The overall results of this population-based cohort study do not support an association between statin use and prostate cancer risk. While some point estimates suggest a reduced risk of prostate cancer among statin users compared to non-users, only hydrophobic statin use and ever use limited to men with a PSA test were statistically significant, and we did not observe a trend with duration of statin use. Point estimates do not suggest a difference in risk by type (hydrophobic versus hydrophilic) of statin use.
This was one of the few large cohort studies conducted in an integrated practice setting where men receive almost all their care within the system, and information on medication use and diagnoses are available. Other strengths of the study include the stability of the population over time, extensive and unbiased data on medication use and covariates, ability to look at hydrophobic statin use, and reliable data on cancer incidence. Our large population-based cohort demonstrates the dramatic increase in statin use over the past decade, which is consistent with the trend of statin use in the United States.
While we found some suggestion of a reduced risk but overall not statistically significant, it is biologically plausible that statins reduce prostate cancer risk. The mechanistic data is relatively strong and suggests statins inhibit cancer cell growth and lead to apoptotic cell death through their inhibition of the mevalonate pathway, although other mechanisms have also been suggested [4
]. Many products of the mevalonate pathway are necessary for critical cellular functions such as membrane integrity, cell signaling, protein synthesis, and cell cycle progression [4
]. Disruptions of these processes in neoplastic cells by statins may result in control of tumor initiation, growth, and metastasis [5
]. Our results on type of statin also support evolving evidence that hydrophobic statins have antiproliferative effects on certain cancer cells [39
]. It has been suggested that hydrophilic statins promote cancer [39
], but our results suggest an inverse association between hydrophilic statin use and prostate cancer risk.
There are several limitations in our study. First, study subjects were from a single healthcare system in western Washington State and may not represent other populations. Second, we cannot rule out exposure misclassification. Subjects who fill prescriptions but do not subsequently take the medication may be misclassified as users. Additionally, pharmacy utilization is only captured for enrollees who fill prescriptions at Group Health pharmacies and for enrollees with a drug benefit through Group Health who fill prescriptions at contracting pharmacies. Therefore, subjects who fill prescriptions at non-Group Health pharmacies may be erroneously classified as non-users. However, mis-classification of medication use is relatively unlikely since previous Group Health studies have found that enrollees obtain 97% of their medications at Group Health pharmacies [31
], and we required 2+ dispensings and a year of use to be considered a statin user. We did not have information on medication use before enrollment in Group Health. While unlikely, misclassifying a user as a non-user could bias our findings toward the null and partly explain why we did not find a significant association between statin use and prostate cancer risk. Last, residual confounding is always possible. We lacked information on potential confounders such as body mass index, diet, socioeconomic status, and race, and men prescribed and adherent to statins may differ from non-users by factors not measured in this study. Statin users had more PSA testing and medical visits compared to non-users, which could lead to earlier detection of prostate cancer and bias results away from finding any true chemopreventive effect. However, results were similar when we limited our analyses to men with at least one PSA test during the study period. While not an aim of this study, there is also preliminary evidence to suggest that statin use may be associated with a decrease in PSA levels [42
]. If such an association exists, prostate cancers could be missed when using PSA testing to screen for prostate cancer among statin users. Missed cases could lead to false conclusions that statins are associated with a reduced risk of prostate cancer but may later appear to be associated with an increased risk of advanced disease.
In conclusion, our study and other epidemiologic studies indicate that statins are safe in relation to prostate cancer risk but any chemopreventive effect remains to be established and recent report of increased prostate cancer risk with pravastatin use from the long-term follow-up of the West of Scotland Coronary Prevention Study are concerning [22
]. To make conclusions about the effect of statins on prostate cancer prevention, mechanistic data suggests that the type, dose, and potency of statin used and the serum concentrations achieved need to be considered in observational studies [39
]. We agree with Platz that the promising and consistent findings from the most recently published studies are remarkable [44
], but many of the specifics on statin use (e.g., individual statins, potency) have not been adequately addressed, and the influence of detection bias [44
] as well as other confounders such as socioeconomic status need further study. The research and clinical community must make decisions about whether further evaluation is warranted and, if so, what types of studies are needed. The evidence must be strong before any drug should be used to prevent disease in a healthy population.