Vitamins and AMD

What should we know about the current state of nutritional supplementation in AMD?

EMILY Y. CHEW, MD

Nutritional status is a risk factor associated with age-related macular degeneration (AMD), as demonstrated by a number of observational studies. The Age-Related Eye Disease Study (AREDS), a randomized, controlled clinical trial, demonstrated that oral supplements of high-dose antioxidant vitamins and minerals reduced the rate of development of advanced AMD by 25%.¹ Such prevention with micronutrient supplements is a promising approach to reducing the burden of AMD. This is particularly important, as the estimated numbers of persons affected with AMD in the United States will double by the year 2020.

LESSONS LEARNED FROM AREDS

The AREDS results showed that daily oral supplementation of a combination of vitamins — vitamin C (500 mg), vitamin E (400 IU), and beta-carotene (15 mg) — and minerals (80 mg zinc oxide and 2 mg cupric oxide) reduced the risk of developing AMD by 25% in five years. Several months following the announcement of the AREDS results, Canadian ophthalmologists surveyed their patients diagnosed with AMD for their nutritional supplement use.² Approximately 80% were taking some form of supplements, with 70% taking at least one of the AREDS ingredients, while none were taking the recommended doses of the AREDS formulation.

In an editorial two years following the initial publication of the AREDS results, Lee Jampol, MD, conducted a small informal survey in his office suggesting that only 42% of eligible patients with AMD were taking the AREDS supplements in proper doses.³ At the end of the randomized trial of AREDS, about 72% of the participants were taking the AREDS supplements, while only 45% of the participants were taking the proper doses of the AREDS supplements in the follow-up phase of the study.³

More recently, investigators have evaluated the usage pattern of AREDS-type supplements in persons diagnosed with AMD at the Wilmer Eye Institute at Johns Hopkins University.⁴ Of those patients who were eligible to take the AREDS supplements because of intermediate AMD or more advanced AMD in one eye, only 61% of them were confirmed to be taking the correct dosage and components of the AREDS supplements. One-fifth of the subset of subjects found to be taking high-dose supplements were not at the severity of AMD anticipated to benefit from AREDS-type supplement usage. Increased patient education is required to achieve better understanding of the formulation and dosage of the AREDS.

A fundus photo showing intermediate age-related macular degeneration.

One can only speculate on some of the reasons why persons who are candidates for the AREDS supplements are either not taking the AREDS formulation or are taking inadequate doses. With increasing age, there is often an accompanying list of a growing number of medications needed for various chronic conditions. Adding either four tablets or two softgels of the AREDS supplements may become too onerous for the elderly. A small fraction of these patients may not tolerate the side effects, which include gastrointestinal upsets.

There are also a number of patients who have been advised by their cardiologists of the dangers of vitamin E. These data come from controversial meta-analyses of the benefits and adverse effects of supplementation with vitamin E. Although one could conclude that taking these vitamins will not have an effect on improving survival from cardiovascular disease, the adverse effects require further analyses.

FORMULATIONS

Since the results of the AREDS trial were reported in 2005, the number of formulations of the AREDS supplements on the market has proliferated. The wide array of available preparations of vitamin C, vitamin E, betacarotene and zinc with copper has proved to be confusing for the patient seeking help, as well as to the physician making the recommendations. During the course of AREDS, other studies of oral supplementation with beta-carotene for the prevention of neoplasms demonstrated an increased risk of lung cancer in the group of participants who were randomly assigned to beta-carotene. This led to an amendment to the AREDS protocol to offer all smokers in the study the chance to stop their participation in the study and consider randomization to placebo or zinc only. The current AREDS formulation containing beta-carotene is not recommended for smokers.

Furthermore, observational data from a number of studies have suggested that the carotenoids lutein and zeaxanthin may play an important role. Lutein and zeaxanthin were not commercially available at the beginning of the AREDS trial. The role of these carotenoids/macular xanthophylls and the elimination of beta-carotene are currently being tested in the AREDS2 trial. Despite the fact that these factors are unproven, a number of compounds have been formulated to include lutein and or zeaxanthin in place of beta-carotene. This has added to the confusion for both the consumer and physicians. It should be emphasized that, at this time, only the AREDS formulation has been proved to be effective in reducing the risk of developing advanced AMD. For smokers, it is reasonable to consider formulations that do not contain beta-carotene.

Another study evaluated the contents of the various formulations purported to be similar to the AREDS supplements sold in the United Kingdom, where the AREDS formulation may be used less frequently than in the United States or other countries. A survey of "eye nutrients" yielded 22 products from local pharmacies, health food shops, and Internet sites. They were collected and analyzed for their nutrient contents. Although 75% contained the vitamins and minerals found in the AREDS formulation, only two preparations contained the exact amounts tested in the AREDS trial. Not all the formulations available in the United States were tested in this analysis.

The authors note that ophthalmologists should be aware of the contents and the accuracies of the amount in the formulations that they recommend for their patients. In general, the products of the larger pharmaceutical companies have provided tablets or gel capsules that contain the adequate doses of vitamin A, vitamin E, beta-carotene, and zinc. However, the regulatory agencies, such as the Food and Drug Administration, do not have the authority to regulate the industry that manufactures nutrient supplements, making it difficult to ensure that all formulations provide the needed vitamins and minerals in adequate doses.

THE ROLE OF B VITAMINS

Another commonly asked question is what the role is of vitamin B complex in AMD therapy. A randomized, controlled trial of folic acid and vitamins B₆ and B₁₂ was conducted to evaluate the role of lowering homocysteine in a population of women health professionals who have had cardiovascular disease or who are at high risk of developing cardiovascular disease.⁵ The therapy was not beneficial in decreasing the risk of cardiovascular disease, but there was a beneficial effect in AMD. The study, although conducted in a large population of over 5,000 participants, found only a small incidence of advanced AMD. This was a secondary outcome of the study, and the endpoints were obtained using self-reports and medical confirmation of the diagnosis of AMD. This finding has generated interest in the area and may be promising for future prevention of AMD. Further data are needed before making the recommendations to use folic acid and other vitamin B supplements for the treatment of AMD.

CONCLUSION

The AREDS2 trial continues to follow enrolled participants who have intermediate AMD (bilateral large drusen) or advanced AMD in one eye. The roles of lutein/zeaxanthin and omega-3 long-chain polyunsaturated fatty acids (both docosahexaenoic acid and eicosapentaenoic acid) in the treatment of AMD are being evaluated. In a secondary randomization, the elimination of beta-carotene and the reduction of zinc oxide from 80 mg to 25 mg are also being tested.

The results of this study will not be available for several more years. For those persons with less-severe AMD, the benefits of AREDS supplementation are unproven and should not be promoted. We should continue to recommend the full dose of the AREDS formulation for persons who are not currently smoking and who have at least intermediate AMD or advanced AMD in one eye. The public-health impact of the use of AREDS supplements on prevention of advanced AMD in at-risk individuals is significant.⁶ RP

REFERENCES

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;119:1417-1436. Erratum in: Arch Ophthalmol. 2008; 126:1251.
2. Chang CW, Chu G, Hinz BJ, Greve MD. Current use of dietary supplementation in patients with age-related macular degeneration. Can J Ophthalmol. 2003;38: 27-32.
3. Jampol LM. AREDS — two years later. Arch Ophthalmol. 2003;121:1634-1636.
4. Charkoudian LD, Gower EW, Solomon SD, Schachat AP, Bressler NM, Bressler SB. Vitamin usage patterns in the prevention of advanced age-related macular degeneration. Ophthalmology. 2008;115:1032-1038.e4.
5. Christen WG, Glynn RJ, Chew EY, Albert CM, Manson JE. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study. Arch Intern Med. 2009;169:335-341.
6. Bressler NM, Bressler SB, Congdon NG, et al.; Age-Related Eye Disease Study Research Group. Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11. Arch Ophthalmol. 2003;121:1621-1624.