Risk of Cataract in Patients Treated with Statins
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ORIGINAL INVESTIGATION Risk of Cataract in Patients Treated With Statins Raymond G. Schlienger, PhD; Walter E. Haefeli, MD; Hershel Jick, MD; Christoph R. Meier, PhD, MSc Background: Studies in dogs showed that some hy- Results: We identified 7405 cases and 28327 controls. droxymethylglutaryl coenzyme A reductase inhibitors Long-term use of statins (eg, $30 prescriptions) was not (statins) are associated with cataract when adminis- associated with an increased cataract risk (adjusted odds tered in excessive doses. Clinical safety data of statins re- ratio [OR], 0.9; 95% confidence interval [CI], 0.5-1.6), garding cataract development in humans have been of nor was use of fibrates or of other lipid-lowering drugs limited value so far. (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 concomi- Objective: To determine whether long-term use of stat- tant use of simvastatin and erythromycin, a potent in- ins is associated with an increased risk of cataract. hibitor of simvastatin metabolism, is associated with an increased cataract risk (adjusted odds ratio, 2.2; 95% con- Methods: We conducted a case-control analysis using data fidence interval, 1.2-4.1). from the United Kingdom–based General Practice Re- search Database. The main outcome was a first-time diag- Conclusions: Our study provides evidence that long- nosis of cataract and/or cataract extraction in patients aged term use of therapeutic statin doses does not increase the 40 to 79 years. Controls were matched to cases on age, sex, risk of developing cataract. Concomitant use of eryth- practice, calendar time, and duration of medical history in romycin and simvastatin may increase the cataract risk. 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. Arch Intern Med. 2001;161:2021-2026 NHIBITORS OF hydroxymethylglu- other lipid-lowering drugs, or no lipid- taryl coenzyme A reductase (stat- lowering drug. In animal models, a direct ins) are effective drugs to de- relationship between systemic statin ex- crease morbidity and mortality in posure (plasma drug levels) and cataract patients with hypercholesterol- was demonstrated.5 Therefore, we hypoth- From the Basel Iemia.1-3 Although the overall safety pro- esized that increased systemic availabil- Pharmacoepidemiology Unit, file of the marketed statins has been shown ity of statins, potentially resulting from Division of Clinical to be favorable in humans,4 concerns have concomitant administration of inhibitors Pharmacology, Department of arisen on the basis of long-term animal of cytochrome P-450 with statins show- Internal Medicine, University studies showing that some statins (eg, sim- ing extensive cytochrome P-450 metabo- Hospital of Basel, Basel, vastatin, fluvastatin) are cataractogenic lism, may modify the risk of cataract. Switzerland (Drs Schlienger 5,6 and Meier); Institute of Clinical when administered at excessive doses. Pharmacy, Department of Although isolated case reports have RESULTS Pharmacy, University of Basel related the use of simvastatin with the de- (Dr Schlienger); Department of velopment of cataract in humans,7 clini- We included 7405 case patients and 28327 Internal Medicine VI, Clinical cal examination of patients treated with matched control patients in the analysis. Pharmacology and statins has not demonstrated any catarac- The distributions of age, sex, body mass Pharmacoepidemiology, togenic risk.8-15 However, most previous index, smoking status, use of corticoste- University Hospital of studies reporting on statin effects on the roids, and number of practice visits pre- Heidelberg, Heidelberg, human lens have been of limited value for ceding the index date of case and control Germany (Dr Haefeli); and Table 1 Boston Collaborative Drug a variety of reasons. patients are shown in . In the case Surveillance Program, Boston We conducted a case-control analy- group, 3445 patients (46.5%) had a di- University, School of Medicine, sis to explore the risk of developing cata- agnosis of cataract only; the remaining Lexington, Mass ract in patients treated with statins, com- 3960 had cataract removal. The mean re- (Drs Jick and Meier). pared with those treated with fibrates, corded medical history in the database be- (REPRINTED) ARCH INTERN MED/ VOL 161, SEP 10, 2001 WWW.ARCHINTERNMED.COM 2021 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 PATIENTS AND METHODS 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 This study is based on data derived from the General Prac- patients to have ophthalmologic examinations on a regular tice Research Database (GPRD), which was previously de- basis.23 scribed in detail elsewhere.16-18 Since 1987, more than 3 mil- To each case patient we randomly identified and lion residents in the United Kingdom have been enrolled matched 4 control patients from the base population on age with selected general practitioners who have agreed to pro- (±2 years), sex, practice, calendar time (by using the same vide data for research purposes to the GPRD. The age and index date), and number of years of recorded medical his- sex distribution of the patients enrolled is representative tory in the GPRD before the index date. The same exclu- of the entire United Kingdom population. The general prac- sion criteria were applied to control as to case patients. titioners received 12 months of instruction on the stan- For each case and control patient, we assessed the ex- dardized data recording on computer of anonymous infor- posure history for lipid-lowering drugs from the comput- mation, which they agreed to supply continuously to erized patient profile. Patients were categorized as users of academic researchers. The information recorded includes (1) statins (ie, atorvastatin calcium, cerivastatin sodium, patient demographics and characteristics (eg, height, weight, fluvastatin sodium, pravastatin sodium, or simvastatin [lo- and smoking status), symptoms, medical diagnoses, re- vastatin was not included in our analysis because it was not ferrals to consultants, hospital admissions, and drug available in the United Kingdom]), (2) fibrates (ie, beza- prescriptions, including the specific preparation, route of fibrate, ciprofibrate, clofibrate, fenofibrate, or gemfibro- administration, dose, and number of tablets for each pre- zil), (3) users of other lipid-lowering drugs (ie, acipimox, scription. On request, hospital discharge and referral cholestyramine resin, or colestipol hydrochloride), or (4) letters are available for review to validate the diagnoses re- “mixed users” (ie, patients who switched between differ- corded in the computer record. The GPRD currently en- ent lipid-lowering drug classes or concomitant users of 2 compasses some 30 million person-years of follow-up. It or more lipid-lowering drug classes). Patients with a has been the source for numerous epidemiologic studies history of lipid-lowering drug therapy were further char- in recent years, including studies on statins19 or cataract20; acterized according to the number of prescriptions for the accuracy and completeness of GPRD data have been lipid-lowering drugs before the index date (ie, 1-9, 10-19, well documented and validated.17,21,22 20-29, or $30 prescriptions). We further assessed a cu- mulative dose based on the number of prescriptions, num- CASES AND CONTROLS ber of doses per prescription, and dose per tablet. We also explored relative risk estimates of statin use We identified all patients who had a first-time diagnosis of when given concomitantly with erythromycin, clarithro- cataract (International Classification of Diseases, Eighth Revi- mycin, verapamil hydrochloride, cyclosporine, flucona- sion [ICD-8] codes 374.x) followed by a referral to a special- zole, ketoconazole, or itraconazole, drugs known to sig- ist or by a hospitalization because of cataract diagnosis, sur- nificantly increase simvastatin availability to the systemic gical cataract extraction (Oxford Medical Information System circulation.24-26 procedure code 156), or both, between January 1, 1994, and September 30, 1998. We included case patients who were 40 ANALYSIS to 79 years old at the time of a first-time diagnosis of cata- ract (subsequently referred to as index date), and who had a We conducted a matched analysis (conditional logistic recorded medical history in the GPRD of at least 3 years be- regression) to explore the association between type of fore the index date. Cases were identified in the absence of exposure (statins, fibrates, other lipid-lowering drugs, or any exposure information. From previous experience, we none), exposure duration or cumulative dose, and the risk knew that a high percentage of computer-recorded cataract of developing cataract. In addition to controlling for age, diagnoses (.95%) in the GPRD are correct and can be vali- sex, practice attended, and calendar time (by matching), dated by surgery reports and/or documented ophthal- we controlled the analysis for the potential confounders mologic assessments.20 Patients with ophthalmologic smoking status, body mass index, exposure to corticoste- disorders defined as cataract (ICD-8 code 374.x), corneal roids, and number of general practitioner visits before the opacities (ICD-8 code 371.x), uveitis (ICD-8 code 366.x), eye index date (as a marker for the degree of medical attention). inflammation (ICD-8 code 369.x), glaucoma (ICD-8 code All analyses were performed with the statistical soft- 375.x), retina detachment (ICD-8 code 376.x), retinal dis- ware SAS, version 6.12 (SAS Institute Inc, Cary, NC). Odds eases (ICD-8 code 377.x), or uveal disease (ICD-8 code 378.x) ratios (ORs) are presented with 95% confidence intervals before the index date were excluded. Furthermore, we (CIs); P values are 2-tailed. fore the index date was 6.2 years in both the case and all, long-term use of statins (eg, $30 prescriptions) was control groups.