Statins increase the risk of prostate cancer: A population-based case-control study

Statins Increase the Risk of Prostate Cancer:

A Population-Based Case^Control Study

Chih-Ching Chang,

Shu-Chen Ho,

Hui-Fen Chiu,

and Chun-Yuh Yang

*

1

Department of Environmental and Occupational Health, National Cheng Kung University,Tainan,Taiwan

2

Institute of Occupational Safetyand Health,College of Health Sciences, Kaohsiung Medical University,

Kaohsiung,Taiwan

3

Institute of Pharmacology,College of Medicine, Kaohsiung Medical University, Kaohsiung,Taiwan

4

Faculty of Public Health,College of Health Sciences, Kaohsiung Medical University, Kaohsiung,Taiwan

5

Division of Environmental Health and Occupational Medicine, National Health Research Institute, Miaoli,Taiwan

BACKGROUND. Experimental studies have shown that statins have potential protective effects against cancer. The aim of this study was to investigate whether the use of statins was associated with prostate 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 diag-nosis of prostate cancer for the period between 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 by using multiple logistic regression.

RESULTS. We examined 388 prostate cancer cases and 1,552 controls. We found that ever-use of any statin was associated with a significant increase in prostate cancer risk (OR¼ 1.55, 95%CI¼ 1.09–2.19). Compared with no use of statins, the adjusted ORs (95%CI) were 1.17 (0.60–2.28) for the group with cumulative dose
29.44 DDD, 1.59 (1.02–2.48) for the group with cumulative dose between 29.44 DDD and 321.33 DDD, and 1.86 (1.03–3.37) for the group with the highest cumulative dose (321.33 DDD). Also, there was a significant trend toward increasing prostate cancer risk with increasing cumulative dose (x2_{for linear trend¼ 7.23,}

P ¼ 0.007).

CONCLUSIONS. The results of this case–control study suggest that statins may increase the risk of prostate cancer.Prostate 71: 1818–1824, 2011. # 2011 Wiley Periodicals, Inc.

KEY WORDS: pharmacoepidemiology; statins; prostate cancer; case–control study INTRODUCTION

Statins are inhibitors of 3-hydroxy-3-methyl glu-taryl coenzyme A (HMG-CoA) reductase which is a key enzyme in the rate-limiting step in cholesterol synthesis [1]. Statins are commonly used as choles-terol-lowering medications and have shown effective-ness in the primary and secondary prevention of heart attack and stroke [2,3]. The extensive evidence has led to widespread use of these drugs.

Rodent studies indicate that statins are carcino-genic [4]. In contrast, several recent studies of human cancer cell lines and animal tumor models indicate that statins may have chemopreventive properties through the arresting of cell cycle progression [5],

inducing apoptosis [6,7], suppressing angiogenesis [8,9], and inhibiting tumor growth and metastasis [10,11].

Results of epidemiologic studies examining statin use and the risk of prostate cancer have been incon-sistent. Two studies reported an overall inverse

Grant sponsor: National Health Insurance Research.

*Correspondence to: Chun-Yuh Yang, PhD, MPH, Faculty of Public Health, Kaohsiung Medical University, 100 Shih-Chuan 1st RD, Kaohsiung 80708, Taiwan. E-mail: [email protected]

Received 10 August 2010; Accepted 16 March 2011 DOI 10.1002/pros.21401

Published online 7 April 2011 in Wiley Online Library (wileyonlinelibrary.com).

association between statin use and risk of prostate cancer [12,13], while others demonstrated no overall association between statin use and risk of prostate cancer [14–23]. An increase in overall prostate cancer risk was observed for statin users in two studies [24,25]. One study reported that statin use increased the risk of prostate cancer only limited to obese men [22]. The reasons for the varying results are unclear but may relate to methodologic issues, including small sample size and short follow-up periods [18]. However, recent studies consistently report that statins reduce advanced prostate cancer risk [12,19,20,25]. Clinical trials of statin use recently reported a trend toward an increased risk of prostate cancer among the pravastatin group compared with placebo [26].

Since large number of people utilize statins on a long-term basis, and because epidemiologic evidence for a link between statin use and risk of prostate can-cer is inconclusive, we undertook the present study in Taiwan to evaluate the association between statin use and prostate cancer.

MATERIALS AND METHODS Data Source

The National Health Insurance (NHI) program, which provides compulsory universal health insur-ance, was implemented in Taiwan on March 1, 1995. Under the NHI, 98% of the island’s population receives 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 data-base 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, offers a good opportunity to explore the relation between the use of statins and risk of prostate cancer. These database have pre-viously been used for epidemiological research, and information on prescription use, diagnoses, and hospitalizations has been shown to be of high quality [27–29].

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 pros-tate cancer (International Classification of Diseases, 9th revision, Clinical Modification [ICD-9-CM] Code 185) over a 4-year period, from January 1, 2005 to December 31, 2008, and who had no previous diagno-sis of cancer.

Controls comprised patients who were admitted to the hospital for diagnoses that were unrelated to sta-tin use including orthopedic conditions, trauma (excluding wrist and hip fractures), and other con-ditions (acute infection, hernia, kidney stones, chole-cystitis) [15,16]. Wrist and hip fractures were excluded because previous studies have reported a reduced risk of osteoporosis among statin users [30– 33]. We identified four control patients per case patient. Control patients were matched to the cases by sex, year of birth, and index date and they were with-out 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 prostate cancer) of their matched case.

Exposure to Statins

Information on all statin prescription were extracted from the NHRI prescription database. We collected the date of prescription, the daily dose, the number of days supplied. The defined daily doses (DDD) recommended by the WHO [34] were used to quantify usage of statins. Cumulative DDDs was esti-mated as the sum of dispensed DDD of any statins (lovastatin, pravastatin, rosuvastatin, fluvastatin, sim-vastatin, or atorvastatin) from January 1, 1996 to the index date.

Potential Confounders

For all individuals in the study population, we identify variables which might confound the associations between statin use and prostate cancer, including diabetes mellitus (DM), histories of cardio-vascular disease (CHD), hypertension, and benign prostatic hyperplasia (BPH), recorded between Janu-ary 1, 1996, and 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 potentially could confound the association between

statin use and the risk of prostate cancer. We defined users of the above mentioned medications as patients with at least one prescription over 1 year prior to index date. Furthermore, number of physician visits and number of hospitalizations 1 year before index date were treated as confounders.

Statistics

For comparisons of proportions, Chi-square stat-istics were used. A conditional logistic regression model was used to estimate the relative magnitude of association in relation to the use of statins. Exposure was defined as patients who received at least one pre-scription for a statin at any time between January 1, 1996 and the index date. In the analysis, the subjects were categorized into one of the four statins exposure categories: no use (subjects with no prescription for any statins at any time between January 1, 1996 and the index date), low (the lowest 25th percentile;
29.44 DDDs); medium (25th–75th percentile; >29.44–321.33 DDD); and high (above the 75th per-centile; >321.33 DDD) 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 388 prostate cancer cases and 1,552 selected matched controls are included in the analyses of prostate cancer risk. Table I presents the distribution of demographic characteristics and selected medical conditions of the prostate cancer cases and controls. The mean age was 71.98 for prostate cancer cases and 71.95 for the controls. The case group had a significant higher rate of diabetes and BPH. Use of other lipid-lowering drugs and

NSAIDs were not significantly different between cases and controls.

The relationship between the use of statins and prostate cancer risk is shown in Table II. 21.4% of the cases and 15.4% of the controls had used any quantity of at least one prescription for a statin. Ever-use of any statin was associated with an elevated prostate cancer risk (crude OR¼ 1.49, 95%CI ¼ 1.13–1.97). Adjustments for possible confounders (matching vari-ables, diabetes, hypertension, CHD, BPH, use of NSAIDs, use of other lipid-lowering drugs, number of physician visits, and number of hospitalizations) only slightly alter the odds ratio, patients that received any prescriptions of statins had a 55% increase in risk of prostate cancer compared with non-users (adjusted OR¼ 1.55, 95%CI ¼ 1.09–2.19).

When statin use was categorized by cumulative dose, the adjusted ORs (95%CI) were 1.17 (0.60–2.28) for the group with cumulative dose
29.44 DDD, 1.59 (1.02–2.48) for the group with cumulative dose between 29.44 DDD and 321.33 DDD, and 1.86 (1.03– 3.37) for the group with the highest cumulative dose (321.33 DDD) compared with nonusers. Also, there was a significant trend toward increasing prostate cancer risk with increasing cumulative dose (x2 _for

linear trend¼ 7.23, P ¼ 0.007). DISCUSSION

In this population-based case–control study, ever-use of any statin was associated with a significant increase in prostate cancer risk (OR¼ 1.55, 95%CI¼ 1.09–2.19). We also found that there was a significant trend toward increasing prostate cancer risk with increasing cumulative dose after controlling for potential confounders.

Our findings are consistent with three recent stud-ies [22,24,25]. Data from the United Kingdom General Practice Research Database, Kaye and Jick [24] reported an increase in overall prostate cancer risk associated with statin use (OR¼ 1.3, 95%CI ¼ 1.0– TABLE I. Demographic Characteristics of Prostate Cancer Cases and Controls

Variable Cases (n¼ 388) Controls (n¼ 1,552) OR (95%CI)

Age (mean SD) 71.98 9.43 71.95 9.41 —

No. of physician visits 36.07 27.11 35.94 30.44 P ¼ 0.94

No. of hospitalizations 0.38 0.77 0.29 0.76 P ¼ 0.03 Diabetes (%) 139 (35.82) 447 (28.8) 1.38 (1.09–1.75) Hypertension (%) 115 (29.64) 454 (29.25) 1.02 (0.80–1.30) CHD (%) 11 (2.84) 50 (3.22) 0.88 (0.45–1.70) BPH (%) 352 (90.72) 681 (43.88) 12.51 (8.75–17.88) NSAIDs (%) 235 (60.57) 944 (60.82) 0.99 (0.79–1.24)

1.9). A large population-based case–control study conducted in Finland by Murtola et al. [25] found an elevated risk for statin users (OR¼ 1.07, 95%CI¼ 1.0–1.16). Due to the comprehensive national health care registers in Taiwan, we were able to carry out a population-based case–control study with designs similar to the above-mentioned two studies with a minimal influence of chance or selec-tion bias. Also, being able to obtain the detailed exposure information in an objective manner from the prescription database allowed us to evaluate statin use accurately. Recently, Agalliu et al. [22] conducted a population-based case–control study in King County, Washington (USA) to evaluate statin use and prostate cancer risk. No association was observed among nonobese men, but, for obese men (BMI 30 kg/m2), current use of a statin was associ-ated with an increased risk of prostate cancer (OR¼ 1.5, 95%CI ¼ 1.0–2.24), which was stronger for those with extended durations of use (5 years of use) (OR¼ 1.8, 95%CI ¼ 1.06–3.03). The risk increase observed in our study is of similar magnitude to those observed in the study of Agalliu et al.

There are at least two epidemiologic studies which have reported a decreased risk of prostate cancer associated with statin use. A case–control study con-ducted in Oregon, Shannon et al. [12] reported a 65% reduction in prostate cancer risk associated with ever use of statins compared with never use (OR¼ 0.35, 95%CI¼ 0.20–0.64). It must be noted that the study population in Shannon et al. [12] study consists solely of veterans and mostly of older men with active access to health care. It is possible that these men are more likely to receive regular lipid screening and to be prescribed statins than our study population. In the California Men’s Health Study [13], there was a decreased risk of prostate cancer in long-term statin

users (5 or more years, RR¼ 0.72, 95%CI ¼ 0.53– 0.99). These two studies were conducted in the United States during the PSA era (i.e., 1990s and 2000s), which could lead to earlier detection of prostate cancer. This would increase the observed OR or RR of the overall prostate cancer for statin users and mask a possible protective effect of statin use, which was not the case in the above-two mentioned studies. By contrast, we observed a positive associ-ation between statin use and the risk of prostate cancer. The reasons for the differences in the findings are unknown.

The biologic mechanisms by which statin use may increase risk of prostate cancer remains unknown, but they may relate to sex hormone-binding globulin levels. A recent meta-analysis of studies of endogen-ous sex hormones and prostate cancer revealed that men with lower levels of sex hormone-binding globulin are at higher risk of developing prostate cancer [35]. Also levels of sex hormone-binding glob-ulin have been found to be significantly lower in statin users compared with nonusers [36]. Another potential mechanism is that statins may increase the level of regulatory T cells which may suppress antitumor T-cell response and thereby enhance cancer risk [37].

While we found some suggestion of an increased risk, it is biologically plausible that statins reduce prostate cancer risk. The mechanism whereby statin use may decrease prostate cancer risk is not well understood. Yet, several potential mechanisms have been investigated, including the following: (1) inhibit-ing downstream products of the mevalonate path-way, primary geranylgeranyl pyrophospate (GGPP) and farnesylpyrophophosphate (FPP) [38–40]. Deriva-tives of the mevalonate pathway GGPP and FPP are important in the activation of a number of cellular TABLE II. Associations Between Statin Use and Prostate Cancer Risk in a Population-Based Case^Control Study,Taiwan, 2005 ^2008

No. of cases/no. of controls Crude OR (95%CI) Adjusted OR (95%CI)a Overall

No statin use 305/1,313 1.00 1.00

Any statin use 83/239 1.49 (1.13–1.97) 1.55 (1.09–2.19)

Cumulative use 0 305/1,313 1.00 1.00 1–29.44 DDD 15/59 1.11 (0.62–1.99) 1.17 (0.60–2.28) 29.45–321.33 DDD 45/120 1.59 (1.11–2.28) 1.59 (1.02–2.48) >321.33 DDD 23/60 1.66 (1.00–2.75) 1.86 (1.03–3.37) P for trend x2_{¼ 9.18, P ¼ 0.002 x}2_{¼ 7.23, P ¼ 0.007} a

Adjusted for matching variable, diabetes, hypertension, CHD, BPH, use of NSAIDs, use of other lipid-lowering drugs, number of physician visits, and number of hospitalizations.

proteins, including small guanosine-50-triphosphate binding proteins, such as K-ras, N-ras, and the Rho family [38–40]. Statins interfere with the production of GGPP and FPP and disrupt the growth of malignant cells, eventually leading to apotosis [1]. (2) Statins inhibit the activation of the proteosome pathway, limiting the breakdown of both p21 and p27, allowing these molecules to exert their growth-inhibitory effects and in turn to retard cancer cell mitosis [41,42].

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 prostate cancer from 2005 to 2008, and because the control subjects in this study were selected from a simple random sampling of insured general population, we can rule out the possibility of selection bias. Statins were available only on prescription. Because statin use data were obtained from an historical database which collects all prescription information before the date of prostate cancer, therefore recall bias for statin use was 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 body mass index, smoking, and alcohol consumption, which are associated with prostate cancer were not included in our database. Second, we were not able 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 underesti-mate the effect of statin use. Third, lovastain and pra-vastatin (available in 1990), Simpra-vastatin (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 since 1996. Such misclassification, however, was likely to be nondifferential, which would tend to underestimate rather than overestimate the associ-ation. Fourth, we are unable to separately analyze the risks for users of distinct statins due to the relatively small number of cases and the relatively small

number of statin users. Fifth, data on the accuracy of discharge diagnoses is 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. For example, if statin users had more pros-tate-specific antigen (PSA) testing and medical visits, this could lead to earlier detection of prostate cancer and bias results away from finding any protective effect of statins overall. There is unfortunately no information available on this variable for individual study subjects, and this could not be adjusted for directly in the analysis. However, the confounding effect of medical attention could be corrected for by introducing the number of physician visits and the number of hospitalizations into the conditional logis-tic regression model.

In summary, results of this study suggest that sta-tin use is associated with an increased risk of prostate cancer. Given the widespread use of statins, any change in cancer risk may have a substantial public health impact. Further and larger studies, particularly prospective randomized trial studies, are necessary to confirm our findings.

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 Bureau of National Health Insurance, Department of Health or National Health Research Institutes.

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