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Cataract and the use of statins: a case‐control study

L. Smeeth, R. Hubbard, A.E. Fletcher
DOI: http://dx.doi.org/10.1093/qjmed/hcg064 337-343 First published online: 1 May 2003

Abstract

Background: In animal studies, statins have induced cataract formation. Because incident cataract is relatively uncommon, studies in humans have been unable to exclude a clinically important effect.

Aims: To assess the risk of cataract associated with the use of statins, and whether it is increased by concurrent use of drugs that inhibit the cytochrome P450 system.

Design: Population‐based case‐control study.

Methods: Patients were randomly sampled from the UK General Practice Research Database. The study included 15 479 people with cataract and 15 479 controls matched for age, sex, practice and observation period.

Results: The crude odds ratio (OR) for the association between any recorded exposure to statins and cataract was 1.41 (95%CI 1.21–1.65), but this reduced to 1.04 (95%CI 0.89–1.23, p=0.6) after adjustment for consultation rate. There was no evidence that the risk increased with higher doses or longer duration of statin use, or that the risk varied by individual statin. There was no evidence that the risk of cataract was increased by concurrent use of statins and drugs that inhibit the cytochrome P450 system.

Discussion: In the short‐ and medium‐term, statins do not seem to be associated with an increased risk of cataract. The need to assess the effects of long‐term statin exposure on the eye remains.

Introduction

Cataract is the main cause of low vision and blindness in the world.1,,2 Any common exposure that increases the risk of cataract is therefore of great public health importance. Increased cataract formation has been found in dogs treated with statins, and a dose‐response relationship between plasma drug levels and risk of cataract was demonstrated.3 Opacification of rat lenses, and adverse effects on lens cell proliferation and structure in cultured epithelial cells from human and rabbit lenses, have also been shown.4 Studies in humans have not found an increased risk of cataract associated with statin exposure,5–,13 but because incident cataract is relatively uncommon, these studies have lacked adequate power to exclude a clinically important effect.

There is mounting evidence that statins are beneficial to a wide range of people at risk of cardiovascular disease.14 Increasing recognition of the beneficial effects of statins, combined with the expiry of drug patents for some of the earlier statins, mean that the use of statins is likely to increase markedly, particularly in the developing world,15 where cataract is the leading cause of blindness. We therefore undertook a large matched case‐control study to assess the risk of cataract associated with exposure to statins using the UK General Practice Research Database.

Methods

The General Practice Research Database

The General Practice Research Database (GPRD), previously known as the VAMP Research Bank, was set up in 1987.16 It contains complete prescribing and diagnostic information, and represents the largest source of continuous data on illness and prescribing habits in the UK. The practices are broadly representative of all practices in England and Wales in terms of geographical distribution and size, and the age and sex distributions of the population included in the GPRD are very similar to those of the UK population as a whole.17 The data available directly from the database include all drug prescriptions and their indication, and a record of every consultation and of every diagnosis. The prescription information includes details of dosage and quantity. The data collected are audited regularly, and the participating general practices are subjected to a number of quality checks. The quality of the information in the database has been validated in a number of independent studies, and has been found to be high.18 The diagnosis of cataract in the GPRD was validated in a recent study.19 Among 262 cases identified from their electronic general practice record, 94% had their diagnosis confirmed by a review of hospital eye service discharge summaries.

The information obtained from the database is entirely anonymous. Ethical approval for the study was obtained from the Scientific and Ethical Advisory Group of the General Practice Research Database.

Selection of participants

The source population was all patients currently registered with general practices actively contributing to the General Practice Research Database in June 2001. A total of 1 441 782 people registered with 177 general practices were included in the source population. Eligible cases were defined as any person aged 40 years or more who had a first diagnosis of cataract while registered with a practice participating in the GPRD. The date of the first diagnosis of cataract was the index date, and all participants had to have at least 180 days of observation period prior to the index date. Using simple random sampling, 15 588 cases were selected. For each case, one control with no record of cataract anywhere in their medical record was selected. Controls were alive and registered with the GPRD on the index date of their matched case and were matched on age (within 1 year), sex, and practice. If the observation periods differed between the case and matching control, the data were truncated to the same number of days to ensure that, within each case‐control set, the duration of observation period was the same.

Data processing and analysis

Data from the electronic records were extracted and set up as a relational database. Only drug exposures prior to the index date were included in the analyses. Statin exposure was defined as ‘ever’ or ‘never’, based on whether a person had a prescription for any statin drug recorded in their electronic medical record. The mean daily dose of statin was categorized as low (≤10 mg/day), moderate (>10 mg/day but <40 mg/day), or high (≥40 mg/day). In addition, the total number of prescriptions for any statin was extracted, as was information about the type of statin prescribed. Data on the following potential confounding factors were extracted: smoking habit; body mass index; diabetes mellitus; glaucoma; hypertension; and exposure to aspirin, oestrogen (as hormone replacement therapy) and systemic corticosteroids.

Because frequency of consultation with the general practitioner could affect both the likelihood of a diagnosis of cataract and be associated with drug exposure, consultation rate was considered as a potential confounding factor. The mean annual consultation rate for each participant was calculated, defined as the total number of consultations divided by the years of observation period.

Following the initial descriptive analysis, exposure to statins was modelled as a binary ever/never exposure using conditional logistic regression. We then fitted a series of bivariate models, retaining variables that led to a change in the odds ratio for statins by 10% or more. The primary analysis determined the relation between the use of statins and the incidence of diagnosed cataract. We assessed the effects of different daily doses of and total number of prescriptions for statins, and whether the effects differed by type of statin. All analyses used Stata software.20

The cytochrome P450 (CYP) enzyme system, in particular the CYP3A4 isoform, plays a central role in the metabolism of the various statins, with the exception of pravastatin.21 Concurrent use of CYP450 inhibitors increases statin bioavailability, and is associated with an increased risk of adverse effects such as myositis and rhabdomyolysis.22,,23 We therefore extracted data on prescriptions for all CYP450‐inhibiting drugs, including macrolide antibiotics (erythromycin and clarithromycin), calcium channel blockers (diltiazem, nicardipine and verapamil), azole antifungals (itraconazole, ketoconazole and fluconazole), cyclosporine and nefazodone. Individuals with concurrent administration of any of the above drugs with statins (with the exception of pravastatin as it is not a substrate of cytochrome P‐450) were considered in a separate group and were compared with people exposed to statins with no concurrent use of a CYP450 inhibitor. Concurrent use was defined as any prescription of a CYP450 inhibitor in the period from the first recorded prescription for a statin until 30 days after the last recorded prescription for a statin.

Results

A total of 15 588 people with a diagnosis of cataract were sampled. People with diagnoses of congenital or traumatic cataract were excluded (109 cases), leaving 15 479 case‐control pairs. Descriptive details of cases and controls are shown in Table 1. The mean age of participants was 75.0 years and 64.6% were female. The mean observation period prior to the index date was 4.5 years. Cases consulted their general practitioners considerably more often than controls, reflected in the higher mean annual consultation rate.

Table 2 shows the association between exposure to statins and a diagnosis of cataract. Among cases, 2.6% (403/15 479) had one or more recorded prescriptions for a statin, the corresponding figure for controls being 1.9% (293/15 479). The mean period of exposure to statins was relatively short (1.6 years for cases and 1.8 years for controls). Overall, of the 696 participants exposed to statins, only 41 (5.9%) were exposed for >5 years. The crude odds ratio for the association between statin exposure and a diagnosis of cataract was 1.41 (95%CI 1.21–1.65). The association was reduced when adjusted for mean annual consultation rate, but was not affected by further adjustment for smoking, BMI, diabetes mellitus, glaucoma, hypertension or previous exposure to systemic steroids, aspirin or oestrogen. For any recorded exposure to statin, the odds ratio for the association with cataract adjusted for consultation rate was 1.04 (95% CI 0.89–1.23, p=0.6). There was no evidence that the association differed by dose or number prescriptions.

The numbers of people exposed to individual statins and the associations with cataract are shown in Table 3. Of study participants with one or more prescriptions recorded for a statin, around 60% were exposed to simvastatin only (58.6% of exposed cases and 61.8% of exposed controls). The numbers of people receiving prescriptions for other types of statin were low, as were the numbers of participants with prescriptions recorded for more than one type of statin. None of the adjusted odds ratios approached significance and no clear pattern for different statins was evident.

Table 4 shows the numbers of people prescribed specific cytochrome P450 inhibitors during the period in which they were prescribed a statin. There was no evidence that concurrent exposure to a P450‐inhibiting drug altered the association between statin exposure and cataract, but the numbers of people exposed to both types of drug concurrently were too small to provide clear evidence on this issue.

View this table:
Table 1

Description of cases and controls: univariate associations and controlled for consultation rate

Cases (n=15 479)Controls (n=15 479)Univariate OR (95%CI)Adjusted OR (95%CI)**
Number (%) female*10 006 (64.6)10 006 (64.6)
Mean age in years (SD)*75.0 (10.0)75.0 (10.0)
Mean observation period in years (SD)*4.5 (2.6)4.5 (2.6)
Mean annual consultation rate
<21898 (12.3%)4733 (30.6%)Baseline
⩾2, <54467 (28.9%)4446 (28.7%)2.83 (2.63–3.05)
⩾5, <83879 (25.1%)3029 (19.6%)3.85 (3.56–4.16)
≥85235 (33.8%)3271 (21.1%)5.06 (4.67–5.49)
BMI
15–212189 (14.1%)1718 (11.1%)Baseline
22–243022 (19.5%)2589 (16.7%)0.93 (0.85–1.01)0.96 (0.88–1.04)
25–272819 (18.2%)2446 (15.8%)0.92 (0.84–1.00)0.90 (0.82–0.98)
28+2938 (19.0%)2486 (16.1%)0.95 (0.87–1.03)0.90 (0.83–0.99)
Missing data4511 (29.1%)6240 (40.3%)
Smoking status
Non‐smoker9131 (59.0%)7801 (50.4%)Baseline
Ex‐smoker2040 (13.2%)1711 (11.1%)1.03 (0.96–1.11)0.98 (0.90–1.06)
Current smoker2272 (14.7%)2082 (13.5%)0.96 (0.89–1.03)1.00 (0.93–1.08)
Missing data2036 (13.2%)3885 (25.1%)
Medical history
Diabetes1735 (11.2)790 (5.1)2.37 (2.17–2.59)1.78 (1.62–1.96)
Hypertension5028 (32.5)4235 (27.4)1.29 (1.23–1.35)0.98 (0.92–1.03)
Glaucoma1125 (7.3)577 (3.7)2.03 (1.83–2.25)1.71 (1.53–1.91)
Prior exposure to:
Aspirin3285 (21.2)2504 (16.2)1.43 (1.35–1.52)1.06 (0.99–1.13)
Oestrogen611 (4.0)551 (3.6)1.15 (1.00–1.31)0.83 (0.72–0.95)
Systemic corticosteroids2395 (15.5)1618 (10.5)1.61 (1.50–1.73)1.17 (1.08–1.26)
  • OR, odds ratio. *Matching variables, so no ORs given. **Adjusted for mean annual consultation rate.

View this table:
Table 2

Association between exposure to statins and cataract: adjusted models and dose‐response relationship

Cases (n=15 479)Controls (n=15 479)Univariate OR (95%CI)Adjusted OR (95%CI)**p
Statins
Never15076 (97.4%)15186 (98.1%)BaselineBaseline
Ever403 (2.6%)293 (1.9%)1.41 (1.21–1.65)1.04 (0.89–1.23)0.6
Mean (SD) exposure (years)1.6 (1.6)1.8 (1.9)
Daily dose
Never15076 (97.4)15186 (98.1)BaselineBaseline0.8*
≤10 mg260 (1.7)169 (1.1)1.59 (1.30–1.94)1.19 (0.97–1.47)
10.1–39.9 mg114 (0.7)103 (0.7)1.14 (0.87–1.50)0.85 (0.64–1.12)
≥40 mg27 (0.2)21 (0.1)1.32 (0.74–2.36)0.86 (0.46–1.58)
Missing2 (0.01)0 (0.0)
Number of prescriptions
015076 (97.4)15186 (98.1)BaselineBaseline0.7*
1–9203 (1.3)131 (0.9)1.58 (1.26–1.97)1.20 (0.95–1.52)
10–19105 (0.7)76 (0.5)1.41 (1.05–1.91)1.01 (0.74–1.38)
20–2946 (0.3)49 (0.3)0.97 (0.64–1.46)0.71 (0.46–1.08)
≥3049 (0.3)37 (0.2)1.39 (0.90–2.14)0.99 (0.63–1.55)
  • *p value for trend. **Adjusted for mean annual consultation rate. ***Mean period of exposure to statins among those exposed.

View this table:
Table 3

Individual statins: recorded exposure and association with cataract

VariableCases (n=15 479)Controls (n=15 479)Adjusted OR (95%CI)**p
No statin15076 (97.40)15186 (98.11)1
Any statin exposure403 (2.6)293 (1.9)1.04 (0.89–1.23)0.6
Atorvastatin only48 (0.31)29 (0.19)1.29 (0.79–2.11)0.3
Cerivastatin only12 (0.08)8 (0.05)1.17 (0.46–2.94)0.7
Fluvastatin only17 (0.11)9 (0.06)1.45 (0.62–3.40)0.4
Pravastatin only30 (0.19)33 (0.21)0.69 (0.41–1.17)0.2
Simvastatin only236 (1.52)181 (1.17)0.98 (0.80–1.21)0.9
Mixed*60 (0.39)33 (0.21)1.41 (0.90–2.23)0.1
  • *People who received a prescription for more than one type of statin. **Adjusted for mean annual consultation rate.

View this table:
Table 4

The effect of concurrent administration of cytochrome P450 inhibitors with statins (excluding pravastatin which is included in the statin‐only group).

VariableCases (n=15 479)Controls (n=15 479)Adjusted OR (95%CI)*p
No statin15076 (97.4)15186 (98.1)
Statin alone303 (2.0)228 (1.5)Baseline
Concurrent administration of statin with:
Any P450 inhibitor100 (0.7)65 (0.4)1.06 (0.76–1.48)0.7
Calcium‐channel blockers55 (0.4)38 (0.3)0.94 (0.59–1.50)0.8
Cyclosporin3 (0.02)0 (0.0)
Azole anti‐fungal3 (0.02)3 (0.02)0.65 (0.12–3.46)0.6
Macrolide antibiotics39 (0.3)24 (0.2)1.12 (0.64–1.97)0.7
  • *Adjusted for mean annual consultation rate.

Discussion

The results of this study suggest that at the usual doses used in clinical practice, short‐ to medium‐term exposure to statins is not associated with an increased risk of cataract. While the mean observation period of participants was 4.5 years, the duration of period of exposure to statins was relatively short, with only small numbers of participants exposed for >5 years. This is likely to be a reflection of statins only being introduced in the late 1980s, with their use increasing progressively since then.

Cases included in the study were patients with a clinical diagnosis of cataract. It is likely therefore that some people with early cataracts would have been missed and could have been included in the control group. However there is no reason to suspect that this misclassification would be differential with regards to exposure status, and thus while there may have been a small reduction in power, this misclassification is unlikely to have biased the effect estimate. A recent study demonstrated a high degree of validity (94%) for a recorded diagnosis of cataract in the GPRD.19 Clinical presentation will be determined largely by two factors. Firstly by the severity of the opacity, meaning that diagnosis is one way of assessing the stage of the disease. Cataract is not an all‐or‐nothing disease: there is a continuous spectrum of severity from blinding cataract to minor opacities that would only be found on detailed examination. Using clinical presentation as an indicator of severity is in line with modern epidemiological thinking about risk factors: assessing how much disease is present rather than whether there is any or none. The second factor likely to determine clinical diagnosis is frequency of clinic attendance. We were able to control for the confounding effect of consultation rate on the association between statins and diagnosed cataract.

We had no information about type of cataract. However, the large numbers of cases and the mixed population in this study mean we would have had a representative mix of different types of cataract. The important issues both for individuals and for public health involve the risks associated with having any type of cataract, not a specific sub‐category. Cases were selected from the existing cohort of patients within the GPRD using simple random sampling, so there was no potential for selection bias. Prescription data were recorded prior to the subject becoming a case, so there was no potential for recall bias. Drug prescriptions from practices participating in the GPRD are generated by the practice computers, ensuring the accuracy of the electronic prescribing records. We lacked information about drug exposures prior to participants registering with the General Practice Research Database. In addition, our estimate of exposure was based on drugs prescribed rather than drugs known to have been taken. While this may have led to a small degree of misclassification of exposure status, there is again no reason to suspect this would be differential with regards to diagnosis, and thus it is unlikely to have biased the effect estimate.

The observed lack of association between cataract and current or ex‐smoking is inconsistent with smoking being an established risk factor for the disease.24While the prevalence of current smoking is consistent with that recorded in a large representative household survey in the UK, the level of ex‐smoking is much lower than would be expected.25 We have previously shown that for people recorded as being current smokers, the magnitude and direction of the dose‐response relationship with the risk of lung cancer are what would be expected,26suggesting that a code for current smoking is accurate. A likely explanation for the observed lack of association between cataract and either current or ex‐smoking when compared with non‐smoking is that many people recorded as being non‐smokers are in fact ex‐smokers. However, when the analysis was restricted to smokers only, the association between exposure to statins and cataracts was virtually identical to the result for all participants (adjusted odds ratio for all participants 1.04 and for smokers only 1.06), suggesting that smoking misclassification had little effect on the main result.

There has been one previous large epidemiological study of the risk of cataract associated with statins.27 The previous study was smaller, based on 7405 cases of cataract compared with the 15 479 included in our study. While the previous study also showed no effect of statins on the risk of cataract, the 95%CI was considerably wider, and thus the effect estimate more uncertain than that obtained in the present study. Although the previous study was based on the General Practice Research Database, the population from which the study participants were selected differed substantially from ours.

In the short and medium term, statins do not seem to be associated with an increased risk of cataract. However, treatment with a statin is likely to be lifelong for most people. With the increasing trend for initiating statin therapy among younger people at high risk of cardiovascular disease, the need to assess the effects of long‐term statin exposure on the eye remains.

Acknowledgments

We would like to thank Chris Smith for help with data processing. The study was funded by the Gift of Thomas Pocklington. Liam Smeeth is supported by an MRC clinical scientist fellowship. Richard Hubbard is supported by a Wellcome Trust advanced fellowship.

Footnotes

  • Address correspondence to Dr L. Smeeth, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT. e‐mail: liam.smeeth{at}lshtm.ac.uk

References

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