Are Antioxidant Vitamins and Minerals Dangerous? The Role of Antioxidants, Minerals, and Nutrition in AMD

EMILY Y. CHEW, MD

Age-related macular degeneration (AMD) is the leading cause of vision loss in older persons in the United States. Nutritional status is a risk factor associated with 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%. 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 2030. Treatment with antioxidant vitamin supplements, however, must be balanced with potential adverse effects. More recent data from meta-analyses have suggested that harmful effects may be associated with oral supplements with vitamins. The assessment and interpretation of such studies are included in this report.

BACKGROUND OBSERVATION

A number of observational studies have shown the protective association of increased dietary intake of antioxidant vitamins with decreased risk of AMD.^1-3 The Rotterdam Study investigators found that regular dietary intake of antioxidants was associated with a lower risk of incident AMD.⁴ In this study, a high dietary intake of beta carotene, vitamins C and E, and zinc (similar to the AREDS-type formulation, see below) was also associated with a substantially reduced risk of AMD in elderly persons. The Reykjavik Eye Study evaluated the 5-year risk factors for incident AMD in a random sample of individuals 50 years and older and found that consuming dietary-fiber-rich vegetables was also associated with a lower risk of developing drusen.⁵ People who eat meat and meat products once a week or less, compared with those who eat it more frequently, experienced decreased risk of pigmentary abnormalities. These studies all implicate the role of nutrition in AMD.

THE AGE-RELATED EYE DISEASE STUDY (AREDS)

The Age-Related Eye Disease Study was designed as a study of the clinical course of age-related lens opacity and AMD and a randomized controlled trial of high-dose antioxidants and zinc to reduce progression of eye diseases common in the elderly.⁶ Participants with small and few intermediate drusen (category 2), extensive intermediate drusen or large drusen (category 3), or advanced AMD in 1 eye, either geographic atrophy in the center or neovascular AMD (category 4), were randomized in a factorial design to antioxidant vitamins and/or zinc. This formulation included vitamin C (500 mg), vitamin E (400 IU), beta carotene (15 mg), zinc (80 mg of zinc oxide), and copper (2 mg of cupric oxide). The results of this study demonstrated a statistically significant benefit of the combination of high-dose antioxidant vitamins and zinc in providing a moderate reduction in the risk (25% reduction for the entire study population [categories 2 to 4]; 34% reduction for the population of patients with AREDS [categories 3 or 4]) of developing advanced AMD over a median of 6.3 years of follow-up in persons at high risk.

Following the termination of the randomized, controlled clinical trial in October 2001, follow-up of the AREDS participants continued until December 2005. The beneficial effects of the AREDS-type supplements were demonstrated to persist at a similar level of protection. Persons with AREDS category 3 AMD (bilateral large drusen; see Figure) or patients with advanced AMD (neovascular AMD or geographic atrophy) in 1 eye should consider taking the AREDS-type formulation to prevent the development of advanced AMD. For persons with early AMD, however, the AREDS-type supplements did not prevent the progression from category 2 to category 3. The risk of developing advanced AMD was also exceedingly low, making it unlikely that persons with less severe AMD than category 3 will benefit from the use of AREDS-type supplements.

ADVERSE EFFECTS

Observed side effects were minimal for the AREDS participants. A potential for an increase in genitourinary hospitalizations (eg, unspecified urinary tract infection and prostatic hyperplasia in men and stress incontinence in women) was more frequent in participants randomly assigned to the zinc arms (7.5% vs 4.9%, P=.001), compared with those not assigned to zinc.³ Results from other studies suggested that persons who smoke should not take beta carotene because of the increased risk of developing lung cancer and its associated mortality.^7,8 Although there were data suggesting that zinc supplementation may result in Alzheimer's disease, no impact of any of the AREDS-type treatments was detected on cognition in the study participants.⁹ An analysis of zinc vs no zinc found a significant benefit in mortality reduction (relative risk, 0.73; 95% CI: 0.61-0.89).^8,10

OTHER REPORTS OF VITAMINS AND MINERALS

More recent meta-analyses have questioned the beneficial effects of multivitamins or specific ingredients of the AREDS-type formulation. This has led to concerns among physicians recommending the AREDS-type formulation for patients at risk of developing AMD. The first study was a meta-analysis of 19 studies, including AREDS, for the effects of vitamin E on mortality.¹¹ The investigators arbitrarily considered vitamin E doses of 400 IU and higher as a "high dose" that increased the risk of mortality. Further analyses of the 3 studies using doses of approximately 400 IU of vitamin E showed no increased mortality with a risk ratio of 0.998.¹² Vitamin E did not show a benefit in prolonging survival, but at doses around 400 IU, there was no suggestion of harmful effects. The combination treatment with antioxidant vitamins and zinc showed no increased mortality, but a 14% reduction in mortality risk in the AREDS population. This lack of harmful effect on mortality, along with the beneficial effects of the AREDS formulation on the reduction of development of advanced AMD, would suggest persons who had been taking the AREDS formulation should continue to take it, in consultation with their physicians.

In March 2007, another meta-analysis of 68 randomized trials was published in JAMA, again suggesting that antioxidant vitamins, vitamin A, vitamin E, and beta carotene may increase mortality.¹³ The overall results of this study showed no differences in mortality (relative risk of 1.02, 95% CI: 0.98-1.06). The investigators conducted subgroup analyses using flawed statistical methodology and concluded that antioxidant vitamins were harmful. These subgroup analyses were refuted by other investigators.¹⁴ Others were concerned that the major contributions to the analyses were large trials, especially those of beta carotene, in which heavy smokers were included, creating negative bias toward the final analyses.¹⁵ These investigators conducted similar analyses for the Cochrane Review and drew similar conclusions in a more recent publication.¹⁶ It must be noted that the main effect was that there was no difference in mortality between those taking antioxidant vitamins and placebo. Again, this suggests that the AREDS-type supplement should not be withheld from individuals who are at intermediate or higher risk of AMD.

A report regarding a possible link between multivitamins and prostate cancer risk also raised alarm among patients who are taking the AREDS-type supplements.¹⁷ This is a prospective study in which 295 344 men were surveyed for the development of prostate cancer over a period of 5 years. Multivitamin use was assessed at baseline as part of a self-administered food frequency questionnaire. Overall, there was no association observed between multivitamin use and the risk of localized prostate cancer. However, there appeared to be an increased risk of advanced prostate cancer in patients taking multivitamins more than 7 times per week. This association was found to be strongest in those men with a family history of prostate cancer or men who took individual micronutrient supplements that included selenium, beta carotene, or zinc. These are observational data and have not been proved by randomized, controlled clinical trials. Men who take high doses of the multivitamins may be very different from their peers. Already, they are more likely to have a family history of prostate cancer, which may indeed indicate latent disease that becomes manifest later. These men were also more likely to undergo prostate-specific-antigen screening for prostate cancer. In addition, most of the other studies of randomized trials of beta carotene did not show an increased risk of prostate cancer. The results of the AREDS study, which had the longest duration of therapy and the largest dose of zinc given in any study, showed that the rate of prostate cancer was similar in those taking zinc compared to those not taking zinc (1% in each arm). The evidence for the harmful effects of antioxidants for prostate cancer will require further evaluation. Currently, there is a trial, the SELenium and vitamin E Cancer prevention Trial (SELECT) that is testing a number of antioxidant vitamins, selenium, and vitamin E in more than 32 400 participants.¹⁸ The study is continuing to enroll and follow patients at risk of prostate cancer.

AGE-RELATED EYE DISEASE STUDY 2 (AREDS2)

AREDS-type supplements will be evaluated further in a current study sponsored by the National Eye Institute, the Age-Related Eye Disease Study 2 (AREDS2). The original AREDS-type supplement doses will be compared with formulations with lower zinc levels (25 mg) and/or no beta carotene in a secondary randomization. The main focus is to examine the role of oral supplementation with macular xanthophylls lutein/zeaxanthin and omega-3 fatty acids for the treatment of AMD. Data from AREDS and other studies showed that increased dietary intake of lutein/zeaxanthin (found in green leafy vegetables) and omega-3 long-chain polyunsaturated fatty acids (LCPUFAs, found in fish) were associated with a decreased risk of advanced AMD. These observational data are being tested with a randomized, controlled clinical trial in AREDS2.

Until AREDS2 is completed, the current recommendation for patients with bilateral large drusen and those with advanced AMD in 1 eye is to take the AREDS-type supplements. Patients who are smokers should avoid taking beta carotene. We will continue to monitor the adverse effects, including mortality, in these participants taking the various forms of the AREDS-type formulation, as well as those associated with lutein/zeaxanthin and/or omega-3 LCPUFAs. At the conclusion of AREDS2, we will have more data to address the issues of adverse effects of vitamins, minerals, and omega-3 LCPUFAs for the therapy of AMD. RP

REFERENCES

1. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA. 1994;272:1413-1420.
2. Snellen EL, Verbeek AL, Van Den Hoogen GW, Cruysberg JR, Hoyng CB. Neovascular age-related macular degeneration and its relationship to antioxidant intake. Acta Ophthalmol Scand. 2002;80:368-871.
3. The Age-Related Eye Disease Study Research Group; SanGiovanni JP, Chew EY, Clemon TE, et al. The relationship of dietary carotenoids, vitamin E, and vitamin C with age-related macular degeneration: a case-control study in the Age-Related Eye Disease Study. AREDS Report Number 22. Arch Ophthalmol. 2007;125:1225-1232.
4. van Leeuwen R, Boekhoorn S, Vingerling JR, et al Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA. 2005;294: 3101-3107.
5. Arnarsson A, Sverrisson T, Stefansson E, et al. Risk factors for five-year incident age-related macular degeneration: the Reykjavik Eye Study. Am J Ophthalmol. 2006;142:419-428.
6. The Age-Related Eye Disease Study Research Group. A randomized, placebocontrolled, 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.
7. 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, 334:1150-1155.
8. 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;330:1029-1035
9. The Age-Related Eye Disease Study Research Group. Impact of antioxidants, zinc, and copper on cognition in the elderly. A randomized, controlled trial. AREDS Report No. 12. Neurology. 2004;63:1705-1707.
10. The Age-Related Eye Disease Study Research Group. Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the Age-Related Eye Disease Study. AREDS Report No. 13. Arch Ophthalmol. 2004;122:716-726.
11. Miller ER, Pastor-Barrluso R, Darshan D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Inter Med. 2005;142:37-46.
12. Chew EY, Clemons T. The Age-Related Eye Disease Study supplementation for age-related macular degeneration. Arch Ophthalmol. 2005;123:395-396.
13. Bjelakovic G, Nikolova D, Lotte Gluud L, Simonetti R, Gluud C. Mortality in randomized trial of antioxidant supplements for primary and secondary prevention. Systematic review and meta-analysis. JAMA. 2007;297:842-857.
14. Albanes D. Letter to the Editor. JAMA. 2007;298:400.
15. Huang HY, Teutsch S, Bass E. Letter to the Editor. JAMA. 2007;298:400-401. Response from Authors 402-403.
16. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases (Review) Cochrane Library 2008; Issue 2:1-187.
17. Lawson KA, Wright ME, Subar A, et al Multivitamin use and risk of prostate cancer in the National Institutes of Health – AARP Diet and Health Study. J Natl Cancer Inst. 2007;99:754-764.
18. Lippman SM, Goodman PJ, Klein EA, et al. Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Natl Cancer Inst. 2005;97: 94-102.