In this study, there were no associations between detailed measures of statin use and risk of either prostate cancer overall or more aggressive disease. Interestingly, analyses stratified by BMI showed that obese men (BMI ≥30 kg/m2) who reported current use of a statin had an increased odds ratio of prostate cancer (OR = 1.5, 95 percent CI: 1.0, 2.1), which was stronger for those with extended durations of use (OR = 1.8 for >5 years of use).
Several randomized clinical trials of cardiovascular disease (13
), as well as observational studies (19
), have examined risk of prostate cancer in relation to statin use. The randomized trials data revealed no associations (13
), but the trials were not designed to test the statin–prostate cancer hypothesis. Moreover, these trials involved short durations of statin use and limited periods of follow-up, which are likely inadequate for assessing statin use in relation to cancer occurrence (16
Several observational studies have examined the association between statin use and prostate cancer (19
). Most utilized hospital- or clinic-based populations or computerized pharmacy data for analyses. The prevalence of statin use varied widely across studies, ranging from 5 percent to 49 percent, and in some studies increased over time. Two studies reported an overall inverse association between any statin use and prostate cancer risk (18
), while others reported no association (24
) or a positive association (23
). Shannon et al. (19
) conducted a study within a Veterans Administration hospital population and reported an odds ratio of 0.4 (95 percent CI: 0.2, 0.7) for prostate cancer in relation to ever use of a statin and an odds ratio of 0.3 for more than 2 years' duration of use. Graaf et al. (18
) used a pharmacy database to define exposure and observed a similar reduction in risk (OR = 0.4) of prostate cancer in relation to statin prescriptions. However, both of these studies had small sample sizes. Recently, Flick et al. (22
) used data from the California Men's Health Study cohort to evaluate statin exposure and also reported an inverse association between 5 or more years of statin use and overall prostate cancer risk (relative risk = 0.72, 95 percent CI: 0.53, 0.99). The remaining studies reported no associations with overall prostate cancer risk, with the exception of two studies. Data from the United Kingdom General Practice Research Database (28
) revealed a modest increase in prostate cancer risk (OR = 1.3, 95 percent CI: 1.0, 1.9) associated with use of a statin drug, and a large population-based study from Finland (23
) also reported an elevated risk estimate for statin users (OR = 1.07, 95 percent CI: 1.0, 1.2).
With respect to clinical features of prostate cancer, Shannon et al. (19
) reported an odds ratio of 0.3 (95 percent CI: 0.1, 0.5) for men with a Gleason score of higher than 7 in relation to ever use of a statin. In another recent analysis based on the Health Professionals Follow-up Study, Platz et al. (20
) reported a significant reduction in risk of advanced-stage disease (relative risk = 0.5, 95 percent CI: 0.3, 0.9) and metastatic or fatal prostate cancer (relative risk = 0.4, 95 percent CI: 0.2, 0.8) among users of cholesterol-lowering medications. An inverse association between statin use and advanced prostate cancer was also noted in some other studies (21
). In the Cancer Prevention Study II Nutrition Cohort, long-term (≥5 years) statin use was associated with a reduction in risk of advanced prostate cancer (stage III, IV, or fatal; relative risk = 0.60, 95 percent CI: 0.36, 1.00) (21
). Similar findings were observed in the California Men's Health Study Cohort regarding risk of regional/distant-stage disease in relation to statin use of 5 or more years (relative risk = 0.57, 95 percent CI: 0.2, 1.4), although this result was not statistically significant. In a third study that included 24,723 prostate cancer cases identified via the Finnish Cancer Registry, Murtola et al. (23
) also reported an inverse association between statin use that was limited to advanced-stage disease (OR = 0.75, 95 percent CI: 0.62, 0.91), with a dose-response relation (p
trend = 0.001).
In our study, we evaluated several measures of statin use (ever use, current use, duration of use) in relation to clinical features of prostate cancer such as Gleason score, tumor stage, and a composite measure of more aggressive disease, but we found no associations. In the subset of cases with regional or distant-stage disease, we found a nonsignificant reduction in risk for current statin users relative to nonusers (OR = 0.73, 95 percent CI: 0.5, 1.1). We also analyzed data according to distant-stage or fatal prostate cancer and found an inverse association between ever use of a statin medication (OR = 0.24, 95 percent CI: 0.05, 1.02) and metastatic or fatal disease, but there were only two exposed cases in this analysis, and both had used a statin for less than 1 year. These findings, however, are consistent with the hypothesized antimetastatic activity of statins (3
In relation to BMI, the Cancer Prevention Study II Nutrition Cohort investigators reported an interaction between long-term use of cholesterol-lowering drugs and BMI (p
= 0.02) for advanced prostate cancer, but not for overall prostate cancer (21
). However, in that study, there were no obese cases with advanced disease among long-term users of cholesterol-lowering drugs. Our study included 74 obese cases with more aggressive disease features; of these, 13 (18 percent) had used a statin for 5 or more years. The prevalence of long-term (≥5 years) statin use in the obese, more-aggressive-disease subgroup was not markedly different in comparison to the prevalence of long-term use (22 percent, p
= 0.3) among obese men with less-aggressive disease. No clear biologic mechanism explains why statin use may preferentially increase risk of prostate cancer in obese men. Data from our control group show that statin users have higher BMIs and are more likely to have comorbid conditions that may be indications for statin use. These medical conditions may also be associated with altered hormone levels that could affect prostate cancer risk. Of interest in this regard is a recently published study that found no difference in circulating levels of androgens between statin users compared with nonusers (34
), but levels of sex hormone-binding globulin were significantly lower in statin users. With respect to the latter finding, a recent meta-analysis of studies of endogenous 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
). Another potential mechanism described by Goldstein et al. (36
) is the ability of statin medications to increase the level of regulatory T cells, which may suppress antitumor T-cell response and thereby enhance cancer risk.
Our study has several strengths and limitations that should be considered when interpreting these results. Strengths are its population-based approach, sample size, and the fact that it was designed to test the association between statin use and risk of prostate cancer. In addition, we had detailed information about statin use that enabled us to evaluate duration of use, time since first use, time since last use, age at first use, and type of statin used. One concern in observational studies is the accuracy of self-reported exposures. In an attempt to address this issue, we compared self-reported use of statins (162 cases, 162 controls) with data from a computerized pharmacy database maintained by Group Health Cooperative of Puget Sound. There was 87 percent agreement for any use of a statin (90 percent and 85 percent agreement for cases and controls, respectively).
Another issue is that of potential confounding by prostate cancer screening, which is correlated with statin use and prostate cancer diagnosis. We evaluated the statin–prostate cancer relation after adjusting for various measures of prostate cancer screening: 1) any tests (none, digital rectal examination only, PSA) conducted within the 5-year period before the reference date; 2) the number of PSA tests (0, 1–2, 3–4, ≥5) performed within the 5-year period before the reference date; and 3) the time interval since the most recent PSA test and the reference date. Prostate cancer screening questions were asked in such a way so as to exclude diagnostic tests, and only 25 cases and 38 controls reported having a PSA screening test within 4 months of the reference date. We also analyzed our data by excluding men (84 cases, 46 controls) who reported that they “had a problem or symptom” at the time of the most recent PSA test prior to the reference date, and we performed separate analyses of men who reported having a PSA screening test within the 5 years before the reference date and of men who reported no such screening. Results from these analyses were similar to the risk estimates presented, which are adjusted for any prostate cancer screening tests within the 5 years prior to the reference date.
Other concerns include potential selection bias and recall bias. There is a possibility that men who did not participate had a different prevalence of statin use than those who joined the study. Although we had no data on nonparticipants, it is reassuring that the prevalence of statin use in our control group (28 percent) is similar to the prevalence estimates of 25 percent (21
) and 27 percent (22
) for statin use reported in other recently conducted studies. Standardized interviews, medication show cards, and trained interviewers were used to enhance reporting of drug use. Lastly, the prevalence of long-term statin use (>10 years) is low (4 percent in controls) since these medications became available in the United States only in 1987. Thus, our study, as well as other studies reported to date, was underpowered to address the relation between extended periods of statin use (>10 years) and risk of developing prostate cancer.
In conclusion, results of this study suggest that statin use is not associated with overall prostate cancer risk. However, obese men who use statin medications, particularly for longer durations, have an increased risk of prostate cancer relative to obese nonusers. This latter observation warrants further investigation, particularly given the high prevalence of both statin use and of obesity in the general population.