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

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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. No other authors reported disclosures.

Figures

Figure 1. Comparison of lutein/zeaxanthin vs. no lutein/zeaxanthin for the development of advanced age-related macular degeneration (AMD), neovascular AMD, and central geographic atrophy

Analyses were conducted for all Age-Related Eye Disease Study 2 (AREDS2) participants and then subdivided by the baseline age-related macular degeneration (AMD) status: bilateral (OU) large drusen and bilateral large drusen with late AMD in one eye.

Figure 2. Comparison of lutein/zeaxanthin plus Age-Related Eye Disease Study (AREDS) supplements without beta-carotene vs. AREDS supplements with beta-carotene (and no lutein/zeaxnathin). Hazards ratios and 95% confidence intervals

This is a head-to-head analysis of lutein/zeaxanthin vs. beta-carotene for progression to late age-related macular degeneration (AMD) and the two forms of late AMD, neovascular AMD and central geographic atrophy. These were also subdivided by the baseline AMD status, bilateral (OU) large drusen or bilateral large drusen with late AMD in one eye. L/Z: Lutein/zeaxanthin ATS: Age-Related Eye Disease Study (AREDS) type supplement BC: beta-carotene

Figure 3

Comparison of lutein/zeaxanthin vs. no lutein/zeaxanthin for effects on visual acuity loss: ≥10 letters, ≥15 letters, ≥30 letters lost compared to baseline and the development of worse than 20/100. Comparison of lutein/zeaxanthin plus AREDS supplement without beta-carotene vs. AREDS formulation with beta-carotene (without lutein/zeaxanthin) on visual acuity outcomes. legend: This head-to-head comparison of lutein/zeaxanthin vs. beta-carotene on visual acuity outcomes include the following visual acuity outcomes: ≥10 letters, ≥15 letters, ≥30 letters lost compared to baseline and the development of worse than 20/100.

Figure 3

Comparison of lutein/zeaxanthin vs. no lutein/zeaxanthin for effects on visual acuity loss: ≥10 letters, ≥15 letters, ≥30 letters lost compared to baseline and the development of worse than 20/100. Comparison of lutein/zeaxanthin plus AREDS supplement without beta-carotene vs. AREDS formulation with beta-carotene (without lutein/zeaxanthin) on visual acuity outcomes. legend: This head-to-head comparison of lutein/zeaxanthin vs. beta-carotene on visual acuity outcomes include the following visual acuity outcomes: ≥10 letters, ≥15 letters, ≥30 letters lost compared to baseline and the development of worse than 20/100.