Abstract (as published in JAMA)
Importance Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C and E, beta carotene, and zinc) has been shown to reduce the risk of progression to advanced age-related macular degeneration (AMD). Observational data suggest that increased dietary intake of lutein+zeaxanthin (carotenoids), omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA]+eicosapentaenoic acid [EPA]), or both might further reduce this risk.
Objectives To determine whether adding lutein+zeaxanthin, DHA+EPA, or both to the AREDS formulation decreases the risk of developing advanced AMD and to evaluate the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation.
Design, Setting, and Participants The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, randomized, double-masked, placebo-controlled phase 3 study with a 2x2 factorial design, conducted in 2006-2012 and enrolling 4203 participants aged 50 to 85 years at risk for progression to advanced AMD with bilateral large drusen or large drusen in 1 eye and advanced AMD in the fellow eye.
Interventions Participants were randomized to receive lutein (10 mg)+zeaxanthin (2 mg), DHA (350 mg)+EPA (650 mg), lutein+zeaxanthin and DHA+EPA, or placebo. All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta carotene, lowering of zinc dose, or both.
Main Outcomes and Measures Development of advanced AMD. The unit of analyses used was by eye.
Results Median follow-up was 5 years, with 1940 study eyes (1608 participants) progressing to advanced AMD. Kaplan-Meier probabilities of progression to advanced AMD by 5 years were 31% (493 eyes [406 participants]) for placebo, 29% (468 eyes [399 participants]) for lutein+zeaxanthin, 31% (507 eyes [416 participants]) for DHA+EPA, and 30% (472 eyes [387 participants]) for lutein+zeaxanthin and DHA+EPA. Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced AMD (hazard ratio [HR], 0.90 [98.7% CI, 0.76-1.07]; P=.12 for lutein+zeaxanthin; 0.97 [98.7% CI, 0.82-1.16]; P=.70 for DHA+EPA; 0.89 [98.7% CI, 0.75-1.06]; P=.10 for lutein+zeaxanthin and DHA+EPA). There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. More lung cancers were noted in the beta carotene vs no beta carotene group (23 [2.0%] vs 11 [0.9%], nominal P=.04), mostly in former smokers.
Author’s Conclusions and Relevance Addition of lutein+zeaxanthin, DHA+EPA, or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD. However, because of potential increased incidence of lung cancer in former smokers, lutein+zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation.
Omega-3s and Eye Health
The Age-Related Eye Disease Study 2 (AREDS2) Research Group (Epub 2013 May 5). Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial. JAMA: doi:10.1001/jama.2013.4997.
This was a secondary prevention study where all subjects had intermediate age-related macular degeneration (AMD) in at least one eye. This study did not assess primary prevention. While past research (Augood et al., 2008) suggests a role for EPA+DHA in decreasing the risk of developing AMD, the present research does not address this issue. Prevention is always more effective than treatment.
While EPA+DHA did not attenuate the progression from intermediate to advanced AMD, it’s possible that earlier stages of AMD may be more responsive to treatment.
What Else Should You Know?
There was no true placebo group, rather an active placebo group, making it more difficult to demonstrate a benefit of any of the treatments. More specifically, all subjects assigned to the control group received some variation of the supplement formula used in the original AREDS, which demonstrated that use of high-dose antioxidant and zinc supplements reduced progression of intermediate to late AMD (Age-Related Eye Disease Study Research Group, 2001). Because this treatment was shown to attenuate the progression of AMD, it would be considered unethical to deprive any of the study participants access to this regimen.
More research is being reported on nutritional interactions with genetic factors. Given that genetics appear to explain a large proportion of the variability in risk of AMD, future research should consider subject recruitment based on certain known genetic risk factors. In such population subgroups, EPA + DHA may prove to be beneficial in individuals with intermediate to advanced AMD (Ho et al., 2011).
Given the importance of DHA to eye health, the amount supplemented may have been too low to have an effect.
The present results are similar to results from another recent investigation in which EPA+DHA had no effect on AMD progression (Souied et al., 2013).
In a recent investigation, EPA + DHA increased optical density in subjects with AMD (Arnold et al., 2013).
Lutein + DHA increased macular pigment ocular density (MPOD) in patients with early AMD (García-Layana et al., 2013).
Global Organization for EPA and DHA Omega-3s (2013). Omega-3s and Macular Degeneration [Peer commentary on the paper “Lutein+Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial” by The Age-Related Eye Disease Study 2 (AREDS2) Research Group (Epub 2013 May 5). JAMA doi:10.1001/jama.2013.4997.].
Age-Related Eye Disease Study Research Group (2001). 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 Ophthalmol 119:1417-36.
Arnold C Winter L Fröhlich K Jentsch S Dawczynski J Jahreis G and Böhm V (Epub ahead of print 2013 March 21). Macular Xanthophylls and ω-3 Long-Chain Polyunsaturated Fatty Acids in Age-Related Macular Degeneration: A Randomized Trial. JAMA Ophthalmol.
Augood C Chakravarthy U Young I Vioque J de Jong PT Bentham G Rahu M Seland J Soubrane G Tomazzoli L Topouzis F Vingerling JR and Fletcher AE (2008). Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr 88:398-406.
García-Layana A Recalde S Alamán AS and Robredo PF (2013). Effects of Lutein and Docosahexaenoic Acid Supplementation on Macular Pigment Optical Density in a Randomized Controlled Trial. Nutrients 5:543-551.
Ho L van Leeuwen R Witteman JC van Duijn CM Uitterlinden AG Hofman A de Jong PT Vingerling JR and Klaver CC (2011). Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and ω-3 fatty acids: the Rotterdam study. Arch Ophthalmol 129:758-66.
Souied EH Delcourt C Querques G Bassols A Merle B Zourdani A Smith T and Benlian P for the Nutritional AMD Treatment 2 Study Group (Epub ahead of print 2013 Feb 7). Oral Docosahexaenoic Acid in the Prevention of Exudative Age-Related Macular Degeneration: The Nutritional AMD Treatment 2 Study. Ophthalmology.