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Cited by 415Retinal Diseases and TreatmentsAntioxidant Activity and Oxidative StressRetinal Imaging and Analysis

Secondary Analyses of the Effects of Lutein/Zeaxanthin on Age-Related Macular Degeneration Progression: AREDS2 Report No. 3

Chew, Emily Y., Clemons, Traci E., SanGiovanni, John Paul, Danis, Ronald P., Ferris, Frederick L., Elman, Michael J., Antoszyk, Andrew N., Ruby, Alan J. +15 more·2014·JAMA Ophthalmology
DOI 10.1001/jamaophthalmol.2013.7376PMC PMC4636082
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Abstract

IMPORTANCE: 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. OBJECTIVE: To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURE: 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. CONCLUSION AND RELEVANCE: 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: clinicaltrials.gov Identifier: NCT00345176.

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  • For treatment of age-related macular degeneration, the original AREDS formulation that included beta-carotene was replaced with the AREDS2 formula, where beta-carotene was substituted with lutein and zeaxanthin.

    “Therefore, for treatment of age-related macular degeneration (AMD), the original Age-Related Eye Disease Study (AREDS) formulation that included beta-carotene was replaced with the AREDS2 formula, where beta-carotene was substituted with lutein and zeaxanthin [23].”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [23]

    The Interventions section identifies beta-carotene in the original AREDS formulation, and the Lutein/zeaxanthin vs. Beta-carotene section compares it with a formulation containing lutein/zeaxanthin instead. But the Conclusion and Relevance section says only that lutein/zeaxanthin *could* be more appropriate; it does not establish that the original formulation was definitively replaced. Page numbers are not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Regular use of AREDS2 has been shown to reduce the risk of developing severe AMD.

    “Regular use of AREDS2 has been shown to reduce the risk of developing severe AMD [21,22,23].”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [23]

    The Introduction and Abstract Results (page not specified) report a reduced risk of progression to late AMD with lutein/zeaxanthin supplementation in a prespecified comparison, with supporting exploratory findings. But the primary AREDS2 comparisons found no benefit, and the participants were already at high risk of progression. The unqualified claim that regular use of AREDS2 has been shown to reduce severe AMD risk overstates these findings. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Treatment with vitamin A in retinal diseases associated with vitamin A is not straight-forward because of fear of accumulation of excessive amounts of toxic retinoids formed as byproducts of vitamin A pathways.

    “Treatment with vitamin A in these cases is not straight-forward, as there is a fear of accumulation of excessive amounts of toxic retinoids that are formed as byproducts of vitamin A pathways.”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [23]

    The Introduction discusses supplements for age-related macular degeneration, and Methodology > Interventions identifies a safety concern about beta-carotene and lung cancer in smokers. Neither passage addresses vitamin A treatment being complicated by the accumulation of toxic retinoid byproducts; searches for that mechanism and vitamin A treatment found no supporting passage. Page numbers were not available in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • In ABCA4-retinopathy, toxic products of vitamin A accumulate excessively in the retina.

    “A good example of this toxicity is ABCA4-retinopathy where toxic products of vitamin A accumulate excessively in the retina [9,23,76,77,78].”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [23]

    The Introduction and Comment discuss age-related macular degeneration and lutein/zeaxanthin, not ABCA4-retinopathy. Searches for ABCA4 and for toxic vitamin A products accumulating in the retina found no passage addressing the claim in our copy; no page numbers were provided. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cites

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Authors
Chew, E. Y., Clemons, T. E., SanGiovanni, J. P., Danis, R. P., Ferris, F. L., Elman, M. J., Antoszyk, A. N., Ruby, A. J., Orth, D., Bressler, S. B., Fish, G. E., Hubbard, G. B., Klein, M. L., Chandra, S. R., Blodi, B. A., Domalpally, A., Friberg, T., Wong, W. T., Rosenfeld, P. J., Agrón, E., Toth, C. A., Bernstein, P. S., & Sperduto, R. D.
Affiliations
  • National Institutes of Health (US)
  • Emmes (United States) (US)
  • National Eye Institute (US)
  • University of Wisconsin–Madison (US)
  • Elman Retina Group (US)
  • Charlotte Eye Ear Nose & Throat Associates (US)
  • Corewell Health William Beaumont University Hospital (US)
  • Ingalls Memorial Hospital (US)
  • Johns Hopkins University (US)
  • Texas Retina Associates (United States) (US)
  • Emory University (US)
  • Oregon Health & Science University (US)
  • University of Pittsburgh (US)
  • University of Miami (US)
  • Duke Medical Center (US)
  • University of Utah (US)
Corresponding author
Chew, Emily Y.
ORCID
Venue
JAMA Ophthalmology
Publisher
American Medical Association (AMA)
Published
2014-02-01
Volume
132
Issue
2
Pages
142
ISSN
2168-6165 (ISSN-L)
DOI
10.1001/jamaophthalmol.2013.7376
PMC
PMC4636082
OpenAlex
W2105811828
Cited by
415
References
8
Citations by year
2026: 23 · 2025: 33 · 2024: 21 · 2023: 33 · 2022: 35 · 2021: 48 · 2020: 41 · 2019: 34 · 2018: 27 · 2017: 42 · 2016: 28 · 2015: 36 · 2014: 14
FWCI
37.51
Type
journal article
Language
en
Open access
closed
Locations
  • JAMA Ophthalmology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • U.S. Public Health Service (HHS-N-260-2005-00007-C)
  • National Eye Institute (R01EY021532, ZIAEY000485, N01-EY-5-0007)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
Keywords
lutein, zeaxanthin, age-related macular degeneration, AREDS2, omega-3 fatty acids, beta-carotene, neovascular AMD, drusen, dietary supplementation, lung cancer risk, retinal pigment epithelium, macular pigment optical density
MeSH terms
Administration, Oral, Aged, Aged, 80 and over, Diet, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Trace Elements, Visual Acuity, Vitamins, Lutein, Fatty Acids, Omega-3, Retinal Drusen, Treatment Outcome, Disease Progression, beta Carotene, Dietary Supplements, Xanthophylls, Geographic Atrophy, Wet Macular Degeneration, Zeaxanthins

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