Recent American College of Cardiology/American Heart Association guidelines on statin initiation on the basis of total atherosclerotic cardiovascular disease risk argue that the preventive effect of statins on cardiovascular events outweigh the side effects, although this is controversial. Studies indicate a possible effect of statin therapy on reducing risk of lens opacities. However, the results are conflicting. The Simvastatin and Ezetimibe in Aortic Stenosis study ( NCT00092677 ) enrolled 1,873 patients with asymptomatic aortic stenosis and no history of diabetes, coronary heart disease, or other serious co-morbidities were randomized (1:1) to double-blind 40 mg simvastatin plus 10 mg ezetimibe versus placebo. The primary end point in this substudy was incident cataract. Univariate and multivariate Cox models were used to analyze: (1) if the active treatment reduced the risk of the primary end point and (2) if time-varying low-density lipoproteins (LDL) cholesterol lowering (annually assessed) was associated with less incident cataract per se. During an average follow-up of 4.3 years, 65 patients (3.5%) developed cataract. Mean age at baseline was 68 years and 39% were women. In Cox multivariate analysis adjusted for age, gender, prednisolone treatment, smoking, baseline LDL cholesterol and high sensitivity C-reactive protein; simvastatin plus ezetimibe versus placebo was associated with 44% lower risk of cataract development (hazard ratio 0.56, 95% confidence interval 0.33 to 0.96, p = 0.034). In a parallel analysis substituting time-varying LDL-cholesterol with randomized treatment, lower intreatment LDL-cholesterol was in itself associated with lower risk of incident cataract (hazard ratio 0.78 per 1 mmol/ml lower total cholesterol, 95% confidence interval 0.64 to 0.93, p = 0.008). In conclusion, randomized treatment with simvastatin plus ezetimibe was associated with a 44% lower risk of incident cataract development. This effect should perhaps be considered in the risk-benefit ratio of statin treatment.
The most recent American College of Cardiology/American Heart Association guidelines recommend statin initiation on the basis of total atherosclerotic cardiovascular disease risk rather than low-density lipoproteins (LDL) per se. However, this has been controversial and sparked intense debate. As such, it has been estimated that an additional 8.2 million adults in the United States will be recommended statin therapy with the new guidelines. However, recent evidence suggests that the preventive effect on cardiovascular events outweigh the side effects including a possibly greater risk of diabetes. Recently, some registry-based studies have reported an association between LDL cholesterol–lowering drugs, that is, simvastatin, and reduced risk of nuclear cataract. The exact mechanism whereby statin therapy might reduce cataract development is unknown. However, statins have proved invaluable in reducing the risk of cardiovascular disease, by inhibiting the direct and indirect effects of LDL-cholesterol deposition throughout the body. Only 2 randomized studies have assessed the effect of statin therapy on preventing cataract development; one including patients with high cardiovascular risk and another with only 48 weeks of follow-up. Moreover, the first study had small sample size greatly limiting the external validity. The aim of this study was therefore to assess whether randomized treatment with a combination of simvastatin plus ezetimibe versus placebo was associated with reduced risk of incident cataract during long-term follow-up in a large middle-aged western population without a priori established ischemic cardiovascular disease.
Methods
All data originate from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, a randomized, multicenter, double-blind, placebo-controlled study investigating whether intensive lipid lowering with simvastatin plus ezetimibe versus placebo in 1,873 patients (aged 45 to 85 years) with asymptomatic aortic stenosis (AS) (defined as echocardiographic aortic valve thickening accompanied by Doppler-measured aortic peak flow velocity between 2.5 and 4.0 m/sec, normal left ventricular systolic function, and absence of symptoms according to independent local investigators based on patient interviews) could decrease AS progression and the risk of cardiovascular morbidity and mortality. The main outcome, design, and baseline characteristics of the SEAS study have been published. Patients were seen at 6-month intervals, with a clinical examination, query about adverse outcomes, and safety laboratory and lipid tests performed at every visit. The present study complies with the Declaration of Helsinki, locally appointed ethics committees have approved the research protocol and informed consent has been obtained. The primary outcome in this post hoc substudy was association of randomized treatment to LDL cholesterol lowering with simvastatin plus ezetimibe with incident cataract. Incident cataract was reported by local SEAS investigators blinded to treatment assignment, who were instructed to perform full medical examination including questionnaires on adverse events including cataract, as agreed a priori in the SEAS protocol safety event data set. The diagnosis of incident cataract included reporting date of onset as assigned by the treating ophthalmologist.
SAS statistical software package version 9.2 for PC (SAS Institute Inc., Cary, North Carolina) was used for statistical analysis. Continuous variables are presented as mean ± SD and categorical as number and percentages. Variables not normally distributed were log transformed as appropriate and expressed as median interquartile range. Differences in categorical variables were evaluated by the chi-square tests and in continuous variables by the Student t test. Randomized treatment with simvastatin and ezetimibe and time-varying LDL-cholesterol were assessed for association with incidence cataract using univariate and multivariable Cox models to estimate hazard ratios (HRs) and confidence intervals (CIs). Interaction was tested between randomized treatment and both baseline, 1 year and time-varying LDL-cholesterol. Proportionality was tested by cumulative residuals. Differences in risk of incident cataract and randomized treatment are shown by plots of cumulative incidence. A 2-tailed p value <0.05 was regarded as statistically significant.
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