Center-involved Diabetic Macular Edema Research Articles

Characterisation of progression of macular oedema in the initial stages of diabetic retinopathy: a 3-year longitudinal study

Background/objectivesTo characterise the prevalence and three-year progression of centre-involving diabetic macular oedema (CI-DMO) in minimal to moderate non-proliferative diabetic retinopathy, using optical coherence tomography (OCT) and measurements of retinal fluid using tissue optical reflectivity ratios (OCT-Leakage).Methods/methodsSeventy-four eyes from 74 patients were followed in a 3-year prospective longitudinal observational cohort of type 2 diabetes (T2D) patients using spectral-domain optical coherence tomography (SD-OCT), OCT-Angiography (OCT-A) and OCT-Leakage (OCT-L). Eyes were examined four times with 1-year intervals. Sixteen eyes (17.8%) were excluded from the analysis due to quality control standards. Retinal oedema was measured by central retinal thickness and retinal fluid by using optical reflectivity ratios obtained with the OCT-L algorithm. Vessel density was measured by OCT-A. Thinning of the ganglion cell and inner plexiform layers (GCL + IPL) was examined to identify retinal neurodegenerative changes. Diabetic retinopathy ETDRS classification was performed using the seven-field ETDRS protocol.ResultsCI-DMO was identified in the first visit in 9% of eyes in ETDRS groups 10–20, 10% of eyes in ETDRS group 35 and 15% of eyes in ETDRS groups 43–47. The eyes with CI-DMO and subclinical CI-DMO showed a progressive increase in retinal extracellular fluid during the 3-year period of follow-up. The eyes with CI-DMO and increased retinal extracellular fluid accumulation were associated with vision loss.ConclusionsThe prevalence of subclinical CI-DMO and CI-DMO in the initial stages of NPDR occurs independently of severity grading of the retinopathy, showing progressive increase in retinal extracellular fluid and this increase is associated with vision loss (82% 9 out of 11 cases).

One-year outcomes of the treat-and-extend regimen using aflibercept for the treatment of diabetic macular edema.

Optimal regimen using intravitreal aflibercept injections for diabetic macular edema (DME) in clinical practice remains to be elucidated. The purpose of this study is to evaluate a treat-and-extend (TAE) approach using intravitreal aflibercept in participants with center-involved DME. A 52-week open-label, prospective, multicenter, interventional study was conducted between August 2015 and November 2017 in Taiwan. Adults with diabetes mellitus and center-involved DME who have best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study letters and central retinal thickness (CRT) >300 μm were included. Participants received five monthly loading doses of 2 mg intravitreal aflibercept, followed by a TAE regimen with a four-week increment/decrement interval over 48 weeks; the maximum interval was 12 weeks. Main outcomes included changes in BCVA and CRT from baseline to week 52, additional anatomical outcomes, and treatment burden parameters. Forty-five participants with mean (SD) age of 63.7 (8.3) years were analyzed. At baseline, mean (SD) BCVA and CRT were 58.3 (11.9) letters and 434.4 (116.8) μm, respectively. Changes from baseline in BCVA and CRT were +8.3 (9.3) letters and -138.2 (150.0) μm (both p < 0.001) at week 52, respectively. In addition, 22% (10/45) of patients gained ≥15 letters, 14% (6/44) of participants achieved ≥2-level improvement in diabetic retinopathy severity, and 51% (23/45) demonstrated dry retina at week 52 compared with 13% (6/45) at baseline. In total, 87% (39/45) of patients reached disease stability, entering TAE at week 20. Subsequently, 89% (40/45) of patients reached maximum interval at week 52. Mean (SD) number of injections was 7.7 (1.5) over a period of 52 weeks. This straightforward and practical TAE regimen using intravitreal aflibercept injections resulted in favorable clinical outcomes with minimal treatment burden for DME at week 52.

YOSEMITE and RHINE: Phase 3 Randomized Clinical Trials of Faricimab for Diabetic Macular Edema: Study Design and Rationale.

PurposeFaricimab is a novel anti–angiopoietin-2 and anti–vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME.DesignTwo identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE).ParticipantsAdults with center-involving DME secondary to type 1 or 2 diabetes mellitus.MethodsThese studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden.Main Outcome MeasuresWe describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab.ResultsYOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately.ConclusionsYOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME.

OCT-based biomarkers for predicting treatment response in eyes with centre-involved diabetic macular oedema treated with anti-VEGF injections: a real-life retina clinic-based study

Background/aimsTo determine whether a combination of baseline and change in spectral domain-optical coherence tomography (SD-OCT)-based biomarkers can predict visual outcomes in eyes with diabetic macular oedema (DMO) treated with antivascular...

Contrast Sensitivity Changes in Center Involving Diabetic Macular Edema Treated with Aflibercept.

PurposeTo characterize the changes in contrast sensitivity (CS) and retinal anatomy in patients with center involving diabetic macular edema (CDME) measured from baseline to post-loading doses of aflibercept.Patients and MethodsThis single center, prospective, open-label, non-controlled evaluation of five aflibercept intravitreal injections for treatment of CDME over a 16-week period. One eye in each of the forty patients will receive aflibercept every 4 weeks. Subject testing includes measurements of central retinal thickness (CRT), best corrected visual acuity (BCVA), Pelli–Robson (PR) CS, and CamBlobs (CB) CS at 20 weeks post baseline.ResultsA total of 40 eyes from 40 patients with CDME were analyzed. The mean age was 62.9 ±10.6 years and 55% were male. At baseline, CRT was 365 ±94.6µm with logMAR BCVA 0.25±0.20. CS PR at baseline was 1.46±0.13 logCS compared to the normal population 1.79±0.10 logCS (P=<0.01), and the CS CB was 1.55±0.16 logCS compared to 1.92±0.08 logCS in the normal population (P=<0.01). At the completion of the study, CRT was decreased to 289 ±43.7µm (P=<0.001), and the logMAR BCVA improved to 0.18±0.02 (P=<0.05). At the same point the CS PR was 1.52±0.16 and CS CB was 1.62±0.16 logCS. At the end of the study 85% of eyes obtained BCVA of 0.3 logMAR or better. There was a reduction from baseline of 82.5% to 57.5% in the number of patients that had a CS that was two standard deviations below the mean. The greatest improvement in CS was associated with those patients that had the greatest reduction in CRT.ConclusionCS impairment in patients with CDME is significant. Although treatment can be associated with improvement, there still remains a group with decreased CS that could impact activities of daily living. Earlier intervention using reduction in CS as a metric may be associated with reduced residual deficit associated with treatment.

Comparison of the 1-Year Visual and Anatomical Outcomes between Subthreshold Red (670 nm) and Yellow (577 nm) Micro-Pulse Laser Treatment for Diabetic Macular Edema

We investigated the efficacy and safety of red (670 nm) subthreshold micropulse laser (SMPL) treatment for diabetic macular edema (DME) and compared the 1-year treatment outcomes of red and yellow (577 nm) SMPL for DME. A medical chart review was performed in 43 consecutive eyes of 35 patients who underwent red or yellow SMPL treatment for DME and were followed up for 12 months. There were 26 and 17 eyes in the yellow and red SMPL groups, respectively. The mean best-corrected visual acuity (BCVA) was maintained throughout the follow-up period of 12 months in the yellow and red SMPL groups (p = 0.39, p = 0.70, respectively). The central retinal thickness (CRT) measured by spectral-domain optical coherence tomography (SD-OCT) was significantly decreased at 12 months from baseline in the yellow and red SMPL groups (p = 0.047, p = 0.03, respectively). Although the amount of CRT reduction in the red SMPL group was significantly greater than that in the yellow SMPL group at 8 months from baseline (p = 0.02), the significance disappeared at the final follow-up period (p = 0.44). The red SMPL maintained the BCVA in patients with center-involving DME. The mean CRT in the red SMPL group significantly decreased, and the amount of CRT reduction was equivalent to that in the yellow SMPL group.

Temporal variation of optical coherence tomography biomarkers as predictors of anti-VEGF treatment outcomes in diabetic macular edema.

To report a longitudinal analysis of specific optical coherence tomography (OCT) features in eyes with diabetic macular edema (DME) treated with anti-VEGF. A total of 133 eyes of 103 consecutive patients with center-involving DME were included in the study. The eyes were treated between August 2008 and April 2019 with three monthly intravitreal anti-VEGF injections, either with or without prompt or deferred laser, followed by pro re nata (PRN) re-treatment. The following OCT biomarkers were evaluated: subfoveal neuroretinal detachment (SND) (defined as present (SND+) or absent (SND-)), hyperreflective retinal foci (HRF) number (defined as: absent/few(HRF-) or moderate/many (HRF+)), external limiting membrane (ELM) integrity, central macular thickness (CMT), and central retinal thickness (CRT). Changes in SND status and in the number of HRF were evaluated at each DME recurrence throughout the follow-up(FU) period. Mutual correlation among OCT biomarkers and their relationship with visual and anatomic outcomes were assessed both at baseline and over the FU period. The mean FU was 71.2 months (SD 28.4; min. 12-max. 111). At baseline, the prevalence of SRD+ was 27.8% and a high number of HRF were detected in 41.4% of the eyes. A significant reduction in the number of HRF, CMT, CRT, and in the prevalence of SND was recorded in the post-loading phase (p-value <0.0001). In DME recurrences, the presence of SND+ and HRF+ was significantly more frequent in eyes with baseline SND+ and HRF+ compared to eyes presenting baseline SND- and HRF- (p-value <0.0001). No role of SND (p-value: 0.926) and HRF (p-value: 0.281) as baseline predictors of visual and anatomic outcomes was demonstrated, while a worse visual outcome was significantly correlated with a higher incidence of relapsing SND+ (p-value <0.0001) and HRF+ (p-value <0.0028) throughout the FU period. In this study, SND and HRF were frequently present in DME recurrences with the same pattern exhibited at baseline, suggesting that these OCT biomarkers may characterize a specific pattern of DME that repeats over time. Moreover, the results suggested that the persistence and recurrence of SND and HRF may account for a decrease in visual function more than the baseline prevalence of these biomarkers. Further studies are required to confirm these findings.

Factors affecting the response to subthreshold micropulse laser therapy used in center-involved diabetic macular edema.

The purpose of this study was to investigate the effect of the status of retinal pigment epithelium (RPE) and HbA1c levels on the efficacy of the subthreshold micropulse laser (SMPL) in the treatment of center-involving diabetic macular edema (DME). A total of 20 eyes of 20 patients (mean age 57.9 ± 9.7years) who were diagnosed with center-involving DME and treated with SMPL for refusing intravitreal injection and 20 eyes of 20 age- and sex-matched healthy participants were enrolled. All patients were followed up in the 1st and 3rd months after SMPL. For measurement of RPE area central 1000 microns, macular EDI-OCT scans were binarized by using the public domain software ImageJ, with a semi-automated technique. There was a significant increase in BCVA values and a significant decrease in CMT values during follow-up. The area of RPE before SMPL was significantly thinner in the patient group (p: 0.004). When the areas of RPE before and 3months after SMPL were compared, no significant change was observed (p: 0.437). When the relationship between pre-treatment area of RPE and HbA1c was examined, an inverse correlation was observed (p: 0.018). The patients were evaluated by dividing them into 2 groups as 2nd session SMPL required and not required, and the area of RPE was smaller in the group requiring 2nd session SMPL (p: 0.030). The status of central RPE may be a determining factor on the response to treatment. Additionally, HbA1c levels may have an impact on treatment efficacy.

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

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. Phase 2 randomized clinical trial. 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. 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. Change in CST on spectral-domain OCT at 4 months. 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. 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.

NATURAL HISTORY AND PREDICTORS OF VISION LOSS IN EYES WITH DIABETIC MACULAR EDEMA AND GOOD INITIAL VISUAL ACUITY.

To identify clinical and anatomic factor-associated vision loss in eyes with treatment-naïve diabetic macular edema and good initial visual acuity. Retrospective cohort study after long-term history of eyes with untreated center-involving diabetic macular edema and baseline visual acuity ≥ 20/25 seen at the University of California, Davis Eye Center between March 2007 and March 2018. We collected characteristics including diabetes type, hemoglobin A1c, presence of visual symptoms, visual acuity, and diabetic retinopathy severity; and spectral-domain optical coherence tomography biomarkers including central subfield thickness, intraretinal cyst size, intraretinal hyperreflective foci, disorganization of retinal inner layers, and outer layer disruptions to determine factors associated with vision loss as defined by DRCR Protocol V as threshold for initiating aflibercept therapy. Fifty-six eyes (48 patients) with untreated diabetic macular edema and mean baseline visual acuity of logMAR 0.05 ± 0.05 (Snellen 20/22) were followed for an average of 5.1 ± 3.3 years, with a median time to vision loss of 465 days (15 months). Older age (hazard ratio [HR] 1.04/year, P = 0.0195) and eyes with severe NPDR (HR 3.0, P = 0.0353) or proliferative diabetic retinopathy (HR 7.7, P = 0.0008) had a higher risk of a vision loss event. None of the spectral-domain optical coherence tomography biomarkers were associated with vision loss except central subfield thickness (HR 0.98, P = 0.0470) and cyst diameter (HR 1.0, P = 0.0094). In eyes with diabetic macular edema and good initial vision, those with older age and worse diabetic retinopathy severity should be monitored closely for prompt treatment initiation when vision loss occurs.

A Cost-Effectiveness Analysis of Intravitreal Aflibercept for the Prevention of Progressive Diabetic Retinopathy

To calculate costs required to prevent center-involved diabetic macular edema (CI-DME) or proliferative diabetic retinopathy (PDR), and to improve the diabetic retinopathy severity score (DRSS) with intravitreal anti-VEGF injections, as reported for aflibercept in 2 randomized control trials. Cost-effectiveness analysis modeling based on published data. None. Results from PANORAMA and the Diabetic Retinopathy Clinical Research Network Protocol W were analyzed. Parameters collected included DRSS, risk reduction of PDR, risk reduction of CI-DME, and the number of treatments required. Costs were modeled based on 2020 Medicare reimbursement data practice settings of hospital-based facility and nonfacility. Cost to prevent cases of PDR and CI-DME and to improve DRSS stage. Over 2 years in Protocol W, the cost required to prevent 1 case of PDR was $83 000 ($72 400) in the facility (nonfacility) setting; in PANORAMA, the corresponding 2-year costs were $89 400 ($75 000) for the 2-mg aflibercept every 16 weeks (2Q16) arm, and $91 200 ($89 900) for the 2-mg aflibercept every 8 weeks as needed (2Q8PRN) arm. To prevent 1 case of CI-DME with vision loss in Protocol W, the cost was $154 000 ($133 000). For all CI-DME, with and without vision loss, in PANORAMA, the costs to prevent a case were $70 900 ($59 500) for the 2Q16 arm and $90 000 ($88 800) for the 2Q8PRN arm. In Protocol W, the overall accumulated total for cost/DRSS unit change at the 2-year point for facility (nonfacility) setting was $2700 ($2400)/DRSS. In the first year alone, it was $2100 ($1800)/DRSS and in the second year, it was $6100 ($5300)/DRSS. There is a considerable cost associated with the prevention of PDR and CI-DME with intravitreal aflibercept injections. A price per unit of change in DRSS is a new parameter that might serve as a benchmark in future utility analyses that could be used to bring the perspective to cost-utility considerations.

Comparison of Intravitreal Dexamethasone Implant and Ranibizumab in Vitrectomized Eyes with Diabetic Macular Edema.

Purpose This retrospective study aimed to compare the efficacy of intravitreal ranibizumab (IVR) and intravitreal dexamethasone implant (IDI) for pseudophakic vitrectomized eyes with diabetic macular edema (DME) in a single institution. Methods Pseudophakic vitrectomized eyes with treatment-naïve center-involved DME were enrolled, with one eye in each patient. They were divided into two groups: one group receiving IDI every 3 to 4 months and another group receiving IVR using 3 monthly plus treat-and-extend injections, all with monthly follow-up for 6 months. Switch of intravitreal drugs or deferred macular laser was not allowed. Primary outcome measures included change in central foveal thickness (CFT) in 1 mm by spectral-domain optical coherence tomography and best-corrected visual acuity (BCVA) at Month 6. Results Twenty-two eyes were included in the IDI group and 26 eyes in the IVR group. The baseline demographics, glycosylated hemoglobin level, intraocular pressure (IOP), BCVA, and CFT did not significantly differ (p > 0.05). Compared to baseline data, CFT decreased and BCVA improved significantly after either IDI or IVR at Month 6 (p < 0.05). Significantly better mean final BCVA (0.38 logMAR vs. 0.62 logMAR, p=0.04), more mean visual gain (−0.30 logMAR vs. −0.15 logMAR, p=0.02), lower mean final CFT (310.9 μm vs. 384.2 μm, p=0.04), and larger mean CFT decrease (−150.0 μm vs. −60.1 μm, p=0.03) were found in the IDI group compared to those in the IVR group. A smaller mean treatment number (2.6 vs. 5.6, p < 0.001) and higher rate of postinjection ocular hypertension requiring topical hypotensive agent therapy (27.3% vs. 0%, p=0.0002) were demonstrated in the IDI group than those in the IVR group. Conclusion We concluded that IDI and IVR can both effectively treat vitrectomized eyes with DME. Dexamethasone implants had significantly better visual/anatomical improvement, smaller treatment number, and higher rate of elevated IOP after injection than IVR in pseudophakic vitrectomized eyes with DME in a 6-month period.

A Multitask Deep-Learning System to Classify Diabetic Macular Edema for Different Optical Coherence Tomography Devices: A Multicenter Analysis.

Diabetic macular edema (DME) is the primary cause of vision loss among individuals with diabetes mellitus (DM). We developed, validated, and tested a deep learning (DL) system for classifying DME using images from three common commercially available optical coherence tomography (OCT) devices. We trained and validated two versions of a multitask convolution neural network (CNN) to classify DME (center-involved DME [CI-DME], non-CI-DME, or absence of DME) using three-dimensional (3D) volume scans and 2D B-scans, respectively. For both 3D and 2D CNNs, we used the residual network (ResNet) as the backbone. For the 3D CNN, we used a 3D version of ResNet-34 with the last fully connected layer removed as the feature extraction module. A total of 73,746 OCT images were used for training and primary validation. External testing was performed using 26,981 images across seven independent data sets from Singapore, Hong Kong, the U.S., China, and Australia. In classifying the presence or absence of DME, the DL system achieved area under the receiver operating characteristic curves (AUROCs) of 0.937 (95% CI 0.920-0.954), 0.958 (0.930-0.977), and 0.965 (0.948-0.977) for the primary data set obtained from CIRRUS, SPECTRALIS, and Triton OCTs, respectively, in addition to AUROCs >0.906 for the external data sets. For further classification of the CI-DME and non-CI-DME subgroups, the AUROCs were 0.968 (0.940-0.995), 0.951 (0.898-0.982), and 0.975 (0.947-0.991) for the primary data set and >0.894 for the external data sets. We demonstrated excellent performance with a DL system for the automated classification of DME, highlighting its potential as a promising second-line screening tool for patients with DM, which may potentially create a more effective triaging mechanism to eye clinics.

Prevention of vision-threatening complications in diabetic retinopathy: two perspectives based on results from the DRCR Retina Network Protocol W and the Regeneron-sponsored PANORAMA.

The use of intravitreous antivascular endothelial growth factor to prevent center-involved diabetic macular edema (CI-DME) with vision loss and proliferative diabetic retinopathy (PDR) has been investigated and recently reported in two randomized clinical trials. Although both trials showed substantial superiority of aflibercept at preventing the development of vision-threatening complications (VTCs) of CI-DME or PDR compared with sham at 1 or 2 years, without a concomitant benefit in visual acuity outcomes, the interpretation of the results and its application to clinical practice resulted in two disparate opinions. In this review, we discuss these two trials including their similarities and differences, other relevant studies, and considerations regarding the interpretation and the application of these results into clinical practice. The Diabetic Retinopathy Clinical Research Retina Network Protocol W and the PANORAMA study demonstrated significantly lower probabilities of developing CI-DME or PDR at 2 years with intravitreous aflibercept compared with sham in eyes with moderate (Protocol W) or moderately severe (PANORAMA) to severe non-PDR (NPDR). However, visual acuity outcomes were not different. Although intravitreous aflibercept injections reduce the risk of VTCs in eyes with moderate-to-severe NPDR, the absence of visual acuity benefits supports the need for four-year results.

Evaluation of Intravitreal Aflibercept for the Treatment of Severe Nonproliferative Diabetic Retinopathy

Proactive treatment of nonproliferative diabetic retinopathy (NPDR) reduces the risk of progression to vision-threatening complications. To evaluate vascular endothelial growth factor blockade therapy with intravitreal aflibercept injections in eyes with severe NPDR without diabetic macular edema (DME). The Study of the Efficacy and Safety of Intravitreal Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy (PANORAMA) was a double-masked 100-week randomized clinical trial conducted in multiple centers worldwide. The study included 402 adults with Diabetic Retinopathy Severity Scale (DRSS) level 47 or 53 with no DME and best-corrected visual acuity of 20/40 or better. Intravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval (aflibercept 2q16 group); intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56 (aflibercept 2q8/PRN group); or sham injections (control group). Proportions of eyes with a 2-step or greater improvement in DRSS level, vision-threatening complications, and center-involved DME from baseline to weeks 24, 52, and 100. Among 402 participants (1 eye per participant), the mean (SD) age was 55.7 (10.5) years; 225 (56.0%) were male, and 310 (77.1%) were White. A total of 135 were randomized to the aflibercept 2q16 group, 134 to the aflibercept 2q8/PRN group, and 133 to the control group. At 24 weeks, treatment with aflibercept resulted in a 2-step or greater improvement in DRSS level in 157 of 269 eyes (58.4%) in the combined aflibercept groups vs 8 of 133 eyes (6.0%) in the control group (adjusted difference, 52.3%; 95% CI, 45.2%-59.5%; P < .001). At 52 weeks, 88 of 135 eyes (65.2%) in the aflibercept 2q16 group (adjusted difference, 50.1%; 95% CI, 40.1%-60.1%) and 107 of 134 eyes (79.9%) in the aflibercept 2q8/PRN group (adjusted difference, 64.8%; 95% CI, 55.8%-73.9%) compared with 20 of 133 eyes (15.0%) in the control group (P < .001 for both comparisons) showed a 2-step or greater improvement in DRSS level. Fewer eyes treated with aflibercept vs sham injections developed vision-threatening complications and/or center-involved DME through week 100 (22 of 135 eyes [16.3%] in the 2q16 group [adjusted difference, -34.2%; 95% CI, -44.6 to -23.8] and 25 of 134 eyes [18.7%] in the 2q8/PRN group [adjusted difference, -31.7%; 95% CI, -42.5 to -20.9] compared with 67 of 133 eyes [50.4%] in the control group; P < .001 for both comparisons). No new safety signals were identified. In this study, significantly more eyes with moderately severe to severe NPDR that were treated with aflibercept showed a 2-step or greater improvement in DRSS level at 24, 52, and 100 weeks, and significantly fewer eyes treated with aflibercept vs sham developed vision-threatening complications and center-involved DME. Outcomes on the DRSS between year 1 and 2 emphasize the need for ongoing vascular endothelial growth factor suppression and adherence. ClinicalTrials.gov Identifier: NCT02718326.

Phase 1 Study of THR-687, a Novel, Highly Potent Integrin Antagonist for the Treatment of Diabetic Macular Edema

PurposeTo evaluate the safety and preliminary efficacy of THR-687 in patients with center-involved diabetic macular edema (DME).DesignPhase 1, open-label, multicenter, 3 + 3 dose-escalation study with 3-month follow-up.ParticipantsPatients 18 years of age or older with visual impairment resulting from DME.MethodsSingle intravitreal injection of THR-687 (0.4 mg, 1.0 mg, or 2.5 mg).Main Outcome MeasuresThe primary outcome measure was the incidence of dose-limiting toxicities (DLTs). The secondary outcome measure was the incidence of adverse events (AEs), including the occurrence of laboratory abnormalities. Exploratory outcome measures included changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST), assessments of ischemia and leakage on fluorescein angiography, and THR-687 levels in plasma.ResultsTwelve patients were treated: 3 patients received 0.4 mg of THR-687, 3 patients received 1.0 mg of THR-687, and 6 patients received 2.5 mg of THR-687. Most patients were men (9/12 patients). Their mean age was 57.8 years. No DLTs or serious AEs were reported at any of the dose levels tested. Overall, 9 AEs in the study eye were reported for 5 of 12 patients. Of those, 4 AEs in 3 of 12 patients were deemed treatment related by the investigator, all of which were mild, started on the day of the injection, and had resolved within 28 days without treatment. Overall, mean gains from baseline in BCVA were observed at all study visits with a rapid onset (7.2 Early Treatment Diabetic Retinopathy Study [ETDRS] letters at day 7) and a durability up to the end of the study (8.3 ETDRS letters at month 3). A mean decrease in CST was observed up to month 1. Overall, the mean BCVA gains and CST decreases were highest at the highest THR-687 dose level tested. THR-687 was undetectable in plasma at 7 days after the injection.ConclusionsAt all dose levels tested, a single intravitreal injection of THR-687 was safe and well tolerated. Preliminary efficacy was observed by a rapid gain in BCVA with 3 months’ durability and a decrease in CST up to 1 month after the injection.

Evaluation of standard of care intravitreal aflibercept treatment of diabetic macular oedema treatment-naive patients in the UK: DRAKO study 12-month outcomes

ObjectivesDRAKO (NCT02850263) is a 24-month, prospective, non-interventional, multi-centre cohort study which enroled patients diagnosed with centre-involving diabetic macular oedema (DMO). The study aims to evaluate standard of care with intravitreal aflibercept (IVT-AFL) treatment in the UK. This analysis describes the anti-vascular endothelial growth factor (anti-VEGF) treatment-naive patient cohort after 12-month follow-up.MethodsStudy eyes were treated with IVT-AFL as per local standard of care. The mean change in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline at 12 months were measured and stratified by baseline factors. The number of injections and safety data were also evaluated.ResultsA total of 507 patients were enroled from 35 centres. Mean (SD) baseline BCVA was 71.4 (12.0) letters and CST was 448.7 (88.7) µm, with 63.1% of patients presenting with baseline BCVA ≥ 70 letters (mean 78.1). Mean (SD) change in BCVA of 2.5 (12.2) letters and CST of −119.1 (116.4) µm was observed at month 12. A 7.3 letter gain was observed in patients with baseline BCVA < 70 letters. Mean number (SD) of injections in year one was 6.4 (2.1). No significant adverse events were recorded.ConclusionYear one results indicated that IVT-AFL was an effective treatment for DMO in standard of care UK clinical practice, maintaining or improving visual acuity in treatment-naive patients with good baseline visual acuity, despite some patients being undertreated versus the summary of product characteristics. These results also demonstrated the clinical importance and meaningful impact of diabetic retinopathy screening in the UK.

Aflibercept versus Ranibizumab as a Second Line Therapy After Bevacizumab for Diabetic Macular Edema.

PurposeTo compare the visual and anatomic outcomes of aflibercept versus ranibizumab as a second line treatment for persistent diabetic macular edema (DME) after initial bevacizumab injections.MethodsIn this retrospective cohort study, patients with center-involved DME of ≥ 300 μm thickness after bevacizumab intravitreal injections in 2015–2019 were included. Those treated with ranibizumab (R) and aflibercept (A) were grouped as group R and group A, respectively. The change in central macular thickness (CMT) measured by optical coherence tomography (OCT) and the best corrected distance visual acuity (BCVA) before and after three-monthly anti-VEGF injections (anti-VEGF) in group R and group A were compared and reviewed.ResultsThere were 80 eyes of 75 patients in group R and 80 eyes of 72 patients in group A. The initial bevacizumab injections in group R and group A varied significantly (p = 0.01). The median change of the CMT after the three injections was not significantly different in group R (80 μm) and group A (81.5μm) (p = 0.7). The improvement of BCVA in group R and group A was not significant (p = 0.5). Dry macula was noted in 1 vs 14 eyes in group R vs group A.ConclusionAfter treating refractory DME with initial bevacizumab injections, 3 injections of either aflibercept or ranibizumab had similar anatomic and functional outcomes. Aflibercept achieved dry macula in more eyes with refractory DME compared to ranibizumab.

Guidelines for the Management of Center-Involving Diabetic Macular Edema: Treatment Options and Patient Monitorization

Diabetic macular edema (DME) is the main cause of visual impairment associated with diabetic retinopathy (DR) and macular laser, during approximately three decades, and was the single treatment option. More recently, intravitreous injections of anti-angiogenics and corticosteroids modified the treatment paradigm associated with significant vision improvements. Nevertheless, not all patients respond satisfactorily to anti-VEGF or corticosteroid injections, so an adequate treatment choice and a prompt switch in therapeutic class is recommended. Several algorithms and guidelines have been proposed for treating center involving DME to improve patients’ vision and quality of life. However, in Portugal, such guidelines are lacking. The present review aimed to provide guidelines for the treatment options and patient monitorization in the management of center-involving DME. We recommend anti-vascular endothelial growth factor (VEGF) as first-line therapy after a clinical evaluation accompanied by a rigorous metabolic control. Depending on the response obtained after 3–6 monthly intravitreal injections we suggest switching outside the class in case of a non-responder, maintaining the anti-VEGF-therapy in responders to anti-angiogenics. The treatment regimen for Dexamethasone intravitreal implant (DEXii) should be pro-re-nata with bi-monthly or quarterly monitoring visits (with a scheduled visit at 6–8 weeks after DEXii for intraocular pressure control). If a patient does not respond to DEXii, switch again to anti-VEGF therapy, combine therapies, or re-evaluate patients diagnose. There is a resilient need to understand the disease, its treatments, regimens available, and convenience for all involved to propose an adequate algorithm for the treatment of diabetic retinopathy (DR) and DME in an individualized regimen. Further understanding of the contributing factors to the development and progression of DR should bring new drug discoveries for more effective and better-tolerated treatments.

Is immediate treatment necessary for diabetic macular edema after pars plana vitrectomy for tractional complications of proliferative diabetic retinopathy?

To assess the treatment benefit of eyes with diabetic macular edema (DME) in vitrectomized eyes for tractional complications of proliferative diabetic retinopathy (PDR). In a retrospective multicentre observational study in India, the clinical outcomes of eyes with center-involving DME in vitrectomized eyes for tractional complications of PDR in people with type 2 diabetes with at least 12months follow-up data were assessed. The DME status and visual acuity outcomes were compared between those who received treatment versus those observed. In the 10-year study period, 45 eyes of 44 patients from 5 tertiary centers in India met the inclusion criteria. Center-involving DME was documented after a mean of 7 ± 7months following pars plan vitrectomy (PPV) for tractional complications of PDR. More than half of the (n = 25) eyes were immediately treated for DME, and treatment was deferred for the rest. At one year, there was a statistically significant reduction in mean central subfield thickness in treated (467.9 ± 124.8μm to 367.8 ± 143.7μm; p < 0.001) as well as observed (405.2 ± 132.6μm to 325.6 ± 149μm; p < 0.001) eyes, and the change was comparable (p = 0.574). The change in vision was also comparable (0.12 ± 0.31 and 0.22 ± 0.54 Log MAR in the treated and observed group, respectively; p = 0.443). Treatment for pre-existing or new-onset DME after PPV for tractional complications of PDR may be deferred for up to one year because the DME may resolve spontaneously with time.