Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration.
The Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial
This Research brief is summarized from a published clinical study. All the information and statistics cited below were taken directly from the original publication authored by the Age-Related Eye Disease Study 2 (AREDS2) Research Group. Doctor’s Advantage Products, LLC has restructured or paraphrased some sections of this brief in an attempt to more succinctly summarize the research.
Age-related macular degeneration (AMD), the leading cause of blindness in the developed world, accounts for more than 50% of all blindness in the United States. Although intraocular drugs that inhibit vascular endothelial growth factor are currently available for treatment of neovascular AMD, no effective therapies are proven for atrophic AMD.
The Age-Related Eye Disease Study (AREDS) demonstrated that daily oral supplementation with antioxidant vitamins and minerals reduced the risk of developing advanced AMD by 25% at 5 years. Observational studies suggest that higher dietary intake of lutein + zeaxanthin, omega-3 long-chain polyunsaturated fatty acids and eicosapentaenoic acid, or both are associated with a decreased risk of developing advanced AMD.
Lutein and zeaxanthin are the main components of the macular pigment, DHA is a major structural component of the retina, and EPA may play a role as a precursor to signaling molecules with potential to influence retinal function, providing biological bases for testing these nutrients.
The study was designed to test if adding lutein + zeaxanthin, DHA + EPA, or lutein + zeaxanthin and DHA + EPA would reduce the risk of progression to advanced AMD.
Between October 2006 and September 2008, 4203 participants were enrolled in 82 clinical sites. Participants had to be between the age of 50 and 85 and at high risk of progression to advanced AMD. Participants were required to consent to follow-up of at least 5 years.
Likelihood of adherence to the study regimen was evaluated during a run-in phase using study placebo and the AREDS formulation. Participants were eligible for randomization if they took at least 75% of the run-in supplements and agreed to stop the use of other supplements containing lutein, zeaxanthin, DHA, EPA, vitamin C, vitamin E, beta carotene, zinc, or copper. They could not have other ocular diseases such as high myopia, glaucoma, clinically significant diabetic retinopathy and other diseases that might confound the assessment of the ocular outcome measurements.
Institutional review boards approved the AREDS2 research protocol, and all participants provided written informed consent.
A second-tier randomization was conducted to evaluate the effect of eliminating beta carotene and lowering the zinc doses in the original AREDS formulation. A zinc dose of 80 mg was used in the original AREDS formulation because it was the dose used in an earlier trial suggesting efficacy. The AREDS formulation was tested with a lower dose of zinc (25 mg) because data suggested that this may be the maximal level absorbed. Participants who consented to the optional secondary randomization were randomly assigned to receive either the original AREDS formulation, AREDS formulation without beta carotene, AREDS formulation with lower zinc dose or the AREDS formulation with no beta carotene and lower zinc dose.
Follow up and Adherence
Participants were required to appear for follow up study visits once a year. Follow-up also included telephone contact 3 months after randomization and subsequent telephone contacts at 6 months between study visits.
Adherence to the treatment regimen was assessed by pill count at each annual visit. In 545 participants from a subset of centers, blood was drawn to measure serum levels of lipids, lutein + zeaxanthin, fat-soluble vitamins, zinc, and copper at baseline and at years 1, 3, and 5.
The primary outcome was the development of advanced AMD. Secondary outcomes included progression to moderate vision loss from baseline or treatment for choroidal neovascularization. Safety outcomes included serious adverse events and mortality.
The unit of analysis for ophthalmic outcomes was by eye. The primary efficacy outcome, time to progression to advanced AMD, was assessed using a Cox proportional hazards model incorporating the method of Wei et al for obtaining robust variance estimates that allows for dependence among multiple event times. The models were adjusted for baseline AMD status, with and without stratification by the secondary interventions.
A total of 4203 participants were enrolled, with a mean age of 73.1 years. A total of 3036 participants agreed to the secondary randomization. Of the remaining participants, 1148 chose to take the original commercial AREDS formulation. Of the 4203 randomized participants, 141 were lost to follow up and 368 died during the course of the study.
In the primary randomization, 3420 participants in each treatment group took at least 75% the study medications; in the secondary randomization, 2431 participants in each group took at least 75% of the variations of the AREDS supplements, as assessed by pill count.
Participants who chose to take the original AREDS supplements outside of the secondary randomization, 989 took at least 75% of the AREDS supplements.
Serum Levels of Study Nutrients
The baseline serum levels of study nutrients were balanced across the treatment groups. The median serum levels of lutein in participants randomized to receive lutein increased by 190% to 210% at years 1, 3, and 5 from baseline, whereas participants randomized to receive placebo showed little change.
Dietary Levels of Lutein + Zeaxanthin and DHA + EPA
Baseline dietary intake of the study nutrients, including those in the AREDS supplements, was balanced across treatment groups. The AREDS2 participants are relatively well nourished.
Progression to Advanced AMD
Primary Randomization: A total of 1608 participants had experienced at least 1 advanced AMD event by the end of the study. In the primary analyses, comparisons with placebo demonstrated no statistically significant reductions in progression to advanced AMD.
The analyses of the main effects of the 2 × 2 randomization are considered exploratory secondary analyses. The results presented were also analyzed with stratification by the secondary interventions.
Secondary Randomization: The exploratory analyses of the secondary randomization were restricted to participants randomized to the 4 variations of the AREDS supplements. The secondary randomization analyses showed that lowering zinc dose and eliminating beta carotene had no statistically significant effect on progression to advanced AMD.
A further exploratory analysis of the main effect of lutein + zeaxanthin by stratifying by quintiles of dietary lutein + zeaxanthin intake was conducted to examine whether supplementation may have relatively different treatment effects within subgroup of dietary intake.
None of the nutrients affected development of moderate or worse vision loss, defined as a reduction of 15 or more letters from baseline or treatment for neovascular AMD. Furthermore, there was no apparent effect on vision with the elimination of beta carotene and reducing the zinc dose.
Serious Adverse Effects: No clinically or statistically significant differences in reported serious adverse events, including rates of development of neoplasms, were noted across the treatment groups in the primary or secondary randomization.
Mortality: Dietary supplementation with lutein + zeaxanthin, DHA + EPA, zinc, or beta carotene had no statistically significant effect on mortality.
In this large, multicenter, placebo-controlled clinical trial in people at high risk for progression to advanced AMD, daily supplementation with lutein + zeaxanthin, DHA + EPA, or lutein + zeaxanthin and DHA + EPA in addition to the original AREDS formulation showed no statistically significant overall effect on progression to advanced AMD or changes in visual acuity.
The limitations of this study include a complicated study design involving a secondary randomization, which may have affected the ability to evaluate the role of adding lutein + zeaxanthin and DHA + EPA to the AREDS formulation. Not all participants were taking the original AREDS formulation, with some taking only certain components of the AREDS formulation. It is not known whether a single specific ingredient is important or if the combination is essential for its therapeutic effect.
In summary, addition of lutein + zeaxanthin, DHA + EPA, or lutein + zeaxanthin and DHA + EPA to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD. However, two randomized controlled clinical trials of beta carotene reported an increase in lung cancer rates and associated mortality in cigarette smokers. Post hoc analyses suggest that lutein and zeaxanthin may play a role for reducing the risk of progression to advanced AMD when given without beta carotene. Also, a comparison of low-dose vs. high-dose zinc did not show evidence of a statistically significant effect.