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Risk of Cataract in Patients Treated With Statins
Raymond G. Schlienger, PhD;
Walter E. Haefeli, MD;
Hershel Jick, MD;
Christoph R. Meier, PhD, MSc
Arch Intern Med. 2001;161:2021-2026.
ABSTRACT
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Background Studies in dogs showed that some hydroxymethylglutaryl coenzyme A reductase
inhibitors (statins) are associated with cataract when administered in excessive
doses. Clinical safety data of statins regarding cataract development in humans
have been of limited value so far.
Objective To determine whether long-term use of statins is associated with an
increased risk of cataract.
Methods We conducted a case-control analysis using data from the United Kingdom–based
General Practice Research Database. The main outcome was a first-time diagnosis
of cataract and/or cataract extraction in patients aged 40 to 79 years. Controls
were matched to cases on age, sex, practice, calendar time, and duration of
medical history in the database. Use of statins, fibrates, or other lipid-lowering
drugs was compared with nonuse of any lipid-lowering drug, stratified by exposure
duration and dose.
Results We identified 7405 cases and 28 327 controls. Long-term use of
statins (eg,  30 prescriptions) was not associated with an increased cataract
risk (adjusted odds ratio [OR], 0.9; 95% confidence interval [CI], 0.5-1.6),
nor was use of fibrates or of other lipid-lowering drugs (adjusted OR, 0.5;
95% CI, 0.3-1.1; and OR, 0.7; 95% CI, 0.1-5.6, respectively). We found evidence
that concomitant use of simvastatin and erythromycin, a potent inhibitor of
simvastatin metabolism, is associated with an increased cataract risk (adjusted
odds ratio, 2.2; 95% confidence interval, 1.2-4.1).
Conclusions Our study provides evidence that long-term use of therapeutic statin
doses does not increase the risk of developing cataract. Concomitant use of
erythromycin and simvastatin may increase the cataract risk.
INTRODUCTION
INHIBITORS OF hydroxymethylglutaryl coenzyme A reductase (statins) are
effective drugs to decrease morbidity and mortality in patients with hypercholesterolemia.1-3 Although the overall
safety profile of the marketed statins has been shown to be favorable in humans,4 concerns have arisen on the basis of long-term animal
studies showing that some statins (eg, simvastatin, fluvastatin) are cataractogenic
when administered at excessive doses.5-6
Although isolated case reports have related the use of simvastatin with
the development of cataract in humans,7 clinical
examination of patients treated with statins has not demonstrated any cataractogenic
risk.8-15
However, most previous studies reporting on statin effects on the human lens
have been of limited value for a variety of reasons.
We conducted a case-control analysis to explore the risk of developing
cataract in patients treated with statins, compared with those treated with
fibrates, other lipid-lowering drugs, or no lipid-lowering drug. In animal
models, a direct relationship between systemic statin exposure (plasma drug
levels) and cataract was demonstrated.5 Therefore,
we hypothesized that increased systemic availability of statins, potentially
resulting from concomitant administration of inhibitors of cytochrome P-450
with statins showing extensive cytochrome P-450 metabolism, may modify the
risk of cataract.
PATIENTS AND METHODS
This study is based on data derived from the General Practice Research
Database (GPRD), which was previously described in detail elsewhere.16-18 Since 1987, more
than 3 million residents in the United Kingdom have been enrolled with selected
general practitioners who have agreed to provide data for research purposes
to the GPRD. The age and sex distribution of the patients enrolled is representative
of the entire United Kingdom population. The general practitioners received
12 months of instruction on the standardized data recording on computer of
anonymous information, which they agreed to supply continuously to academic
researchers. The information recorded includes patient demographics and characteristics
(eg, height, weight, and smoking status), symptoms, medical diagnoses, referrals
to consultants, hospital admissions, and drug prescriptions, including the
specific preparation, route of administration, dose, and number of tablets
for each prescription. On request, hospital discharge and referral letters
are available for review to validate the diagnoses recorded in the computer
record. The GPRD currently encompasses some 30 million person-years of follow-up.
It has been the source for numerous epidemiologic studies in recent years,
including studies on statins19 or cataract20; the accuracy and completeness of GPRD data have
been well documented and validated.17, 21-22
CASES AND CONTROLS
We identified all patients who had a first-time diagnosis of cataract
(International Classification of Diseases, Eighth Revision [ICD-8] codes 374.x) followed by a referral
to a specialist or by a hospitalization because of cataract diagnosis, surgical
cataract extraction (Oxford Medical Information System procedure code 156),
or both, between January 1, 1994, and September 30, 1998. We included case
patients who were 40 to 79 years old at the time of a first-time diagnosis
of cataract (subsequently referred to as index date),
and who had a recorded medical history in the GPRD of at least 3 years before
the index date. Cases were identified in the absence of any exposure information.
From previous experience, we knew that a high percentage of computer-recorded
cataract diagnoses (>95%) in the GPRD are correct and can be validated by
surgery reports and/or documented ophthalmologic assessments.20
Patients with ophthalmologic disorders defined as cataract (ICD-8 code 374.x), corneal opacities (ICD-8
code 371.x), uveitis (ICD-8 code 366.x), eye inflammation
(ICD-8 code 369.x), glaucoma (ICD-8 code 375.x), retina detachment (ICD-8
code 376.x), retinal diseases (ICD-8 code 377.x),
or uveal disease (ICD-8 code 378.x) before the index
date were excluded. Furthermore, we excluded all patients with a history of
diabetes (ICD-8 code 250.x), because diabetic patients
have a high prevalence of various eye diseases and are therefore more likely
than other patients to have ophthalmologic examinations on a regular basis.23
To each case patient we randomly identified and matched 4 control patients
from the base population on age (±2 years), sex, practice, calendar
time (by using the same index date), and number of years of recorded medical
history in the GPRD before the index date. The same exclusion criteria were
applied to control as to case patients.
For each case and control patient, we assessed the exposure history
for lipid-lowering drugs from the computerized patient profile. Patients were
categorized as users of (1) statins (ie, atorvastatin calcium, cerivastatin
sodium, fluvastatin sodium, pravastatin sodium, or simvastatin [lovastatin
was not included in our analysis because it was not available in the United
Kingdom]), (2) fibrates (ie, bezafibrate, ciprofibrate, clofibrate, fenofibrate,
or gemfibrozil), (3) users of other lipid-lowering drugs (ie, acipimox, cholestyramine
resin, or colestipol hydrochloride), or (4) "mixed users" (ie, patients who
switched between different lipid-lowering drug classes or concomitant users
of 2 or more lipid-lowering drug classes). Patients with a history of lipid-lowering
drug therapy were further characterized according to the number of prescriptions
for lipid-lowering drugs before the index date (ie, 1-9, 10-19, 20-29, or 30
prescriptions). We further assessed a cumulative dose based on the number
of prescriptions, number of doses per prescription, and dose per tablet.
We also explored relative risk estimates of statin use when given concomitantly
with erythromycin, clarithromycin, verapamil hydrochloride, cyclosporine,
fluconazole, ketoconazole, or itraconazole, drugs known to significantly increase
simvastatin availability to the systemic circulation.24-26
ANALYSIS
We conducted a matched analysis (conditional logistic regression) to
explore the association between type of exposure (statins, fibrates, other
lipid-lowering drugs, or none), exposure duration or cumulative dose, and
the risk of developing cataract. In addition to controlling for age, sex,
practice attended, and calendar time (by matching), we controlled the analysis
for the potential confounders smoking status, body mass index, exposure to
corticosteroids, and number of general practitioner visits before the index
date (as a marker for the degree of medical attention).
All analyses were performed with the statistical software SAS, version
6.12 (SAS Institute Inc, Cary, NC). Odds ratios (ORs) are presented with 95%
confidence intervals (CIs); P values are 2-tailed.
RESULTS
We included 7405 case patients and 28 327 matched control patients
in the analysis. The distributions of age, sex, body mass index, smoking status,
use of corticosteroids, and number of practice visits preceding the index
date of case and control patients are shown in Table 1. In the case group, 3445 patients (46.5%) had a diagnosis
of cataract only; the remaining 3960 had cataract removal. The mean recorded
medical history in the database before the index date was 6.2 years in both
the case and control groups.
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Table 1. Characteristics of Case and Control Patients in Relation to
Risk of Developing Cataract in Univariate Analyses*
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Within the case population, we identified 111 patients who were using
statins (simvastatin, 72%; pravastatin, 18%; other, 10%). The relative risk
estimates (ORs) of having a first-time diagnosis of cataract and/or cataract
removal in relation to lipid-lowering drug use adjusted for smoking, body
mass index, corticosteroid use, and number of practice visits are shown in Table 2. Overall, long-term use of statins
(eg, 30 prescriptions) was not associated with an increased risk of cataract,
yielding an adjusted risk estimate (OR) of 0.9 (95% CI, 0.5-1.6) in comparison
with nonusers of lipid-lowering drugs; the adjusted ORs for fibrates and other
lipid-lowering drugs were 0.5 (95% CI, 0.3-1.1) and 0.7 (95% CI, 0.1-5.6),
respectively. Stratification of drug use into current (ie, 1 prescription
for any lipid-lowering drug  1 year before the index date) or past (ie,
last prescription for any lipid-lowering drug >1 year before the index date)
did not modify the risk of developing cataract.
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Table 2. Exposure to Lipid-Lowering Drugs and Risk of Developing Cataracts*
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Since there was no material evidence that use of fibrates or of other
lipid-lowering drugs was associated with an altered risk of developing cataract,
we combined users of these drugs with nonusers of any lipid-lowering drug
into one reference group for further analyses. Patients in the mixed group
who had exposure to statins were categorized as statin users. As compared
with nonuse of statins, the longest duration of statin exposure (ie, use of
statins with 30 prescriptions) yielded an adjusted OR of 1.0 (95% CI,
0.6-1.5). No evidence of effect modification was found when we stratified
by age (40-59 vs 60-79 years), sex, and diagnosis (cataract only vs cataract
removal). We further assessed the total cumulative doses of simvastatin and
pravastatin, the 2 statins most often prescribed in our study population,
and found no evidence of an elevated risk in relation to increasing cumulative
doses.
In the analysis of potential risk modification by coadministration of
cytochrome P-450–inhibiting drugs, we found some evidence that concomitant
use of erythromycin with statins may be associated with an increased risk
of cataract (OR, 2.2; 95% CI, 1.2-4.1; adjusted for body mass index and smoking);
this association was slightly diminished by further adjusting for corticosteroid
use and number of general practitioner visits (Table 3). For subjects with 2 or more concomitant courses of erythromycin,
the OR was 3.3 (95% CI, 1.0-10.9); in this stratum, all but 1 patient were
simvastatin users (1 used fluvastatin). To exclude the possibility of observing
an erythromycin effect, we also analyzed the risk of developing cataract in
association with use of erythromycin in the absence of statin exposure. As
compared with nonusers of erythromycin, the relative risk estimate for subjects
who received 4 or more erythromycin courses before the index date was 1.1
(95% CI, 0.9-1.3).
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Table 3. Exposure to Statins and Concomitant Use of Drugs Known to
Inhibit Simvastatin Metabolism* and Risk of Developing Cataract
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The use of other drugs known to inhibit the metabolism of certain statins
did not modify the risk of cataract, or the numbers of subjects in substrata
were too small to yield informative results.
We also found an association between use of inhaled corticosteroids
and cataract development. Users of 30 or more prescriptions of inhaled corticosteroids
only (ie, without exposure to oral corticosteroids) had a relative risk estimate
of 1.2 (95% CI, 1.0-1.6; adjusted for body mass index, smoking, number of
general practitioner visits, and use of statins). Users of 30 or more prescriptions
of oral corticosteroids only (ie, without exposure to inhaled corticosteroids)
had a relative risk estimate of 1.8 (95% CI, 1.4-2.3; adjusted for body mass
index, smoking, number of general practitioner visits, and use of statins).
COMMENT
Long-term administration of simvastatin and other statins (eg, lovastatin
and fluvastatin) has been associated with cataract development in dogs,5-6 while atorvastatin and pravastatin
lacked a cataractogenic effect in dogs.27-28
Data from observational and clinical studies did not show an increased cataract
risk associated with use of statins in humans so far.8, 13-15,29
However, most previous studies reporting on statin effects on the human lens
have been of limited value for a variety of reasons, such as absence of a
control group, small numbers of patients involved, short duration of treatment,
and/or the deficiencies of the ophthalmic assessments conducted.
This large case-control analysis provides evidence that therapy with
statins at therapeutic doses is not associated with an increased risk of cataract
development in humans. However, since the majority of patients analyzed in
this study were exposed to statin doses at the lower therapeutic range (eg,
20 mg of simvastatin per day), we do not know whether our finding is also
true for patients exposed to high therapeutic statin doses. The exact mechanism
of statin-induced cataract in animals is unclear. In animals, no relationship
could be established between decrease in circulating cholesterol levels at
pharmacologically equipotent statin doses and the incidence of lenticular
opacities, but a direct relationship between plasma statin levels and cataract
incidence was observed. Statins producing high circulating plasma levels were
associated with a higher incidence of cataract formation.5
The currently approved maximal simvastatin dose for use in patients with hyperlipidemia
(40 mg per day) produces plasma levels approximately 14 times lower than the
minimally cataractogenic dose in dogs (50 mg/kg per day) and is approximately
5 times lower than the noncataractogenic dose in dogs (10 mg/kg per day).30 Since a dose-dependent effect has been established
for statins with proved cataractogenic potential,30
we hypothesized that while long-term administration of therapeutic statin
doses may not increase the risk of cataract, concomitant administration of
drugs that significantly increase the systemic availability of statins might
modify the cataract risk in association with statin therapy. Human in vivo
and in vitro data have shown that statins, with the exception of pravastatin,31 are substrates of the cytochrome P-450 system (CYP450),4 especially CYP3A4 (ie, atorvastatin, cerivastatin,
lovastatin, and simvastatin)31-33
or CYP2C9 (ie, fluvastatin).33 Drug interaction
studies have shown that concomitant administration of CYP3A4 inhibitors with
simvastatin is associated with elevated systemic availability with the potential
to increase the risk of serious adverse effects of statins, such as myopathy
and rhabdomyolysis.4, 34 Among
the substances that have been shown to lead to a 5-fold to 10-fold increase
in systemic availability or peak concentrations of simvastatin are erythromycin,24 itraconazole,25 ketoconazole,35 verapamil,24 and cyclosporine.34 The enzymes responsible for the biotransformation
of pravastatin are less well known,36 but CYP3A4
contributes only negligibly to its metabolic fate, if at all.37
Our analysis indicates that concomitant exposure to erythromycin with
statins (which was almost exclusively exposure to simvastatin) may be associated
with an approximately 2-fold to 3-fold increased risk of developing cataract
in comparison with nonusers of statins. An additional analysis provided evidence
that the relative risk of developing cataract was not increased for subjects
who repeatedly used erythromycin, but not statins, suggesting that the elevated
relative risk estimate was seen only in subjects using both simvastatin and
erythromycin concomitantly. Because of relatively small numbers in these cells,
however, these results need to be interpreted cautiously. Additional results
such as increased cataract risk associated with smoking or exposure to oral
or inhaled corticosteroids are in agreement with previous findings.23, 38-39
As with observational studies in general, we cannot rule out unknown
biases or confounders as possible alternative causes for our findings. However,
our results were adjusted for age, sex, geography, and calendar time (by matching
cases to controls) as well as for smoking status, body mass index, corticosteroid
use, and degree of medical attention (by adjusting the multivariate analysis),
and substantial distortions by these potential confounders seem unlikely.
A potential difficulty of this observational study is that cataract is a disease
of slow onset; thus, the index date is relatively poorly defined. This can
potentially lead to a certain exposure misclassification, ie, exposure before
the index date is taken into account in the analysis even though use of study
drugs occurred after the real onset of the disease. To reduce the risk of
getting distorted results, we did an additional analysis in which we did not
take any exposure to lipid-lowering drugs into account that occurred in the
year immediately preceding the index date. This assessment did not yield different
results.
In conclusion, the present large case-control analysis provides further
evidence that therapy with statins at therapeutic doses is not associated
with an increased risk of cataract development. However, we cannot extrapolate
our findings to those beyond the observed period of exposure. It has been
suggested that the ocular safety of statins can be established only in light
of 10 to 20 years of clinical experience.40
We found evidence that concomitant administration of simvastatin and erythromycin,
a drug known to significantly increase simvastatin bioavailability, may be
associated with an increased risk of developing cataract, similar to the well-documented
interaction of certain statins with cytochrome P-450 inhibitors leading to
myopathy.4 This potentially important finding
needs to be explored further.
AUTHOR INFORMATION
Accepted for publication December 5, 2000.
Dr Meier is the recipient of grant 32-056 751 from the Swiss National
Science Foundation, Berne, Switzerland. Research projects on drug-drug interactions
of the Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology,
University Hospital of Heidelberg, Heidelberg, Germany, are supported by BMBF
grant 01EC9902 from the Federal Ministry for Education and Research in Bonn,
Germany.
The Boston Collaborative Drug Surveillance Program is partly supported
by grants from AstraZeneca, Sodertalje, Sweden; Bayer AG, Leverkusen, Germany;
Berlex Laboratories, Wayne, NJ; Boots Healthcare International, Nottingham,
England; Bristol-Myers Squibb, Princeton, NJ; GlaxoWellcome Inc, Research
Triangle Park, NC; RW Johnson Pharmaceutical Research Institute, Raritan,
NJ; McNeil Consumer Products, Fort Washington, Pa; and Hoffman-La Roche and
Novartis Pharmaceuticals, Basel, Switzerland. This study was not directly
funded by any of these companies.
Presented in part at the 16th International Conference on Pharmacoepidemiology
of the International Society for Pharmacoepidemiology, Barcelona, Spain, August
21, 2000.
We thank the participating general practitioners for their excellent
cooperation.
Corresponding author and reprints: Christoph R. Meier, PhD, MSc,
Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacology, University
Hospital of Basel, Petersgraben 4, CH-4031 Basel, Switzerland (e-mail: Christoph.Meier{at}unibas.ch).
From the Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacology,
Department of Internal Medicine, University Hospital of Basel, Basel, Switzerland
(Drs Schlienger and Meier); Institute of Clinical Pharmacy, Department of
Pharmacy, University of Basel (Dr Schlienger); Department of Internal Medicine
VI, Clinical Pharmacology and Pharmacoepidemiology, University Hospital of
Heidelberg, Heidelberg, Germany (Dr Haefeli); and Boston Collaborative Drug
Surveillance Program, Boston University, School of Medicine, Lexington, Mass
(Drs Jick and Meier).
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Discordant expression of the sterol pathway in lens underlies simvastatin-induced cataracts in Chbb: Thom rats
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J. Lipid Res. 2003;44:198-211.
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