Drug Saf (2014) 37:735742

DOI 10.1007/s40264-014-0212-5

ORIGINAL RESEARCH ARTICLE

Association Between Statin Use and Bells Palsy:

A Population-Based Study
Shih-Han Hung Li-Hsuan Wang
Herng-Ching Lin Shiu-Dong Chung

Published online: 31 July 2014

Springer International Publishing Switzerland 2014

Abstract statins between the cases and controls. The associations of

Background Several reports mention that statin (HMG- regular and irregular statin users with Bells palsy were
CoA reductase inhibitor) use seems to be associated with further analyzed.
several neurologic disorders and that the lipid-lowering Results By Chi-square test, there was a significant dif-
effect of statins may contribute to some neural toxicity. ference in the prevalence of statin use between cases and
Objective This study aimed to evaluate the association controls (23.2 vs. 16.4 %, p \ 0.001). Conditional logistic
between statin use and Bells palsy using a population- regression analysis revealed that after adjusting for diabe-
based health insurance database. tes mellitus, hypertension, and hyperlipidemia, the OR for
Methods This case-control study identified 1,977 subjects prior statin use was 1.47 (95 % CI 1.281.69) for cases
with Bells palsy as cases and 5,931 sex- and age-matched compared with controls. Bells palsy was significantly
subjects without Bells palsy as controls from the Taiwan associated with previous regular statin use (C60 days
Longitudinal Health Insurance Database 2000. Conditional within 6 months) (adjusted OR: 1.46, 95 % CI 1.281.67).
logistic regressions was used to estimate the odds ratio However, there was no increased adjusted OR of irregular
(OR) and 95 % confidence interval (CI) for previous use of statin use (\60 days within 6 months) for cases compared
with controls (OR: 1.09, 95 % CI 0.821.46).
S.-H. Hung Conclusions Our present data suggest a potential associ-
Department of Otolaryngology, Taipei Medical University
ation between regular statin use and Bells palsy.
Hospital, Taipei, Taiwan

L.-H. Wang
School of Pharmacy, Taipei Medical University, Taipei, Taiwan
Key Points
L.-H. Wang
Department of Pharmacy, Taipei Medical University Hospital, There is a significant difference in the prevalence of
Taipei, Taiwan
statin use between subjects with Bells palsy and
H.-C. Lin healthy controls (23.2 vs. 16.4 %; p \ 0.001)
School of Health Care Administration, Taipei Medical
University, Taipei, Taiwan The adjusted odds ratio (OR) for prior statin use was
e-mail: [email protected] 1.47 (95 % CI 1.281.69) for subjects with Bells
palsy, compared with controls
S.-D. Chung (&)
Division of Urology, Department of Surgery, Far Eastern Bells palsy is significantly associated with previous
Memorial Hospital, No.21, Sec. 2, Nanya S. Rd., Banqiao Dist., regular statin use (C60 days within 6 months)
New Taipei City 220, Taiwan
(adjusted OR: 1.46)
e-mail: [email protected]
There is no increased adjusted OR of irregular statin
S.-D. Chung
use (\60 days within 6 months) for subjects with
Sleep Research Center, Taipei Medical University Hospital,
Taipei, Taiwan Bells palsy compared with controls
736 S.-H. Hung et al.

1 Introduction National Health Insurance (NHI) program, was provided to

scientists in Taiwan for research purposes. The LHID2000
mainly included the medical claims of 1,000,000 enrollees,
Statins (3-hydroxy-3-methyl-glutaryl (HMG)-CoA reduc-
who were randomly selected from all enrollees under the
tase inhibitors) are used to lower cholesterol levels by
NHI program, and has been used to publish studies in
inhibiting the enzyme HMG-CoA reductase, which plays a
internationally peer-reviewed journals [25]. It provides
central role in the production of cholesterol in the liver.
researchers with an opportunity to trace all medical utili-
Increased cholesterol levels have been associated with
zations of these 1,000,000 enrollees since the start of the
cardiovascular diseases (CVDs) [13] and research has
NHI program in 1995.
found that statins are effective in preventing and treating
This study was exempt from full review by the Institu-
CVDs [47???].
tional Review Board of Taipei Medical University because
Aside from their cholesterol-lowering effect and pri-
the LHID2000 consisted of de-identified secondary data
mary and secondary prevention of CVDs, statins have
released to the public for research purposes.
recently been associated with other benefits involving
various body systems. Tonelli et al. [8] reported that statins
may be of some benefit in preserving renal function in 2.2 Selection of Cases and Controls
patients with moderate chronic renal insufficiency. Statin
use has even been reported to improve outcomes of patients Cases were selected by identifying 1,977 subjects aged
with sepsis and infections [9, 10]. Simvastatin, in particu- C40 years with a first-time principal diagnosis of Bells
lar, has been found to strongly reduce levels of b-amyloid palsy [International Classification of Diseases, Ninth
peptides associated with Alzheimers disease and, possibly, Revision, Clinical Modification (ICD-9-CM) code 351.0]
to have some potential in preventing the development of in an ambulatory care visit (including the outpatient
dementia [11]. However, there are also reports in which departments of hospitals and clinics) from 1 January 2008
statins seem to be associated with several neurologic dis- to 31 December 2011. Subjects aged \40 years were not
orders [1215]. It is believed that the lipid-lowering effect included because of the low prevalence of statin use in this
of statins may contribute to some neural toxicity [16]. age group. The first ambulatory care visit for treatment of
Interestingly, most reports on statin neurotoxicity are facial nerve disorders was assigned as the index date for
regarding effects on the peripheral nervous system [17, 18]. cases.
In our previous study, we found that sudden sensorineural Three controls for each case were selected from the
hearing loss (SSNHL) was significantly associated with remaining beneficiaries of the LHID2000. First, all subjects
previous statin use [19], suggesting that the central nervous who had received a diagnosis of Bells palsy since the
system (CNS) can also be affected. However, associations beginning of the NHI program were excluded. Then, 5,931
between statin use and cranial nerve neuropathy, such as controls were randomly selected to match the cases in
Bells palsy, remain unknown. terms of age, sex, and index year. For cases, the year of
Bells palsy is commonly used to describe an acute index date was the year in which the cases received their
peripheral facial palsy of unknown cause [20]. Currently, first diagnosis of Bells palsy; for controls, the year of
this condition is suspected to mostly originate from a index date was simply a matched year in which controls
herpes simplex-mediated viral inflammatory/immune had a medical utilization. For the controls, the first utili-
mechanism [21, 22]. Although other mechanisms such as zation of medical care occurring in the index year was also
genetic predisposition or facial nerve ischemia have been defined as the index date.
proposed, only the multi-factorial nature of the disease is
certain [23, 24]. The present study aimed to evaluate the
2.3 Exposure Assessment
association of statin use with Bells palsy using a popula-
tion-based coverage database.
From the file of ambulatory care medical orders, prior use
of simvastatin, lovastatin, atorvastatin, fluvastatin, prava-
statin, and rosuvastatin before the index date was selected.
2 Methods We defined those subjects who had ever received statin
prescriptions within 1 year before the index date as statin
2.1 Database users. Therefore, all statin users included in this study are
considered as current users. Those subjects who had never
The study sample for this case-control study was retrieved received statin prescriptions within 1 year before the index
from the Longitudinal Health Insurance Database 2000 date were defined as non-users in this study. Since most
(LHID2000). The LHID2000, derived from the Taiwan statin use is continuous, we also found that all non-users
Statin Use and Bells Palsy 737

had never received statin prescriptions since the start of the the Governments definition of minimum wage for full-
NHI program in 1995. In addition, the information on time employees in Taiwan.
prescription date and duration was recorded in the file of
ambulatory care medical orders. This allows us to under- 2.4 Statistical Analysis
stand the continuity and duration of prescription for each
subject. Subjects who had received continuous statin pre- SAS for Windows, version 8.2 (SAS Institute, Cary, NC,
scriptions for C60 days within 6 months before the index USA) was used to perform all statistical analyses. Chi-
date were further defined as regular statin users in accor- square tests were conducted to compare statistical differ-
dance with a prior study [26]. The remaining subjects who ences in monthly income, urbanization level, geographic
had been prescribed statins for \60 days within 6 months location, diabetes, hypertension, hyperlipidemia, coronary
before the index date were regarded as irregular statin heart disease, obesity, and tobacco use disorder between
users. cases and controls. Conditional logistic regression analysis
In this study, we also took the variables of monthly (conditioned on age, sex, and index year) was also used to
income [new Taiwan dollars ($NT) 015,840, estimate the odds ratio (OR) and 95 % confidence interval
15,84125,000, and C25,001), urbanization level, geo- (CI) for previous statin use between cases and controls
graphic location (northern, central, eastern, and southern after adjusting for medical co-morbidities. We only took
Taiwan), diabetes mellitus, hypertension, hyperlipidemia, medical co-morbidities that were significantly associated
coronary heart disease, obesity, and tobacco use disorder with Bells palsy into consideration in the regression
into consideration. The method of monthly income classi- models. The associations of regular and irregular statin
fication was based on a previous study [27]. $NT15,840 users with Bells palsy were also further analyzed. Statis-
was used as the first income level cutoff point since that is tical significance was set at p B 0.05.

Table 1 Demographic
Variable Patients with Bells palsy (n = 1,977) Controls (n = 5,931) p value
characteristics of patients with
Bells palsy and controls Total no. % Total no. %
(N = 7,908)
Age (years) 58.1 (11.9) 58.1 (11.9) [0.999
Sex [0.999
Male 942 47.6 2,826 47.6
Female 1,035 52.4 3,105 52.4
Monthly income ($NT)a 0.284
B15,840 696 35.2 2,131 35.9
15,84125,000 784 39.7 2,237 37.7
C25,001 497 25.1 1,563 26.4
Geographic region 0.278
Northern 899 45.5 2,807 47.3
Central 459 23.2 1,258 21.2
Southern 564 28.5 1,701 28.7
Eastern 55 2.8 165 2.8
Urbanization level 0.645
1 (most urbanized) 589 29.8 1,819 30.7
2 615 31.1 1,753 29.6
3 279 14.1 845 14.2
4 263 13.3 772 13.0
5 (least urbanized) 231 11.7 742 12.5
Diabetes mellitus 478 24.2 904 15.2 \0.001
Hypertension 708 35.8 1,734 29.2 \0.001
Hyperlipidemia 570 28.8 1,425 24.0 \0.001
Tobacco use disorder 70 3.5 192 3.2 0.680
$NT New Taiwan dollars Obesity 28 1.4 63 1.1 0.201
a
The average exchange rate in Coronary heart disease 168 8.5 500 5,931 0.926
2010 was US$1.00 & $NT30.0
738 S.-H. Hung et al.

3 Results demonstrates that Bells palsy is significantly associated

with previous statin use and the adjusted OR of statin use
Among the 1,977 cases and 5,931 controls, the mean age before the index date of diagnosis of Bells palsy is 1.47
was 58.1 11.9 years and 52.4 % were females. After (95 % CI 1.281.69) for cases compared with controls.
matching for age, sex, and index year, there were no sig- This suggests that possible neurotoxicity associated with
nificant differences between cases and controls in terms of statin use may not be limited to the peripheral nervous
monthly income, geographic region, or urbanization level system as previously reported in literature and may instead
(Table 1). However, cases were more likely to have dia- also affect the facial nerve, with an increasing incidence of
betes (24.2 vs. 15.2 %), hypertension (35.8 vs. 29.2 %), developing Bells palsy [14].
and hyperlipidemia (28.8 vs. 24.0 %) than the controls. The earliest study regarding statin use and peripheral
In terms of the distribution of prior statin use in the neuropathy was published in 1995 by Phan et al. [28], who
7,908-person study sample, 1,431 (18.1 %) were statin reported four cases that developed sensori-motor neurop-
users prior to the index date (Table 2). Chi-square test athy while under treatment with simvastatin and who had
further demonstrated a significant difference in the preva- complete or partial resolution of the clinical abnormalities
lence of prior statin use in cases and controls (23.2 vs. after cessation of treatment. A few years later, Ziajka and
16.4 %, p \ 0.001). Conditional logistic regression ana- Wehmeier [29] reported another case that further demon-
lysis (conditioned on age, sex, and index year) also strated the cross-reactivity of neuropathic processes to
revealed that the OR for prior statin use among cases was different statins. As more evidence emerged from many
1.54 (95 % CI 1.361.74, p \ 0.001) compared with con- subsequent studies, researchers mostly agreed that physi-
trols. After adjusting for diabetes, hypertension, and cians should be alert to the potential risk of peripheral
hyperlipidemia, the OR for prior statin use was 1.47 (95 % neuropathy in patients receiving any of the statins and that
CI 1.281.69) for cases. statins should be considered the cause of peripheral neu-
Tables 3 and 4 present the association of Bells palsy ropathy when other etiologies have been excluded [14].
with statin use stratified by diabetes and hypertension. The It has been proposed that statins interfere with choles-
results all suggested that there was a significant association terol synthesis, thereby altering myelin and nerve mem-
between Bells palsy and statin use regardless of the status brane functions, and preventing mitochondrial respiratory
of diabetes or hypertension. chain enzyme synthesis, which may disturb neuron energy
In terms of the association of Bells palsy with regular/ use [16]. If these proposed mechanisms are correct, then
irregular statin use (Table 5), Bells palsy was statistically the CNS can also be affected in the same way. Interest-
and significantly associated with previous regular statin use ingly, there are some reports regarding certain mental and
(OR: 1.46, 95 % CI 1.281.67) after adjusting for diabetes, depressive symptoms associated with statin use [3032].
hypertension, and hyperlipidemia. However, there was no Symptoms including behavioral alterations, cognitive and
increase in the adjusted OR of irregular statin use for cases memory impairments, sleep disturbance, and sexual dys-
compared with controls (OR: 1.09, 95 % CI 0.821.46). function were reported to be associated with statin treat-
ment [33]. However, involvement of the cranial nerves
after statin use has never been reported.
4 Discussion In a previous study, SSNHL was significantly associated
with previous statin use [19]. The adjusted OR of statin use
To date, this is the first study to report an association before the index date of an SSNHL diagnosis was 1.43
between statin use and Bells palsy. This study (95 % CI 1.231.67) for cases compared with controls.

Table 2 Prevalence, odds ratios, and 95 % confidence intervals for statin use among sampled patients
Variable Patients with Bells palsy Controls Crude OR Adjusted ORa
(n = 1,263) [n (%)] (n = 6,315) [n (%)] (95 % CI) (95 % CI)

Presence of prior statin use

Yes 344 (27.2) 1,344 (21.3) 1.54*** (1.361.74) 1.47*** (1.281.69)
No 919 (72.8) 4,971 (78.7)
The OR was calculated using a conditional logistic regression conditioned on age and sex
CI confidence interval, OR odds ratio
*** p \ 0.001
a
Adjusted for diabetes mellitus, hypertension, and hyperlipidemia
Statin Use and Bells Palsy 739

Table 3 Prevalence, odds

Variable Patients with Bells palsy Controls Crude OR Adjusted ORa
ratios, and 95 % confidence
(n = 1,263) [n (%)] (n = 6,315) [n (%)] (95 % CI) (95 % CI)
intervals for statin use among
sampled patients stratified by With diabetes
diabetes mellitus
Presence of prior statin use
The OR was calculated using a Yes 227 (47.5) 373 (41.3) 1.32* (1.061.66) 1.31* (1.101.57)
conditional logistic regression No 251 (52.5) 531 (58.7)
conditioned on age and sex Without diabetes
CI confidence interval, OR odds Presence of prior statin use
ratio
Yes 231 (15.4) 600 (11.9) 1.36*** (1.151.60) 1.34*** (1.141.55)
* p \ 0.05; *** p \ 0.001
a No 1,268 (84.6) 4,427 (88.1)
Adjusted for hypertension

Table 4 Prevalence, odds

Variable Patients with Bells palsy Controls Crude OR Adjusted ORa
ratios, and 95 % confidence
(n = 1,263) [n (%)] (n = 6,315) [n (%)] (95 % CI) (95 % CI)
intervals for statin use among
sampled patients stratified by With hypertension
hypertension
Presence of prior statin use
Yes 235 (33.2) 479 (27.6) 1.34** (1.111.63) 1.30** (1.081.57)
The OR was calculated using a
conditional logistic regression No 473 (66.8) 1,255 (72.4)
conditioned on age and sex Without hypertension
CI confidence interval, OR odds Presence of prior statin use
ratio Yes 223 (17.6) 494 (11.8) 1.63*** (1.361.94) 1.60*** (1.351.90)
** p \ 0.01; *** p \ 0.001 No 1,046 (82.4) 3,703 (88.2)
a
Adjusted for diabetes mellitus

Table 5 Odds ratios and 95 %

Use of statin Total Patients with Controls
confidence intervals for statin
(N = 7,908) Bells palsy (n = 5,931)
use among patients with Bells
(n = 1,977)
palsy and controls
Regular use of statin (C60 days within 6 months)
The OR was calculated using a
conditional logistic regression Yes [n (%)] 1,172 (14.8) 383 (19.4) 789 (13.3)
conditioned on age and sex Crude OR (95 % CI) 1.57*** (1.371.79) 1.00
CI confidence interval, OR odds Adjusted OR (95 % CI)a 1.46*** (1.281.67) 1.00
ratio Irregular use of statin (\60 days within 6 months)
*** p \ 0.001 Yes [n (%)] 259 (3.3) 75 (3.8) 184 (3.1)
a
Adjusted for diabetes Crude OR (95 % CI) 1.23 (0.941.62) 1.00
mellitus, hypertension, and
Adjusted OR (95 % CI)a 1.09 (0.821.46) 1.00
hyperlipidemia

This implied that the CNS was also susceptible to the certain neuroprotective effects for treating specific neuro-
adverse effects of statins. degenerative diseases such as Parkinsons and Alzheimers
There are several possible mechanisms that can explain disease [35]. While seemingly paradoxical, if Bells palsy
the increased incidence of Bells palsy under regular statin is considered to be a peripheral type of facial nerve dis-
use. First, statins have been reported to induce a distur- order, it is possible that the neuroprotective effect of statins
bance in neurite outgrowth and/or maintenance. Schulz is mostly restricted to neuron bodies but not to nerve
et al. [34] reported that atorvastatin treatment caused a sheaths [36]. This hypothesis is further supported by sev-
profound reduction in neurite length, neurite loss, and, eral studies reporting that statins might negatively impact
ultimately, cell death in undifferentiated and pre-differen- oligodendrocytes and myelin formation [37, 38]. Miron
tiated PC12 cells and in rat primary cortical neurons. et al. [39] even reported that simvastatin inhibited CNS re-
Interestingly, many others reported that statins might have myelination by blocking progenitor differentiation,
740 S.-H. Hung et al.

implying that patients using statins might be more vul- Although Bells palsy was recently reported to be associ-
nerable to demyelination of nerves induced by viral ated with hepatitis B vaccination administration [46],
infections, as seen in Bells palsy. information of previous vaccinations was also unavailable.
Second, statins are commonly reported to have anti- Thus, the impacts of these factors on Bells palsy have not
inflammatory effects such as decreased plasma levels of the been evaluated.
acute-phase inflammatory marker C-reactive protein [15]. Third, like most research that utilizes health insurance
However, there are also reports showing that statins are databases, there is a possibility of a surveillance bias,
capable of stimulating pro-inflammatory responses, which which means that it is possible that patients who used
appears to be undesirable in the pathogenesis of Bells statins visited doctors more often. However, this bias may
palsy [40, 41]. have a limited impact on the conclusions since Bells
Lastly, statins can trigger autoimmunity. Mammen et al. palsy appears to be an acute event easily noticed by
[42] described a novel autoantibody that recognizes *200- affected individuals. Bells palsy is unlikely to have been
and *100-kDa proteins associated with autoimmune diagnosed in a medical visit related to hyperlipidemia and
myopathy and statin use. Two other reports also showed statin use.
that statins induced systemic immune reactions, including Fourth, the dataset used in this study only included the
dermatomyositis, polymyalgia rheumatica, and serum anti- medical claims of 1,000,000 enrollees. In the present study,
neutrophil cytoplasmic antibody-associated systemic vas- controls have been selected to match the cases in terms of
culitis [43, 44]. Although the role of autoimmunity in the age and sex. We do not have enough of a sample popula-
development of Bells palsy remains unclear, it is possible tion to allow us to match each control to case in terms of
that statin-triggered autoimmune reactions may contribute age, sex, and exact index day of the case.
to the development of Bells palsy. Lastly, regular use of statins is difficult to define. To
While evidence might indirectly support the role of establish a more direct, causal relationship, subjects who
statin facial palsy effect, considering the marginal increase had received continuous statin prescriptions for C60 days
in risk, this contribution of statin use might actually not be within 6 months prior to the index date were defined as
causal. As stated previously, Bells palsy is a disease of regular statin users. However, the duration of statin use
multifactorial nature with predisposing conditions includ- sufficient to affect the development of Bells palsy or other
ing viral infections, inflammations, genetic predisposition, related facial nerve neuropathy remains unknown. Fur-
and ischemia of the facial nerve. Therefore, it is difficult to thermore, this study is designed as a case-control study. It
include all the co-morbidities and adjust these covariates. is difficult to obtain reliable information about an indi-
Diabetes was reported to be associated with the severity of viduals exposure duration to statins over time; therefore,
Bells palsy and therefore was adjusted [45]. The CVDs this study did not examine the association between drug
and hyperlipidemia, which are commonly seen in statin duration and Bells palsy.
users, were also adjusted. However, it remained difficult to Nevertheless, this study provides an understanding of
include and adjust factors such as genetic predisposition the adverse effects of statins greater than before. Although
and definite herpes infections based on our health insurance more studies are needed to further clarify the true rela-
databases. tionship between statin use and the development of Bells
This study has several limitations. First, the study was palsy, it can be recommend that physicians be more alert in
performed on the Taiwanese population and it is possible managing patients under regular statin use, as this popular
that the study findings cannot be extended to different therapy may cause more problems than previously thought.
ethnic groups. Second, limited by the data retrieved from
the health insurance database, the actual administered
doses of statins might have been inconsistent among these 5 Conclusions
patients. Moreover, the statin concentrations in patients
plasma were unavailable and there was no information on Our present data suggest the possible relationship between
the severity of or recovery from Bells palsy. Thus, a dose- regular statin use and Bells palsy. Further studies are
dependent relationship cannot be assessed and this may needed to clarify and confirm the significance of our
compromise the significance of the findings. Although we findings.
tried to control for diseases factors such as hypertension
and diabetes, we were not able to control and adjust for the Acknowledgments This study is based, in part, on data from the
severity of these diseases. In addition, the LHID2000 data National Health Insurance Research Database provided by the Bureau
of National Health Insurance, Department of Health, Taiwan and
provides no information on the patients body mass index, managed by the National Health Research Institutes. The interpreta-
race/ethnicity, smoking habits, alcohol consumption, tions and conclusions contained herein do not represent those of the
physical activity, or non-prescription medication use. said agencies.
Statin Use and Bells Palsy 741

Sources of Funding None. 18. Tierney EF, Thurman DJ, Beckles GL, et al. Association of statin
use with peripheral neuropathy in the U.S. population 40 years of
Conflict of interest disclosures Shih-Han Hung, Li-Hsuan Wang, age or older. J Diabetes. 2013;5(2):20715.
Herng-Ching Lin, and Shiu-Dong Chung have no conflicts of interest 19. Chung SD, Chen CH, Hung SH et al. A population-based study
to declare. on the association between statin use and sudden sensorineural
hearing loss. Otolaryngol Head Neck Surg (in press).
20. May M, Klein SR. Differential diagnosis of facial nerve palsy.
Otolaryngol Clin North Am. 1991;24(3):61345.
21. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bell palsy and
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