Proof of Concept, Randomized, Placebo-Controlled Study of the Effect of Simvastatin on the Course of Age-Related Macular Degeneration

Abstract

BackgroundHMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined.Methodology/Principal Findings Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA≥20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1∶1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18–0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27–3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07–0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02–0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected.Conclusion/SignificanceSimvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted.Trial RegistrationAustralian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

Pathways of cholesterol homeostasis in mouse retina responsive to dietary and pharmacologic treatments

“…Perhaps simvastatin and other lipophilic statins should be considered for the effect on the formation, reduction, or removal of drusen, cholesterol-containing deposits (>40%, v/v) appearing with age under the RPE and being a pathologic hallmark of AMD ( 55 ). Combined with the recent investigation showing signifi cant improvements in the ultrastructure and function of the PR/RPE/Bruch's membrane region in the simvastatin-treated mice fed high-fat atherogenic diet ( 56 ), the present work supports the idea of revisiting statins for the treatment or prevention of AMD ( 13,56,57 ). Testing of statins is also warranted by their cholesterol-independent effects ( 58, 59 ), some of which (e.g., improvement of endothelial function, reduction of infl ammation and angiogenesis) could be of therapeutic value for AMD ( 57 ).…”

Interpretation of the evidence for the efficacy and safety of statin therapy

“…270 Statin therapy has been associated with lower rates of progression of age-related macular degeneration in observational studies, but there is limited evidence from randomized trials to support this apparent protective effect. 271 The refutation of the claims of large effects of statin therapy on cataract, reinforced by the clear lack of effects on more sensitive measures of lens opacities, provides another illustration of how the combination of large size and the inherent biases of non-randomized studies can lead to associations of a treatment with an outcome that may be precise (i.e. involve small random errors) but not causal.…”

Cholesterol in mouse retina originates primarily from in situ de novo biosynthesis

“…However, recently a prospective randomized controlled trial has been carried out (114 participants) and demonstrated that the cumulative AMD progression rates were lower in the simvastatin-treated group (54%) than in the placebo group (70%) ( 45 ). The treatment rate reduction was even more signifi cant when the post hoc analysis was stratifi ed by the baseline AMD severity and CFH genotype: >4-fold decrease in people with nonadvanced AMD and >12-fold decrease in carriers of CC (Y402H) CFH ( 45 ). These promising results suggest that statins should be reconsidered as therapeutics for AMD and that recent studies in simvastatin treatment in mice ( 41,42 ) along with the fi ndings of the present work may be of human relevance.…”