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Ar27.0
AREDS2 Formula Research
Mostly mechanism / observational
14 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most AREDS2 Formula studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from high-quality meta-analyses and randomised trials published 1994–2025 with a typical study size of 4,203 participants.
Based on 14 studies · 2 meta-analyses · 7 RCTs · 76,001 total participants
Confidence
High confidence
By outcome
Vision & eye healthIn people with intermediate AMD or advanced AMD in one eye: roughly a quarter to a third lower odds of progressing to advanced AMD, and less moderate vision loss. No benefit demonstrated in people without AMD, and no restoration of vision already lost · Measured over years, not weeks — the AREDS trial averaged 6.3 years of follow-up
Mostly mechanism / observational10 studies
Therapeutic & clinical
Mostly mechanism / observational5 studies
Safety profile
Too few graded studies2 studies
Cognitive function
Too few graded studies1 study
Recovery
Too few graded studies1 study
Heart & blood pressure
Too few graded studies1 study
Anemia & hematology
Too few graded studies1 study
Men's vitality
Too few graded studies1 study
1 more outcome with fewer studies not shown.
Active research area
5 studies in the last 5 years · Latest meta-analysis: 2024
199420092025
1RCTCited 947×n=4,203 · very large study2013
In plain English: Adding lutein/zeaxanthin or omega-3 to the AREDS formulation did not further reduce progression to advanced AMD, but lutein/zeaxanthin was judged an appropriate substitute for beta-carotene because of increased lung cancer incidence in former smokers.
Age-Related Eye Disease Study 2 Research Group · JAMA (2013)
Primary analysis was NULL: lutein/zeaxanthin HR 0.90 (98.7% CI 0.76-1.07, P=.12); DHA+EPA HR 0.97 (0.82-1.16, P=.70); both together HR 0.89 (0.75-1.06, P=.10)
5-year Kaplan-Meier probability of progression to advanced AMD: 31% placebo, 29% lutein/zeaxanthin, 31% DHA+EPA, 30% both
More lung cancers with beta-carotene than without: 23 (2.0%) vs 11 (0.9%), nominal P=.04, mostly in former smokers
In plain English: Antioxidants plus zinc significantly reduced the odds of developing advanced AMD (OR 0.72, 99% CI 0.52-0.98), with the benefit confined to participants who already had large drusen or advanced AMD in one eye.
Age-Related Eye Disease Study Research Group · Arch Ophthalmol (2001)
Antioxidants plus zinc vs placebo for advanced AMD: OR 0.72 (99% CI 0.52-0.98). Zinc alone OR 0.75 (0.55-1.03); antioxidants alone OR 0.80 (0.59-1.09) — neither significant on its own
Excluding the 1,063 lower-risk participants, estimates strengthened: antioxidants plus zinc OR 0.66 (0.47-0.91); zinc OR 0.71 (0.52-0.99); antioxidants OR 0.76 (0.55-1.05)
Moderate visual acuity loss (>=15 letters) was significantly reduced only by antioxidants plus zinc: OR 0.73 (99% CI 0.54-0.99)
In plain English: People with AMD taking antioxidant vitamins were less likely to progress to late AMD (OR 0.72, 95% CI 0.58-0.90, moderate-certainty evidence), with most of the evidence coming from AREDS.
Progression to late AMD with multivitamins: OR 0.72 (95% CI 0.58-0.90), 3 studies, 2,445 participants, moderate certainty
Absolute translation: ~4 fewer progressions per 1,000 in early AMD (1 to 6 fewer), but ~78 fewer per 1,000 in intermediate AMD (26 to 126 fewer) — the benefit tracks baseline risk
AREDS also showed lower risk of neovascular AMD (OR 0.62, 0.47-0.82), geographic atrophy (OR 0.75, 0.51-1.10) and losing 3+ lines of acuity (OR 0.77, 0.62-0.96), all moderate certainty
In plain English: Vitamin E did not prevent any AMD (RR 0.97, high-certainty, 55,614 participants) and neither did beta-carotene (RR 1.00, high-certainty, 22,083 men) — and the one multivitamin Cochrane assessed slightly INCREASED risk of any AMD (RR 1.21, 1.02-1.43, moderate certainty). This formula is not a preventive.
Vitamin E vs placebo: any AMD RR 0.97 (95% CI 0.90-1.06), HIGH certainty; late AMD RR 1.22 (0.89-1.67), moderate certainty — a possible slight increase. 4 studies, 55,614 participants, 4-10 years
Beta-carotene vs placebo: any AMD RR 1.00 (95% CI 0.88-1.14), HIGH certainty; late AMD RR 0.90 (0.65-1.24), moderate certainty. 2 studies, 22,083 participants, men only
One trial reported excess haemorrhagic strokes in the vitamin E group: 39 vs 23 events, HR 1.74 (95% CI 1.04-2.91), low certainty
In plain English: Among 29,133 male smokers, beta-carotene supplementation unexpectedly increased lung cancer incidence by 18% and total mortality by 8%.
Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group · N Engl J Med (1994)
Lung cancer incidence with beta-carotene: +18% (95% CI 3% to 36%) compared with those not receiving it — an unexpected harm
Total mortality was 8% higher (95% CI 1% to 16%) with beta-carotene, primarily from lung cancer and ischaemic heart disease
Alpha-tocopherol showed no reduction in lung cancer (-2%, 95% CI -14% to 12%) and more deaths from haemorrhagic stroke, though fewer prostate cancers
In plain English: The Beta-Carotene and Retinol Efficacy Trial was stopped 21 months early after beta-carotene plus retinol raised lung cancer risk by 28% in smokers, former smokers and asbestos-exposed workers.
Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Barnhart S, Hammar S · N Engl J Med (1996)
Lung cancer relative risk in the active-treatment group: 1.28 (95% CI 1.04-1.57, P=0.02) versus placebo
Relative risk of death from any cause 1.17 (95% CI 1.03-1.33); from lung cancer 1.46 (1.07-2.00); from cardiovascular disease 1.26 (0.99-1.61)
The trial was stopped 21 months earlier than planned because of these findings
In plain English: At 10 years, beta-carotene usage nearly doubled the risk of lung cancer (OR 1.82) while lutein/zeaxanthin showed no significant increase — and lutein/zeaxanthin was modestly favourable for late AMD progression.
Chew EY, Clemons TE, Agrón E, Domalpally A, Keenan TDL, Vitale S, Weber C, Smith DC, Christen W; AREDS2 Research Group · JAMA Ophthalmol (2022)
10-year lung cancer odds ratio: 1.82 (95% CI 1.06-3.12, P=.02) for beta-carotene assignment vs 1.15 (0.79-1.66, P=.46) for lutein/zeaxanthin
Progression to late AMD, lutein/zeaxanthin vs none: HR 0.91 (95% CI 0.84-0.99, P=.02); restricted to those assigned beta-carotene, HR 0.80 (0.68-0.92, P=.002)
Direct comparison lutein/zeaxanthin vs beta-carotene for late AMD: HR 0.85 (95% CI 0.73-0.98, P=.02)
In plain English: Five years after the trial ended, the AREDS formulation's benefit persisted for advanced and neovascular AMD but not for central geographic atrophy.
Chew EY, Clemons TE, Agrón E, Sperduto RD, Sangiovanni JP, Kurinij N, Davis MD; Age-Related Eye Disease Study Research Group · Ophthalmology (2013)
At 10 years, in AREDS categories 3 and 4: advanced AMD OR 0.66 (95% CI 0.53-0.83) and neovascular AMD OR 0.60 (0.47-0.78), both P<0.001
No significant reduction for central geographic atrophy: OR 1.02 (95% CI 0.71-1.45, P=0.93)
Moderate visual acuity loss (>=15 letters) was significantly reduced: OR 0.71 (95% CI 0.57-0.88, P=0.002)
In plain English: There were no statistically significant differences in change of cognitive function scores for participants randomized to receive supplements versus those who were not.
Chew EY, Clemons TE, Agrón E, Launer LJ, Grodstein F, Bernstein PS; Age-Related Eye Disease Study 2 (AREDS2) Research Group · JAMA (2015)
Yearly change in the composite cognitive score was -0.19 (99% CI -0.25 to -0.13) with long-chain PUFAs vs -0.18 (-0.24 to -0.12) without; difference in yearly change -0.03 (99% CI -0.20 to 0.13), P=.63
Lutein/zeaxanthin was likewise not significantly different from no lutein/zeaxanthin on the composite score
Cognitive testing used a validated battery administered by telephone at baseline and every 2 years across the 5-year study; composite score range -22 to 17
In plain English: Daily supplementation with lutein/zeaxanthin had no statistically significant overall effect on rates of cataract surgery or vision loss.
Age-Related Eye Disease Study 2 (AREDS2) Research Group; Chew EY, et al. · JAMA Ophthalmol (2013)
Progression to cataract surgery, lutein/zeaxanthin vs none: HR 0.96 (95% CI 0.84-1.10, P=.54) — null
Three or more lines of vision loss: HR 1.03 (95% CI 0.93-1.13, P=.61) — null
In the lowest quintile of dietary lutein/zeaxanthin intake, HR was 0.68 (95% CI 0.48-0.96, P=.03) — a subgroup finding, not a primary result
In plain English: In exploratory analyses, lutein/zeaxanthin outperformed beta-carotene for progression to late AMD (HR 0.82) and neovascular AMD (HR 0.78) — the basis for substituting it into the formula.
Age-Related Eye Disease Study 2 (AREDS2) Research Group; Chew EY, Clemons TE, Sangiovanni JP, et al. · JAMA Ophthalmol (2014)
Exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin: HR 0.90 (95% CI 0.82-0.99, P=.04) for late AMD
Direct comparison lutein/zeaxanthin vs beta-carotene: late AMD HR 0.82 (0.69-0.96, P=.02); neovascular AMD HR 0.78 (0.64-0.94, P=.01); central geographic atrophy HR 0.94 (0.70-1.26, P=.67) — no atrophy benefit
Restricted to eyes with bilateral large drusen at baseline: late AMD HR 0.76 (0.61-0.96, P=.02); neovascular AMD HR 0.65 (0.49-0.85, P=.002); central geographic atrophy HR 0.98 (0.69-1.39, P=.91)
In plain English: Supplementation slowed the spread of geographic atrophy toward the central macula, while leaving total lesion area unchanged.
Keenan TDL, Agrón E, Keane PA, Domalpally A, Chew EY; AREDS and AREDS2 Research Groups · Ophthalmology (2025)
AREDS eyes with non-central geographic atrophy (n=208): progression toward the central macula 50.7 µm/year (95% CI 38.0-63.4) with antioxidants vs 72.9 µm/year (61.3-84.5) without, P=0.012
AREDS2 eyes with non-central atrophy assigned AREDS antioxidants without beta-carotene (n=325 eyes): 80.1 µm/year (60.9-99.3) with lutein/zeaxanthin vs 114.4 µm/year (96.2-132.7) without, P=0.011
Area-based progression was NOT significantly different in either trial (AREDS n=392 eyes, P=0.63; AREDS2 n=505 eyes, P=0.64) — the benefit is directional, not a reduction in lesion size
In plain English: All antioxidant-supplemented groups significantly increased macular pigment optical density and contrast sensitivity at low spatial frequency, but the evidence quality was low.
Hu W, Seah V, Huang V, Kim JE · Adv Nutr (2024)
Every one of the 8 antioxidant-supplemented groups significantly increased macular pigment optical density and low-spatial-frequency contrast sensitivity versus placebo
Lutein + zeaxanthin + fatty acid ranked best for macular pigment optical density (SUCRA 99.3%) and second for contrast sensitivity (67.7%)
Only the antioxidant mixture + lutein + fatty acid combination significantly improved visual acuity (HR -0.15, 95% CI -0.28 to -0.02)
In plain English: Intake above recommended levels can produce anemia, neutropenia and zinc-induced copper deficiency; EFSA sets the tolerable upper intake at 25 mg/day and the FDA allows 40 mg/day.
Schoofs H, Schmit J, Rink L · Molecules (2024)
Excess zinc intake can cause anaemia, neutropenia and zinc-induced copper deficiency
EFSA tolerable upper intake level for zinc: 25 mg/day; the FDA figure is 40 mg/day — both far below the 80 mg in the AREDS formulation