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QUESTION

HOW DO I COUNSEL MY PATIENTS WITH DRY AGE-RELATED MACULAR DEGENERATION AND WHAT ABOUT VARIOUS VITAMIN SUPPLEMENTS?

T. Y. Alvin Liu, MD
Catherine B. Meyerle, MD

Let us first review the rationale and results of the original Age-Related Eye Disease Study (AREDS). Beginning in the early 1990s, several observational studies showed the protective association of increased antioxidant vitamin intake with decreased risk of age-related macular degeneration (AMD) development. AREDS, beginning in 2001 under National Eye Institute sponsorship, was designed to evaluate this suggested nutritional role in a prospective clinical trial. Specifically, AREDS was a 5-year randomized study of 4757 participants evaluating whether high-dose antioxidants and zinc could reduce progression of both AMD and age-related lens opacity. Participants were categorized according to drusen size. Small drusen were defined as less than 63 μm, intermediate drusen as 63 μm to 124 μm, and large drusen as greater than or equal to 125 μm. Patients were then randomized to oral supplementation of high-dose antioxidant vitamins and/or zinc. Final analysis demonstrated that 500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene, and 80 mg zinc oxide (along with 2 mg cupric oxide to prevent copper-deficiency anemia) reduced the risk of advanced AMD, defined as neovascular AMD or geographic atrophy (GA) involving the fovea, by 25% in participants with intermediate AMD (extensive intermediate drusen and/or any large drusen) or with advanced AMD in one eye.¹

A second trial known as AREDS2 further refined the antioxidant clinical trial data. The impetus for this randomized clinical trial of 4203 participants was dietary data obtained from the original AREDS participants and nutritional concerns regarding beta-carotene and zinc. During AREDS, all participants completed a food frequency questionnaire. Baseline intake of lutein/zeaxanthin and carotenoids found in dark green leafy vegetables, such as spinach, collard greens, and kale, was inversely associated with neovascular AMD, GA, and large or extensive intermediate drusen.2 This is noteworthy because macular pigment is composed primarily of lutein/zeaxanthin, and these carotenoids are postulated to protect the retina from oxidative stress. Lutein and zeaxanthin were not included in the original AREDS study because they were not readily available for manufacturing in a research formulation at that time. A second dietary factor that was significant was the baseline intake of omega-3 long-chain polyunsaturated fatty acids derived from fish. Higher fish consumption was inversely associated with neovascular AMD.³ Based on these nutritional associations, AREDS2 enrollment began in 2006 to determine whether oral supplementation with macular xanthophylls (lutein 10 mg/day and zeaxanthin 2 mg/day) and/or omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] 350 mg/day and eicosapentaenoic acid [EPA] 650 mg/day, for a total of 1 g of fish oil/day) would decrease the risk of progression to advanced AMD as compared to the control group of those receiving the original AREDS formula. Given the increased risk of lung cancer with beta-carotene use among smokers and the fact that beta-carotene is not found within human ocular tissue unlike lutein/zeaxanthin, a secondary randomization in AREDS2 evaluated whether it would be worthwhile to remove beta-carotene from the AREDS2 formula. The final research question involved zinc. Although there was decreased mortality overall in the zinc group in AREDS, nutritional experts have been increasingly concerned about high-dose zinc usage. In addition to the increased genitourinary complications found in AREDS, zinc has been reported to have an adverse effect on cholesterol levels in other studies. Based on these concerns, the second randomization in AREDS2 investigated whether lowering zinc to 25 mg/day would be beneficial.

As the original AREDS study detected an overall low risk for early AMD cases converting to advanced disease, the AREDS2 study did not include early AMD cases and only enrolled patients with a higher risk of progression to advanced AMD: bilateral large drusen or large drusen in one eye and advanced AMD in the fellow eye. The results, published in 2013,⁴ were as follows: The primary randomization showed that the addition of lutein + zeaxanthin, DHA + EPA or lutein + zeaxanthin + DHA + EPA to the original AREDS formulation, as compared to the original formulation alone, did not reduce the chance of progression to advanced AMD or vision loss. However, an exploratory, ad hoc, subgroup analysis showed that the addition of lutein and zeaxanthin was beneficial in patients with baseline low dietary intake of lutein and zeaxanthin (bottom quintile), so it may help those with a diet lacking in green leafy vegetables or other dietary sources of lutein. It is also interesting to note that the addition of omega-3 fatty acid (DHA and EPA) did not confer any benefits, which was in contrast to a previous study that showed higher fish consumption was inversely associated with neovascular AMD.³ Perhaps, there is a biochemical difference between the omega-3 fatty acid in pill form and that found in traditional dietary intake; more studies are needed in this area. In the secondary randomization, it was shown that removing beta-carotene, reducing the zinc dosage, or removing beta-carotene plus reducing the zinc dosage also did not confer any additional benefits.

Now that we have reviewed the basic principles of the AREDS and AREDS2 studies, let us discuss how we apply these clinical trial results to our everyday practice. First, we believe both the original AREDS and AREDS2 formulae are equally efficacious for nonsmoking patients with intermediate or advanced AMD in one eye. However, if our patient with intermediate or advanced AMD in one eye smokes, we do not initiate the original antioxidant formula given the aforementioned risk of beta-carotene among smokers. As it is not known if a past smoking history in conjunction with beta-carotene puts patients at additional risk, we recommend AREDS2 for both current and prior smokers. Second, we do not recommend either AREDS formulation for patients with early AMD defined as multiple small drusen or rare intermediate drusen. These patients had a low rate of developing advanced AMD during AREDS (1.3% in 5 years), so antioxidant supplementation is not beneficial in such cases. Instead, we counsel these early AMD patients about the importance of regular dilated eye examinations and a healthy diet, including lots of fruits and vegetables. Third, for reasons discussed previously, we do not recommend antioxidant therapy for the offspring of affected individuals unless they personally meet the criteria for intermediate or advanced AMD in one eye. Fourth, when patients with bilateral advanced AMD inquire if they should take the original AREDS formula, we tell them that the study was designed to evaluate risk reduction for progressing to advanced AMD so there is no data to answer the question of whether these patients still benefit from the formulation or not. The long-term effects (10 years) of the original AREDS formula were published in 2013, showing that patients with intermediate or advanced AMD in one eye who were originally assigned to the AREDS formulation, as compared to the placebo group, continued to show statistically significant reduction in the development of moderate vision loss, advanced AMD, and neovascular AMD but not central GA. Also, patients with central GA have been shown to be at a high risk for developing neovascular AMD, as high as 40% over 10 years.5 Hence, it is reasonable to extrapolate that patients with bilateral advanced AMD, in the form of central GA, may benefit from continuation of the AREDS formulation by potentially decreasing the chance of conversion to neovascular AMD that will further affect their vision. However, further research is needed for definitive answers in this bilaterally advanced patient group. Lastly, for patients already taking the original AREDS formulation, there is no definite contraindication for them to take additional over-the-counter vitamin supplements. The concentration of vitamins in typical over-the-counter supplements is much lower than that in the AREDS formulation and general multivitamins often contain additional nutritional supplementation that is not included in the AREDS formula. In fact, about 67% of AREDS participants chose to take Centrum along with the study medication and there was no definitive evidence that a higher rate of adverse events occurred in this group.¹

While the AREDS antioxidant formula has had a major public health impact in terms of preventing advanced AMD, it can have side effects just like all medications. Fortunately, the adverse event rate is low. As mentioned previously, beta-carotene supplementation is contraindicated in smokers. Beta-carotene occasionally caused yellow discoloration of the skin in both smokers and nonsmokers, but this was of no health consequence. Also, patients randomized to zinc had an increase in genitourinary complications, such as urinary tract infection, prostate hyperplasia, and stress incontinence. However, an analysis of zinc vs no zinc found a statistically significant reduction in mortality in the zinc group (relative risk 0.73, 95% CI: 0.61 to 0.89), so, overall, the original AREDS formulation is safe. In AREDS2, addition of lutein and zeaxanthin to the original formula, as compared to the original formula alone, did not increase the rate of serious adverse events. More lung cancers were observed in the beta-carotene group as compared to the no–beta-carotene group, but 91% of participants who developed lung cancer were former smokers. Finally, there was no difference in the rates of reported gastrointestinal disorders and hospitalizations for genitourinary diseases between the high- and low-dose zinc groups.⁴

Some meta-analyses have warned of increased morbidity and mortality associated with vitamin therapy.^6,7 The methodology of these meta-analyses, however, is questionable. Some used flawed subgroup analysis to support their claims. Others focused on large beta-carotene trials that included smokers, thus creating a negative bias. Due to the low adverse event rate in AREDS, we feel that the original AREDS formula is safe in nonsmokers. Additionally, availability of AREDS2 now offers a formula that is safe for smokers as it contains lutein instead of beta-carotene. Both AREDS studies have had a significant impact on risk reduction for progression to advanced AMD, but further nutritional research is required to help those who already have bilateral advanced AMD.

1.     Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.

2.     SanGiovanni JP, Chew EY; Age-Related Eye Disease Study Research Group. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthalmol. 2007;125(9):1225-1232.

3.     SanGiovanni JP, Chew EY, Clemons TE, et al. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol. 2007;125(5):671-679.

4.     Age-Related Eye Disease Study 2 Research G. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005-2015.

5.     Chew EY, Clemons TE, Agron E, et al. Long-term effects of vitamins C and E, beta-carotene, and zinc on age-related macular degeneration: AREDS report no. 35. Ophthalmology. 2013;120(8):1604-1611, e1604.

6.     Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007;297(8):842-857.

7.     Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37-46.

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