Article

An Update on AREDS2 Supplements and the Role of Genetic Testing

The NEI’s deputy clinical director discusses the findings.

An Update on AREDS2 Supplements and the Role of Genetic Testing

The NEI’s deputy clinical director discusses the findings.

EMILY Y. CHEW, MD

The Age-Related Eye Disease Study (AREDS) Research Group published the beneficial results of a randomized, controlled clinical trial of antioxidant vitamins and minerals for the treatment of age-related macular degeneration in 2001.1

The AREDS supplement, a combination of antioxidant vitamins (vitamins C and E, and beta-carotene) plus zinc oxide and copper, reduced the risk of progression to late AMD by 25% in five years.

A question that remained unanswered was whether lutein played a role in the AREDS supplement because lutein is found in the macular pigment of the eye. Lutein and its close cousin zeaxanthin were thought to serve a variety of functions, including filtering of potentially damaging blue and ultraviolet light and providing antioxidant capability.2

However, lutein was not commercially available at the launch of AREDS. The observational data from AREDS and numerous studies suggested that people with a high dietary intake of green leafy vegetables, such as kale, spinach, and collard greens, had a marked reduction in the risk of having late AMD in case-control studies.3-6

Similarly, observational data showed that high consumption of fish products rich in omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) was associated with a decreased risk of developing late AMD.7-11

Emily Y. Chew, MD, is deputy director of the division of epidemiology and clinical applications at the National Eye Institute. Dr Chew has no financial interests in any products mentioned in this article. She can be reached at echew@nei.nih.gov.

Such observational data were put to the test in a randomized clinical trial. AREDS2 evaluated the effects of adding lutein/zeaxanthin and/or omega-3 LCPUFAs to the AREDS supplement.12

We announced the results of the study in 2013, recommending that the beta-carotene be replaced by lutein/zeaxanthin in the AREDS supplement without adding omega-3 LCPUFAs.13

In this article, I will discuss these decisions, as well as the current recommendations from AREDS Research Group on the merits of genetic testing prior to prescribing AREDS and AREDS2 supplements.

WHY NOT ADD OMEGA-3 LCPUFAS TO AREDS2 SUPPLEMENTS?

The data from AREDS2 did not show a beneficial or harmful effect of adding omega-3 LCPUFAs to the AREDS supplements.13 Even when evaluating participants with the lowest level of dietary intake of omega-3 LCPUFAs, there was no beneficial effect.

The observational data from other studies, including AREDS, suggested a beneficial effect with an almost 40% to 50% reduction in the risk of having AMD in subjects with the highest intake compared to the lowest intake of fish. Could this be an inadequate dose?

This is potentially possible, but other studies testing the use of omega-3 LCPUFAs in diseases such as cardiovascular disease and dementia also assessed similar doses of omega-3 LCPUFAs. Were these doses and formulations bioavailable?

The two-fold increase in the serum levels of AREDS2 participants of different components of omega-3 LCPUFAs suggests that adequate doses were absorbed, and presumably, sufficient doses reached the ocular tissues.

In evaluating this question of the use of omega-3 LCPUFAs, a review of the recent results from the trials of omega-3 LCPUFAs for other disease may provide important insight.

Omega-3 LCPUFAs have been used for a variety of diseases, including attention deficit disorder, depression, dementia, and cardiovascular diseases. Limitations of space allow us to discuss only cardiovascular diseases and the use of omega-3 LCPUFAs.

Following the initial GISSI prevention study, which found a reduction in sudden death with fish oils,14 this favorable beneficial effect on cardiovascular disease was not confirmed by more recent clinical trials.15-17

A meta-analysis of the diet and supplementation studies found no reduction in cardiovascular disease using omega-3 LCPUFAs.18 Reviews of clinical trials of other diseases have not revealed significant beneficial effects of omega-3 LCPUFAs.

WHY ADD LUTEIN/ZEAXANTHIN TO AREDS2 SUPPLEMENTS?

The analyses that involved lutein vs beta-carotene were considered exploratory secondary analyses, but some were prespecified in the analysis plans.19

The direct comparisons of lutein/zeaxanthin vs beta-carotene always resulted in a beneficial effect favoring lutein/zeaxanthin to reduce the risk of AMD, especially neovascular AMD. The effect was modest, ranging from 10% to 35%.

More importantly, previous studies showed the harmful effects of beta-carotene in increasing the risk of lung cancer in cigarette smokers. In AREDS2, smokers were not randomized to beta-carotene, and there was a doubling of the risk of developing lung cancer in subjects randomized to beta-carotene, compared with those randomized to lutein/zeaxanthin.

More than 90% of these subjects affected with lung cancer were former smokers. A large proportion of the persons affected with AMD are former or current smokers. The totality of evidence from these analyses supports the substitution of lutein/zeaxanthin for beta-carotene.

David C. Musch, PhD, MPH, wrote an editorial stating the following: “While based mostly on exploratory analyses of subsets, the evidence from AREDS2 presents a consistent picture of a beneficial effect for reducing the risk for the neovascular form of advanced AMD and serves to enhance a small body of other supportive evidence for why lutein/zeaxanthin would reduce the risk for progression to neovascular AMD.”20

The inclusion of lutein/zeaxanthin in the AREDS2 supplement also has biological plausibility. Lutein and zeaxanthin, the major components of macular pigment, as well as throughout the retina, may prevent damage from oxidation and harmful wavelengths of light.

RECOMMENDATIONS FOR AREDS2 SUPPLEMENTS

Based on the analyses from AREDS2, we recommend that patients with intermediate AMD (bilateral large drusen) or late AMD in one eye be given the AREDS2 formulation, based upon the totality of data regarding the use of lutein/zeaxanthin and especially in light of the safety concerns. Omega-3 LCPUFAs appear to have no role in the treatment of AMD.

However, it is important to note that the observational data overwhelmingly suggest that eating fish has a favorable effect. Despite the lack of beneficial effects in the clinical trials of cardiovascular disease, physicians continue to recommend eating fish at least twice a week to prevent cardiovascular disease. It would be prudent to recommend a diet replete with fish and green leafy vegetables for people at risk for AMD.

IS GENETIC TESTING NECESSARY PRIOR TO PRESCRIBING SUPPLEMENTS?

Genetic testing for AMD prior to supplementation with AREDS supplements was recommended by researchers who conducted a retrospective analysis of the data from a subgroup of AREDS participants.21

In two separate reports,21, 22 they suggested that, based upon genetic testing, treatment with zinc could be harmful in certain genotypes and could accelerate the development of late AMD. In the second report, the genetic groups were reclassified, and the analyses were repeated with the same data from this subgroup of AREDS participants.22

They analyzed each component of the AREDS supplement (antioxidant vitamins, zinc, and the combination of the antioxidants and zinc). With this second report, they found that not only zinc alone (although zinc alone has never been recommended as treatment for AMD) but the combination of zinc and antioxidant vitamins may be harmful in persons with certain complement factor H (CFH) risk alleles.22

The AREDS investigators found no significant influence of genotype on the response to AREDS supplements.23 The AREDS research team assembled another group of AREDS participants who were not part of the cohort analyzed by the other investigators to replicate the results.24

Using the exact genetic groupings, as suggested by the other investigators, the AREDS investigators’ analyses did not replicate their findings.24 A beneficial effect of the AREDS supplement was found in all the genotype groups.

The conflicting results of these reports were carefully interpreted in an exceptional editorial authored by Wittes and Musch,25 who wrote, “The genetic subgroups in the report by Awh et al22 are both post hoc and improper. The approach that Awh et al22 used in defining their genotype subgroups is circular: After selecting post-randomization outcomes observed by Awh et al22 to define subgroups in the study by Awh et al,22 they then tested those subgroups with the very same data.”

Wittes and Musch agree with the recommendation of the AREDS investigators that persons with intermediate AMD or late AMD in one eye should consider taking the AREDS supplement, regardless of the genotype. No genetic testing should be conducted prior to initiating the AREDS or ARESD2 supplement, because such analyses were only reasonable for generating new hypotheses to be tested.

We still believe, however, that genetic testing is important in research; it could help us understand the pathogenesis of AMD and eventually uncover pathways for targeted therapies for both the prevention and treatment of AMD.

CONCLUSION

We recommend that persons at risk for developing late AMD consider AREDS2 supplements to reduce the risk of developing late AMD. We also recommend diets replete with fish and green leafy vegetables to our patients who are at risk for developing late AMD.

Genetic testing is not recommended prior to treatment with AREDS or AREDS2 supplements because genotype does not have an influence on the response to therapy with the supplements. Genetic testing, however, is strongly recommended for research into potential causes and targets for therapies. RP

REFERENCES

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2. Krinsky NI, Johnson EJ. Carotenoid actions and their relation to health and disease. Mol Aspects Med. 2005;26:459-516.

3. SanGiovanni JP, Chew EY, Clemons TE, et al and the Age-Related Eye Disease Study Research Group. The relationship of dietary carotenoids, vitamin E, and vitamin C with age-related macular degeneration: a case-control study in the Age-Related Eye Disease Study. AREDS Report Number 22. Arch Ophthalmol. 2007;125:1225-1232.

4. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA. 1994;272:1413-1420.

5. 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): ancillary study of the Women’s Health Initiative. Arch Ophthalmol. 2006;124:1151-1162.

6. Tan JS, Wang JJ, Flood V, Rochtchina E, Smith W, Mitchell P. Dietary antioxidants and the longer-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology. 2008;115:334-341.

7. Seddon JM, Rosner B, Sperduto RD, et al. Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol. 2001;119:1191-1199.

8. Chua B, Flood V, Rochtchina E, et al. Dietary fatty acids and the 5-year incidence of age-related maculopathy. Arch Ophthalmol. 2006;124:981-986.

9. Augood C, Chakravarthy U, Young I, et al. Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr. 2008;88:398-406.

10. Swenor BK, Bressler S, Caulfield L, West SK. The impact of fish and shellfish consumption on age-related macular degeneration. Ophthalmology. 2010;117:2395-2401.

11. SanGiovanni JP, Chew EY, Agrón E, et al for the Age-Related Eye Disease Study Research Group. The relationship of dietary lipid intake with incident age-related macular degeneration: AREDS Report Number 23. Arch Ophthalmol. 2008;126:1274-1279.

12. Chew EY, Clemons T, SanGiovanni JP, et al; AREDS2 Research Group. The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). Ophthalmology. 2012;119:2282-2289.

13. 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;309:2005-2015.

14. Marchioli R, Barzi F, Bomba E, et al; GISSI-Prevenzione Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids afte rmyocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105:1897-1903

15. Bosch J, Gerstein HC, Dagenais GR, et al. ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367:309-318.

16. Blacher J, Czernichow S, Paillard F, Ducimetiere P, Hercberg S, Galan P. Cardiovascular effects of B-vitamins and/or N-3 fatty acids: The Su.Fol.Om3 trial. Int J Cardiol. 2013;167:508-513.

17. Roncaglioni MC, Tombesi M, Avanzini F, et al; Risk and Prevention Study Collaborative Group. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368:1800-1808.

18. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308:1024-1033.

19. The Age-Related Eye Disease Study 2 (AREDS2) Research Group. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report no. 3. 2014;132:142-149.

20. Musch DC. Editorial: evidence for including lutein and zeaxanthin in oral supplements for age-related macular degeneration. JAMA Ophthalmology. 2014;132:139-141.

21. Awh CC, Lane A-M, Hawken S, et al. CFH and ARMS2 genetic polymorphism predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120:2317-2323.

22. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study. Ophthalmology. 2015;122:162-169.

23. Chew EY, Klein ML, Clemons TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS Report Number 38. Ophthalmology. 2014;121:2173-2180.

24. Chew EY, Klein ML, Clemons TE. Genetic testing in persons with age-related macular degeneration and the use of AREDS supplements: to test or not to test? Ophthalmology. 2015;122:212-215.

25. Wittes J, Musch DC. Should we test for genotype in deciding on Age-Related Eye Disease Study Supplementation? Ophthalmology. 2015;122:3-5.