AMD + Antioxidants

Prescribing of Antioxidants in Age-Related Macular Degeneration (AMD)

 

Summary

Several observation studies and randomized controlled studies of varying quality have shown conflicting results with AMD progression and consumption of antioxidants. The main trial that is quoted in this area is the AREDS study in which the only statistically significant reduction in rates of visual acuity loss occurred in patients with more severe disease assigned to receive antioxidants plus zinc (OR 0.73; 99% CI 0.54 to 0.99). This analysis was underpowered. These results have not been replicated in other RCTs. These products are food supplements and are not licensed medicinal products and so the prescriber take full responsibility for prescribing.

 

Background

Age-related macular degeneration (AMD) is a condition affecting the central area of the retina. The retina can deteriorate with age and some people get lesions that can lead to loss of central vision. It has been suggested that progression of the disease may be slowed down in people who eat a diet rich in antioxidant vitamins (carotenoids, vitamins C and E) or minerals (selenium and zinc).

Many nutritional supplements containing antioxidants and/or zinc are available over-the-counter and are promoted for the improvement of ocular health; their unlicensed status precludes their promotion for AMD, although some can be prescribed on the NHS for this indication

These products are classed as a food supplements and do not have a medicinal product license. This means that the prescriber takes full responsibility for prescribing, and does not have a Summary of Product Characteristics (SPC) to refer to.

Two products, PreserVision and Viteyes Original, closely match the combination of antioxidants and minerals used in the AREDS study (zinc 80mg, vitamin E 400 units, vitamin C 500mg and beta-carotene 15mg daily). However, as they contain beta-carotene, people who smoke or are recent ex-smokers should not take them. Similar formulations in which beta-carotene has been substituted with lutein (PreserVision Lutein, Viteyes Smoker’s Formula plus Lutein) lack the evidence base of the original formulation.

 

What's the evidence?

Observational studies

A number of observational studies have examined the relationship between AMD and the consumption of antioxidants and zinc. These studies have several limitations, including difficulty in assessing nutrient intake, problems of data collection, and inability to control for confounding factors, which may account for inconsistencies in results. In addition, the low prevalence of AMD, particularly the more advanced stages, in some of these studies limits their ability to detect any modest protective effect.

Several studies have found no association between antioxidant and zinc intake and AMD. They include the Beaver Dam Eye Study which examined the effects of diet on the 5-year incidence of early AMD among 1,586 participants [1]. This study did, however, observe a modest, but statistically significant inverse association between vitamin E and pro-vitamin A carotenoids (including alpha- and beta-carotene) and the incidence of large drusen, and between zinc (diet plus supplements) and pigment abnormalities; these factors are predictors of advanced AMD. A 5-year follow up of 2,335 participants in the Blue Mountains Eye Study similarly found no association between the occurrence of early AMD and baseline intake of pro-vitamin A carotenoids, other carotenoids (including lutein and zeaxanthin), vitamin A and zinc [2]. A harmful effect of vitamin C was suggested but this finding may have been due to chance.

Among 1,787 participants from the Women’s Health Initiative study assessed to have either a high or low intake of lutein plus zeaxanthin at baseline, there was no significant difference in the prevalence of intermediate AMD when they were examined 4 to 7 years later [3]. Moderate zinc intake from food or supplements was not found to have any protective effect against AMD among 66,572 subjects from the Nurses’ Health Study (NHS) followed up for 10 years, or 37,636 participants in the Health Professionals Study (HPS) after 8 years [4].

In contrast, further analyses of cohorts from the same studies (NHS, n=77,562; HPS, n=40,866; followed up for up to 18 and 10 years, respectively) found that fruit intake was inversely associated with the risk of wet AMD. Participants who consumed three or more servings of fruit a day had a pooled multivariate relative risk of 0.64 (95% CI 0.44 to 0.93; P=0.004 for the trend) compared with those who ate fewer than 1.5 portions daily. However, intake of vegetables, antioxidant vitamins or carotenoids, or use of vitamin supplements was not strongly correlated with AMD [5]. The Rotterdam Study, involving 4,170 persons followed up for a mean of 8 years, reported a 35% decrease (hazard ratio 0.65; 95% CI 0.46 to 0.92) in incident AMD (all stages) among subjects with an above median intake of beta-carotene, vitamins C and E and zinc. Exclusion of those subjects using supplements did not substantially affect this finding [6].

The Eye-Disease Case-Control Study, in which 356 case subjects with wet AMD were compared with 520 controls, found that a higher dietary intake of carotenoids was associated with a lower risk of AMD [7]. Subjects with the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with the lowest quintile (odds ratio (OR) 0.57; 95% CI 0.35 to 0.92; P=0.02 for the trend). The carotenoids, lutein and zeaxanthin, which were primarily obtained from dark green leafy vegetables, were most strongly associated with a reduced risk for AMD (P=0.001 for the trend). Intake of preformed vitamin A (retinol), and vitamins C and E appeared to have no protective effect.

Randomised controlled studies

Several randomised controlled trials (RCTs) have investigated the effect of dietary supplements on the development and progression of AMD. One four-year placebo-controlled study (VECAT, n=1,179), which examined the effect of vitamin E supplements (500 units/day) found no benefit in relation to early AMD [8]. Of two small placebo-controlled trials of 200mg zinc supplement daily, one in patients with early or intermediate AMD and the other in patients with wet AMD in one eye, only the first documented benefit, with subjects in the zinc-treated group less likely to lose vision than controls [9]. A large trial among 22,071 US physicians randomised to beta-carotene 50mg or placebo every other day for 12 years, found beta-carotene did not affect the primary outcome of the risk of developing visually significant AMD (relative risk 0.96; 95% CI 0.78 to 1.20) or the secondary outcomes of AMD with or without vision loss, and advanced AMD [10].

The most frequently cited study of nutritional supplements in the development and progression of AMD is the Age-Related Eye Disease Study (AREDS) [11]. Researchers reported outcomes for three baseline categories of participants; 1,063 with early or borderline AMD features, 1,621 with intermediate AMD, and 956 subjects with advanced (dry or wet) AMD or reduced visual acuity due to AMD in one eye. Participants were randomised (double-blind) to one of four arms:

  • zinc alone (80mg as zinc oxide daily with 2mg copper [prolonged use of zinc can lead to secondary copper deficiency])

  • antioxidants alone (vitamin C 500mg, vitamin E 400units and beta-carotene 15mg daily)

  • zinc plus antioxidants

  • placebo

While AREDS was ongoing, it became evident from other studies that beta-carotene was associated with a higher incidence of lung cancer in smokers. As a consequence, four percent of participants in AREDS who were current or former smokers discontinued or changed their study medication.

Follow up was for a mean 6.3 years and the trial had two primary outcomes: progression to advanced AMD and reduction in visual acuity (ï?³15-letter decrease). Overall, there was a statistically significant odds reduction for the progression to advanced AMD in patients treated with antioxidants plus zinc compared with placebo (OR 0.72; 99% CI 0.52 to 0.98). The ORs for zinc and antioxidants alone were 0.75 (99% CI 0.55 to 1.03) and 0.80 (99% CI 0.59 to 1.09), respectively, and not statistically significant.

In the early AMD group, only 1.3% of patients (12 in the treatment arms and 3 in the placebo arm) developed advanced AMD by year 5. This was a much lower rate than the researchers had expected so they conducted a post-hoc analysis excluding this group. The analysis of subjects with more severe disease showed a greater reduction in risk of progression of AMD, with ORs for antioxidants plus zinc and for zinc alone being statistically significant: [antioxidants plus zinc (0.66; 99% CI 0.47 to 0.91), zinc alone (0.71; 99% CI 0.52 to 0.99), antioxidants alone (OR 0.76; 99% CI 0.55 to 1.05)]. These results must be interpreted cautiously as the study was not powered for this analysis.

The only statistically significant reduction in rates of visual acuity loss occurred in patients with more severe disease assigned to receive antioxidants plus zinc (OR 0.73; 99% CI 0.54 to 0.99). Again this analysis was underpowered.

Three other RCTs of multivitamin supplements have been published [9]. They were small and of relatively short duration (6 to 18 months) and included patients with intermediate or advanced AMD. One study (n=71) employed a supplement containing vitamins B2, C and E, beta-carotene, zinc, bioflavonoids and minerals (Ocuguard, US) and another (n=20), a supplement containing vitamins C and E, beta-carotene and buphenine (Visaline, Swiss). The third study, the Lutein Antioxidant Supplementation Trial (LAST, n=90) was conducted following AREDS, and employed the carotenoid, lutein 10mg daily, with or without a multivitamin and mineral preparation (OcuPower, US). In a pooled analysis of these trials there was little effect of treatment on visual acuity, with a standardised mean difference of 0.16 (95% CI -0.19 to 0.51) [9]. Only one trial reported on progression of AMD and noted little evidence of a treatment effect at 18 months. An analysis of the lutein vs. placebo arms in LAST found no significant effect of lutein on visual acuity [9]. As a corollary to this, the US Food and Drug Administration recently concluded that there is no credible evidence that lutein or zeaxanthin reduce the risk of AMD [12]. Despite this, these carotenoids are included in an increasing number of ocular health products.

Of these studies, only AREDS has examined the safety of supplements in any detail. It provides some reassurance about the safety of high-dose zinc and antioxidants used for six years. The incidence of adverse effects was not statistically different between groups but patients taking zinc had increased hospital admissions for genitourinary symptoms and patients reported yellowing of the skin associated with beta-carotene. However, the safety of some of the components of the AREDS supplements has been questioned in other studies [13-16].

A higher incidence of lung carcinoma in smokers taking high doses of beta-carotene has been noted above. Recent meta-analyses have reported increased risks of all-cause mortality and cardiovascular deaths with beta-carotene [13] and of all-cause mortality with vitamin E [14], although some of the included studies used doses considerably higher than those used in AREDS. High doses of vitamins C and E (twice those used in AREDS) have been associated with worsening disease in women with pre-existing heart conditions [15]. More recently, the Heart Outcomes Prevention Evaluation (HOPE) study found a higher risk of heart failure among people with vascular disease or diabetes taking vitamin E 400mg daily, the dose taken in AREDS [16]. A post-hoc review of data from AREDS found patients in the antioxidant plus zinc group had a 14% relative reduction in mortality risk after an average of 6.5 years compared with those on placebo, and there was no difference in the incidence of congestive heart failure between the two groups [17]. However, AREDS participants were generally healthy and well nourished and may differ from subjects in other trials.

The safety of supplements will be explored further in AREDS 2. This study will enrol 4,000 subjects with a primary objective of determining whether supplementation with lutein and zeaxanthin, and omega-3 long-chain polyunsaturated fatty acids, will influence development of advanced AMD. The effect of eliminating beta-carotene and reducing the dose of zinc will also be assessed [18]. This study is due to finish December 2012 and so will report in 2013.

 

Conclusion

For patients who do not have AMD or who have early disease, there is no evidence from randomised controlled trials to support the use of nutritional supplements. Epidemiological evidence for benefit of a high dietary intake of antioxidants and zinc in preventing the development of AMD is conflicting. However it would seem reasonable to advise people without AMD or with only mild signs of the disease to follow Department of Health dietary guidelines and increase consumption of fruit and vegetables. Dietary sources of antioxidants include orange, yellow and green fruit, and dark green leafy vegetables; spinach and cabbage are particularly good sources of lutein and zeaxanthin. Dietary advice should be supplemented with smoking cessation advice if relevant, as smoking is a risk factor for AMD.

For patients with intermediate AMD or advanced AMD in one eye, there is evidence from one study (AREDS) that the specific combination of zinc 80mg, vitamin E 400 units, vitamin C 500mg and beta-carotene 15mg daily may be modestly beneficial in slowing disease progression. Products available in the UK that most closely match this combination are PreserVision and Viteyes Original. However, as these products contain beta-carotene, people who smoke or are recent ex-smokers should not take them. Similar formulations in which beta-carotene has been substituted with lutein (PreserVision Lutein, Viteyes Smoker’s Formula plus Lutein) lack the evidence base of the original formulation.

These supplements are not licensed medicinal products and so they have not undergone regulatory assessment. They contain doses that are significantly higher than recommended daily allowances and the safety profile of these products when used long-term is unknown. In view of recent findings of possible harm from high doses of vitamins C and E, the benefits and risks of supplementation in patients with pre-existing diabetes, heart or vascular conditions should be considered on an individual basis.

 

References

  1. VanderLangenberg GM, Mares-Perlman JA, Klein R et al. Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study. Am J Epidemiol 1998; 148: 204-214.

  2. Flood V, Smith W, Wang JJ et al. Dietary antioxidant intake and incidence of early age-related maculopathy; The Blue Mountains Eye Study. Ophthalmol 2002; 109: 2272-2278.

  3. Moeller SM, Parekh N, Tinker L et al. Associations between intermediate age-related macular degeneration and lutein and zeaxanthin in the Carotenoids in Age-Related Eye Disease Study (CAREDS). Arch Ophthalmol 2006; 124: 1151-1162.

  4. Cho E, Stampfer MJ, Seddon JM et al. Prospective study of zinc intake and the risk of age-related macular degeneration. Ann Epidemiol 2001; 11: 328-336.

  5. Cho E, Seddon JM, Rosner B et al. Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Opthalmol 2004; 122: 883-892.

  6. van Leeuwen R, Boekhoorn S, Vingerling JR et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA 2005; 294: 3101-3107.

  7. Seddon JM, Ajani UA, Sperduto RD et al for the Eye Disease Case-Control Study Group. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA 1994; 272: 1413-1420.

  8. Taylor HR, Tikellis G, Robman LD et al. Vitamin E supplementation and macular degeneration: randomised controlled trial. BMJ 2002; 325: 11-16.

  9. Evans JR. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD000254. DOI 10.1002/14651858.CD000254.pub2.

  10. Christen WG, Manson JE, Glynn RJ et al. Beta carotene supplementation and age-related maculopathy in a randomized trial of US physicians. Arch Ophthalmol 2007; 125: 333-339.

  11. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthlamol 2001; 119: 1417-1436.

  12. Trumbo PR and Ellwood KC. Lutein and zeaxanthin intakes and the risk of age-related macular degeneration and cataracts: an evaluation using the Food and Drug Administration’s evidence-based review system for health claims. Am J Clin Nutr 2006; 84: 971-974.

  13. Vivekananthan DP, Penn MS, Sapp SK et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003; 361: 2017-2023.

  14. Miller ER, Pastor-Barriuso R, Dalal D et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005; 142: 37-46.

  15. Waters DD, Alderman EL, Hsia J et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomised controlled trial. JAMA 2002; 288: 2432-2440.

  16. Lonn E, Bosch J, Yusuf S et al. The HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005; 293: 1338-1347.

  17. Chew EY and Clemons TE. Heart Outcomes Prevention Evaluation – the ongoing outcomes study, vitamin E, and age-related macular degeneration. Arch Ophthalmol 2006; 124: 1665-1666.

  18. Clinical Studies Database. Age-Related Eye Disease Study 2 (AREDS2). Accessed viahttp://www.nei.nih.gov/neitrials/viewStudyWeb.aspx?id=120 on 13/07/2007.

Adapted from the Medicines Q and A prepared by ukmi available at nelm.nhs.uk