Ronald P. Danis

Effects of medical therapies on retinopathy progression in type 2 diabetes.

BACKGROUND We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. METHODS In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. RESULTS At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). CONCLUSIONS Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

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

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, 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. INTERVENTIONS 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. 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 clinicaltrials.gov Identifier: NCT00345176.

INTRAVITREAL TRIAMCINOLONE ACETONIDE IN EXUDATIVE AGE-RELATED MACULAR DEGENERATION

Purpose: To examine the effects of intravitreal injection of 4.0 mg triamcinolone acetonide on the visual and clinical course of exudative age‐related macular degeneration. Methods: A randomized clinical trial of a single injection of triamcinolone acetonide into the vitreous cavity of experimental eyes at baseline versus observation of untreated subjects was performed in 27 patients followed up for 6 months. Inclusion criteria included exudative age‐related macular degeneration with subfoveal or occult choroidal neovascularization, and visual acuity between 20/40 and 20/400. Examination, acuity assessment, fundus photography, and fluorescein angiography were performed at baseline and at 3 and 6 months after enrollment. LogMAR visual acuity was compared between groups by a repeated measures analysis of variance model. Masked assessment of photographic studies was performed and groups were compared with Fishers exact test. Results: Visual acuity was significantly better in the treated group compared with control subjects at 3 and 6 months (P < 0.005). Fundus photography and angiography were more likely to show stability or improvement at 3 and 6 months in the treated group (P = 0.05). Intraocular pressure elevation was seen in 25% of treated patients, but was controlled with topical medications. Progression of cataract was more frequently seen in the treated group. Conclusions: Intravitreal triamcinolone acetonide may provide short‐term improvement in visual acuity and fundus findings in exudative macular degeneration. These findings must be considered preliminary and should be followed by multicenter, masked, placebocontrolled trials with long‐term follow‐up.Purpose:To examine the effects of intravitreal injection of 4.0 mg triamcinolone acetonide on the visual and clinical course of exudative age-related macular degeneration.Methods:A randomized clinical trial of a single injection of triamcinolone acetonide into the vitreous cavity of experimental eye

Inhibition of Preretinal and Optic Nerve Head Neovascularization in Pigs by Intravitreal Triamcinolone Acetonide

PURPOSE The authors tested the antiangiogenic properties of intravitreally administered triamcionolone acetonide in a pig model of preretinal neovascularization to determine the effectiveness of this therapy in preventing neovascularization. METHODS In 14 eyes of seven pigs, branch retinal vein occlusions were created in a standardized manner using photodynamic thrombosis with rose bengal dye and thermal burns from the argon green laser. Intravitreal injection of approximately 4 mg of triamcinolone acetonide was performed in one eye of each animal, and eyes were followed clinically for 12 weeks with ophthalmoscopy and fundus photography. A standardized grading system was developed to permit masked assessment of disc proliferations from fundus stereophotographs. After death, all neovascularization was confirmed histopathologically and a final grade was assigned to each eye. Statistical analysis employed use of a nonparametric test of the paired data. RESULTS Significant inhibition of neovascularization was observed in triamcinolone-treated eyes (P = 0.0156). Although none of the steroid-injected eyes demonstrated clinically evident new vessels, histopathologic and photographic analysis results demonstrated fine new vessels on the optic disc in four eyes. In all of the untreated eyes, neovascularization of a moderate (II) to high (III to IV) grade developed. CONCLUSIONS Intravitreal triamcinolone acetonide effectively inhibited preretinal and optic nerve head neovascularization in the pig model. The grading system used permitted masked assessment of outcome and paired analysis allowed a conclusion to be drawn from a relatively small number of eyes. The mechanisms by which triamcinolone acetonide inhibits neovascularization remain to be elucidated.

Intravitreal triamcinolone with photodynamic therapy for subfoveal choroidal neovascularisation in age related macular degeneration

Aims: To report the effects of intravitreal triamcinolone acetonide (iTAAC) injections as an adjunctive treatment to photodynamic therapy (PDT) with verteporfin for new subfoveal choroidal neovascularisation (CNV) in age related macular degeneration (AMD). Methods: We retrospectively reviewed the records of all AMD patients who had iTAAC within 6 weeks of their first PDT and had a follow up of one year or longer. The proportion of eyes after one year follow up that lost or gained ⩾15 and ⩾30 ETDRS letters, baseline and one year lesion greatest linear dimension (GLD), number of PDTs, and side effects were assessed. Results: Fourteen patients were evaluated. Eleven received one initial combined treatment and three received an additional combined treatment after 6 months. Median follow up was 18 months (range 12 to 25 months). Overall, 7% gained ⩾30 letters, 50% maintained stable vision, 14% lost 15–29 letters, and 29% lost ⩾30 letters. Overall, mean GLD increased from 2580 (SD 1088) µm to 3946 (SD 1503) µm (p = 0.01). The mean number of PDTs during the first year was 2.57. Side effects were mild intraocular pressure elevation in 28.5% and cataract progression in 50% of phakic eyes. Conclusions: iTAAC with PDT in AMD was found to be relatively safe and had reasonable results for lesions with some classic component.

Macular pigment optical density in a midwestern sample

OBJECTIVE To assess the distribution of the macular pigments (MPs) lutein (L) and zeaxanthin (Z) in a healthy sample more representative of the general population than past studies and to determine which dietary factors and personal characteristics might explain the large interindividual differences in the density of these MPs. DESIGN Prevalence study in a self-selected population. PARTICIPANTS Two hundred eighty healthy adult volunteers, consisting of 138 men and 142 women, between the ages of 18 and 50 years, recruited from the general population. METHODS MP optical density was measured psychophysically at 460 nm by use of a 1 degrees test field. Serum was analyzed for carotenoid and vitamin E content with reversed-phase high-performance liquid chromatography. Usual intakes of nutrients over the past year were determined by means of a food frequency questionnaire. MAIN OUTCOME MEASURES MP optical density. RESULTS Mean MP optical density measured 0.211 +/- 0.13, which is approximately 40% lower than the average reported in smaller, less representative studies. MP density was 44% lower in the bottom versus the top quintile of serum L and Z concentrations. Similarly, MP density was 33% lower in the bottom compared with the top quintile of L and Z intake. MP density was 19% lower in blue-grey-eyed subjects than in subjects with brown-black irises. When all variables were considered together in a general linear model of determinants of MP, statistically significant (P < 0.05) relationships were found between MP density and serum L and Z, dietary L and Z intake, fiber intake, and iris color. CONCLUSIONS These data suggest that MP values in this healthy adult population are lower than in smaller select samples. Moreover, these data indicate that MP is related to serum L and Z, dietary L and Z intake, fiber intake, and iris color.

Secondary Analyses of the Effects of Lutein/Zeaxanthin on Age-Related Macular Degeneration Progression: AREDS2 Report No. 3

IMPORTANCE The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina. OBJECTIVE To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. INTERVENTIONS In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. MAIN OUTCOMES AND MEASURE S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. CONCLUSION AND RELEVANCE The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00345176.

Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/EDIC: comparison of adults and adolescents.

OBJECTIVE The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents. RESULTS During 10 years of follow-up, HbA1c (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P = 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%). CONCLUSIONS Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.

Optical Coherence Tomography Measurements and Analysis Methods in Optical Coherence Tomography Studies of Diabetic Macular Edema

OBJECTIVE To evaluate optical coherence tomography (OCT) measurements and methods of analysis of OCT data in studies of diabetic macular edema (DME). DESIGN Associations of pairs of OCT variables and results of 3 analysis methods using data from 2 studies of DME. PARTICIPANTS Two hundred sixty-three subjects from a study of modified Early Treatment of Diabetic Retinopathy Study (mETDRS) versus modified macular grid (MMG) photocoagulation for DME and 96 subjects from a study of diurnal variation of DME. METHODS Correlations were calculated for pairs of OCT variables at baseline and for changes in the variables over time. Distribution of OCT measurement changes, predictive factors for OCT measurement changes, and treatment group outcomes were compared when 3 measures of change in macular thickness were analyzed: absolute change in retinal thickness, relative change in retinal thickness, and relative change in retinal thickening. MAIN OUTCOME MEASURES Concordance of results using different OCT variables and analysis methods. RESULTS Center point thickness correlated highly with central subfield mean thickness (CSMT) at baseline (0.98-0.99). The distributions of changes in CSMT were approximately normally distributed for absolute change in retinal thickness and relative change in retinal thickness, but not for relative change in retinal thickening. Macular thinning in the mETDRS group was significantly greater than in the MMG group when absolute change in retinal thickness was used, but not when relative change in thickness and relative change in thickening were used. Relative change in macular thickening provides unstable data in eyes with mild degrees of baseline thickening, unlike the situation with absolute or relative change in retinal thickness. CONCLUSIONS Central subfield mean thickness is the preferred OCT measurement for the central macula because of its higher reproducibility and correlation with other measurements of the central macula. Total macular volume may be preferred when the central macula is less important. Absolute change in retinal thickness is the preferred analysis method in studies involving eyes with mild macular thickening. Relative change in thickening may be preferable when retinal thickening is more severe.

Choroidal perfusion perturbations in non-neovascular age related macular degeneration.

Aim: Choroidal perfusion, affected in age related macular degeneration (AMD), is difficult to objectively assess given the overlying retinal circulation. This study more objectively compared choroidal perfusion parameters in a group with non-neovascular AMD to an unaffected age matched control group. Methods: 21 non-neovascular AMD subjects and 21 age matched control subjects without evidence of AMD underwent assessment of their choroidal blood flow in a case-control study. Scanning laser ophthalmoscope indocyanine green (ICG) angiograms were analysed by a new area dilution analysis technique. Four areas in the perifoveal region and two areas in the temporal peripapillary retina were evaluated by producing a graph of intensity of fluorescence of each area over time. The mean of the filling times and the heterogeneity of the filling times were assessed. Results: The means of the filling times within the perifoveal regions and the hetereogeneity of the filling times between regions within the same eyes were significantly greater in the AMD patients compared with the control subjects. Conclusions: Delayed and heterogeneous filling of the choroid was objectively demonstrated in eyes with non-neovascular AMD compared with age matched controls without evidence of AMD, using an area dilution analysis technique applied to ICG angiography.