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Since the first Age-Related Eye Disease Study (AREDS) was released in 2001,1 the relationships among nutrition, supplementation, and progression of age-related macular degeneration (AMD) have been established in the ophthalmic literature. Shortly after its publication, most eye care practitioners started recommending the supplements assessed in this landmark study—15 mg beta-carotene, 500 mg vitamin C, 400 IU vitamin E, 80 mg zinc, and 2 mg copper—for their patients with moderate or worse AMD.
In 2013, a follow-up study, AREDS2,2 helped to clarify some issues that were not addressed in the original study and to answer some questions that arose in the years between the studies. One of those questions was whether the addition of lutein, zeaxanthin, and omega-3 fatty acids to the supplements could provide additional benefit over the original components. Another was whether reducing the amount of zinc and eliminating beta-carotene, which has been associated with increased risk of lung cancer in current and past smokers, could be advantageous. Although AREDS2 answered these questions, it also created some controversies.
One thing that seems clear is that lutein and zeaxanthin are helpful for patients with moderate or worse AMD. Eliminating beta-carotene and substituting lutein 10 mg and zeaxanthin 2 mg was shown to provide an additional 10% risk reduction for progression and vision loss in patients with moderate or worse AMD. Further, in patients with the lowest dietary intake of lutein and zeaxanthin, the additional effect was higher, at 26%.2 Many people feel that this group with the lowest dietary intake probably represents our average patient. That is, the patients included in AREDS2 were in general well nourished, and this may not reflect the average patient seen in clinical practice.
These results, combined with the increased safety profile of lutein and zeaxanthin, make it reasonable to substitute 10 mg of lutein and 2 mg of zeaxanthin for beta-carotene in the supplement formulation. Most commercially available products have made this change, as it does not seem advisable to use beta-carotene based on what we know now.
Two other issues that arose with the publication of AREDS2 are more controversial. First, the results did not seem to show that omega-3s were helpful in reducing the risk of progression of AMD. This was contrary to what earlier, smaller studies had suggested. As a result, many eye care providers are not as likely to recommend omega-3 supplementation for their AMD patients. However, some believe that the amount or type of omega-3s used in AREDS2 may not have been ideal, while others point to numerous additional health benefits of omega-3s, such as boosting cardiovascular health, providing dry eye relief, etc. These individuals still feel that omega-3s are valuable and that the role of omega-3s should be discussed with AMD patients to see if omega-3 supplementation would be best for them.
The second issue that arose from AREDS2 concerns zinc. AREDS2 evaluated two levels of zinc, 80 mg and 25 mg. The study found no difference between the two levels, so the authors recommended that the amount of zinc in the original formula remain unchanged. Many disagreed with this recommendation, arguing that, if the two amounts were clinically comparable, it would make sense to use the smaller amount.
Additionally, some reports have noted an interaction of certain genetic characteristics and zinc. Particularly, a study by Awh et al,3 analyzing data from the AREDS database, found that patients with one or two high-risk CFH alleles and no ARMS2 alleles derived maximum benefit from antioxidants only, and that zinc was harmful in these patients, being associated with an increased risk of progression to advanced AMD. Another study by Chew et al disputed these findings, demonstrating a positive effect for AREDS supplementation across all genetic subgroups.4 A second article by Awh and colleagues seemed to corroborate the interaction between genetics and zinc.5
WHAT IS CLEAR
Given all of this, it seems clear that AREDS2 supplementation is helpful in slowing the progression of AMD in patients with moderate to severe AMD. Further, the substitution of lutein 10 mg and zeaxanthin 2 mg for beta-carotene is advised on the basis of its improved safety profile and increased benefit in the majority of patients.
Some things are less clear. The proper amount of zinc and the interactions between zinc and genetics are topics that must be studied further before answers can be determined. Likewise, the role omega-3 supplementation in AMD is somewhat unclear at this time, although it does not appear to be helpful in the majority of cases.
Lastly, the million dollar question—are these supplements helpful in patients with mild AMD?—may never be determined in a large study.
Until these questions are answered, an open discussion of risks versus benefits should be conducted with all AMD patients, and individual plans should be developed based on each patient’s needs, risk factors, level of AMD, and chance of meaningful progression. Hopefully, further studies and more clinical experience with nutritional supplements will help clear up the remaining muddy waters. n
1. Age-Related Eye Disease Study Group. A randomized, placebo-controlled, clinical trial of high dose supplementation with vitamin C and E, beta-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
2. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005-2015.
3. Awh CC, Lane AM, Hawken S, et al. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120(11):2317-2323.
4. Chew EY, Klein ML, Clemons, TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements. AREDS report number 38. Ophthalmology. 2014;121(11):2173-2180.
5. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age Related Eye Disease Study. Ophthalmology. 2015;122(1):162-169.
Steven Ferrucci, OD, FAAO
• Chief of optometry, Sepulveda Veterans Administration, Sepulveda, California
• Professor, Southern California College of Optometry at Marshall B. Ketchum University, Fullerton, California
• Financial disclosure: a member of the advisory board or speakers panel for Alcon, Macula Risk, and Science Based Health