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June 2007
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Should Lutein and Other Nutritional Supplements Be Given for the Therapy of Age-Related Macular Degeneration?
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Our colleagues and patients often question the role of lutein in the treatment of age-related macular degeneration (AMD). According to observational data, individuals with a high dietary intake of lutein/zeaxanthin have a lower risk of advanced AMD than those with a low intake of lutein/zeaxanthin.1,2,3 Although this finding was not consistent among other studies, especially the population-based studies,4,5 pharmaceutical companies have marketed a number of formulations which contain lutein and other antioxidant vitamins and minerals. Patients often experience confusion when they are confronted with a number of such products labeled for eye health on the store shelf. The media has also played a role in promoting the unproven benefits of lutein for AMD.
Currently, there are supporting data mainly from observational studies, in which patients with disease are compared with those without the disease. Such studies are important in generating hypotheses to test, but may not provide data to support treatment recommendations. There are no conclusive results based on limited data from a randomized controlled trial of lutein for the therapy of AMD.6
The proven treatment for prevention of advanced AMD is the formulation tested in the Age-Related Eye Disease Study (AREDS) which contains vitamins C (500 mg), E (400 International Units [IU]), beta carotene (15 mg), zinc oxide (80 mg) and copper (as cupric oxide 2 mg). The AREDS formulation reduced the risk of advanced AMD, defined as neovascular AMD or geographic atrophy involving the center of the macula, by 25% compared with the placebo group at five years follow-up.7 Similarly, the risk of moderate visual loss (decrease of 15 or more letters of vision) was reduced by 19%. This formulation is recommended to persons with intermediate AMD (those with large drusen) in both eyes or those with advanced AMD in one eye and NOT for individuals with early AMD.
The National Eye Institute/National Institutes of Health is conducting a new controlled, randomized trial, the Age-Related Eye Disease Study 2 (AREDS2), to assess the roles of lutein (10 mg)/zeaxanthin (2 mg) and omega-3 long chain polyunsaturated fatty acids or LCPUFAs (docosahexanoic acid [DHA] and eicosapentanoic acid [EPA], total of 1 gm).8 Observational data have shown a decreased risk of advanced AMD in those participants with higher fish consumption or higher intake of omega-3 fatty acids compared to those with lower intake or fish or omega-3 fatty acids.9 Of the 4,000 participants to be randomly enrolled into AREDS2, 1000 will be in the control group, 1000 in the lutein/zeaxanthin group, 1000 in the LCPUFA group, and 1000 in the group with combination of both supplements.
The secondary randomization in AREDS2 will test the following changes to the AREDS formulation in those participants who will consent to it (otherwise, the original AREDS formulation will be provided for them). Because beta-carotene has been associated with an increased risk of lung cancer when given to cigarette smokers,10,11 the AREDS formulation will be evaluated as to the merits of eliminating beta-carotene from the formulation. The dose of zinc tested in AREDS was the dose supported in the past by a small clinical trial.12 Current data suggest that only 25 mg of zinc may be maximally absorbed13. AREDS2 will evaluate the lowering of the zinc oxide to 25 mg.
All participants of AREDS2 will also be offered the opportunity to take a multivitamin. This study will follow all enrolled participants through five years. Enrollment has started in over 80 clinic sites in the US, in both academic institutions and private practices. To find the participating site nearest you, please visit http://www.nei.nih.gov/AREDS2. Working together, we hope to provide our colleagues and patients answers to questions regarding the role of these nutritional supplements for the therapy of AMD, a disease of significant public health importance.
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Reference(s):
1 Eye Disease Case-Control Study Group. Antioxidant status and neovascular age-related macular degeneration. Arch Ophthalmol 1993;111:104-109.
2 Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA 1994;272:1413-20.
3 Snellen EL, Verbeek Al, Van Den Hoogen GW, Cruysberg JR, Hoyng CB. Neovascular age-related macular degenegeration and its relationship to antioxidant intake. Acta Ophthalmol Scan 2002;80:368-71.
4 Flood V, Smith W, Wang JJ, Manzi F, Webb K, Mitchell P. Dietary antioxidant intake and incidence of early age-related maculopathy: the Blue Mountains Eye Study.
Ophthalmology 2002;109(12):2272-8.
5 VandenLangenberg GM, Mares-Perlman JA, Klein R, Klein BE, Brady WE, Palta M. Associations between antioxidant and zinc intake and 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study. Am J Epidemiol 1998;148:204-14.
6 Richer S, Stiles W, Statkute L, Pulido J, Frankowski J, Rudy D, Pei K, Tsipursky M, Nyland J. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related marcular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementaion Trial). Optometry 2004;75:216-30.
7 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: 1417-36.
8 http://www.areds2.org
9 Seddon JM, George S, Rosner B. Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneratioin. Arch Ophthalmol 2006;124:995-1001.
10 The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330:1029-35.
11 Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-5.
12 Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc in macular degeneration.
Arch Ophthalmol. 1988;106:192-198.
13 Hambidge M, Underwood Memorial Lecture: Human zinc homeostasis: Good but not perfect. 11th International Symposium on Trace Elements in Man and Animals. J Nutr. 2003 May;133(5 Suppl 1):1438S-42S.
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About our author(s):
 Emily Y. Chew, MD
National Eye Institute, National Institutes of Health, Bethesda, MD
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