AREDS was the first large scale randomized controlled clinical trial to demonstrate the benefit of vitamin and mineral supplementation in preventing progression to advanced AMD. The AREDS formulation of vitamin C 500 mg, vitamin E 400 IU, beta-carotene 15 mg and zinc (zinc oxide 80 mg and cupric oxide 2 mg) showed a 25% risk reduction in progression to advanced AMD over 5 years in patients with intermediate AMD (extensive intermediate drusen in one or both eyes, one or more large drusen in at least one eye, or non-subfoveal geographic atrophy in one eye) or advanced AMD (subfoveal geographic atrophy or choroidal neovascular membrane) in one eye [5
]. The risk of losing vision of three or more lines (doubling of the visual angle) also was reduced by 19% with this combination treatment. In fact, when available nutritional studies were reviewed by the Cochrane collaboration, the main evidence regarding the effectiveness of vitamin supplementation in preventing AMD progression was attributed as deriving primarily from AREDS [6
A recent report from the Blue Mountain Eye Study [7
], a population-based study, supported the AREDS finding of a beneficial effect of zinc in AMD progression. Of the original cohort, 2454 patients were re-examined with stereoscopic fundus photography 5 and 10 years after initial study enrolment, and energy-adjusted nutrient intakes were assessed. In threshold analyses, patients in the top decile of total zinc intake (≥15.8 mg/day) were significantly less likely to develop any AMD (relative risk [RR], 0.56; 95% confidence interval [CI], 0.32–0.97) or early AMD (RR, 0.54; 95% CI, 0.30–0.97) when compared with the remaining population. Unlike AREDS, however, the Blue Mountain Eye study also found that higher beta carotene intake was associated with an increased risk of neovascular AMD, even after adjusting for smoking status. The authors suggested that this result be taken with caution as the cause for this negative association is not known. It is also important to note that this was an observational study, and that the number of cases with advanced AMD was limited.
While the AREDS demonstrated protective benefits of supplementation in delaying AMD progression, the role of vitamins and minerals in the primary prevention of AMD is more difficult to ascertain. The AREDS formulation showed no effect in preventing the development of large drusen in participants who had small drusen at baseline, and the incidence of advanced AMD in this group was exceeding low (<1%). In 2005, the Rotterdam Study [8
] suggested that high dietary intake of beta-carotene, vitamins C and E, and zinc was associated with a 35% reduction in incident AMD risk in elderly persons. More recently, the Women's Health Study randomized 39 876 women were randomized to low dose aspirin and vitamin E. After 10 years of treatment and follow-up, aspirin therapy had no large or harmful effect on risk of AMD [9
], with 111 cases of AMD in the aspirin group and 134 cases in the placebo group (HR, 0.82; 95% CI, 0.64-1.06).
The Physicians Health Study II may shed some further insights into the role of vitamins C, E, and beta carotene supplementation in preventing AMD. In this study, 14 642 men were randomized to one of 16 possible combinations of vitamin C (500 mg), vitamin E (400 IU), beta-carotene (50 mg), and a multivitamin to assess their role in the primary prevention of cardiovascular disease, cancer, cataract, and AMD [10
]. Follow-up was completed in December 2007 and data analysis is in progress.
Despite these results, a recent Cochrane library review [11•
] of three large scale clinical trials randomizing 23 000 patients did not show a benefit to supplementation with beta-carotene or vitamin E in preventing AMD. The review concluded that there was insufficient evidence to recommend routine supplementation with antioxidant vitamins or minerals in healthy adults to delay or prevent AMD onset.