Evidence-based Synthesis Program Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program 

Nutritional Supplements 

for Age-related 

Macular Degeneration:

A Systematic Review

Department of Veterans Affairs

Health Services Research & Development Service

January 2012

Investigators:

Principal Investigator: 

Devan Kansagara, MD, MCR

Co-Investigators: 

Ken Gleitsmann, MD, MPH

Melanie Gillingham, PhD, RD

Michele Freeman, MPH

Ana Quiñones, PhD

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Portland VA Medical Center

Portland, OR

Devan Kansagara, MD, MCR, Director
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Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

EXECUTIVE SUMMARY

BACKGROUND

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the 

developed world. In 2004, AMD affected 1.75 million persons in the United States, a number 

that is expected to rise to nearly 3 million by 2020 due to the aging of the population. 

The severity of macular degeneration ranges from Category 1 (least severe) to Category 4 (most 

severe), and “advanced AMD” is defined as having geographic atrophy involving the center of 

the macula or features of choroidal neovascularization.

Observational studies suggest that people with dietary intakes higher in various carotenoids, 

antioxidants and omega-3 fatty acids have a lower risk of developing AMD. This has led to 

several supplementation trials designed to examine the ability of nutritional supplement with 

carotenoids, antioxidants, or omega-3 fatty acids to prevent the progression of AMD. 

Our report focuses on the evidence documenting the potential benefits and harms of certain 

dietary supplements in patients with AMD. We conducted a systematic review of published 

literature to address the following key questions:

1) In patients with age-related macular degeneration, do nutritional supplements containing 

carotenoids, antioxidants, or omega-3 fatty acids alone or in combination prevent functional 

visual loss?

2) In adult populations, what are the harms of carotenoid, antioxidant, and omega-3 fatty acid 

supplementation?

METHODS

We conducted searches in Medline® Embase, Scopus, Conference Papers Index, and the 

Cochrane Library (Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews 

of Effects; Cochrane Central Register of Controlled Trials) from 1947 or database inception 

through February 2011. We obtained additional articles from systematic reviews, reference 

lists of pertinent studies, reviews, editorials, and by consulting experts. Reviewers trained 

in the critical analysis of literature assessed for relevance the abstracts of citations identified 

from literature searches. Full-text articles of potentially relevant abstracts were retrieved for 

further review. We assessed the internal validity of each study using the Cochrane Risk of Bias 

tool. We assessed the overall quality of the body of evidence for each outcome by considering 

the consistency, coherence, and applicability across studies, as well as the internal validity of 

individual studies, using a method developed by the Grades of Recommendation, Assessment, 

Development, and Evaluation (GRADE) Working Group. We critically analyzed the evidence on 

efficacy and adverse effects, and compiled a narrative synthesis of findings. 

RESULTS

We reviewed 4,335 titles and abstracts from the electronic search, and identified 22 additional 

references through manual searching of reference lists or from input from technical advisors. 
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Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

After applying inclusion/exclusion criteria at the abstract level, 347 full-text articles were 

reviewed. Of the full-text articles, we rejected 308 that did not meet our inclusion criteria.

Key Question #1. In patients with age-related macular degeneration, do nutritional 

supplements containing carotenoids, antioxidants, or omega-3 fatty acids alone 

or in combination prevent functional visual loss?

We identified seven randomized controlled trials (RCTs) of nutritional supplements in AMD 

patients. A significant effect in preventing functional loss was found only in the two largest trials. 

The weight of evidence was dominated by the Age Related Eye Disease Study (AREDS) in terms 

of sample size (N=3640) and duration of follow-up (7 years). The sample sizes in the other six 

studies ranged from 60 to 164 subjects, with follow-up ranging from 6 to 24 months. Given that 

progression of AMD occurs slowly and with low frequency, the smaller studies might have been 

of insufficient duration or power to detect a treatment effect. 

In the AREDS study, a beneficial effect was observed with a combination of antioxidants (500 

mg vitamin C, 400 IU vitamin E, and 15 mg beta carotene) plus zinc (80 mg zinc oxide and 2 

mg cupric oxide) but only among subjects with Categories 3 and 4 AMD. No significant change 

was reported in mild AMD subjects (Category 1 or 2) in any of the three treatment arms (i.e., 

antioxidants alone; zinc alone; or antioxidants plus zinc) compared with placebo. The protective 

effect of greatest magnitude among all of the supplement treatment arms was noted in the zinc 

plus antioxidant group (OR 0.63, 99% CI 0.44-0.92).

Key Question #2. In adult populations, what are the harms of carotenoid, antioxidant, and omega-3 fatty acid supplementation?

Vitamin E at high doses (>=400 IU/day) may be associated with increased risk of mortality, 

congestive heart failure, and prostate cancer. 

Beta-carotene may be associated with an increased risk of lung cancer among active smokers. 

In the Beta-Carotene and Retinol Efficacy Trial (CARET) and Alpha-Tocopherol and BetaCarotene (ATBC) trials, beta-carotene was associated with increased mortality and increased risk 

of lung cancer among smokers. Two other large trials, the Women’s Health Study (WHS) and the 

Physicians’ Health Study (PHS), did not find an excess risk of lung cancer among smokers using 

beta-carotene, but a meta-analysis combining these four studies determined that the overall risk 

of lung cancer among current smokers treated with beta-carotene was significantly elevated (OR 

1.24 (95% CI, 1.10-1.39)). No increase in lung cancer incidence was observed among former 

smokers and nonsmokers in these studies. In prospective cohort studies that used lower doses 

than RCTs, a small inverse association between carotenoids and lung cancer among current 

smokers has been observed. 

Zinc was associated with urinary tract infections and hospital admissions due to genitourinary 

causes in one study. 

Yellowish discoloration of the skin was frequently reported in trials of beta-carotene, and has 

also been noted in trials of lutein. Gastrointestinal symptoms were also commonly reported in 

trials of various supplements. 
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Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

DISCUSSION

We found good evidence mainly from one large RCT (AREDS) that supplementation with 

carotenoids and antioxidants decreased the risk of functional vision loss among patients with 

Category 3 or 4 AMD. One smaller RCT also found zinc supplementation may decrease the risk 

of clinically significant visual loss among patients with Category 3 or 4 AMD. The effects of 

carotenoids or omega-3 fatty acids alone have not been well-studied. An ongoing study (AREDS 

II) is currently being conducted to evaluate the effects of carotenoids (lutein and zeaxanthin) and 

omega-3 fatty acids (DHA and EPA) on AMD progression in approximately 4,200 subjects with 

Categories 3 to 4 AMD. 

In the AREDS trial, there was no detectable effect on vision loss in any of the treatment arms 

among subjects with Category 1 or 2 AMD, due to the very slow rate of disease progression in 

these subjects. Based on the findings of AREDS, we estimate that a trial of Category 2 AMD 

patients would need an approximate sample size of 17,000 subjects, followed for at least five 

years, to detect a significant difference in functional vision loss associated with supplementation.

Higher doses of vitamin E (>400 IU per day) have been associated with an estimated four 

percent increase in mortality; a 13 to 17 percent increase in risk of prostate cancer; and a 13 

to 50 percent increase in risk of congestive heart failure among those with existing CVD risk 

factors such as left ventricular dysfunction, diabetes mellitus, recent myocardial infarction, or 

renal insufficiency. Carotenoids such as beta-carotene have been associated with an estimated 

24 percent increase in risk of lung cancer among smokers. Whether the balance of benefits 

and harms favors supplementation in AMD patients likely depends on the population being 

considered. There is strong evidence for benefit in patients with more advanced AMD, and in 

these patients, the very small risk of harm is likely to be outweighed by the potential benefit. 

CONCLUSION

Evidence of benefit from supplementation with carotenoids and antioxidants on functional 

vision loss in patients with AMD is based mainly on the results of one large trial. The observed 

benefit occurred only among subjects with Category 3 or 4 AMD. There is evidence for a low 

risk of harm from some nutritional supplements at high doses. As with any clinical intervention, 

the balance of benefits and harms regarding supplementation in AMD patients depends on 

the population being considered. Given that AMD patients are older and have additional 

medical comorbidities, many would be at risk for some of the potential harms associated with 

supplementation. The precautionary principle should be observed while further evidence evolves. 

While our report notes the uncertainty in the conclusions of many of the included studies, 

reasonable recommendations can be extended:

• Carotenoid and antioxidant supplements significantly decrease visual loss and can be 

recommended for patients with Categories 3 and 4 AMD.

• Current literature does not support the use of these supplements for patients with mild AMD.

• Certain nutritional supplements have significant potential harms:

◦ Increased mortality and congestive heart failure in high risk patients with vitamin E.

◦ Increased risk of prostate cancer with vitamin E.

◦ Increased risk of lung cancer among smokers with beta-carotene.
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Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

The table below summarizes the evidence on the benefits and harms of oral supplements for 

AMD.

EXECUTIVE SUMMARY TABLE

Summary of the evidence of the effects of nutritional supplements in patients with age-related 

macular degeneration

Outcome Treatment Population Effect* GRADE 

Classification† Comment

Functional 

vision loss

Carotenoids Early AMD (~) Low Single study (N=90) found a small 

increase in visual acuity after 12 

months, but the improvement was not 

clinically significant (i.e. <15 letters).

Antioxidants‡ Categories 

3-4 AMD

(+) Moderate Evidence of benefit from 1 large 

multicenter trial (AREDS) and 1 smaller 

trial. 4 small trials found neutral effects 

on functional vision loss.

Antioxidants Category 2 

AMD

(~) Low No evidence of benefit after 7 years 

of treatment in 1 large multicenter trial 

(AREDS) that included 1,063 Category 

2 subjects. 

Omega-3 fatty acids Early AMD 

(94% in 

Categories 

1- 2)

(~) Very low 1 study found evidence of slowed 

visual acuity loss but not to a clinically 

significant degree. Very few subjects in 

this study (6.4%) had Categories 3-4 

AMD. 

Quality of life Carotenoids AMD (~) Low No significant findings on night driving in 

one study (N=90). 

Antioxidants N/A (0) N/A No evidence.

Omega-3 fatty acids N/A (0) N/A No evidence.

Mortality Beta-carotene Smokers (–) Moderate High-dose beta-carotene (20 to 30 mg/

day) was linked with increased mortality 

in 2 large trials in smokers and asbestos 

workers. 

Vitamin E General 

population

(–) High High-dose vitamin E (>=400 IU/day) 

was associated with a slight increase in 

mortality in a meta-analysis of 11 trials. 

Lung cancer Beta-carotene Smokers (–) Moderate High-dose beta-carotene (20 to 30 mg/

day) was linked with increased lung 

cancer incidence among smokers in 

a meta-analysis of 4 large trials. No 

increase in lung cancer was observed 

among former and non-smokers.

Prostate cancer Vitamin E General 

population

(–) Low High-dose vitamin E (400 IU/day) was 

associated with an increase in prostate 

cancer in one study.

Gastrointestinal 

cancers

Antioxidants General 

population

(~) High Supplements had no effect on incidence 

of gastrointestinal cancers in a metaanalysis of 12 good-quality trials. 
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Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

Outcome Treatment Population Effect* GRADE 

Classification† Comment

Congestive 

heart failure

Vitamin E DM, CVD, or 

post-infarction

(–) Low Vitamin E (300-400 IU/day) was linked 

with increased CHF hospitalization in 2 

trials of high-risk patients.

Urinary tract 

infections 

(UTIs)

Zinc AMD (–) Low Zinc (80 mg/day) was associated with 

more UTIs and hospital admissions due 

to genitourinary causes compared with 

non-zinc treated subjects in one large 

study. 

Yellowing of the 

skin

Beta-carotene 

Lutein

AMD and 

general 

population

(–) High Transient yellowing of the skin was 

frequently reported in trials of betacarotene and in two trials of lutein.

Gastrointestinal 

(GI) symptoms

Antioxidants AMD (–) High GI symptoms were the most common 

adverse effect that led to withdrawal 

from studies, according to a systematic 

review of 10 RCTs of antioxidant 

supplements for AMD.

GRADE = Grades of Recommendation, Assessment, Development, and Evaluation; ICU = intensive care unit; RCT = randomized controlled 

trial; AMD = age-related macular degeneration; CHF = congestive heart failure.

* Effect: (+) benefit; (–) harm; (~) mixed findings/no effect; (0) no evidence.

† GRADE classification: high = further research is very unlikely to change our confidence on the estimate of effect; moderate = further research 

is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low = further research is very 

likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very low = any estimate of 

effect is very uncertain.

‡ Trials of antioxidants included treatment with antioxidants alone or combined with carotenoids or other supplements.