Macular Degeneration and AREDS 2 Supplements

What AMD does to vision

What AMD does to vision

Four years ago I wrote about the premature marketing of a diet supplement for macular degeneration before the results of a trial to test it were available. Now that we know the results of that trial, a follow-up post is in order.

Age-related macular degeneration (AMD) is a leading cause of blindness. The incidence increases with age; it affects 10% of people by age 66-74 and 30% of people by age 75-85. There are known risk factors including genetics and smoking, but there is no effective prevention. There are multiple diet supplement products on the market that are advertised as “supporting eye health.” Some are based on evidence from randomized, controlled studies; but the advertising hype goes beyond the evidence and tends to mislead consumers. There is evidence that supplementation may slow the progression of moderate to severe AMD, but there is no evidence that supplements are effective in milder disease or for preventing AMD from developing in the first place.

The AREDS trial

The original AREDS (Age-Related Eye Disease Study), was a large, multicenter trial of patients with established AMD to evaluate the effect of a combination of 3 antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and vitamin A in the form of beta carotene, 25,000 IU), with zinc and copper. Over 5 years, patients taking the antioxidant and zinc supplement had a 23% chance of developing vision loss from advanced AMD compared to a 29% chance of developing vision loss from advanced AMD for patients taking a placebo pill. This effect was statistically significant, but modest. Concerns were raised about the high dose of vitamin A, since beta carotene was known to cause harm at those levels, so another study was designed to evaluate a different combination that omitted the vitamin A and added other possibly beneficial components.

The AREDS 2 trial

In the new trial, there were four groups: (1) a control group got the original AREDS formula, and the other 3 got a formula that omitted the vitamin A and added (2) lutein and zeaxanthin, (3) the omega 3s DHA and EPA, and (4) both lutein/zeaxanthin and DHA/EPA. There was no control group of patients not taking any supplement.

They concluded:

Addition of lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD. However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation.

AREDS 2 had a number of strengths. It was large (4,203 subjects), it lasted 5 years during which 1940 eyes progressed to advanced AMD, the drop-out rate was low, it assessed adherence, and it measured blood levels of the study nutrients.

It also had some weaknesses. They didn’t use a no-supplement control group because they assumed that the original AREDS had proved the benefit of supplementation. This is a bit worrisome, since we know it is risky to rely on a single study. The AREDS trial has not been replicated, and a Cochrane systematic review concluded:

People with AMD may experience delay in progression of the disease with antioxidant vitamin and mineral supplementation. This finding is drawn from one large trial conducted in a relatively well-nourished American population. The generalisability of these findings to other populations is not known. Although generally regarded as safe, vitamin supplements may have harmful effects. A systematic review of the evidence on harms of vitamin supplements is needed.

A personal note

I have macular degeneration that is due to myopia, not AMD. It has not yet caused any loss of visual acuity, but I am being monitored by a retinal specialist. A couple of years ago, she suggested I take a supplement based on AREDS 2, but with the addition of bilberry and omega 3’s, available directly from the manufacturer as a mail-order subscription service. She offered it more as an option than a recommendation, and she didn’t push it. I declined, because that particular formulation has not been studied, and because the AREDS evidence is only for AMD, not for myopic macular degeneration. I can understand her wanting to “do something,” and the rationale that it might help and couldn’t hurt, but that wasn’t enough to convince me.


The AREDS trial provided evidence that a mixture of diet supplements slowed the progression of moderate-to-advanced macular degeneration, and the AREDS 2 trial found that a safer formulation was equally effective. The evidence would be more convincing if there were confirmatory studies with no-supplement control groups. There is no evidence of benefit for patients with mild AMD, and no evidence that supplements can prevent AMD. Advertising that products “support eye health” is misleading.

I found it interesting that 50% of the AMD patients were smokers or former smokers, a much higher rate than in the general population. This suggests that smoking cessation might be as important or more important than any supplement (at least in well-nourished people), and it is an intervention that has many other health benefits.

Posted in: Clinical Trials, Herbs & Supplements

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