[1] Statins are arguably the easiest prescription drug to get hold of in the U.S. IMO they are heavily over-prescribed, based on a simplistic out-of-date view of cholesterol & its role in CVD.
On the other hand, as someone with PCa, I'm a big fan of statins.
I have mentioned before that:
i) cholesterol accumulation in solid tumors was first noted almost a hundred years ago.
ii) cholesterol accumulation in PCa cells is well-documented, & associated with poorer outcomes.
iii) regardless of its general role in cancer progression, cholesterol in PCa cells can be used to make androgen.
iv) if PCa cells are faced with a limited supply of circulating cholesterol, the cells can manufacture it. Having low cholesterol may accelerate the development of that ability, i.e. low is not protective. Statins prevent PCa cells from making their own.
v) for anyone on ADT & not on a statin, (iii) & (iv) represent open barn doors, allowing the cancer to escape from treatment.
[2] Studies - oldest first. We get off to a shakey start with [2a], but things look good until [2q]. I could have included many more supportive studies, but an extra dozen papers confirming that statins lower PSA would be even more annoying than the length of this very long post.
Just as with Metformin & diabetics, we should be careful when comparing statin users to non-users. Ideally, studies should use controls that at least match on CVD risk factors, but of course they don't.
There is no suggestion that cholesterol has a role in PCa onset. Unless a statin has some secondary action that affects PCa initiation, we would not expect statins to affect PCa incidence. However, there is a delay between onset & diagnosis. Statins might delay progression & therefore diagnosis.
Screening hastens diagnosis & one might expect U.S. statin users to be more inclined to screen for PCa. If so, this would serve to overstate the PCa rate in statin users.
[2a] (2002 - U.S.)
It is known that men with PCa have a greater risk for CVD, even if not on ADT. Thus, men with CVD risk could be said to be at greater risk for PCa. Statin users would have to overcome that excess risk before a benefit was visible. In other words, if there was no benefit, we would expect more PCa in the statin user population.
"Cases were ... 1,009 men with prostate cancer; controls were ... 1,387 men admitted for conditions unrelated to statin use."
"The odds ratio for prostate cancer overall was 1.2 .., and it was 1.4 ... for Stage A."
[2b] (2005 - U.S.)
"The treatment group was composed of 15 men with hypercholesterolemia who received statins and the comparison group of 85 with normal serum lipid levels ..."
"Serum PSA was significantly higher in the treatment group at baseline ..."
"Interestingly there was no significant difference between the groups on subsequent followup."
"There was a 41.6% decrease in mean serum PSA in the treated group by visit 4. Simultaneously mean serum PSA increased by 38% in the untreated group."
"Our results suggest that treatment with statins may lower serum PSA with time."
[2c] (2005 - U.S.)
"Prostate cancer cases (n = 100), recruited upon referral for prostate biopsy, and frequency age-matched, prostate-specific antigen-normal clinic controls (n = 202) were recruited from the Portland, Oregon, Veterans Affairs Medical Center."
"Thirty-six percent of cases and 49 percent of controls had a record of any statin use."
"statin use was associated with a significant reduction in prostate cancer risk (odds ratio = 0.38 ...)"
"Furthermore, in analyses stratified by Gleason score, the inverse association with statin use was maintained only among men with Gleason scores of > or =7 (odds ratio = 0.24 ...)"
"The results of this case-control study suggest that statins may reduce the risk of total prostate cancer and, specifically, more aggressive prostate cancer."
[2d] (2006 - U.S. - Elizabeth Platz / Edward Giovannucci)
"We analyzed data from an ongoing prospective cohort study of 34,989 US male health professionals who were cancer free in 1990 and were followed to 2002"
"... we ascertained 2579 prostate cancer cases, 316 of which were advanced (regionally invasive, metastatic, or fatal)."
"The ... relative risk of advanced disease was 0.51 ... and of metastatic or fatal disease was 0.39 ... for current statin use compared with no current use."
"The associations remained after adjusting for prostate-specific antigen screening history (advanced disease: RR = 0.57 ...; metastatic or fatal disease: RR = 0.35 ...)."
"Risk of advanced disease was lower with longer statin use ..; compared with never use, the relative risk for less than 5 years of use was 0.60 ... and for 5 or more years of use was 0.26 ..."
"We found no association between statin use and risk of total prostate cancer ..."
[2dx] (2008 - same as [2d]) Not a statin study.
"We previously found that statin users had a lower risk of advanced and possibly high-grade prostate cancer compared with nonusers. We hypothesize that statins' effects on cholesterol synthesis may explain those findings because prostate cancer cells exhibit cholesterol dysregulation."
"Low cholesterol (<25th percentile vs. > or =25th percentile) was not associated with total (OR = 0.93 ...), organ-confined (OR = 0.87 ...) or low-grade (OR = 1.06 ...) disease. However, men with low cholesterol had a lower risk of high-grade disease (OR = 0.61 ...), especially if organ-confined (OR = 0.54 ...)."
[2e] (2007 - U.S.)
"We examined the association between use of cholesterol-lowering drugs and prostate cancer incidence by disease stage and grade among 55,454 men in the Cancer Prevention Study II Nutrition Cohort."
"... we identified 3,413 cases of incident prostate cancer, including 317 cases of advanced prostate cancer. After adjustment for age, history of prostate-specific antigen testing, and other potential prostate cancer risk factors, current use of cholesterol-lowering drugs for 5 or more years was not associated with overall prostate cancer incidence .., but was associated with a marginally statistically significant reduction in risk of advanced prostate cancer (rate ratio, 0.60 ...)"
[2f] (2008 - U.S.)
"Among 83,372 men studied, median follow-up time was 5.7 years and 2,532 prostate cancer cases were identified. About 14.4% used statins over the study period and median duration of use was 3.3 years. Compared to non-users, hydrophobic statin users had a reduced risk of prostate cancer (HR = 0.79 ...)"
Note: "hydrophobic" = "lipophilic".
In spite of that finding:
"Overall, this study does not support an associated between statin use and prostate cancer but a reduced risk cannot be ruled out."
[2g] (2008 - U.S.)
"... a population-based study of 1,001 incident prostate cancer cases diagnosed in 2002-2005 and 942 age-matched controls from King County, Washington ..."
This study found "No overall association ... between statin use and prostate cancer risk"
However, for obese men, the risk of PCa was 50% higher among the statin users. Here again, can one assume that obese users & non-users are otherwise equal? One must assume that the user group contained a higher number of men with CVD or CVD risk.
[2gx] (2009 - comment by Platz on [2g])
"This commentary discusses the findings of Agalliu and colleagues, who performed a population-based, case-control study on the association between statin drugs and prostate cancer risk. Consistent with recent studies, statins were not associated with overall prostate cancer risk, but users had a possible lower risk of advanced disease. Obese men taking a statin had a higher risk of prostate cancer than those not taking a statin; however, a previously conducted, large, prospective, cohort study did not observe this association. This unexpected finding by Agalliu et al. could be a chance result, or could have arisen because of complex bias."
[2h] (2008 - U.S. - Freedland)
"We conducted a longitudinal study of 1214 men who were prescribed a statin between 1990 and 2006 at the Durham Veterans Affairs Medical Center who were free of prostate cancer, had not undergone prostate surgery or taken medications known to alter androgen levels and who had at least one PSA value within 2 years before and at least one PSA value within 1 year after starting a statin."
"After starting a statin, the median LDL decline was 27.5%, and the median PSA decline was 4.1%"
"For every 10% decrease in LDL after starting a statin, PSA levels declined by 1.64 ..."
"Among men most likely to be under consideration for prostate biopsy (prestatin PSA levels > or =2.5 ng/mL, n = 188), those with >41% declines in LDL (highest quartile) after starting a statin experienced a 17.4% ... decline in serum PSA."
Freedland comments:
"By lowering PSA levels, statins may complicate cancer detection ..."
which would be true if the effect was only on the PSA & not on the cancer.
[2i] (2009 - U.S. - Platz)
"We conducted a cohort study of 5,586 men aged ≥ 55 years old who were randomized to the placebo arm of the PCPT {Prostate Cancer Prevention Trial} between 1993 and 1996."
"Men with low cholesterol had a lower risk of Gleason 8-10 prostate cancer (OR=0.41 ...) than men with high cholesterol. No association was present for prostate cancer overall (OR=0.97 ...), Gleason 2-6 disease (OR=1.03 ...), or Gleason 7 disease (OR=0.93 ...)"
[2j] (2010 - U.S. - Johns Hopkins - Catalona)
"From 2003 to 2009, 1351 men with data on preoperative statin use had RP by one surgeon. The clinical and pathological tumour features were compared between 504 users of statins and 847 who were not users."
"Statin users were significantly older and had a higher mean body mass index than non-users. The preoperative serum prostate-specific antigen levels, tumour volume and percentage of cancer in the RP specimen were significantly lower in patients taking statins. Overall, statin users had a proportionately lower rate of adverse tumour pathology features, including a significantly lower risk of positive (cancerous) surgical margins."
[2k] (2010 - U.S. - Freedland)
"Cholesterol-lowering drugs known as statins have been reported to have significant anti-inflammatory properties. Given that inflammation may contribute to prostate cancer progression and that statins may reduce the risk for advanced prostate cancer, we investigated whether statin use was associated with reduced intratumoral inflammation in radical prostatectomy (RP) specimens."
"Inflammation within index tumors of 236 men undergoing RP from 1996 to 2004 was graded by a single pathologist as grade 0 (absent), 1 (mild: < or =10%), and 2 (marked: >10%)."
"Preoperative statin use was significantly associated with lower risk for any (grade > or =1) intratumoral inflammation (odds ratio, 0.31 ...) on multivariable analysis, with doses > or =20 mg simvastatin equivalents being more strongly associated (relative to nonuse; odds ratio, 0.22 ...)"
[2l] (2011 - U.S. - Freedland)
"The authors examined 1319 men treated with RP from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. Time to PSA recurrence was compared between users and nonusers of statin at surgery"
"After adjusting for multiple clinical and pathological factors, statin use was associated with a 30% lower risk of PSA recurrence ..."
[2m] (2011 - U.S.)
"Using electronic and administrative files from the Veterans Affairs New England Healthcare System, we identified 55,875 men taking either a statin or antihypertensive medication. We ... calculate(d) hazard ratios (HRs) ... for prostate cancer incidence among patients taking statins (n = 41,078) compared with patients taking antihypertensive medications (n = 14,797)."
"Compared with men taking an antihypertensive medication, statin users were 31% less likely ... to be diagnosed with prostate cancer. Furthermore, statin users were 14% less likely ... to be diagnosed with low-grade prostate cancer and 60% less likely ... to be diagnosed with high-grade prostate cancer compared with antihypertensive medication users."
[2n] (2012 - U.S.)
"Cases were residents of New Jersey ages 55 – 79 who died from prostate cancer between 1997–2000."
"We identified 718 cases and obtained cooperation from 77% of their spouses (N=553). After review of medical records, 387 were eligible and 380 were matched to a control. The unadjusted odds ratio was 0.49 ... which decreased to 0.37 ...) after adjustment for education, waist size, BMI, comorbidities, and anti-hypertensive medication."
"Statin use is associated with substantial protection against prostate cancer death ..."
[2o] (2012 - U.S.)
"The study cohort consisted of 5,042 type 2 diabetic male patients seen in the Veteran Administration Health Care System ..."
"Among men with type 2 diabetes, PCa incidence among metformin users varied by their statin use. The potential beneficial influence on PCa by combination use of metformin and statin may be due to synergistic effects."
[2p] (2013 - Canada)
"Postdiagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR, 0.76 ...) and all-cause mortality (HR, 0.86 ...). These decreased risks of prostate cancer mortality and all-cause mortality were more pronounced in patients who also used statins before diagnosis (HR, 0.55 ... and HR, 0.66 .., respectively), with weaker effects in patients who initiated the treatment only after diagnosis (HR, 0.82 ... and HR, 0.91...)"
[2q] (2016 - U.S.) If only every big study agreed with the consensus!
"Statin usage may offer chemoprotection against the development of advanced or lethal prostate cancer. Hypothesized mechanisms of action, primarily based on preclinical studies, include effects on cholesterol lowering and lipid metabolism, which may in turn increase cell proliferation, inflammation, and intratumoral steroidogenesis, and decrease apoptosis. Several studies (including our own; {[2d]} suggest an inverse relation between long-term prediagnostic statin use and incidence of advanced or lethal prostate cancer. A recent meta-analysis concluded that there was a nonstatistically significant inverse association between statin use after diagnosis and risk of recurrence among men with prostate cancer, although the benefit appeared limited to men treated with radiation. Several, but not all, studies published later reported inverse associations of statin use after prostate cancer diagnosis and risk of recurrence or death; and two reported inverse associations for “ever use” and prostate cancer death. We examined postdiagnostic statin use among men diagnosed with localized disease and risk of lethal prostate cancer in the Health Professionals Follow-Up Study."
"We found no statistically significant association between postdiagnostic current use of statins or duration of statin usage and the outcome of lethal prostate cancer ..."
"Further study may be warranted for the potential benefit among men diagnosed with stage T2+ versus T1 disease."
[2r] (2016 - U.S.)
"Of 1,930 cases from The North Carolina-Louisiana Prostate Cancer Project, 344 (18%) were classified as aggressive ..."
"There was an inverse association between statin use and prostate cancer aggressiveness [OR, 0.74 ...]"
"Statin use was associated with reduced prostate cancer aggressiveness .., with strongest inverse associations in nonsmokers." {OR=0.42}
...
At this point in my PCa journey, I am only interested in the effect of statins on survival. It's a pity about [2q], but virtually everything above is too positive for me to conclude that statins aren't useful.
The latest paper ("are we there yet?") is by Steve Freedland & perhaps makes a good summing up [2s]:
"An increasing amount of data supports an inverse association between statin use and cancer risk. The findings for prostate cancer, particularly advanced disease, are the most promising of all cancers studied. Use of these agents seems to also be associated with improved prostate- cancer-specific survival, particularly in men undergoing radiotherapy, suggesting usefulness of statins in secondary and tertiary prevention. Some study results might be influenced by increased PSA screening and health-conscious behaviour in statin users but these factors are unlikely to completely account for observed beneficial effects. The epidemiological evidence is supported by preclinical studies that show that statins directly inhibit prostate cancer development and progression in cell-based and animal-based models. The antineoplastic effect of statins might arise from a number of cholesterol-mediated and non-cholesterol-mediated mechanisms that affect pathways essential for cancer formation and progression. Understanding these mechanisms is instrumental in drug discovery research for the development of future prostate cancer therapeutics, as well as in designing clinical trials to test a role for statins in prostate cancer prevention. Currently, sufficient data are lacking to support the use of statins for the primary prevention of prostate cancer and further research is clearly warranted. Secondary and tertiary prevention trials in men who have been diagnosed with prostate cancer might soon be performed."
-Patrick
[2a] ncbi.nlm.nih.gov/pubmed/119...
[2b] ncbi.nlm.nih.gov/pubmed/158...
[2c] aje.oxfordjournals.org/cont...
[2d] jnci.oxfordjournals.org/con...
[2dx] ncbi.nlm.nih.gov/pmc/articl...
[2e] cebp.aacrjournals.org/conte...
[2f] ncbi.nlm.nih.gov/pmc/articl...
[2g] ncbi.nlm.nih.gov/pmc/articl...
[2gx] ncbi.nlm.nih.gov/pubmed/191...
[2h] jnci.oxfordjournals.org/con...
[2i] ncbi.nlm.nih.gov/pmc/articl...
[2j] ncbi.nlm.nih.gov/pmc/articl...
[2k] cebp.aacrjournals.org/conte...
[2l] ncbi.nlm.nih.gov/pmc/articl...
[2m] ncbi.nlm.nih.gov/pmc/articl...
[2n] ncbi.nlm.nih.gov/pmc/articl...
[2o] ncbi.nlm.nih.gov/pmc/articl...
[2p] ncbi.nlm.nih.gov/pubmed/241...
[2q] ncbi.nlm.nih.gov/pmc/articl...
