Antioxidant vitamin and mineral supplements to prevent the development of age-related macular degeneration (AMD)

What is the aim of this review?
The aim of this Cochrane Review was to find out whether taking antioxidant vitamin and mineral supplements prevents the development of AMD. Cochrane researchers collected and analysed all relevant studies to answer this question and found five studies.

Key messages
Taking vitamin E or beta-carotene supplements will not prevent the onset of AMD in people who do not have signs of the condition. The same probably applies to vitamin C and multivitamin tablets. There is no evidence for other supplements, such as lutein and zeaxanthin.

What was studied in the review?
AMD is a condition of the central area (macula) of the back of the eye (retina). The macula degenerates with age. In some people, this deterioration happens more quickly, and is associated with a particular appearance at the back of the eye. In its earliest stage (early AMD), yellow spots (drusen) can be seen under the retina by an eye health professional on examining the eye. The affected person will probably be unaware that they have a problem. As AMD progresses, it can lead to the loss of the cells in the back of the eye, which are needed for vision. This is known as geographic atrophy. Sometimes, new (harmful) blood vessels grow in the macula. These new blood vessels may bleed and cause scarring. This is known as neovascular or wet AMD. Any damage to the macula can affect vision, particularly central vision. Neovascular AMD and geographic atrophy are known as late AMD.

It is possible that antioxidant vitamins may help to protect the macula against this deterioration and loss of vision. Vitamin C, E, beta-carotene, lutein, zeaxanthin, and zinc are examples of antioxidant vitamins commonly found in vitamin supplements.

The Cochrane researchers only looked at the effects of these supplements in healthy people in the general population who did not yet have AMD. There is another Cochrane Review on the effects of these supplements in people who already have AMD.

What are the main results of the review?
The Cochrane researchers found five relevant studies. The studies were large and included a total of 76,756 people. They took place in Australia, Finland, and the USA. The studies compared vitamin C, vitamin E, beta-carotene, and multivitamin supplements with placebo.

The review showed that, compared with taking a placebo:

∙ Taking vitamin E supplements made little or no difference to the chances of developing AMD (high-certainty evidence).
∙ Taking vitamin E supplements made little difference, or slightly increased, the chances of developing late AMD (moderate-certainty evidence).
∙ Taking beta-carotene made little or no difference to the chances of developing any AMD (high-certainty evidence) or late AMD (moderate-certainty evidence).
∙ Taking vitamin C made little or no difference to the chances of developing any AMD (high-certainty evidence) or late AMD (moderate-certainty evidence).
∙ Taking multivitamin tablets may slightly increase the chances of developing any AMD or late AMD (moderate-certainty evidence).
∙ 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.

How up-to-date is this review?
The Cochrane researchers searched for studies that had been published up to 29 March 2017.

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.

Read the full 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 strategy: 

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.

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