Damian McNamara

May 07, 2013

SEATTLE, Washington — Antioxidant and omega-3 supplements do not reduce the risk for advanced macular degeneration, according to results from the highly anticipated Age-Related Eye Disease Study (AREDS2).

Although the primary results are disappointing, important clinical messages emerged during its presentation here at the Association for Research in Vision and Ophthalmology 2013 Annual Meeting. The results were published online May 5 in the JAMA: The Journal of the American Medical Association to coincide with their presentation.

The new data point to ways to change the nutritional formulation from the initial AREDS trial to reduce potential risks without sacrificing benefit for people at high risk for advanced age-related macular degeneration (Arch Ophthalmol. 2001;119:1417-1436).

"AREDS resulted in a formulation of vitamin C, beta carotene, zinc, and vitamin E that reduced the risk of progression of advanced disease by 25%" at 5 years, Emily Chew, MD, from the National Eye Institute in Bethesda, Maryland, told Medscape Medical News. "We wanted to see if we could tweak it a bit by adding components to it."

Bolstered by promising evidence from animal and observational studies, Dr. Chew and her team sought to determine if the addition of the carotenoids lutein and zeaxanthin and/or the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) could further forestall progression to advanced macular degeneration.

It didn't work. "In the overall analysis, using 3 treatment groups, we found no significant difference in rates of macular degeneration," Dr. Chew said. In fact, risk was not significantly reduced with any treatment, compared with placebo (hazard ratio [HR], 0.90; 98.7% confidence interval [CI], 0.76 - 1.07; P = .04), over a median of 4.9 years of follow-up.

A total 4203 participants were randomized to placebo with no additional supplementation or to 1 of 3 treatment groups. The first group received a tablet of 10 mg lutein plus 2 mg zeaxanthin — both antioxidants found in green leafy vegetables. The second group received a gel cap with 350 mg DHA plus 650 mg EPA. The third group received both the tablet and gel cap on a daily basis.

Risk for Advanced Age-Related Macular Degeneration

Treatment Group 5-Year Progression (%) Reduced Risk (Hazard Ratio)
Placebo (n = 1012) 31
Antioxidants (n = 1044) 29 0.90
Omega-3 fatty acids (n = 1068) 31 0.97
Both supplements (n = 1079) 30 0.89


When asked by Medscape Medical News to comment on the findings, Abdhish Bhavsar, MD, said, "I was quite surprised to see that AREDS2 did not show any difference between the primary outcome treatment groups. However, the study involved a very complex clinical trial design and tried to answer some difficult questions on lutein plus zeaxanthin and DHA plus EPA." Dr. Bhavsar, a retinal surgeon, is director of clinical research at the Retina Center in Minneapolis, Minnesota, and national clinical spokesperson for the American Academy of Ophthalmology.

Although no significant additional overall benefit emerged, a subanalysis showed that lutein plus zeaxanthin supplementation might help some patients. When stratified by dietary intake of these antioxidants at baseline, participants in the lowest quintile who took the supplements showed a 26% risk reduction against progression to advanced macular degeneration (HR, 0.74; 95% CI, 0.59 - 0.94; P = .01).

"That is not exactly small," Dr. Chew said. "People who are not eating enough show a benefit."

Silver Lining

Another secondary analysis of the data yielded a 10% risk reduction in progression to advanced macular degeneration in patients who took lutein plus zeaxanthin, compared with those who did not. "So this appeares to have an effect," Dr. Chew said.

"Secondary-level analyses seem to point in the direction that lutein and zeaxanthin are associated with a reduction in progression to advanced and neovascular age-related macular degeneration," Dr. Bhavsar said. "Thus, at the present time — although based on secondary analyses — it seems that the best medical evidence points to considering lutein and zeaxanthin in addition to the AREDS formula."

The best medical evidence points to considering lutein and zeaxanthin in addition to the AREDS formula.

The researchers also performed a secondary randomization of 3036 participants to evaluate refinements in the initial formulation — specifically, daily supplementation with lower zinc levels, without beta carotene, or both.

Dr. Chew and colleagues responded to concerns from nutritionists that the amount of zinc in AREDS exceeds the absorbable amount. They assessed the potential removal of beta carotene to reduce the risk for lung cancer in smokers that has been seen in other randomized controlled trials (J Natl Cancer Inst. 1996;88:1550-1559 and Am J Clin Nutr. 1995;62:1427S-1430S).

Lowering zinc dose did not significantly alter progression to advanced macular degeneration (HR, 1.06; 95% CI, 0.95 - 1.19; P = .32), nor did the removal of the beta carotene (HR, 1.07; 95% CI, 0.94 - 1.20; P = .31). A recommendation to change the zinc dose, therefore, was not made based on the findings.

For this reason, smokers were randomized to 1 of 2 formulations without beta carotene in AREDS2. In the second randomization component of AREDS2, more lung cancers still occurred in the beta carotene group than in the no beta carotene group (2.0% vs 0.9%). The vast majority of participants (91%) who developed lung cancer were former smokers, "so former smokers are at risk for lung cancer with beta carotene," Dr. Chew said.

"The bottom line is that we have enough data to suggest we can remove the beta carotene in the AREDS formulation and substitute it with the lutein and zeaxanthin," she pointed out. "This way there is one formulation for people to take whether they have ever smoked or not."

Researchers enrolled participants in AREDS2 from October 2006 to September 2008 at 82 clinical sites. All were 50 to 85 years of age (mean, 73 years) and at high risk for progression to advanced macular degeneration because of bilateral large drusen or large drusen in one eye and advanced macular degeneration in the other.

Low rates of loss to follow-up (3%) and good adherence to the treatment regimen are strengths of the study. Generalizability of results is a potential limitation, as is the inability to determine if the null findings are attributable to lack of efficacy of the supplements, inadequate dose, inadequate duration, or a combination of these.

This study was supported by the National Institutes of Health. Dr. Chew and Dr. Bhavsar have disclosed no relevant financial relationships.

JAMA. Published online May 5, 2013. Abstract

Association for Research in Vision and Ophthalmology 2013 Annual Meeting. Presented May 5, 2013.