Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration

Our plain-English summary of Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration, by J.R. Evans, J.G. Lawrenson (The Cochrane Database of Systematic Reviews, 2017).

The study

• Authors: J.R. Evans, J.G. Lawrenson
• Journal: The Cochrane Database of Systematic Reviews
• Published: 2017;7(7):CD000253
• Type of article: Meta-analysis, Systematic review
• Cited by: 81 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: There is inconclusive evidence from observational studies to suggest that people who eat a diet rich in antioxidant vitamins (carotenoids, vitamins C, and E) or minerals (selenium and zinc) may be less likely to develop age-related macular degeneration (AMD).

Objectives: To determine whether or not taking antioxidant vitamin or mineral supplements, or both, prevent the development of AMD.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 2), MEDLINE Ovid (1946 to 29 March 2017), Embase Ovid (1947 to 29 March 2017), AMED (Allied and Complementary Medicine Database) (1985 to 29 March 2017), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/); searched 29 March 2017, the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 29 March 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 29 March 2017 and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 29 March 2017. We did not use any date or language restrictions in the electronic searches for trials.

Selection Criteria: We included all randomised controlled trials (RCTs) comparing an antioxidant vitamin or mineral supplement (alone or in combination) to control.

Data Collection And Analysis: Both review authors independently assessed risk of bias in the included studies and extracted data. One author entered data into RevMan 5; the other author checked the data entry. We pooled data using a fixed-effect model. We graded the certainty of the evidence using GRADE.

Main Results: We included a total of five RCTs in this review with data available for 76,756 people. The trials were conducted in Australia, Finland, and the USA, and investigated vitamin C, vitamin E, beta-carotene, and multivitamin supplements. All trials were judged to be at low risk of bias.Four studies reported the comparison of vitamin E with placebo. Average treatment and follow-up duration ranged from 4 to 10 years. Data were available for a total of 55,614 participants. There was evidence that vitamin E supplements do not prevent the development of any AMD (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.90 to 1.06; high-certainty evidence), and may slightly increase the risk of late AMD (RR 1.22, 95% CI 0.89 to 1.67; moderate-certainty evidence) compared with placebo. Only one study (941 participants) reported data separately for neovascular AMD and geographic atrophy. There were 10 cases of neovascular AMD (RR 3.62, 95% CI 0.77 to 16.95; very low-certainty evidence), and four cases of geographic atrophy (RR 2.71, 95% CI 0.28 to 26.0; very low-certainty evidence). Two trials reported similar numbers of adverse events in the vitamin E and placebo groups. Another trial reported excess of haemorrhagic strokes in the vitamin E group (39 versus 23 events, hazard ratio 1.74, 95% CI 1.04 to 2.91, low-certainty evidence).Two studies reported the comparison of beta-carotene with placebo. These studies took place in Finland and the USA. Both trials enrolled men only. Average treatment and follow-up duration was 6 years and 12 years. Data were available for a total of 22,083 participants. There was evidence that beta-carotene supplements did not prevent any AMD (RR 1.00, 95% CI 0.88 to 1.14; high-certainty evidence) nor have an important effect on late AMD (RR 0.90, 95% CI 0.65 to 1.24; moderate-certainty evidence). Only one study (941 participants) reported data separately for neovascular AMD and geographic atrophy. There were 10 cases of neovascular AMD (RR 0.61, 95% CI 0.17 to 2.15; very low-certainty evidence) and 4 cases of geographic atrophy (RR 0.31 95% CI 0.03 to 2.93; very low-certainty evidence). Beta-carotene was associated with increased risk of lung cancer in people who smoked.One study reported the comparison of vitamin C with placebo, and multivitamin (Centrum Silver) versus placebo. This was a study in men in the USA with average treatment duration and follow-up of 8 years for vitamin C and 11 years for multivitamin. Data were available for a total of 14,236 participants. AMD was assessed by self-report followed by medical record review. There was evidence that vitamin C supplementation did not prevent any AMD (RR 0.96, 95% CI 0.79 to 1.18; high-certainty evidence) or late AMD (RR 0.94, 0.61 to 1.46; moderate-certainty evidence). There was a slight increased risk of any AMD (RR 1.21, 95% CI 1.02 to 1.43; moderate-certainty evidence) and late AMD (RR 1.22, 95% CI 0.88 to 1.69; moderate-certainty evidence) in the multivitamin group. Neovascular AMD and geographic atrophy were not reported separately. Adverse effects were not reported but there was possible increased risk of skin rashes in the multivitamin group.Adverse effects were not consistently reported in these eye studies, but there is evidence from other large studies that beta-carotene increases the risk of lung cancer in people who smoke or who have been exposed to asbestos.None of the studies reported quality of life or resource use and costs.

Authors' Conclusions: Taking vitamin E or beta-carotene supplements will not prevent or delay the onset of AMD. The same probably applies to vitamin C and the multivitamin (Centrum Silver) investigated in the one trial reported to date. There is no evidence with respect to other antioxidant supplements, such as lutein and zeaxanthin. Although generally regarded as safe, vitamin supplements may have harmful effects, and clear evidence of benefit is needed before they can be recommended. People with AMD should see the related Cochrane Review on antioxidant vitamin and mineral supplements for slowing the progression of AMD, written by the same review team.

In plain English

This Cochrane review of randomised controlled trials asked whether antioxidant vitamin or mineral supplements prevent age-related macular degeneration (AMD) in the general population. It included five trials with 76,756 people in Australia, Finland and the USA; in one, 18% of participants had AMD at baseline. The trials compared vitamin E, beta-carotene, vitamin C and a multivitamin (Centrum Silver) with placebo. For any AMD, risk ratios versus placebo were 0.97 (95% CI 0.90 to 1.06) for vitamin E, 1.00 (0.88 to 1.14) for beta-carotene, 0.96 (0.79 to 1.18) for vitamin C and 1.21 (1.02 to 1.43) for the multivitamin. In one trial, men given vitamin E had more haemorrhagic strokes than men given placebo (39 versus 23 events; hazard ratio 1.74, 95% CI 1.04 to 2.91; low-certainty evidence). The review did not study asbestos; citing other trials that found more lung cancer with beta-carotene, the authors called it contra-indicated in smokers and people exposed to asbestos. The authors concluded vitamin E or beta-carotene supplements will not prevent or delay AMD, and the same probably applies to vitamin C and the multivitamin.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Systematic review and meta-analysis (Cochrane Review) of randomised controlled trials comparing antioxidant vitamin or mineral supplements with control. Data were pooled with a fixed-effect model and the certainty of evidence was graded with GRADE.
• Who was studied: Five randomised trials with data on 76,756 people from the general population in Australia, Finland and the USA, identified by searches up to 29 March 2017. Three trials enrolled men only, one enrolled women only, and one enrolled both. In one trial (VECAT), 18% of participants had AMD at baseline.
• Exposure: Antioxidant supplements compared with placebo. Vitamin E was given at 50 mg/day, 400 IU on alternate days, 600 IU on alternate days, or 500 IU/day. Beta-carotene was given at 20 mg/day or 50 mg on alternate days. Vitamin C was given at 500 mg/day. The multivitamin was Centrum Silver. Asbestos exposure was not studied.
• Main results:
  • Vitamin E versus placebo (4 trials, 55,614 participants): the risk ratio for any AMD was 0.97 (95% CI 0.90 to 1.06; high-certainty evidence). The risk ratio for late AMD was 1.22 (95% CI 0.89 to 1.67; moderate-certainty evidence).
  • Vitamin E versus placebo, one trial (ATBC, 941 participants): there were 10 cases of neovascular AMD (RR 3.62, 95% CI 0.77 to 16.95) and four cases of geographic atrophy (RR 2.71, 95% CI 0.28 to 26.0). Both results were very low-certainty evidence.
  • In the PHS II trial of male physicians, more haemorrhagic strokes occurred in the vitamin E group than in the placebo group (39 versus 23 events; hazard ratio 1.74, 95% CI 1.04 to 2.91; low-certainty evidence).
  • Beta-carotene versus placebo (2 trials, men only, 22,083 participants): the risk ratio for any AMD was 1.00 (95% CI 0.88 to 1.14; high-certainty evidence). The risk ratio for late AMD was 0.90 (95% CI 0.65 to 1.24; moderate-certainty evidence).
  • Vitamin C versus placebo (1 trial of men in the USA, 14,236 participants): the risk ratio for any AMD was 0.96 (95% CI 0.79 to 1.18; high-certainty evidence). The risk ratio for late AMD was 0.94 (0.61 to 1.46; moderate-certainty evidence).
  • Multivitamin (Centrum Silver) versus placebo (1 trial of men in the USA, 14,233 participants): the risk ratio for any AMD was 1.21 (95% CI 1.02 to 1.43). The risk ratio for late AMD was 1.22 (95% CI 0.88 to 1.69). Both results were moderate-certainty evidence.
  • The review did not itself study lung cancer or asbestos. The authors reported that the main ATBC trial found an increased risk of lung cancer with beta-carotene supplementation, a finding repeated in the CARET trial. They stated that beta-carotene supplementation is contra-indicated in people who smoke or have been exposed to asbestos.
• The authors' conclusion: The authors concluded that taking vitamin E or beta-carotene supplements will not prevent or delay the onset of AMD. They added that the same probably applies to vitamin C and the multivitamin (Centrum Silver) tested in the one trial reported to date.
• Limitations the authors state:
  • The included eye studies did not consistently report adverse effects.
  • The ATBC trial was conducted in Finnish male smokers, and the authors cautioned against extrapolating its findings to other groups.
  • In the ATBC trial, there was no information on eye (maculopathy) status before supplementation began.
  • The studies were underpowered to examine late-stage disease.
  • In the Physicians' Health Study, AMD was identified through medical record review, which may have been less accurate.
  • The review gives no evidence on other antioxidant supplements, including commonly marketed vitamin combinations.

Topics

Medical terms in this study, explained in our Lexicon: Clinical Trial, confidence interval, Hazard Ratio, Lung Cancer, Quality of Life.

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• The potential role of antioxidant vitamins in preventing cardiovascular diseases and cancers — S. Hercberg, P. Galan, et al. (1998)
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