An Editorial Response to Dr. Gierhart
An AREDS Researcher Comments
EMILY Y. CHEW, MD

The primary objective of AREDS II is to determine whether oral supplementation with macular xanthophylls (lutein at 10mg/d + zeaxanthin at 2mg/d) and/or omega-3 long-chain polyunsaturated fatty acids (LCPUFAs, docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) at a total of 1g/d) will decrease the risk of progression to advanced AMD, as compared to placebo. Because the subjects enrolled in AREDS II will have intermediate risk of AMD or have advanced AMD in 1 eye, the AREDS formulation will be offered because it reduces the risk of developing advanced AMD by 25%.

AREDS II will also provide an opportunity to assess further refinement of the vitamins and minerals found in the AREDS formulation. We agree with Dr. Gierhart's assessment of the enormous challenge of determining the appropriate formulation for the AREDS II study. Using data from AREDS and from other epidemiologic studies of nutrition and the advice of our nutritional colleagues, we hope to give our best estimate of what may be appropriate components and reasonable therapeutic doses to be evaluated in AREDS II.

Oral supplementation with beta-carotene was proven by 2 large, randomized, controlled clinical trials to increase the risk of lung cancer among cigarette smokers. Because the AREDS formulation is not recommended for smokers, AREDS II will be evaluating a formulation that will eliminate beta-carotene. Approximately one half of the participants enrolled in AREDS II will receive a formulation without beta-carotene. This will offer us an opportunity to evaluate beta-carotene's importance.

Eighty mg of zinc oxide was chosen initially by the AREDS investigators because of the reported beneficial results of treatment in a single-center, randomized, controlled clinical trial of small sample size with short duration of follow-up.¹ The AREDS investigators felt compelled to use this dosage because any negative results using lower doses of zinc would have caused the supporters of zinc therapy to cite the insufficient dose as the reason for failure. Thus this high dose has become a standard of treatment for AMD. Nutritional experts continue to raise concerns about this large dose and its potential side effects. Hospitalization for genitourinary conditions was the main adverse effect reported among participants in the zinc arm of AREDS.

A relationship of zinc with Alzheimer's Disease has been reported in vitro, so we evaluated AREDS participants with cognitive function testing and were not able to find a decrease in such function in participants who were assigned to zinc compared to those assigned to placebo.² As we remain concerned about the high dose of zinc, the AREDS II will have a factorial design in which half of the participants will be given 80 mg zinc oxide while the other half will be given 40 mg of zinc oxide daily.

The 40 mg zinc dosage is being studied because this is the upper tolerable level and recent studies of zinc absorption showed oral doses greater than 25 mg did not increase absorption.

Another interesting and somewhat curious finding from AREDS is that zinc treatment at 80 mg dose was also shown to be associated with decreased mortality (relative risk = 0.73; 95% confidence interval 0.60 – 0.89).³ The significance of this finding is not known as this is a selected population of volunteers in a randomized trial of vitamins and minerals. This needs to be evaluated further in future trials.

Vitamin E is typically given in doses of 400 IU or higher and thus this dose was chosen for AREDS. A recent meta-analysis of vitamin E concluded that doses of vitamin E of 400 IU or higher were associated with an increased risk of mortality.⁴ There were limitations with this analysis because it did not weigh studies on the basis of sample size or follow-up duration. In addition, the analysis used prevalence data rather then incidence data from 19 studies. The distribution-based cut point for exposure was arbitrarily set to 400 IU or higher.

An analysis of studies using 400 – 440 IU of vitamin E in more than 15000 subjects did not yield the same results; there was no strong basis for inferring increased mortality among participants exposed to those vitamin E levels. The pooled risk ratio for these 3 studies was 0.998 with a risk difference of -1.8 per 10000 persons in the direction of benefit. Based on these data, it would appear to be safe to take this dose of vitamin E in the AREDS formulation.⁵ We plan to include 400 IU of vitamin E in the AREDS II formulation.

Similar to AREDS, we will continue to have a dialogue with our nutritional experts regarding the ingredients and their doses for the AREDS II formulation. We have had 2 nutritional workshops to help us determine the appropriate factors and dosages to test in this trial. Although we do not have clear evidence to pick a winning combination, we do have the expertise of nutritionists, epidemiologic data and dietary studies from AREDS to give us the best estimate for the formulation. In addition, we must balance the potential effects of the different doses on important design features such as minimizing the number of tablet or soft gels to improve compliance.

We must also be practical in developing a formulation for our aging population who may be on fixed incomes. Some ingredients such as lutein/zeaxanthin may increase the price of this formulation enormously. Although compelling arguments regarding the ratio of zeaxanthin to lutein (1:1 to mimic the macular ratio) have been set forth by Dr. Gierhart, other experts have pointed to the relationship of beta-carotene and lung cancer as an example for concern. It was hypothesized the high dose of beta-carotene suppressed other important members of the carotenoids family, resulting in malignancy. In general, it is important to give the nutritional supplements in ratios found in nature, such as our serum or dietary ratios of lutein/zeaxanthin intake which consists of 5 parts lutein to 1 part zeaxanthin.

One must maintain this delicate balance in all these factors in establishing the formulations to be tested in AREDS II. We will continue to work with our nutritional colleagues to meet this challenge in improving a formulation that may play an important role in preventing this devastating disease, age-related macular degeneration.

From the National Eye Institute/National Institutes of Health, Bethesda, MD. The author has no financial interest n the information contained in this article.

REFERENCES

1. Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc in macular degeneration. Arch Ophthalmol. 1988;106:192-198.

2. The Age-Related Eye Disease Study (AREDS) 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.

3. The Age-Related Eye Diseases Study (AREDS) 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.

4. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37-46.

5. Chew EY, Clemons T. Vitamin E and the age-related eye disease study supplementation for age-related macular degeneration. Arch Ophthalmol. 2005;123:395-396.