Official Word

The leader of the AREDS2 research group analyzes data, recommendations and current practices from her perspective at the National Eye Institute.

By Emily Y. Chew, MD

Data on the role of vitamin and nutritional therapy accumulates quickly from around the globe these days, producing an array of confusing and sometimes conflicting claims. I would like to respond to common questions with an update on AREDS2 and evidence-based recommendations.

1. What will AREDS2 accomplish — and when will we know?

AREDS2 is a 5-year, controlled clinical trial involving 4,203 subjects at 82 centers. Our primary objective is to determine whether oral supplementation with macular xanthophylls and omega-3 long-chain polyunsaturated fatty acids will decrease the risk of progression to advanced age-related macular degeneration (AMD) when compared to placebo. The xanthophylls include lutein (10 mg/d) and zeaxanthin (2 mg/d). The omega-3 fatty acids include docosahexaenoic acid (DHA 350 mg/d) and eicosapentaenoic acid (EPA, 650 mg/d). AREDS2 is also studying the effects of these nutritional supplements on moderate vision loss and on the development of cataracts.

The results of AREDS2 will likely be ready for publication in the spring of 2013, after the final study visits conclude in December of 2012.

2. What other issues are being addressed in AREDS2?

Other issues include:

■ Measurement of macular pigment
■ Longitudinal study of OCT findings in AREDS2 participants
■ Genetic studies
■ Study of fundus autofluorescence
■ Detection of peripheral drusen for phenotyping, using wide-angle fundus views provided by the optomap Retinal Exam (Optos)
■ Evaluating the role of early detection of choroidal neovascularization using the ForeseeHome AMD Monitor (Notal Vision)

3. What types of patients are being studied in AREDS2?

Study subjects, aged 50 to 85 years, were determined to have sufficiently clear media to allow for quality fundus photographs at the time of enrollment. The subjects also have either:

■ Bilateral large drusen or
■ Large drusen in one eye and advanced AMD (neovascular AMD or central geographic atrophy) in the fellow eye.

We enrolled study participants who primarily had simple scale scores of 3 and 4. The AREDS simplified severity scale¹ is derived from the complex nine-step severity scale.² The simplified scale was based on gradings of fundus photographs in AREDS. Rates of progression to advanced AMD were assessed by cross-tabulating the presence or absence of drusen and pigment abnormalities. Large drusen and pigment changes were particularly predictive of developing advanced AMD.

The scoring system developed for patients assigns to each eye one risk factor for the presence of one or more large drusen (≥ 125 µm, equivalent to the width of a large vein at the disc margin) and one risk factor for the presence of any pigment abnormality. Risk factors are summed across both eyes, yielding a 5-step scale (0-4) on which the approximate 5-year risk of developing advanced AMD in at least one eye increases.

Here is the easily remembered sequence:

■ 0 factors, 0.5%
■ 1 factor, 3%
■ 2 factors, 12%
■ 3 factors, 25%
■ 4 factors, 50%

For patients with no large drusen, presence of intermediate drusen in both eyes is counted as 1 risk factor. One intermediate-sized drusen in one eye counts as a 0.5 risk factor. Advanced AMD in one eye is represented as 2 risk factors.

This simplified scale provides convenient risk categories for development of advanced AMD that can be determined by clinical examination or by less-demanding photographic procedures than the procedures that were used in AREDS.

4. How are lutein, zeaxanthin, EPA and DHA being compared to the original AREDS formulation?

The AREDS2 formulation is not being compared directly to the AREDS formulation. Instead, this is an opportunity to evaluate the original AREDS formulation with a secondary randomization. Because the study population in AREDS2 has at least a moderate risk of developing AMD, it is necessary to offer all AREDS2 subjects the original daily AREDS formulation (vitamin C, 500 mg/d; vitamin E, 400 IU/d; 15 mg beta-carotene, 15 mg/d; zinc, 80 mg/d; and cupric oxide [copper], 2 mg). However, beta-carotene has been shown to increase the risk of lung cancer in smokers³ and is not one of the carotenoids naturally found in the eye. The main adverse effect associated with zinc use in the AREDS study was increased hospitalizations for genitourinary disease, mainly prostate hypertrophy in men.⁴

Because of these factors, we have conducted a second randomization to evaluate the possibility of deleting beta-carotene and reducing the level of zinc. All subjects are required to enroll in the first randomization of lutein/zeaxanthin and omega-3 fatty acids. They are then offered the opportunity to be randomly assigned to the second randomization involving the different doses of the AREDS formulation, including:

■ Original AREDS formulation
■ Original AREDS formulation without beta-carotene
■ Original AREDS formulation with a lower amount of zinc (25 mg)
■ A formulation that includes the combination of lower zinc and no beta-carotene.

5. Do we have enough new information from AREDS2 to recommend any changes in vitamin therapy, diagnostic techniques and counseling on lifestyle and diet?

The answer to this commonly asked question is no. We will know if any changes are recommended following the completion of all AREDS2 study visits in December 2012. As I mentioned earlier, the results will likely be announced in 2013. Certainly, observational data from other studies suggest that higher dietary intake of lutein/zeaxanthin and omega-3 fatty acids are associated with fewer cases of advanced AMD.^5-15 One cannot determine whether these supplements are effective without the data from a randomized, controlled clinical trial.

Think of what's at stake here. The economic benefit associated with preventing or slowing progression to advanced AMD in even a low percentage of patients is substantial, resulting in major cost savings to individuals and society because it is a condition of marked public health significance.¹⁶ Yes, admittedly, the observational evidence that diet and nutrition play crucial roles in the pathogenesis of early AMD and its progression to advanced AMD is compelling. However, AREDS2 will help to determine the significance of these nutritional factors because these factors are being evaluated in a randomized, controlled clinical trial.

6. Why is it unlikely that AREDS-type supplements will prevent progression from category 2 (small and few intermediate drusen) to category 3 (extensive intermediate drusen or large drusen)?

We do not know why these supplements failed to prevent category 2 from progressing to category 3 in the AREDS trial. A clinical trial cannot give you the answers about the mechanisms. Clearly, this formulation curbed neovascularization, but had less effect on the atrophic type of AMD. One can speculate that it may mediate through its antioxidant effect. Does the use of zinc affect the immune process, which may be important in the pathogenesis of AMD? This and other questions cannot be answered at this time.

7. Why is the risk of developing advanced AMD also exceedingly low for category 2 patients?

Unless you have large drusen in both eyes, your risk of advanced AMD is very low — even at 10 years follow-up. Taking a “just in case” approach by recommending AREDS-type supplements to category 2 patients may mean result in you treating a very large proportion of people who will not develop AMD. But if a patient develops large drusen, then he or she should be taking this formulation. To answer the primary question of prevention with an appropriate study, we would need tens of thousands of patients.

8. Are there adverse effects associated with AREDS and AREDS2 formulations that should be sources of concern?

We are well aware of the adverse effects associated with the AREDS formulation. As previously stated, there is an increased risk of lung cancer associated with beta-carotene in cigarette smokers. There were increased hospitalizations for participants assigned to zinc, particularly in men who experienced increased prostate hypertrophy. It should be noted, however, AREDS formulations have been in the market for 10+ years and have demonstrated a good safety profile.

The AREDS2 study is carefully monitored by the Data and Safety Monitoring Committee regularly during the course of the study. We have been able to continue to follow our participants, which suggests that we have not encountered serious side effects to date that have been associated with the AREDS2 formulations being evaluated. We look forward to the final results to report on any beneficial or adverse effects of the AREDS2 formulation.

KEY POINTS TO REMEMBER ► Observational data suggest that higher dietary intake of lutein/zeaxanthin and omega-3 fatty acids are associated with fewer cases of advanced AMD. Their effectiveness will ultimately be determined by AREDS2, a randomized controlled clinical trial.6-16 ► The simplified severity scale provides convenient risk categories for development of advanced AMD that can be determined by clinical examination or by less-demanding photographic procedures than the procedures that were used in AREDS.2 ► Beta-carotene has been shown to increase the risk of lung cancer in smokers.3 The elimination of beta-carotene is being tested in AREDS2. ► Zinc was considered to be at an extremely high level in the AREDS study and was associated with increased hospitalizations for genitourinary disease.5 AREDS2 is also testing a lower dose of zinc.

REFERENCES

1. Ferris FL, Davis MD, Clemons TE, Lee LY, Chew EY, Lindblad AS, Milton RC, Bressler SB, Klein R; Age-Related Eye Disease Study (AREDS) Research Group. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005;123(11):1570-1574.
2. Davis MD, Gangnon RE, Lee LY, Hubbard LD, Klein BE, Klein R, Ferris FL, Bressler SB, Milton RC; Age-Related Eye Disease Study Group. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol. 2005;123(11):1484-1498.
3. Goodman GE, Thornquist MD, Balmes J, et al. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 2004;96(23):1743-1750.
4. Johnson AR, Munoz A, Gottlieb JL, Jarrard DF. High dose zinc increases hospital admissions due to genitourinary complications. J Urol. 2007;177(2):639-643.
5. Gale CR, Hall NF, Phillips DI, Martyn CN. Lutein and zeaxanthin status and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2003;44(6):2461-2465.
6. SanGiovanni JP, Chew EY, Clemons TE, et al; for Age-Related Eye Disease Study Research Group. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthalmol. 2007;125(9):1225–1232.
7. Tan JS, Wang JJ, Flood V, Rochtchina E, Smith W, Mitchell P. Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology. 2008;115(2):334-341.
8. SanGiovanni JP, Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res.2005;24(1):87-138.
9. SanGiovanni JP, Chew EY, Clemons TE, et al. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol. 2007;125(5):671-679.
10. SanGiovanni JP, Chew EY, Agrón E, et al. The relationship of dietary omega-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration: AREDS report no. 23. Arch Ophthalmol. 2008;126(9):1274-1279.
11. Sangiovanni JP, Agrón E, Meleth AD, et al. {omega}-3 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study. Am J Clin Nutr.2009;90(6):1601-1607.
12. Chiu CJ, Klein R, Milton RC, Gensler G, Taylor A. Does eating particular diets alter the risk of age-related macular degeneration in users of the Age-Related Eye Disease Study supplements? Br J Ophthalmol. 2009;93(9):1241-1246.
13. Chua B, Flood V, Rochtchina E, et al. Dietary fatty acids and the 5-year incidence of age-related maculopathy. Arch Ophthalmol. 2006;124(7):981-986.
14. Augood C, Chakravarthy U, Young I, et al. Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr. 2008;88(2):398-406.
15. Christen WG, Schaumberg DA, Glynn RJ, Buring JE. Dietary {omega}-3 fatty acid and fish intake and incident age-related macular degeneration in women. Arch Ophthalmol. 2011;129(7):921-929.
16. The Age-Related Eye Disease Study Group. Potential public health impact of the Age-Related Eye Disease Study Results. AREDS Report No. 11. Arch Ophthalmol. 2003;121:1621-1624.

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Dr. Chew is deputy director of the division of Epidemiology and Clinical Applications at the National Eye Institute (NEI). She is also the AREDS2 study chair.