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Complementary Therapy Assessment:

Antioxidant Supplements and Age-Related Macular Degeneration

SUMMARY
INTRODUCTION TO THE TOPIC
The role of antioxidant supplements in the development of age-related macular degeneration (AMD) has received a great deal of interest. Antioxidants are found naturally in food and include vitamin C (ascorbic acid), vitamin E (alpha-tocopherol), carotenoids, selenium, and zinc. Antioxidants neutralize the damage to cells caused by free radicals and may be relevant to AMD if oxidative damage to the retina leads to AMD.

CONCLUSIONS
The role of antioxidant supplements in the prevention and treatment of AMD is unknown. Randomized controlled trials available to date do not answer the question as to whether antioxidant supplements will either prevent the development or stop the progression of AMD. Observational studies have returned conflicting results. It is possible that there are risks in high levels of supplementation of specific antioxidants.

Because of the lack of strong scientific evidence and conflicting study results, a general recommendation for use of antioxidant supplements by healthy patients to prevent or treat AMD cannot be supported at this time. The scientific community is waiting for the results of several large studies that may allow for an evidence-based recommendation on the safety and effectiveness of supplements. Patients can be encouraged to maintain a healthy diet, with consumption of fresh fruits and vegetables, for a variety of health benefits.

BENEFITS
A Cochrane Library systematic review included only one randomized controlled study that demonstrated a positive, if limited, effect of a nutritional supplement on vision and progression of AMD. In this study, people in the zinc-treated group were less likely to lose 10 or more letters on the ETDRS chart than controls were. The other studies found no beneficial effect or a benefit of marginal statistical significance. The one randomized controlled trial of supplements for prevention of AMD showed no apparent effect.

RISKS
The risk, if any, of supplementation with antioxidants is unknown. There are two randomized controlled trials of supplementation in groups of people at high risk for cancer (smokers and asbestos-exposed workers) where high levels of beta-carotene were associated with significantly higher cancer incidence and mortality rates. One theory on the risk of supplementation with a single product is that protection may require multiple nutrients consumed in a balanced combination at nutritional doses.

The economic risk of using antioxidant supplements is high because the cost can be significant and is seldom covered by health insurance.

REPORT
DESCRIPTION OF ANTIOXIDANT SUPPLEMENTS
Antioxidant substances are found naturally in food and include vitamin C (ascorbic acid), vitamin E (alpha-tocopherol), carotenoids, anthocyanidins, selenium, and zinc. Carotenoids, nutrients that are not classified as vitamins, include beta-carotene, alpha-carotene, the lycopenes, lutein, and zeaxanthin. The carotenoids are found in leafy green vegetables, corn, kiwi, and many other green, red, or yellow fruits and vegetables. The anthocyanidins are responsible for the blue color of blueberries and bilberries. Antioxidants neutralize the damage to cells caused by free radicals, and may be relevant to AMD if oxidative damage to the retina leads to AMD. Many different brands of antioxidant supplements are sold singly and in various combinations as tablets, capsules, or sprays. The manufactured quality and formulation of the supplement can influence absorption and therefore potential benefit.

MECHANISM OF ACTION
The exact mechanism of antioxidant in the retina is unknown. A hypothesis is that damage to the retinal photoreceptors is caused by oxidation, leading to impaired function and eventually to degeneration of the macula. Antioxidants could prevent cellular damage in the retina by eliminating free radicals and harmful oxidants that are generated by light absorption and by normal metabolic processes.1,2

DEFINITION OF THE PROBLEM
Age-related macular degeneration is a disorder of the macula that occurs most often in patients 50 years of age or older and is characterized by one or more of the following findings: drusen formation, retinal pigment epithelial (RPE) abnormalities, geographic atrophy of the RPE and choriocapillaris, and exudative maculopathy. Although most people with macular degeneration have the nonexudative (atrophic, or dry) form, the majority of patients with severe visual loss from AMD have the exudative form associated with choroidal neovascularization (CNV) and/or pigment epithelial detachment. Age-related macular degeneration is the leading cause of irreversible severe central visual loss in Cauca-sians 50 years old and older in the United States. As yet, there is no proven effective therapy for the nonexudative form of AMD or for the majority of patients with exudative maculopathy.

FDA STATUS/LEGAL STATUS
According to the NIH Office of Dietary Supplements,3 the Dietary Supplement Health and Education Act of 1994 defines dietary supplements as a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, mineral, amino acid, herb, or other botanical; or a dietary substance for use to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above. Any of these must be intended for ingestion in the form of a capsule, powder, tablet, softgel, liquid, or gelcap, and must not be represented as a conventional food or as a sole item of a meal or the diet.

Dietary supplements are widely available through many commercial sources including health food stores, grocery stores, and pharmacies and by mail and on the Internet. Historically in the United States, the most prevalent type of dietary supplement was a multivitamin/mineral tablet or capsule that was available in pharmacies by prescription or “over the counter.” Supplements containing strictly herbal preparations were less widely available. Currently in the United States, a wide array of supplement products are available, including vitamins, minerals, and other nutrients; botanical supplements; and ingredients and extracts of animal and plant origin, but producers of supplements are not allowed to attribute any potential health benefit to their products.

The Dietary Supplement Health and Education Act of 1994 limits the authority of the Food and Drug Administration (FDA) over these products since they are not classified as drugs. The FDA requirement for pre-market review of dietary supplements is less than that over other products it regulates, such as drugs and many additives used in conventional foods. The FDA oversees safety, manufacturing, and product information such as claims, in a product’s labeling, package inserts, and accompanying literature. The Federal Trade Commission, which oversees advertising, has issued advertising guidelines, and has taken a number of enforcement actions against companies whose advertisements contained false and misleading information.

SUMMARY OF EVIDENCE

Search Methods and Study Selection

MEDLINE and the Cochrane Library were searched using the keywords macular degeneration, nutrition, antioxidants, and vitamins. The MEDLINE search was restricted to review articles and to English language. A search of the Cochrane Controlled Trials Register and MEDLINE revealed two systematic reviews on this subject in the Cochrane Library. A search of MEDLINE for additional articles after the submission date of these papers was undertaken using the same keywords.

Statistical Issues and Study Design
According to a Cochrane Library systematic review4 published in November 1998, there have been four published randomized trials where antioxidant vitamin and/or mineral supplementation, alone or in combination, for AMD was compared with a control group. Two of these studies are from the United States,5,6 one is from Austria,7 and one is from Switzerland.8 The Austrian study and one of the US studies6 used zinc sulfate 200 mg daily compared to placebo. The Swiss study and the second US study, the AMD Study Group,5 used a combination antioxidant product compared to placebo. These four trials were small; the number of participants for which data were analyzed ranged from 20 to 151 and the average age was 70 years. The trials used different outcome measures for visual function and AMD progression.

A second Cochrane Library review,9 substantively amended in July 1999, examined evidence supporting the role of supplements in preventing AMD. Only one randomized trial with reported outcomes was eligible for inclusion in the review. This study was added to a larger study of Finnish male smokers, the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC trial).10 In this subgroup of the ATBC trial of 941 subjects (50 to 69 years old), 5 to 8 years of supplementation with alpha-tocopherol or beta-carotene, alone or in combination, was compared to placebo. Only 14 participants were diagnosed with late AMD during the study, which limited the power to detect differences for this group, and 269 cases of early AMD were diagnosed during the study period.

A recent review article,11 which summarized epidemiologic studies of antioxidants and AMD, noted that these are mainly of cross-sectional, longitudinal, or case-control design, with no attempt to control subject intake of antioxidants. This paper reported the results of several large studies with combined participation of over 25,000 subjects. These data, as well as two of the randomized trials in the Cochrane Review, are discussed in another recent review paper.12

Two additional studies were not included in the review papers. One is part of the Blue Mountains Eye Study, a cross-sectional population-based study that included 2900 participants age 49 years and older.13 The second is the Pathologies Oculaires Liées à l’Age (POLA) Study, a population-based study of 1,791 participants.14

Observational studies have returned inconsistent results and must be interpreted with caution. In these studies there is no control on the intake of antioxidants. Those who eat a diet rich in antioxidant substances or who use supplements and those who do not may differ in important ways that may not be adequately controlled for with statistical analyses.4 In cross-sectional and case-control studies, the temporal relationship between nutritional intake and AMD can be difficult or impossible to determine.

Specification of Level of Evidence
The studies cited in the Cochrane Reviews were randomized controlled trials, conducted in such a manner as to produce accurate and reliable data, and they are rated as Level I evidence. However, the conflicting results returned in these studies and in observational studies does not allow for a recommendation based on the evidence.

ONGOING STUDIES
There are five large ongoing studies, four in the United States and one in Australia, with initial results from some of these expected in 2001. In the United States, 4,757 people have been enrolled in the Age-Related Eye Disease Study (AREDS) to examine the effect of vitamin C, E, beta-carotene, and zinc on the clinical course, risk factors, and prognosis for cataract and AMD. This is a multicenter randomized cohort study with a minimum of 5 years of follow-up for each participant, and recruitment ended in August 1997.

Three additional trials in the United States will include AMD in the study outcomes. The Women’s Health Study has randomized 39,876 women to low-dose aspirin and vitamin E. The Physician’s Health Study II will randomize 15,000 male physicians to one of four groups, including beta-carotene and placebo groups. The Women’s Antioxidant Cardiovascular Study has 8,171 women at high risk for cardiovascular disease randomized to vitamin C, E, folate, vitamin B6, and vitamin B12 supplementation.

In the VECAT study in Melbourne, Australia, a total sample of 1,204 people have been enrolled in a trial of vitamin E 500 IU/day and placebo over 5 years. The participants are enrolled based on their cataract status, but presence of AMD at baseline is known and AMD will be an outcome.

BENEFITS

Of the four randomized controlled trials on supplements for AMD in the 1998 Cochrane Library review, one study (n = 151) demonstrated a positive, if limited, effect of a nutritional supplement on vision and progression of AMD.6 Patients in the zinc-treated group were less likely to lose 10 or more letters on the ETDRS chart than controls were and they had slower progression of disease.6 One study compared zinc with placebo (n=40) and found no beneficial effect on visual function or progression of AMD.7 The AMD Study Group compared an antioxidant complex with placebo (n=59) and found a positive effect, but the trial was too small to find a significant effect.5 The last study (n=20) found no difference in objective measures of visual functioning, but more people reported worse visual function in the control group. This study was also too small to detect differences.8

Investigators for the ATBC trial (included in the second Cochrane Library Review), the one randomized controlled trial of supplementation for primary prevention, found no association of either vitamin E or beta-carotene supplement with the development of early AMD.10

A number of observation studies have examined antioxidant micronutrients and AMD, but not always supplements per se. In a review article, Congdon points out the contradictory findings of studies and the need for prospective randomized clinical trials.11 After an extensive review of the literature, Snow and Seddon concluded that supplementation with antioxidant substances has not been demonstrated to decrease the risk of AMD.12 They did suggest that diets with antioxidant-rich fruits and vegetables may be related to a decreased risk of exudative AMD, but these findings should be validated with prospective studies.

In the Blue Mountain Eye Study population (2,900 subjects 49 years old and older), Smith et al did not find associations between age-related maculopathy and dietary antioxidants, (Vitamins A, C, zinc, and carotene) either from diet alone or from supplements.13 In the POLA Study, a population-based study of 1,791 patients, an association was found between late AMD development and plasma vitamin E levels, but not with vitamin C or retinol.14

RISKS
The risk, if any, of supplementation with anti-oxidants is unknown. There are two randomized controlled trials of supplementation in groups of people at high risk for cancer (smokers and asbestos-exposed workers) where high levels of beta-carotene were associated with significantly higher cancer incidence and mortality rates.15,16 One theory on the risk of supplementation with a single product is that protection may require multiple nutrients consumed in a balanced combination at nutritional doses.17

Zinc sulfate supplementation may depress copper levels and cause copper deficiency anemia. Zinc can cause gastrointestinal symptoms, which may deter patients from taking the supplement.

The economic risk of using nutritional supplements is high because the cost can be significant and is seldom covered by health insurance.

QUESTIONS FOR SCIENTIFIC INQUIRY
To understand the role of antioxidant supplements in the prevention and treatment of AMD, the following questions should be answered.

INFORMATION FOR PATIENTS
This material is excerpted from An FDA Guide to Dietary Supplements,11 which is available at http://vm.cfsan.fda.gov/~dms/fdsupp.html

  1. Look for ingredients in products with the U.S.P. notation that indicates that the manufacturer followed standards established by the United States Pharmacopœia.
  2. Realize that the label term “natural” doesn’t guarantee that a product is safe.
  3. Supplement users who suffer a serious harmful effect or illness that they think is related to supplement use should call a doctor or other health care provider.

CONCLUSIONS
The role of antioxidant supplements in the prevention and treatment of AMD is unknown. None of the randomized controlled trials cited in the Cochrane Reviews4,9 adequately answer the question as to whether antioxidant supplements will either prevent the development or stop the progression of AMD. Observational studies have returned conflicting results. It is possible that there are risks in high levels of supplementation of specific antioxidants and minerals.

A general recommendation for use of antioxidant supplements by healthy patients to prevent or treat AMD cannot be clinically supported due to lack of adequate scientific evidence and conflicting study results. The scientific community is waiting for the results of studies such as AREDS and VECAT, which may allow for an evidence-based recommendation on the safety and effectiveness of supplements. Patients can be encouraged to maintain a healthy diet, with consumption of fresh fruits and vegetables, for a variety of health benefits.

DEVELOPMENT OF COMPLEMENTARY THERAPY ASSESSMENTS
Complementary, or alternative therapies, are a growing part of health care in America. Americans spend an estimated $14 billion a year on alternative treatments. Mainstream medicine is recognizing a need to learn more about alternative therapies and determine their true value. Most medical schools in the United States offer courses in alternative therapies. The editors of the Journal of the American Medical Association announced that publishing research on alternative therapies will be one of its priorities. The National Institutes of Health National Center for Complementary and Alternative Medicine has broadly defined complementary and alternative medicine as those treatments and health care practices not taught widely in medical schools, not generally used in hospitals, and not usually reimbursed by medical insurance companies. More scrutiny and scientific objectivity is being applied to determine whether evidence supporting their effectiveness exists.

In the fall of 1998, the Board of Trustees appointed a Task Force on Complementary Therapy to evaluate complementary therapies in eye care and develop an opinion on their safety and effectiveness, based on available scientific evidence, in order to inform ophthalmologists and their patients. A scientifically grounded analysis of the data will help ophthalmologists and patients evaluate the research and thus make more rational decisions on appropriate treatment choices.

The Academy believes that complementary therapies should be evaluated similarly to traditional medicine: evidence of safety, efficacy, and effectiveness should be demonstrated.18 Many therapies used in conventional medical practice also have not been as rigorously tested as they should be. Given the large numbers of patients affected and the health care expenditures involved it is important that data and scientific information be used to base all treatment recommendations. In this way, we can encourage high-quality, rigorous research on complementary therapies.19

Ideally, a study of efficacy compares a treatment to a placebo or another treatment, using a double-masked controlled trial and well-defined protocol. Reports should describe enrollment procedures, eligibility criteria, clinical characteristics of the patients, methods for diagnosis, randomization method, definition of treatment, control conditions, and length of treatment. They should also use standardized outcomes and appropriate statistical analyses.

The goal of these assessments is to provide objective information of complementary therapies and provide a scientific basis for physicians to advise their patients, when asked.

To accomplish these goals, the assessments, in general, are intended to do the following:

REFERENCES

  1. Eye Disease Case-Control Study Group. Antioxidant status and neovascular age-related macular degeneration. Arch Ophthalmol 1993; 111:104–9.
  2. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA 1994; 272:1413–20.
  3. NIH Office of Dietary Supplements, www.nal.usda.gov/fnic/IBIDS/. Accessed May 28, 1999.
  4. Evans JR. Antioxidant vitamin and mineral supplements for age-related macular degeneration (Cochrane Review). In: The Cochrane Library, Issue 1, 1999. Oxford: Update Software.
  5. Richer S. Multicenter ophthalmic and nutritional age-related macular degeneration study-part 2: antioxidant intervention and conclusions. J Am Optometric Association 1996; 67:30–49.
  6. Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc in macular degeneration. Arch Ophthalmol 1988; 106:192–8.
  7. Stur M, Tittl M, Reitner A. Meisinger V. Oral zinc and the second eye in age-related macular degeneration. Invest Ophthalmol Vis Sci 1996; 37:1225–35.
  8. Kaiser HJ, Flammer J, Stumpfig D, Hendrickson P. Visaline in the treatment of age-related macular degeneration: a pilot study. Ophthalmologica 1995; 209:302–5.
  9. Evans JR, Henshaw K. Antioxidant vitamin and mineral supplementation for preventing age-related macular degeneration (Cochrane Review). In: The Cochrane Library, Issue 4, 1999. Oxford: Update Software.
  10. Teikari JM, Laatikainen L, Virtamo J, et al. Six-year supplementation with alpha-tocopherol and beta-carotene and age-related maculopathy. Acta Ophthalmol Scand 1998; 76:224–9.
  11. Congdon NG, West KP Jr. Nutrition and the eye. Curr Opin Ophthalmol 1999; 10:464–73.
  12. Snow KK, Seddon JM. Do age-related macular degeneration and cardiovascular disease share common antecedents? Ophthalmic Epidemiol 1999; 6:125–43.
  13. Smith W. Mitchell P, Webb K, Leeder SR. Dietary antioxidants and age-related maculopathy. The Blue Mountains Eye Study. Ophthalmology 1999; 106:761–7.
  14. Delcourt C, Cristol JP, Tessier F, et al. Age-related macular degeneration and antioxidant status in the POLA Study. Arch Ophthalmol 1999; 117:1384–90.
  15. The Alpha Tocopherol, Beta Carotene Cancer Prevention Study Group (ATBC). 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.
  16. 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.
  17. Hercberg S, Galan P, Preziosi P. Antioxidant vitamins and cardiovascular disease: Dr. Jekyll or Mr. Hyde? (editorial). Am J Public Health 1999; 89:289-91.
  18. Fontanaros PB, Lundberg GD: Alternative medicine meets science (editorial). JAMA 1998; 280:1618-19.
  19. Margolin A, Avants SK, Kleber HD: Investigating alternative medicine therapies in randomized controlled trials (editorial). JAMA 1998; 280:1626-8.

Additional Resources

FDA Center for Food Safety and Applied Nutrition’s Dietary Supplement Web page available at http://vm.cfsan.fda.gov/~dms/supplment.html

Federal Trade Commission available at http://www.ftc.gov

NIH/NEI Statement on Lutein and its Role in Eye Disease Prevention. Available at http://www.nei.nih.gov/news/lutein.htm

NIH Office of Dietary Supplements available at http://dietary-supplements.info.nih.gov/

Prepared by the American Academy of Ophthalmology Complementary Therapy Task Force

Ivan R. Schwab, MD, Chair
Roger Husted, MD
Jeffrey Todd Liegner, MD Harold P. Koller, MD
Sayoko E. Moroi, MD, PhD
Denise Satterfield, MD
Peter R. Holyk, MD, Consultant

Academy Staff:
Nancy Collins, RN, MPH
Margo Leslie
Flora Lum, MD

Approved by the Quality of Care Secretariat January 30, 2000

© Copyright 2000 American Academy of Ophthalmology