The Association Between Statin Use and the Diagnosis of Prostate Cancer in a Population Based Cohort
Article Outline
Purpose
The effect of statin medication use on the risk of prostate cancer is unknown.
Materials and Methods
We examined data from a longitudinal, population based cohort of 2,447 men between 40 and 79 years old who were followed from 1990 to 2007. Information on statin use was self-reported and obtained by biennial questionnaires. A randomly selected subset of men (634, 26%) completed biennial urological examinations that included serum prostate specific antigen measurements. Information on prostate biopsy and prostate cancer was obtained through review of community medical records.
Results
Of 634 statin users 38 (6%) were diagnosed with prostate cancer vs 186 (10%) of 1,813 nonstatin users. Statin use was associated with a decreased risk of undergoing prostate biopsy (HR 0.31; 95% CI 0.24, 0.40), receiving a prostate cancer diagnosis (HR 0.36; 95% CI 0.25, 0.53) and receiving a high grade (Gleason 7 or greater) prostate cancer diagnosis (HR 0.25; 95% CI 0.11, 0.58). Statin use was also associated with a nonsignificantly decreased risk of exceeding a prostate specific antigen threshold of 4.0 ng/ml (HR 0.63; 95% CI 0.35, 1.13). In addition, a longer duration of statin use was associated with a lower risk of these outcomes (all tests for trend p <0.05).
Conclusions
Statin use is associated with a decreased risk of prostate cancer diagnosis. This association may be explained by decreased detection or cancer prevention.
Key Words: hydroxymethylglutaryl-CoA reductase inhibitors, prostatic neoplasms, population characteristics
Abbreviations and Acronyms: CHD, coronary heart disease, NSAIDs, nonsteroidal anti-inflammatory medications, PSA, prostate specific antigen
Prostate cancer is the second leading cause of cancer mortality in men and is the most commonly diagnosed noncutaneous malignancy.1 The incidence of prostate cancer in the United States was expected to exceed 192,000 cases in 2009,1 and treatments are expensive and associated with adverse events.2 Given the associated societal burden, interventions that prevent the development or growth of prostate cancer could have a large, beneficial impact.
Statins, hydroxymethylglutaryl-CoA reductase inhibitors, are a class of medications that reduce cholesterol levels and prevent cardiovascular events. However, statins may also have antineoplastic effects,3 and induce apoptosis and growth arrest in prostate cancer cell lines.4 Statins may exert these effects through cholesterol mediated5 or noncholesterol mediated mechanisms because these drugs lower potentially carcinogenic isoprenoids and have anti-inflammatory effects that may protect cells from neoplastic transformation.3
Observational studies examining statin use and the risk of prostate cancer have been contradictory.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 Possible explanations for inconsistent findings include heterogeneous patient populations, variable durations of statin exposure and short lengths of followup. Another potential source of confusion is that statins may reduce serum PSA.17, 18 Because increased serum PSA is the most common indication for prostate biopsy, statin use may be associated with a decreased likelihood of undergoing biopsy and subsequent under detection of cancer. In a large, population based cohort study we determined whether statin use was associated with a decreased risk of an increased PSA, performance of prostate biopsy and prostate cancer diagnosis.
Materials and Methods
Study Subjects
The Olmsted County Study of Urinary Symptoms and Health Status among Men is a long-term, population based cohort study of men residing in Olmsted County, Minnesota. A detailed description of this cohort is published elsewhere.19, 20 Men between 40 and 79 years old as of January 1, 1990 were eligible for a longitudinal cohort study designed to describe the natural history of benign urological disease in the community. Men were excluded from the study if they had a history of prostate cancer, had undergone prostatectomy or had other urological conditions. Overall 2,115 men (55%) agreed to participate and completed a self-administered questionnaire biennially. The questionnaires assessed smoking, alcohol use, current medication use and demographic characteristics, as well as urological function. A randomly selected subset (476 of 537, 89%) of men participated in a biennial clinical examination. In 1992 and 1994 men who did not participate in this active followup were replaced by randomly selected men from the Olmsted County population (332 total replacements, 158 clinic subset participants). The recruitment and attrition of study participants at each round of followup are shown in figure 1. Participants who refused to participate in 1 round remained eligible for participation in remaining rounds of followup. All men were also passively followed through their community medical records for the duration of the study.
Figure 1.
Study participation in each round of followup
Statin Exposure
At baseline each participant reported all prescribed and over-the-counter medications taken on a daily basis, and the date at which the medication was first taken. Medications were grouped into classes by the research team on receipt of the questionnaires. Current medication use and starting dates were ascertained again by questionnaires in 1996, 2000 and biennially thereafter.
Outcome Variables
Serum PSA was measured in the subset of men who participated in the biennial clinical examination. Serum samples were obtained before any prostatic manipulations, including digital rectal examination and transrectal ultrasound. PSA thresholds were evaluated, including 2.5 ng/ml, 4.0 ng/ml and age specific thresholds.20 Prostate biopsy, prostate cancer, tumor grade (Gleason sum 7 or greater considered high grade) and pathological stage were determined from medical record and pathology report review. The 2002 American Joint Committee on Cancer pathological staging system was used for men treated with radical prostatectomy.
Potential Confounders
Variables that might confound associations between statin use and outcomes were considered. Diabetes was defined as self-report of a diabetes diagnosis or antihyperglycemic medication use. Hypertension was defined as self-report of high blood pressure or antihypertensive medication use. CHD was defined as sudden cardiac death, myocardial infarction and angiographically diagnosed coronary disease. Subjects were classified as ever smoker or never smoker. Anthropometric measures were obtained at baseline by study nurses using a standardized protocol. Body mass index was calculated as weight (kg) divided by height (m2) and individuals with a body mass index of 30 kg/m2 or greater were classified as obese. Analyses were also adjusted for other current medication use.
Data Analysis
Separate analyses were conducted for PSA thresholds, prostate biopsy, prostate cancer and high grade prostate cancer. Men with a prostate biopsy or increased PSA at baseline were excluded from the analyses of these outcomes. For PSA outcomes, followup was from the start of the study until the outcome event in the analysis or the last study visit. PSA measurements after the diagnosis of prostate cancer were censored. For prostate biopsy and prostate cancer outcomes followup was from the start of the study until the outcome event or last followup. Participants who reported statin use before the outcome were considered exposed. Duration of statin use was defined as the time from the reported start of the medication to the event date or date of last followup.
Cox proportional hazard models were used to estimate associations between statin use and each outcome and are presented as hazard ratios and 95% CI. Figures are plotted by age at event for clarity of presentation. Proportional hazards assumptions were assessed using Schoenfeld residuals. Differences between statin users and nonstatin users were examined, and are reported in table 1. Multivariable models were then used to adjust for variables that differed between the groups. Additional models, including a 4-level term representing nonusers and tertile of duration, were used to assess linear trends in duration of statin use.
Table 1. Characteristics of statin users and nonstatin users
| No. Statin Use (%)⁎ | No. No Statin Use (%) | Chi-Square p Value | Age Adjusted Chi-Square p Value | |
|---|---|---|---|---|
| Pt age: | ||||
 40–49 | 245 (38.6) | 898 (49.5) | <0.0001 | |
| 50–59 | 212 (33.4) | 388 (21.4) | ||
| 60–69 | 140 (22.1) | 308 (17.0) | ||
| 70+ | 37 (5.8) | 219 (12.1) | ||
| Diabetes | 143 (22.6) | 142 (7.8) | <0.0001 | <0.0001 |
| Hypertension | 479 (75.6) | 744 (41.0) | <0.0001 | <0.0001 |
| CHD | 257 (40.5) | 285 (15.7) | <0.0001 | <0.0001 |
| Use of NSAIDs | 552 (87.1) | 1,023 (56.4) | <0.0001 | <0.0001 |
| Ever smoked | 413 (65.1) | 1,132 (62.4) | 0.19 | 0.24 |
| Alcohol use once/wk or more | 276 (43.5) | 701 (38.7) | 0.43 | 0.46 |
| Obese | 187 (29.5) | 457 (25.2) | 0.51 | 0.47 |
| 5α-Reductase inhibitor use | 78 (12.3) | 126 (7.0) | <0.0001 | <0.0001 |
| α-Blocker use | 182 (28.7) | 328 (18.1) | <0.0001 | <0.0001 |
| PSA greater than age specific reference range† | 12 (8.1) | 51 (11.2) | 0.29 | 0.30 |
| PSA 2.5 ng/ml or greater† | 19 (15.2) | 104 (24.5) | 0.03 | 0.049 |
| PSA 4.0 ng/ml or greater† | 19 (12.8) | 57 (12.8) | 0.99 | 0.74 |
| Prostate biopsy | 79 (13.7) | 433 (23.6) | <0.0001 | <0.0001 |
| Prostate Ca | 38 (6.0) | 186 (10.3) | 0.001 | 0.002 |
| High grade prostate Ca | 7 (1.1) | 49 (2.8) | 0.01 | 0.02 |
⁎Number of statin users varied with the outcome examined. |
†PSA outcomes only for the 634 men who participated in the in-clinic examinations. |
Results
Overall 634 men used statins. Statin users were older, more likely to have a comorbid disease, and more commonly used NSAIDs, 5α-reductase inhibitors and α-blockers. Median followup was similar for statin users (median 15.7 years; Q1, Q3 = 15.1, 16.5) and nonstatin users (median 15.2 years; Q1, Q3 = 13.1, 16.2).
Statin use was associated with a decreased risk of increased PSA, undergoing prostate biopsy, overall risk of prostate cancer and risk of high grade prostate cancer (fig. 2). After adjusting for age, diabetes, hypertension, CHD, and NSAID, 5α-reductase inhibitor and α-blocker use, associations strengthened slightly (table 2). Study subjects who took statins for the longest period had the lowest risk of each outcome (all tests for trend p <0.05, fig. 3). Of those patients diagnosed with prostate cancer 18 (47%) statin users and 103 (55%) nonstatin users were treated with radical prostatectomy. Tumor stage was available for 106 (88%) of these men, and locally advanced disease (pT3) was present in 4 (22%) statin users and 32 (31%) nonstatin users. No statin user was diagnosed with lymph node metastases vs 3 in the nonstatin group.
Figure 2.
Cumulative incidence of exceeding age specific PSA reference range (A), of prostate biopsy (B), of prostate cancer (C) and of high grade prostate cancer (Gleason 7 or greater, D).
Table 2. Risks of increased PSA, prostate biopsy, prostate cancer and high grade prostate cancer
| Unadjusted HR (95% CI) | Multivariable Adjusted HR (95% CI)⁎ | |
|---|---|---|
| PSA greater than age specific reference range† | 0.47(0.25–0.87) | 0.39(0.19–0.81) |
| PSA 2.5 ng/ml or greater† | 0.39(0.24–0.63) | 0.31(0.18–0.52) |
| PSA 4.0 ng/ml or greater† | 0.65(0.39–1.09) | 0.63(0.35–1.13) |
| Prostate biopsy | 0.47(0.37–0.60) | 0.31(0.24–0.40) |
| Prostate Ca | 0.48(0.34–0.69) | 0.36(0.25–0.53) |
| High grade prostate Ca | 0.32(0.15–0.71) | 0.25(0.11–0.58) |
⁎Adjusted for age, diabetes, hypertension, CHD, NSAID use, 5α-reductase inhibitor use and α-blocker use. |
†PSA outcomes only for the 634 men who participated in the in-clinic examinations. |
Figure 3.
Associations between duration of statin use (stratified by tertiles) and outcome using nonstatin users as referent group. P values represent tests for trend. Asterisk indicates PSA outcomes only for 634 men who participated in in-clinic examinations. Double asterisk indicates adjusted for age, diabetes, hypertension, CHD, and NSAID, 5α-reductase inhibitor and α-blocker use.
Discussion
In this cohort statin use was associated with a decreased risk of exceeding PSA thresholds, undergoing prostate biopsy and receiving a diagnosis of prostate cancer or high grade prostate cancer. Additionally, for all outcomes longer duration of use was associated with lower risk. The association between statin use and prostate cancer diagnosis may be a consequence of less frequent prostate biopsies in statin users due to PSA suppression. Alternatively statins may have antineoplastic effects beyond their established cardiovascular functions.
These data are consistent with findings of some previous studies.17, 18 In a recent observational study statin users experienced a 4.1% median decrease in serum PSA within 1 year of starting therapy.17 Since increased serum PSA is a common indication for proceeding to prostate biopsy, suppression of PSA could explain the lower risk of biopsy among statin users. However, if statins only suppressed PSA and had no effect on prostate cancer, we would expect biopsies of statin users to be delayed, resulting in more advanced stage disease at diagnosis. In our cohort statin users had a decreased risk of high grade tumors. Others have also found a decreased risk of advanced stage prostate cancer in statin users.8, 11, 13, 14, 15 Thus, these data suggest that statin use does not simply delay or prevent prostate cancer diagnosis by suppressing PSA.
The decreased risk of overall prostate cancer observed in our cohort is not consistent with all previous studies. Clinical trials of statins for cardiovascular outcomes showed no association between statin use and prostate cancer incidence (examined as a secondary outcome).21 In addition, several cohort studies with designs similar to ours demonstrated no overall association between statin use and risk of prostate cancer.8, 9, 11, 14 These differences may be explained by duration of statin use. If statins prevent the development of prostate cancer, long periods of exposure may be necessary. In randomized trials the duration of followup before open label use of statins was limited, ranging from 3.9 to 6 years.22, 23, 24, 25, 26, 27 Duration of statin use was also limited in previous cohort studies but there was some suggestion that longer use might be associated with a decreased risk of prostate cancer. For example, in the California Men's Health Study there was a decreased risk of prostate cancer in long-term statin users (5 or more years, RR 0.72, 95% CI 0.53–0.99).8 A similar but nonsignificant association was observed in the Health Professionals Followup Study in men who used statins for 5 or more years (RR 0.85, 95% CI 0.71–1.03).14 In our study more than half of the statin users used these medications for more than 5 years and 33% used them for more than 9 years, with the strongest protective associations observed in men who had used statins for the longest period. If statins are protective against the development of prostate cancer, long duration of use may be necessary for a protective association to emerge.
Several potential limitations should be considered when interpreting our study results. A recent editorial suggested that statin users may be differentially screened for prostate cancer compared to nonstatin users.28 Differential screening would likely result in the detection of more cancers in the group that is more frequently screened. While we do not have detailed screening information on all participants, PSA screening in this cohort was assessed through 1998 and statin users were more likely to have received frequent PSA screenings (more than 3 PSA measurements) vs nonstatin users (34% vs 21%, chi-square p <0.001). Furthermore, a subset of the men in the study received routine PSA screening as part of the longitudinal cohort study regardless of statin use. In a secondary analysis only examining the men who underwent routine PSA screening the associations between statin use and risk of prostate biopsy were similar to those of the entire cohort (multivariable adjusted HR 0.35 for the group with routine PSA testing vs 0.31 for the entire cohort). These data suggest that the association between statin use and risk of prostate cancer was not due to decreased screening in statin users.
Additionally, it is possible that differences in baseline PSA may have confounded associations between statin use and the outcomes if statin users differed from nonstatin users in initial PSA. However, we conducted a secondary analysis, adjusting our study results for baseline PSA in participants who had such measures available. The association between statin use, and prostate biopsy and prostate cancer did not change significantly after adjusting for baseline PSA (HR 0.51; 95% CI 0.34, 0.77 and HR 0.53; 95% CI 0.28, 1.02, respectively). It is unlikely that baseline differences in PSA confounded observed associations.
It is also possible that participation in the study may have influenced participant behavior. For example, participants may have been generally more aware of prostate health issues after enrollment in the study and, thus, may have been more likely to be screened for prostate cancer with subsequent detection of prevalent cancer. Given that statin use increased during the study period, early detection of prevalent prostate cancer would make statins artificially seem protective. However, the proportion of new cancers diagnosed in men between 60 and 69 years old did not differ significantly based on the year of diagnosis (5.4% from 1990 to 1994 vs 6.6% from 2000 to 2004), suggesting that this effect was not occurring in our population.
Statins might also appear protective for prostate cancer if statin users were more likely to die of competing causes of death compared to nonstatin users. However, in our population statin users were less likely to die during followup vs nonusers (age adjusted HR 0.32; 95% CI 0.24, 0.43), suggesting that this explanation of our findings is also unlikely.
Our study results may be biased if men who participated in the study differed from those who did not participate. However, at baseline participants and nonparticipants had similar characteristics.29 In addition, the incidence of prostate cancer in the cohort was similar to what we would expect based on United States incidence rates.1 All men in this study were white and results may not be generalizable to men of other racial or ethnic populations.
Data on diabetes, hypertension and all medications were self-reported, and we lacked information on diet and exercise in this population. Discrepancies between self-report and actual health conditions could bias observed associations. Additionally, while comorbid conditions did not confound the association between statins and prostate cancer, other unmeasured factors such as diet and exercise could account for the observed associations. In the absence of randomized trials with systematic end of study biopsy, the effect of unknown confounders and the potential for detection bias remain limitations to observational studies evaluating prostate cancer prevention.
We had limited information on statin dose as well as start and stop dates for medications used. For these analyses we assumed that once a man reported use of a statin, he continued to take the statin for the duration of followup. A recent review article suggests that up to 60% of patients who are prescribed statins stop use within the first 6 months of prescription.30 However, in this cohort long-term medication adherence appeared to be more common. Of the 350 men who reported statin use at baseline (1990) and who had data available in 2000, 290 (83%) also reported statin use in 2000. Additionally, of the 251 men who reported new use of statins in 2000 and who also had information in 2006, 208 (83%) again reported statin use. However, it was not possible for us to assess interim changes in statin use, nor whether men who reported statin use actually took the medications.
Conclusions
The antineoplastic effects of statins on prostate cancer are supported by an increasing number of observational studies. While most have observed a decrease in advanced stage disease, in this longitudinal cohort study statin use was associated with a large reduction in the risk of overall prostate cancer, particularly in men who used statins for a long period. These data suggest statins may have a preventive effect against prostate cancer.
Acknowledgments
Dr. Veronique L. Roger provided study support and collaboration.
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Supported by the U.S. Public Health Service, National Institutes of Health (Grants DK58859, AR30582 and 1 UL1 RR024150-01) and Merck Research Laboratory.
PII: S0022-5347(10)03277-5
doi:10.1016/j.juro.2010.03.149
© 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc All rights reserved.