Enhanced Oxidative Stress and Other Potential Biomarkers for Retinopathy in Type 2 Diabetics: Beneficial Effects of the Nutraceutic Supplements 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. A 5-Year Follow-Up of Antioxidant Supplementation in Type 2 Diabetic Retinopathy Multicenter ophthalmic and nutritional age-related macular degeneration study--part 2: antioxidant intervention and conclusions. The effect of nutritional supplementation on the multifocal electroretinogram in healthy eyes Carotenoids in Age-Related Maculopathy Italian Study (CARMIS): Two-Year Results of a Randomized Study Sustained supplementation and monitored response with differing carotenoid formulations in early age-related macular degeneration Effect of docosahexaenoic acid supplementation on the macular function of patients with Best vitelliform macular dystrophy: randomized clinical trial. Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: effects of an oral zinc supplementation. Vitamin E supplementation and macular degeneration: randomised controlled trial Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes. Dietary Marine ω-3 Fatty Acids and Incident Sight-Threatening Retinopathy in Middle-Aged and Older Individuals With Type 2 Diabetes: Prospective Investigation From the PREDIMED Trial. Macular xanthophylls and ω-3 long-chain polyunsaturated fatty acids in age-related macular degeneration: a randomized trial. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: results from the General Population Trial in Linxian, China. Central Retinal Enrichment Supplementation Trials (CREST): Design and Methodology of the CREST Randomized Controlled Trials
We have studied the global risk of retinopathy in a Mediterranean population of type 2 diabetes mellitus ( T2DM ) patients , according to clinical , biochemical , and lifestyle biomarkers . The effects of the oral supplementation containing antioxidants/omega 3 fatty acids ( A/ω3 ) were also evaluated . Suitable participants were distributed into two main groups : ( 1 ) T2DMG ( with retinopathy ( + DR ) or without retinopathy ( −DR ) ) and ( 2 ) controls ( CG ) . Participants were r and omly assigned ( + A/ω3 ) or not ( −A/ω3 ) to the oral supplementation with a daily pill of Nutrof Omega ( R ) for 18 months . Data collected including demographics , anthropometrics , characteristics/lifestyle , ophthalmic examination ( best corrected visual acuity , ocular fundus photographs , and retinal thickness as assessed by optical coherence tomography ) , and blood parameters ( glucose , glycosylated hemoglobin , triglycerides , malondialdehyde , and total antioxidant capacity ) were registered , integrated , and statistically processed by the SPSS 15.0 program . Finally , 208 participants ( 130 diabetics ( 68 + DR/62 −DR ) and 78 controls ) completed the follow-up . Blood analyses confirmed that the T2DMG+DR patients had significantly higher oxidative stress ( p < 0.05 ) , inflammatory ( p < 0.05 ) , and vascular ( p < 0.001 ) risk markers than the T2DMG−DR and the CG . Furthermore , the A/ω3 oral supplementation positively changed the baseline parameters , presumptively by inducing metabolic activation and ameliorating the ocular health after 18 months of supplementation 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 PARTICIPANTS The Cardiovascular Outcome Study ( COS ) was an ancillary study of the Age-Related Eye Disease Study 2 ( AREDS2 ) , a factorial- design ed r and omized 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 r and omized . 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 MEASURES A composite outcome of myocardial infa rct ion , 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 clinical trials.gov Identifier : NCT00345176 Purpose This study was design ed to evaluate the effect of antioxidant supplementation on  diabetic retinopathy ( DR )  over a 5-year follow-up period . To our knowledge , this is the first such clinical trial performed . Methods We recruited 105 type 2 diabetic patients with nonproliferative DR . A complete ophthalmic checkup and a plasma determination of oxidative ( malonyldialdehyde [ MDA ] ) and antioxidant parameters ( total antioxidant status [ TAS ] ) were obtained as the baseline . One part of the cohort was r and omly assigned to oral antioxidant supplementation at nutritional doses . The same examinations were performed with 97 diabetic patients who completed the 5-year follow-up period . The best-corrected visual acuity , DR score , MDA , and TAS values were compared at the beginning and the end of the follow-up . Results Best-corrected visual acuity did not change during the follow-up , irrespective of supplementation . However , the retinopathy stage showed a retardation of progression in the subgroup with supplementation , but worsened in the subgroup with no antioxidant supplementation . Furthermore , the antioxidant supplementation group maintained its antioxidant plasma status levels , which was related to decreased oxidative plasma activity . Conclusions Oral antioxidant supplementation could be a useful adjunctive long-term therapy in the treatment of nonproliferative DR BACKGROUND The experimental design , subjects , procedures and baseline data for the prospect i ve double blind dry ARMD-antioxidant intervention study have been described in Part 1 . METHODS At eight DVA medical centers , 32 patients ( group one ) were assigned a placebo and 39 patients ( group two ) a " broad spectrum " antioxidant capsule .  Data was collected in five areas : demographic ; ophthalmic ; dietary analysis of daily food intake ; serum analysis ; and adverse gastrointestinal symptoms . Data was serially acquired at baseline , 6 months , 12 months and 18 months , and was analyzed by univariate repeated factors ANOVA , p = 0.05 . RESULTS Group two ( antioxidant po BID ) maintained their distance LogMAR visual acuity ( p = 0.03 ) , while there was a trend toward both stabilized near M print ( p = 0.07 ) and 6 cycle/degree contrast sensitivity ( p approximately 0.10 ) , in left eyes . However , group two ( antioxidant ) also had increased cortical opacification of the right lens ( p = 0.04 ) , compared to group one ( placebo ) . Self perceived stabilization of vision was reported by subjects in group two and supported the objective data ( Pearson chi square ; p = 0.05 ) . CONCLUSIONS A specific 14 component antioxidant capsule taken twice daily stabilized but did not improve dry ARMD over the study period of 1.5 years . The ARMD stabilized eyes had less advanced disease functionally but not by fundus appearance . Decreased intake of cardioprotective nutrients ( vitamin E , zinc , magnesium , B6 and folate ) in ARMD patients remained constant over the course of the trial Background Previous studies have demonstrated an increase in macular pigment optical density ( MPOD ) with lutein (L)-based supplementation in healthy eyes . However , not all studies have assessed whether this increase in MPOD is associated with changes to other measures of retinal function such as the multifocal ERG ( mfERG ) . Some studies also fail to report dietary levels of L and zeaxanthin ( Z ) . Because of the associations between increased levels of L and Z , and reduced risk of AMD , this study was design ed to assess the effects of L-based supplementation on mfERG amplitudes and latencies in healthy eyes . Methods Multifocal ERG amplitudes , visual acuity , contrast sensitivity , MPOD and dietary levels of L and Z were assessed in this longitudinal , r and omized clinical trial . Fifty-two healthy eyes from 52 participants were r and omly allocated to receive a L-based supplement ( treated group ) , or no supplement ( non-treated group ) . Results There were 25 subjects aged 18–77 ( mean age ± SD ; 48 ± 17 ) in the treated group and 27 subjects aged 21–69 ( mean age ± SD ; 43 ± 16 ) in the non-treated group . All participants attended for three visits : visit one at baseline , visit two at 20 weeks and visit three at 40 weeks . A statistically significant increase in MPOD ( F = 17.0 , p ≤ 0.001 ) and shortening of mfERG ring 2 P1 latency ( F = 3.69 , p = 0.04 ) was seen in the treated group . Conclusions Although the results were not clinical ly significant , the reported trend for improvement in MPOD and mfERG outcomes warrants further investigation Purpose The high concentration of carotenoids in the macula , plus evidence linking oxidative stress to age-related macular degeneration ( AMD ) and carotenoids to antioxidation , generated the hypothesis that higher antioxidant intakes can prevent AMD . The aim of this study was to determine whether nutritional supplementation with a targeted nutritional supplement improves visual acuity and visual function in AMD . Methods In this multicenter , prospect i ve open-label r and omized study , 145 patients were r and omly assigned to 2 different treatment groups . Interventions were lutein ( 10 mg ) , zeaxanthin ( 1 mg ) , astaxanthin ( 4 mg ; AZYR SIFI , Catania , Italy ) , and antioxidants/vitamins supplementation formula or no dietary supplementation for 2 years . Primary outcome was mean changes in visual acuity ( VA ) at 12 and 24 months . Other measures included contrast sensitivity ( CS ) and National Eye Institute visual function question naire ( NEI VFQ-25 ) scores at 12 and 24 months . Results Patients in the treated group showed stabilization of VA with significantly ( p=0.003 ) better VA scores ( 81.4±7.2 ) compared to the nontreated group ( 76.8±8.9 ) at 24-month follow-up . An improvement in CS ( p=0.001 ) and final mean NEI VFQ-25 composite scores at 12 and 24 months higher in treated group compared to nontreated group were also shown ( p<0.001 ) . Conclusions Patients treated with lutein/zeaxanthin and astaxanthin together with other nutrients were more likely to report clinical ly meaningful stabilization/improvements in VA , CS , and visual function through 24 months compared with nontreated subjects . Further studies are needed with more patients and for longer periods of time Purpose To compare the impact of sustained supplementation using different macular carotenoid formulations on macular pigment ( MP ) and visual function in early age-related macular degeneration ( AMD ) . Patients and methods Sixty-seven subjects with early AMD were r and omly assigned to : Group 1 ( 20 mg per day lutein ( L ) , 0.86 mg per day zeaxanthin ( Z ) ; Ultra Lutein ) , Group 2 ( 10 mg per day meso-zeaxanthin ( MZ ) , 10 mg per day L , 2 mg per day Z ; Macushield ; Macuhealth ) , Group 3 ( 17 mg per day MZ , 3 mg per day L , 2 mg per day Z ) . MP was measured using customised heterochromatic flicker photometry and visual function was assessed by measuring contrast sensitivity ( CS ) and best-corrected visual acuity ( BCVA ) . AMD was grade d using the Wisconsin Age-Related Maculopathy Grading System ( AREDS 11-step severity scale ) . Results At 3 years , a significant increase in MP from baseline was observed in all groups at each eccentricity ( P<0.05 ) , except at 1.75 ° in Group 1 ( P=0.160 ) . Between 24 and 36 months , significant increases in MP at each eccentricity were seen in Group 3 ( P<0.05 for all ) , and at 0.50 ° in Group 2 ( P<0.05 ) , whereas no significant increases were seen in Group 1 ( P>0.05 for all ) . At 36 months , compared with baseline , the following significant improvements ( P<0.05 ) in CS were observed : Group 2—1.2 , 6 , and 9.6 cycles per degree ( c.p.d . ) ; Group 1—15.15 c.p.d . ; and Group 3—6 , 9.6 , and 15.15 c.p.d . No significant changes in BCVA , or progression to advanced AMD , were observed . Conclusion In early AMD , MP can be augmented with a variety of supplements , although the inclusion of MZ may confer benefits in terms of panprofile augmentation and in terms of CS enhancement OBJECTIVE Best disease is a slowly progressive macular dystrophy that typically has an onset in early childhood . Multiple lines of evidence suggest that dietary docosahexaenoic acid ( DHA ) protects against the development of macular degeneration . Our trial tested the effect of an oral supplement of DHA on visual function in patients with Best disease . DESIGN Double-masked , r and omized , placebo-controlled , crossover clinical trial . PARTICIPANTS Eight patients with Best disease . METHODS Patients were given either an oral supplement of DHA ( 20 mg/kg daily ) or placebo . Primary outcome measures were the multifocal electroretinogram ( mfERG ) and electro-oculogram ( EOG ) . Plasma DHA was tracked along with visual acuity ( Early Treatment Diabetic Retinopathy Study chart ) , VF-14 scores , and Humphrey visual fields . RESULTS All 8 patients had increased plasma DHA levels ( 2 - 3 fold ) during periods of DHA supplementation compared with periods without supplementation . Differences in visual acuity , VF-14 scores , and EOG Arden ratios during periods with and without DHA supplementation were all statistically insignificant . A positive correlation was found between the plasma concentration of DHA and mfERG amplitudes , but amplitude changes during the treatment periods were not significant . A carryover effect of DHA supplementation was a confounding error . CONCLUSIONS Our pilot trial of DHA supplementation in 8 patients with Best disease did not demonstrate an improvement in macular function . An exp and ed trial would be needed to examine the full effects of DHA supplementation on visual function in Best disease DESIGN Placebo for 3 months , followed by 30 mg/day zinc gluconate in identical capsules . SETTING Diabetic out patients clinic at the University Hospital , Grenoble . SUBJECTS Diabetic patients cared for type I diabetes mellitus . 22 patients began the study , 4 dropped out . 10 patients suffered of an early retinopathy , 8 patients had no retinopathy . INTERVENTIONS In this order : T0 biological measurements , 3 months placebo treatment , T1 biological measurements , 3 months zinc gluconate treatment , T2 biological measurements . Plasma Zn , Cu , Se , thiobarbituric acid reactants and antioxidant enzymes were measured [ plasma and red glutathione peroxidase ( Se-GPx ) , red cell superoxide dismutase ( Cu-Zn-SOD ) ] . RESULTS Lower plasma zinc level in the two groups . An increase in zinc level was observed and was more important in diabetic patients with no retinopathy ( P = 0.05 ) . The thiobarbituric acid reactants were above the reference values in all the patients , and were decreased at T2 ( P < 0.05 ) . Increase of GPx activity after zinc supplementation in patients with retinopathy . CONCLUSIONS Zinc deficiency in insulin-dependent diabetic patients is corrected by a zinc supplementation . Moreover this supplementation decreases lipid peroxidation . The effects of zinc are different in diabetic patients with or without retinopathy . The increase in Se-GPx activity observed in patients with retinopathy could be linked to the protective effect of zinc on the protein itself Objective : To determine whether vitamin E supplementation influences the incidence or rate of progression of  age related maculopathy ( AMD ) . Design : Prospect i ve r and omised placebo controlled clinical trial . Setting : An urban study centre in a residential area supervised by university research staff . Participants : 1193 healthy volunteers aged between 55 and 80 years ; 73 % completed the trial on full protocol . Interventions : Vitamin E 500 IU or placebo daily for four years . Main outcome measures : Primary outcome : development of early age related macular degeneration in retinal photographs . Other measures included alternative definitions of age related macular degeneration , progression , changes in component features , visual acuity , and visual function Results : The incidence of early age related macular degeneration ( early AMD 3 ) was 8.6 % in those receiving vitamin E versus 8.1 % in those on placebo ( relative risk 1.05 , 95 % confidence interval 0.69 to 1.61 ) . For late disease the incidence was 0.8 % versus 0.6 % ( 1.36 , 0.67 to 2.77 ) . Further analysis showed no consistent differences in secondary outcomes . Conclusion : Daily supplement with vitamin E supplement does not prevent the development or progression of early or later stages of age related macular degeneration OBJECTIVE The present study was design ed to assess the effect of magnesium plus zinc , vitamins C plus E , and a combination of these micronutrients on nephropathy indexes in type 2 diabetic patients . RESEARCH DESIGN AND METHODS In a r and omized , double-blind , placebo-controlled clinical trial , 69 type 2 diabetic patients were r and omly divided into four groups , each group receiving one of the following daily supplement for 3 months : group M ( n = 16 ) , 200 mg Mg and 30 mg Zn ; group V ( n = 18 ) , 200 mg vitamin C and 100 IU vitamin E ; group MV ( n = 17 ) , minerals plus vitamins ; and group P ( n = 18 ) , placebo .  Urinary albumin excretion and N-acetyl-beta-d-glucosaminidase activity ( NAG ) in urine were determined at the beginning and at the end of the trial . Treatment effects were analyzed by general linear modeling . RESULTS Results indicate that after 3 months of supplementation , levels of urinary albumin excretion decreased in the V and MV groups ( P = 0.034 and P = 0.005 , respectively ) . Urinary NAG activity did not significantly change in any treatment groups . Levels of systolic , diastolic , and mean blood pressure significantly decreased in the MV group ( P = 0.008 , P = 0.017 , and P = 0.009 , respectively ) . Also , combination of vitamin and mineral supplementation had significant effects in decreasing fasting serum glucose ( P = 0.035 ) and malondialdehyde concentrations ( P = 0.004 ) and in increasing HDL cholesterol and apolipoprotein A1 levels ( P = 0.019 ) . There was no significant change in the levels of these parameters in the other three groups . CONCLUSIONS In conclusion , the results of the present study provide evidence for the effects of vitamins C and E and also combination of magnesium , zinc , and vitamins C and E supplementation on improvement of glomerular but not tubular renal function in type 2 diabetic patients Importance Diabetic retinopathy ( DR ) is a devastating complication of individuals with type 2 diabetes mellitus . The retina is rich in long-chain ω-3 polyunsaturated fatty acids ( LCω3PUFAs ) , which are substrate for oxylipins with anti-inflammatory and antiangiogenic properties . Experimental models support dietary LCω3PUFA protection against DR , but clinical data are lacking . Objective To determine whether LCω3PUFA intake relates to a decreased incidence of sight-threatening DR  in individuals with type 2 diabetes older than 55 years . Design , Setting , and Participants In late 2015 , we conceived a prospect i ve study within the r and omized clinical trial Prevención con Dieta Mediterránea ( PREDIMED ) , testing Mediterranean diets supplemented with extra virgin olive oil or nuts vs a control diet for primary cardiovascular prevention . The trial was conducted in primary health care centers in Spain . From 2003 to 2009 , 3614 individuals aged 55 to 80 years with a previous diagnosis of type 2 diabetes were recruited . Full data were available for 3482 participants ( 48 % men ; mean age 67 years ) . Exposures Meeting the dietary LCω3PUFA recommendation of at least 500 mg/d for primary cardiovascular prevention , as assessed by a vali date d food-frequency question naire . Main Outcomes and Measures The main outcome was incident DR requiring laser photocoagulation , vitrectomy , and /or antiangiogenic therapy confirmed by an external adjudication committee . Results Of the 3482 participants , 48 % were men and the mean age was 67 years . A total of 2611 participants ( 75 % ) met target LCω3PUFA recommendation . During a median follow-up of 6 years , we documented 69 new events . After adjusting for age , sex , intervention group , and lifestyle and clinical variables , participants meeting the LCω3PUFA recommendation at baseline ( ≥500 mg/d ) compared with those not fulfilling this recommendation ( < 500 mg/d ) showed a 48 % relatively reduced risk of incident sight-threatening DR , with a hazard ratio of 0.52 ( 95 % CI , 0.31 - 0.88 ; P = .001 ) . This association was slightly stronger for yearly up date d LCω3PUFA intake ( relative risk , 0.48 ; 95 % CI , 0.28 - 0.82 ; P = .007 ) . Conclusions and Relevance In middle-aged and older individuals with type 2 diabetes , intake of at least 500 mg/d of dietary LCω3PUFA , easily achievable with 2 weekly servings of oily fish , is associated with a decreased risk of sight-threatening DR . Our results concur with findings from experimental models and the current model of DR pathogenesis . Trial Registration clinical trials.gov Identifier : http://www.controlled-trials.com/IS RCT N35739639 IMPORTANCE It has been shown that the functionality of the macula lutea depends on the nutritional uptake of lutein and zeaxanthin and that it is inversely associated with the risk of age-related macular degeneration ( AMD ) . Additionally , ω-3 long-chain polyunsaturated fatty acids ( LC-PUFAs ) may also be protective . OBJECTIVE To investigate the effect of a 12-month intervention with macular xanthophylls and ω-3 LC-PUFAs on xanthophylls and fatty acids in plasma , antioxidant capacity , and optical density of the macular pigment of patients with nonexudative AMD . DESIGN The LUTEGA study was a r and omized , double-blind , placebo-controlled , parallel clinical trial that was conducted for 12 months . SETTING University Eye Hospital and Institute of Nutrition , Friedrich Schiller University Jena , Germany . PARTICIPANTS A total of 172 individuals with nonexudative AMD . INTERVENTION Individuals were enrolled and r and omly divided as follows : placebo group , group 1 ( a capsule containing 10 mg of lutein , 1 mg of zeaxanthin , 100 mg of docosahexaenoic acid , and 30 mg of eicosapentaenoic acid administered each day ) , and group 2 ( same substances but twice the dose used in group 1 ) . One hundred forty-five participants completed the study successfully . MAIN OUTCOME MEASURES Plasma xanthophyll concentrations and fatty acid profiles , optical density of the macular pigment , and antioxidant capacity in plasma ( 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid [ Trolox ] equivalent antioxidant capacity and photochemiluminescence ) . RESULTS The concentrations of the administered carotenoids in plasma as well as the optical density of the macular pigment increased significantly in the groups r and omized to receive supplementary macular xanthophylls and ω-3 LC-PUFAs after 1 month of intervention and remained at this level through the end of the study . Use of the double dose result ed in a beneficial alteration of the fatty acid profile in the plasma of patients with AMD in comparison with the dose in group 1 . The lipophilic antioxidant capacity in plasma was significantly elevated with the intervention . CONCLUSIONS AND RELEVANCE A supplement containing a fixed combination of lutein , zeaxanthin , and ω-3 LC-PUFAs during 12 months significantly improved plasma antioxidant capacity , circulating macular xanthophyll levels , and the optical density of the macular pigment . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00763659 IMPORTANCE 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 . OBJECTIVES 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 , r and omized , 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 . INTERVENTIONS Participants were r and omized 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 r and omization to 4 variations of the AREDS formulation , including elimination of beta carotene , lowering of zinc dose , or both . MAIN OUTCOMES AND MEASURES Development of advanced AMD . The unit of analyses used was by eye . RESULTS 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 . CONCLUSIONS AND RELEVANCE 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 . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00345176 BACKGROUND Experimental and observational data suggest that micronutrients with antioxidant capabilities may retard the development of  age-related cataract .  OBJECTIVE To evaluate the effect of a high-dose antioxidant formulation on the development and progression of  age-related lens opacities and visual acuity loss . DESIGN The 11-center Age-Related Eye Disease Study ( AREDS ) was a double-masked clinical trial . Participants were r and omly assigned to receive daily oral tablets containing either antioxidants ( vitamin C , 500 mg ; vitamin E , 400 IU ; and beta carotene , 15 mg ) or no antioxidants .  Participants with more than a few small drusen were also r and omly assigned to receive tablets with or without zinc ( 80 mg of zinc as zinc oxide ) and copper ( 2 mg of copper as cupric oxide ) as part of the age-related macular degeneration trial . Baseline and annual ( starting at year 2 ) lens photographs were grade d at a reading center for the severity of lens opacities using the AREDS cataract grading scale . MAIN OUTCOME MEASURES Primary outcomes were ( 1 ) an increase from baseline in nuclear , cortical , or posterior subcapsular opacity grade s or cataract surgery , and ( 2 ) at least moderate visual acuity loss from baseline ( > /=15 letters ) . Primary analyses used repeated- measures logistic regression with a statistical significance level of P = .01 . Serum level measurements , medical histories , and mortality rates were used for safety monitoring . RESULTS Of 4757 participants enrolled , 4629 who were aged from 55 to 80 years had at least 1 natural lens present and were followed up for an average of 6.3 years . No statistically significant effect of the antioxidant formulation was seen on the development or progression of age-related lens opacities ( odds ratio = 0.97 , P = .55 ) . There was also no statistically significant effect of treatment in reducing the risk of progression for any of the 3 lens opacity types or for cataract surgery . For the 1117 participants with no age-related macular degeneration at baseline , no statistically significant difference was noted between treatment groups for at least moderate visual acuity loss . No statistically significant serious adverse effect was associated with treatment . CONCLUSION Use of a high-dose formulation of vitamin C , vitamin E , and beta carotene in a relatively well-nourished older adult cohort had no apparent effect on the 7-year risk of development or progression of age-related lens opacities or visual acuity loss A r and omized nutrition intervention trial was conducted among 29,584 adult residents of Linxian , China , to examine the effects of vitamin/mineral supplementation on the occurrence of esophageal/gastric cardia cancer in this high-risk population . A fractional factorial study design allowed evaluations of four different combinations of nutrients : ( A ) retinol and zinc ; ( B ) riboflavin and niacin ; ( C ) vitamin C and molybdenum ; and ( D ) beta-carotene , vitamin E , and selenium . During the 5.25-year intervention , significant reductions in total mortality , total cancer mortality , and stomach cancer mortality occurred among those receiving beta-carotene , vitamin E , and selenium . At the end of intervention , an endoscopic survey was carried out in a sample of subjects to see if the nutritional supplements had affected the prevalence of clinical ly silent precancerous lesions and early invasive cancers of the esophagus or stomach . Endoscopy was performed on 391 individuals from two study villages . The prevalences of esophageal and gastric dysplasia and cancer were compared by nutrient factor . Cancer or dysplasia was diagnosed in 15 % of the participants . No statistically significant reductions in the prevalence of esophageal or gastric dysplasia or cancer were seen for any of the four vitamin/mineral combinations . The greatest reduction in risk ( odds ratio , 0.38 ; P = 0.09 ) was seen for the effect of retinol and zinc on the prevalence of gastric cancer . Although no significant protective effects were seen in this endoscopic survey , there was a suggestion that supplementation with retinol and zinc may protect against the development of gastric neoplasia in this high-risk population . Additional studies with larger numbers of endpoints will be needed to further evaluate this possibility Abstract Purpose : The Central Retinal Enrichment Supplementation Trials ( CREST ) aim to investigate the potential impact of macular pigment ( MP ) enrichment , following supplementation with a formulation containing 10 mg lutein ( L ) , 2 mg zeaxanthin ( Z ) and 10 mg meso-zeaxanthin ( MZ ) , on visual function in normal subjects ( Trial 1 ) and in subjects with early age-related macular degeneration ( AMD ; Trial 2 ) . Methods : CREST is a single center , double-blind , r and omized clinical trial . Trial 1 ( 12-month follow-up ) subjects are r and omly assigned to a formulation containing 10 mg L , 10 mg MZ and 2 mg Z ( n = 60 ) or placebo ( n = 60 ) . Trial 2 ( 24-month follow-up ) subjects are r and omly assigned to a formulation containing 10 mg L , 10 mg MZ , 2 mg Z plus 500 mg vitamin C , 400 IU vitamin E , 25 mg zinc and 2 mg copper ( Intervention A ; n = 75 ) or 10 mg L and 2 mg Z plus 500 mg vitamin C , 400 IU vitamin E , 25 mg zinc and 2 mg copper ( Intervention B ; n = 75 ) . Contrast sensitivity ( CS ) at 6 cycles per degree represents the primary outcome measure in each trial . Secondary outcomes include : CS at other spatial frequencies , MP , best-corrected visual acuity , glare disability , photostress recovery , light scatter , cognitive function , foveal architecture , serum carotenoid concentrations , and subjective visual function . For Trial 2 , AMD morphology , reading speed and reading acuity are also being recorded . Conclusions : CREST is the first study to investigate the impact of supplementation with all three macular carotenoids in the context of a large , double-blind , r and omized clinical trial
The review of trials identifies positive effects of these nutrients on various outcome measures relating to insulin resistance and cardiovascular factors .
A majority of the trials found a positive effect of chromium on fasting plasma glucose .
Isoflavones were found to have a positive effect on insulin resistance and cardiovascular outcome measures , but only when combined with soy proteins .
Vitamin E is reported to reduce oxidative stress at levels of 200 mg day(-1 ) or more
The role of nutritional supplementation is of increasing interest with regard to ocular disease .
R and omised controlled trials have demonstrated the effectiveness of supplementation for age-related macular degeneration , and formulations are now being developed for use by people with diabetes and diabetic retinopathy .
The aim of this review was to synthesis e the evidence for use of nutritional supplementation in type 2 diabetes .
The potential role of alpha-lipoic acid , chromium , folic acid , isoflavones , magnesium , Pycnogenol , selenium , vitamin C , vitamin E , and zinc in the treatment of type 2 diabetes is discussed .