Double vision: AREDS-2 and AMD

Integrative medicine

The leading causes of impaired vision in the United States are diabetic retinopathy, glaucoma, cataracts, and age-related macular degeneration (AMD).1 According to CDC, almost 2 million adults have AMD, and another 7 million people who have large drusen—yellowish deposits in the macula of the eye—are at significant risk for the disease. The disease affects central vision and the general sharpness of vision, and risk factors include advancing age, white race, smoking, and family history of AMD.

The original Age-Related Eye Disease Study (AREDS), published in 2001, enrolled about 3,600 participants between 55 and 80 years of age who were followed for 6.3 years. The primary objective was to evaluate the effects of different antioxidant combinations on long-term outcomes in patients with AMD and cataracts. A key finding was that the AREDS antioxidant formulation (vitamin C 500 mg, vitamin E 400 IU, and beta carotene 15 mg) plus zinc reduced the progression to advanced AMD by 25% in high-risk individuals.2

Second time around

In May 2013, JAMA published the results of AREDS-2.3 This study enrolled more than 4,200 participants with a mean age of 73.1 years. Among participants, 65% had bilateral large drusen and 35% had advanced AMD in one eye. The primary goal was to evaluate if adding lutein 10 mg plus zeaxanthin 2 mg (LZ), omega-3 fatty acids consisting of docosahexaenoic acid (DHA) 350 mg and eicosapentaenoic acid (EPA) 650 mg or the combination of LZ, DHA, and EPA to the standard AREDS formulation further reduced the progression to advanced AMD. A secondary goal was to assess the effect of eliminating beta carotene, lowering zinc dosage, or both on AMD outcomes associated with the original AREDS formulation.

In recent years, many formulations marketed for eye health have contained lutein and zeaxanthin based on the rationale that these substances are the carotenoids in the macula. Omega-3 fatty acids are also believed to be important because DHA is a component of the retina and EPA is involved with normal retinal function. The AREDS-2 investigators tested removing beta carotene due to its association with lung cancer in smokers and reducing the dosage of zinc to 25 mg in part because this may be the maximal amount that can be absorbed daily. The researchers theorized that reducing the amount of zinc would lessen gastrointestinal adverse effects.3

Progression to advanced AMD occurred in 31% of the group receiving the original AREDS formula (placebo), 29% receiving LZ plus one of the AREDS formulas, 31% receiving DHA, EPA, and one of the AREDS formulas, and 30% receiving LZ, DHA, EPA, and one of the AREDS formulas.3 The differences between the groups were not statistically significant. The secondary analyses showed no effect of lowering zinc dosage or eliminating beta carotene on AMD compared with the original AREDS formula.

The investigators also reported posthoc subgroup analyses. Patients who received LZ and the AREDS formula without beta carotene had an 18% decreased risk of progression to advanced AMD compared with those who received only the original AREDS formula.3 In terms of safety, the researchers observed an increased risk of lung cancer with beta carotene, primarily among former smokers. Change in zinc dosage was not associated with differences in gastrointestinal conditions.

What to tell patients

AMD is a common cause of impaired vision in older adults. Advanced forms of the disease can significantly affect the ability to drive and read. Pharmacists should counsel patients about symptoms of AMD such as needing additional light for activities such as reading and blurred central vision. Routine eye assessments are essential to prevent progression to advanced AMD.
In general, the newer eye health formulations do not offer significant advantages over the older formulas. The replacement of beta carotene with lutein and zeaxanthin may improve safety among former smokers, however.


  1. CDC. Common eye disorders. Accessed at, June 8, 2013.
  2. 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. Arch Ophthalmol. 2001;119(10):1417–36.
  3. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration. JAMA. 2013;309(19):2005–15.