A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9.

AREDS was a multicenter, randomized, double-masked, placebo-controlled trial with a 4-arm design (antioxidants, zinc, antioxidants+zinc, placebo). Eleven centers enrolled 4,757 participants aged 55–80 years; 4,629 had at least 1 natural lens and were followed for a mean of 6.3 years. Randomization was stratified by clinical center and AMD category. Lens opacities were graded using AREDS cataract grading; visual acuity assessed by ETDRS. Baseline characteristics included ~56% female, ~96% white, 8% current smokers, and substantial Centrum multivitamin use; outcomes included lens progression and ≥15-letter visual acuity loss.

Four regimens administered as two tablets in the morning and two tablets in the evening with meals: (1) Antioxidants: vitamin C 500 mg/day, vitamin E 400 IU/day, beta-carotene 15 mg/day; (2) Zinc: zinc 80 mg/day as zinc oxide plus copper 2 mg/day as cupric oxide; (3) Antioxidants + Zinc: combination of the above antioxidants and zinc; (4) Placebo: identical tablets without active ingredients. Duration: mean follow-up of 6.3 years.

High-dose antioxidant supplementation did not reduce the risk of development or progression of age-related lens opacities or cataract surgery over ~6.3 years (odds ratio 0.97, P = .55). For eyes without AMD at baseline, there was no significant difference in risk of losing ≥15 letters (OR 1.03, P = .89). The 5-year probability of a lens event was ~30% in both antioxidant and non-antioxidant groups. No significant adverse effects were found; yellow skin was more common with antioxidants (8.6% vs 6.1%, P = .001); hospitalizations for mild/moderate symptoms were lower in antioxidant arms (7.3% vs 9.3%, P = .01); mortality did not differ (RR 1.06, P = .53). Conclusion: A high-dose vitamin C, vitamin E, and beta-carotene formulation did not affect the 7-year risk of cataract development or vision loss in this relatively well-nourished older adult population.

Participants were relatively well nourished; generalizability to less-nourished populations is unknown. Only a subset of antioxidant nutrients was studied, and the timing/duration may have limited effects (age 55+ at enrollment; average 6.3 years). Some participants used Centrum multivitamins, potentially altering nutrient intake; smoking-related beta-carotene adjustments occurred during the trial. Adherence varied (about 75% of tablets taken by ~70% at 5 years); some participants changed or discontinued treatment due to safety concerns (e.g., beta-carotene in smokers). Lens-opacities assessment and imaging could be affected by changes in photography equipment/techniques over time. Loss to follow-up and missing data (~2.3% to last visit; ~14–15% withdrew); the study may have limited power to detect small or context-specific effects and findings may not apply to different populations or nutrient regimens.