Research suggests that the AREDS formula can help many patients, but depending on genetics, it may not be appropriate for everyone.

In 2001, we had great news for our patients with age-related macular degeneration when results of the Age-Related Eye Disease Study, or AREDS, were announced. The study, launched nine years earlier, provided evidence that individuals who had a high risk of vision loss from age-related macular degeneration could reduce the risk that their AMD would progress to the advanced stages by 25% and reduce their risk of vision loss by 19% by taking a supplement.[1,2] The supplement consisted of 500mg of vitamin C, 400 international units of vitamin E, 15mg of beta-carotene, 80mg of zinc and 2mg of copper.

Five years later, researchers launched AREDS 2, which showed a moderate effect from adding to the AREDS formula lutein and zeaxanthin, the carotenoids that make up the macular pigment, while removing beta-carotene. The AREDS 2 formula also proved effective in slowing the progression to advanced AMD. It also demonstrated that 25mg of zinc was as effective as 80mg of zinc.

Since then, it has made sense to offer patients, especially those individuals at risk, a supplement made up of the AREDS formula. Or has it? Can the supplements, especially the zinc, possibly worsen the patient’s condition? The answer depends not on an individual’s stage of AMD. Rather, researchers later learned, it lies in an individual’s genetic make-up.

In 2013, Carl C. Awh, MD, and colleagues reported on a subgroup of the AREDS population and found that AMD worsened in about 13% of individuals, even though they were taking the AREDS formula.[3] After genotyping patients, they found that individuals who had one or two high-risk alleles on the CFH gene but not the ARMS2 gene worsened when taking the supplement. By contrast, individuals who had the two alleles on the ARMS2 gene did benefit from the supplement. The most likely explanation was that the alleles on the ARMS2 gene were needed to metabolize the zinc.

Awh’s findings were somewhat controversial, and reaction was swift. For example, Emily Chew, MD, and colleagues from the AREDS Research Group examined a larger cohort of 1,237 AREDS participants who were genotyped and considered to be at high risk of AMD progression.[4] Among the 385 individuals (31.1%) who progressed to late AMD, Chew found, CFH and ARMS2 genotypes were associated with the progression. However, she and her colleagues still found that the risk of progression to late AMD was reduced across all genotype groups when using the AREDS formula.

In 2015, Awh and colleagues published another paper showing that patients with two CFH risk alleles and no ARMS2 risk alleles still had a much higher risk of progression when taking a zinc-containing treatment.[5]

In 2017, however, Demetrios G. Vavvas, MD, PhD, Awh and colleagues used a random sampling technique called bootstrapping, which effectively looked at every possible combination.[6] This study, indeed, showed that there is an association between your genetic makeup for these alleles and what nutraceutical you should use. Specifically, the researchers said, these variations at the CFH and ARMS2 genes also determine the effectiveness of prophylaxis using the AREDS formula, with some individuals getting greater-than-average benefit and some individuals worsening with treatment.

Given these findings, I recommend genotyping to all my patients who have intermediate AMD and, occasionally, patients with early AMD. The Vita Risk test from ArcticDx helps determine whether AREDS/AREDS2 vitamin supplements will help the vision of individuals with dry AMD or individuals who have unilateral advanced AMD or whether it could potentially cause progression to advanced AMD (choroidal neovascularization), which could result in loss of vision. The Macula Risk test determines a dry AMD patient’s prognosis to develop advanced AMD in addition to the Vita Risk results.

Insurance carriers typically cover the test as long as the patient has physical signs of AMD (drusen). Carriers’ policies may differ, so you might need to check with your patient’s carrier.

The test itself is easy to perform. After the patient signs a consent form, instruct the patient to roll one of the enclosed brushes inside the left cheek along the jaw line for 30 seconds, and then repeat with the other brush along the right cheek. Allow the brushes to air dry for 30 seconds, and then return them to the original sleeve. Put the sleeve in the mailer that comes with the test and enclose a copy of the patient’s insurance information. Also complete and enclose the form that comes with the test which contains information about the stage of the patient’s AMD along with the patient’s height, weight, gender and smoking status.

ArcticDx sends back its report, which describes the patient’s genetic specific single nucleotide polymorphisms, or SNPs. Given these features and other factors, such as smoking status, gender and weight, the report states the patient’s two-year, five-year and 10-year risk of progressing to choroidal neovascularization or geographic atrophy. And based on the status of the CHF and ARMS2 alleles, the report provides a vitamin recommendation.

The report also assigns the patient a 10-year Macula Risk score ranging from one to five. A score of one or two indicates that the patient has no greater risk than the general population of progressing to advanced AMD, while a score of three to five means the patient is at higher risk than the general population for progressing. Individuals who have a score of five have a risk that ranges from 60% to 100% for progressing to advanced AMD during the next 10 years.

The report can guide us in managing these patients with AMD. For patients who have a macular risk score of one or two, for example, follow-up every six to 12 months may be sufficient. However, individuals with a score of three, four or five may require follow-up every four to six months, depending on the phenotypic presentation of the drusen.

The report also helps clinicians to determine what supplement is most appropriate for the patient. Depending on the patient’s CFH and ARMS2 genotyping, we might recommend that the patient remain on the AREDS formulation or take the AREDS formulation but without the zinc. Or, their genotype may indicate that a supplement won’t increase or decrease their risk of progression. Still, it is recommended to keep these patients on an AREDS supplement. Patients who should not be on zinc can be on a formulation containing lutein and zeaxanthin.

What’s important is if the results come back and suggest that patients should not be taking a supplement containing high zinc. Given that patients talk with friends, read articles or see television commercials about supplements, it’s important that they get this information from their eyecare provider.

Sherry Bass, OD, FAAO, FCOVD, is a distinguished clinical professor at the State University of New York State College of Optometry in Manhattan. She is a stockholder of ArcticDx.

ArcticDx Inc.
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1. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001 Oct;119(10):1417-36.

2. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001 Oct;119(10):1439-52.

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 Nov;120(11):2317-23.

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 Nov;121(11):2173-80.

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 Jan;122(1):162-9.

6. Vavvas DG, Small KW, Awh CC, et al. CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation. Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E696-E704.


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