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JAMA Ophthalmol. 2014 Feb;132(2):142-9. doi: 10.1001/jamaophthalmol.2013.7376.

Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3.

Author information

  • 1Division of Epidemiology and Clinical Research, National Institutes of Health, Bethesda, Maryland.
  • 2EMMES Corp, Rockville, Maryland.
  • 3National Eye Institute, Clinical Trials Branch, Bethesda, Maryland.
  • 4Department of Ophthalmology, University of Wisconsin-Madison.
  • 5National Eye Institute, Bethesda, Maryland.
  • 6Elman Retina Group, Baltimore, Maryland.
  • 7Charlotte Eye Ear Nose and Throat, Charlotte, North Carolina.
  • 8Associated Retinal Consultants, William Beaumont Hospital, Royal Oak, Michigan.
  • 9Ingalls Memorial Hospital, Harvey, Illinois.
  • 10Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland.
  • 11Texas Retina Associates, Dallas, Texas.
  • 12Emory University, Atlanta, Georgia.
  • 13Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland.
  • 14Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison School of Medicine and Public Health.
  • 15Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison School of Medicine and Public Health15Fundus Photograph Reading Center, University of Wisconsin-Madison.
  • 16Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  • 17Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
  • 18Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida.
  • 19Duke University Medical Center, Durham, North Carolina.
  • 20Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah Health Sciences Center, University of Utah, Salt Lake City.



The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina.


To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD.


The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye.


In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination.


S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy.


The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements.

TRIAL REGISTRATION: Identifier: NCT00345176.

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