Effect of Long-Chain ω-3 Fatty Acids and Lutein + Zeaxanthin Supplements on Cardiovascular Outcomes

Abstract

Effect of Long-Chain ω-3 Fatty Acids and Lutein+Zeaxanthin Supplements on Cardiovascular Outcomes Results of the Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial Writing Group for the AREDS2 Research Group IMPORTANCE Dietary supplements have been proposed as a mechanism to improve health and prevent disease.OBJECTIVE To determine if supplementing diet with long-chain ω-3 polyunsaturated fatty acids or with macular xanthophylls results in a reduced rate of cardiovascular disease (CVD). DESIGN, SETTING, AND PARTICIPANTSThe Cardiovascular Outcome Study (COS) was an ancillary study of the Age-Related Eye Disease Study 2 (AREDS2), a factorial-designed randomized clinical trial of 4203 participants recruited from 82 US academic and community ophthalmology clinics, who were followed up for a median of 4.8 years. Individuals were eligible to participate if they were between the ages of 50 and 85 years, had intermediate or advanced age-related macular degeneration in 1 eye, and were willing to be randomized. Participants with stable, existing CVD (>12 months since initial event) were eligible to participate. Participants, staff, and outcome assessors were masked to intervention.INTERVENTIONS Daily supplementation with long-chain ω-3 polyunsaturated fatty acids (350-mg docosahexaenoic acid [DHA] + 650-mg eicosapentaenoic acid [EPA]), macular xanthophylls (10-mg lutein + 2-mg zeaxanthin), combination of the two, or matching placebos. These treatments were added to background therapy of the AREDS vitamin and mineral formulation for macular degeneration. MAIN OUTCOMES AND MEASURESA composite outcome of myocardial infarction, stroke, and cardiovascular death with 4 prespecified secondary combinations of the primary outcome with hospitalized heart failure, revascularization, or unstable angina.RESULTS Study participants were primarily white, married, and highly educated, with a median age at baseline of 74 years. A total of 602 cardiovascular events were adjudicated, and 459 were found to meet 1 of the study definitions for a CVD outcome. In intention-to-treat analysis, no reduction in the risk of CVD or secondary CVD outcomes was seen for the DHA + EPA (primary outcome: hazard ratio [HR], 0.95; 95% CI, 0.78-1.17) or lutein + zeaxanthin (primary outcome: HR, 0.94; 95% CI, 0.77-1.15) groups. No differences in adverse events or serious adverse event were seen by treatment group. The sample size was sufficient to detect a 25% reduction in CVD events with 80% power.CONCLUSIONS AND RELEVANCE Dietary supplementation of long-chain ω-3 polyunsaturated fatty acids or macular xanthophylls in addition to daily intake of minerals and vitamins did not reduce the risk of CVD in elderly participants with age-related macular degeneration. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00345176

Emerging roles for nuclear receptors in the pathogenesis of age-related macular degeneration

“…Specifically, examination of animal models has shown that the omega-3 PUFA, DHA, the main structural lipid of retinal photoreceptor outer segments [77], increases photoreceptor survival and prevents apoptosis [78], while epidemiology studies have shown that omega-3 fatty acids reduce AMD risk by 30–50 % [54, 64] and decrease the risk of progression to advanced disease [62]. Interestingly, AREDS2 did not find a benefit for omega-3 supplementation, likely due to a difference in the dosage of DHA and EPA between studies [71, 79]. …”

Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors

“…This finding has been replicated by several studies, including the AREDS [159, 160] and the Nurses’ Health Study/ Heath Professionals Follow-up Study [161] which found inverse associations for dietary lutein/zeaxanthin and dietary DHA/EPA with AMD. The follow-up to the AREDS, AREDS2 [162], was a double-masked, randomized, controlled trial of nutritional supplementation looking at the effects on AMD progression, which found a significant effect of supplementation with lutein and zeaxanthin to reduce progression to neovascular AMD [162, 163]. However, the AREDS2 [162] also looked at the effects of lutein/zeaxanthin and DHA/EPA supplementation on CVD outcomes and reported no significant effect.…”

“…The follow-up to the AREDS, AREDS2 [162], was a double-masked, randomized, controlled trial of nutritional supplementation looking at the effects on AMD progression, which found a significant effect of supplementation with lutein and zeaxanthin to reduce progression to neovascular AMD [162, 163]. However, the AREDS2 [162] also looked at the effects of lutein/zeaxanthin and DHA/EPA supplementation on CVD outcomes and reported no significant effect. The important role of MXs in this disease suggests a more complicated role for HDL in AMD than simply acting as a cholesterol carrier.…”

An Overview on the Role of Macular Xanthophylls in Ocular Diseases

“…Lutein and zeaxanthin, which are also called macular xanthophylls, show their effects by filtering high energy visible light, mostly with a peak of absorption at 446 nm and ultraviolet radiation lesser, inhibiting lipid peroxidation and reducing reactive species such as singlet oxygen and hydroxyl radical [46][47][48]. These carotenoids have several benefits on human health, including neuroprotective effects [49][50][51], anti-carcinogenic effects [52][53][54][55], anti-diabetic effects [56][57][58], cardioprotective effects [59][60][61], protective effects on skin damages and ocular diseases [62][63][64][65]. Particularly, several studies showed the role of lutein and zeaxanthin in eye diseases.…”