Beyond lesion area: the role of oral antioxidants and lutein/zeaxanthin in slowing geographic atrophy progression toward the fovea

Geographic atrophy (GA), together with neovascular age-related macular degeneration (AMD), represents the advanced stages of AMD and remains a leading cause of irreversible vision loss worldwide (1). GA is characterized by progressive degeneration of the retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris, driven by oxidative stress and inflammation that lead to cellular dysfunction and atrophy in these layers (2-4). More than five million people are currently afflicted with GA, a number projected to increase to almost 20 million by 2040 due to aging demographics of the global population (5). GA causes substantial visual impairment, including reductions in visual acuity (VA), contrast sensitivity, and reading speed, which significantly impact patients’ quality of life (6,7).

Until recently, no treatment modalities were available to prevent the progression of GA. While two pivotal randomized, placebo-controlled clinical trials—the Age-Related Eye Disease Study (AREDS) and AREDS2—showed that oral supplementation with a combination of antioxidants, zinc, and lutein/zeaxanthin reduced the risk of progression to neovascular AMD in high risk individuals (8), these formulations were found to be ineffective against GA—a conclusion largely shaped by reliance on area-based GA measurements performed on fundus photographs.

The AREDS trial enrolled participants with varying stages of AMD, including those with extensive small drusen, intermediate or large drusen, noncentral GA, or pigmentary changes in one or both eyes, as well as individuals with advanced AMD or AMD-related vision loss in one eye, provided they had VA of 20/32 or better in at least one eye. Participants were randomly assigned to one of four groups: (I) oral antioxidants (500 mg vitamin C, 400 IU vitamin E, and 15 mg β-carotene); (II) zinc (80 mg) and copper; (III) the combination of antioxidants and zinc/copper; or (IV) placebo (9). AREDS2 participants—those with large drusen in both eyes or large drusen in one eye and advanced AMD in the other (i.e., category 3 and 4 patients shown to benefit in the AREDS trial)—were initially randomized to receive: (I) lutein (10 mg) and zeaxanthin (2 mg); (II) docosahexaenoic acid (DHA, 350 mg) and eicosapentaenoic acid (EPA, 650 mg); (III) both; or (IV) placebo. Participants were then further randomized to receive one of four formulations: (I) the original AREDS formulation; (II) AREDS without β-carotene; (III) AREDS with 25 mg zinc instead of 80 mg; or (IV) AREDS with 25 mg zinc and no β-carotene. Since beta-carotene increases risk of lung cancer in current or former cigarette smokers, AREDS2 trial assigned these participants to the no beta-carotene groups (10,11). Patients had annual VA testing according to Early Treatment Diabetic Retinopathy Study (ETDRS) protocols along with stereoscopic color fundus photographs (12).

In the AREDS study, GA area was quantified using planimetry on digitized stereoscopic color fundus photographs, which were obtained longitudinally and graded at a central reading center (13). In AREDS2, baseline and annual stereoscopic color fundus photographs were similarly evaluated for GA presence and lesion area, with progression analyzed as change in the square root of GA area over time, a method that reduces variability in rates of progression related to baseline lesion size (14).

While these trials provided evidence for slowing progression to neovascular AMD, no statistically significant differences were observed in development of central GA or area-based GA progression across participant subgroups (13,15). This lack of significance may be partly attributable to the relatively low incidence of central GA, which limited statistical power (16). Among eyes with non-central GA, the median time to progression to central involvement was approximately 2.5 years (13).

More contemporary therapies involve intravitreal complement inhibitors, such as pegcetacoplan and avacincaptad pegol, which were recently approved by the Food and Drug Administration (FDA) to slow the progression of GA, albeit accompanied by the need for frequent injections, high costs, and remaining safety concerns (17-21). In the context of a rapidly evolving therapeutic landscape, Keenan et al. conducted a post hoc analysis of AREDS and AREDS2 trials reexamining the role of oral micronutrient supplementation in GA progression with one crucial difference from the original assessments (14). A unique aspect of Keenan’s work is inclusion of the rate of change in GA proximity to the fovea in addition to the rate of change in GA area, typically assessed in studies (22).

GA progression towards the center of the macula is of clinical importance. Atrophic changes characteristically begin in the perifoveal region of the macula and eventually expand and merge, gradually marching toward the fovea. Though central VA remains unaffected until quite late in the disease course (23-25), expansion of GA towards the fovea eventually leads to severely reduced VA. Conversely, the increases in overall GA area demonstrate only a weak association with VA decline (26-28). The transition from noncentral to central GA is therefore the key determinant of clinically meaningful VA decline. Thus, the rate at which non-central GA progresses to reach the macular center is an important clinical parameter and represents a meaningful outcome measure complementary to the customary area-based GA progression typically employed in therapeutic clinical trials. That is the approach Keenan et al. take in their post hoc analysis of the AREDS and AREDS2 data.

Through the use of mixed-model and repeated measures regression analysis, two primary outcomes were evaluated: (I) change in proximity of GA to the foveal center; and (II) change in square-root of GA area over time, each measured from color fundus photographs at annual visits (13,14,25,29-34). The authors show that in the AREDS eyes with non-central GA, the supplementation of antioxidants (vitamin C, vitamin E, and beta-carotene) significantly slowed foveal encroachment compared to the placebo group, reducing centripetal growth from a mean of 72.9 µm/year to 50.7 µm/year (P=0.01), a relative slowing of approximately 36%, while zinc showed no significant effect. In AREDS2, lutein/zeaxanthin significantly reduced foveal encroachment in eyes with non-central GA. The reduction was most pronounced among patients who were not taking β-carotene, with a slowing of centripetal progression measured from 114.4 µm/year to 80.1 µm/year (P=0.01, ≈35% reduction), consistent with competitive intestinal absorption between carotenoids (35). In contrast, no difference in area-based GA area progression was seen with either antioxidants or zinc in AREDS eyes. The authors pointed out the genuine differential efficacy of antioxidants on proximity-based versus area-based GA progression. Interestingly, in a supplementary subgroup analysis of AREDS data, eyes with incident, new-onset GA demonstrated slower area-based GA progression when randomized to antioxidants. Notably, among AREDS eyes with non-central GA, antioxidant supplementation showed differential treatment effects by cohort: proximity-based progression was reduced in prevalent (preexistent) cases, whereas area-based progression was reduced in incident (new-onset) cases.

In the AREDS2 eyes with any GA, area-based enlargement (measured as change in square root of GA area) did not differ significantly between participants randomized to antioxidants with lutein/zeaxanthin versus those without lutein/zeaxanthin. However, area-based progression was significantly slower in beta-carotene than no beta-carotene participants (14). Thus, the authors conclude that the effects of antioxidants and lutein/zeaxanthin are predominantly in the central and paracentral macula, where these compounds are more naturally abundant than in the peripheral retina, and may therefore contribute to the foveal sparing observed in the distribution of incident GA and to slower rates of progression toward the central macula compared with the periphery.

Changes in VA were modest across the study period. Among AREDS participants, those receiving antioxidants experienced 2 fewer letters of vision loss than those not receiving antioxidants. In AREDS2 participants, slower VA decline was observed among those randomized to lutein/zeaxanthin or β-carotene compared with no β-carotene, as well as among those receiving low-dose zinc compared with high-dose zinc. However, because β-carotene competes with lutein/zeaxanthin for intestinal absorption, does not independently slow progression toward the central macula, and is associated with an increased risk of lung cancer in individuals with a history of smoking, Keenan’s analysis confirmed that a formulation containing vitamins C and E with lutein/zeaxanthin—but without β-carotene—is still most strongly recommended (14) and may effectively slow the atrophic changes within the central and paracentral macula without affecting total lesional growth. An important implication of Keenan’s work is that oral supplementation may influence the efficacy of emerging therapies aimed at slowing GA progression and therefore should be carefully documented and controlled in clinical trials. The biological plausibility of this observation is supported by the known distribution of macular pigment—lutein, zeaxanthin, and meso-zeaxanthin—which is most concentrated in the central macula and varies among individuals based on foveal architecture (36-42).

Along these lines, a post hoc analysis of data from the OAKS and DERBY clinical trials of pegcetacoplan for GA was recently published. Interestingly, it demonstrated no effect of AREDS or AREDS2 supplementation on GA growth toward the fovea or on overall GA growth in either untreated or treated participants, indicating no impact on pegcetacoplan efficacy (43). These analyses were based on GA measurements obtained from fundus autofluorescence (FAF) imaging evaluated by two independent graders, a modality that is more sensitive for GA assessment than color fundus photography. Over 24 months, participants not treated with pegcetacoplan in the control group taking AREDS/AREDS2 (n=226) supplements demonstrated 13 micrometers greater growth towards fovea compared to those not taking supplements, but the difference was not statistically significant (n=290, P=0.50). Over this period, the overall GA growth in the control group was 34 microns greater in subjects taking AREDS/AREDS2 (n=518) compared to those without supplements (n=741, P=0.12). No effect was seen in eyes with either non-center involving or subfoveal lesions. Identical findings, with no effect on slowing GA growth, were observed in participants treated with monthly or every-other-month pegcetacoplan. Moreover, no effect of AREDS/AREDS2 on rates of exudative AMD development was seen in patients treated with pegcetacoplan.

Similarly, another recent retrospective study analyzed data from the Chroma (No. NCT02247479) and Spectri (No. NCT02247531) trials of lampalizumab in AMD to evaluate whether AREDS vitamins or antioxidants/lutein supplements affect GA progression (44). Among 1,881 participants, 72% reported using these supplements, but no statistically significant association was found with GA lesion growth or the distance of the GA border to fovea change from baseline over two years. Consequently, these discrepant findings underscore the need for a prospective clinical trial to more definitively assess the effect of AREDS/AREDS2 supplementation on GA progression.

In summary, Keenan’s analysis suggests that patients with noncentral GA in one or both eyes may derive benefit in minimizing progression toward the fovea from the current AREDS2 formulation containing vitamins C and E with lutein and zeaxanthin without β-carotene. These findings support a potential role for targeted nutritional supplementation in preserving central visual function over the long-term. Strengths of Keenan’s study include the introduction of a novel, clinically meaningful approach to assessing GA progression; the use of randomized controlled data from the AREDS and AREDS2 trials; a large sample size; a mean follow-up of approximately three years; and standardized imaging graded by a masked central reading center. Limitations include reliance primarily on color fundus photography (with FAF images available only in a subset of AREDS2 participants), the absence of optical coherence tomography–based measurements, and the exploratory, post-hoc nature of the analysis.

Taken together, the provocative nature of Keenan’s findings—alongside conflicting results from other retrospective analyses of recent clinical trial data—strongly supports the need for a prospective randomized controlled trial evaluating oral antioxidant and lutein/zeaxanthin supplementation in individuals with non-central GA. If confirmed, these results could inform a revised standard of care for patients with GA. Additionally, given the apparent preferential effect within the central and paracentral macula, future studies could explore targeted antioxidant delivery strategies stratified by progression rate. Specifically, comparing fast versus slow GA progressors may help clarify the impact of antioxidant therapy on delaying visual loss in patients exhibiting features associated with more rapid GA progression.

Acknowledgments

None.

Footnote

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-2026-1-0006/coif). The authors have no conflicts of interest to declare.

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