Risk of Cataract in Patients Treated with Statins

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, Ն30 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 emia.I1-3 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-

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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 Ն30 prescriptions). We further assessed a cumulative 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 cataract (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 (Ͼ95%) 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, Ն30 prescriptions) was control groups. not associated with an increased risk of cataract, yield- Within the case population, we identified 111 pa- ing an adjusted risk estimate (OR) of 0.9 (95% CI, 0.5- tients who were using statins (simvastatin, 72%; prava- 1.6) in comparison with nonusers of lipid-lowering drugs; statin, 18%; other, 10%). The relative risk estimates (ORs) the adjusted ORs for fibrates and other lipid-lowering of having a first-time diagnosis of cataract and/or cata- drugs were 0.5 (95% CI, 0.3-1.1) and 0.7 (95% CI, 0.1- ract removal in relation to lipid-lowering drug use ad- 5.6), respectively. Stratification of drug use into current justed for smoking, body mass index, corticosteroid use, (ie, Ն1 prescription for any lipid-lowering drug Յ1 year and number of practice visits are shown in Table 2. Over- before the index date) or past (ie, last prescription for

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 1. Characteristics of Case and Control Patients in Relation to Risk of Developing Cataract in Univariate Analyses*

No. (%)

Cataract Group Control Group Odds Ratio Characteristics (n = 7405) (n = 28 327) (95% CI) P Age, y 40-49 258 (3.5) 1037 (3.7) NA NA 50-59 671 (9.0) 2611 (9.2) NA NA 60-69 1931 (26.1) 7561 (26.7) NA NA 70-79 4545 (61.4) 17 118 (60.4) NA NA Sex F 4503 (60.8) 17 340 (61.2) NA NA M 2902 (39.2) 10 987 (38.8) NA NA Smoking status Nonsmoker 4007 (54.1) 15 667 (55.3) 1.0 (Reference group) NA Current smoker 1252 (16.9) 4296 (15.2) 1.1 (1.1-1.2) Ͻ.001 Ex-smoker 954 (12.9) 3372 (11.9) 1.1 (1.0-1.2) .004 Unknown 1192 (16.1) 4992 (17.6) 0.9 (0.9-1.0) .06 Body mass index, kg/m2† Ͻ25.0 2321 (31.3) 8517 (30.1) 1.0 (Reference group) NA 25.0-29.9 2061 (27.8) 7945 (28.0) 1.0 (0.9-1.0) .26 Ն30 843 (11.4) 3221 (11.4) 1.0 (0.9-1.1) .45 Unknown 2180 (29.4) 8644 (30.5) 0.9 (0.9-1.0) .06 Hyperlipidemia No 7079 (95.6) 27 116 (95.7) 1.0 (Reference group) NA Yes 326 (4.4) 1211 (4.3) 1.0 (0.9-1.2) .46 Hypertension No 5327 (71.9) 20 117 (71.0) 1.0 (Reference group) NA Yes 2078 (28.1) 8210 (29.0) 1.0 (0.9-1.0) .17 Corticosteroid use None 4884 (66.0) 20 551 (72.5) 1.0 (Reference group) NA Oral (No. of prescriptions) 1-9 655 (8.8) 2343 (8.3) 1.2 (1.1-1.3) Ͻ.001 10-19 51 (0.7) 151 (0.5) 1.4 (1.0-2.0) .03 20-29 36 (0.5) 75 (0.3) 1.9 (1.3-2.9) .002 Ն30 86 (1.2) 191 (0.7) 2.0 (1.5-2.6) Ͻ.001 Inhaled (No. of prescriptions) 1-9 525 (7.1) 2026 (7.2) 1.1 (1.0-1.2) .05 10-19 80 (1.1) 358 (1.3) 1.0 (0.8-1.2) .85 20-29 41 (0.6) 179 (0.6) 1.0 (0.7-1.4) .97 Ն30 91 (1.2) 289 (1.0) 1.3 (1.0-1.7) .03 Mixed 956 (12.9) 2164 (7.6) 1.9 (1.8-2.1) Ͻ.001 No. of general practitioner visits before index date Ͻ5 3058 (41.3) 13 644 (48.2) 1.0 (Reference group) NA 5-9 2221 (30.0) 8297 (29.3) 1.2 (1.2-1.3) Ͻ.001 10-29 1988 (26.8) 6108 (21.6) 1.5 (1.4-1.6) Ͻ.001 30-59 132 (1.8) 270 (1.0) 2.4 (1.9-3.0) Ͻ.001 Ն60 6 (0.1) 8 (0.0) 3.8 (1.3-10.9) .01

*CI indicates confidence interval; NA, not applicable. †Calculated as weight in kilograms divided by the square of height in meters.

any lipid-lowering drug Ͼ1 year before the index date) vs cataract removal). We further assessed the total cu- did not modify the risk of developing cataract. mulative doses of simvastatin and pravastatin, the 2 stat- Since there was no material evidence that use of fi- ins most often prescribed in our study population, and brates or of other lipid-lowering drugs was associated with found no evidence of an elevated risk in relation to in- an altered risk of developing cataract, we combined us- creasing cumulative doses. ers of these drugs with nonusers of any lipid-lowering In the analysis of potential risk modification by coad- drug into one reference group for further analyses. Pa- ministration of cytochrome P-450–inhibiting drugs, we tients in the mixed group who had exposure to statins found some evidence that concomitant use of erythromy- were categorized as statin users. As compared with non- cin with statins may be associated with an increased risk use of statins, the longest duration of statin exposure (ie, of cataract (OR, 2.2; 95% CI, 1.2-4.1; adjusted for body use of statins with Ն30 prescriptions) yielded an ad- mass index and smoking); this association was slightly di- justed OR of 1.0 (95% CI, 0.6-1.5). No evidence of ef- minished by further adjusting for corticosteroid use and fect modification was found when we stratified by age number of general practitioner visits (Table 3). For sub- (40-59 vs 60-79 years), sex, and diagnosis (cataract only jects with 2 or more concomitant courses of erythromy-

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 2. Exposure to Lipid-Lowering Drugs and Risk of Developing Cataracts*

No. of Patients

Cataract Group Control Group Adjusted OR† Exposure (n = 7405) (n = 28 327) (95% CI) P No lipid-lowering drug 7187 27 496 1.0 (Reference group) NA Use of statins only, No. of prescriptions 1-9 58 211 1.0 (0.8-1.4) .87 10-19 28 91 1.2 (0.8-1.9) .38 20-29 10 46 0.9 (0.4-1.7) .70 Ն30 15 61 0.9 (0.5-1.6) .76 Use of fibrates only, No. of prescriptions 1-9 13 79 0.5 (0.2-1.3) .15 10-19 9 38 0.9 (0.4-2.1) .89 20-29 13 39 1.0 (0.5-2.0) .42 Ն30 11 78 0.5 (0.3-1.1) .06 Use of other lipid-lowering drugs only, No. of prescriptions 1-9 11 28 1.5 (0.7-3.0) .26 10-19 1 4 1.0 (0.1-8.9) .99 20-29 0 4 NA NA Ն30 1 6 0.7 (0.1-5.6) .71 Mixed 48 146 1.3 (0.9-1.8) .11

*OR indicates odds ratio; CI, confidence interval; and NA, not applicable. †Adjusted for body mass index, smoking, number of general practitioner visits, and corticosteroid use.

cin, the OR was 3.3 (95% CI, 1.0-10.9); in this stratum, in humans so far.8,13-15,29 However, most previous stud- all but 1 patient were simvastatin users (1 used fluvastatin). ies reporting on statin effects on the human lens have been To exclude the possibility of observing an erythromycin of limited value for a variety of reasons, such as absence effect, we also analyzed the risk of developing cataract in of a control group, small numbers of patients involved, association with use of erythromycin in the absence of statin short duration of treatment, and/or the deficiencies of the exposure. As compared with nonusers of erythromycin, ophthalmic assessments conducted. the relative risk estimate for subjects who received 4 or This large case-control analysis provides evidence more erythromycin courses before the index date was 1.1 that therapy with statins at therapeutic doses is not as- (95% CI, 0.9-1.3). sociated with an increased risk of cataract development The use of other drugs known to inhibit the me- in humans. However, since the majority of patients ana- tabolism of certain statins did not modify the risk of cata- lyzed in this study were exposed to statin doses at the ract, or the numbers of subjects in substrata were too small lower therapeutic range (eg, 20 mg of simvastatin per day), to yield informative results. we do not know whether our finding is also true for pa- We also found an association between use of in- tients exposed to high therapeutic statin doses. The ex- haled corticosteroids and cataract development. Users of act mechanism of statin-induced cataract in animals is 30 or more prescriptions of inhaled corticosteroids only unclear. In animals, no relationship could be estab- (ie, without exposure to oral corticosteroids) had a rela- lished between decrease in circulating cholesterol levels tive risk estimate of 1.2 (95% CI, 1.0-1.6; adjusted for at pharmacologically equipotent statin doses and the in- body mass index, smoking, number of general practi- cidence of lenticular opacities, but a direct relationship tioner visits, and use of statins). Users of 30 or more pre- between plasma statin levels and cataract incidence was scriptions of oral corticosteroids only (ie, without expo- observed. Statins producing high circulating plasma lev- sure to inhaled corticosteroids) had a relative risk estimate els were associated with a higher incidence of cataract of 1.8 (95% CI, 1.4-2.3; adjusted for body mass index, formation.5 The currently approved maximal simvasta- smoking, number of general practitioner visits, and use tin dose for use in patients with hyperlipidemia (40 mg of statins). per day) produces plasma levels approximately 14 times lower than the minimally cataractogenic dose in dogs (50 COMMENT mg/kg per day) and is approximately 5 times lower than the noncataractogenic dose in dogs (10 mg/kg per day).30 Long-term administration of simvastatin and other stat- Since a dose-dependent effect has been established for ins (eg, lovastatin and fluvastatin) has been associated statins with proved cataractogenic potential,30 we hy- with cataract development in dogs,5,6 while atorvastatin pothesized that while long-term administration of thera- and pravastatin lacked a cataractogenic effect in dogs.27,28 peutic statin doses may not increase the risk of cataract, Data from observational and clinical studies did not show concomitant administration of drugs that significantly in- an increased cataract risk associated with use of statins crease the systemic availability of statins might modify

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 3. Exposure to Statins and Concomitant Use of Drugs Known to Inhibit Simvastatin Metabolism* and Risk of Developing Cataract†

No. of Patients

Cataract Group Control Group Adjusted OR‡ Adjusted OR§ Exposure (n = 7405) (n = 28 327) (95% CI) P (95% CI) P None 7252 27 785 1.0 (Reference group) NA 1.0 (Reference group) NA Use of statins without concomitant exposure 129 488 1.0 (0.8-1.2) .84 1.0 (0.8-1.2) .88 to interacting drugs Use of statins and concomitant therapy with erythromycin 16 27 2.2 (1.2-4.1) .01 1.8 (1.0-3.5) .06 1 Concomitant course of erythromycin 11 21 1.8 (0.9-4.0) .10 1.6 (0.8-3.5) .22 Ն2 Concomitant courses of erythromycin 5 6 3.3 (1.0-10.9) .05 2.6 (0.8-8.5) .13 Use of statins and verapamil 4 11 1.4 (0.5-4.5) .54 1.3 (0.4-4.1) .65 Use of statins and other inhibitor࿣ 4 16 1.0 (0.3-3.0) .98 0.7 (0.2-2.3) .61

*Erythromycin, verapamil, cyclosporine, itraconazole, and ketoconazole. †OR indicates odds ratio; CI, confidence interval; and NA, not applicable. ‡Adjusted for body mass index and smoking. §Adjusted for body mass index, smoking, number of general practitioner visits, and corticosteroid use. ࿣Cyclosporine, itraconazole, ketoconazole, fluconazole, or clarithromycin.

the cataract risk in association with statin therapy. Hu- founders seem unlikely. A potential difficulty of this ob- man in vivo and in vitro data have shown that statins, servational study is that cataract is a disease of slow onset; with the exception of pravastatin,31 are substrates of the thus, the index date is relatively poorly defined. This can cytochrome P-450 system (CYP450),4 especially CYP3A4 potentially lead to a certain exposure misclassification, (ie, atorvastatin, cerivastatin, lovastatin, and simvastatin) ie, exposure before the index date is taken into account 31-33 or CYP2C9 (ie, fluvastatin).33 Drug interaction stud- in the analysis even though use of study drugs occurred ies have shown that concomitant administration of after the real onset of the disease. To reduce the risk of CYP3A4 inhibitors with simvastatin is associated with getting distorted results, we did an additional analysis in elevated systemic availability with the potential to in- which we did not take any exposure to lipid-lowering crease the risk of serious adverse effects of statins, such drugs into account that occurred in the year immedi- as myopathy and rhabdomyolysis.4,34 Among the sub- ately preceding the index date. This assessment did not stances that have been shown to lead to a 5-fold to 10- yield different results. fold increase in systemic availability or peak concentra- In conclusion, the present large case-control analy- tions of simvastatin are erythromycin,24 itraconazole,25 sis provides further evidence that therapy with statins at ketoconazole,35 verapamil,24 and cyclosporine.34 The en- therapeutic doses is not associated with an increased risk zymes responsible for the biotransformation of prava- of cataract development. However, we cannot extrapo- statin are less well known,36 but CYP3A4 contributes only late our findings to those beyond the observed period of negligibly to its metabolic fate, if at all.37 exposure. It has been suggested that the ocular safety of Our analysis indicates that concomitant exposure statins can be established only in light of 10 to 20 years to erythromycin with statins (which was almost exclu- of clinical experience.40 We found evidence that con- sively exposure to simvastatin) may be associated with comitant administration of simvastatin and erythromy- an approximately 2-fold to 3-fold increased risk of de- cin, a drug known to significantly increase simvastatin veloping cataract in comparison with nonusers of stat- bioavailability, may be associated with an increased risk ins. An additional analysis provided evidence that the rela- of developing cataract, similar to the well-documented tive risk of developing cataract was not increased for interaction of certain statins with cytochrome P-450 in- subjects who repeatedly used erythromycin, but not stat- hibitors leading to myopathy.4 This potentially impor- ins, suggesting that the elevated relative risk estimate was tant finding needs to be explored further. seen only in subjects using both simvastatin and erythromycin concomitantly. Because of relatively small num- Accepted for publication December 5, 2000. bers in these cells, however, these results need to be in- Dr Meier is the recipient of grant 32-056751 from the terpreted cautiously. Additional results such as increased Swiss National Science Foundation, Berne, Switzerland. Re- cataract risk associated with smoking or exposure to oral search projects on drug-drug interactions of the Depart- or inhaled corticosteroids are in agreement with previ- ment of Internal Medicine VI, Clinical Pharmacology and ous findings.23,38,39 Pharmacoepidemiology, University Hospital of Heidel- As with observational studies in general, we can- berg, Heidelberg, Germany, are supported by BMBF grant not rule out unknown biases or confounders as possible 01EC9902 from the Federal Ministry for Education and alternative causes for our findings. However, our results Research in Bonn, Germany. were adjusted for age, sex, geography, and calendar time The Boston Collaborative Drug Surveillance Program (by matching cases to controls) as well as for smoking is partly supported by grants from AstraZeneca, Sodertalje, status, body mass index, corticosteroid use, and degree Sweden; Bayer AG, Leverkusen, Germany; Berlex Labora- of medical attention (by adjusting the multivariate analy- tories, Wayne, NJ; Boots Healthcare International, Notting- sis), and substantial distortions by these potential con- ham, England; Bristol-Myers Squibb, Princeton, NJ;

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