Nutritional Supplementation and AMD

What lessons can we learn from current studies?

By Steven Ferrucci, OD

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in the United States in individuals older than age 50. As the population ages, the number of people with AMD is projected to double by 2024. The number of advanced AMD cases, those with either neovascular AMD or geographic atrophy, is also expected to double, to nearly 3 million cases, over the same period.1 Therefore, identifying safe and effective means to help slow the progression of the disease is paramount. One such method is through nutritional supplementation.


The original Age-Related Eye Diseases Study (AREDS) was one of the first large-scale clinical trials to evaluate the effect of high-dose antioxidants on the progression of AMD. The investigators found that a formulation of 15 mg beta-carotene, 500 mg vitamin C, 400 IU vitamin E, 80 mg zinc, and 2 mg copper lowered the risk of progression to advanced AMD by 25% in patients with intermediate or advanced AMD.2 The study was unable to show a statistically significant effect in patients with milder forms of AMD. The original AREDS study, however, did not evaluate the use of lutein, zeaxanthin, or omega-3 fatty acids

The AREDS2 study was undertaken in hopes of answering some questions regarding the role of lutein, zeaxanthin, and omega-3 fatty acids in AMD. Its primary goal was to determine if the addition of 10 mg lutein, 2 mg zeaxanthin, and 1,000 mg omega-3 fatty acids to the original AREDS formulation would further reduce the risk of progression to advanced disease in high-risk AMD patients. Further, the study evaluated the role of eliminating beta-carotene and reducing the amount of zinc used in the original study.

This multicenter trial, conducted at 82 clinical sites in the United States from 2006 to 2012, included 4,203 participants aged 50 to 85 years. The AREDS2 participants consented to take either the original AREDS formulation or a randomly assigned variation of the AREDS formulation. The main outcome measure was progression to advanced AMD, either neovascular or central geographic atrophy. Progression to cataract surgery and progression of lens opacity were secondary outcomes.3

According to the primary analysis of the trial results, the addition of lutein and zeaxanthin, or the long-chain omega-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, or both to the AREDS formulation did not further reduce the risk of progression to advanced AMD. However, the authors concluded, because of increased incidence of lung cancer associated with beta-carotene in former smokers, lutein and zeaxanthin may be an appropriate carotenoid substitute for beta-carotene in the original AREDS formulation. The comparison of low-dose versus high-dose zinc showed no evidence of a statistically significant effect, so a clinical recommendation could not be made.3 Finally, daily supplementation with lutein and zeaxanthin had no statistically significant overall effect on rates of cataract surgery or vision loss.4

However, when the results were looked at more critically, it became apparent that lutein and zeaxanthin had a more positive effect than was first recognized.3,4

The AREDS2 investigators determined that the addition of lutein and zeaxanthin to the original formula was associated with an additional 10% decrease in risk of disease progression. Further, if the beta-carotene were removed and replaced with lutein and zeaxanthin, the risk reduction was increased by 18%. Finally, it was determined that patients with the lowest quintile of dietary lutein and zeaxanthin had the greatest reduction (26%) in disease progression when supplemented with 10 mg lutein and 2 mg zeaxanthin.3 Similarly, a small decrease in cataract formation and subsequent need for surgery was also demonstrated in this group with the lowest lutein and zeaxanthin dietary intake when supplemented4


Lately, there has been much discussion regarding genetic testing and its role in determining the most appropriate vitamin supplement for a particular patient. In 2013, Awh and colleagues published a study showing that patients’ responses to vitamin supplements were influenced by their genetic makeup. Their study found that patients with no complement factor H (CFH), risk alleles, and one or two age-related maculopathy susceptibility 2 (ARNS2) risk alleles derived maximum benefit from zinc-only supplementation. Conversely, patients with one or two CFH alleles and no ARMS2 alleles derived maximum benefit from antioxidant- only treatment, and zinc was actually associated with increased progression to advanced AMD in these patients. Therefore, these authors concluded, choosing vitamin supplementation based on patients’ genetic profiles might lead to improved outcomes.5

Recently, however, a study published by Chew and colleagues has challenged the conclusions of Awh et al. The AREDS Research Group found that AREDS supplementation reduced the rate of AMD progression in all genotype groups, and that the numbers of ARMS2 and CFH risk alleles had no effect on the benefits of supplementation. These authors therefore concluded that genetic testing provided no benefit in managing nutritional supplementation for patients at risk for late AMD.6


What does all of this mean for our patients? Based on the results of AREDS2, it seems clear that it is safe, and in most cases advantageous, to replace the beta-carotene in the original AREDS formulation with 10 mg lutein and 2 mg zeaxanthin. Therefore, I have started switching all my patients from the original AREDS supplementation formula with beta-carotene to newer AREDS2 products with lutein and zeaxanthin instead. In my mind, this is good science, and clearly, the switch is in the best interest of patients.

I would, however, like to see additional studies evaluating the role of zinc, to see if the formula with the reduced level of zinc really is clinically equivalent. If so, it would seem to make sense to reduce the amount, as there are some concerns regarding the dangers of high zinc levels.

Additionally, although I believe that genetic testing is important to help stratify risk of progression in our AMD patients and help determine how frequently they may need to be seen, I am not currently using genetic testing to help guide nutritional therapy. I may start to do this in the future, but, due to the conflicting studies, I believe it is best to wait at this time.

As you can see, the issue of nutritional supplementation is not simple. Careful consideration of the appropriate supplement and increased counseling for at-risk patients seems appropriate. Supplementation, combined with lifestyle modifications such as stopping smoking and wearing ultraviolet light protection, offers patients the best chance to preserve their vision as they age.

Steven Ferrucci, OD, is the chief of optometry at the Sepulveda Veterans Administration in Sepulveda, California, and is a professor at Southern California College of Optometry at Marshall B. Ketchum University, in Fullerton. He serves on the advisory board of or has received honoraria from Alcon, Autogenomics, Macula Risk, Maculogix, Nicox, and Science Based-Health. Dr. Ferrucci may be reached at

  1. Eye Diseases Prevalence Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122:564-572.
  2. AREDS Study Group. A randomized, placebo-controlled, clinical trial of high dose supplementation with Vitamin C and E, beta carotene, and zinc for AMD and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
  3. The AREDS2 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.
  4. The AREDS2 Research Group. Lutein/zeaxanthin for the treatment of age-related cataract. The Age- Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA Ophthalmol. 2013;131(7):843-850.
  5. Awh CC, Jane A, Hawken S, et al. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120:2317-2323.
  6. Chew EY, Klein ML, Clemons, TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements. AREDS report 38 [published online ahead of print June 26, 2014]. Ophthalmology. doi: 10.1016/j.ophtha.2014.05.008..