Statin use and risk of Parkinson's disease: a meta-analysis of observational studies

Abstract

Inconsistent results regarding the association between statin use and risk of Parkinson's disease (PD) have been reported. We therefore examined the association between statin use and risk of PD by conducting a detailed meta-analysis of all observational studies published regard-ing this subject. A literature search in the PubMed database was undertaken through April 2012, looking for observa-tional studies evaluating the association between statin use and risk of PD. Combined relative risk (RR) estimates and 95 % confidence intervals (CIs) were calculated using a random-effects model. Subgroup and sensitivity analyses were also performed. A total of eight (five case–control and three cohort) studies contributed to the analysis. There was heterogeneity and publication bias among the studies. Statin use significantly reduced the risk of PD by 23 % (RR 0.77, 95 % CI 0.64–0.92, p = 0.005). However, long-term statin use did not significantly affect the risk of PD (RR 0.72, 95 % CI 0.45–1.13, p = 0.15). Stratification of studies by age and smoking status significantly affected the final estimate (age-adjusted RR 0.61, 95 % CI 0.42–0.86, p = 0.005; age-not-adjusted RR 0.93, 95 % CI 0.83–1.05, p = 0.23 and smoking-adjusted RR 0.60, 95 % CI 0.42–0.87, p = 0.007; smoking-not-adjusted RR 0.92, 95 % CI 0.82–1.02, p = 0.10). Furthermore, sensitivity analysis confirmed the stability of results. Our meta-analysis supports the hypothesis that statin use reduced the risk of PD. Nevertheless, more randomized clinical trials and observational studies are required to confirm this association with underlying bio-logical mechanisms in the future.

Full text

Page 1

123
Journal of Neurology
Official Journal of the European
Neurological Society

ISSN 0340-5354

J Neurol
DOI 10.1007/s00415-012-6606-3
Statin use and risk of Parkinson’s disease: a
meta-analysis of observational studies
Krishna Undela, Kapil Gudala, Swathi
Malla & Dipika Bansal

Page 2

123
Your article is protected by copyright and
all rights are held exclusively by Springer-
Verlag. This e-offprint is for personal use only
and shall not be self-archived in electronic
repositories. If you wish to self-archive your
work, please use the accepted author’s
version for posting to your own website or
your institution’s repository. You may further
deposit the accepted author’s version on a
funder’s repository at a funder’s request,
provided it is not made publicly available until
12 months after publication.

Page 3

ORIGINAL COMMUNICATION
Statin use and risk of Parkinson’s disease: a meta-analysis
of observational studies
Krishna Undela•Kapil Gudala•Swathi Malla•
Dipika Bansal
Received: 6 May 2012/Revised: 9 June 2012/Accepted: 11 June 2012
? Springer-Verlag 2012
Abstract
between statin use and risk of Parkinson’s disease (PD) have
been reported. We therefore examined the association
between statin use and risk of PD by conducting a detailed
meta-analysis of all observational studies published regard-
ing this subject. A literature search in the PubMed database
was undertaken through April 2012, looking for observa-
tional studies evaluating the association between statin use
and risk of PD. Combined relative risk (RR) estimates and
95 % confidence intervals (CIs) were calculated using a
random-effects model. Subgroup and sensitivity analyses
were also performed. A total of eight (five case–control and
three cohort) studies contributed to the analysis. There was
heterogeneity and publication bias among the studies. Statin
use significantly reduced the risk of PD by 23 % (RR 0.77,
95 % CI 0.64–0.92, p = 0.005). However, long-term statin
usedidnotsignificantlyaffect the risk of PD(RR 0.72, 95 %
CI 0.45–1.13, p = 0.15). Stratification of studies by age and
smoking status significantly affected the final estimate (age-
adjusted RR 0.61, 95 % CI 0.42–0.86, p = 0.005; age-
not-adjusted RR 0.93, 95 % CI 0.83–1.05, p = 0.23 and
smoking-adjusted RR 0.60, 95 % CI 0.42–0.87, p = 0.007;
smoking-not-adjusted RR0.92,
p = 0.10). Furthermore, sensitivity analysis confirmed the
stabilityofresults.Ourmeta-analysissupportsthehypothesis
that statin use reduced the risk of PD. Nevertheless, more
randomized clinical trials and observational studies are
required to confirm this association with underlying bio-
logical mechanisms in the future.
Inconsistent results regarding the association
95 %CI 0.82–1.02,
Keywords
Statin ? Parkinson’s disease ? Meta-analysis
Introduction
Parkinson’s disease (PD) is a neurological disorder char-
acterized by the progressive loss of dopaminergic neurons
in the substantia nigra pars compacta [1]. The etiology of
PD is suggested with the involvement of oxidative stress,
neuroinflammation, and mitochondrial dysfunction [2].
Primary or idiopathic PD is the second most common late-
onset neurodegenerative disease, characterized by several
clinical features such as resting tremor, rigidity, akinesia,
depression, and sleep disturbances. The prevalence of idi-
opathic PD in industrialized countries has been reported to
be 0.3 % in the entire population and 1 % in those older
than 60 years; in individuals aged 80 years or above, the
prevalence can be higher than 4 % [3].
Statins[3-hydroxy-3-methyl
(HMG-CoA) reductase inhibitors] are a therapeutic class of
drugs that reduce plasma cholesterol levels and used to
manage and prevent coronary heart disease. As such,
statins are among the most commonly prescribed drugs
worldwide [4]. Recently, statins have been found to have
potent anti-inflammatory and immunomodulating effects,
which led to the hypothesis that statins could be neuro-
protective agents [5–7]. Additionally, statins have been
shown to increase striatal dopamine concentration in ani-
mal models of PD [8]. Several observational studies have
been conducted to examine the association between statin
use and PD risk and have generated mixed results [9–16].
Some randomized clinical trials (RCTs) on statin use in
coronary heart disease [17–19] reported incidence of PD,
but most of the results were ambiguous because of inade-
quate power.
glutaryl-coenzymeA
K. Undela (&) ? K. Gudala ? S. Malla ? D. Bansal
Department of Pharmacy Practice, National Institute
of Pharmaceutical Education and Research, Sector 67,
SAS Nagar 160062, Punjab, India
e-mail: krishna.niperian10@gmail.com
123
J Neurol
DOI 10.1007/s00415-012-6606-3
Author's personal copy

Page 4

Until now, no definite conclusion on this topic has been
made. In the present meta-analysis, we examined the statin
use in relation to risk of PD using epidemiological studies
published up to April 2012. RCTs have been excluded,
since to the best of our knowledge, there were no RCTs
published specifically related to this topic.
Materials and methods
Search strategy
Two authors independently performed the literature search
by using the PubMed database up to April 2012. Search
terms included: ‘‘statin(s)’’ or ‘‘HMG-CoA reductase
inhibitor(s)’’ or ‘‘lipid-lowering agent(s)’’ or ‘‘atorvastatin’’
or ‘‘cerivastatin’’ or ‘‘fluvastatin’’ or ‘‘lovastatin’’ or
‘‘mevastatin’’ or ‘‘pravastatin’’ or ‘‘rivastatin’’ or ‘‘rosu-
vastatin’’ or ‘‘simvastatin’’ and ‘‘PD’’ with limits, humans
and English. The titles and abstracts of the resulting articles
were examined to exclude irrelevant studies. The full texts
of the remaining articles were read to extract information
on the topic of interest. Bibliographies and citation sections
of retrieved articles were also reviewed for additional
pertinent studies.
Inclusion and exclusion criteria
The studies considered in this meta-analysis were all
observational (case–control or cohort) studies that evalu-
ated exposure to statins and risk of PD. Any discrepancies
between authors on inclusion of a study were resolved by
joint evaluation of the manuscript. Articles were excluded
if they were reviews, letters to the editor without original
data, editorials, and or case reports. When there were
multiple publications from the same population, only data
from the most recent report were included in the meta-
analysis and the remaining were excluded [20].
Data extraction
Two authors independently reviewed the primary studies to
assess the appropriateness for inclusion in the present
meta-analysis and data were extracted. The following
information was obtained from each study: (1) first author’s
last name, year of publication, and country of the popula-
tion studied, (2) study design, (3) number of subjects and
number of PD cases, (4) effect estimates and 95 % confi-
dence intervals (CIs), (5) assessment of statin usage, (6) PD
assessment, (7) control for confounding factors by match-
ing or adjustments, if applicable. We extracted the effect
estimates that reflected the greatest degree of control for
potential confounders.
Quality assessment
The quality of each study was assessed independently by
two authors by using the Newcastle-Ottawa Scale (NOS)
[21]. The NOS consists of three parameters of quality:
selection, comparability, and outcome (cohort studies) or
exposure (case–control studies). The NOS assigns a max-
imum of four points for selection, two points for compa-
rability, and three points for exposure/outcome. Therefore,
nine points reflects the highest quality, seven to eight
points reflects medium quality, and greater than or equal to
six points reflects low quality. Any discrepancies were
addressed by a joint revaluation of the original article with
the third author.
Data synthesis and analysis
Because the risk of PD is low, the relative risk (RR) in
prospective cohort studies mathematically approximates
the odds ratio [22], therefore permitting the combination
of cohort and case–control studies. Publication bias was
assessed using Begg and Mazumdar adjusted-rank cor-
relation test and Egger regression asymmetry test [23,
24]. To assess the heterogeneity among studies, we used
the Cochran Q and I2statistics: for the Q statistic, a
p value \0.10 was considered statistically significant for
heterogeneity; while for I2, a value [50 % is considered
a measure of heterogeneity [25]. The primary measure
was combined RR of PD from individual studies calcu-
lated using the random-effects model (DerSimonian and
Laird method), which accounts for heterogeneity among
studies. Tests for interaction using summary estimates
were performed using the method described by Altman
and Bland [26]. All analyses were performed using
STATA version 11.0 (StataCorp, College Station, TX).
All statistical tests were two-sided and p\0.05 was
considered statistically significant, except as otherwise
specified.
The primary outcome in this meta-analysis was reported
as RR with 95 % CI of developing PD in statin users. To
assess any link between (1) long-term statin use and risk of
PD and (2) individual statin use and risk of PD, we used the
available data from studies that reported RR estimates for
these particular associations.
Subgroup analyses were performed according to (1)
study design (case–control and cohort), (2) adjustment for
age, (3) adjustment for smoking, and (4) quality of studies
to examine the impact of these factors on the association.
To evaluate the stability of our results, we also performed a
one-way sensitivity analysis. The scope of this analysis was
to evaluate the influence of individual studies by estimating
the average RR in the absence of each study. The present
work was performed as per the guidelines proposed by the
J Neurol
123
Author's personal copy

Page 5

meta-analysis of Observational Studies in Epidemiology
group [27].
Results
Search results
A total of 43 articles were identified during the initial
search (Fig. 1). After reviewing the titles and abstracts of
these articles, 31 were found to be ineligible as they were
reviews, clinical trials, case reports, letters, and others that
did not met the inclusion criteria. After reviewing the
reference list of the remaining 12 articles, one more article
was considered. After detailed evaluation of the remaining
13 full-text articles, five were excluded for reasons as
described in Fig. 1.
Study characteristics
Eight relevant studies were identified, consisting of five
case–control and three cohort studies involving a total of
1,472,938 subjects including 15,102 PD cases. Participants
were followed-up for 2–14 years and the studies have been
published between 2007 and 2012.
Five case–control studies [9, 12–15] were published
between 2007 and 2010. These studies included 43,526
participants, followed-up for 2–11 years, reporting a total
of 1,008 statin users among 10,760 PD cases and 3,610
statin users among 32,766 controls. Of the five, three
studies reported a negative association between statin use
and risk of total PD [9, 14, 15]. Statin use was ascertained
by review of medical records in four studies [9, 12, 13, 15]
and by self-report in one study [14]. Of them, two studies
[9, 14] were conducted in North America, two [12, 15] in
Europe, and one [13] in South America.
Three cohort studies [10, 11, 16] of statin use and risk of
PD were published between 2007 and 2012. These inclu-
ded 1,429,412 participants who were followed-up for
2–14 years, reporting a total of 2,828 incident PD cases
among 8,540,006 statin users. Two studies reported a
negative association between statin use and risk of total PD
[10, 16]. Statin use was ascertained by review of medical
records in one study [10], using database in one study [11],
and self-reported in one study [14]. All of these cohort
studies were conducted in North America.
In a total of eight studies, six [10–14, 16] were popu-
lation-based and two [9, 15] were hospital-based studies.
All studies evaluated exposure to statins and the risk of PD.
Four studies [9, 10, 14, 16] were controlled for potential
8 articles included in the meta-analysis
12 full text articles retrieved for detailed
evaluation
1 full text article added after reviewing
reference list of retrieved articles
5 articles excluded
-4 exposure was not statin use
-1 study reported on similar population
31 articles excluded
-21 review articles
-3 clinical trials
-2 case reports
-2 letters
-2 not relevant based on title reading
-1 not relevant based on abstract
43 articles identified from PubMed and
reviewed
Fig. 1 Flowchart representing
the selection process
J Neurol
123
Author's personal copy

Page 6

confounding factors like age and smoking and only one
study [9] was controlled for low-density lipoprotein cho-
lesterol (LDL-C) by matching or adjustment. The charac-
teristics of the selected studies are presented in Table 1.
Further, three studies [14–16] reported RR estimates on
the association between long-term statin use and risk of PD
(Table 2), and three studies [11, 12, 14] presented an
examination of individual statin use in relation to risk of
PD (Table 3).
Quality assessment results
According to the NOS, we found that one [12] study to be
of high quality, five [9, 10, 14–16] of medium quality, and
two [11, 13] of low quality.
Main analysis
Publicationbiaswasobservedamongstudiesusingpvalueof
the Begg’s (p = 0.03) and Egger’s (p = 0.01) tests and also
thefunnelplotdidnothaveanexpectedfunnelshape(Fig. 2).
Because of significant heterogeneity (pheterogeneity= 0.009,
I2= 63 %) was observed, a random-effects model was
chosen over a fixed-effects model. A combined analysis of
eightstudiesfoundstatinusetobeassociatedwithsignificant
reduction in the risk of PD (RR 0.77, 95 % CI 0.64–0.92,
p = 0.005). Both the multivariable adjusted RR estimates
with 95 % CIs of each study and combined RR are shown in
Fig. 3.
Subgroup and sensitivity analyses
We found a significant inverse association between statin
use and risk of PD among case–control studies (RR 0.77,
95 % CI 0.62–0.96, p = 0.02) as well as cohort studies
(RR 0.74, 95 % CI 0.57–0.97, p = 0.02) as presented in
Table 4. The combined RR of the studies that were able to
control for age and smoking depicted a significant inverse
association (RR 0.61, 95 % CI 0.42–0.86, p = 0.005 and
RR 0.60, 95 % CI 0.42–0.87, p = 0.007, respectively) than
studies that were not adjusted (RR 0.93, 95 % CI
0.83–1.05, p = 0.23 and RR 0.92, 95 % CI 0.82–1.02,
p = 0.10, respectively). Subgroup of studies having med-
ium quality presented significant inverse association (RR
Table 1 Studies included in the meta-analysis
Author (country)a
Study period
(years)
Study
population
PD
cases
Description
of statin used
Definition
of statin use
Number of
variables
adjustede
Quality
rating
(NOS)
Huang et al. [9] (USA)b
de Lau et al. [10] (USA)c
Wolozin et al. [11] (USA)c
Becker et al. [12] (UK)b
Samii et al. [13] (Columbia)b
Wahner et al. [14] (California)b
Ritz et al. [15] (Denmark)b
Gao et al. [16] (USA)c
2 (2002–2004)236124AMedical records1–3, 217
14 (1990–2004)10,2751,008AMedical records1–38
2 (2003–2005)1,290,071 2,690B Database7, 11, 146
11 (1994–2005) 7,2743,637B Medical records3, 8, 12, 13, 159
6 (1997–2003) 23,7804,756B Medical records2, 226
6 (2001–2007)654312ASelf-reported1–67
5 (2001–2006)11,5821,931AMedical records1, 2, 7, 98
12 (1994–2006)1,290,066644A Self-reported 1, 3, 8, 10, 16–207
PD Parkinson’s disease, NOS Newcastle-Ottawa Scale, NR not reported
aCountry of study conducted
bCase–control studies
cCohort studies
dA, ever use of statins versus never use of statins; B, current use of statins versus no current use of statins
e1, age; 2, sex; 3, smoking; 4, race; 5, education; 6, country; 7, Charlson index; 8, body mass index; 9, chronic obstructive pulmonary disease;
10, cardiovascular diseases; 11, dementia; 12, co-morbidities; 13, use of fibrates; 14, use of neuroleptics medication; 15, use of hypertension
drugs; 16, use of ibuprofen; 17, use of caffeine; 18, use of lactose; 19, use of alcohol; 20, physical activity; 21, low-density lipoprotein
cholesterol; 22, use of antipsychotics
Table 2 Studies evaluating the association between long-term statin
use and risk of Parkinson’s disease
Study
RR
95 % CITotal PD
cases
Definition of ‘‘long-
term’’ statin usec
Wahner et al.
[14]a
Ritz et al. [15]a
Gao et al. [16]b
0.37 0.18–0.78 11C5 years
1.060.77–1.48 45
[5 years
C6 years0.70.53–0.93 NR
RR relative risk, CI confidence interval, PD Parkinson’s disease,
NR not reported
aCase–control studies
bCohort studies
cDefinition of long-term statin use was taken from original research
articles
J Neurol
123
Author's personal copy

Page 7

0.60, 95 % CI 0.42–0.86, p = 0.005) than studies having
low quality (RR 0.93, 95 % CI 0.81–1.07, p = 0.35)
(Table 4). Tests for interaction were found to be non-sig-
nificant for subgroups of study design (pinteraction= 0.82)
and significant for subgroups of age and smoking adjust-
ments (pinteraction= 0.03, for both).
To test the robustness of our findings, we also carried
out a sensitivity analysis. To do this, the overall effect size
was calculated by removing one study at a time. This
analysis showed no significant variation in combined RR
on excluding either outlier (very low sample size study) de
Lau et al. [10] (RR 0.78, 95 % CI 0.65–0.96) or any of the
other studies (RR was between 0.71 and 0.84), confirming
the stability of the present results.
Results for long-term statin use
Long-term statin use (mostly C5 years of use) did not
significantly affect the risk of PD (RR 0.72, 95 % CI
0.45–1.13, p = 0.15). However, there was high evidence of
heterogeneity among these studies (pheterogeneity= 0.02,
I2= 75 %) (Table 4). The multivariable-adjusted RR
estimates with 95 % CIs of each study and combined RR
are shown in Fig. 4.
Results for individual statin use
We found that among individual statins, only atorvastatin,
lovastatin, and simvastatin decreased the risk of PD non-
significantly (RR 0.72, 95 % CI 0.45–1.13, p = 0.15; RR
0.61, 95 % CI 0.16–2.35, p = 0.47 and RR 0.60, 95 % CI
0.35–1.03,
p = 0.06,respectively)
showed significant increased risk of PD (RR 2.22, 95 % CI
1.06–4.66, p = 0.03) (Table 4).
whilepravastatin
Discussion
In the past decade, the role of statins in the development of
PD has been increasingly understood. With the present
combined analysis of currently available eight observa-
tional studies, a 23 % reduction in PD risk among statin
-2-1
Relative risk (logarithmic scale)
012
0.8
0.6
0.4
0.2
0.0
Standard error
Fig. 2 Funnel plot (publication bias assessment plot) does not have
the expected funnel shape representing the publication bias in the
study. Relative risks are displayed on a logarithmic scale. Circles
represent studies included in the meta-analysis
0.010.10.2 0.512
Combined estimate (n = 8)0.77 (0.64, 0.92)
0.74 (0.54, 1.00)
0.89 (0.75, 1.04)
0.45 (0.29, 0.71)
0.94 (0.82, 1.09)
0.92 (0.73, 1.16)
0.85 (0.42, 1.29)
0.33 (0.08, 1.35)
0.37 (0.19, 0.72)Huang et al., 2007
de Lau et al., 2007
Wolozin et al., 2007
Becker et al., 2008
Samii et al., 2008
Wahner et al., 2008
Ritz et al., 2010
Gao et al., 2012
Study, Year
RR (95% CI)
Relative risk (95% confidence interval)
Fig. 3 Combined estimate of relative risk and 95 % confidence
intervals of Parkinson’s disease associated with statin use based on
eight studies (five case–control and three cohort) involving 1,472,938
participants including 15,102 PD cases. Squares indicate RR in each
study. The square size is proportional to the weight of the
corresponding study in the meta-analysis; the length of horizontal
lines represents the 95 % CI. The unshaded diamond indicates the
combined RR and 95 % CI (random-effects model)
Table 3 Studies evaluating the association between individual statin
use and risk of Parkinson’s disease
Study
RR
95 % CIPD cases
Atorvastatin
Wolozin et al. [11]b
Wahner et al. [14]a
Becker et al. [12]a
0.990.86–1.14 224
0.390.21–0.71 NR
0.880.5–1.54 31
Lovastatin
Wolozin et al. [11]b
Wahner et al. [14]a
1.090.98–1.22 350
0.270.09–0.87 NR
Pravastatin
Wahner et al. [14]a
Becker et al. [12]a
1.780.43–7.42 NR
2.41 1.01–5.7219
Simvastatin
Wolozin et al. [11]b
Wahner et al. [14]a
Becker et al. [12]a
0.50.49–0.552116
0.38 0.16–0.91 NR
1.01 0.65–1.5753
RR relative risk, CI confidence interval, PD Parkinson’s disease,
NR not reported
aCase–control studies
bCohort studies
J Neurol
123
Author's personal copy

Page 8

users as compared to non-users was observed and this
association remained stable even after the sensitivity
analysis.
The cause of neuronal death in PD remains largely
unknown, but several mechanisms such as inflammation
[28] or oxidative stress [29] are thought to play a major role
in the pathogenesis of this disorder. In this context, statins
may play a beneficial role because they attenuate neuro-
inflammatory processes by inhibiting the expression of
inflammatory mediators such as interleukin-6, tumor
necrosis factor-a, and C-reactive protein [30], and protect
cells against reactive oxygen species [31].
The present finding regarding decreased relative risk of
PD among statin users is also supported by in vitro studies.
In mice, simvastatin was reported to prevent striatal cells
from dopamine depletion in a dose-dependent manner [8].
In another study, fluvastatin demonstrated antioxidant
properties in the extra-cellular space of the rat striatum
[32].
The decreased risk of PD in long-term statin users was
found here to be non-significant. This is likely to be
associated with varying patterns of statin use in the dif-
ferent study populations. In all the cases, drug use can be
irregular, with months of non-use between periods of use
[11, 12, 14]. Hence, cumulative amount of statin defined
daily doses (DDDs) could be small despite its long dura-
tion. Conversely, other studies took into account the use of
statins at high doses, which resulted in high cumulative
amount of DDDs. From this point of view, it should be
noted that the decreasing trend in PD relative risk has been
found to be stronger for cumulative amount of statin use
than for duration of its use [33]. Also, the varying defini-
tion of ‘‘long-term use’’ could have led to non-significant
results. Moreover, the data on long-term statin use is
available only in three studies among total eight studies.
On the other hand, analysis of those reports which
specifically examined individual statin use in relation to PD
(n = 3) suggested a non-significant protective association
Table 4 Overall effect estimates for Parkinson’s disease and statin use according to study characteristics
No. of
studies
Pooled estimateTests of heterogeneity
Pinteraction
Tests of publication bias
RR (95 % CI)
p value
Q value (df)
p value
I2(%) Begg’s P
Egger’s P
All studies8 0.77 (0.64–0.92)0.005b
18.87 (7)0.009 630.030.01
Study design
Case–control50.77 (0.62–0.96)
0.74 (0.57–0.97)a
0.02b
0.02b
16.08 (4) 0.002
0.48d
75 0.820.080.01
Cohort3
1.49 (2)0––
Age
Adjusted5 0.61 (0.42–0.86)
0.93 (0.83–1.05)a
0.005b
14.64 (4)0.006
0.94d
73 0.03e
0.230.03
Not adjusted3
0.230.13 (2)0––
Smoking
Adjusted50.60 (0.42–0.87)
0.92 (0.82–1.02)a
0.007b
13.54 (4)0.009
0.85d
710.03e
0.230.07
Not adjusted3
0.10 0.31 (2)0––
Quality of studies (NOS)
High quality10.92 (0.73–1.16)–
0.005b
––––
0.23f
–
Medium quality5 0.60 (0.42-0.86)
0.93 (0.81–1.07)a
14.63 (4)0.005
0.78d
730.05
Low quality2
0.35 7.5 (1)–––
Results for long-term statin use30.72 (0.45–1.13)0.157.93 (2)0.02 75––
Results for individual statin
Atorvastatin3 0.72 (0.45–1.13) 0.15 7.93 (2)0.02 75––
Lovastatin2 0.61 (0.16–2.35)
2.22 (1.06–4.66)a
0.47
0.03c
5.76 (1) 0.02
0.72d
–––
Pravastatin2
0.13 (1)–––
Simvastatin3 0.60 (0.35–1.03)0.0610.01 (2)0.007 80––
RR relative risk, CI confidence interval, df degree of freedom, NOS Newcastle-Ottawa Scale
aRelative risk from fixed-effects model due to no heterogeneity among the studies (remaining estimates from random-effects model)
bp value representing significant inverse association between statin use and Parkinson’s disease
cp value representing significant direct association between statin use and risk of Parkinson’s disease
dStatistically significant for homogeneity
eTest of interaction was statistically significant
fStatistically significant for no publication bias
J Neurol
123
Author's personal copy

Page 9

with atorvastatin, lovastatin, and simvastatin. Combined
analysis of data from two studies involving pravastatin
users found them to be 1.2 times more prone to incidence
of PD than non-users. This may be due to the lipophilic
character of atorvastatin, lovastatin, and simvastatin,
whereas pravastatin and rosuvastatin are more hydrophilic
[34]. Owing to their lipophilic structure, atorvastatin, lov-
astatin, simvastatin, and fluvastatin act as most powerful
anti-inflammatory drugs on neurons due to their ability to
penetrate more deeply into the phospholipid bilayer of cell
membranes, and also have a higher affinity to the HMG-
CoA reductase [35].
In the subgroup analyses, stratification by study design
did not substantially affect the results. The potential con-
founding variables in detecting PD are age, smoking, and
serum cholesterol levels [16]. Subgroup analysis of studies
that were able to control for age [9, 10, 14–16] and
smoking [9, 10, 12, 14, 16] were performed, and these
revealed more robust inverse association as compared to
the studies which are not adjusted. This represents the
possible influence of age and smoking on the final com-
bined effect estimate. Only one study [9], adjusted LDL-C,
forbade us to perform a subgroup analysis on this con-
founding variable. An additional subgroup analysis of
medium-quality studies showed a greater inverse associa-
tion as compared to low-quality studies and this represents
the influence of quality of studies on the final effect
estimate.
The strength of the present analysis lies in inclusion of
eight observational studies reporting data of more than 1.4
million participants, including 15,102 PD cases. However,
our meta-analysis has several limitations. First, we did not
search for unpublished studies for original data. Secondly,
the included studies were different in terms of study design,
confounder adjustments, and definitions of drug exposure
and long-term statin use. Finally, our analysis was
restricted to articles in the English language, which may
have somewhat biased the results.
In conclusion, our results suggest a decreased relative
risk of PD in statin users as identified by a combined meta-
analysis of eight observational studies. The results support
the hypothesis that cholesterol lowering with statins is
beneficial for PD prevention. More RCTs and observa-
tional studies are needed to confirm this association with
underlying biological mechanisms in the future. Larger
studies involving more patients exposed to statins on a
long-term basis may yield more information to answer the
question of whether statins actually alter the PD risk to a
material degree.
Acknowledgments
scientist (Biostatistician), Centre for excellence, Public Health
Foundation, India for helping with the data analysis.
The authors thank Dr. Dimple Kondal, Senior
Conflicts of interest
article was reported. No funding was provided for this analysis.
No potential conflict of interest relevant to this
References
1. Lang AE, Lozano AM (1998) Parkinson’s disease. First of two
parts. N Engl J Med 339:1044–1053
2. Schapira AH (2006) Etiology of Parkinson’s disease. Neurology
66:S10–S23
3. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J
(2011) Epidemiology and etiology of Parkinson’s disease: a
review of the evidence. Eur J Epidemiol 26:S1–S58
4. Lamb E (2009) Top 200 drugs of 2008. http://www.pharma
cytimes.com/issue/pharmacy/2009/2009-05/RxFocusTop200Drugs-
0509. Accessed 2 May 2012
5. Becker C, Meier CR (2009) Statins and the risk of Parkinson
disease: an update on the controversy. Expert Opin Drug Saf
8:261–271
6. Wood WG, Eckert GP, Igbavboa U, Muller WE (2010) Statins
and neuroprotection: a prescription to move the field forward.
Ann NY Acad Sci 1199:69–76
7. Wang Q, Yan J, Chen X, Li J, Yang Y, Weng J, Deng C, Yenari
MA (2011) Statins: multiple neuroprotective mechanisms in
neurodegenerative diseases. Exp Neurol 230:27–34
8. Selley ML (2005) Simvastatin prevents 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion
and protein tyrosine nitration in mice. Brain Res 1037:1–6
9. Huang X, Chen H, Miller WC, Mailman RB, Woodard JL, Chen
PC, Xiang D, Murrow RW, Wang YZ, Poole C (2007) Lower
low-density lipoprotein cholesterol levels are associated with
Parkinson’s disease. Mov Disord 22:377–381
10. de Lau LM, Stricker BH, Breteler MM (2007) Serum cholesterol,
use of lipid-lowering drugs, and risk of Parkinson disease. Mov
Disord 22:1985–1987
11. Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE (2007)
Simvastatin is associated with a reduced incidence of dementia
and Parkinson’s disease. BMC Med 5:20
0.1 0.2 0.512
Combined estimate (n
) 31 . 1, 5 4 . 0 (2 7 . 0 ) 3=
0.70 (0.53, 0.93)
0.37 (0.18, 0.78)
1.06 (0.77, 1.48)
Study, Year
RR (95% CI)
Ritz et al., 2010
Wahner et al., 2008
Gao et al., 2012
Relative risk (95% confidence interval)
Fig. 4 Combined estimate of relative risk and 95 % confidence
intervals of Parkinson’s disease associated with long-term statin use
based on three studies (two case–control and one cohort) involving
141,302 participants including 56 PD cases. Squares indicate RR in
each study. The square size is proportional to the weight of the
corresponding study in the meta-analysis; the length of horizontal
lines represents the 95 % CI. The unshaded diamond indicates the
combined RR and 95 % CI (random-effects model)
J Neurol
123
Author's personal copy

Page 10

12. Becker C, Jick SS, Meier CR (2008) Use of statins and the risk of
Parkinson’s disease: a retrospective case–control study in the UK.
Drug Saf 31:399–407
13. Samii A, Carleton BC, Etminan M (2008) Statin use and the risk
of Parkinson disease: a nested case control study. J Clin Neurosci
15:1272–1273
14. Wahner AD, Bronstein JM, Bordelon YM, Ritz B (2008) Statin
use and the risk of Parkinson disease. Neurology 70:1418–1422
15. Ritz B, Manthripragada AD, Qian L, Schernhammer E, Wermuth
L, Olsen J, Friis S (2010) Statin use and Parkinson’s disease in
Denmark. Mov Disord 25:1210–1216
16. Gao X, Simon KC, Schwarzschild MA, Ascherio A (2012) Pro-
spective study of statin use and risk of Parkinson disease. Arch
Neurol 69:380–384
17. The Long-Term Intervention with Pravastatin in Ischaemic Dis-
ease (LIPID) Study Group (1998) Prevention of cardiovascular
events and death with pravastatin in patients with coronary heart
disease and a broad range of initial cholesterol levels. N Engl J
Med 339:1349–1357
18. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere
PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr (1998)
Primary prevention of acute coronary events with lovastatin in
men and women with average cholesterol levels: results of AF-
CAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis
Prevention Study. JAMA 279:1615–1622
19. Heart Protection Study Collaborative Group (2002) MRC/BHF
Heart Protection Study of cholesterol lowering with simvastatin
in 20,536 high-risk individuals: a randomised placebo-controlled
trial. Lancet 360:7–22
20. Simon KC, Chen H, Schwarzschild M, Ascherio A (2007)
Hypertension, hypercholesterolemia, diabetes, and risk of Par-
kinson disease. Neurology 69:1688–1695
21. Ottawa Hospital Research Institute (2011) The Newcastle-Ottawa
Scale (NOS) for assessing the quality of nonrandomised studies
inmeta-analyses.http://www.ohri.ca/programs/clinical_epid
emiology/oxford.asp. Accessed 2 May 2012
22. Zhang J, Yu KF (1998) What’s the relative risk? A method of
correcting the odds ratio in cohort studies of common outcomes.
JAMA 280:1690–1691
23. Begg CB, Mazumdar M (1994) Operating characteristics of a rank
correlation test for publication bias. Biometrics 50:1088–1101
24. Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-
analysis detected by a simple, graphical test. BMJ 315:629–634
25. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Mea-
suring inconsistency in meta-analyses. BMJ 327:557–560
26. Altman DG, Bland JM (2003) Interaction revisited: the difference
between two estimates. BMJ 326:219
27. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD,
Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000)
Meta-analysis of observational studies in epidemiology: a pro-
posal for reporting. Meta-analysis Of Observational Studies in
Epidemiology (MOOSE) group. JAMA 283:2008–2012
28. Whitton PS (2007) Inflammation as a causative factor in the
aetiology of Parkinson’s disease. Br J Pharmacol 150:963–976
29. Greenamyre JT, Hastings TG (2004) Biomedicine. Parkinson’s—
divergentcauses,convergentmechanisms.Science304:1120–1122
30. Devaraj S, Chan E, Jialal I (2006) Direct demonstration of an
antiinflammatory effect of simvastatin in subjects with the met-
abolic syndrome. J Clin Endocrinol Metab 91:4489–4496
31. Resch U, Tatzber F, Budinsky A, Sinzinger H (2006) Reduction
of oxidative stress and modulation of autoantibodies against
modified low-density lipoprotein after rosuvastatin therapy. Br J
Clin Pharmacol 61:262–274
32. Obata T, Yamanaka Y (2000) Protective effect of fluvastatin, a
new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A
reductase, on MPP(?)-induced hydroxyl radical in the rat stria-
tum. Brain Res 860:166–169
33. Murtola TJ, Tammela TL, Mllttlnen L, Huhtala H, Platz EA, Ala-
Opas M, Stenman UH, Auvinen A (2010) Prostate cancer and
PSA among statin users in the Finnish Prostate Cancer Screening
Trial. Int J Cancer 127:1650–1659
34. Schachter M (2004) Chemical, pharmacokinetic and pharmaco-
dynamic properties of statins: an update. Fundam Clin Pharmacol
19:117–125
35. Mason RP, Walter MF, Day CA, Jacob RF (2005) Intermolecular
differences of 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors contribute to distinct pharmacologic and pleiotropic
actions. Am J Cardiol 96:11–23
J Neurol
123
Author's personal copy