Statins Associated With Reduction in PSA Levels But Implications Are Unclear and Questioned

Nick Mulcahy

October 29, 2008

October 29, 2008 — In an observational study, the use of cholesterol-lowering statins was associated with a 4% median decline in prostate-specific antigen (PSA) levels in men without prostate cancer, from a mean of 0.9 ng/mL to 0.86 ng/mL. The decline is statistically significant, according to a report published online October 28 in the Journal of the National Cancer Institute.

The reduction in PSA was most pronounced — with a median of 17.4% — in men with the highest PSA levels and in those with the largest declines in low-density-lipoprotein (LDL) cholesterol.

The use of statins could also "complicate prostate cancer screening because cancers may be missed [because of] the lower PSA levels, and this fact should be kept in mind when evaluating men taking statins," write the study authors, led by senior author Stephen J. Freedland, MD, associate professor of surgery in the Division of Urology at Duke University School of Medicine in Durham, North Carolina.

However, an accompanying editorial — entitled Prostate-Specific Antigen: A Misused and Maligned Prostate Cancer Biomarker — questions the value of the observational study, including the clinical significance of the results, and says that only a randomized trial can reveal whether statins affect PSA levels in any way.

Findings Reported and Questioned

The study involved 1214 men without prostate cancer who were prescribed a statin between 1990 and 2006 at the Durham Veterans Affairs Medical Center in North Carolina and who had at least 1 PSA value in the 2 years before and 1 year after starting a statin.

The reduction in PSA was greatest among men with levels that would make them candidates for prostate biopsy and among those with the largest declines in LDL cholesterol. Specifically, men with prestatin PSA levels of 2.5 ng/mL or greater and those in the highest quartile for decline in LDL cholesterol experienced a 17.4% median decline in serum PSA after starting statins.

However, the editorialists, led by Ian M Thompson, MD, professor and chair of the Department of Urology at University of Texas Health Sciences Center at San Antonio, say that the higher PSA declines among the men with the highest PSA levels is a consequence of the "well-understood statistical phenomenon" of regression to the mean. "Simply stated, in any sample with repeated measures, those with the highest values will on average go down and those with the lowest values will on average go up," they write.

The study results are also challenged by the bias of excluding men in the database who had a diagnosis of prostate cancer, who were taking statins, and who had rising PSA levels (thus prompting a biopsy and diagnosis). As a result of these exclusions, these statin-using men and their rising PSA levels were not included in the statistical mix, say the editorialists.

The editorialists also question the study's method of using PSA values as a "dichotomous measure," where PSA values are seen as either elevated or normal (ie, above or below a threshold — in this case, 2.5 ng/mL). "We recognize that PSA values are often reduced to a dichotomous measure, a practice we strongly discourage based on the overwhelming evidence that it is a continuous marker of risk," they write.

Perhaps most important, the editorialists cast doubt on the clinical value of the findings. In an attempt to make the study's findings clinically relevant, the editorialists used the Prostate Cancer Prevention Trial (PCPT) prostate cancer risk calculator — a tool that uses "multiple measures of risk, including PSA" — and find unimpressive results. Using the risk calculator, the editorialists evaluate a sample patient who uses statins and experiences a PSA decline on par with study's decline.

"Taking a PSA level from the highest-risk range (>4.0 ng/mL), let us assume a man with a PSA of 4.5 achieves the median absolute decline in PSA after beginning a statin (0.6 ng/mL) to 3.9 ng/mL. If he is age 60 and has no other risk factors, his calculated risk of prostate cancer would drop from 37% to 34% and his risk of high-grade prostate cancer from 8% to 7%. These changes are clinically insignificant," write the editorialists.

Will PSA Reductions Result in Reduced Cancer Risk?

The study authors note that "some evidence" suggests that statin treatment prevents prostate cancer, particularly advanced prostate cancer. However, that evidence is mixed and inconclusive, as the authors note and as Medscape Oncology has previously reported. To date, there is no evidence that statins reduce PSA and thus cancer risk, say the editorialists. As reported by Medscape Oncology, finasteride (Propecia, Merck) has been shown to reduce PSA and prostate cancer risk, but finasteride is "not an effective prostate cancer treatment," observe the editorialists. "Using PSA as a surrogate marker of prostate cancer risk may ultimately be correct for some interventions, but currently there is little or no support for doing so," they write.

Dr. Freedland does not argue this point. "Are there data to support its use [as a surrogate marker of prostate cancer risk with an intervention]? None that I am aware of. However, if that turned out to be true, it would be a great benefit to patients and clinicians alike."

Further Study Needed — But What Kind?

The study authors state that "the clinical relevance of lowering PSA values among statin users requires further study."

"If confirmed in other studies, these findings would warrant investigation of the mechanism by which statins influence PSA and whether statins directly affect prostate biology. Most importantly, from a clinical standpoint, given the prevalence of both PSA testing and statin use, the potential influence a statin-mediated reduction in PSA could have on cancer detection must be further quantified," they write.

The editorialists do not discuss or dispute the potential value of biological studies of the effect of statins on the prostate. However, "the most important question is whether statins might be preventive, therapeutic, or simply affect PSA level itself," they write. Prevention clinical trials are large-scale and expensive, and therapeutic trials are "no less difficult," with a decade of follow-up needed; an end-of-study biopsy is also needed to eliminate "detection bias." Ultimately, testing whether statins affect PSA requires a randomized trial, they say. "If statins do lower PSA, only a randomized trial with histological end points can determine whether statins affect a man's risk of prostate cancer."

The study was supported by the Department of Veterans Affairs, Department of Defense Prostate Cancer Research Program, and the American Urological Association Foundation/Astellas Rising Star in Urology Award. The authors have disclosed no relevant financial relationships.

J Natl Cancer Inst. 2008;100:1487-1488, 1511-1518.

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