to genitourinary problems, most commonly prostate enlargement. Other studies have reported that zinc may cause a decrease in highdensity lipoprotein (“good”) cholesterol or an increase in low-density lipoprotein (“bad”) cholesterol, but this was not evident in the AREDS results. Nutritional experts continue to raise concerns about the widespread, common, and chronic use of such a large dose. AREDS2 will study the effects of reducing the dose of zinc from the original AREDS formulation (from 80 to 25 mg) on the development and progression of AMD.
Vitamin E is commonly used at doses of 400 IU. A meta-analysis of 19 studies concerning vitamin E concluded that 400 IU and higher doses were associated with an increased mortality risk.48 However, a follow-up analysis of studies using 400–440 IU of vitamin E in more than 15 000 participants showed that there was no strong basis for inferring increased mortality among participants exposed to these levels of vitamin E. The pooled risk ratio for these three studies was 0.998 with a risk difference of −1.8 per 10 000 persons in the direction of benefit or reduced mortality. Based on these data, it appears to be safe to take the 400-IU dose of vitamin E found in the AREDS formulation.49
EPIDEMIOLOGIC DATA OF ASSOCiATION OF FAT AND ω-3 LCPUFAs WITH AMD
In the Beaver Dam Study, patients with the highest intake of saturated fat and cholesterol were at an 80% increased risk of early AMD. Similar results were found for advanced AMD, but were not statistically significant.50 Saturated, monounsaturated, polyunsaturated, and trans unsaturated fats increased the likelihood of progression for the highest fat intake quartile relative compared with the lowest fat intake quartile.
Docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA) are part of the family of omega-3 long-chain polyunsaturated fatty acids (ω-3 LCPUFAs) that are found in high concentrations in the retinal tissue. ω-3 LCPUFAs may influence factors and processes important in the angiogenesis cascade, gene expression, and may be potent regulators of retinal cell survival, inflammation, and energy balance. The main sources of ω-3 LCPUFAs are fish products.
In people reporting the highest levels of ω-3 LCPUFAs and fish intake (two or more servings a week), there is a decreased likelihood of having advanced neovascular AMD relative to people reporting the lowest levels of intake.51 This was noted especially when intake was in conjunction with lower levels of another fatty acid, linoleic acid. The Blue Mountains Eye Study, a population-based study, showed that eating fish 3 times per week could reduce the incidence of advanced AMD (odds ratio, 0.25; 95% CI, 0.06–1.00).52 These results and those from other observational analytic investigations41,53 suggest that modifying diet to include more foods rich in ω-3 LCPUFAs could result in a reduction in the risk of having neovascular AMD.54–58
AVAILABLE SUPPLEMENTS FOR MACULAR DEGENERATION
At the time of study development, lutein and zeaxanthin were not commercially available as supplements. Therefore, the supplements evaluated by the AREDS researchers contained:
● 500 mg vitamin C ● 400 mg vitamin E ● 15 mg beta-carotene
● 80 mg zinc as zinc oxide
● 2 mg copper as cupric oxide.
With the availability of the new antioxidants and their benefit reports, several formulations of supplements became available with the original AREDS combination, as well as variations for smokers and with additional antioxidants (Table 8.1).
Table 8.1 Vitamin supplements for age-related macular degeneration
Supplement
AREDS formula
AREDS formula for smokers or ex-smokers (without beta-carotene)
AREDS lutein and/or zeaxanthin formulas
Brand name and manufacturer
Ocuvite PreserVision: Bausch & Lomb
Icaps AREDS Formula: Alcon ProtectRx: ScienceBased Health VisiVite Original Formula: VisiVite
Viteyes Original Formula: Vitamin Health, LLC
Retinavites Smoker’s Formula
MaculaRx Plus (1/10th AREDS beta-carotene dose)
VisiVite Smoker’s Formula (lutein 10 mg)
Viteyes Smoker’s Formula (lutein 10 mg and zeaxanthin 2 mg)
Preservision Lutein Soft gels (lutein 10 mg)
Ocuvite Lutein (6 mg)
ICaps Lutein and Zeaxanthin Formula (lutein 4 mg zeaxanthin 4 mg)
Visivite Premier Ocular formula 2 (lutein 10 mg zeaxanthin 2 mg)
AREDS, Age-Related Eye Disease Study.
IMPLICATIONS OF RETINAL SUPPLEMENT PHARMACOLOGY
Dietary supplements are intended to enhance the diets of some people, but should not aim to replace the important balance of a variety of foods. Physicians and patients need to take diet into consideration when choosing the right supplement. Patients should be counseled to discuss any dietary supplement intake with their primary physician to ensure that there are no interactions with underlying medical conditions as well as with regular prescription and other over-the-counter medicines. If elective surgery is planned, supplement intake should be reviewed in detail several weeks prior.
Dietary supplement products are not reviewed by the government before they are marketed. Manufacturers are responsible for making sure their product is safe before it goes to market, but the Food and Drug Administration (FDA) has the responsibility to take action against any unsafe dietary supplement product. Adverse effects should be reported to the FDA by calling 1-800-FDA-1088, by faxing 1-800-FDA-0178 or online at the FDA website www.fda.gov/medwatch/how.htm. More information on what dietary supplements are and how they are regulated, including the labeling and claims that can be made for supplements, can be found at www.cfsan.fda.gov/~dms/ ds-faq.html.59
FUTURE DIRECTIONS: AREDS2
Based on all of the available nutritional evidence, the National Eye Institute developed the AREDS2 study, which started enrolling in September 2006 and completed enrollment in September 2008. It is
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Degeneration Macular Related-Age for Supplements• 8 chapterand Vitamins
Table 8.2 The four formulations of the original AgeRelated Eye Disease Study (AREDS) formulation that will be tested in the secondary randomization of AREDS2
|
1 |
2 |
3 |
4 |
Vitamin C |
500 mg |
500 mg |
500 mg |
500 mg |
Vitamin E |
400 IU |
400 IU |
400 IU |
400 IU |
Beta- |
15 mg |
0 mg |
0 mg |
15 mg |
carotene |
|
|
|
|
Zinc |
80 mg |
80 mg |
25 mg |
25 mg |
oxide |
|
|
|
|
Cupric |
2 mg |
2 mg |
2 mg |
2 mg |
oxide |
|
|
|
|
|
|
|
|
|
currently in the follow-up phase. Its primary objective is to determine whether oral supplementation with macular xanthophylls (lutein at 10 mg/day + zeaxanthin at 2 mg/day) and/or ω-3 LCPUFAs (DHA 350 mg and EPA 650 mg for a total of 1 g/day) will decrease the risk of progression to advanced AMD, compared with placebo. AREDS2 will also study the effects of these nutritional supplements on moderate vision loss and on the development of cataracts. The study has enrolled 4203 participants aged 50–85 years, who at the time of enrollment have sufficiently clear lenses for quality fundus photographs and have either bilateral large drusen or large drusen in one eye and advanced AMD (neovascular AMD or central geographic atrophy) in the fellow eye. Of the primary randomization agents, one-quarter of the patients will be assigned placebo, another quarter lutein/zeaxanthin, one-quarter ω-3 LCPUFAs, and the final quarter a combination of the two.
Because the study population in AREDS2 is at least moderately at risk of AMD, all participants will be offered the original AREDS formulation. Because of this opportunity, a second randomization was designed to evaluate the possibility of deleting beta-carotene and decreasing the current dose of zinc. The secondary randomization agents (AREDS-type supplement) formulations are divided into the four inclusion groups listed in Table 8.2. Participants who are smokers are also then included in AREDS2 and they would be randomly assigned to either formulation 2 or formulation 3 in the AREDS supplements in the secondary randomization. It is also recognized that some participants may consider it difficult not to take the original AREDS formulation, the proven formulation for persons with moderate AMD, and they would be allowed to do so. It is also possible that some participants may not be able to tolerate the AREDS formulation and they would also be allowed to withdraw from this secondary randomization.
SUMMARY AND KEY POINTS
The savings gained from preventive therapy for AMD are enormous. It is estimated that about 55 million people in the USA may be at risk of advanced AMD. Of these, 8 million are at high risk, and are thus likely to benefit from the current vitamin formulation of zinc and antioxidant therapy. The economic benefits associated with the prevention of progression to advanced AMD in even a small proportion of cases is significant and will result in major cost savings to individuals and society at large.60
● If all 8 million people at a high risk of advanced AMD took the supplement therapy, more than 300 000 of them could be saved from developing loss of vision in the next 5 years.
The evidence that oxidative stress, diet, and nutrition play crucial roles in the pathogenesis of early AMD and its progression to AMD is now
compelling. Further studies, like the ongoing AREDS2, are essential in order to find the key micronutrients that may be effective in the prevention of AMD in the future.
● AREDS showed that antioxidant intake reduced the risk of developing advanced AMD by 25% compared with placebo at 5-year follow-up.
● Observational data suggest that higher dietary intakes of lutein, zeaxanthin, and ω-3 LCPUFAs were associated with decreased risk of AMD.
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