Intensive Glycemic Management Is Associated With Reduced Retinal Structure Abnormalities on Ocular Coherence Tomography in the DCCT/EDIC Study.

OBJECTIVE: To investigate quantitative and qualitative changes in retinal structure using optical coherence tomography (OCT) and their associations with systemic or other risk factors in individuals with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, OCT images were obtained during study years 25-28 (2019-2022) in 937 participants; 54% and 46% were from the original intensive (INT) and conventional (CONV) glycemic management treatment groups, respectively. RESULTS: Average age for participants was 61 years old, diabetes duration 39 years, and HbA1c 7.6%. Participants originally in the CONV group were more likely to have disorganization of retinal inner layers (DRIL) (CONV 27.3% vs. INT 18.7%; P = 0.0003), intraretinal fluid (CONV 24.4% vs. INT 19.2%; P = 0.0222), and intraretinal cysts (CONV 20.8% vs. INT 16.6%; P = 0.0471). In multivariable models, sex, age, smoking, mean updated systolic blood pressure, and history of "clinically significant" macular edema (CSME) and of anti-VEGF treatment were independently associated with changes in central subfield thickness, while HbA1c, BMI, and history of CSME and of ocular surgery were associated with DRIL. Visual acuity (VA) decline was associated with significant thinning of all retinal subfields except for the central and inner nasal subfields. CONCLUSIONS: Early intensive glycemic management in T1D is associated with a decreased risk of DRIL. This important morphological abnormality was associated with a history of macular edema, a history of ocular surgery, and worse VA. This study reveals benefits of intensive glycemic management on the retina beyond features detected by fundus photographs and ophthalmoscopy.

Optical coherence tomography in the management of diabetic macular oedema.

Diabetic macular oedema (DMO) is the major cause of visual impairment in people with diabetes. Optical coherence tomography (OCT) is now the most widely used modality to assess presence and severity of DMO. DMO is currently broadly classified based on the involvement to the central 1 mm of the macula into non-centre or centre involved DMO (CI-DMO) and DMO can occur with or without visual acuity (VA) loss. This classification forms the basis of management strategies of DMO. Despite years of research on quantitative and qualitative DMO related features assessed by OCT, these do not fully inform physicians of the prognosis and severity of DMO relative to visual function. Having said that, recent research on novel OCT biomarkers development and re-defined classification of DMO show better correlation with visual function and treatment response. This review summarises the current evidence of the association of OCT biomarkers in DMO management and its potential clinical importance in predicting VA and anatomical treatment response. The review also discusses some future directions in this field, such as the use of artificial intelligence to quantify and monitor OCT biomarkers and retinal fluid and identify phenotypes of DMO, and the need for standardisation and classification of OCT biomarkers to use in future clinical trials and clinical practice settings as prognostic markers and secondary treatment outcome measures in the management of DMO.

INTEGRATING MACULAR OPTICAL COHERENCE TOMOGRAPHY WITH ULTRAWIDE-FIELD IMAGING IN A DIABETIC RETINOPATHY TELEMEDICINE PROGRAM USING A SINGLE DEVICE.

PURPOSE: To determine the effect of combined macular spectral-domain optical coherence tomography (SD-OCT) and ultrawide field retinal imaging (UWFI) within a telemedicine program. METHODS: Comparative cohort study of consecutive patients with both UWFI and SD-OCT. Ultrawide field retinal imaging and SD-OOCT were independently evaluated for diabetic macular edema (DME) and nondiabetic macular abnormality. Sensitivity and specificity were calculated with SD-OCT as the gold standard. RESULTS: Four hundred twenty-two eyes from 211 diabetic patients were evaluated. Diabetic macular edema severity by UWFI was as follows: no DME 93.4%, noncenter involved DME (nonciDME) 5.1%, ciDME 0.7%, ungradable DME 0.7%. SD-OCT was ungradable in 0.5%. Macular abnormality was identified in 34 (8.1%) eyes by UWFI and in 44 (10.4%) eyes by SD-OCT. Diabetic macular edema represented only 38.6% of referable macular abnormality identified by SD-OCT imaging. Sensitivity/specificity of UWFI compared with SD-OCT was 59%/96% for DME and 33%/99% for ciDME. Sensitivity/specificity of UWFI compared with SDOCT was 3%/98% for epiretinal membrane. CONCLUSION: Addition of SD-OCT increased the identification of macular abnormality by 29.4%. More than 58.3% of the eyes believed to have any DME on UWF imaging alone were false-positives by SD-OCT. The integration of SD-OCT with UWFI markedly increased detection and reduced false-positive assessments of DME and macular abnormality in a teleophthalmology program.

Performance of Automated Machine Learning for Diabetic Retinopathy Image Classification from Multi-field Handheld Retinal Images.

PURPOSE: To create and validate code-free automated deep learning models (AutoML) for diabetic retinopathy (DR) classification from handheld retinal images. DESIGN: Prospective development and validation of AutoML models for DR image classification. PARTICIPANTS: A total of 17 829 deidentified retinal images from 3566 eyes with diabetes, acquired using handheld retinal cameras in a community-based DR screening program. METHODS: AutoML models were generated based on previously acquired 5-field (macula-centered, disc-centered, superior, inferior, and temporal macula) handheld retinal images. Each individual image was labeled using the International DR and diabetic macular edema (DME) Classification Scale by 4 certified graders at a centralized reading center under oversight by a senior retina specialist. Images for model development were split 8-1-1 for training, optimization, and testing to detect referable DR ([refDR], defined as moderate nonproliferative DR or worse or any level of DME). Internal validation was performed using a published image set from the same patient population (N = 450 images from 225 eyes). External validation was performed using a publicly available retinal imaging data set from the Asia Pacific Tele-Ophthalmology Society (N = 3662 images). MAIN OUTCOME MEASURES: Area under the precision-recall curve (AUPRC), sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), accuracy, and F1 scores. RESULTS: Referable DR was present in 17.3%, 39.1%, and 48.0% of the training set, internal validation, and external validation sets, respectively. The model's AUPRC was 0.995 with a precision and recall of 97% using a score threshold of 0.5. Internal validation showed that SN, SP, PPV, NPV, accuracy, and F1 scores were 0.96 (95% confidence interval [CI], 0.884-0.99), 0.98 (95% CI, 0.937-0.995), 0.96 (95% CI, 0.884-0.99), 0.98 (95% CI, 0.937-0.995), 0.97, and 0.96, respectively. External validation showed that SN, SP, PPV, NPV, accuracy, and F1 scores were 0.94 (95% CI, 0.929-0.951), 0.97 (95% CI, 0.957-0.974), 0.96 (95% CI, 0.952-0.971), 0.95 (95% CI, 0.935-0.956), 0.97, and 0.96, respectively. CONCLUSIONS: This study demonstrates the accuracy and feasibility of code-free AutoML models for identifying refDR developed using handheld retinal imaging in a community-based screening program. Potentially, the use of AutoML may increase access to machine learning models that may be adapted for specific programs that are guided by the clinical need to rapidly address disparities in health care delivery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy.

Importance: Anti-vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, Setting, and Participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME. Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main Outcomes and Measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P < .001). The mean (SD) change in visual acuity from baseline to 4 years was -2.7 (6.5) letters with aflibercept and -2.4 (5.8) letters with sham (adjusted mean difference, -0.5 letters [97.5% CI, -2.3 to 1.3]; P = .52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and Relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. Trial Registration: ClinicalTrials.gov Identifier: NCT02634333.

DEFINING "STRONG" VERSUS "WEAK" RESPONSE TO ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT FOR CENTER-INVOLVED DIABETIC MACULAR EDEMA.

BACKGROUND/PURPOSE: To define "strong" versus "weak" antivascular endothelial growth factor (anti-VEGF) treatment response in eyes with center-involved diabetic macular edema (CI-DME). METHODS: Exploratory analyses of three DRCR Retina Network randomized trials of eyes with CI-DME treated with aflibercept, bevacizumab, or ranibizumab. Thresholds of 5-, 10-, and 15-letter gain defined strong visual acuity (VA) response when baseline VA was 20/25-20/32, 20/40-20/63, or 20/80-20/320, respectively. Thresholds of 50, 100, or 200- µ m reduction defined strong anatomical response when baseline central subfield thickness (CST) was <75, ≥75 to <175, or ≥175- µ m above standard thresholds. Additional thresholds from regression equations were calculated. RESULTS: At 24 weeks, outcomes for strong response were achieved by 476 of 958 eyes (50%) for VA and 505 eyes (53%) for CST. At 104 weeks among the 32% of eyes with strong VA and CST response at 24 weeks, 195 of 281 (69%) maintained strong VA and CST response, whereas 20 (7%) had neither strong VA nor strong CST response. Outcomes rates were similar across protocols and when defined using regression equations. CONCLUSION: These phenotypes are suitable for efforts to identify predictive biomarkers for response to anti-VEGF therapy for DME and might facilitate comparison of treatment response among diverse cohorts with DME.

Cost-effectiveness of Aflibercept Monotherapy vs Bevacizumab First Followed by Aflibercept If Needed for Diabetic Macular Edema.

Importance: The DRCR Retina Network Protocol AC showed no significant difference in visual acuity outcomes over 2 years between treatment with aflibercept monotherapy and bevacizumab first with switching to aflibercept for suboptimal response in treating diabetic macular edema (DME). Understanding the estimated cost and cost-effectiveness of these approaches is important. Objective: To evaluate the cost and cost-effectiveness of aflibercept monotherapy vs bevacizumab-first strategies for DME treatment. Design, Setting, and Participants: This economic evaluation was a preplanned secondary analysis of a US randomized clinical trial of participants aged 18 years or older with center-involved DME and best-corrected visual acuity of 20/50 to 20/320 enrolled from December 15, 2017, through November 25, 2019. Interventions: Aflibercept monotherapy or bevacizumab first, switching to aflibercept in eyes with protocol-defined suboptimal response. Main Outcomes and Measures: Between February and July 2022, the incremental cost-effectiveness ratio (ICER) in cost per quality-adjusted life-year (QALY) over 2 years was assessed. Efficacy and resource utilization data from the randomized clinical trial were used with health utility mapping from the literature and Medicare unit costs. Results: This study included 228 participants (median age, 62 [range, 34-91 years; 116 [51%] female and 112 [49%] male; 44 [19%] Black or African American, 60 [26%] Hispanic or Latino, and 117 [51%] White) with 1 study eye. The aflibercept monotherapy group included 116 participants, and the bevacizumab-first group included 112, of whom 62.5% were eventually switched to aflibercept. Over 2 years, the cost of aflibercept monotherapy was $26 504 (95% CI, $24 796-$28 212) vs $13 929 (95% CI, $11 984-$15 874) for the bevacizumab-first group, a difference of $12 575 (95% CI, $9987-$15 163). The aflibercept monotherapy group gained 0.015 (95% CI, -0.011 to 0.041) QALYs using the better-seeing eye and had an ICER of $837 077 per QALY gained compared with the bevacizumab-first group. Aflibercept could be cost-effective with an ICER of $100 000 per QALY if the price per dose were $305 or less or the price of bevacizumab was $1307 per dose or more. Conclusions and Relevance: Variability in individual needs will influence clinician and patient decisions about how to treat specific eyes with DME. While the bevacizumab-first group costs still averaged approximately $14 000 over 2 years, this approach, as used in this study, may confer substantial cost savings on a societal level without sacrificing visual acuity gains over 2 years compared with aflibercept monotherapy.

Comparison of Snellen Visual Acuity Measurements in Retinal Clinical Practice to Electronic ETDRS Protocol Visual Acuity Assessment.

PURPOSE: Evaluate the differences between clinical visual acuity (VA) as recorded in medical records and electronic Early Treatment Diabetic Retinopathy Study (eETDRS) protocol VA measurements and factors affecting the size of the differences. DESIGN: Retrospective chart review. PARTICIPANTS: Study and fellow eyes of participants enrolled in DRCR Retina Network Protocols AC and AE (diabetic macular edema), and W (nonproliferative diabetic retinopathy) with clinical VA recorded within 3 months before the protocol visit. METHODS: Differences and their association with patient and ocular factors were evaluated using linear mixed models with random effects for correlations within sites and participants. MAIN OUTCOME MEASURE: Difference between VA letter scores measured by eETDRS during a study visit versus measured by Snellen during a regular clinical visit (Snellen fraction converted to eETDRS). RESULTS: Data from 1016 eyes (511 participants) across 74 sites were analyzed. The mean VA measurements were 68.6 letters (Snellen equivalent 20/50) at the clinical visit and 76.3 letters (Snellen equivalent 20/32) at the protocol visit, with a mean (standard deviation [SD]) of 26 (21) days between visits. Mean (SD) protocol VA was better than clinical VA by 7.6 (9.6) letters overall, 10.7 (12.6) letters in eyes with clinical VA ≤ 20/50 (n = 376), and 5.8 (6.6) letters in eyes with clinical VA ≥ 20/40 (n = 640). On average, the difference between clinical and protocol VA was 1.3 letters smaller for every 1-line (5 letters) increase in clinical VA (P < 0.001). Mean (SD) differences by clinical correction of refractive error were 3.9 (9.0) letters with refraction, 6.9 (9.2) letters with glasses/contact lenses, 7.9 (11.5) letters with pinhole, and 9.8 (9.3) letters without correction (P = 0.06). CONCLUSIONS: On average, clinical Snellen VA is 1 to 2 lines worse than eETDRS protocol refraction and VA testing, which may partly explain why clinical practice does not always replicate clinical trial results. Eyes with lower clinical measurements and eyes tested without clinical refraction tended to have larger differences. Considering the potential discrepancies between clinical and protocol VA measurements, refracting eyes in the clinic may benefit patients when determining treatment plans and study referrals based on vision. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Association of Predominantly Peripheral Lesions on Ultra-Widefield Imaging and the Risk of Diabetic Retinopathy Worsening Over Time.

Importance: Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. Objective: To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Results: Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P < .001). Conclusions and Relevance: Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.

Association of Ultra-Widefield Fluorescein Angiography-Identified Retinal Nonperfusion and the Risk of Diabetic Retinopathy Worsening Over Time.

Importance: Presence of predominantly peripheral diabetic retinopathy (DR) lesions on ultra-widefield fluorescein angiography (UWF-FA) was associated with greater risk of DR worsening or treatment over 4 years. Whether baseline retinal nonperfusion assessment is additionally predictive of DR disease worsening is unclear. Objective: To assess whether the extent and location of retinal nonperfusion identified on UWF-FA are associated with worsening in Diabetic Retinopathy Severity Scale (DRSS) score or DR treatment over time. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study with data for 508 eyes with nonproliferative DR and gradable nonperfusion on UWF-FA at baseline. All images were graded at a centralized reading center; 200° ultra-widefield (UWF) color images were graded for DR at baseline and annually for 4 years. Baseline 200° UWF-FA images were graded for nonperfused area, nonperfusion index (NPI), and presence of predominantly peripheral lesions on UWF-FA (FA PPL). Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Association of baseline UWF-FA nonperfusion extent with disease worsening, defined as either 2 or more steps of DRSS worsening within Early Treatment Diabetic Retinopathy Study fields on UWF-color images or receipt of DR treatment. Results: After adjusting for baseline DRSS, the risk of disease worsening over 4 years was higher in eyes with greater overall NPI (hazard ratio [HR] for 0.1-unit increase, 1.11; 95% CI, 1.02-1.21; P = .02) and NPI within the posterior pole (HR for 0.1-unit increase, 1.35; 95% CI, 1.17-1.56; P < .001) and midperiphery (HR for 0.1-unit increase, 1.08; 95% CI, 1.00-1.16; P = .04). In a multivariable analysis adjusting for baseline DRSS score and baseline systemic risk factors, greater NPI (HR, 1.11; 95% CI, 1.02-1.22; P = .02) and presence of FA PPL (HR, 1.89; 95% CI, 1.35-2.65; P < .001) remained associated with disease worsening. Conclusions and Relevance: This 4-year longitudinal study has demonstrated that both greater baseline retinal nonperfusion and FA PPL on UWF-FA are associated with higher risk of disease worsening, even after adjusting for baseline DRSS score and known systemic risk. These associations between disease worsening and retinal nonperfusion and FA PPL support the increased use of UWF-FA to complement color fundus photography in future efforts for DR prognosis, clinical care, and research.

Elevated Retinol Binding Protein 3 Concentrations Are Associated With Decreased Vitreous Inflammatory Cytokines, VEGF, and Progression of Diabetic Retinopathy.

OBJECTIVE: To correlate inflammatory cytokines and vascular endothelial growth factor (VEGF) in vitreous and plasma with vitreous retinol binding protein 3 (RBP3), diabetic retinopathy (DR) severity, and DR worsening in a population with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: RBP3, VEGF, and inflammatory cytokines were measured in plasma and vitreous samples (n = 205) from subjects of the Joslin Medalist Study and Beetham Eye Institute. RESULTS: Higher vitreous RBP3 concentrations were associated with less severe DR (P < 0.0001) and a reduced risk of developing proliferative DR (PDR) (P < 0.0001). Higher RBP3 correlated with increased photoreceptor segment thickness and lower vitreous interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and TNF-ß (P < 0.05). PDR was associated with lower vitreous interferon-γ and IL-10 and higher VEGF, IL-6, and IL-15 (P < 0.05), but was not associated with their plasma concentrations. CONCLUSIONS: Higher vitreous RBP3 concentrations are associated with less severe DR and slower rates of progression to PDR, supporting its potential as a biomarker and therapeutic agent for preventing DR worsening, possibly by lowering retinal VEGF and inflammatory cytokines.

Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema.

BACKGROUND: In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear. METHODS: At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed. RESULTS: A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group. CONCLUSIONS: In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).

Comparison of Handheld Retinal Imaging with ETDRS 7-Standard Field Photography for Diabetic Retinopathy and Diabetic Macular Edema.

PURPOSE: To compare nonmydriatic (NM) and mydriatic (MD) handheld retinal imaging with standard ETDRS 7-field color fundus photography (ETDRS photographs) for the assessment of diabetic retinopathy (DR) and diabetic macular edema (DME). DESIGN: Prospective, comparative, instrument validation study. SUBJECTS: A total of 225 eyes from 116 patients with diabetes mellitus. METHODS: Following a standardized protocol, NM and MD images were acquired using handheld retinal cameras (NM images: Aurora, Smartscope, and RetinaVue-700; MD images: Aurora, Smartscope, RetinaVue-700, and iNview) and dilated ETDRS photographs. Grading was performed at a centralized reading center using the International Clinical Classification for DR and DME. Kappa statistics (simple [K], weighted [Kw]) assessed the level of agreement for DR and DME. Sensitivity and specificity were calculated for any DR, referable DR (refDR), and vision-threatening DR (vtDR). MAIN OUTCOME MEASURES: Agreement for DR and DME; sensitivity and specificity for any DR, refDR, and vtDR; ungradable rates. RESULTS: Severity by ETDRS photographs: no DR, 33.3%; mild nonproliferative DR, 20.4%; moderate DR, 14.2%; severe DR, 11.6%; proliferative DR, 20.4%; no DME, 68.0%; DME, 9.3%; non-center involving clinically significant DME, 4.9%; center-involving clinically significant DME, 12.4%; and ungradable, 5.3%. For NM handheld retinal imaging, Kw was 0.70 to 0.73 for DR and 0.76 to 0.83 for DME. For MD handheld retinal imaging, Kw was 0.68 to 0.75 for DR and 0.77 to 0.91 for DME. Thresholds for sensitivity (0.80) and specificity (0.95) were met by NM images acquired using Smartscope and MD images acquired using Aurora and RetinaVue-700 cameras for any DR and by MD images acquired using Aurora and RetinaVue-700 cameras for refDR. Thresholds for sensitivity and specificity were met by MD images acquired using Aurora and RetinaVue-700 for DME. Nonmydriatic and MD ungradable rates for DR were 15.1% to 38.3% and 0% to 33.8%, respectively. CONCLUSIONS: Following standardized protocols, NM and MD handheld retinal imaging devices have substantial agreement levels for DR and DME. With mydriasis, not all handheld retinal imaging devices meet standards for sensitivity and specificity in identifying any DR and refDR. None of the handheld devices met the established 95% specificity for vtDR, suggesting that lower referral thresholds should be used if handheld devices must be utilized. When using handheld devices, the ungradable rate is significantly reduced with mydriasis and DME sensitivity thresholds are only achieved following dilation.

ASSESSMENT OF FLUORESCEIN ANGIOGRAPHY NONPERFUSION IN EYES WITH DIABETIC RETINOPATHY USING ULTRAWIDE FIELD RETINAL IMAGING.

PURPOSE: Evaluate association of retinal nonperfusion (NP) on ultrawide field (UWF) fluorescein angiography (FA) with diabetic retinopathy (DR) severity and predominantly peripheral lesions (PPL). METHODS: Multicenter observational study, 652 eyes (361 participants) having nonproliferative DR (NPDR) without center-involved diabetic macular edema in at least one eye. Baseline 200° UWF-color and UWF-FA images were graded by a central reading center for color-PPL and FA-PPL, respectively. UWF-FA was graded for NP index within concentric zones: posterior pole (<10 mm from fovea), midperiphery (10-15 mm), and far periphery (>15 mm). RESULTS: Baseline Early Treatment Diabetic Retinopathy Study DR severity was 31.7% no DR/mild NPDR, 24.1% moderate NPDR, 14.0% moderately severe NPDR, 25.6% severe/very severe NPDR, and 4.6% proliferative DR. Worse DR severity was associated with increased NP index overall (P = 0.002), in the posterior pole (P < 0.001), midperiphery (P < 0.001), and far periphery (P = 0.03). On average, 29.6% of imaged retinal NP was in the posterior pole, 33.7% in midperiphery, and 36.7% in far periphery. Increased NP index was associated with FA-PPL (P < 0.001) but not with color-PPL (P = 0.65). CONCLUSION: Approximately, 70% of NP in diabetic eyes is located outside the posterior pole. Increased NP is associated with the presence of FA-PPL, suggesting UWF-FA may better predict future DR worsening than UWF-color alone.

Association of Maximizing Visible Retinal Area by Manual Eyelid Lifting With Grading of Diabetic Retinopathy Severity and Detection of Predominantly Peripheral Lesions When Using Ultra-Widefield Imaging.

IMPORTANCE: Methods that increase visible retinal area (VRA; measured in millimeters squared) may improve identification of diabetic retinopathy (DR) lesions. OBJECTIVE: To evaluate the association of dilation and manual eyelid lifting (MLL) with VRA on ultra-widefield imaging (UWFI) and the association of VRA with grading of DR severity and detection of predominantly peripheral lesions (PPLs). DESIGN, SETTING, AND PARTICIPANTS: Retrospective, comparative case-control study at the Joslin Diabetes Center, Boston, Massachusetts. Nonmydriatic UWFI with MLL was acquired from a DR teleophthalmology program (Joslin Vision Network [JVN]). A second cohort of mydriatic UWFI was acquired at an academic retina practice (Beetham Eye Institute [BEI]) from November 6, 2017, to November 6, 2018, and with MLL thereafter until November 6, 2019. Fully automated algorithms determined VRA and hemorrhage and/or microaneurysm (HMA) counts. Predominantly peripheral lesions and HMAs were defined as present when at least 1 field had greater HMA number in the peripheral retina than within the corresponding Early Treatment Diabetic Retinopathy Study field. Participants included 3014 consecutive patients (5919 eyes) undergoing retinal imaging at JVN and BEI. EXPOSURES: Dilation and MLL performed at the time of UWFI. MAIN OUTCOMES AND MEASURES: Visible retinal area, DR severity, and presence of PPLs. RESULTS: Of the 3014 participants, mean (SD) age was 56.1 (14.5) years, 1302 (43.2%) were female, 2450 (81.3%) were White, and mean (SD) diabetes duration was 15.9 (11.4) years. All images from 5919 eyes with UWFI were analyzed. Mean (SD) VRA was 665.1 (167.6) mm2 for all eyes (theoretical maximal VRA, 923.9 mm2), 550.8 (240.7) mm2 for nonmydriatic JVN with MLL (1418 eyes [24.0%]), 688.1 (119.9) mm2 for mydriatic BEI images (3650 eyes [61.7%]), and 757.0 (69.7) mm2 for mydriatic and MLL BEI images (851 eyes [14.4%]). Dilation increased VRA by 25% (P < .001) and MLL increased VRA an additional 10% (P < .001). Nonmydriatic MLL increased VRA by 11.0%. With MLL, HMA counts in UWFI fields increased by 41.7% (from 4.8 to 6.8; P < .001). Visible retinal area was moderately associated with increasing PPL-HMA overall and in each cohort (all, r = 0.33; BEI, r = 0.29; JVN, r = 0.36; P < .001). In JVN images, increasing VRA was associated with more PPL-HMA (quartile 1 [Q1], 23.7%; Q2, 45.8%; Q3, 60.6%; and Q4, 69.2%; P < .001). CONCLUSIONS AND RELEVANCE: Using fully automated VRA and HMA detection algorithms, pupillary dilation and eyelid lifting were shown to substantially increase VRA and PLL-HMA detection. Given the importance of HMA and PPL for determining risk of DR progression, these findings emphasize the importance of maximizing VRA for optimal risk assessment in clinical trials and teleophthalmology programs.

It is time for a moonshot to find "Cures" for diabetic retinal disease.

Diabetic retinal disease (DRD), the most common complication of diabetes and a leading cause of blindness in working age individuals, is now understood to be a form of sensory neuropathy or neurovascular degeneration. Current treatments are focused on advanced vision-threatening disease and a single molecular target, vascular endothelial growth factor, has an approved therapy. We trace the evolution of understanding of DRD pathogenesis, identify new approaches to clinical assessment, trials infrastructure and design, and target identification to accelerate selection and evaluation of new therapeutics that will speed development of potentially curative interventions. Critically, the "Restoring Vision Moonshot" framework will address gaps in knowledge to be filled to achieve the goal of restoring sight and preventing vision loss in persons with diabetes.

Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials.

BACKGROUND: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. METHODS: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). FINDINGS: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). INTERPRETATION: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. FUNDING: F Hoffmann-La Roche.

A Randomized Trial of Photobiomodulation Therapy for Center-Involved Diabetic Macular Edema with Good Visual Acuity (Protocol AE).

PURPOSE: To determine if treatment with a photobiomodulation (PBM) device results in greater improvement in central subfield thickness (CST) than placebo in eyes with center-involved diabetic macular edema (CI-DME) and good vision. DESIGN: Phase 2 randomized clinical trial. PARTICIPANTS: Participants had CI-DME and visual acuity (VA) 20/25 or better in the study eye and were recruited from 23 clinical sites in the United States. METHODS: One eye of each participant was randomly assigned 1:1 to a 670-nm light-emitting PBM eye patch or an identical device emitting broad-spectrum white light at low power. Treatment was applied for 90 seconds twice daily for 4 months. MAIN OUTCOME MEASURES: Change in CST on spectral-domain OCT at 4 months. RESULTS: From April 2019 to February 2020, 135 adults were randomly assigned to either PBM (n = 69) or placebo (n = 66); median age was 62 years, 37% were women, and 82% were White. The median device compliance was 92% with PBM and 95% with placebo. OCT CST increased from baseline to 4 months by a mean (SD) of 13 (53) µm in PBM eyes and 15 (57) µm in placebo eyes, with the mean difference (95% confidence interval [CI]) being -2 (-20 to 16) µm (P = 0.84). CI-DME, based on DRCR Retina Network sex- and machine-based thresholds, was present in 61 (90%) PBM eyes and 57 (86%) placebo eyes at 4 months (adjusted odds ratio [95% CI] = 1.30 (0.44-3.83); P = 0.63). VA decreased by a mean (SD) of -0.2 (5.5) letters and -0.6 (4.6) letters in the PBM and placebo groups, respectively (difference [95% CI] = 0.4 (-1.3 to 2.0) letters; P = 0.64). There were 8 adverse events possibly related to the PBM device and 2 adverse events possibly related to the placebo device. None were serious. CONCLUSIONS: PBM as given in this study, although safe and well-tolerated, was not found to be effective for the treatment of CI-DME in eyes with good vision.