Key Points

•Age-related macular degeneration (AMD) has multifactorial etiology. Nutrition, cigarette smoking, and plasma homocysteine may be modifiable risk factors that provide therapeutic targets in the management of AMD.

•Data regarding therapeutic interventions for primary prevention of AMD are limited and thus far inconclusive.

•A limited number of randomized controlled trials are available to validate observational data regarding risk factors and potential therapeutic interventions for AMD.

The Age-Related Eye Disease Study (AREDS) demonstrated that daily oral supplementation of a combination of antioxidant vitamins and zinc has been shown to reduce progression to advanced AMD among patients who are at intermediate to high risk of progression of disease [1].

The Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) demonstrated that daily long-term supplementation with folic acid, pyridoxine, B12, and cyanocobalamin reduced risk of advanced AMD in a population of female healthcare

A.D. Meleth (*)

Department of Epidemiology and Clinical Applications, National Eye Institute/National Institutes of Health,

10 Center Drive, Bethesda, MD 20892, USA e-mail: echew@nei.nih.gov

professionals with, or at risk for, cardiovascular disease.

•The more efficacious combination of nutrients and antioxidants has not yet been determined.

•Preliminary observational data suggests that omega-3 fatty acids and carotenoids, specifically lutein and zeaxanthin, may play a role in prevention and treatment of AMD. At present, there is insufficient data from randomized controlled clinical trials to make therapeutic recommendations.

Introduction

Age related macular degeneration (AMD) is the leading cause of blindness among adults over the age of 65 in the Western world. The prevalence of AMD is expected to increase dramatically, from 1.75 million in 2000 to 2.95 million in 2020, due to the rapidly aging population [2]. Given the large and now increasing burden of disease, the identification of modifiable risk factors and new avenues for preventive treatment has become increasingly important. The pathogenesis of macular degeneration is multi-factorial with genetic, environmental, and physiologic components. The retina is uniquely susceptible to oxidative damage, given its high metabolic activity and daily exposure to light. In addition, the presence of large numbers of lipids with double bonds makes it an ideal target for reactive oxygen species. The increasing incidence of macular degeneration with advancing age may be related to gradual

dysfunction and degeneration of retinal tissues as oxidative damage accumulates. This cumulative damage may result in physiologic dysfunction, in additiontoimpairedauto-regulationwithrestricted exchange and processing of nutrients and metabolic byproducts with progressive disease. Nutrients which may modulate this oxidative damage include lutein, zeaxanthin, beta-carotene, C, E, and B vitamins, and zinc [3–7]. A growing body of scientific evidence also implicates inflammatory processes in the pathogenesis and progression of macular degeneration [8]. Clinical evidence suggests a role for a combination of antioxidants in reducing progression of AMD and a potential role for omega-3 fatty acids and macular xanthophylls in the prevention and treatment of macular degeneration. The Age Related Eye Disease Study 2 (AREDS2) will further examine the role of these micronutrients in the treatment of AMD.

The data regarding the impact of modifiable risk factors and micronutrients on macular degeneration comes from both large observational studies and a small number of randomized controlled trials. Major studies that have studied the impact of micronutrients in macular degeneration include the Age Related Eye Disease Study, the Rotterdam Study, and the Blue Mountain Eye Disease study.

AREDS

The Age-Related Eye Disease Study (AREDS) was a multicenter randomized placebo-controlled trial designed to assess the impact of an antioxidant and micronutrient combination on the incidence and progression of AMD and age-related cataract. The AREDS supplement contained 15 mg beta-carotene, 500 mg Vitamin C, 400 IU Vitamin E, 80 mg zinc oxide, and 2 mg of copper as cupric oxide. Participants were stratified into four categories of AMD of varying severities of disease as well as rates of progression to advanced AMD:

•Category 1: none to few drusen; 0.44% developed advanced AMD by year 5.

•Category 2: Extensive small drusen, pigment abnormalities, or at least 1 intermediate size druse; 1.3% probability of progression to advanced AMD by year 5.

•Category 3: Extensive intermediate drusen, large drusen, or noncentral geographic atrophy (GA); 18% probability of progression. Patients within category 3 who had bilateral large drusen or noncentral GA in at least 1 eye at enrollment were 4 times more likely to progress to AMD than the remaining participants in category 3; 27% vs. 6% in 5 years.

•Category 4: Advanced AMD in one eye or patients with vision loss due to nonadvanced AMD in 1 eye; 43% probability of progression to advanced AMD in 5 years.

The AREDS found that there was a 27% reduc-

tion in risk of progression of disease in participants taking AREDS supplements in Categories 3 and 4. Patients with category 1 or 2 AMD had a very low risk of progression to advanced AMD; 0.4% and 1.3%, respectively. Due to the low event rate, it was not possible to establish a treatment effect for the AREDS formulation for these participants. The widespread use of the AREDS supplements in appropriate patients can have significant impacts on cost and overall morbidity in the population [9]. Mortality rates are higher in patients with AMD in a number of studies. This is likely secondary to the shared risk factors that also affect mortality. Patients with advanced AMD also had higher rates of cardiovascular deaths in the AREDS trial [10, 11]. Interestingly, participants taking zinc supplements, either alone or in combination with other antioxidants, had improved survival in the AREDS than those not taking zinc (RR 0.78; 95% CI, 0.41–1.47) [11]. Overall mortality among AREDS participants taking supplementation was reduced by 14% (RR 0.86, CI 0.65–1.12) [11, 12].

Pearl

AREDS [13]

•Randomized placebo controlled trial

•Designed to assess impact of antioxidant and micronutrient combination on:

Incidence of progression of AMD

Incidence of progression of cataract

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