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After AREDS: Translating research evidence into clinical practice

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Dr Laura Downie
BOptom PhD(Melb) PGCertOcTher FACO DipMus(Prac) AMusA FAAO

There continues to be significant interest in the potential role that antioxidant therapy may have in preventing the development and/or progression of age-related macular degeneration (AMD). Early interest in this area began in the 1990s, when several epidemiologic studies published data to suggest that antioxidants may reduce the risk of cancer, cardiovascular disease and age-related ocular disease.1-3

At that time, there were limited management options for AMD and as is still the case now, a lack of effective prophylactic treatment. The findings from these studies,1-3 in combination with extensive advertising by the manufacturers of dietary supplements, resulted in the widespread consumption of high-dose vitamin and mineral formulations containing antioxidants and zinc.4 This was despite the lack of compelling evidence to support the efficacy or safety of such interventions.

Enter AREDS

The AMD clinical trial within the original Age Related Eye Disease Study (AREDS) was designed, in part, to evaluate whether pharmacologic doses of antioxidant vitamins and zinc were effective and safe in reducing the onset and/or progression of AMD. Post hoc analyses of the data suggested that daily, long-term oral supplementation with a formulation containing vitamin C (500 mg), vitamin E (400 IU), beta-carotene (15 mg), zinc (80 mg as zinc oxide) and copper (2 mg as cupric oxide) reduced the risk of progression to late AMD from 28 per cent to 20 per cent at five years, in subjects with at least intermediate AMD.

These findings come with some important provisos.

First, it is important to understand the currently-accepted clinical classification of AMD.5 `Intermediate AMD' is defined by the presence of large drusen (> 125 micron in diameter) and/or any definite hyper- and hypo-pigmentary abnormalities with at least one medium drusen (more than 63 microns but no more than 125 microns in size) located within two disc diameters of the fovea. Late disease constitutes `neovascular AMD' or `geographic atrophy'.

Essentially, patients with less than intermediate disease (in other words, early AMD) did not show any significant reduction in progression to late AMD.

Second, AREDS considered only one formulation, which contained the specific combination of nutrients, as detailed. AREDS therefore does not contribute to understanding whether a single component or a combination of components is required to achieve a beneficial effect, or understanding what the minimum effective dose(s) are.

On further review

Two important systematic reviews, published by the Cochrane Collaboration in 2012, summarised available evidence from randomised controlled clinical trials (RCTs) regarding the benefit of nutritional interventions for attenuating both the development6 and progression7 of AMD.

With regard to the use of antioxidant supplements to prevent AMD onset, the Cochrane meta-analysis included four high-quality RCTs, conducted in Australia, Finland and the United States. This analysis indicated that there was no significant effect of antioxidant therapy for preventing the development of AMD.6

It is important to emphasise that `evidence for no benefit' is distinct from `an absence of evidence' to support the benefit of antioxidant therapy. In relation to AMD progression, a total of 13 RCTs were included in the analyses; AREDS was described as one of the primary sources of evidence for the benefit of antioxidant supplementation in reducing the risk of progression to late AMD.7

In relation to the safety of antioxidant supplements, while AREDS was underway evidence became available to indicate that high-dose beta-carotene supplementation was associated with an increased risk of lung-cancer related mortality among patients who were heavy smokers.8,9 As a result, caution has been urged regarding the use of dietary supplements containing beta-carotene for smokers. The high daily dose of zinc in the AREDS formula was also associated with a significant number of participants reporting gastro-intestinal disturbances.

Could the AREDS formulation be improved to enhance both its safety and efficacy?

Enter AREDS2

The eagerly anticipated results from AREDS2, also co-ordinated by the National Eye Institute in the United States, were published earlier this year.10 AREDS2 sought to examine the effect of daily nutritional supplementation with lutein + zeaxanthin and/or omega-3 essential fatty acids (EFAs) on AMD progression, in subjects with at least intermediate disease.

The major finding was that there was no additional benefit in adding lutein + zeaxanthin and/or omega-3 EFAs to the original AREDS formulation; there was also no significant effect on mortality.

A sub-group analysis demonstrated that participants who had the lowest natural (dietary) intake of lutein and zeaxanthin (= 0.823 mg/day) but who took the AREDS formulation plus lutein + zeaxanthin, had their risk of developing late AMD reduced from 35 per cent to 27 per cent, compared with participants with a similar dietary intake who were not supplemented with the xanthophyll carotenoids.

While it has been claimed that based on the findings from AREDS2, replacing beta-carotene with lutein and zeaxanthin `appears to be a safer and more effective form of antioxidant therapy',11 it is imperative that these findings are not over-stated. The AREDS2 exploratory analyses found that when sub-groups of participants from secondary randomisation were considered overall, there was the suggestion of a further reduction in the rate of progression of AMD when beta-carotene was replaced by lutein + zeaxanthin.

That said, the merit of replacing lutein + zeaxanthin for beta-carotene was not a predefined outcome of AREDS2. In fact, the AREDS study group emphasised the need for further investigation of this hypothesis.

AREDS2 in practice

What does AREDS2 mean for clinical practice? Adding lutein + zeaxanthin and/or omega-3 EFAs does not enhance the antioxidant protective effect. Formulations with these additional components are not supported by evidence as being more effective than the original AREDS formulation.

It is less clear whether AREDS2 supports the finding from the original AREDS clinical trial that specific combination(s) of antioxidant vitamins and minerals, including the original AREDS formulation, are of any benefit in reducing the risk of progression to late AMD in `at risk' patients, that is, patients with intermediate AMD.

This position requires further consideration and is based on an observation that the probability of progression to advanced AMD was found, for all primary randomisation treatment groups in AREDS2, to be higher (29 to 31 per cent) than those with category 3 or 4 AMD who received placebo (no treatment) in AREDS (28 per cent).

The AREDS2 findings do suggest that there could be benefit in clinicians surveying the dietary intake of lutein and zeaxanthin in high-risk AMD patients, in order to recommend appropriate dietary changes to boost their consumption of these carotenoids and thus reduce the risk of progression to late AMD. Obtaining essential nutrients from food sources is preferred to supplementation, as it is considered to be sustainable, less costly and has significantly lower risk of side-effects.12

The question of whether beta-carotene should be replaced by lutein + zeaxanthin in the AREDS formulation has not yet been answered definitively. Given the potential for an increased risk of lung cancer in current and former smokers who take beta-carotene supplements, it may well be reasonable for one carotenoid (beta-carotene) to be replaced by another set of carotenoids (lutein + zeaxanthin) to enhance the safety profile of the formulation. However, clinicians need to be aware that this is not a recommendation that can be made based solely on the data provided in AREDS2.

Many important questions relating to the role of nutrition and AMD still remain to be answered. For instance, is optimising diet alone actually safer and more effective than dietary supplements? It is already established that when beta-carotene is consumed from dietary sources it does not confer the same risk of lung cancer to current or former smokers as when sourced from dietary supplements.

It is also unclear which specific components of the AREDS and AREDS2 formulations are actually providing the therapeutic effect. What is the minimum dose of the particular component or combination of components that provides protection against progressive AMD?

It is vital that clinicians understand the available evidence and can reconcile this evidence to assess the merit of claims by third parties. Providing individualised patient care that is based on the most recent available evidence, that is, the adoption of evidence-based practice, is essential for delivering the highest standards of clinical care to our AMD patients.

Nutritional supplements survey

Dr Laura Downie and Dr Peter Keller are conducting a survey on behalf of the University of Melbourne to assess the use of nutritional supplements by Australian optometrists and the recommendations they make to patients about nutrition.

To participate in the survey, visit www.surveymonkey.com/s/OptometryNutrition.

The questionnaire is anonymous and will take about seven minutes to complete.

  1. Buring JF, Hennekens CH. Nutrients in Cancer Prevention and Treatment. Totowa, NJ: Humana.
  2. Stampfer MJ, Hennekens CH, Manson JE et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993; 328: 1444-1449.
  3. Sperduto RD, Ferris FLI, Kurinji N. Do we have a nutritional treatment for age-related cataract or macular degeneration? Arch Ophthalmol 1990; 108: 1403-1405.
  4. The Age-Related Eye Disease Study (AREDS) Group. The Age-Related Eye Disease Study (AREDS): Design Implications AREDS Report No. 1. Control Clin Trials 1999; 20: 6: 573-600.
  5. Ferris FL III, Wilkinson CP, Bird A et al. Clinical classification of age-related macular degeneration. Ophthalmology 2013; 120: 844-851.
  6. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev. June 13, 2012.
  7. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. November 14, 2012.
  8. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330: 1029-1035.
  9. Omenn GS, Goodman GE, Thornquist MD et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996; 334: 18: 1150-1155.
  10. The Age-Related Eye Disease Study (AREDS) Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration. The Age-Related Eye Disease Study 2 (AREDS) randomized clinical trial. JAMA 2013; 309: 19: 2005-2015.
  11. Harvey B. AREDS 2: what does it mean in practice? Optician 2013; 24 May.
  12. Thomson CD, Chisholm A, McLachlan SK et al. Brazil nuts: an effective way to improve selenium status. Am J Clin Nutr 2008; 87: 2: 379-384.


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