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Ar27.0
AREDS2 Formula Research
Too few graded studies
39 peer-reviewed studies
What the evidence says
Too few graded studies
AREDS2 Formula doesn't have enough studies with structured effect-size data yet to pool a verdict. Browse the studies below for individual findings.
Most evidence is from high-quality meta-analyses and randomised trials published 1994–2026 with a typical study size of 4,203 participants.
Based on 39 studies · 2 meta-analyses · 17 RCTs · 87,953 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
Too few graded studies33 studies
Therapeutic & clinical
Too few graded studies5 studies
Safety profile
Too few graded studies3 studies
Micronutrient & trace-element status
Mostly mechanism / observational3 studies
Cognitive function
Too few graded studies2 studies
Neuroprotection & brain agingNone demonstrated. The AREDS2 cognitive-function substudy tested 3,501 participants over 5 years and found no significant difference in cognitive decline for any supplement arm · n/a — the trial was null at 5 years
Too few graded studies1 study
Recovery
Too few graded studies1 study
Heart & blood pressure
Too few graded studies1 study
5 more outcomes with fewer studies not shown.
Active research area
25 studies in the last 5 years · Latest meta-analysis: 2024
199420102026
1RCTCited 986×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)
3Systematic ReviewCited 51×n=11,952 · very large study2023
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: 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: 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: 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: 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: 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: 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: Two-year progression of AMD score was associated with progression to clinically meaningful anatomic (late AMD) and vision (≥2-line or ≥3-line loss) outcomes, suggesting that this scale may be useful for future clinical trials designed to slow the progression of AMD.
Vitale S et al. · JAMA ophthalmology (2020)
Among 3868 participants in the AREDS free of late AMD at baseline, the mean (SD) age was 68.3 (5.0) years, and 2180 of 3868 (56.4%) were women.
In the first 2 years after randomization to the AREDS, 669 of 7458 (9.0%) of eyes had at least 2-step 2-year progression, and 275 of 7458 (3.7%) of eyes had at least 3-step 2-year progression.
In the 5-year follow-up period (years 2-7), 486 of 7223 (6.7%) of eyes developed NV AMD, 339 of 7253 (4.7%) developed CGA, 726 of 7246 (10.0%) developed any GA, 2622 of 7095 (37.0%) had at least 2-line BCVA loss, and 1494 of 7155 (20.9%) had at least 3-line BCVA loss.
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: Cataract surgery did not increase the risk of developing late AMD among AREDS2 participants with up to 10 years of follow-up.
Bhandari S et al. · Ophthalmology (2022)
The Cox regression model showed no increased risk of developing late AMD after cataract surgery: hazard ratio, 0.96; 95% confidence interval (CI), 0.81-1.13 (P = 0.60) for right eyes and hazard ratio, 1.05; 95% CI, 0.89-1.25 (P = 0.56) for left eyes.
Of the matched pairs, late AMD was identified in 408 eyes that received cataract surgery and in 429 phakic controls: odds ratio (OR) 0.92 (95% CI, 0.77-1.10; P = 0.34).
The risk of late AMD after cataract surgery from the logistic regression model was not statistically significant (risk ratio, 0.92; 95% CI, 0.56-1.49; P = 0.73).
In plain English: In this cohort, eyes with GA involving or within 1 mm of the foveal center and a baseline BCVA of ≥ 40 letters appeared more likely to experience significant BCVA loss, suggesting these eyes may benefit more from therapies that slow GA progression.
Shen LL et al. · Ophthalmology (2025)
Higher baseline BCVA, smaller baseline GA proximity to the foveal center, and greater GA growth rate were each independently associated with larger BCVA loss over 4 years (each P < 0.001).
In this cohort, eyes with GA involving or within 1 mm of the foveal center and a baseline BCVA of ≥ 40 letters appeared more likely to experience significant BCVA loss, suggesting these eyes may benefit more from therapies that slow GA progression.
Our findings support a personalized approach to managing patients with GA, potentially guiding the design of future GA trials.
In plain English: Closer adherence to a Mediterranean-type diet was associated with lower risk of progression to late AMD and to large drusen.
Keenan TD et al. · Ophthalmology (2020)
Over a median follow-up of 10.2 years, of the 13 204 eyes, 34.0% progressed to late AMD.
Hazard ratios (HRs) for progression in aMedi tertile 3 versus 1 were 0.78 (95% confidence interval [CI], 0.71-0.85, P < 0.0001) for late AMD, 0.71 (0.63-0.80, P < 0.0001) for GA, and 0.84 (0.75-0.95, P = 0.005) for neovascular AMD.
For fish consumption, HRs for late AMD in quartile 4 versus 1 were 0.69 (0.58-0.82, P < 0.0001; AREDS) and 0.92 (0.78-1.07, P = 0.28; AREDS2).
In plain English: In this review, we will discuss the potential use of apocarotenoids to slowdown the progression of iAMD, to reduce the incidence of both forms of late AMD.
Camelo S et al. · Oxidative medicine and cellular longevity (2020)
The antioxidant formulation AREDS (Age-Related Eye Disease Studies), contains β-carotene, which has been replaced by lutein and zeaxanthin in AREDS2, are given to patients with iAMD but have a limited effect on the incidence of nAMD and GA.
Thus, to avoid or slowdown the development of late stages of AMD (nAMD or GA), new therapies targeting iAMD are needed such as crocetin obtained through hydrolysis of crocin, an important component of saffron (Crocus sativus L.), and norbixin derived from bixin extracted from Bixa orellana seeds.
We have shown that these apocarotenoids preserved more effectively RPE cells against apoptosis following blue light exposure in the presence of A2E than lutein and zeaxanthin.
In plain English: Advancing these strategies holds the potential to improve patient outcomes, optimize AMD management, and pave the way for precision nutrition in ophthalmology.
Figueiredo I et al. · Nutrients (2024)
Adjusting carotenoid intake, such as lutein and zeaxanthin, based on genetic susceptibility exemplifies emerging precision nutritional approaches.
Ongoing research seeks to integrate nutrigenomic testing into clinical settings, enabling clinicians to tailor interventions to individual genetic profiles.
Conclusions: Further studies are needed to assess the long-term effects of personalized interventions, investigate additional genetic variants, and develop tools for clinical implementation of nutrigenomics.
In plain English: The AREDS AMD simplified severity scale has been modernized with 2 important updates.
Agrón E et al. · Ophthalmology (2024)
In the AREDS, after the first scale update, the 5-year rates of progression to late AMD for levels 0 to 4 were 0.3%, 4.5%, 12.9%, 32.2%, and 55.6%, respectively.
As the final simplified severity scale, the 5-year progression rates for levels 0 to 4 were 0.3%, 4.3%, 11.6%, 26.7%, and 50.0%, respectively, for participants without RPD at baseline and 2.8%, 8.0%, 29.0%, 58.7%, and 72.2%, respectively, for participants with RPD at baseline.
In external validation on the AREDS2, for levels 2 to 4, the progression rates were similar: 15.0%, 27.7%, and 45.7% (RPD absent) and 26.2%, 46.0%, and 73.0% (RPD present), respectively.
In plain English: Higher dietary intake of multiple nutrients, including minerals, vitamins, and carotenoids, is associated with decreased risk of progression to late AMD.
Agrón E et al. · Ophthalmology (2021)
Over median follow-up of 10.2 years, of the 14 135 eyes, 32.7% progressed to late AMD.
Higher dietary intake of multiple nutrients, including minerals, vitamins, and carotenoids, is associated with decreased risk of progression to late AMD.
These associations are stronger for GA than for neovascular AMD.