In a large, multicenter, randomized clinical trial that included persons at high risk for progression to advanced age-related macular degeneration (AMD), adding the carotenoids lutein and zeaxanthin, the omega-3 fatty acids DHA and EPA, or both to a formulation of antioxidant vitamins and minerals that has shown effectiveness in reducing risk did not further reduce risk of progression to advanced AMD, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the Association for Research in Vision and Ophthalmology annual meeting.
"Age-related macular degeneration, the leading cause of blindness in the developed world, accounts for more than 50 percent of all blindness in United States," according to background information in the article. In 2004 it was estimated that 8 million individuals had intermediate AMD and approximately 2 million had advanced AMD, with no effective proven therapies for atrophic AMD. "Without more effective ways of slowing progression, the number of persons with advanced AMD is expected to double over the next 20 years, resulting in increasing socioeconomic burden," the authors write. "Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C, E, and beta carotene and zinc) has been shown to reduce the risk of progression to advanced AMD. Observational data suggest that increased dietary intake of lutein and zeaxanthin, omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), or both might further reduce this risk."
Emily Y. Chew, M.D., of the National Eye Institute, National Institutes of Health, Bethesda, Md., and colleagues with the Age-Related Eye Disease Study 2 (AREDS2) Research Group examined whether adding lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation might further reduce the risk of progression to advanced AMD. A secondary goal was to evaluate the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation. AREDS2, a multicenter, randomized phase 3 study was conducted in 2006-2012, enrolling 4,203 participants 50 to 85 years of age at risk for progression to advanced AMD with bilateral large drusen (tiny yellow or white deposits in the retina of the eye or on the optic nerve head) or large drusen in 1 eye and advanced AMD in the fellow eye.
Participants were randomized to receive lutein (10 mg) and zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), lutein + zeaxanthin and DHA + EPA, or placebo. All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta carotene, lowering of zinc dose, or both.
A total of 1,608 participants had experienced at least 1 advanced AMD event by the end of the study (1,940 events in 6,891 study eyes). The researchers found that the probabilities of progression to advanced AMD by 5 years were 31 percent for placebo, 29 percent for lutein + zeaxanthin, 31 percent for DHA + EPA, and 30 percent for lutein + zeaxanthin and DHA + EPA. In the primary analyses, comparisons with placebo demonstrated no statistically significant reductions in progression to advanced AMD.
"There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. More lung cancers were noted in the beta carotene vs. no beta carotene group (23 [2 percent] vs. 11 [0.9 percent]), mostly in former smokers," the authors write.
None of the nutrients affected development of moderate or worse vision loss.
The researchers add that "these null results may be attributable to the true lack of efficacy. Other factors to consider include inadequate dose, inadequate duration of treatment, or both."
"Based on apparent risks of beta carotene and possible benefits that are only evident within exploratory subgroup analyses, lutein + zeaxanthin requires further investigation for potential inclusion in the AREDS supplements."