Nutritional Supplementation: AREDS > AREDS2 > Where are we going?
Ivan Y-F Leung1, BSc(Hons)Optom, PhD, FAAO
Key Words: AREDS2, lutein, zeaxanthin, beta-carotene, DHA, EPA
1 University of Manchester, Singapore,
FSI Optometry Degree Programme,
Singapore Polytechnic, Singapore;
The Age-Related Eye Disease Study (AREDS) was a ground breaking clinical trial for nutritional research twenty years ago. AREDS was the first large-scale, randomized, double-blind, population based clinical trial of dietary supplementation in the ophthalmic industry.1 The results from AREDS suggested that the combination of high dose of vitamin C (500 mg), Vitamin E (400 IU), beta-carotene (15 mg) and zinc (80 mg) can reduce the risk to develop advanced age-related macular degeneration (AMD).2 The prescription of AREDS formula or similar ingredient became a routine practice in ophthalmology and optometry for decades. However, the combinations of other micronutrients or antioxidants do not have conclusive scientific evidence to show beneficial effect for degenerative eye diseases.
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With the successive and positive results from AREDS, National Eye Institute (NEI) of the National Institutes of Health (NIH) started a new but similar clinical trial – AREDS2 study in 2006.3 In order to investigate the possible role of macular carotenoids and polyunsaturated fatty acids, lutein (10 mg) and zeaxanthin (2 mg) were added with or without omega-3 fatty acids, docosahexaenoic acid (DHA, 350 mg) and eicosapentaenoic acid (EPA, 650 mg). Carotenoids lutein and zeaxanthin were strong candidates for inclusion in AREDS 20 years ago but these macular carotenoids were not commercially available when AREDS started in late 1992.1 The AREDS2 study recruited 4203 participants aged 50 to 85 with intermediate or advanced AMD. The patients were followed for 5 year and the primary results were published in May 2013.4 In this article, I am going to describe the study design and the major outcome of the AREDS2. Lastly, the future role of optometrist regarding oral nutritional supplement in vision care is discussed.
Study Designs of AREDS2
AREDS2 was a Phase III, multicenter, randomized, double blind clinical trial conducted from 2006 to 2012. The study design was considered as the highest standard in clinical trial with large sample size and good statistical power based on the progression rate of AMD in AREDS.3 The primary objective of the AREDS2 was to evaluate the effect of dietary xanthophyll (lutein and zeaxanthin) with and without long chain polyunsaturated fatty acids (DHA and EPA). Since the investigators attempted to address many issues (Table 1), AREDS2 involved a complex study design (Figure 1) with secondary randomization and many secondary analyses.
|Major items addressed by AREDS2||Conclusion drawn from AREDS2|
|1. Did lutein and zeaxanthin work better than AREDS formula towards progression to advanced AMD?||No|
|2. Did lutein and zeaxanthin work better than AREDS formula towards progression to neovascular AMD OR central geographic atrophy?||No|
|3. Did lutein and zeaxanthin work better than AREDS formula towards better visual acuity?||No|
|4. Did DHA and EPA work well with lutein and zeaxanthin with respect to the outcome in questions 1, 2 and 3?||No, DHA and EPA did not reduce the risk of advanced AMD at all|
|5. Was there any addition risk reduction towards advanced AMD when comparing formulation with and without lutein/zeaxanthin?||Yes, additional 10% risk reduction with lutein/zeaxanthin|
|6. Did lutein and zeaxanthin reduce the risk towards cataract progression?||No|
|7. Was beta-carotene working well compare with lutein/zeaxanthin?||No|
|8. Did beta-carotene increase the risk of lung cancer in former-smokers?||Yes|
|9. Was there any serious adverse event in those treatment groups other than beta –carotene in ex-smokers?||No|
|10. Was the dosage of zinc in AREDS too high?||Unsure|
Although sub-group analyses of lutein/zeaxanthin supplementation was working pretty well with 10 % reduction in the risk of progression to advanced AMD, macular carotenoids are not magic bullet. Comparisons with placebo demonstrated no statistical significant reduction in progress to advanced AMD (HR, 0.90[98.7% CI, 0.76-1.07]; P=0.12). In fact placebo was the modified AREDS formulation under secondary randomization. Sub-group analyses of the dietary intake of lutein/zeaxanthin stratified by quintiles showing that subjects with lower dietary intake of lutein/zeaxanthin supplement with lutein/zeaxanthin had a significant lower risk to develop advanced AMD. It suggested that serum and/or dietary intake of carotenoids affect the outcome of supplementation. In general, AREDS2 suggested a replacement of beta-carotene with 10 mg lutein and 2 mg zeaxanthin. The dosage of vitamin C, E and zinc remain unchanged in the newly proposed AREDS2 formulation. Surprisingly, omega 3 fatty acids (DHA/EPA) did not have any effect on progression to advanced AMD and they were not recommended.
AREDS was a ground breaking study to investigate the use of supplementation for eye diseases. It utilized the gold standard in clinical trial to test a nutritional formulation. AREDS2 further explored the questions in advanced AMD and cataract according to the current knowledge in eye research. The composition of the AREDS formula is now modified and improved base on the solid data from the long term follow-up. However, AREDS2 only open the door a bit wider in nutritional supplementation in optometry/ophthalmology. There are still a lot of unanswered questions; will AREDS2 formulation work well for early AMD patients? Do we need to consider dosage effect? Will a higher dose work better or a lower dose is more than enough? Should we consider young adult to start taking AREDS2 formulation to delay or prevent onset of AMD? Will the AREDS2 formulation work for other retinal diseases? Is it safe for children to take these multi-vitamins and antioxidants? Will the AREDS2 formulation affect visual functions other than visual acuity? There is strong evidence that macular pigment in the retina increased with oral supplementation of lutein/zeaxanthin. 5-7 Should we need to measure macular pigment in an optometric practice to monitor the level of lutein/zeaxanthin in the eye?
Clinical trial is an expensive business and there is no guarantee for success. Nutraceutical companies are happy to see their products selling well without any clinical prove of efficacy. How can optometrists determine whether any supplementation is effective or not? As a primary care practitioner, we should always update our professional knowledge continuously. The current role of optometrists includes detection and prevention of eye diseases. Early determination of risk factors such as smoking, family history of genetic eye diseases is essential in a regular eye examination. Optometrists should encourage healthy living styles and may consider prescribing dietary supplements for patients at risk. As scientific knowledge is increasing with new technology, our role will expand to monitor chronic eye diseases by giving nutritional supplement, assessing more visual functions or even evaluating health marker (such as macular pigment) in the eye.8
- The Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study (AREDS): Design implications AREDS Report No. 1. Control Clin Trials. 1999;20:573-600.
- The Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamin C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS Report No. 8 Arch Ophthalmol. 2001;119:1417-1436.
- The Age-Related Eye Disease Study 2 (AREDS2) Research Group. The Age-Related Eye Disease Study 2 (AREDS2): Study design and baseline characrteristics (AREDS2 Report No.1). Ophthalmology. 2012;119:2282-2289.
- The Age-Related Eye Disease Study 2 (AREDS2) Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration. The Age-Related Eye Disease Study 2 (AREDS2): Randomized clinical trial. JAMA. 2013;309.E1-19.
- Connolly EE, Beatty S, Loughman J et al. Supplementation with all three macular carotenoids: response, stability and safety. Inves Ophthalmol Vis Sci. 2011;52:9207-9217.
- Hammond BR, Johnson EJ, Russell RM, et al. Dietary modification of human macular pigment density. Inves Ophthalmol Vis Sci. 1997b;38:795-801.
- Landrum JT, Bone RA, Joa H, et al. A one year study of the macular pigment: the effect of 140 days of a lutein supplement. Exp Eye Res. 1997;65:57-62.
- Leung YFI. Macular pigment: New Clinical methods of detection and the role of carotenoids in age-related macular degeneration. Optometry 2008;79:266-272.