Age-Related Eye Disease Studies (AREDS/AREDS2): major findings

The NEI conducted the Age-Related Eye Disease Study (AREDS) and the follow-on AREDS2 to study cataract and age-related macular degeneration (AMD). Study researchers tested whether taking nutritional supplements could prevent or slow these diseases. The formulations tested in the trials are now sold as the AREDS and the AREDS2 formulas.

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Major AREDS/AREDS2 findings:

  1. Taking AREDS or AREDS2 supplements reduces the risk of progression from intermediate to advanced AMD by about 25 percent
  2. AREDS and AREDS2 supplements do not prevent AMD onset
  3. AREDS and AREDS2 supplements do not have an effect on cataract
  4. Omega-3 fatty acid supplements do not have an effect on cataract or AMD
  5. Current and former smokers should take the AREDS2 formula and avoid the AREDS formula with beta-carotene, which increases lung cancer risk
Commercially available formulas based on AREDS/AREDS2
Nutrient AREDS formula* AREDS2 formula
Vitamin C 500 mg 500 mg
Vitamin E 400 IU 400 IU
Beta-carotene 15 mg -
Copper (cupric oxide)** 2 mg 2 mg
Lutein - 10 mg
Zeaxanthin - 2 mg
Zinc 80 mg 80 mg

*Not recommended for current or former smokers
**Added to avoid zinc-related copper deficiency
mg = milligrams
IU = international units

Age-Related Eye Disease

AMD and cataract are leading causes of visual impairment and blindness in the United States. Risk dramatically increases after age 65.

AMD is a progressive disease of the light-sensing tissue at the back of the eye called the retina. In later stages, AMD can lead to the loss of central vision and blindness. Learn more about AMD.

Cataract is a clouding of the lens of the eye, which causes blurry vision and can lead to blindness. The condition is common during aging and is usually treated with surgery to replace the lens. Learn more about cataract.

Basis for AREDS/AREDS2

NEI sponsored AREDS/AREDS2 based on laboratory experiments, epidemiologic studies, and clinical data that suggested antioxidants and zinc might reduce AMD and cataract risk, or slow progression of these diseases.

AREDS/AREDS2 were designed to

  • assess the clinical course, prognosis, and risk factors of AMD and cataract
  • evaluate the effects of nutrients, including high-dose antioxidants, omega-3 fatty acids, and zinc, on the progression of AMD, cataract, and related vision loss

AREDS design

AREDS included 4,757 participants, ages 55-80 years, with cataract, AMD, or both. AMD results are based on 3,640 participants who had early or worse AMD. Cataract results are based on 4,629 of the participants with cataract in one or both eyes.

AREDS included participants with AMD ranging from none in either eye to advanced AMD in one eye but good vision (at least 20/30) in the other eye. The participants were enrolled at 11 clinics nationwide and their clinical progression was followed for 5 years. Fifty-six percent were female. The median age was 69 years. Enrollment began in November 1992 and ended in January 1998.

Stages of age-related macular degeneration
Category Description
Category 1 - No AMD A few small or no drusen
Category 2 - Early stage AMD Many small drusen or a few medium-sized drusen in one or both eyes
Category 3 - Intermediate AMD Many medium-sized drusen or one or more large drusen in one or both eyes
Category 4 - Advanced AMD In one eye only, either a breakdown of light-sensitive cells and supporting tissue in the central retinal area (advanced dry form) or abnormal and fragile blood vessels under the retina (wet form)

 

AREDS randomization

The participants in each category were randomly selected to receive daily oral tablets for one of four treatments:

  1. antioxidant formulation (see below) and zinc (80mg) + copper (2mg)
  2. zinc (80mg) + copper (2mg)
  3. antioxidant formulation
  4. a placebo (a pill with no active ingredients)

The antioxidant formulation contained a combination of the following nutrients:

  1. vitamin C (500 mg)
  2. vitamin E (400 IU)
  3. beta-carotene (15 mg)

 

AREDS results

AREDS: Risk reduction for each formulation, compared to placebo
Result Antioxidants, zinc + copper (AREDS formula) Zinc + copper Antioxidants
Progression from intermediate to advanced AMD 25% 21% 17%
Vision loss 19% 11% 10%
Cataract surgery - - -

 

AREDS scientists found that people at high risk for developing advanced AMD—those with intermediate AMD, and those with advanced AMD in one eye only—reduced their risk of developing advanced by about 25 percent when treated with the combination of antioxidants and zinc + copper (final AREDS formula).  The AREDS formula also reduced the risk of central vision loss by 19% in the same group. None of the formulations decreased cataract risk.

AREDS follow-up

AREDS investigators followed participants for an additional five years. Ten years after enrollment, about 70% of participants were taking the antioxidants plus zinc + copper formulation (AREDS formula). The investigators found that participants who had been assigned to antioxidants plus zinc + copper formulation in the trial were 25-30% less likely to develop advanced AMD than those who had originally been assigned to placebo. Among participants at the highest risk for AMD, 34% who had taken the antioxidants plus zinc + copper (AREDS formula) in the trial progressed to advanced AMD, compared to 44% who had taken the placebo.

Age-Related Eye Disease Study 2 design

NEI launched AREDS2 in 2006 to test if adding omega-3 fatty acids or lutein + zeaxanthin would make the AREDS formula more effective. Omega-3 fatty acids are produced by plants, including algae, and are present in oily fish such as salmon. Lutein and zeaxanthin are carotenoids, a class of plant-derived vitamins that includes beta-carotene. Additionally, AREDS2 investigators tested the effect of eliminating beta-carotene, which in some studies increased lung cancer risk in smokers. They also tested lowering the zinc dose.

AREDS2 investigators enrolled 4,203 participants, ages 50-85, at one of 82 clinical sites across the country. AREDS2 included only people with intermediate AMD in both eyes or intermediate AMD in one eye and advanced AMD in the other eye. AREDS2 excluded people without AMD or with early AMD because AREDS data showed no benefit for these individuals. AREDS2 investigators excluded current smokers from receiving the formulation containing beta-carotene. 

AREDS2 randomization

Primary randomization: AREDS2 investigators randomly assigned participants to one of the following groups:

  1. Omega-3 fatty acids (350 mg docosahexanoic acid + 650 mg eicosapentanoic acid)
  2. Lutein (10 mg) + zeaxanthin (2 mg)
  3. Lutein + zeaxanthin and omega-3 fatty acids
  4. Placebo

Secondary randomization: Additionally, 3549 AREDS2 participants were randomized to take one of the following:

  1. AREDS formula
  2. AREDS formula minus beta-carotene
  3. AREDS formula with low (25 mg) zinc
  4. AREDS formula minus beta-carotene and with low (25 mg) zinc

The remaining participants were not randomized and generally took the AREDS formula.

 

AREDS2 results

In the AREDS2 trial, adding omega-3 fatty acids or lutein + zeaxanthin to the AREDS formula had no additional overall effect on the risk of advanced AMD. However, AREDS2 participants who took antioxidants minus beta-carotene but with lutein + zeaxanthin (AREDS2 formula) had an incremental increase in benefit, compared to those who took the AREDS formula.

AREDS2 participants who were former smokers who took a formulation with beta-carotene had a higher incidence of lung cancer. The investigators found no significant changes in the effectiveness of the formulation when they removed beta-carotene or reduced the zinc dose.

Adding omega-3 fatty acids or lutein + zeaxanthin to antioxidants plus zinc (AREDS formula), had no overall effect on the need for cataract surgery. 

Last updated: November 19, 2020