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Randomized Controlled Trial
. 2025 Jan;132(1):14-29.
doi: 10.1016/j.ophtha.2024.07.014. Epub 2024 Jul 16.

Oral Antioxidant and Lutein/Zeaxanthin Supplements Slow Geographic Atrophy Progression to the Fovea in Age-Related Macular Degeneration

Tiarnán D L Keenan  1 , Elvira Agrón  2 , Pearse A Keane  3 , Amitha Domalpally  4 , Emily Y Chew  2 ; Age-Related Eye Disease Study Research Group; Age-Related Eye Disease Study 2 Research Group
Affiliations
Randomized Controlled Trial

Oral Antioxidant and Lutein/Zeaxanthin Supplements Slow Geographic Atrophy Progression to the Fovea in Age-Related Macular Degeneration

Tiarnán D L Keenan et al. Ophthalmology. 2025 Jan.

Abstract

Purpose: To determine whether oral micronutrient supplementation slows geographic atrophy (GA) progression in age-related macular degeneration (AMD).

Design: Post hoc analysis of Age-Related Eye Disease Study (AREDS) and AREDS2, multicenter randomized placebo-controlled trials of oral micronutrient supplementation, each with 2 × 2 factorial design.

Participants: A total of 392 eyes (318 participants) with GA in AREDS and 1210 eyes (891 participants) with GA in AREDS2.

Methods: The AREDS participants were randomly assigned to oral antioxidants (500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene), 80 mg zinc, combination, or placebo. The AREDS2 participants were randomly assigned to 10 mg lutein/2 mg zeaxanthin, 350 mg docosahexaenoic acid/650 mg eicosapentaenoic acid, combination, or placebo. Consenting AREDS2 participants were also randomly assigned to alternative AREDS formulations: original; no beta-carotene; 25 mg zinc instead of 80 mg; both.

Main outcome measures: (1) Change in GA proximity to central macula over time and (2) change in square root GA area over time, each measured from color fundus photographs at annual visits and analyzed by mixed-model regression according to randomized assignments.

Results: In AREDS eyes with noncentral GA (n = 208), proximity-based progression toward the central macula was significantly slower with randomization to antioxidants versus none, at 50.7 μm/year (95% confidence interval [CI], 38.0-63.4 μm/year) versus 72.9 μm/year (95% CI, 61.3-84.5 μm/year; P = 0.012), respectively. In AREDS2 eyes with noncentral GA, in participants assigned to AREDS antioxidants without β-carotene (n = 325 eyes), proximity-based progression was significantly slower with randomization to lutein/zeaxanthin versus none, at 80.1 μm/year (95% CI, 60.9-99.3 μm/year) versus 114.4 μm/year (95% CI, 96.2-132.7 μm/year; P = 0.011), respectively. In AREDS eyes with any GA (n = 392), area-based progression was not significantly different with randomization to antioxidants versus none (P = 0.63). In AREDS2 eyes with any GA, in participants assigned to AREDS antioxidants without β-carotene (n = 505 eyes), area-based progression was not significantly different with randomization to lutein/zeaxanthin versus none (P = 0.64).

Conclusions: Oral micronutrient supplementation slowed GA progression toward the central macula, likely by augmenting the natural phenomenon of foveal sparing.

Financial disclosure(s): Proprietary or commercial disclosure may be found after the references.

Keywords: Age-related macular degeneration; Antioxidants; Foveal sparing; Geographic atrophy; Progression.

PubMed Disclaimer

Conflict of interest statement

All authors declare no support from any other organization for the submitted work. PK has acted as a consultant for Roche, Novartis, Boehringer-Ingelheim, Adecco, Bitfount, and is an equity owner in Big Picture Medical, has received speaker fees from Novartis, Gyroscope, Bayer, Thea, Boehringer-Ingleheim, Apellis, Abbvie, Alimera, Roche, Genentech, Specsavers, Heidelberg Engineering, Topcon, and Santen, has received travel support from Bayer, Topcon, and Roche, and has attended advisory boards for Boehringer-Ingelheim, RetinAI, Novartis, Apellis, Abbvie, and Roche.

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