AREDS2: Insights Into Optimal Supplements for AMD
AREDS2: Insights Into Optimal Supplements for AMD
Although AREDS1 demonstrated significant reduction in risk for advanced AMD in high-risk AMD patients, it left many unanswered questions. Hence, AREDS2 picked up where AREDS1 left off. There were many important distinctions between the trials.
AREDS2, for which I was an investigator, had a complex yet elegant trial design. The trial used 2 tiers of randomization. Primary randomization assessed the ability of 2 additional supplements to reduce the risk for advanced AMD beyond the beneficial effect of the AREDS1 formulation. As such, in contrast to the AREDS1 trial, there was no placebo arm; all patients received at least the AREDS1 formulation with the addition of 1 or both of the following:
• Omega-3 long-chain polyunsaturated fatty acids: docosahexaenoic acid (DHA) 350 mg, and eicosapentaenoic acid (EPA) 650 mg. EPA is an essential dietary precursor to DHA, a critical structural and protective component of phospholipid membranes that accounts for more than 50% of the lipid in photoreceptor membranes. Several epidemiologic studies have reported an inverse relationship between dietary intake of EPA and risk for AMD.
• Carotenoids: lutein 10 mg and zeaxanthin 2 mg. These carotenoids are found at 100- to 1000-fold higher concentrations in the macula than elsewhere in the human body. In the retina, they probably function as antioxidants, filtering potentially damaging short-wavelength light and stabilizing cell membranes. Multiple nonrandomized studies have demonstrated that macular levels decline with age, dietary supplementation can increase macular density, and intake correlates with a reduced risk for AMD.
Second-tier randomization in AREDS2 evaluated modifications of the AREDS1 formulation, because of concerns related to adverse effects associated with beta-carotene and zinc. Therefore, 4 AREDS1 formulations were evaluated:
• AREDS1 formulation with no modification;
• AREDS1 formulation with no beta-carotene;
• AREDS1 formulation with low zinc (25 mg instead of 80 mg); and
• AREDS1 formulation with no beta-carotene and low zinc (25 mg instead of 80 mg).
From 2006-2008, 82 US-based clinical centers enrolled 4203 patients between 50 and 85 years of age. All eyes were at high risk for progression to advanced AMD; 65% had bilateral large drusen and 35% had large drusen in the study eye and advanced AMD in the fellow eye. Most AREDS2 participants had significant exposure to smoking: 7% were current smokers and 50% were past smokers. These participants were largely white (96%), and 57% were women. Over 5 years, 9% of the patients died and 3% were lost to follow-up. Most (84%) participants consumed at least 75% of the prescribed supplements.
AREDS2: Are More Supplements Better?
Although AREDS1 demonstrated significant reduction in risk for advanced AMD in high-risk AMD patients, it left many unanswered questions. Hence, AREDS2 picked up where AREDS1 left off. There were many important distinctions between the trials.
AREDS2, for which I was an investigator, had a complex yet elegant trial design. The trial used 2 tiers of randomization. Primary randomization assessed the ability of 2 additional supplements to reduce the risk for advanced AMD beyond the beneficial effect of the AREDS1 formulation. As such, in contrast to the AREDS1 trial, there was no placebo arm; all patients received at least the AREDS1 formulation with the addition of 1 or both of the following:
• Omega-3 long-chain polyunsaturated fatty acids: docosahexaenoic acid (DHA) 350 mg, and eicosapentaenoic acid (EPA) 650 mg. EPA is an essential dietary precursor to DHA, a critical structural and protective component of phospholipid membranes that accounts for more than 50% of the lipid in photoreceptor membranes. Several epidemiologic studies have reported an inverse relationship between dietary intake of EPA and risk for AMD.
• Carotenoids: lutein 10 mg and zeaxanthin 2 mg. These carotenoids are found at 100- to 1000-fold higher concentrations in the macula than elsewhere in the human body. In the retina, they probably function as antioxidants, filtering potentially damaging short-wavelength light and stabilizing cell membranes. Multiple nonrandomized studies have demonstrated that macular levels decline with age, dietary supplementation can increase macular density, and intake correlates with a reduced risk for AMD.
Second-tier randomization in AREDS2 evaluated modifications of the AREDS1 formulation, because of concerns related to adverse effects associated with beta-carotene and zinc. Therefore, 4 AREDS1 formulations were evaluated:
• AREDS1 formulation with no modification;
• AREDS1 formulation with no beta-carotene;
• AREDS1 formulation with low zinc (25 mg instead of 80 mg); and
• AREDS1 formulation with no beta-carotene and low zinc (25 mg instead of 80 mg).
From 2006-2008, 82 US-based clinical centers enrolled 4203 patients between 50 and 85 years of age. All eyes were at high risk for progression to advanced AMD; 65% had bilateral large drusen and 35% had large drusen in the study eye and advanced AMD in the fellow eye. Most AREDS2 participants had significant exposure to smoking: 7% were current smokers and 50% were past smokers. These participants were largely white (96%), and 57% were women. Over 5 years, 9% of the patients died and 3% were lost to follow-up. Most (84%) participants consumed at least 75% of the prescribed supplements.