AREDS2 Refines Our Knowledge of Dietary Supplements for AMD
Key findings include that lutein/zeaxanthin can be an effective and potentially safer alternative to beta carotene in the AREDS vitamin formulation.
BY SEENU M. HARIPRASAD, MD
The presentation of the eagerly anticipated results from the Age-Related Eye Disease Study 2 (AREDS2) was streamed live from the podium during the annual meeting of the Association for Vision and Research in Ophthalmology in May. Investigators reported that the addition of lutein and zeaxanthin and/or omega-3 fatty acids to the original AREDS oral supplement formulation had no statistically significant effect on progression to advanced AMD (AAMD).1 The investigators reported several other important findings from the study, which are more easily understood if we first review some key background information.
AREDS2 was designed as a follow-up to the original AREDS study, which showed that people at high risk (category 3 or 4) for developing AAMD, i.e., choroidal neovascularization (CNV) or central geographic atrophy (CGA), can reduce that risk by 25% by taking a supplement containing antioxidants and zinc.2 (See “AREDS Supplement Ingredients.”) The benefits persisted at 10 years as well. By that time, approximately 70% of AREDS1 participants were taking the AREDS formulation. Those who had been assigned to the AREDS formulation in the original trial were 25-30% less likely to develop AAMD (for CNV but not CGA) at 10 years than those who had originally been assigned to the placebo group.3
Several observational and epidemiologic studies conducted before, during and after AREDS1 had shown an association between a reduced risk of AAMD and the macular xanthophylls lutein and zeaxanthin, as well as omega-3 long-chain polyunsaturated fatty acids. In addition, other studies suggested connections between high doses of zinc and prostate enlargement and between beta carotene supplementation and lung cancer in smokers. The goal of AREDS2, therefore, was to test different variations of the original AREDS supplements to rigorously explore these issues. Could the positive effects achieved in AREDS1 be duplicated or enhanced with the addition of lutein and zeaxanthin and/or omega-3 fatty acids, a lower dose of zinc and/or the elimination of beta carotene?
“Based on the results of the comparison between lutein/zeaxanthin and beta carotene and because of the potential increased risk of lung cancer in former smokers, lutein and zeaxanthin are an appropriate carotenoid substitute for beta carotene in the AREDS formulation.”
—Seenu M. Hariprasad, MD Reporting on AREDS2 Key Results
AREDS2 Overview and Key Results
AREDS2, sponsored by the National Eye Institute as was AREDS1, was a multi-center randomized controlled clinical trial. It was conducted at 82 clinical sites, both academic and community-based, in the United States from 2006 to 2012. It included 4,203 subjects aged 50-85. In contrast to AREDS1, all subjects were at high risk for developing AAMD.
All subjects were required to enroll in the primary randomization to one of four groups: placebo/control (original AREDS supplement), AREDS supplement plus lutein and zeaxanthin, AREDS supplement plus omega-3 fatty acids, or AREDS supplement plus lutein and zeaxanthin and omega-3 fatty acids (Table 1). They were then offered the opportunity to participate in a secondary randomization to one of four groups: original AREDS supplement, AREDS supplement with no beta carotene, AREDS supplement with lower-dose zinc or AREDS supplement with lower-dose zinc and no beta carotene (Table 2).
|Table 1. AREDS2 Primary Randomization: AREDS with Lutein and Zeaxanthin, DHA and EPA, or Both|
|Randomized Participants 4,203 (6,916 eyes)|
|Placebo/Control/AREDS 1,012 (1,695 eyes)||Lutein 10 mg + Zeaxanthin 2 mg 1,044 (1,714 eyes)||Docosahexaenoic Acid (DHA) 350 mg + Eicosapentaenoic Acid (EPA) 650 mg 1,068 (1,753 eyes)||Lutein 10 mg + Zeaxanthin 2 mg + Docosahexaenoic Acid (DHA) 350 mg + Eicosapentaenoic Acid (EPA) 650 mg 1,079 (1,754 eyes)|
In addition to the primary finding that adding lutein and zeaxanthin and/or omega-3 fatty acids to the original AREDS formulation did not further reduce the risk of progression to AAMD, the investigators reported:
■ The probabilities of progression to AAMD by 5 years in the study were 31% for control, 29% for lutein and zeaxanthin, 31% for omega-3 fatty acids and 30% for lutein and zeaxanthin plus omega-3 fatty acids.
|AREDS Supplement Ingredients|
Original AREDS supplement
■ Vitamin E (400 IU)
Recommended supplement based on AREDS2
■ Vitamin E (400 IU)
■ 1,940 eyes (1,608 subjects) progressed to advanced AMD.
■ The primary, secondary and subgroup analyses of the omega-3 fatty acids produced null results, i.e., these nutrients had no beneficial or harmful effects. The researchers pointed out that the null results could reflect a true lack of efficacy, but that dose levels and duration of use could also be factors.
■ Overall, neither elimination of beta carotene nor lower-dose zinc had an effect on progression to AAMD.
■ The comparison of low-dose zinc with high-dose zinc did not show evidence of a statistically significant effect, leading the researchers to state that there is insufficient evidence to make a clinical recommendation regarding zinc.
■ Lutein/zeaxanthin appeared to have some benefit for reducing the risk of developing AAMD in the subgroup of patients who had the lowest levels of these two carotenoids in their diets (measured with blood analysis and the Harvard semi-quantitative food frequency questionnaire). Within that group, subjects who took lutein/zeaxanthin-containing supplements had a 26% reduced risk compared with those who did not receive those supplements. The investigators noted that overall, AREDS2 participants tended to be well-nourished and have higher dietary levels of lutein/zeaxanthin than the general population.
■ Lutein/zeaxanthin appeared to have some benefit for reducing the risk of developing AAMD in the subgroup of patients who received the AREDS supplement without beta carotene. Compared with participants who took the beta carotene-containing supplement (no lutein/zeaxanthin), those who took the lutein/zeaxanthin-containing supplement (no beta carotene) had an 18% lower risk of progressing to AAMD. The investigators pointed out that because lutein, zeaxanthin and beta carotene are all carotenoids, they compete with each other for absorption in the body. Among the participants taking the original AREDS formulation, the beta carotene it contained would be expected to limit absorption of lutein/zeaxanthin, which was confirmed through blood analysis. This could explain, in part, they said, why lutein/zeaxanthin had no overall effect.
|Table 2. AREDS2 Secondary Randomization: AREDS with No Beta Carotene, with Low-Dose Zinc, or Both|
|Randomized Participants 3,036 (4987 eyes)|
|AREDS Supplement 659 (1,101 eyes)||AREDS Supplement with No Beta Carotene 863 (1,410 eyes)||AREDS Supplement with Lower-dose Zinc (25 mg) 689 (1,127 eyes)||AREDS Supplement with Supplement with No Beta Carotene and with Lower-dose Zinc (25 mg)825 (1,349 eyes)|
|Smokers were not randomized to groups receiving beta carotene|
■ Subjects who took the lutein/zeaxanthin-containing supplement had a 16% reduction in the risk of losing 30 or more letters of visual acuity from baseline compared with those who took the beta carotene-containing supplement. Also, subjects who took the lutein/zeaxanthin-containing supplement had an 18% reduction in the risk of progressing to legal blindness (20/100) at 5 years compared with those who took the beta carotene-containing supplement.
■ More lung cancers were noted in the beta carotene vs. no beta carotene group, mostly in former smokers.
■ Based on the results of the comparison between lutein/zeaxanthin and beta carotene and because of the potential increased risk of lung cancer in former smokers, lutein and zeaxanthin are an appropriate carotenoid substitute for beta carotene in the AREDS formulation. (See “AREDS Supplement Ingredients.”)
|AREDS2 Secondary Outcome: Progression to Cataract Surgery|
The AREDS2 research group also evaluated whether the various AREDS supplement formations they tested had an effect on the need for cataract surgery.* As reported in AREDS1, the original supplement formulation does not protect against cataract. In AREDS2, neither omega-3 fatty acids nor lutein/zeaxanthin, when added to the original AREDS formulation, had any overall effect on the need for cataract surgery. However, when the participants were ranked into five equal-sized groups according to their dietary lutein/zeaxanthin intake, supplementation with lutein/zeaxanthin appeared to make a difference for the group with the lowest dietary levels. Within that group, lutein/zeaxanthin was associated with a 32% reduction in progression to cataract surgery.
* The Age-Related Eye Disease Study 2 Research Group. Lutein/zeaxanthin for the treatment of age-related cataract. AREDS2 Randomized Trial Report No. 4. JAMA Ophthalmology, published online May 5, 2013.
“The release of the initial AREDS2 results should serve as an impetus for retina specialists to redouble our efforts to educate patients on the benefits of the AREDS supplements.”
—Seenu M. Hariprasad, MD
An Impressive Research Endeavor With a Wide Reach
AREDS1 and AREDS2 are the largest retinal clinical trials ever conducted. Because they followed so many patients for such long periods of time, they are statistically strong enough to overcome the challenges of studying an intervention for a disease that progresses slowly. The implications of the results of these trials are enormous. AMD takes a heavy toll on individuals, society and healthcare resources, a toll that is expected to increase as the population continues to age. A recent study of Medicare beneficiaries4 provides a clear illustration of this. It found that 20.4% of 1,184 people who were diagnosed with dry AMD in 1998 progressed to wet AMD. Between 1999 and 2009, average annual Medicare costs increased from $11,265 to $24,494 for AMD patients who did not progress to wet AMD and from $11,712 to $34,308 in patients who did.4
AREDS1 taught us that with use of the recommended dietary supplements, a significant number of our patients can reduce their risk of converting from dry to wet AMD. The impact of this on an individual level can’t be underestimated. For an elderly patient, it could mean being able to live the rest of his or her life with good vision and the accompanying good quality of life. AREDS2 confirmed this information and refined our knowledge.
We should stay closely tuned to the subsequent reports to be released by the AREDS2 researchers, including results from the ForeseeHome and cardiovascular substudies. In addition, an approved ancillary study is being conducted among AREDS2 participants at the Moran Eye Center trial site in Utah.5 This study is evaluating the effects of supplementation with carotenoids on macular pigment optical density (MPOD). Lutein and zeaxanthin, major components of macular pigment, are believed to support the morphologic and functional integrity of the retina and potentially protect against the oxidative damage that has been implicated in AMD. The clinical implications of these theories are not yet clear, so the results of this study will be of great interest.
Spreading the Word to Our Patients
In the meantime, the release of the initial AREDS2 results should serve as an impetus for retina specialists to redouble our efforts to educate patients on the benefits of the AREDS supplements. We can remind them of the AREDS1 results, make them aware of the AREDS2 results, and steer them toward the appropriate versions of the many available supplement products. We should strive to make ourselves their best source of information on this extremely important topic. ■
Dr. Hariprasad is an associate professor, chief of the Vitreoretinal Service and director of Clinical Research in the Department of Ophthalmology and Visual Science at the University of Chicago Medical Center.
1. Age-Related Eye Disease Study 2 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(19):2005-2015.
2. 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 Ophthalmol 2001;119(10):1417-1436.
3. Chew EY, Clemons TE, Agrón E, et al. Long-term effects of vitamins C and E, b-carotene, and zinc on age-related macular degeneration: AREDS Report No. 35. Ophthalmology 2013;S0161-6420.
4. Schmier JK, Covert DW, Lau EC. Patterns and costs associated with progression of age-related macular degeneration. Am J Ophthalmol 2012;154(4):675-681.
5. Bernstein PS, Ahmed F, Liu A, et al. Macular pigment imaging in AREDS2 participants: an ancillary study of AREDS2 subjects enrolled at the Moran Eye Center. Invest Ophthalmol Vis Sci 2012;53(10):6178-6186.