Antioxidant vitamin and mineral supplements to slow down the progression 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 slows down the progression of AMD and prevents visual loss. Cochrane researchers collected and analysed all relevant studies to answer this question and found 19 studies.

Key messages
Taking an antioxidant multivitamin supplement may slow down the progression of AMD. Most benefit will be seen in people who have a higher chance of progression. Although vitamin supplements are generally regarded as safe, the studies included in this review did not provide good evidence as to safety as they were generally too small.

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 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 people with AMD. There is another Cochrane Review on the effects of these supplements in people who do not already have AMD.

What are the main results of the review?
The Cochrane researchers found 19 relevant studies. Ten studies were from Europe, six from USA, two from China, and one from Australia. These studies compared multivitamin supplements, zinc, vitamin E and lutein and zeaxanthin with placebo.

•Taking antioxidant vitamins plus zinc probably slows down the progression to late AMD and vision loss (moderate-certainty evidence). This may result in a small improvement in quality of life (low-certainty evidence).
•Taking lutein alone (or combined with zeaxanthin) may have little or no effect on progression to late AMD and vision loss (low-certainty evidence).
•Taking vitamin E alone may have little or no effect on the progression to late AMD and vision loss (low-certainty evidence).

Although vitamin supplements are generally regarded as safe, the studies included in this review did not provide good evidence as to safety as they were generally too small and adverse effects were reported inconsistently.

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

Authors' conclusions: 

People with AMD may experience some delay in progression of the disease with multivitamin antioxidant vitamin and mineral supplementation. This finding was largely drawn from one large trial, conducted in a relatively well-nourished American population. We do not know the generalisability of these findings to other populations. Although generally regarded as safe, vitamin supplements may have harmful effects. A systematic review of the evidence on harms of vitamin supplements is needed. Supplements containing lutein and zeaxanthin are heavily marketed for people with age-related macular degeneration but our review shows they may have little or no effect on the progression of AMD.

Read the full abstract...
Background: 

It has been proposed that antioxidants may prevent cellular damage in the retina by reacting with free radicals that are produced in the process of light absorption. Higher dietary levels of antioxidant vitamins and minerals may reduce the risk of progression of age-related macular degeneration (AMD).

Objectives: 

The objective of this review was to assess the effects of antioxidant vitamin or mineral supplementation on the progression of AMD in people with AMD.

Search strategy: 

We searched CENTRAL (2017, Issue 2), MEDLINE Ovid (1946 to March 2017), Embase Ovid (1947 to March 2017), AMED (1985 to March 2017), OpenGrey (System for Information on Grey Literature in Europe, the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 29 March 2017.

Selection criteria: 

We included randomised controlled trials (RCTs) that compared antioxidant vitamin or mineral supplementation (alone or in combination) to placebo or no intervention, in people with AMD.

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 graded the certainty of the evidence using GRADE.

Main results: 

We included 19 studies conducted in USA, Europe, China, and Australia. We judged the trials that contributed data to the review to be at low or unclear risk of bias.

Nine studies compared multivitamins with placebo (7 studies) or no treatment (2 studies) in people with early and moderate AMD. The duration of supplementation and follow-up ranged from nine months to six years; one trial followed up beyond two years. Most evidence came from the Age-Related Eye Disease Study (AREDS) in the USA. People taking antioxidant vitamins were less likely to progress to late AMD (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.58 to 0.90; 2445 participants; 3 RCTs; moderate-certainty evidence). In people with very early signs of AMD, who are at low risk of progression, this would mean that there would be approximately 4 fewer cases of progression to late AMD for every 1000 people taking vitamins (1 fewer to 6 fewer cases). In people at high risk of progression (i.e. people with moderate AMD) this would correspond to approximately 8 fewer cases of progression for every 100 people taking vitamins (3 fewer to 13 fewer). In one study of 1206 people, there was a lower risk of progression for both neovascular AMD (OR 0.62, 95% CI 0.47 to 0.82; moderate-certainty evidence) and geographic atrophy (OR 0.75, 95% CI 0.51 to 1.10; moderate-certainty evidence) and a lower risk of losing 3 or more lines of visual acuity (OR 0.77, 95% CI 0.62 to 0.96; 1791 participants; moderate-certainty evidence). Low-certainty evidence from one study of 110 people suggested higher quality of life scores (National Eye Institute Visual Function Questionnaire) in treated compared with the non-treated people after 24 months (mean difference (MD) 12.30, 95% CI 4.24 to 20.36).

Six studies compared lutein (with or without zeaxanthin) with placebo. The duration of supplementation and follow-up ranged from six months to five years. Most evidence came from the AREDS2 study in the USA. People taking lutein or zeaxanthin may have similar or slightly reduced risk of progression to late AMD (RR 0.94, 95% CI 0.87 to 1.01; 6891 eyes; low-certainty evidence), neovascular AMD (RR 0.92, 95% CI 0.84 to 1.02; 6891 eyes; low-certainty evidence), and geographic atrophy (RR 0.92, 95% CI 0.80 to 1.05; 6891 eyes; low-certainty evidence). A similar risk of progression to visual loss of 15 or more letters was seen in the lutein and control groups (RR 0.98, 95% CI 0.91 to 1.05; 6656 eyes; low-certainty evidence). Quality of life (measured with Visual Function Questionnaire) was similar between groups in one study of 108 participants (MD 1.48, 95% -5.53 to 8.49, moderate-certainty evidence).

One study, conducted in Australia, compared vitamin E with placebo. This study randomised 1204 people to vitamin E or placebo, and followed up for four years. Participants were enrolled from the general population; 19% had AMD. The number of late AMD events was low (N = 7) and the estimate of effect was uncertain (RR 1.36, 95% CI 0.31 to 6.05, very low-certainty evidence). There were no data on neovascular AMD or geographic atrophy.There was no evidence of any effect of treatment on visual loss (RR 1.04, 95% CI 0.74 to 1.47, low-certainty evidence). There were no data on quality of life.

Five studies compared zinc with placebo. The duration of supplementation and follow-up ranged from six months to seven years. People taking zinc supplements may be less likely to progress to late AMD (OR 0.83, 95% CI 0.70 to 0.98; 3790 participants; 3 RCTs; low-certainty evidence), neovascular AMD (OR 0.76, 95% CI 0.62 to 0.93; 2442 participants; 1 RCT; moderate-certainty evidence), geographic atrophy (OR 0.84, 95% CI 0.64 to 1.10; 2442 participants; 1 RCT; moderate-certainty evidence), or visual loss (OR 0.87, 95% CI 0.75 to 1.00; 3791 participants; 2 RCTs; moderate-certainty evidence). There were no data reported on quality of life.

Very low-certainty evidence was available on adverse effects because the included studies were underpowered and adverse effects inconsistently reported.

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