Men who used statin drugs had a lower risk of prostate cancer but only with prolonged use or higher doses, a retrospective cohort study showed.
A history of treatment with statins was associated with a 15% reduction in the relative risk of low-grade prostate cancer and a 46% lower risk of developing high-grade disease. However, the association was limited to men who took statins for at least 11 months or who had a defined daily dose (DDD) ≥121, based on a reference dose of 20-mg simvastatin.
Lipophilic statins (fluvastatin, lovastatin, simvastatin, atorvastatin, and cerivastatin) appeared to be more protective against prostate cancer than did hydrophilic drugs, Kai Wang, MBBS, PhD, of the Harvard School of Public Health in Boston, and coauthors reported in Cancer Medicine.
“The protective association of statin use with PCa [prostate cancer] risk is in line with in vitro studies,” the authors wrote in their discussion of the findings. “Mechanistically, statins reduce intracellular and serum cholesterol, thus may affect cell membrane organogenesis, steroidogenesis, and proliferation. Growth inhibition in prostate-derived cells lines was indeed observed at clinically relevant statin concentrations.”
“In addition, to clarify the overall association of statin use on PCa risk, a further effort is needed to determine whether this association is duration-/dose-dependent,” they continued. “In our study, risks of both low- and high-Gleason grade PCa were observed to decrease with increasing cumulative duration and cumulative dose of statin use, and significant PCa risk reduction was observed only when statins had been used for a relatively longer duration. This is in agreement with a cell culture study which reported that only long-term statin exposure could induce cell apoptosis, G1 cell cycle arrest, autophagy, and degradation of androgen receptors.”
The study adds to numerous others that preceded it, which collectively showed that statin use is associated with a lower risk of prostate cancer, said Stephen Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles. The cumulative data, however, suggests only a modest effect on prostate cancer diagnosis.
Despite the inherent limitations of a case-control study, “nonetheless, it contributes to increasing data that statins may have some benefits, but the benefits are likely modest,” Freedland told MedPage Today via email. “What we really need to understand is which tumors are most sensitive to statins and which are not. This is not likely to be identical to Gleason score but rather a deeper understanding of tumor biology.”
Statins and Prostate Cancer
Over the past 15 years, statin use has increased dramatically, and as a class, the drugs are among the most widely prescribed medications in the world, Wang and coauthors noted. Lowering serum and tissue levels of cholesterol may disrupt cellular lipid rafts, leading to reduced raft-dependent signaling and cell proliferation. By extension, statins may have chemopreventive effects that reduce carcinogenesis, including prostate cancer carcinogenesis.
Studies of statins and PCa risk have yielded mixed results, the authors continued. Detection bias is one possible explanation for the varied results. Statin users maybe have a higher need for health services, increasing opportunities for prostate-specific antigen (PSA) testing and PCa diagnosis (“healthy user bias”). Lack of statistical adjustment for PSA testing and PCa grade would limit statistical power on statin use and PCa risk.
Previous studies left unanswered a number of other questions: Does statin use and PCa risk have a Gleason score-specific relationship? Does the relationship have duration or dose-specific properties? Do lipophilic and hydrophilic statins differ in their relationship to PCa risk?
To address the questions, the authors queried a large hospital-based longitudinal dataset. They searched for patients who had at least one urologic clinic visit for any prostate condition and at least 12 months of follow up. The search identified 13,065 with medical records ranging from November 1994 to January 2016.
The analysis included all statins currently available in the U.S. Patients were classified as statin users if they had at least one prescription for a drug in the class. Investigators separated statin users into quintiles on the basis of duration of use. They calculated cumulative statin dose from the DDD of simvastatin 20 mg as a reference, converting all the other drugs in the class to simvastatin-equivalent doses and dividing patients into quintiles by DDD.
The primary outcome was newly diagnosed PCa. During a median follow-up of 6.6 years, 2,976 prostate cancers were diagnosed, 2,308 of which were low grade (Gleason score <7) and 668 high grade (Gleason score ≥7). Medical records showed that 3,839 men used statins during the study period,.
Key Findings
After adjustment, statin use was associated with a 20% reduction in the risk of PCa (95% CI 0.71-0.90) overall. Investigators observed an inverse association between PCa risk and cumulative duration of statin use and cumulative dose (P<0.001 for both). The protective effect on PCa risk was limited to longer duration of statin use. Patients who used statins for 1-10 months had an increased risk of PCa (HR 1.88, 95% CI 1.63-2.17).
Statin use was associated with a reduced risk of low- and high-grade PCa, as compared with no statin use. The risk of low-grade PCa decreased with increasing duration of statin use and cumulative dose (P<0.001), with the beneficial effect limited to patients who used statins for at least 30 months or who had DDDs ≥121. Increasing duration and DDD also were associated with decreased risk of high-grade PCa (P<0.001).
Only lipophilic statins had a significant association with decreased PCa risk (HR 0.83, 95% CI 0.72-0.95 for low-grade disease; HR 0.63, 95% CI 0.48-0.83 for high-grade disease).
The authors said their findings argued against “healthy user bias” as an explanation for statins’ association with PCa risk. If the explanation were true, diagnosis of high-grade disease would be predicted to decrease, and diagnosis of low-grade disease might increase among statin users. Instead, statin use was associated with lower rates of low- and high-grade disease.
The authors reported having no relevant relationships with industry.
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Source: MedicalNewsToday.com
