Removing beta-carotene, adding lutein/zeaxanthin show clear patient benefits
The Age-Related Eye Disease Study 2 showed that adding lutein/zeaxanthin and eliminating beta-carotene increased the efficacy and safety of the formulation for reducing progression to advance age-related macular degeneration.
By Lynda Charters; Reviewed by Emily Y. Chew, MD
Seattle-Investigators had already determined that the Age-Related Eye Disease Study (AREDS) formulation slowed the progression to advanced age-related macular degeneration (AMD), with a 25% decrease in the likelihood of progression to advanced AMD compared with placebo.
In 2006, the National Eye Institute started the AREDS2 trials to determine if the original AREDS formulation could be taken a step further to refine its effects with the addition or subtraction of various supplements. While no increased benefit of the formulation was discerned during the primary analyses of comparison of three treatment groups with the placebo group, the secondary analyses of subpopulations of patients provided clinical guidelines for modifications of the AREDS supplements.
Emily Y. Chew, MD, described those results for the AREDS Research Group at the annual meeting of the Association for Research in Vision and Ophthalmology. She is the deputy director, Division of Epidemiology and Clinical Applications, and the deputy clinical director, at the National Eye Institute, National Institutes of Health, Bethesda, MD.
In the AREDS2, a multicenter, double-masked, randomized trial with a 2 x 2 factorial design, the primary analysis evaluated the treatment effects in patients randomly assigned to either daily placebo or addition of the omega-3 long-chain polyunsaturated fatty acids (1 g), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); 10 mg of lutein and 2 mg of zeaxanthin, or both to the original AREDS formulation (500 mg vitamin C, 400 international units of vitamin E, 15 mg beta-carotene, 80 mg of zinc, and 2 mg copper). Lutein and zeaxanthin, according to Dr. Chew, are components of the macular pigment, which might be involved in the pathogenesis of AMD. DHA and EPA, also components of the retina, might be instrumental in controlling inflammation.
In the secondary analysis, the investigators studied the effects of the AREDS formulation without beta-carotene and the AREDS formulation with low zinc (25 mg). Beta-carotene was identified in two randomized clinical trials to cause lung cancer in smokers. The lower dose of zinc was evaluated because nutritional data suggested that the body absorbs only a lower amount of the mineral.
The findings of the study were published online on May 5, 2013, by the Journal of the American Medical Association. A total of 4,203 patients (median age, 74 years) were enrolled in AREDs and followed for almost 5 years.
The primary analysis, which included half of the study population, showed that none of the effects of three treatment groups compared with placebo had a significant effect in stopping progression to advanced AMD.
However, Dr. Chew reported that a beneficial effect of lutein/zeaxanthin was identified when the entire study population was included, specifically, lutein/zeaxanthin decreased the risk of progression to advanced neovascular AMD by 10%; in the secondary analysis, patients who had the lowest dietary intake of lutein/zeaxanthin had a 26% decrease in the risk of disease progression.
Subgroup analysis showed additional benefits. The patients who took the AREDS formulation with lutein/zeaxanthin and no beta-carotene had a decrease in their risk of developing advanced AMD over the course of study of about 18% compared with those who took the AREDS formulation with beta-carotene and no lutein/zeaxanthin and a 22% decrease in progression to neovascular AMD, Dr. Chew said.
Adding DHA and EPA to the AREDS formulation, using a lower dose of zinc, and eliminating beta-carotene from the formulation did not further reduce the risk of progression to advanced AMD.
An important safety issue was the finding that patients who were randomly assigned beta-carotene had an increased incidence of lung cancer (p = 0.04) and the majority of these were former smokers. Dr. Chew noted the important implications that this finding has for treatment.
“The fact that 8% of the AREDS2 participants were smokers and about 50% were former smokers underscores the importance of this finding as a public health issue,” she said.
“Long-term use of AREDS supplements appears safe and protective against advanced AMD,” Dr. Chew said. “While zinc is an important component of the AREDS formulation, based on evidence from AREDS2, it is unclear how much zinc is necessary. Omega-3 fatty acids and beta-carotene clearly do not reduce the risk of progression to advanced AMD. The substitution of beta-carotene by lutein and may further improve the formulation.”
Emily Y. Chew, MD
Dr. Chew has no financial interest in any aspect of this report.