Article Date: 5/1/2006

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Vitamins and Age-Related Macular Degeneration
What we know so far and where we are headed.
SHANTAN REDDY, MD, MPH & HOWARD F. FINE, MD. MHSC

Age-related macular degeneration is the leading cause of severe, irreversible visual loss in developed countries. It affects 4 to 10 million Americans between the ages of 45 and 75. The disease process is considered to begin as a non-neovascular form after which some patients may develop a neovascular form. Though neovascular AMD may be responsible for the majority of those with severe visual loss, 80% of AMD patients are expected to have the non-neovascular form. No treatment to date has been found to prevent the occurrence of AMD.

Table. AREDS Formulation Dosages
Vitamin	Dosage
Vitamin C	500 milligrams
Vitamin E	400 international units
Beta-carotene	15 milligrams
Zinc oxide	80 milligrams
Cupric oxide	2 milligrams

The pathogenesis of this disease is believed to be multifactorial, involving genetic factors, inflammatory factors, oxidative stress, and other factors. The macula may be highly susceptible to oxidative stress since it has a high concentration of polyunsaturated fatty acids and is continuously exposed to light and oxygen.¹ There is strong evidence suggesting that lipofuscin is derived from oxidatively damaged photoreceptors. It has also been shown that age-related oxidation occurred more aggressively in groups assigned to no antioxidant supplementation as compared to those who received supplementation.² The retina's defenses to such processes include enzymes, such as selenium-dependent glutathione (GSH) peroxidases and catalases, and antioxidant nutrients such as vitamins E and C and carotenoids.¹ With this understanding, it has been hypothesized that people with low levels of these antioxidants may be more prone to oxidative damage in the retina, which may ultimately lead to AMD. Taking this a step forward, consuming higher levels of these antioxidants may protect an individual from developing AMD.

BEFORE AREDS

Prior to the Age-Related Eye Disease Study (AREDS), many epidemiologic studies have provided some support to this hypothesis, though the results were inconsistent. The National Health and Nutrition Examination Survey (NHANES) found that the intake of fruits and vegetables rich in vitamin A was lower in those subjects with AMD.³ The Pathologies Oculaires Liees a l'Age (POLA) Study demonstrated a relationship between alpha-tocopherol and AMD, finding a weak protective association with late AMD only.⁴ Given the lack of definitive evidence for the beneficial effect of antioxidant supplementation and the growing concern of widespread use of unproven, high-dose supplements, the National Eye Institute performed a randomized, multi-centered, placebo controlled clinical trial designed to evaluate the effect of high doses of zinc, vitamins C and E, and beta-carotene on the incidence and progression of AMD.

AREDS I

Figure 1. Fundus photograph to illustrate drusen size. (Excerpted with permission from AREDS report no.18) In the 8-o'clock meridian, about 1 disc diameter from the center of the macula, there is a large druse, slightly larger than the minimum required to meet the �125 μm (width of an average large vein at the disc margin) definition. At 5:30, near the edge of the photograph, there is an intermediate druse, defined as �63 μm but <125 μm in diameter.

The first AREDS study enrolled 3640 subjects, who had an average follow-up of 6.3 years, few of whom (2.4%) were lost to follow-up. Subjects in the intervention group were assigned to vitamin doses that were 5 to 15 times the recommended dietary allowances (RDA) [C (500 mg) and E (400 IU), beta-carotene (15 mg), zinc oxide (80 mg with 2 mg of copper)] (Table).⁵ The initial high dose of zinc at 80 mg was chosen in AREDS because of a reported beneficial effect at this dose in a previous study.⁶

The participants were divided into 4 groups. One group received the antioxidants alone, 1 received the antioxidants plus zinc, the other zinc alone, and 1 group received placebo, serving as the control. Participants could be enrolled with few to no drusen, and 1 eye had to have a visual acuity (VA) of 20/32 or better. Patients were categorized into 4 groups. Category 1 was intended to evaluate the effect of supplementation on cataract progression. Category 2 had multiple small drusen, few intermediate drusen, or pigmentary changes. Category 3 had extensive intermediate drusen or any amount of large drusen. And Category 4 had advanced AMD in only 1 eye, which was defined as geographic atrophy involving the fovea, choroidal neovascularization, or exudative detachments (Figures 1, 2). The study reported that zinc alone, antioxidants alone, or the combination of the 2 modestly prevented the progression to advanced AMD from Categories 3 and 4. Furthermore, they found that the combination of antioxidants and zinc was more effective than either group alone. Specifically, the vitamin formulation decreased the risk of advanced AMD by 25% for participants with intermediate AMD. Participants who began the study with early AMD were so unlikely to develop advanced AMD (1.3%) during the course of their study that the beneficial effect on this group could not be evaluated. Combination formulations also decreased the risk of moderate visual loss of 3 lines or more at 5 years compared to baseline by about 19%. Those receiving either antioxidants alone or zinc alone failed to achieve statistical significance.⁵

The AREDS group also examined the effects of treatment with AREDS formulation on the progression of further vision loss in eyes with advanced AMD and the effects on mortality.⁷ They found that persons assigned to the antioxidants alone had a reduced risk of progression to VA loss of
3 lines. Those in the zinc group alone or the combination group also enjoyed a protective effect. They reported that after a median follow-up of 6.5 years, 11% of the
4753 AREDS participants had died. Mortality increased with worsening macular pathology. Though a relationship between zinc and Alzheimer's disease has been reported, AREDS found a decreased mortality (relative risk = 0.73) associated with a dose of 80 mg and there were no cognitive deficiencies found in participants. Furthermore, vitamin E was not found to increase the risk of mortality. They concluded that the AREDS formulation is safe for patients with intermediate AMD and those with advanced disease in 1 eye.

Jampol illustrated potential weakness in this study that should be considered when interpreting the data.⁸ First, the exclusion of Category 2 patients from many of the analyses is troubling because it occurred after reviewing the data. Second, the trial was only marginally powerful in demonstrating a beneficial effect of the vitamins, though it had a long follow-up. Third, many of the results were reported as trends since they did not meet statistical significance set a priori. Fourth, we cannot determine which or if all of the antioxidants provided the protective effect.

SINCE AREDS

Since the publications of AREDS results, many studies have looked at the effects of supplementation and dietary intake on early AMD. The Blue Mountain Eye Study in Australia used a questionnaire to assess the intake of 11 micronutrients which included, among others, lutein, zeaxanthin, vitamin A and C via diet, zinc via diet, and
supplements.⁹ The study found no significant associations or trends between dietary intake or dietary intake combined with zinc and the incidence of early AMD, the 5-year incidence of AMD, or the 5-year progression from category 1 or 2 to category 3 or 4. The Blue Mountain Eye Study also reported on the association between vitamin and zinc supplementation and the prevalence of AMD.¹⁰ They found no benefit for any type of supplement. The results of these
2 studies cannot be overlooked given their large sample sizes (2335 patients and 2873 patients, respectively). The vitamin E, cataract, and age-related maculopathy trial (VECAT), a double-masked randomized, placebo controlled trial, found no benefit of daily vitamin E supplements in reducing the risk of early AMD or preventing the progression of AMD.¹¹

Figure 2. Fundus photographs from participants in the AREDS illustrating eyes in AMD Categories 2 and 3. (Excerpted with permission from AREDS report no. 8)(5) A. Left eye in Category 2 shows nonextensive intermediate drusen, mostly located superotemporal to the center of the macula. No druse is 125 μm or greater in diameter, although some are 63 μm or greater and their cumulative area is less than AREDS circle O-2 (about 0.2 disc areas). B. One left eye in Category 3 depicts the lower limit of the category, having 1 large druse (�125 μm in diameter) in the 8-o'clock position from the center of the macula, while another left eye (C) shows many large drusen (totaling at least 1 disc area) scattered throughout the macula.

THE SOCIAL IMPACT

Bressler and associates more recently estimated the potential public health impact of the findings of AREDS on reducing the number persons developing advanced AMD over 5 years.¹² They determined that more than 300 000 people with intermediate AMD would avoid advanced AMD and any associated visual loss over 5 years if they were compliant with the recommendations. However, Jampol found that only 42% of his patients were on the correct dosage of supplementation in his office.¹³ A trial following AREDS found that only 45% of participants eligible for supplementation were taking the AREDS type formulation (Frederick Ferris, MD, unpublished data 2003).

Though compliance may not be as high as reported in the AREDS study (75%), many patients have become informed about the availability of antioxidant products and the claims made for their benefit. Consequently, their use is becoming more widespread. A survey was conducted to compare the ingredients of various products with the current AREDS recommendations. The survey identified
22 eye nutrient products. Although 75% of the products contained all the constituents present in the AREDS formulation, only 2 contained the dosages recommend by the AREDS study.¹⁴ Then, in order to reap the entire benefits put forth by Bressler and associates, ophthalmologists need not only stress compliance, but must also familiarize themselves with the various products and educate their patients on which brands of supplements they should take.

ADVERSE OUTCOMES

Like any intervention, the potential for adverse outcomes cannot be overlooked. The AREDS reported an increased risk for genitourinary hospitalization (urinary tract infections, prostatic hyperplasia, and stress incontinence) in patients taking zinc; however, this was only a trend.⁵ Vitamin E may not be advisable for patients with bleeding problems or who are on anticoagulation. There have been findings of an increased risk of intracerebral and subarachnoid hemorrhage during treatment with carotene and alpha-tocopherol.¹⁵ Other evidence has shown that large amounts of vitamin A may lead to osteoporosis and hip fractures.¹⁶ More importantly, in light of strong evidence showing that beta-carotene may be harmful in smokers, most ophthalmologists now recommend high doses of vitamins E and C and zinc without beta-carotene to smokers or ex-smokers. However, we still cannot say with certainty that this combination without beta-carotene is as effective as the combination given in AREDS.

OTHER CAROTENOIDS

Figure 3. Approximate 5-year rates of progression to advanced AMD. EXCERPTED WITH PERMISSION FROM AREDS REPORT NO.18(27)

This brings up another issue, which is the beneficial effect of other carotenoids such as leutin and zeaxanthin, since ophthalmologists are now reluctant to use beta-carotene. A case-control study in the Netherlands found that the prevalence of AMD in patients with low-antioxidant intake and low-lutein intake was twice that found in patients with high intake.¹⁷ Other epidemiologic studies showed that patients with low-dietary intake of leutin and omega-3 fatty acids have an increased risk associated with AMD.^18,19

AREDS II

The National Eye Institute is conducting another study, AREDS II, to determine whether oral supplementation with leutin at 10 mg/d and zeaxanthin at 2 mg/d and/or omega-3 long-chain polyunsaturated fatty acids (LCPUFA, docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA] at a total of 1 g/d) will decrease the risk of progression to advanced AMD.²⁰ Again, the participants are divided into 4 groups. One group in the study will be assigned to placebo, 1 to leutin/zeaxanthin, 1 to omega-3 LCPUFA, and 1 to the combination of the 2. The AREDS II will include patients in AREDS Category 3 and 4 and the sample size will be approximately 4000 patients. Approximately half of the participants enrolled who choose to take the AREDS formulation will receive a new preparation without beta-carotene. This will help determine the benefit beta-carotene made in the formulation. In addition, the dose of zinc will be lowered by one half (40 mg) in those who choose to take the AREDS formulation.

ALTERNATIVE THERAPY AND USES

Other unconventional nutrients have been suggested to play a protective role in AMD. The best known is the extract anthocyanosides of the vaccinium myrtillus (bilberry) plant, which is a potent antioxidant. Studies have shown that bilberry has a strong affinity for the retinal pigment epithelial cells and it may prevent macular degeneration in rat models.²¹ However, these results should be taken with caution since clinical trials have not demonstrated its efficacy in humans as of yet.

Vitamins have been used to treat retinal diseases other than AMD. Vitamin A with docosahexaenoic acid had been shown to reduce the progression of retinitis pigmentosa over 2 years.²² Vitamin A has also been shown to help slow the progression of hereditary abetalipoproteinemia (Bassen-Kornzweig syndrome),²³ and may be helpful as well in Sorsby fundus dystrophy.²⁴ Refsum's disease may be treated with a diet low in phytanic acid.²⁵ Finally, vitamin B6 along with a diet restricting arginine may be helpful in slowing the progression of gyrate atrophy.²⁶

CONCLUSIONS

Dietary supplementation with the AREDS formulation of vitamins has clearly been shown in the AREDS I trial, a large, prospective, randomized, placebo-controlled trial, to be of benefit in patients with intermediate and advanced AMD (Categories 2-3). Ophthalmologists should educate themselves and their patients as to which products and dosages are consistent with the AREDS recommendations. Additionally, instructing patients to consume diets rich in fruits and vegetables, particularly green leafy and yellow-orange vegetables, is reasonable.

Clinicians can use a simplified severity score from the AREDS I study to better inform patients of their risk of AMD progression.²⁷ Patients are evaluated for both macular drusen size and the presence or absence of pigmentary abnormalities. Large drusen are those with a diameter >125 μm (the width of a retinal vein emerging from the optic disc). Patients receive a point for each eye with at least 1 large druse, and a point for each eye with pigment abnormalities. The maximum risk score therefore is 4. The risk of advanced AMD within 5 years with risk factor scores of 0, 1, 2 ,3, and 4, respectively are: 0.5%, 3%, 12%, 25%, and 50% (Figure 3).

Understanding the beneficial effects of vitamin supplementation has drastically changed how we approach patients with non-neovascular AMD. It allows us an avenue to halt a relentless and destructive disease. Preventing disease progression is far preferable to treating it once vision loss has occurred. We are anxiously waiting to learn if lutein, zeaxanthin, and omega-3 fatty acids will prove to be protective against the development of advanced AMD. The results from AREDS II will ultimately determine whether these should be added to the currently accepted formulations. As we continue to make headways in understanding the various etiologies of AMD, we will be empowered to develop newer and more effective means of prevention, and hopefully someday find a cure.

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Shantan Reddy, MD, is from the Department of Ophthalmology, New York University School of Medicine. Howard F. Fine, MD, is from the Vitreous-Retina-Macula Consultants of New York and the LuEsther T. Mertz Retina Research Center, Manhattan Eye, Ear, and Throat Hospital. Neither author has financial interest in the information in this article. Dr. Fine can be reached by e-mail at vrmny@aol.com.

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Retinal Physician, Issue: May 2006