BACKGROUND\nObservational and experimental data suggest that antioxidant and/or zinc supplements may delay progression of age-related macular degeneration (AMD) and vision loss.\n\n\nOBJECTIVE\nTo evaluate the effect of high-dose vitamins C and E, beta carotene, and zinc supplements on AMD progression and visual acuity.\n\n\nDESIGN\nThe Age-Related Eye Disease Study, an 11-center double-masked clinical trial, enrolled participants in an AMD trial if they had extensive small drusen, intermediate drusen, large drusen, noncentral geographic atrophy, or pigment abnormalities in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye. At least 1 eye had best-corrected visual acuity of 20/32 or better. Participants were randomly assigned to receive daily oral tablets containing: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg); (2) zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide; (3) antioxidants plus zinc; or (4) placebo.\n\n\nMAIN OUTCOME MEASURES\n(1) Photographic assessment of progression to or treatment for advanced AMD and (2) at least moderate visual acuity loss from baseline (> or =15 letters). Primary analyses used repeated-measures logistic regression with a significance level of.01, unadjusted for covariates. Serum level measurements, medical histories, and mortality rates were used for safety monitoring.\n\n\nRESULTS\nAverage follow-up of the 3640 enrolled study participants, aged 55-80 years, was 6.3 years, with 2.4% lost to follow-up. Comparison with placebo demonstrated a statistically significant odds reduction for the development of advanced AMD with antioxidants plus zinc (odds ratio [OR], 0.72; 99% confidence interval [CI], 0.52-0.98). The ORs for zinc alone and antioxidants alone are 0.75 (99% CI, 0.55-1.03) and 0.80 (99% CI, 0.59-1.09), respectively. Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD. Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91; zinc: OR, 0.71; 99% CI, 0.52-0.99; antioxidants: OR, 0.76; 99% CI, 0.55-1.05). Both zinc and antioxidants plus zinc significantly reduced the odds of developing advanced AMD in this higher-risk group. The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99). No statistically significant serious adverse effect was associated with any of the formulations.\n\n\nCONCLUSIONS\nPersons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study.

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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

Objective. —To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults. Design. —The multicenter Eye Disease Case-Control Study. Setting. —Five ophthalmology centers in the United States. Patients. —A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex. Main Outcome Measures. —The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses. Results. —A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92;Pfor trend=.02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (Pfor trend=.001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (Pfor trend Conclusion. —Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. These findings support the need for further studies of this relationship. (JAMA. 1994;272:1413-1420)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=382145&pdfFileName=jama_272_18_032.pdf

Dietary Carotenoids, Vitamins A, C, and E, and Advanced Age-Related Macular Degeneration

IMPORTANCE\nOral 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.\n\n\nOBJECTIVES\nTo 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.\n\n\nDESIGN, SETTING, AND PARTICIPANTS\nThe 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.\n\n\nINTERVENTIONS\nParticipants 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.\n\n\nMAIN OUTCOMES AND MEASURES\nDevelopment of advanced AMD. The unit of analyses used was by eye.\n\n\nRESULTS\nMedian 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.\n\n\nCONCLUSIONS AND RELEVANCE\nAddition 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.\n\n\nTRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00345176.

Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial

Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies.

Conclusion: In this study, visual function is improved with lutein alone or lutein together with other nutrients. Further studies are needed with more patients, of both genders, and for longer periods of time to assess long-term effects of lutein or lutein together with a broad spectrum of antioxidants, vitamins, and minerals in the treatment of atrophic age-related macular degeneration.

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Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial).

Macular degeneration associated with age and drusen, an important cause of severe visual loss in older persons, is of unknown cause. The sensory retina and retinal pigment epithelium, which are cell layers in zinc, appear to be prominently involved in the disease process. Because zinc plays a role in the metabolic function of several important enzymes in the chorioretinal complex, we undertook a prospective, randomized, double-masked, placebo-controlled investigation of the effects of oral zinc administration on the visual acuity outcome in 151 subjects with drusen or macular degeneration. Although some eyes in the zinc-treated group lost vision, this group had significantly less visual loss than the placebo group after a follow-up of 12 to 24 months. This is the first controlled oral intervention study to show a positive, if limited, treatment effect in macular degeneration, a major public health problem. Because of the pilot nature of the study and the possible toxic effects and complications of oral zinc administration, widespread use of zinc in macular degeneration is not now warranted.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=OPHTH&articleId=637111&pdfFileName=archopht_106_2_026.pdf

Nicholas C. Leone

Papers

Oral zinc in macular degeneration.