]
34.  Chiang CW, Chen CY, Chiu HF, Wu HL, Yang CY. Trends in the use of antihypertensive drugs by outpatients with diabetes in Taiwan, 1997-2003. Pharmacoepidemiol Drug Saf. 2007;16:412-421.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 26]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
35.  Tiao MM, Tsai SS, Kuo HW, Chen CL, Yang CY. Epidemiological features of biliary atresia in Taiwan, a national study 1996-2003. J Gastroenterol Hepatol. 2008;23:62-66.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Coogan PF, Rosenberg L, Palmer JR, Strom BL, Zauber AG, Shapiro S. Statin use and the risk of breast and prostate cancer. Epidemiology. 2002;13:262-267.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 114]  [Cited by in F6Publishing: 120]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
37.  Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA. 2000;283:3205-3210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 317]  [Cited by in F6Publishing: 301]  [Article Influence: 12.5]  [Reference Citation Analysis (0)]
38.  Wang PS, Solomon DH, Mogun H, Avorn J. HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA. 2000;283:3211-3216.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 286]  [Cited by in F6Publishing: 267]  [Article Influence: 11.1]  [Reference Citation Analysis (0)]
39.  Rejnmark L, Plsen ML, Johnsen SP, Vestergaard P, Sorensen HT, Mosekilde L. Hip fracture risk in statin users- a population-based Danish case-control study. Osteoporos Int. 2004;15:452-458.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 59]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
40.  Jadhav SB, Jain GK. Statins and osteoporosis: new role for old drugs. J Pharm Pharmacol. 2006;58:3-18.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 116]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
41.  World Health Organization Collaborating Center for Drugs Statistics Methodology. ATC Index with DDDs 2003. Oslo: WHO 2003; .  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst. 2005;97:1679-1687.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 719]  [Cited by in F6Publishing: 729]  [Article Influence: 38.4]  [Reference Citation Analysis (0)]