Diabetic Retinopathy Severity Scale Research Articles

Automated feature-based grading and progression analysis of diabetic retinopathy

BackgroundIn diabetic retinopathy (DR) screening programmes feature-based grading guidelines are used by human graders. However, recent deep learning approaches have focused on end to end learning, based on labelled data at the whole image level. Most predictions from such software offer a direct grading output without information about the retinal features responsible for the grade. In this work, we demonstrate a feature based retinal image analysis system, which aims to support flexible grading and monitor progression.MethodsThe system was evaluated against images that had been graded according to two different grading systems; The International Clinical Diabetic Retinopathy and Diabetic Macular Oedema Severity Scale and the UK’s National Screening Committee guidelines.ResultsExternal evaluation on large datasets collected from three nations (Kenya, Saudi Arabia and China) was carried out. On a DR referable level, sensitivity did not vary significantly between different DR grading schemes (91.2–94.2.0%) and there were excellent specificity values above 93% in all image sets. More importantly, no cases of severe non-proliferative DR, proliferative DR or DMO were missed.ConclusionsWe demonstrate the potential of an AI feature-based DR grading system that is not constrained to any specific grading scheme.

Real-Time Photographic- and Fluorescein Angiographic-Guided Management of Diabetic Retinopathy: Randomized PRIME Trial Outcomes

To assess the safety and efficacy of as-needed (PRN) intravitreal aflibercept injections (IAI) in managing diabetic retinopathy (DR) guided by the real-time DR severity scale (DRSS) level or panretinal leakage index (PLI) assessment among eyes without diabetic macular edema (DME). Prospective, randomized phase 2 trial (PRIME). A total of 40 eyes with nonproliferative (NPDR) or proliferative DR (PDR) received monthly IAIs until a DRSS improvement of ≥2 steps was achieved and eyes were randomized (1:1) to DRSS-guided or PLI-guided management strategies graded by a central reading center. Main outcome measurements included safety and changes in DRSS and PLI. Through week 52, 95% of eyes achieved a DRSS improvement of ≥2 steps. Following DRSS improvement, 97% of eyes required at least 1 PRN IAI. In eyes requiring PRN IAI and completing week 52, 100% and 59% experienced DRSS worsening (P=.01) in the DRSS- and PLI-guided arms, respectively. Through week 52, mean PLI decreased 18.2% (P=.49) and 54.6% (P <.0001), respectively, in the DRSS- and PLI-guided arms. NPDR versus PDR eyes at baseline achieved a DRSS improvement of ≥2 steps after a mean 4.9 and 3.6 IAIs (P=.03). Two eyes developed a PDR event at week 52 following 5 months of quiescence. The randomized PRIME study analyzed 2 imaging-based biomarkers to guide PRN management with IAI of DR without DME: DRSS level and PLI. Within the context of this study with limitations, most patients required IAI re-treatment every 3-4 months, and deterioration of PLI appeared to precede DRSS level worsening. Finally, these findings reaffirm the fact that close clinical follow-up is important even among eyes that achieve substantial DRSS improvements with apparently quiescent disease.

Non‐invasive structural and metabolic retinal markers of disease activity in non‐proliferative diabetic retinopathy

Metabolic and structural microvascular retinal alterations are essential components in diabetic retinopathy (DR). The present study aimed to measure changes at different stages of non-proliferative DR (NPDR) and to explore interactions of imaging-based metrics. This cross-sectional, cohort study included 139 eyes from 80 diabetic patients. Each patient underwent dilated fundal examinations including colour fundus photography, retinal oximetry and optical coherence tomography angiography (OCTA), analysed by semi-automated and automated software. Diabetic retinopathy (DR) severity was classified according to the International Clinical Diabetic Retinopathy (ICDR) Severity Scale, ranging from no DR to severe NPDR (level 0-3). Retinal metabolism was evaluated by oximetry as retinal arteriolar (raSatO2 ) and venular oxygen saturation (rvSatO2 ), and macular microvascular structure was measured by OCTA as the area of foveal avascular zone (FAZ), vessel density (VD), vessel diameter index (VDI), FAZ circularity and fractal dimension (FD) in the superficial and deep retinal capillary plexus. A trend for increasing rvSatO2 was found with increasing DR severity (51.3%, 53.3%, 54.2%, 59.8%, p=0.02). Increasing severity of DR associated with decreasing FD in the superficial and deep plexus (p<0.001 and p=0.014), and in the superficial plexus decreasing VD (p<0.001), increasing VDI (p=0.003) and decreasing FAZ circularity (p=0.006). A few interactions were identified between raSatO2 , rvSatO2 and VDI, but only in the deep capillary plexus (p<0.01 and p<0.01). Alterations of the venular retinal vascular oxygen saturation and microvascular structural abnormities were found continuously throughout the DR-spectrum. Given the sparse correlations between metabolic and structural abnormalities, it seems that these occur independently in DR.

Clinical spectrum of diabetic retinopathy and its correlation with risk factors

Objectives: To study the clinical spectrum of diabetic retinopathy and its correlation with its risk factors.Material and Methods: A prospective, cross sectional and unmasked study was done in patients of diabetes mellitus presenting in OPD of RIO, PGIMS Rohtak. Total 60 patients were included in the study which were divided into 3 groups each of 20 patients, based on the duration of DM: Group A < 5 years, Group B 6-10 years and Group C > 10 years. Staging of retinopathy was done on the basis of International diabetic retinopathy and diabetic macular edema severity scale. Demographical factors like age and sex were correlated with duration of DM. Various clinical forms of diabetic retinopathy ranging from no apparent DR to severe NPDR to PDR were correlated to different laboratory parameters like degree of hyperglycemia, Hb, lipid profile, blood pressure, renal function tests to ascertain correlation between them.Results: Total prevalence of diabetic retinopathy in our study was 56.66%. Males were at higher risk in comparison to females. In our study, duration of disease was found to be strongly associated with diabetic retinopathy and macular edema. Hyperglycemia as measured by FBS and HbA1c is found to be an important risk factor in diabetic retinopathy. Hypertension, hypertriglyceridemia, deranged RFT and anaemia is statistically associated with diabetic retinopathy and its severity.Conclusion: Diabetic retinopathy is a leading cause of preventable blindness. Therefore early diagnosis, timely screening and control of diabetes mellitus is of utmost importance.

Retrospective exploratory analyses on gender differences in determinants for incidence and progression of diabetic retinopathy in Japanese patients with type 2 diabetes mellitus.

Gender differences in risks for macrovascular complications in type 2 diabetes mellitus (T2DM) have been well established. However, the impact of gender differences on diabetic retinopathy (DR) has not been fully elucidated. We therefore retrospectively explored gender-specific determinants for DR in patients with T2DM in a small sized Japanese cohort in Okinawa. There were 214 patients who were diagnosed as no DR (n = 142) and non-proliferative DR (n = 72) in 2009. During the follow-up of median 7 years, 41/142 of incidence, 26/72 of progression, and 67/214 of incidence and progression were observed, respectively. DR was assessed using the modified international clinical DR severity scales. The risks for incidence, progression as well as incidence and progression of DR were comparable between men and women, respectively. Cox proportional hazard models in multivariate analyses demonstrated that the only common determinant in both men and women for DR was the duration of T2DM. Regarding gender-specific determinants, lower level of serum albumin in men as well as higher HbA1c, lower level of estimated glomerular filtration rate, and lower level of serum uric acid in women were extracted, respectively. Although precise mechanisms for such gender-specific determinants of DR still remain unsolved, the present study would highlight a couple of factors associated with gender-specific determinants for DR in a limited numbers of Japanese cohort. Prospective observational studies on gender-specific determinants of DR in a large scale cohort are warranted to further clarify underlying mechanisms.

Prevalence of diabetic retinopathy in self-reported diabetics among various ethnic groups and associated risk factors in North-East India: A hospital-based study.

Purpose:To describe the prevalence and severity of diabetic retinopathy (DR) among different ethnic groups of North-East India and to study the associated risk factors.Methods:In this hospital based cross sectional study 7,133 individuals among the age group of 20-79 years, attending the OPD, were screened for presence of Diabetes Mellitus (DM) (HbA1c >7% or previously diagnosed). Among them, 780 (10.94%) had diabetes; they were evaluated for presence of any retinopathy (based on fundus photograph and fluorescein angiography), its grade (based on International DR severity scale), and risk factors. DR patients were further grouped into different ethnicities (Assamese, Bengali, minor tribes, and other immigrants).Results:Of the 780 patients with diabetes, 58 patients had type 1 DM and 722 patients had type 2 DM. The overall prevalence of DR was 30.0% with vision-threatening retinopathy and maculopathy being 10.00% and 4.49%, respectively. The prevalence of retinopathy range was the highest in the immigrants’ group (50.00% among type 1 DM and 44.93% among type 2 DM) and lowest in the tribal's groups (16.67% among type 1 DM and 22.35% among type 2 DM). The risk factors showing significant association with DR were longer diabetes duration, older age, family history of diabetes, higher HbA1c level, associated hypertension, hypertriglyceridemia, and pregnancy state (P value <0.05).Conclusion:Every third patient with diabetes had some form of DR with Vision Threatening DR (VTDR) affecting every tenth patient. There was also a wide variation in the prevalence of DR among ethnic groups and this difference could not be attributed to variation in the known measurable risk factors among different ethnic groups, thus signifying the role of ethnicity in occurrence and severity of DR.

Severity of diabetic retinopathy and its relationship with age at onset of diabetes mellitus in India: A multicentric study.

Purpose:To present clinical profile and risk factors of sight-threatening diabetic retinopathy (STDR) among people with age of onset of diabetes (AOD) <25 versus ≥25 years.Methods:A retrospective chart analysis of consecutive patients with diabetic retinopathy (DR) n = 654) treated at 14 eye care centers across India between 2018 and 2019 was performed. Patients were divided into two groups, Group 1: AOD <25 years and Group 2: AOD ≥25 years. DR and diabetic macular edema (DME) were classified using the International Clinical Classification of DR severity scale. STDR included severe nonproliferative DR (NPDR), proliferative DR (PDR), and moderate to severe DME. A multilevel mixed-effects model was used for comparison between two groups: 1) Patients with DR and AOD <25 years and 2) Patients with DR and AOD ≥25 years. Bivariate and multivariate regression analyses were used to evaluate risk factors between the two groups.Results:A total of 654 patients were included, 161 (307 eyes) in AOD <25 and 493 (927 eyes) in AOD >25 group. There was a higher prevalence of PDR with high-risk characteristics in AOD <25 group (24% vs. 12%) at baseline and 12-month follow-up (25% vs. 6%); P < 0.001. Systolic hypertension and poor glycemic control were risk factors in both groups, with no difference in these modifiable risk factors between groups.Conclusion:People with youth-onset DM are likely to present with severer form of STDR despite similar modifiable risk factors. Therefore, strict control of systolic blood pressure, glycemic status, and regular screening for DR are recommended to reduce the risk of STDR irrespective of the age of onset of diabetes.

Sensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale.

BackgroundThe Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (DRSS) is a standard approach to measure diabetic retinopathy (DR) severity. Many clinical trials evaluating drug intervention for DR rely upon demonstration of a therapeutic effect through measurement of a 2- or 3-step improvement or progression on the DRSS; however, these binary endpoints require a relatively large sample size for a reliable estimate of therapeutic efficacy, especially when the SOC (eg, anti-VEGF) is used as a control. This study was designed to evaluate the sensitivity and statistical efficiency of detecting a drug effect in DR across different DRSS endpoints, and present alternative analytical approaches to enable smaller-size DR trials for detecting a reliable efficacy signal before moving into larger confirmatory DR trials.MethodsData from two randomized, double-blinded, controlled Phase III trials, that enrolled patients with decreased vision due to center-involved DME and the presence of macular edema documented on optical coherence tomography and simulated data, were used for this study. Changes in DRSS steps during a 3-month period from patients (n=205) with no active intervention were used to confirm the reliability of DRSS outcomes. A simulation study compared sensitivity and statistical efficiency across different DRSS endpoints.ResultsThe standard deviation of step change between baseline and month 3 DRSS across different steps at baseline were all within 1 step, confirming the reliability of DRSS measure by each step. Efficiency of detecting reliable therapeutic efficacy was augmented when treatment effect in improvement and progression was evaluated together; highest sensitivity was observed when change in DRSS steps was used directly as an endpoint.ConclusionDRSS step change may provide more robust sensitivity and statistical efficiency. It is therefore a more cost-effective endpoint for the detection of therapeutic efficacy signal in drug discoveries in DR.

Two-year outcomes of the treat-and-extend regimen using aflibercept for treating diabetic macular oedema

This study was performed to investigate the efficacy of the treat-and-extend regimen using aflibercept for treating diabetic macular oedema (DME). This prospective, multicentre, interventional, single-arm, 104-week clinical trial included 48 patients with DME visual impairment. The patients’ eyes received five consecutive intravitreal injections (2 mg aflibercept) every four weeks with two-week adjustments based on central subfield macular thickness (CSMT) changes. Injections were deferred when CSMT was stable. The number of injections, best-corrected visual acuity (BCVA), CSMT, and diabetic retinopathy severity scale scores were analysed. Compared to baseline, BCVA improved by + 9.1 letters at 52 weeks and was maintained with + 9.4-letter gain at 104 weeks (P < 0.001). Between baseline and 104 weeks, CSMT decreased from 489 to 298 μm (P < 0.001) and eyes with vision ≥ 20/40 increased from 17.4 to 43.5% (P = 0.007). The mean number of injections decreased from 8.5 in year one to 3.9 in year two. The injection interval was extended to ≥ 12 weeks in 56.5% of patients. The treat-and-extend regimen of aflibercept in DME showed 2-year efficacy comparable to that of fixed dosing regimens. The flexible dosing of this regimen reduced the number of injections in year two while maintaining efficacy.

Intensive treat-to-target statin therapy and severity of diabetic retinopathy complicated by hypercholesterolaemia.

To compare the effects of intensive and standard statin therapy on severity of diabetic retinopathy (DR) complicated by hypercholesterolaemia in a prespecified substudy of the standard vs. intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study. Among 5144 patients in the multicentre, prospective, randomized EMPATHY study, this substudy considered 157 patients with seven-field fundus photographs of sufficient quality taken during study enrolment and at the 3-year visit. Eighty-five and seventy-two patients received intensive and standard statin treatments, respectively, in a treat-to-target manner. The primary endpoint was a two-step change in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR severity scale at 36 months. Surrogate markers included changes in hard exudates, changes in visual acuity, and additional ocular treatments during study follow-up. Intensive and standard treatment groups did not differ significantly in terms of changing two or more steps on the DR severity scale (P = 0.4380). In patients with severe DR, defined as ≥47 on the severity scale, exploratory analysis showed more frequent improvement of DR, by at least one step, with intensive vs. standard treatment (83.3% vs. 40.0%; P = 0.0346). The intensive and standard groups did not differ in changes on the hard exudates severity scale (P = 0.3460), logarithm of minimum angle of resolution visual acuity (P = 0.5500), or additional ocular treatment during follow-up. Intensive and standard statin treatment may have similar effects on DR in the population of all patients with DR and hypercholesterolaemia, but intensive therapy may be more beneficial in patients with severe DR.

Comparison of 2-Year Outcomes between Intravitreal Ranibizumab and Intravitreal Aflibercept for Diabetic Macular Edema with "Treat-and-Extend" Regimen-Its Usefulness and Problems.

Background: To compare the effectiveness of intravitreal ranibizumab (IVR) and intravitreal aflibercept (IVA) performed with the treat-and-extend (TAE) regimen on eyes with diabetic macular edema (DME). Patients and methods: This is a retrospective study of 125 eyes of 125 treatment-naïve DME patients who received anti-VEGF injections at three consecutive monthly intervals as the loading phase. The changes in the best-corrected visual acuity (BCVA), central retinal thickness (CRT), diabetic retinopathy severity scale (DRSS), and total injection numbers were compared between the two anti-VEGF agents. Results: Among 125 eyes, 26 eyes completed the treatment with the TAE regimen for 24 months (20.8%). Thirteen eyes of 13 patients (mean age, 70.9 ± 6.0 years) received intravitreal injections of 0.5 mg ranibizumab, and 13 eyes of 13 patients (65.9 ± 8.6 years) received 2 mg aflibercept. No significant differences were detected in the baseline demographics. At 24 months, BCVA was significantly improved in both groups; from 0.31 ± 0.19 to 0.10 ± 0.12 logMAR units for IVR and 0.41 ± 0.19 to 0.16 ± 0.28 logMAR units for IVA (p = 1.29 × 10−9). CRT was significantly reduced in both groups; 440.9 ± 69.3 to 307.5 ± 66.4 μm for IVR and 473.9 ± 71.5 to 317.8 ± 71.2 μm for IVA (p = 3.55 × 10−9). No significant differences were detected in the improvements of BCVA, CRT in both groups, and the total injection numbers for 24 months (11.0 ± 1.2 for the IVA group and 12.0 ± 1.0 the IVR group). DRSS was significantly improved in both groups (p = 0.0004 for IVR and p = 0.009 for IVA). Conclusion: No significant differences were detected in the improvements of BCVA or CRT and injection numbers between the IVR and IVA groups treated with the TAE regimen. These results indicate that the results of the treatment with both agents with the TAE regimen were equally effective, but only 20.8% of patients completed 24 months of continuous treatment with the TAE regimen. Synopsis: There are no significant differences regarding effectiveness between the IVR and IVA groups treated with the TAE regimen for DME eyes.

Effect of Aflibercept on Diabetic Retinopathy Severity and Visual Function in the RECOVERY Study for Proliferative Diabetic Retinopathy

To evaluate the effect of intravitreal aflibercept on diabetic retinopathy (DR) severity and visual function in patients with proliferative DR (PDR) without diabetic macular edema (DME). Prospective, longitudinal, multicenter clinical trial. Forty eyes of 40 patients with PDR and no DME were enrolled in this study. Patients were randomized into monthly and quarterly 2-mg aflibercept injection cohorts and were treated over a period of 12 months. All patients underwent ultra-widefield fundus imaging including pseudocolor and fluorescein angiography using an Optos 200Tx device. Severity of DR at baseline, month 6, and month 12 was evaluated using the DR severity scale (DRSS). The DRSS scores were correlated with the 25-item Visual Function Questionnaire (VFQ-25) and 39-item Visual Function Questionnaire (VFQ-39) scores at baseline and month12. Mean age of the patients was 48.2 years (range, 25-75 years), mean duration of diabetes mellitus was 16.1 years (range, 2-36 years), and median glycated hemoglobin level was 8.8% (IQR, 7.4%-10%). Both monthly and quarterly groups demonstrated a statistically significant regression in DRSS from baseline to month 12 (P < 0.001). The monthly group demonstrated a statistically significant greater regression of DRSS score at the month 6 visit compared with the quarterly group (P= 0.019). However, the difference between the two groups became statistically insignificant at month 12 visit (P= 0.309). Also no difference was found in mean VFQ-25 and VFQ-39 composite scores between the monthly and quarterly groups at month 12 (P= 0.947 and P= 0.921, respectively). The improvement in mean VFQ-25 and VFQ-39 composite scores at month 12 was correlated significantly with improvement in DRSS score (r= 0.384 and P= 0.039, and r= 0.361 and P= 0.046, respectively). In this study of eyes with PDR without DME, both monthly and quarterly aflibercept injection groups showed significant improvement in DR severity at month 12 compared with baseline. The improvement in DRSS score was associated with an improvement in VFQ-25 and VFQ-39 composite score.

Ultra-Response to Ranibizumab: Improvement by 4 or More Steps in Diabetic Retinopathy Severity in Diabetic Retinopathy Clinical Research Network Protocol S

To quantify and evaluate patients with diabetic retinopathy (DR) who had at least a 4-step improvement on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) in response to treatment with ranibizumab in the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S study, and factors predictive of such improvements. Post hoc retrospective analysis of 2-year outcomes in the phase 3 Protocol S study. Patients randomized to treatment with ranibizumab 0.5 mg with sufficient baseline DRSS severity (≥47) to allow for an at least 4-step improvement (n= 181). Study eyes received a ranibizumab 0.5 mg injection at baseline and every 4 weeks for 12 weeks, with subsequent as-needed injections. Fundus photographs graded at baseline and years 1 and 2 using DRSS were used for this analysis. The data source is DRCR.net, but analyses, content, and conclusions of this report are solely the responsibility of the authors. Proportion of eyes achieving at least a 4-step DRSS improvement (DR ultra-response) at years 1 and 2; treatment course for eyes achieving ultra-response; mean change in best-corrected visual acuity (BCVA) in eyes with and without ultra-response; factors associated with ultra-response (identified by univariate and multivariable analyses). Approximately 30% of ranibizumab-treated eyes achieved DR ultra-response at year 1 (43/148; 29.1%) and year 2 (38/136; 27.9%); 74% of eyes with ultra-response at year 1 maintained their response at year 2. At year 2, patients with DR ultra-response had gained more than 5 additional ETDRS letters compared with those without DR ultra-response. Multivariable analyses identified presence of vitreous hemorrhage at baseline, increasing age, absence of epiretinal membrane, and glycated hemoglobin below 9 as predictive of DR ultra-response. Mean number of injections received was similar for eyes with versus without DR ultra-response to ranibizumab (mean, 7.4 vs. 7.6 in year 1; mean, 4.2 vs. 3.9 in year 2). Approximately 30% of eyes with a DRSS score of at least 47 receiving ranibizumab 0.5 mg per study protocol experienced at least a 4-step DR severity improvement on the DRSS, accompanied by meaningful improvements in BCVA.

Macular and Peripapillary Optical Coherence Tomography Angiography Metrics Predict Progression in Diabetic Retinopathy: A Sub-analysis of TIME-2b Study Data

To identify optical coherence tomography angiography (OCTA)-derived vessel metrics of the macula and optic nerve head (ONH) that predict diabetic retinopathy (DR) disease progression. Secondary analysis of clinical trial data. This was a sub-analysis of prospectively collected data from 73 subjects that participated in the TIME-2b study (Aerpio Pharmaceuticals), a multicenter clinical trial for patients with moderate-to-severe DR treated with AKB-9778 and followed over a 12-month period. Eligible subjects were tested every 3months with color fundus photography, spectral-domain OCT, and slit-lamp biomicroscopy. OCTA of the macula and ONH was obtained for a subset of patients enrolled at participating sites. En face, full-depth retinal projections centered at the macula were analyzed for multiple metrics including foveal avascular zone (FAZ) area and perimeter, nonperfusion area, vessel density (VD), and presence of intraretinal microvascular abnormalities (IRMA). VD of the radial peripapillary capillaries was evaluated in 4 quadrants surrounding the optic disc for ONH images. Progression was defined as a ≥2-step increase in DR severity scale score or development of diabetic macular edema. Over a follow-up period of 12months, 15 of 73 (20.5%) subjects progressed. At pretreatment baseline, larger FAZ area, presence of IRMA, and reduced peripapillary VD in the superior temporal and inferior temporal regions were significantly associated with increased odds of progression. FAZ area and temporal peripapillary VD are predictors of DR progression. OCTA metrics may improve progression risk assessment in DR when compared to established risk factors alone.

326-OR: Faricimab for Diabetic Macular Edema: A Novel Anti–Angiopoietin-2/Anti–Vascular Endothelial Growth Factor Bispecific Antibody in Clinical Trials

In the United States, diabetic retinopathy (DR) and diabetic macular edema (DME) are a leading cause of blindness among working-age adults. The introduction of vascular endothelial growth factor-A (VEGF) inhibitors has improved the management of DME and allowed regression of DR severity. However, DR/DME is a multifactorial disease, and targeting additional pathways holds promise for better outcomes. Angiopoietin-2 (Ang-2) is upregulated in the eyes of patients with diabetes and promotes vascular destabilization and inflammation. Faricimab, a novel bispecific antibody targeting both Ang-2 and VEGF, was evaluated in the BOULEVARD (NCT02699450) phase 2 trial for DME. Patients (N = 168 treatment-naïve [TN]; N = 61 previously anti-VEGF treated) were randomized 1:1:1 to intravitreal ranibizumab 0.3 mg, faricimab 1.5 mg (TN only), or faricimab 6.0 mg, every 4 weeks for 20 weeks followed by 16 weeks of observation. BOULEVARD met its primary outcome: faricimab 6.0 mg achieved greater mean gains (letters) from baseline in best-corrected visual acuity than ranibizumab at week 24 in TN patients (faricimab 6.0 mg, +13.9; faricimab 1.5 mg, +11.7; ranibizumab, +10.3; faricimab 6.0 mg vs. ranibizumab, +3.6; P = 0.03; 80% CI, 1.5, 5.6). The Early Treatment Diabetic Retinopathy Study DR Severity Scale (DRSS) was used to score vascular abnormalities and disease severity on color fundus images. A change of ≥ 2 steps is considered clinically significant. The proportion of TN patients with ≥ 2-step improvement from baseline at week 24 on the DRSS was 38.6%, 27.7%, and 12.2%, respectively. There were no new or unexpected safety outcomes with faricimab. In conclusion, faricimab achieved better vision outcomes versus anti-VEGF monotherapy in TN patients, suggesting Ang-2 is a viable target for DR/DME. Phase 3 trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) for faricimab in DME are ongoing. Disclosure V. Sheth: Consultant; Self; Genentech, Inc. J. Sahni: Employee; Self; Roche Pharma. Stock/Shareholder; Self; Roche Pharma. I. Stoilov: Employee; Self; Genentech, Inc. J.R. Willis: Employee; Self; Genentech, Inc. R. Weikert: Employee; Self; Roche Pharma. Funding F. Hoffmann-La Roche, Ltd.; Genentech, Inc.

Predictors of Early Diabetic Retinopathy Regression with Ranibizumab in the RIDE and RISE Clinical Trials.

PurposeTo investigate the predictors of early diabetic retinopathy (DR) improvement in the RIDE/RISE (NCT00473382/NCT00473330) clinical trials.Patients and MethodsIn RIDE/RISE, adult patients with vision loss due to diabetic macular edema (DME) were randomized to monthly intravitreal ranibizumab 0.3 or 0.5 mg (n=502 total) or sham (n=257). DR severity was graded (using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale). In this post hoc analysis of RIDE/RISE, eyes with baseline DR score ≥35 were evaluated for ≥2-step improvements, and eyes with baseline DR score ≥43 were evaluated for ≥3-step improvements. The characteristics associated with ≥2- or ≥3-step DR improvement at months 3 or 6 were assessed using univariate and/or multivariable analyses.ResultsThe percentage of eyes with a ≥2- or ≥3-step DR improvement was 20.1% and 3.7% at month 3 and 31.2% and 5.8% at month 6. Odds of ≥2-step DR improvement at months 3 or 6 were significantly greater in eyes with moderately severe to severe nonproliferative DR (NPDR) at baseline versus less severe or more severe DR (both P<0.0001). At month 6, odds of ≥2-step DR improvement were significantly greater in eyes with no DME at month 3 (P=0.008). Most patients with ≥3-step DR improvement at months 3 or 6 had proliferative DR (PDR) at baseline (83.3% and 66.7%).ConclusionThe strongest predictors of DR response to ranibizumab at month 6 were baseline DR severity and DME quiescence at month 3. Eyes with the most robust early improvements had moderately severe or severe NPDR or PDR at baseline.

Impact of Systemic Dipeptidyl Peptidase-4 Inhibitor Use in Diabetic Macular Edema

To evaluate impact of baseline systemic dipeptidyl peptidase-4 (DPP-4) inhibitor use in diabetic macular edema (DME). This was a post hoc exploratory analysis of previously completed randomized, controlled clinical trials (VISTA and VIVID) in patients with DME evaluating intravitreal aflibercept injection (IAI) every 4 weeks (2q4) or every 8 weeks (2q8) or macular laser photocoagulation. Overall, a small number of patients (12.2% [n = 35], 9.7% [n = 28], and 15.4% [n = 44]) in the laser control, 2q4, and 2q8 groups reported baseline DPP-4 inhibitor use. There were no differences in changes from baseline in best-corrected visual acuity, central subfield thickness, or rates of 2-or-greater-step improvement in Diabetic Retinopathy Severity Scale score based on DPP-4 inhibitor use within each treatment group. DPP-4 inhibitor use at baseline did not influence the magnitude of visual and anatomic benefit in patients with DME being treated with IAI or laser. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:226-234.].

Functional correlation between choroidal and retinal vascularity in low-grade diabetic retinopathy.

To perform an automated functional assessment of retinal and choroidal microvasculature in eyes with low-grade diabetic retinopathy (DR) using optical coherence tomography angiography (OCT-A) and to identify potential perfusion changes in case of early vascular damage. This is an observational, case-control study of consecutive diabetic patients with level 20 DR severity scale score and age-matched healthy subjects. A prototypal OCT-angiography was used to obtain the OCT-angiograms of the superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris (CC) layer. A validated automated microstructural analysis provided data on SCP, DCP and CC vascular perfusion density (VPD). A comparative assessment between different vascular layers and different groups was performed. Twenty-nine diabetic patients (7 females, 24%) and 20 healthy controls were enrolled. VPD values were significantly lower in the DCP (25.1% vs. 26.5%; p = 0.04) and CC (71.2% vs. 86.6%; p = 0.0001) of diabetic patients compared with controls. A statistically significant negative linear correlation was reported between CC VPD and DCP VPD in diabetic patients; at the reverse, a positive linear correlation between the same parameters was noticed in controls. Retinal and choroidal vascular networks, although distinct entities, seem functionally interconnected: varying the degree of perfusion may be a mutual compensatory mechanism in response to an ischemic injury.

Characterization of Disease Progression in the Initial Stages of Retinopathy in Type 2 Diabetes: A 2-Year Longitudinal Study.

PurposeTo characterize 2-year changes occurring in neurodegeneration, edema, and capillary dropout in nonproliferative diabetic retinopathy.MethodsTwo-year prospective longitudinal observational cohort of eyes/patients with type 2 diabetes using spectral domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCTA). Eyes were examined three times with intervals of 1 year. Thickness of the full retina and layer-by-layer measurements were used to identify edema or neurodegeneration. OCTA vessel density maps of the retina were used to identify capillary dropout. Early Treatment Diabetic Retinopathy Study (ETDRS) classification was performed using the seven-field ETDRS protocol.ResultsA total of 62 eyes from 62 patients with diabetes were followed for 2 years. After verification for image quality, a total of 44 eyes from 44 patients (30% women) aged 52 to 80 years were retained for data analysis. There were 18 eyes with ETDRS grades 10 to 20, 17 eyes with ETDRS grade 35, and 9 eyes with ETDRS grades 43 to 47. During the 2-year follow-up period, there was a progressive increase in capillary dropout, whereas edema and neurodegeneration remained stable. In multivariate analysis, considering a model adjusted for age, sex, hemoglobin A1C, visual acuity, and diabetes duration, vessel density remained significantly different between Diabetic Retinopathy Severity Scale groups (Wilks’ λ = 0.707; P = 0.015) showing association with disease progression.ConclusionsCapillary dropout increased in a period of 2 years in eyes with minimal, mild, and moderate diabetic retinopathy, whereas the presence of edema and neurodegeneration remained stable.

Profile of non-responder and late responder patients treated for diabetic macular edema: systemic and ocular factors.

Diabetic macular edema (DME) treatment represents a challenge for the ophthalmologists, and several aspects of real treatment expectancy are still being discussed and not yet fully elucidated. A univocal definition of responsiveness to treatment has not been reached. How the clinicians can evaluate the therapeutic success? The evaluation of systemic and ocular factors should help in this complex management. The age influences the long-term outcomes, and the role of glycemic control is confounded by contrasting correlations between hemoglobin glycated A1c and DME. Long-term treatment success is influenced by baseline best-corrected visual acuity (BCVA), central macular thickness (CMT) and early BCVA response. Also baseline diabetic retinopathy severity scale score is useful to evaluate the chances of improvement before and during treatments. The time-switching was influenced by early BCVA response, however considering a delayed response in a percentage of patients. Several structural optical coherence tomography (OCT) findings could predict long-term success, as the presence of serous retinal detachment, hyperreflective retinal spots, the disruption of external limiting membrane and ellipsoid zone, the disorganization of inner retinal layers and continued increase in CMT were considered predictors of poor response to treatment. Foveal avascular zone enlargement, high number of microaneurysms (Mas), lower vessel density (VD) in deep capillary plexus and lower parafoveal VD in superficial capillary plexus were considered as OCT angiography biomarkers of poor responsiveness. The aim of this review is to report the factors that could influence the response to treatment of DME patients.