Pearl (continued)

•AREDS supplement: 15 mg betacarotene, 500 mg Vitamin C, 400 IU Vitamin E, 80 mg zinc oxide, 2 mg copper (as cupric oxide)

•Results:

27% reduction in progression to advanced AMD in patients taking AREDS supplement with intermediate to high risk of progression:

M Extensive intermediate size drusen M At least 1 large druse

M Noncentral geographic atrophy in one or both eyes

M Advanced AMD or vision loss due to AMD in 1 eye

The widespread use of the AREDS supplements in appropriate patients can have significant impacts on cost and overall morbidity in the population [9]

Patients with advanced AMD also had higher rates of cardiovascular deaths in the AREDS trial [10, 11] M Overall, patients in AREDS on

supplementation had a 14% reduction in mortality risk (RR 0.86, CI 0.65–1.12) [11, 12]

Carotenoids

Beta-Carotene

Beta-carotene is a carotenoid, which is not found in high concentrations in the macula. Major sources of beta-carotene in the diet include cantaloupe, citrus fruits, carrots, and broccoli [14–16]. Beta-carotene was the major carotenoid used in the AREDS trial due to availability of a supplement and presence of several trials underway investigating the impact of beta-carotene supplementation on cancer and cardiovascular disease [13]. The AREDS, as reviewed above, showed that supplementation with combination high-dose

zinc, 15 mg beta-carotene, vitamins C and E, and copper was associated with a reduction in risk of advanced AMD among patients with Stage 3 or greater AMD. [13]. Other data regarding a potential therapeutic role for beta-carotene in AMD has been mixed. A trial examining supplementation of 20 mg of beta-carotene and 50 mg of alpha-tocopherol in a Finnish population failed to demonstrate a significant effect on the incidence of AMD [17]. Subsequent observational data has been mixed regarding the role of beta-carotene. In the Blue Mountain Eye Study, beta-carotene was a risk factor for the development of incident neovascular AMD [18] (RR 2.4 when comparing top tertile of intake with bottom tertile). In the Rotterdam study, beta-carotene when combined with Vitamin E and zinc showed a protective effect on incident AMD (adjusted RR 0.65, 95% CI 0.46–0.92). In univariate analysis, beta-caro- tene alone was not shown to have a significant effect on the development of AMD [19]. A similar multivariate analysis performed studied dietary intake in the AREDS population, and found that patients taking combination antioxidants with zinc, omega-3 fatty acids, and macular carotenoids had a reduced risk of both early and advanced AMD. Dietary beta-carotene was not found to be a significant contributor in this analysis or in the Physicians Health Study Cohort [20, 21].

Important data from large randomized controlled clinical trials demonstrated an increased lung cancer risk with beta-carotene supplementation [22, 23] using higher doses (20–30 mg) of beta-carotene than the AREDS formulation (15 mg). The Physicians Health Study, a randomized controlled trial of beta-carotene (50 mg every other day) vs. placebo did not show a significant difference in mortality in the treated and untreated groups [24].

Given the above data, it is evident that much remains to be learned regarding a role for betacarotene in the treatment of AMD. It is unclear whether beta-carotene has a beneficial effect when not used in combination with antioxidants and zinc in the treatment of macular degeneration. It is also unclear what dose of beta-carotene would be ideal, if used for therapy of AMD. The AREDS2 will attempt to address this issue

by including two formulations without betacarotene in the secondary randomization of the study [3, 25].

Macular Xanthophylls

The retinal carotenoids, lutein and zeaxanthin, are selectively concentrated in the macula. They represent the major source of macular pigment and are responsible for the yellow appearance of the macula lutea. They are derived entirely from the diet, as humans cannot synthesize them de novo [26]. The average western diet contains 1.3–3 mg/day of lutein and zeaxanthin combined, with lutein representing the majority of intake [14, 15]. Lutein is primarily derived from green leafy vegetables, such as spinach, kale, and collard greens, while zeaxanthin is primarily found in corn, orange peppers, and citrus fruit. Both are found in high concentrations in egg yolk [16]. Due to their high number of double bonds, the macular carotenoids are capable of quenching reactive oxygen species, limiting oxidative stress and increasing membrane stability. The macular pigments may also act as filters for blue light and limit retinal photo-stress [26–28].

Macular pigment can be measured using a variety of noninvasive techniques. Data correlating age with macular pigment levels or presence of AMD have been equivocal [29]. These data are likely noisy due to the multitude of factors that affect uptake and distribution of these carotenoids in vivo. A recent large cross-sec- tional study in a homogenous Caucasian population showed a reduction in macular pigment with age and in patients with risk factors for macular degeneration (family history, tobacco use) [29]. A prospective study demonstrated that dietary supplementation of lutein and zeaxanthin increased macular pigment optical density (MPOD) most in patients with a low baseline MPOD. These changes, however, did not correlate with a change in serum concentration of the macular pigments [30]. In another recent interventional trial, lutein and zeaxanthin supplementation increased serum levels of

lutein, zeaxanthin and macular pigment levels by approximately 15% [31].

A small prospective study examining dose ranges and adverse effects of supplementation with lutein and zeaxanthin showed an increase in serum levels of the carotenoids, which was unaffected by other serum antioxidant vitamin con- centrationsorco-supplementationoflong-chained polyunsaturated fatty acids. In the same study, serum concentrations rose in response to supplementation over three months and then stabilized. No adverse effects of supplementation were demonstrated with lutein supplementation up to 10 mg per day; however, these studies tended to be small in sample size with limited follow-up. [32]. These data suggest that changes in serum levels of lutein and zeaxanthin do not necessarily correlate with a change in MPOD [30, 32].

A number of studies have examined the association between risk of macular degeneration and supplementation with the macular xanthophylls. The majority of data suggests a protective role of the macular carotenoids in macular degeneration. An analysis of dietary intake in the AREDS using a compound score taking into consideration consumption of Vitamins C and E, zinc, lutein, zeaxanthin, docosahexaenoic acid, eicosapentaenoic acid, and low-dietary glycemic index (dGI) showed a higher intake of these nutrients was associated with a lower risk of both early and advanced AMD (OR = 0.727 for drusen, and 0.616 for advanced AMD) [20]. When comparing the highest with the lowest quintiles of intake in the AREDS population, lutein and zeaxanthin intake was independently inversely associated with neovascular AMD (OR 0.65), geographic atrophy (OR, 0.45), and large or extensive intermediate drusen (OR, 0.73) [33].

Among participants in the Blue Mountain Eye Disease Study, those in the top tertile of intake for lutein and zeaxanthin intake had a reduced risk of incident neovascular AMD (RR, 0.35), and those with above median intakes had a reduced risk of indistinct soft or reticular drusen (RR, 0.66) [34]. A large retrospective crosssectional cohort study within the Nurses Health Study showed a statistically nonsignificant