Preoperative Statin Use Associated with Lower PSA But Similar Prostate Size and Histopathologic
Outcomes: Implications for Active Surveillance?
Kristian Stensland1, Russell B. McBride1,2, Michael Leapman1, Adele Hobbs1, Seyed Behzad Jazayeri 3, David B.
Samadi MD3,*
Purpose: The potential effects of statins on clinical and histopathologic variables, prostate size, or PSA density
(PSAD) and resulting influences on active surveillance eligibility have not been adequately explored. This study
examines the effect of statins on prostate specimens following prostatectomy.
Materials and Methods: Patients that received robotic-assisted laparoscopic prostatectomy (RALP) (n = 2,632)
were dichotomized according to preoperative statin use. Logistic regression was used to evaluate associations be-
tween statin use and patient clinical and pathological characteristics.
Results: Men using statins at the time of prostatectomy were older (61.6 ± 6.4 versus 58.8 ± 7.2 years, P < .001),
and had poorer health status (P < .001). Biopsy Gleason grade, clinical stage and prostate size were similar among
the two groups, although statin users had lower diagnostic PSA levels (5.5 ± 3.6 versus 6.3 ± 4.9 ng/mL, P < .001)
and PSAD (.12 versus .13, P = .001).
Conclusion: Men taking statins at the time of prostatectomy had similar histopathologic characteristics to non-us-
ers, despite having significantly lower serum PSA, being older and having similar sized prostates. This supports
prior studies suggesting a PSA reduction effect of statins may warrant consideration of statin usage in decision
algorithms for active surveillance.
Keywords: active surveillance; neoplasm; PSA; robotic prostatectomy; prostate; Statins.
INTRODUCTION
Statins (3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors) are one of the most-prescribed classes of
medications worldwide.(1) They have long been used in
the management of cholesterol related conditions, but
their potential role as a chemopreventive agent is the
subject of recent debate. Many investigations have fo-
cused specifically on their relationship to prostate can-
cer. Though evidence are equivocal on the link between
statin use and prostate cancer incidence(2,3). Several
studies have shown decreased rates of aggressive dis-
ease(4,5) and disease recurrence(6-8) with statin use, poten-
tially due to either the anti-inflammatory properties or
nascent anti-neoplastic effects of the statins themselves.
Statins were not related to recurrence rate in other stud-
ies.(9,10)
In contradistinction, one recent report demonstrated in-
creased rates of aggressive disease and higher risk of
biochemical recurrence in patients on statins.(11) It is
possible that the varied findings in aggressive and re-
current outcomes may be due to the lower serum PSA
concentrations found among patients taking statins
confounding referral and biopsy/treatment patterns.
(12-14) The use of statins have been clearly shown to re-
duce serum PSA concentration but to our knowledge
has not yet been fully evaluated in the context of active
surveillance (AS) for low-risk prostate cancer. AS pro-
tocols are largely based on parameters that include bi-
opsy Gleason score and PSA concentration, with some
protocols also incorporating other factors such as PSA
density (PSAD: PSA concentration divided by prostate
volume).(15)
Other drugs, such as 5-alpha reductase inhibitors, have
been shown to lower both PSA and prostate size.(16)
Similarly, statins have been shown to lower PSA to a
greater degree than prostate size, potentially leading to
an “artificially” lowered PSAD.(17) Thus, it is possible
that statin use may affect the qualification of certain pa-
tients for AS protocols based on an “artificially low”
PSA and/or PSAD. In this context we sought to investi-
gate the effects of statins on preoperative PSA, prostate
size, and the resulting implications for AS eligibility.
MATERIALS AND METHODS
Under institutional review board approval at Lenox Hill
Hospital, 2,632 patients were considered for enrollment
in this study who underwent robotic assisted laparo-
scopic prostatectomy (RALP) at our institution between
May 2004 and July 2012. This is a retrospective analysis
on a database of patients diagnosed with prostate can-
cer. Patients’ diagnosis was based on pathology proven
presence of prostate adenocarcinoma. No patient was
considered for surgery based on an abnormal PSA lev-
el per se. Investigated variables included demograph-
ic information, American Society of Anesthesiology
score, preoperative diagnosis of diabetes, preoperative
1Department of Urology, Mount Sinai School of Medicine, New York, NY, USA.
2Institute for Translational Epidemiology, Mount Sinai School of Medicine, New York, NY, USA.
3Department of Urology, Lenox Hill Hospital, New York, NY, USA.
*Correspondence: Chairman, Department of Urology. Chief of Robotic Surgery. Lenox Hill Hospital. 485 Madison Avenue, Floor 21.
New York, NY 10022.
Phone: 212-241-8766. Fax: 212-308-6107. Email: robotmd@yahoo.com.
Received September 2016 & Accepted April 2017
UROLOGICAL ONCOLOGY
Vol 14 No 03 May-June 2017 3064
5-alpha reductase inhibitor usage, statin use, body mass
index (BMI), and standard histopathologic outcomes
(pathologic Gleason score, prostate weight, pathologic
stage, margin status, extracapsular extension, perineural
invasion, seminal vesicle involvement, lymphovascular
invasion). Prostatectomy specimens were sectioned in
quadrants and mounted in standard fashion. All radical
prostatectomy specimens were examined by dedicated
genitourinary pathologists.
Statin use was defined as any hMG-CoA reductase in-
hibitor taken by the patient prior to surgery. This infor-
mation was driven from the patient chart at the hospital
and self-reported list of drugs at office visit. Positive
surgical margins on pathologic examination were cat-
egorized as either focal or extensive (< 3 or ≥ 3 mm,
respectively).(18) Biochemical recurrence was defined as
a single serum PSA measurement greater than .2 ng/mL
beyond 6 weeks after surgery.
Pathologic weight was used as a surrogate for pros-
tate volume, which has been validated as the preferred
measurement of prostate size in RALP cohorts in previ-
ous studies.(19) PSA density was then approximated by
dividing preoperative PSA by this surrogate volume.
Baseline characteristics and histopathologic outcomes
were reported using means for continuous variables and
proportions for categorical variables. A logistic regres-
sion was performed utilizing log-transformed values for
PSA. T-tests or ANOVA were used to compare continu-
ous variables and chi-square tests were used to compare
categorical variables between statin users and non-us-
ers. A Cox proportional hazards model was created to
assess predictors of biochemical recurrence using enter
method. Age at diagnosis, race, ASA scale, pathologic
Gleason score, pathologic stage, clinical stage, prostate
weight, statin use and preoperative PSA level were used
in the analysis. Significance was defined as a two-sid-
ed p value < .05. Analyses were performed using SPSS
version 20 (IBM Inc., Armonk, NY).
RESULTS
In total, 1,913 of 2,632 patients had complete clinical
and medication records and were included in analysis.
Whites comprised 77% of the cohort, blacks comprised
11%, and all other races comprised 9%. Of all patients,
630 (33%) were taking statins preoperatively. Demo-
graphics of the two groups are presented in Table 1.
The group of statin users were older (61.6 ± 6.4 versus
58.8±7.2 years, P < .001), more likely to be diabetic
(12% vs. 4%, P=.001), had fewer blacks (7% vs. 14%,
P < .001), and had slightly higher, but not significantly
different, BMI (27.8 vs 27.5, P = .09). The statin group
also had more comorbidities as measured by the pro-
portion with ASA scores >2 (40% vs. 19%, P < .001).
Forty-nine patients (23 statin users, 26 non-users, P =
.03) were taking 5-alpha reductase inhibitors preopera-
tively. Patients taking 5-alpha reductase inhibitors were
excluded from the analysis in PSA level.
Preoperative disease characteristics of the two groups
are presented in Table 2, and histopathologic outcomes
among the two groups are presented in Table 3. Preop-
erative clinical staging and D’Amico risk were similar
with the vast majority of both groups having a clini-
cal stage of T1c or below, and low or intermediate risk
prostate cancer. Proportions of biopsy Gleason sums
were also similar between the groups.
The mean preoperative PSA was significantly lower
among the statin group than among the non-statin group
(5.6 vs. 6.4 ng/mL, P < .001). This finding persisted in
multiple subanalyses that divided patients into groups
of similar ages, prostate weights, tumor volumes and
pathologic stages. Statin users were also more likely to
have presented with initial PSA values less than 4 ng/
mL (32% vs. 24%, P < .001) and less likely to have pre-
sented with initial PSA values ≥ 10 ng/mL (7% vs. 11%,
P < .001). There were no differences in clinical stage
between statin users and non-users who were above and
below each respective PSA threshold.
Additionally, the mean prostate weight was similar be-
Statins’ effect on PSA level and AS-Stensland et al.
Table 1. Demographic and clinical characteristic of patients in the study
No Statin Use Statin Use p value
N = 1283 (67%) N = 630 (33%)
Age, years; mean ± SD 58.8 ± 7.2 61.6 ± 6.4 < .001
Race; N(%) White 990 (77%) 543 (86%) < .001
Black 176 (14%) 42 (7%)
Other 117 (9%) 45 (7%)
BMI Categories; N(%) < 24.9 318 (25%) 129 (21%) .11
25.0-29.9 680 (53%) 349 (55%)
> 30 285 (22%) 152 (24%)
Diabetes; N(%) No 1225 (96%) 554 (88%) < .001
Yes 58 (4%) 76 (12%)
ASA; N(%) 1 71 (6%) 5 (1%) < .001
2 974 (75%) 375 (59%)
3 234 (18%) 243 (39%)
4 4 (1%) 7 (1%)
Urological Oncology 3065
tween both groups (51.0 g vs. 51.6 g, P = .52). PSA
density, calculated using preoperative PSA divided by
pathologic weight, was significantly lower among sta-
tin users compared to non-statin users (.12 vs. .13, P =
.001). Further, the range of PSAD was much smaller
among statin users (.02-.75) than non-statin users (0 -
1.31).
There were no significant differences in pathologic
staging, tumor volume or pathologic Gleason scores
between statin users and non-users. Median and mean
follow-up were similar between the two groups (medi-
an 16.4 and 14.4 months for statin users and non-users,
respectively (P = .19), both with a mean of 20 months).
Biochemical disease-free survival (BDFS) rates 2 years
post-operatively were also similar (94% vs. 92% for
statin users and non-users, respectively, P = .23). In
logistic regression models (Table 4), preoperative sta-
tin usage was a significant predictor of PSA concen-
tration (95% confidence interval (CI) = -.069 - -.023),
P < .001), along with age (95% CI = .002 - .005, P <
.001), Gleason score on biopsy (95% CI = .081 - .113,
P < .001), and prostate weight (CI 95% = .002 - .003, P
< .001). In cox regression analysis, pathologic Gleason
score (hazard ratio (HR) = 9.3, 95% CI = 2.2 - 38.8, P
= .002), pathologic stage (HR = 3.2, 95% CI = 2.1 - 4.9,
P < .001) and preoperative PSA level (HR = 4.9, 95%
CI = 2.5 - 9.5, P < .001) but not statin usage (HR = .77,
95% CI = .48 - 1.08, P = .11) were predictive of bio-
chemical recurrence.
DISCUSSION
Statins are the most commonly prescribed medications
for hypercholesterolemia, and are currently used by
over 24 million Americans,(20) a number that continues
to rise.(21) Aside from their use in primary, secondary
and tertiary prevention of cardiovascular morbidity
and mortality, many studies have focused on possible
antineoplastic effects as they relate to prostate cancer
prognosis and PSA screening.(22) Despite early studies
that demonstrated an inverse relationship between pros-
tate cancer incidence and statin use, recent reviews and
meta-analyses have not shown conclusive evidence to
support such an association.(2,3) However, a recent me-
ta-analyses on 13 paper with 100,536 patients conclude
that statin use is associated with better overall and pros-
tate cancer specific survival.(23) Some studies have sug-
gested that statins decrease the likelihood of advanced
or aggressive disease, rather than preventing de novo
prostate cancer incidence.(4,5) Possible mechanisms pro-
posed include statins’ effect on inflammation and an-
giogenesis.(24) It has also been postulated that statins’
reduction of cholesterol-based lipid rafts, which regu-
late certain apoptotic signaling pathways such as Akt,
may be an important mechanism behind these findings.
(25) Loss of low density Lipoprotein receptor regulation
with a possible role for statins has been proposed in
prostate cancer cells as well.(26) In our study we could
not find any difference in pathologic characteristics and
pathologic stage of the prostate cancer between statin
users and non-users.
Aside from a potential therapeutic benefit, statins’ ef-
fect on clinical parameters may have an impact on
screening and treatment options for prostate cancer.
Statins have been consistently shown to reduce serum
levels of PSA.(12-14) In this higher PSA population, in
whom prostate cancer is heavily screened, the impact
of lowered PSA values in relation to delayed diagnosis
remains to be defined. Our study demonstrated that pa-
tients using statins had lower PSA level at all stages of
the disease. Though the effects of statins on screening
and surgically treated populations have been described,
the influence on eligibility for AS protocols, and the po-
Table 1. Preoperative characteristics of patients in the study
No Statin Use Statin Use p value
N = 1283 N = 630
PSA Density; mean ± SD ⃰ 0.13 ± 0.10 0.11 ± 0.08 .001
PSA; mean ± SD ⃰ 6.3 ± 4.9 5.5 ± 3.6 < .001
PSA Categories; N(%) < 2.5 64 (5%) 51 (8%) < .001
2.5-4.0 246 (19%) 149 (24%)
4.1-9.9 828 (65%) 387 (61%)
> 10 145 (11%) 43 (7%)
Biopsy Gleason Sum; N(%) < 6 696 (54%) 333 (53%) .84
7 476 (37%) 240 (38%)
> 8 111 (9%) 57 (9%)
Clinical Stage; N(%) T1c and Below 1092 (85%) 530 (84%) .57
T2 and Above 191 (15%) 100 (16%)
D'Amico Risk; N(%) Low 649 (51%) 313 (50%) .88
Intermediate 498 (39%) 252 (40%)
High 136 (11%) 65 (10%)
⃰ Patients taking 5-alpha reductase are not included in the analysis
Statins’ effect on PSA level and AS-Stensland et al.
Vol 14 No 03 May-June 2017 3066
tential treatment benefit for patients on such protocols,
has not yet been explored. The ability to forego or defer
treatment in active surveillance hinges on prognostica-
tion: the ability to identify parameters that will predict
low-risk disease with an acceptable degree of certain-
ty. These protocols tend to be based on biopsy Gleason
score, clinical stage, total PSA, and often PSA density
in addition to other factors.(15) Imaging studies including
multiparametric magnetic resonance imaging (mpMRI)
are under investigation to provide sound information in
patients undergoing AS protocols. Although primary
investigations have provided promising results, the role
Table 3. Surgical pathology characteristics of patients in the study
Non-Statin Users Statin Users p value
N = 1283 N = 630
Gleason Sum; N(%) < 6 308 (24%) 152 (24%) .40
7 905 (71%) 434 (69%)
> 8 70 (6%) 44 (7%)
Prostate Weight (g): mean 51.6 (20.3) 50.9 (17.6) .52
Pathological Staging; N(%) < T2 993 (77%) 493 (78%) .67
> T3 290 (23%) 137 (22%)
Lymph node involvement; N(%) 9 (0.9%) 1 (0.2%) .12
Margins; N(%) Negative 1021 (80%) 516 (82%) .43
Focal 182 (14%) 82 (13%)
Extensive 80 (6%) 32 (5%)
Extracapsular Extensions; N(%) No 1000 (78%) 503 (80%) .34
Yes 283 (22%) 127 (20%)
Tumor in Seminal Vesicles; N(%) No 1204 (94%) 592 (94%) .91
Yes 79 (6%) 38 (6%)
Perineural Invasion; N(%) No 277 (22%) 132 (21%) .75
Yes 1006 (78%) 498 (79%)
Lymphovascular Invasion; N(%) No 1230 (96%) 612 (97%) .17
Yes 53 (4%) 18 (3%)
Figure 1. Hypothetical influence of statin use in patient eligibility for active surveillance protocols
Statins’ effect on PSA level and AS-Stensland et al.
Urological Oncology 3067
of imaging in AS is still to be determined.(27)
As statins lower PSA levels, patients may “inappropri-
ately” qualify for active surveillance protocols that are
driven by PSA thresholds. This may shift some patients
from a higher risk into a lower risk group based on the
AS protocol cut-offs. Studies have shown that higher
PSA values are more affected by statin use than low-
er values. Hamilton et al. reported that in men with a
pre-statin PSA above 4 ng/mL, median PSA declined
by 12.5%, but when analyzed in men with pre-statin
PSA above 2.5 ng/mL this decline was only 9.5%.(28)
Notably, they also reported that in men with baseline
PSA between 2.5 and 10 ng/mL, those receiving robust
LDL responses with statin usage experienced median
PSA declines of 17%.(29) In our study population, sta-
tin users had an average 8.7% lower PSA levels. While
studies have not yet directly described the effect of stat-
ins on men with PSA above 10 ng/mL, the trend at low-
er levels potentially makes it more likely that a patient
with a PSA value around the AS protocol eligibility
cutoffs (i.e. a PSA of 10 or 15 ng/mL) may have their
PSA lowered below the cutoff. For example, a PSA of
11 ng/mL would render a man ineligible for many AS
protocols, but a reduction as reported by Hamilton et al.
brings him to 9 ng/mL and would not exclude eligibility
for any protocol based on PSA alone. (Figure 1)
Further, our study demonstrated that while PSA was
lower among statin users, prostate size was similar be-
tween the two groups. As a result, PSA Density was
lower among statin users compared to non-statin users.
The use of a PSAD cutoff as a common inclusion cri-
terion in AS protocols, combined with the increasing
prevalence of statin use in this population, raises the
concern that a common pharmacologic intervention
may distort a standard prognostic biomarker. The ex-
tent to which statins mask the true PSA level, without
offering any actual reduction in risk, could result in a
non-trivial number of statin users enrolled in AS trials
having a disproportionately higher risk profile at entry,
as well as worse survival outcomes. The unclear nature
of the relationship between statins and prostate cancer
risk underscores the need for more careful monitoring
of statin use in these study populations.
While the effect of statins on PSA is clear, the explan-
atory mechanism remains elusive. One possible expla-
nation for our results involves the previously reported
anti-inflammatory effects of statins.(12) Prostatic inflam-
mation is a known cause of elevated serum PSA in men
without prostate cancer.(30) Decreased inflammation
could thus theoretically lower PSA while not affecting
prostate size or tumor characteristics, a scenario that
would be consistent with our findings.
The observed demographic differences in ASA, BMI,
age and history of diabetes are expected, as hyperlipi-
demia shares a pathophysiologic relationship associat-
ed with other comorbid conditions such as diabetes and
obesity. It has been postulated that statins’ lowering
effect on PSA may be influenced by hemodilution in
obese, statin-using cohorts.(31) Drugs such as 5-alpha
reductase inhibitors can also directly decrease serum
PSA.(32) However, in our cohort, differences in BMI
were minimal and not statistically significant, and after
controlling for BMI and use of 5-alpha reductase inhib-
itors our results were unaffected.
While some studies support our histopathologic find-
ings,(2,17) others studies have reported a protective ben-
efit of statins against prostate cancer, in contrast to our
findings.(4,6,33) Similarly, lower prostate cancer recur-
rence rates have been reported for statin users, and at-
tributed variously to statins’ purported anti-neoplastic
activity, protective effects against aggressive disease or
a reduction in prostate cancer cells’ ability to produce
PSA.(6-8) These studies used clinical staging and biopsy
characteristics to determine histopathologic risk, which
is known to be suboptimal given the inaccuracies of
clinical prostate cancer staging.(34) Additionally, Ritch
and colleagues(11) observed a higher recurrence rate 5
years after surgery among statin users, and suggested
this may be due the masking of aggressive disease by an
artificially lowered PSA, as is suggested by our results.
While our follow-up may be too short (median 14.7
months) to reveal true differences in biochemical recur-
rence, no differences in early BCR were noted. Similar
findings were noted in the study of Cattarino et al. with
a medial follow up time of 42.3 months.(10)
The similarity of histopathologic outcomes between
groups despite disparate PSA and PSAD values appears
to imply the necessity for inclusion of PSA and PSA
density modulation by statins in clinical decision mak-
ing. As higher PSA values are generally associated with
both a higher Gleason score and poorer prognosis,(33) an
artificially lowered PSA and/or PSAD as observed in
our cohort of patients on statins may lead to an under-
estimation of risk of high-grade disease, recurrence or
subsequently higher-grade disease on pathologic spec-
imen. In this sense, it may be important to weigh other
arms of protocols (e.g. Gleason sum, number of posi-
tive cores) more highly in prognosticating patients on
statins, or account for their lower PSA concentration.
Our study does have additional notable findings. Our
patient cohort was 11% black, a higher proportion than
most published studies of statins and PSA or prostate
cancer.(35) Our cohort in this sense may better repre-
sent the American population than other published
studies. Additionally, our findings of a reduced PSA
density in the setting of prognosticating patients and
selecting treatment plans underscore the current debate
on prostate cancer treatment selection and suggest the
Table 4. Clinical Features Predicting Log Transformed PSA ⃰
Beta 95% CI p value
Statin Usage -.046 -.069, -.023 < .001
Age .004 .002, .005 < .001
Race .026 .009, 0.044 .004
Year of Surgery .002 -.005, 0.009 .57
Biopsy Gleason .097 .081, 0.113 < .001
Clinical Stage -.020 -.050, 0.011 .20
BMI -.001 -.017, 0.015 .87
ASA .008 -.013, 0.029 .45
Diabetes Status .013 -.029, 0.056 .54
Path Weight .003 .002, 0.003 < .001
⃰ Patients taking 5-alpha reductase inhibitors are not included in
the analysis
Statins’ effect on PSA level and AS-Stensland et al.
Vol 14 No 03 May-June 2017 3068
importance of further studies into both the selection
of patients for treatment options and the potential for
chemoprevention of prostate cancer.
We lacked specific data regarding the duration of pre-
operative statin treatment, which has previously been
shown to impact statins’ overall effect on PSA.(4,35) We
recognize that our cohort was comprised entirely of pa-
tients who underwent surgical extirpation for prostate
cancer following prostate biopsy. The inherent biases
of such study design prevent screening-based epide-
miologic conclusions from being drawn from such a
cohort. Further, there may be variations in some meas-
ures between a RALP cohort and actual active surveil-
lance cohort, such as prostate size between the TRUS
calculated values and pathologic weight, though previ-
ous studies have shown prostate weight to be the best
measure of prostate size for use in PSAD corrections.(19)
These measure must of course be taken under consider-
ation and validated in a cohort considering active sur-
veillance. However, given the large number of patients
with standardized histopathologic analysis by dedicated
genitourinary pathologists, our findings are interesting
and hypothesis-generating. Prospective studies involv-
ing larger cohorts are needed to confirm our findings
with detailed information of the type, dosage and dura-
tion of statin usage.
CONCLUSIONS
PSA levels were lower in statin users than non-statin
users among men presenting for robotic-assisted laparo-
scopic prostatectomy. Despite this difference, prostate
size, histopathologic outcomes and short term biochem-
ical recurrence were similar between the two groups.
Further investigation is needed to test causal hypotheses
for these findings, to establish whether differential ac-
tive surveillance criteria are warranted for statin users,
and to explore the potential therapeutic benefits of stat-
ins in the active surveillance population.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest
to state.
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