Diabetic Eye Disease

Diabetic Eye Disease Publications

Sun JK, Wang P-W, Taylor S, Haskova Z. Durability of Diabetic Retinopathy Improvement with As-Needed Ranibizumab: Open-label Extension of RIDE and RISE Studies. Ophthalmology 2018;Abstract
OBJECTIVE: To evaluate durability of diabetic retinopathy (DR) improvements after a change in ranibizumab dosing from monthly to individualized pro re nata (PRN) therapy. DESIGN: Pooled analysis of the open-label extension (OLE) of RIDE/RISE (NCT00473382/NCT00473330) patients with DR and diabetic macular edema (DME). PARTICIPANTS: Patients who completed 36-month participation in RIDE/RISE and entered the OLE. METHODS: In the RIDE/RISE studies, patients (N = 759) were randomized 1:1:1 to ranibizumab 0.3 mg monthly, 0.5 mg monthly, or monthly sham injections with rescue macular laser available after 6 months, per protocol-specified criteria. After 24 months, sham patients crossed over to ranibizumab 0.5 mg monthly. After 36 months in the core studies, patients in the OLE (n = 500) could receive ranibizumab 0.5 mg through an individualized PRN dosing regimen based on predefined DME re-treatment criteria. DR severity was evaluated photographically using the Early Treatment Diabetic Retinopathy Study DR severity scale. MAIN OUTCOME MEASURE: Change in DR severity from months 36 to 48 by re-treatment status. RESULTS: Among patients who entered the OLE, 121/500 (24%) did not require additional ranibizumab injections. In total, 442 patients had evaluable DR outcomes during the OLE; 367 had evaluable DR at months 36 and 48. Among patients not requiring ranibizumab re-treatment from months 36 to 48 (88/367), 57% to 78%, 0% to 7%, and 22% to 36% experienced DR severity stability, ≥2-step improvement, and ≥2-step worsening, respectively. Among patients requiring ranibizumab re-treatment (279/367), 84% to 94%, 2%, and 3% to 14% experienced DR severity stability, ≥2-step improvement, and ≥2-step worsening, respectively. On average, vision improvements were maintained during the OLE regardless of change in DR severity. CONCLUSIONS: DR severity improvements with ranibizumab were maintained in the majority of patients in the OLE after switching from ranibizumab monthly to an individualized best-corrected visual acuity- and optical coherence tomography-based ranibizumab 0.5 mg PRN dosing regimen. Because nearly one-third of OLE patients not requiring further therapy for DME experienced DR worsening, once DME resolves, patients should be watched carefully for worsening of DR and possible need for more frequent follow-up and/or treatment of vision-threatening disease with anti-VEGF or other modalities.
Pollack S, Igo RP, Jensen RA, Christiansen M, Li X, Cheng C-Y, Ng MCY, Smith AV, Rossin EJ, Segrè AV, Davoudi S, Tan GS, Chen Y-DI, Kuo JZ, Dimitrov LM, Stanwyck LK, Meng W, Hosseini MS, Imamura M, Nousome D, Kim J, Hai Y, Jia Y, Ahn J, Leong A, Shah K, Park KH, Guo X, Ipp E, Taylor KD, Adler SG, Sedor JR, Freedman BI, Family Investigation of Nephropathy and Diabetes-Eye Research Group DCCT/EDICRG, Lee I-T, Sheu WH-H, Kubo M, Takahashi A, Hadjadj S, Marre M, Tregouet D-A, McKean-Cowdin R, Varma R, McCarthy MI, Groop L, Ahlqvist E, Lyssenko V, Agardh E, Morris A, Doney ASF, Colhoun HM, Toppila I, Sandholm N, Groop P-H, Maeda S, Hanis CL, Penman A, Chen CJ, Hancock H, Mitchell P, Craig JE, Chew EY, Paterson AD, Grassi MA, Palmer C, Bowden DW, Yaspan BL, Siscovick D, Cotch MF, Wang JJ, Burdon KP, Wong TY, Klein BEK, Klein R, Rotter JI, Iyengar SK, Price A, Sobrin L. Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes 2018;Abstract
To identify genetic variants associated with diabetic retinopathy (DR), we performed a large, multiethnic genome-wide association study (GWAS). Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value < 1 X 10 were investigated in replication cohorts that included 18,545 Europeans, 16,453 Asians and 2,710 Hispanics. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts (P = 2.1 x 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR (PDR) was found to have significant connectivity (P=0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.
Lammer J, Karst SG, Lin MM, Cheney M, Silva PS, Burns SA, Aiello LP, Sun JK. Association of Microaneurysms on Adaptive Optics Scanning Laser Ophthalmoscopy With Surrounding Neuroretinal Pathology and Visual Function in Diabetes. Invest Ophthalmol Vis Sci 2018;59(13):5633-5640.Abstract
Purpose: We evaluate diabetic microaneurysm (MA) features on high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) and their correlations with visual acuity (VA) and local retinal pathology on spectral domain optical coherence tomography (SDOCT). Methods: Diabetic participants underwent VA testing and AOSLO and SDOCT imaging of MAs. AOSLO images were graded for MA dimension, wall hyperreflectivity (WH), intraluminal hyperreflectivity (IH), and perfusion pattern. SDOCTs centered on each MA were graded for disorganization of the retinal inner layers (DRIL) and other neuroretinal pathology. Results: We imaged 109 MAs (30 eyes). Multivariate modeling, including statistically significant covariates from bivariate analyses, associated WH with greater MA size (P = 0.001) and DRIL (P = 0.04). IH was associated with perfusion (P = 0.003) and MA visibility on photographs (P = 0.0001), and larger MA size with partial perfusion (P = 0.03), MA ring signs (P = 0.0002), and photographic visibility (P = 0.01). Multivariate modeling revealed an association of WH and VA with DRIL. Conclusions: AOSLO imaging demonstrates associations of hyperreflective MA walls with MA size and adjacent DRIL, as well as the presence of DRIL with lower VA. This study identifies a correlation between vascular and neural pathology associated with VA decline. Further studies of MA structure and neuroretinal disorganization may enable novel approaches to assess anatomic and functional outcomes in the diabetic eye.
de Boer IH, Zelnick LR, Lin J, Schaumberg D, Wang L, Ruzinski J, Friedenberg G, Duszlak J, Bubes VY, Hoofnagle AN, Thadhani R, Glynn RJ, Buring JE, Sesso HD, Manson JAE. Vitamin D and omega-3 trial to prevent and treat diabetic kidney disease: Rationale, design, and baseline characteristics. Contemp Clin Trials 2018;74:11-17.Abstract
Diabetic kidney disease (DKD), defined as reduced glomerular filtration rate (GFR), elevated urine albumin excretion, or both that is clinically attributable to diabetes, is a common and morbid diabetes complication. Animal-experimental data, observational human studies, and short-term clinical trials suggest that vitamin D and omega-3 fatty acid supplements may be safe and inexpensive interventions to reduce the incidence and progression of DKD. The Vitamin D and Omega-3 Trial to Prevent and Treat DKD (VITAL-DKD) was designed as an ancillary study to the VITAL trial of 25,871 US adults. In a 2 × 2 factorial design, VITAL participants were randomly assigned to vitamin D (cholecalciferol, 2000 IU daily) or placebo and to marine omega-3 fatty acids (eicospentaenoic acid and docosahexaenoic acid, 1 g/d) or placebo. VITAL-DKD enrolled a subset of 1326 VITAL participants with type 2 diabetes at baseline to test the effects of vitamin D and omega-3 fatty acids on changes in estimated GFR and urine albumin excretion. Over five years of follow-up, VITAL-DKD collected blood and urine samples to quantify changes in estimated GFR (the primary study outcome) and urine albumin excretion. At baseline, mean age of VITAL-DKD participants was 67.6 years, 46% were women, 30% were of racial or ethnic minority, and the prevalence of DKD (estimated GFR <60 mL/min/1.73m or urine albumin-creatinine ratio ≥ 30 mg/g) was 17%. In this type 2 diabetes population, VITAL-DKD will test the hypotheses that vitamin D and omega-3 fatty acids help prevent the development and progression of DKD.
Chaly Y, Barr JY, Sullivan DA, Thomas HE, Brodnicki TC, Lieberman SM. Type I Interferon Signaling Is Required for Dacryoadenitis in the Nonobese Diabetic Mouse Model of Sjögren Syndrome. Int J Mol Sci 2018;19(10)Abstract
Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland autoimmunity spontaneously occurs only in males with testosterone playing a role in promoting lacrimal gland inflammation, while female lacrimal glands are protected by regulatory T cells (Tregs). The mechanisms of this male-specific lacrimal gland autoimmunity are not known. Here, we studied the effects of Treg depletion in hormone-manipulated NOD mice and lacrimal gland gene expression to determine early signals required for lacrimal gland inflammation. While Treg-depletion was not sufficient to drive dacryoadenitis in castrated male NOD mice, chemokines (, ) and other potentially disease-relevant genes (, ) were upregulated in male lacrimal glands. Expression of and , in particular, remained significantly upregulated in the lacrimal glands of lymphocyte-deficient NOD-severe combined immunodeficiency (SCID) mice and their expression was modulated by type I interferon signaling. Notably, -deficient NOD mice did not develop dacryoadenitis. Together these data identify disease-relevant genes upregulated in the context of male-specific dacryoadenitis and demonstrate a requisite role for type I interferon signaling in lacrimal gland autoimmunity in NOD mice.
Aiello LP, Odia I, Glassman AR, Melia M, Jampol LM, Bressler NM, Kiss S, Silva PS, Wykoff CC, Sun JK, Sun JK. Comparison of Early Treatment Diabetic Retinopathy Study Standard 7-Field Imaging With Ultrawide-Field Imaging for Determining Severity of Diabetic Retinopathy. JAMA Ophthalmol 2018;Abstract
Importance: Moderate to substantial agreement between Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field imaging and ultrawide-field (UWF) imaging has been suggested in single-center studies. Comparing images obtained by multiple centers could increase confidence that UWF images can be used reliably in place of ETDRS imaging in future clinical trials. Objective: To compare diabetic retinopathy (DR) severity from modified ETDRS 7-field imaging and UWF imaging. Design, Setting, and Participants: This preplanned, cross-sectional analysis included modified ETDRS 7-field images obtained using the Diabetic Retinopathy Clinical Research Network acquisition protocol and UWF images obtained captured with the Optos 200Tx system (Optos, PLC) from adult participants (≥18 years old) with type 1 or type 2 diabetes. Both image types were evaluated by trained graders masked to clinical data. Data collection occurred from February 2015 to December 2015, and data analysis from June 2016 to December 2017. Main Outcomes and Measures: Agreement between UWF images, UWF imagesmasked to include only the ETDRS 7-field area, and ETDRS 7-field images were calculated using κ statistics. Results: A total of 764 eyes from 385 participants were included; participants had a median (IQR) age of 62.2 (53.6-69.2) years, 194 (50.4%) were women, and 256 (66.5%) were white. Of 742 eyes with both ETDRS 7-field images and UWF masked images graded, 359 (48.4% [95% CI, 44.4%-52.4%]) eyes had exact agreement, and 653 eyes (88.0% [95% CI, 85.2%-90.3%]) agreed within 1 step (weighted κ, 0.51 [95% CI, 0.44-0.58]). After open adjudication by an independent senior grader of all images with more than a 2-step discrepancy, perfect agreement was found in 435 eyes (59.0% [95% CI, 55.1%-62.8%]) and agreement within 1 step in 714 eyes (96.9% [95% CI, 95.1%-98.0%]; κ, 0.77 [95% CI, 0.73-0.82]). Ability of the imaging modalities to detect retinopathy severity in an individual eye was considered similar in 59 eyes (50.9% [95% CI, 41.3%-60.4%]), better for ETDRS 7-field imaging in 22 eyes (19.0% [95% CI, 12.5%-27.7%]), and better for UWF-masked images in 31 eyes (26.7% [95% CI 18.8%-36.5%]). Comparing UWF masked and unmasked images, 94 of 751 eyes (12.5%) had DR graded as at least 1 step more severe on UWF unmasked images vs UWF masked images. Predominantly peripheral DR lesions were present in 308 of 751 eyes (41.0%); this suggested increased DR severity by 2 or more steps in 34 eyes (11.0%). Conclusions and Relevance: Imaging by the ETDRS 7-field and UWF imaging systems have moderate to substantial agreement when determining the severity of DR within the 7 standard fields. Disparities in an individual eye are equivalently distributed between imaging modalities and can be better or worse on 1 or the other. Longitudinal follow-up will evaluate the primary outcome of this study to determine if peripheral retinal findings are associated with future retinopathy outcomes.
Meng W, Shah KP, Pollack S, Toppila I, Hebert HL, McCarthy MI, Groop L, Ahlqvist E, Lyssenko V, Agardh E, Daniell M, Kaidonis G, Craig JE, Mitchell P, Liew G, Kifley A, Wang JJ, Christiansen MW, Jensen RA, Penman A, Hancock HA, Chen CJ, Correa A, Kuo JZ, Li X, Chen Y, Rotter JI, Klein R, Klein B, Wong TY, Morris AD, Doney ASF, Colhoun HM, Price AL, Burdon KP, Groop PH, Sandholm N, Grassi MA, Sobrin L, Palmer CNA, markers for and hard endpoints for Innovative WTCCC (WTCCC2); SM-M-vascular2. A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes. Acta Ophthalmol 2018;Sept 4Abstract

PURPOSE:

Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.

METHODS:

A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts.

RESULTS:

Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10-8 and 1.23 × 10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429).

CONCLUSION:

This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

Bernabeu MO, Lu Y, Abu-Qamar O, Aiello LP, Sun JK. Estimation of Diabetic Retinal Microaneurysm Perfusion Parameters Based on Computational Fluid Dynamics Modeling of Adaptive Optics Scanning Laser Ophthalmoscopy. Front Physiol 2018;9:989.Abstract
Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Microaneurysms (MAs), which are abnormal outpouchings of the retinal vessels, are early and hallmark lesions of DR. The presence and severity of MAs are utilized to determine overall DR severity. In addition, MAs can directly contribute to retinal neural pathology by leaking fluid into the surrounding retina, causing abnormal central retinal thickening and thereby frequently leading to vision loss. Vascular perfusion parameters such as shear rate (SR) or wall shear stress (WSS) have been linked to blood clotting and endothelial cell dysfunction, respectively in non-retinal vasculature. However, despite the importance of MAs as a key aspect of diabetic retinal pathology, much remains unknown as to how structural characteristics of individual MAs are associated with these perfusion attributes. MA structural information obtained on high resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) was utilized to estimate perfusion parameters through Computational Fluid Dynamics (CFD) analysis of the AOSLO images. The HemeLB flow solver was used to simulate steady-state and time-dependent fluid flow using both commodity hospital-based and high performance computing resources, depending on the degree of detail required in the simulations. Our results indicate that WSS is lowest in MA regions furthest away from the feeding vessels. Furthermore, areas of low SR are associated with clot location in saccular MAs. These findings suggest that morphology and CFD estimation of perfusion parameters may be useful tools for determining the likelihood of clot presence in individual diabetic MAs.
Bressler NM, Beaulieu WT, Maguire MG, Glassman AR, Blinder KJ, Bressler SB, Gonzalez VH, Jampol LM, Melia M, Sun JK, Wells JA, Wells JA. Early Response to Anti-Vascular Endothelial Growth Factor and Two-Year Outcomes Among Eyes With Diabetic Macular Edema in Protocol T. Am J Ophthalmol 2018;195:93-100.Abstract
PURPOSE: Assess associations of 2-year visual acuity (VA) outcomes with VA and optical coherence tomography central subfield thickness (CST) after 12 weeks of anti-vascular endothelial growth factor treatment for diabetic macular edema in DRCR.net Protocol T. DESIGN: Randomized clinical trial. METHODS: Setting: Multicenter (89 U.S. sites). PATIENT POPULATION: Eyes with VA and CST data from baseline and 12-week visits (616 of 660 eyes randomized [93.3%]). INTERVENTION: Six monthly injections of 2.0 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab; subsequent injections and focal/grid laser as needed for stability. MAIN OUTCOME MEASURES: Change in VA from baseline and VA letter score at 2 years. RESULTS: Twelve-week VA response was associated with 2-year change in VA and 2-year VA letter score for each drug (P < .001) but with substantial individual variability (multivariable R = 0.38, 0.29, and 0.26 for 2-year change with aflibercept, bevacizumab, and ranibizumab, respectively). Among eyes with less than 5-letter gain at 12 weeks, the percentages of eyes gaining 10 or more letters from baseline at 2 years were 42% (20 of 48), 31% (21 of 68), and 47% (28 of 59), and median 2-year VA was 20/32, 20/32, and 20/25, in the aflibercept, bevacizumab, and ranibizumab groups, respectively. Twelve-week CST response was not strongly associated with 2-year outcomes. CONCLUSIONS: A suboptimal response at 12 weeks did not preclude meaningful vision improvement (ie, ≥ 10-letter gain) in many eyes at 2 years. Eyes with less than 5-letter gain at 12 weeks often had good VA at 2 years without switching therapies.
Sun JK, Glassman AR, Beaulieu WT, Stockdale CR, Bressler NM, Flaxel C, Gross JG, Shami M, Jampol LM. Rationale and Application of the Protocol S Anti-Vascular Endothelial Growth Factor Algorithm for Proliferative Diabetic Retinopathy. Ophthalmology 2018;Abstract
OBJECTIVE: Present rationale, guidelines, and results of ranibizumab treatment for proliferative diabetic retinopathy (PDR) in Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S. DESIGN: Post hoc analyses from a randomized clinical trial. PARTICIPANTS: Three hundred and five participants with 394 study eyes having PDR without prior PRP. INTERVENTION: Post hoc analyses from a randomized clinical trial of 0.5-mg intravitreous ranibizumab versus panretinal photocoagulation (PRP) for PDR. Eyes assigned to ranibizumab (N=191) received monthly injections for 6 months unless resolution after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits (sustained stability). If neovascularization worsened, monthly treatment resumed. PRP could be initiated for failure or futility criteria. MAIN OUTCOME MEASURES: Neovascularization status through 2 years. RESULTS: At 1 month, 19% (35 of 188) of ranibizumab-assigned eyes had complete neovascularization resolution (including fibrous proliferans) and an additional 60% (113) were improved. At 6 months, 52% (80 of 153) had neovascularization resolution, 3% (4) were still improving, 37% (56) were stable, and 8% (13) had worsened since the last visit. Among eyes with versus without resolved neovascularization at 6 months, the median (interquartile range) number of injections between 6 months and 2 years was 4 (1-7; N = 73) versus 7 (4-11; N = 67) (P<.001). Injections were deferred in 68 of 73 eyes (93%) meeting sustained stability at least once during the study; 62% (42 of 68) resumed injections within 16 weeks after deferral. At 2 years, 43% (66 of 154) had neovascularization resolution, 5% (7) were improved, 23% (36) were stable, and 27% (42) had worsened since the last visit. Only 3 eyes met criteria for failure or futility through 2 years. CONCLUSIONS: The DRCR Network treatment algorithm for PDR can provide excellent clinical outcomes through two years for patients initiating anti-VEGF therapy for PDR. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided by consideration of the relative advantages of each therapeutic modality and anticipated patient compliance with follow-up and treatment recommendations.
Gross JG, Glassman AR, Liu D, Sun JK, Antoszyk AN, Baker CW, Bressler NM, Elman MJ, Ferris FL, Gardner TW, Jampol LM, Martin DF, Melia M, Stockdale CR, Beck RW, Beck RW. Five-Year Outcomes of Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA Ophthalmol 2018;136(10):1138-1148.Abstract
Importance: Ranibizumab is a viable treatment option for eyes with proliferative diabetic retinopathy (PDR) through 2 years. However, longer-term results are needed. Objective: To evaluate efficacy and safety of 0.5-mg intravitreous ranibizumab vs panretinal photocoagulation (PRP) over 5 years for PDR. Design, Setting, and Participants: Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial evaluated 394 study eyes with PDR enrolled February through December 2012. Analysis began in January 2018. Interventions: Eyes were randomly assigned to receive intravitreous ranibizumab (n = 191) or PRP (n = 203). Frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group. Main Outcomes and Measures: Mean change in visual acuity (intention-to-treat analysis) was the main outcome. Secondary outcomes included peripheral visual field loss, development of vision-impairing diabetic macular edema, and ocular and systemic safety. Results: The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in visual acuity letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95% CI, -2.3 to 3.5; P = .68); the mean visual acuity was 20/25 (approximate Snellen equivalent) in both groups at 5 years. The mean (SD) change in cumulative visual field total point score was -330 (645) vs -527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively (adjusted difference, 208 dB; 95% CI, 9-408). Vision-impairing diabetic macular edema developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively (cumulative probabilities: 22% vs 38%; hazard ratio, 0.4; 95% CI, 0.3-0.7). No statistically significant differences between groups in major systemic adverse event rates were identified. Conclusions and Relevance: Although loss to follow-up was relatively high, visual acuity in most study eyes that completed follow-up was very good at 5 years and was similar in both groups. Severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing diabetic macular edema and less visual field loss. Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for patients with PDR. These findings support either anti-vascular endothelial growth factor therapy or PRP as viable treatments for patients with PDR. Trial Registration: ClinicalTrials.gov Identifier: NCT01489189.
Liu Y, Rajamanickam VP, Parikh RS, Loomis SJ, Kloek CE, Kim LA, Hitchmoth DL, Song BJ, Xerras DC, Pasquale LR. Diabetic Retinopathy Assessment Variability Among Eye Care Providers in an Urban Teleophthalmology Program. Telemed J E Health 2018;Abstract
BACKGROUND: Teleophthalmology is an evidence-based method for diabetic eye screening. It is unclear whether the type of eye care provider performing teleophthalmology interpretation produces significant variability. INTRODUCTION: We assessed grading variability between an optometrist, general ophthalmologist, and retinal specialist using images from an urban, diabetic retinopathy teleophthalmology program. METHODS: Three readers evaluated digital retinal images in 100 cases (178 eyes from 90 patients with type 2 diabetes). Fisher's exact test, percent agreement, and the observed proportion of positive (P) or negative agreement (P) were used to assess variability. RESULTS: Among cases deemed gradable by all three readers (n = 65), there was substantial agreement on absence of any retinopathy (88% ± 4.6%, P = 0.91-0.95), presence of moderate nonproliferative or worse retinopathy (87% ± 3.9%, P = 0.67-1.00), and presence of macular edema (99% ± 0.9%, P = 0.67-1.00). There was limited agreement regarding presence of referable nondiabetic eye pathology (61% ± 11%, P = 0.21-0.59) and early, nonroutine referral for a follow-up clinical eye exam (66% ± 8.1%, P = 0.19-0.54). Among all cases (n = 100), there was acceptable agreement regarding which had gradable images (77% ± 5.0%, P = 0.50-0.90). DISCUSSION: Inclusion of multiple types of eye care providers as teleophthalmology readers is unlikely to produce significant variability in the assessment of diabetic retinopathy among high-quality images. Greater variability was found regarding image gradability, nondiabetic eye pathology, and recommended clinical referral times. CONCLUSIONS: Our results suggest that more extensive training and uniform referral standards are needed to improve consensus on image gradability, referable nondiabetic eye pathology, and recommended clinical referral times.
Wong TY, Sun J, Kawasaki R, Ruamviboonsuk P, Gupta N, Lansingh VC, Maia M, Mathenge W, Moreker S, Muqit MMK, Resnikoff S, Verdaguer J, Zhao P, Ferris F, Aiello LP, Taylor HR. Guidelines on Diabetic Eye Care: The International Council of Ophthalmology Recommendations for Screening, Follow-up, Referral, and Treatment Based on Resource Settings. Ophthalmology 2018;125(10):1608-1622.Abstract
Diabetes mellitus (DM) is a global epidemic and affects populations in both developing and developed countries, with differing health care and resource levels. Diabetic retinopathy (DR) is a major complication of DM and a leading cause of vision loss in working middle-aged adults. Vision loss from DR can be prevented with broad-level public health strategies, but these need to be tailored to a country's and population's resource setting. Designing DR screening programs, with appropriate and timely referral to facilities with trained eye care professionals, and using cost-effective treatment for vision-threatening levels of DR can prevent vision loss. The International Council of Ophthalmology Guidelines for Diabetic Eye Care 2017 summarize and offer a comprehensive guide for DR screening, referral and follow-up schedules for DR, and appropriate management of vision-threatening DR, including diabetic macular edema (DME) and proliferative DR, for countries with high- and low- or intermediate-resource settings. The guidelines include updated evidence on screening and referral criteria, the minimum requirements for a screening vision and retinal examination, follow-up care, and management of DR and DME, including laser photocoagulation and appropriate use of intravitreal anti-vascular endothelial growth factor inhibitors and, in specific situations, intravitreal corticosteroids. Recommendations for management of DR in patients during pregnancy and with concomitant cataract also are included. The guidelines offer suggestions for monitoring outcomes and indicators of success at a population level.
Jampol LM, Glassman AR, Liu D, Aiello LP, Bressler NM, Duh EJ, Quaggin S, Wells JA, Wykoff CC, Wykoff CC. Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema. Ophthalmology 2018;125(7):1054-1063.Abstract
PURPOSE: To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS: Participants with available plasma samples (N = 436). METHODS: Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS: These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.
Fu Z, Wang Z, Liu C-H, Gong Y, Cakir B, Liegl R, Sun Y, Meng SS, Burnim SB, Arellano I, Moran E, Duran R, Poblete A, Cho SS, Talukdar S, Akula JD, Hellström A, Smith LEH. Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice. Diabetes 2018;67(5):974-985.Abstract
Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1β (IL-1β) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1β expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes.

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