JAMA. 2013 May 15;309(19):2005-15. doi: 10.1001/jama.2013.4997.
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.
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 2 × 2 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.
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.
Development of advanced AMD. The unit of analyses used was by eye.
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.
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.
clinicaltrials.gov Identifier: NCT00345176.
口服补充年龄相关性眼病研究（AREDS）配方（抗氧化维生素 C 和 E、β-胡萝卜素和锌）已被证明可降低进展为晚期年龄相关性黄斑变性（AMD）的风险。观察性数据表明，增加叶黄素+玉米黄质（类胡萝卜素）、ω-3 长链多不饱和脂肪酸（二十二碳六烯酸 [DHA]+二十碳五烯酸 [EPA]）或两者的摄入量可能会进一步降低这种风险。
确定在 AREDS 配方中添加叶黄素+玉米黄质、DHA+EPA 或两者是否会降低发展为晚期 AMD 的风险，并评估消除β-胡萝卜素、降低锌剂量或两者在 AREDS 配方中的作用。
设计、地点和参与者：年龄相关性眼病研究 2（AREDS2）是一项多中心、随机、双盲、安慰剂对照的 3 期研究，采用 2×2 析因设计，于 2006-2012 年进行，共纳入 4203 名年龄在 50 至 85 岁之间的参与者，这些参与者有双侧大玻璃膜疣或一眼大玻璃膜疣，且对进展为双侧大玻璃膜疣或一眼大玻璃膜疣伴对侧眼晚期 AMD 的风险较高。
参与者被随机分配接受叶黄素（10mg）+玉米黄质（2mg）、DHA（350mg）+EPA（650mg）、叶黄素+玉米黄质和 DHA+EPA 或安慰剂。所有参与者还被要求服用原始的 AREDS 配方或接受对 AREDS 配方的 4 种变体的二次随机分配，包括消除β-胡萝卜素、降低锌剂量或两者都降低。
晚期 AMD 的发展。分析单位为眼。
中位随访时间为 5 年，共有 1940 只研究眼（1608 名参与者）进展为晚期 AMD。5 年内进展为晚期 AMD 的 Kaplan-Meier 概率分别为安慰剂组 31%（493 只眼[406 名参与者]）、叶黄素+玉米黄质组 29%（468 只眼[399 名参与者]）、DHA+EPA 组 31%（507 只眼[416 名参与者]）和叶黄素+玉米黄质和 DHA+EPA 组 30%（472 只眼[387 名参与者]）。与安慰剂相比，初级分析中未发现进展为晚期 AMD 的风险有统计学显著降低（风险比[HR]，0.90[98.7%置信区间，0.76-1.07]；P =.12 对于叶黄素+玉米黄质；0.97[98.7%置信区间，0.82-1.16]；P =.70 对于 DHA+EPA；0.89[98.7%置信区间，0.75-1.06]；P =.10 对于叶黄素+玉米黄质和 DHA+EPA）。消除β-胡萝卜素或降低锌剂量对进展为晚期 AMD 似乎没有影响。β-胡萝卜素组比无β-胡萝卜素组（23[2.0%] vs 11[0.9%]，名义 P =.04）发现更多的肺癌，主要是在曾经吸烟的人群中。
在主要分析中，在 AREDS 配方中添加叶黄素+玉米黄质、DHA+EPA 或两者都没有进一步降低进展为晚期 AMD 的风险。然而，由于前吸烟者肺癌的发病率可能增加，叶黄素+玉米黄质可能是 AREDS 配方中合适的类胡萝卜素替代品。
clinicaltrials.gov 标识符：NCT00345176。
