To compare intravitreal aflibercept alone versus aflibercept combined with oral anti-inflammatory supplementation in patients with diabetic macular edema.

A prospective, randomized study included 134 treatment-naive eyes with central-involving diabetic macular edema. Participants were assigned to receive either intravitreal aflibercept (Group A) or aflibercept with oral Lenidase supplementation (Group B, containing baicalin, bromelain, and escin). Both groups followed a treat-and-extend regimen. The primary outcome was the number of injections over 24 months. Secondary outcomes included changes in best-corrected visual acuity, central macular thickness, and safety assessments.

At 24 months, Group A required a mean of 14.34 ± 0.51 injections, while Group B required 12.96 ± 0.44 ( P < 0.0001). Both groups showed significant improvement in best-corrected visual acuity: from 0.62 ± 0.12 logMAR (20/83 Snellen) to 0.43 ± 0.13 logMAR (20/54 Snellen) in Group A and from 0.64 ± 0.13 logMAR (20/87 Snellen) to 0.42 ± 0.15 logMAR (20/53 Snellen) in Group B ( P < 0.0001 for both). Central macular thickness also significantly decreased in both groups ( P < 0.0001). No significant differences were found between the groups for vision improvement ( P = 0.918) or central macular thickness reduction ( P = 0.777). No ocular complications were reported.

Oral supplementation with Lenidase showed similar efficacy to aflibercept monotherapy in diabetic macular edema, with fewer injections, potentially reducing treatment burden.

Diabetic retinopathy (DR), the prevalence of which continues to rise, is one of the most common causes of vision loss worldwide. Experimental and clinical research in recent years has contributed to a better understanding of the pathogenesis of DR, which is complex and results from many interrelated processes leading to abnormal permeability and occlusion of the retinal vasculature, with ischemia and subsequent neovascularization. According to the absence or presence of neovascularization, DR is divided into two main forms: nonproliferative and proliferative DR. From nonproliferative to proliferative disease, diabetic macular edema (DME) can develop anywhere along the spectrum. As the majority of diabetics have no ophthalmologic symptoms, screening plays an important role in preventing the development of retinal disease. Specific treatment options beyond metabolic risk factor control, including intravitreal administration of anti-vascular endothelial growth factor (VEGF) agents or corticosteroids, laser photocoagulation, and vitreous surgery, are effective approaches for ocular diabetic complications.

To evaluate the visual and anatomical outcomes of switching diabetic macular oedema (DMO) patients with suboptimal response to aflibercept 2mg to faricimab over a 12-month period.

This retrospective single centre study enrolled 62 eyes from 50 patients with diabetic macular oedema (DMO) who demonstrated a sub-optimal response to aflibercept 2mg. Sub-optimal response was defined by a central subfield thickness (CST) exceeding 325µm or greater than 20% increase from the best CST despite receiving aflibercept 2mg at intervals of 8 weeks or less. Patients had received at least six 4-weekly doses of aflibercept 2mg. Faricimab was administered as four intravitreal loading injections at 4-weekly intervals, followed by a treat-and-extend approach. Outcome measures, including best-recorded visual acuity (BRVA), CST, and treatment intervals, were assessed at baseline, post-loading (6.5 ± 1.9 weeks) and at the latest clinic review (57.1 ± 19.7 weeks). Statistical analysis included paired t-tests (normal distribution) and Wilcoxon signed-rank tests (non-normal distribution), with p < 0.05 considered statistically significant.

Mean age was 63.9 (±11.4) years, 56% participants were male. At baseline, the mean BRVA was 67.6 (±11.8) letters, and CST measured 406.4 (±105.9) µm. The initial mean treatment interval was 6.5 (±1.8) weeks. BRVA increased to 70.4 (±12.7) letters (p=0.008), while CST reduced to 372.8 (±132.0) µm (p=0.002). The mean injection interval extended to 7.4 (±2.6) weeks (p=0.03). At the latest follow-up BRVA was maintained at 68.7 (±14.6) letters (p=0.572), and CST reduced further to 343.1 (±117.5) µm (p=0.020). At the final follow-up 53.2% were on ≥8-weekly intervals. The mean injection interval increased to 9.2 (±3.2) weeks (p < 0.001), and a mean of 7.92 (±2.53) faricimab injections was administered.

DMO patients with sub-optimal response to aflibercept 2mg experienced improved anatomical outcomes and extended treatment intervals while maintaining vision on faricimab, with no new safety concerns.

Using spectral-domain optical coherence tomography (SD-OCT) in patients with diabetic macular edema (DME), we studied the relationships between consecutive aflibercept treatments, soluble CD14 (sCD14) in the aqueous humor (AH), and anatomical features, including hyper-reflective foci (HFs) and other morphologic characteristics. This prospective study included 23 eyes of 23 patients with DME treated with five consecutive monthly intravitreal aflibercept injections. At each visit, sCD14 and VEGF levels in the AH were measured using ELISA. The number of HFs, central macular thickness (CMT), and volume of intraretinal fluid (IRF) and subretinal fluid (SRF) were also assessed. One month after fifth injections, there were significant decreases in CMT, the number of HFs, and the volumes of IRF and SRF. The level of sCD14 also decreased. Although sCD14 levels showed a downward trend, the change was not statistically significant. The group with reduced sCD14 exhibited improvements in all the factors, including visual acuity. In contrast, the group with increased sCD14 only showed significant decreases in CMT. When the data were categorized into two groups based on the final visual outcome, patients with good final visual acuity had consistently lower levels of sCD14 at all visits. This study highlights sCD14 as a potential biomarker for assessing treatment response to aflibercept in DME.

To investigate the risk factors associated with recurrent hemorrhage following vitrectomy surgical intervention for diabetic retinopathy (DR).

A retrospective analysis was conducted on 579 eyes diagnosed with DR necessitating surgical intervention. These cases were categorized into two groups: recurrent hemorrhage and non-recurrent hemorrhage. Comparative, random forest (RF), and regression analyses were subsequently performed to evaluate variables pertaining to patients' demographic information, clinical examination and blood test results, treatment approaches, lifestyle habits, and overall health status.

This study compared patients with recurrent and non-recurrent hemorrhages, revealing significant differences in factors such as endodiathermy, anticoagulant use, cerebrovascular diseases, smoking status, glycosylated hemoglobin levels and BMI. Patients with no recurrent hemorrhage have faster vision recovery. The univariable logistic regression analysis indicated that cerebrovascular disease (OR = 7.87, P < 0.001), anticoagulant use (OR = 16.72, P < 0.001), and elevated glycated hemoglobin levels (OR = 21.22, P < 0.001) exhibited strong associations with recurrent hemorrhage. The multivariable logistic regression analysis indicated that recurrent hemorrhage risk factors include anticoagulant use (OR = 120.77, P = 0.020) and glycated hemoglobin levels (OR = 18.41, P = 0.001).

Recurrent postoperative hemorrhage is influenced by several factors, notably the use of intraoperative endodiathermy, adjustments in ocular therapy, and management of the patient's systemic condition. In clinical practice, careful consideration of these factors is essential to mitigate postoperative hemorrhage in patients.

We tested the ability of a single intravitreal injection of foselutoclax (hereafter UBX1325), a novel senolytic small molecule inhibitor of antiapoptotic protein B-cell lymphoma-extra large, to mitigate the impact of diabetic macular edema.

Patients with diabetic macular edema with prior suboptimal response to anti-vascular endothelial growth factor treatment were randomly assigned (1:1) to either a single intravitreal injection of 10 μg of UBX1325 or sham and were followed for up to 48 weeks. The primary trial objective was to evaluate the safety and side-effect profile of UBX1325 as assessed by ocular and systemic treatment-emergent adverse events (TEAEs). Our secondary objective was to probe efficacy, defined as mean changes from baseline for UBX1325 versus sham in best corrected visual acuity measured in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (range, 0-100 letters, higher scores indicate better vision) and retinal structure.

Between June 2021 and April 2022, 65 participants (32.3% women) were randomly assigned to either UBX1325 (n=32) or sham (n=33). There were four TEAEs of Grade 3 or greater in the sham group, of which three were considered serious, while there were five in the UBX1325 group of Grade 3 or greater and considered serious. There were no apparent between-group differences with respect to vital signs, electrocardiograms, or routine blood chemistries. For the secondary outcome of efficacy, the difference between UBX1325 and sham in mean change to week 48 in best corrected visual acuity was 5.6 more ETDRS letters (95% confidence interval, -1.5 to 12.7).

In this sham-controlled trial there were no TEAEs that led to discontinuation of treatment with UBX1325 compared with sham. There were trends suggestive of potential efficacy; larger trials are needed to further evaluate these findings. (Funded by UNITY Biotechnology; ClinicalTrials.gov number, NCT04857996.).

Radiomics-based characterization of fluid and retinal tissue compartments of spectral-domain optical coherence tomography (SD-OCT) scans has shown promise to predict anti-VEGF therapy treatment response in diabetic macular edema (DME). Radiomics features are sensitive to different image acquisition parameters of OCT scanners such as axial resolution, A-scan rate, and voxel size; consequently, the predictive capability of the radiomics features might be impacted by inter-site and inter-scanner variations.

The main objective of this study was (1) to develop a more generalized classifier by identifying the OCT-derived texture-based radiomics features that are both stable (across multiple scanners) as well as discriminative of therapeutic response in DME and (2) to identify the relative stability of individual radiomic features that are associated with specific spatial compartments (e/g. fluid or tissue) within the eye.

A combination of 151 optimal responders and rebounders of anti-VEGF therapy in DME were included from the PERMEATE (imaged using Cirrus HD-OCT scanner) and VISTA clinical trials (imaged using Cirrus HD-OCT and Spectralis scanners). For each patient within the study, a set of 494 texture-based radiomics features were extracted from the fluid and the retinal tissue compartment of OCT images. The training set (S t ${{S}_t}$ ) included 76 patients and the independent test set( S v $({{S}_v}$ ) comprised of 75 patients. Features were ranked based on (i) only discriminability criteria, that is, maximizing area under the receiver operating characteristic curve (AUC) and (ii) both stability and discriminability criteria. The subset of radiomic features for which the feature expression remained relatively consistent between the two datasets, as assessed by Wilcoxon rank-sum test, were considered to be stable. Different machine learning (ML) classifiers (such as k-nearest neighbors, Random Forest, Linear Discriminant Analysis, Quadratic Discriminant Analysis, Support Vector Machine using linear and radial basis kernel, Naive Bayes) were trained using the features selected based on both the stability and discriminability criteria onS t ${{S}_t}$ and then subsequently validated onS v ${{S}_v}$ . The ML classifier (M g ${{M}_g}$ ) that yielded maximum AUC onS v ${{S}_v}$ was considered to be more generalized and stable for distinguishing anti-VEGF therapy treatment response as well as less sensitive to the effect of inter-site and inter-scanner variability.

The modelM g ${{M}_g}$ (based on both stability and discriminability criteria) achieved higher AUC compared to the criteria based off feature discrimination alone onS v ${{S}_v}$ (maximum AUCs of 0.9 versus 0.81; p-value = 0.048). The texture-based radiomic features pertaining to the retinal tissue compartment were found to be more stable compared to the fluid related features across the two datasets.

Our study suggests that incorporating both stable and discriminatory texture-based radiomic features extracted from fluid and retinal tissue compartments of OCT scans, a more generalized radiomic classifier can be developed to predict therapeutic response in DME. Also, the feature stability was found to be a function of the spatial location within the eye from where the features were extracted.

The primary ocular effect of diabetes is diabetic retinopathy (DR), which is associated with diabetic microangiopathy. Diabetic macular edema (DME) can cause vision loss for people with DR. For this reason, deciding on the appropriate treatment and follow-up has a critical role in terms of curing the disease. Current artificial intelligence (AI) approaches focus on OCT images and may ignore clinical, laboratory, and demographic information obtained by the specialist. This study presents a novel deep learning (DL) framework for evaluating the visual outcome of the TREX anti-VEGF intravitreal injection regimen. DL models are trained to extract deep features from OCT and ILM topographic images and the obtained deep features are combined with patients' demographic, clinical, and laboratory findings to predict the direction of the treatment process. When the ResNet-18 network is used, the proposed DL framework is able to predict the prognosis status of patients with the highest accuracy.

Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of vision loss globally. This is a comprehensive review focused on both medical and surgical management strategies for DR and DME. This review highlights the epidemiology of DR and DME, with a particular emphasis on the Asia-Pacific region, urban-rural disparities, ethnic variations, and grading methodologies. We examine various risk factors for DR, including glycemic control, hypertension, hyperlipidemia, obesity, chronic kidney disease, sex, myopia, pregnancy, and cataract surgery. Furthermore, we explore potential biomarkers in serum, proteomics, metabolomics, vitreous, microRNA, and genetics that may aid in the detection and management of DR. In addition to medical management, we review the evidence supporting systemic and ocular treatments for DR/DME, including anti-vascular endothelial growth factor (anti-VEGF) agents, anti-inflammatory agents, biosimilars, and integrin inhibitors. Despite advancements in treatment options such as pan-retinal photocoagulation and anti-VEGF agents, a subset of cases still progresses, necessitating vitrectomy. Challenging diabetic vitrectomies pose difficulties due to complex fibrovascular proliferations, incomplete posterior vitreous detachment, and fragile, ischemic retinas, making membrane dissection risky and potentially damaging to the retina. In this review, we address the question of challenging diabetic vitrectomies, providing insights and strategies to minimize complications. Additionally, we briefly explore newer modalities such as 3-dimensional vitrectomy and intra-operative optical coherence tomography as potential tools in diabetic vitrectomy. In conclusion, this review provides a comprehensive overview of both medical and surgical management options for DR and DME. It underscores the importance of a multidisciplinary approach, tailored to the needs of each patient, to optimize visual outcomes and improve the quality of life for those affected by these sight-threatening conditions.

To evaluate the treatment outcomes of subthreshold micropulse laser (SMPL) with a wavelength of 670 nm (red) for treatment-naïve diabetic macular edema (DME).

A retrospective observational study which included 42 eyes in 34 patients diagnosed with treatment-naïve DME was conducted. Twenty-one eyes underwent red SMPL and the other 21 eyes underwent intravitreal injection of aflibercept (IVA) as initial treatment and were followed up for 12 months. Best-corrected visual acuity (BCVA), central retinal thickness (CRT) on optical coherence tomography (OCT), vessel density (VD), and foveal avascular zone area on OCT angiography (OCTA) were measured and compared between the two groups.

In the red SMPL group, the mean BCVA slightly improved from 0.29 ± 0.28 at baseline to 0.22 ± 0.29 at 12 months (p = 0.18), while the mean CRT significantly decreased from 472 ± 200 µm at baseline to 320 ± 136 µm at 12 months (p = 0.003). At 12 months from baseline, the mean change in BCVA and CRT were similar between the red SMPL and IVA groups (p = 0.79 and p = 0.31, respectively). No significant change was detected in OCTA parameters except for VD at the nasal section in the red SMPL group.

Red SMPL for treatment-naïve DME maintained BCVA and significantly reduced CRT at 12 months. These treatment outcomes were equivalent to IVA in real-world settings, which tend to be inferior to clinical trials.

The aim of this study was to compare the efficacy of the treat-and-extend (TAE) regimen versus the pro re nata (PRN) regimen in patients with bevacizumab-resistant diabetic macular edema (DME) treated with aflibercept, with or without adjunctive laser therapy.

Ninety-one eyes from 91 patients who were switched to aflibercept after three consecutive intravitreal bevacizumab injections for the treatment of DME were included in this retrospective real-world study. The patients were categorized into three groups: TAE (n = 30), TAE + laser (n = 31), and PRN (n = 30). Changes in best-corrected visual acuity and central macular subfield thickness (CMST) at 12, 24, and 52 weeks were defined as the primary functional and anatomical outcomes.

A total of 91 eyes from 91 patients (49.5% female) with a mean age of 63.9 ± 7.1 years were included in the analysis. At 52 weeks, the mean letter gains were 8.03, 8.90, and 10.23 in the TAE, TAE + laser, and PRN groups, respectively. Anatomical improvements, as measured by CMST reduction, were 55.33 µm, 33.35 µm, and 48.96 µm in the TAE, TAE + laser, and PRN groups, respectively. The average number of injections administered was 7.7, 8.1, and 8.1, respectively. The final extension interval for the TAE group was 8.7 weeks, compared to 9.5 weeks in the TAE + laser group.

The PRN group demonstrated the highest functional improvement while the TAE group showed the greatest anatomical improvement. Overall, both anatomical and functional outcomes in the TAE regimen were comparable to the PRN regimen in patients with bevacizumab-resistant diabetic macular edema.

The discovery of antivascular endothelial growth factor medications has resulted in a substantial change in diabetic retinopathy treatment. The most common cause of diabetic retinopathy blindness is Diabetic Macular Edema. The pathophysiology of Diabetic Macular Edema is thought to include the well-known pro-angiogenic and pro-permeability factor vascular endothelial growth factor. Over the past decade, drugs that impede the functions of vascular endothelial growth factors have established themselves as a standard-of-care treatment for a range of ocular ailments and improved patients' clinical results with diabetic retinopathy and Diabetic Macular Edema, and their frequency has grown exponentially with the introduction of these agents Pegaptanib, Ranibizumab, and Aflibercept which are approved for ophthalmic indications, while Bevacizumab is used off-label. These medications delivered intravitreally have halted the vascular development of diabetic retinopathy. Various randomized trials have proven that antivascular endothelial growth factor medication is safe and effective in preserving vision. Following an extensive period of preclinical development aimed at enhancing and defining its biological impacts, these drugs were shown in clinical trials to be effective in treating diabetic retinopathy and other ophthalmic conditions. Data from various sources suggest that Pegaptanib, Ranibizumab, and Aflibercept are costly, while Bevacizumab is cost-effective, and in low and middle-income nations, it is thus a desirable therapy choice. However, issues with compounding, counterfeiting, and off-label usage restrict its availability in many nations. The pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, and contraindications of antivascular endothelial growth factor agents are discussed, and the results of clinical trials evaluating their efficacy are summarized.

Diabetes mellitus (DM) is a chronic metabolic non-communicable disease with the ability to cause serious microvascular and macrovascular complications throughout the body, including in the eye. Diabetic retinopathy (DR), present in one-third of patients with diabetes, is a vision-threatening complication caused by uncontrolled diabetes, which greatly affects the retinal blood vessels and the light-sensitive inner retina, eventually leading to blindness. Several epidemiological studies elucidate that DR can vary by age of onset, duration, types of diabetes, and ethnicity. Recent studies show that the pathogenesis of diabetic retinopathy has spread its roots beyond merely being the result of hyperglycemia. The complexity of its etiopathology and diagnosis makes therapeutic intervention challenging. This review throws light on the pathological processes behind DR, the cascade of events that follow it, as well as the available and emerging treatment options.

To assess efficacy and safety of brolucizumab versus aflibercept in patients with diabetic macular edema (DME).

We performed a systematic review and meta-analysis with trial sequential analysis (TSA). We searched Embase, Cochrane Central Register of Controlled Trials and PubMed databases from inception to February 16, 2024 for randomized controlled trials (RCTs) comparing brolucizumab with aflibercept in patients with DME and reporting any of the visual, anatomical and safety outcomes of interest. We conducted a TSA of safety outcomes to assess the risk of statistical errors.

1253 patients (1253 eyes) from 3 RCTs were included, of whom 57% received brolucizumab and 43% received aflibercept. Mean follow-up ranged from 52 to 100 weeks. Brolucizumab was non-inferior to aflibercept when comparing the mean change of best-corrected visual acuity from baseline (least squares mean difference [LSMD] 0.29; 95% confidence interval [CI] -1.37 to 1.95; p = 0.73). Change in central subfield thickness was significantly greater in the brolucizumab group compared with aflibercept (LSMD -24.5 μm; 95% CI -48.2 to -0.7 μm; p < 0.05). Incidence of adverse events of special interest (AESIs) (risk ratio [RR] 1.7; p = 0.08) and incidence of ≥1 ocular adverse events (AEs) (RR 0.95; p = 0.45) were not significantly different between groups.

Brolucizumab was non-inferior in functional outcomes and was superior to aflibercept in anatomical parameters. Ocular AEs and AESIs were numerically low and not statistically significant. Our findings underscore the importance of new RCTs powered to assess safety outcomes in order to suggest brolucizumab as an alternative to the treatment of DME.

To derive estimates of clinically meaningful change (improvement) on the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) in patients with diabetic macular edema (DME) using anchor- and distribution-based methods.

In this exploratory post hoc analysis of data from the RIDE/RISE (NCT00473382/NCT00473330) clinical trials of ranibizumab for DME, the NEI VFQ-25 was completed at baseline and six, 12, 18, and 24 months. Anchor-based (≥5-, ≥10-, and ≥15-letter gain in best-corrected visual acuity [BCVA]) and distribution-based estimates were calculated. Subgroup analyses included outcomes when the study eye was the better- or worse-seeing eye.

Baseline characteristics were balanced between the trials (RIDE, N = 382; RISE, N = 377). Anchor-based estimates of clinically meaningful improvement in composite scores (for ≥15-letter gain in BCVA) were 3.78 and 2.23 for RIDE and RISE, respectively. Estimates appeared similar for most subscales: near activities (4.11 and 3.31), distance activities (3.53 and 3.74), driving difficulties (5.15 and 3.15), and vision-specific dependency (4.70 and 1.83). Supportive distribution-based meaningful change composite score estimates also were similar between RIDE and RISE for values based on 0.5 standard deviation (9.85 and 9.70, respectively) or standard error of the mean (5.10 and 4.82, respectively).

These analyses suggest improvement of three to five points on the NEI VFQ-25 composite score and four individual subscales as clinically meaningful in patients with DME.

This analysis supports considering these thresholds when assessing the clinical risk-benefit of DME treatment from the patient perspective using the NEI VFQ-25.

To assess the anatomic and functional outcomes in eyes with diabetic macular edema (DME) switched from intravitreal aflibercept to faricimab in a real-world setting.

Retrospective, interventional consecutive case series. Patients with DME were switched from aflibercept to faricimab and categorized based on central subfield thickness (CST) 4 weeks after last aflibercept injection into responding DME (rDME, CST reduction >20% or CST ≤ 250 µm) and nonresponding DME (nrDME, CST unchanged or increased). Patients received a loading dose of two monthly faricimab injections followed by a treat-and-extend regimen. Differences in response between rDME and nrDME were analyzed based on injection interval, change in CST, and visual acuity (VA) 12 weeks postswitch.

Fifty-two eyes of 40 patients met inclusion criteria (rDME: n = 26, nrDME: n = 26). Baseline and week 12: VA (logMAR) rDME 0.29 ± 0.23 and 0.22 ± 0.28, nrDME 0.42 ± 0.32 and 0.36 ± 0.29; CST (µm) rDME 370 ± 99 and 288 ± 80, nrDME 384 ± 85 and 380 ± 129. After 12 weeks, 54% rDME and 25% nrDME eyes showed a CST decrease of >20% or CST ≤ 250 µm. Forty-six percent rDME and 50% nrDME eyes had a ±20% CST change, 25% of nrDME eyes had a >20% CST increase, and 73% of rDME eyes and 47% of nrDME eyes reached an extended interval of 8 weeks or longer after 12 weeks.

Most DME eyes previously responding or not responding to aflibercept experienced a reduction or stabilization of DME after 12 weeks of faricimab treatment. rDME showed a better anatomic response, and treatment intervals could be extended earlier and longer than nrDME.

To demonstrate the therapeutic similarity of CT-P42 compared with reference aflibercept (Eylea) in adult patients with diabetic macular edema (DME).

Randomized, active-controlled, double-masked, phase III clinical trial PARTICIPANTS: Patients with a diagnosis of either type 1 or 2 diabetes mellitus with DME involving the center of the macula.

Patients were randomized (1:1) to receive either CT-P42 or reference aflibercept (2 mg/0.05 ml) by intravitreal injection every 4 weeks (5 doses), then every 8 weeks (4 doses), in the main study period. Results up to week 24 are reported herein.

The primary end point was mean change from baseline at week 8 in best-corrected visual acuity (BCVA) using the ETDRS chart. Equivalence between CT-P42 and reference aflibercept was to be concluded if the 2-sided 95% confidence interval (CI) (global assumptions) and 2-sided 90% CI (United States Food and Drug Administration [FDA] assumptions) for the treatment difference fell entirely within the equivalence margin of ±3 letters, as assessed in the full analysis set.

Overall, 348 patients were randomized (CT-P42: 173; reference aflibercept: 175). Best-corrected visual acuity improved from baseline to week 8 in both groups, with a least squares mean (standard error) improvement of 9.43 (0.798) and 8.85 (0.775) letters in the CT-P42 and reference aflibercept groups, respectively. The estimated between-group treatment difference was 0.58 letters, with the CIs within the predefined equivalence margin of ±3 letters (95% CI, -0.73 to 1.88 [global]; 90% CI, -0.52 to 1.67 [FDA]). Through week 24, other efficacy results for the 2 groups, in terms of change in BCVA and retinal central subfield thickness, as well as ETDRS Diabetic Retinopathy Severity Scale score, supported therapeutic similarity. Pharmacokinetics, usability, safety (including the proportions of patients experiencing ≥1 treatment-emergent adverse event [CT-P42: 50.3%; reference aflibercept: 53.7%]), and immunogenicity were also comparable between groups.

This study in patients with DME demonstrated equivalence between CT-P42 and reference aflibercept (2 mg/0.05 ml) in terms of efficacy, with similar pharmacokinetic, usability, safety, and immunogenicity profiles.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

AURIGA is the largest prospective real-world study to evaluate intravitreal aflibercept (IVT-AFL) treatment of diabetic macular edema (DME) and macular edema secondary to retinal vein occlusion. This article presents 24-month data from the German cohort of treatment-naïve patients with DME.

Treatment-naïve patients (≥ 18 years) with DME were treated with IVT-AFL at the discretion of the physician in clinical practice. The primary endpoint was mean change in visual acuity (early treatment diabetic retinopathy, ETDRS, letters) at month 12 compared to baseline. Statistical analyses were descriptive.

The analysis included data from 150 DME patients (54.7% male). At months 6, 12 and 24, mean (95% confidence interval) visual acuity gains of 4.6 (2.6; 6.5), 4.0 (2.1; 6.5) and 5.0 (3.0; 6.9) letters from baseline (mean ±SD: 65.0 ± 15.3 letters) and reductions in retinal thickness of 86µm (109; 64µm), 70µm (94; 43µm) and 75µm (103; 47µm) from baseline (mean ±SD: 391 ± 132 µm), respectively, were achieved. At month 24, 54% of patients gained ≥ 5 letters and 22% ≥ 15 letters. Patients received a mean number of 5.0 ± 1.6 injections until month 6, 7.1 ± 3.2 until month 12 and 9.0 ± 5.3 until month 24, 68% of patients received ≥ 5 injections until month 6 and 56% ≥ 7 injections within the first year. The safety profile was consistent with previous studies.

In the German AURIGA cohort, treatment-naïve DME patients achieved a clinically relevant gain in visual acuity as well as reduction in central retinal thickness following IVT-AFL treatment in clinical practice. From month 6 onwards, improvements were maintained despite a low injection frequency over 24 months. In comparison with previous real-world studies, care of DME patients in clinical practice seems to have improved; however, there is still room for further improvement.

One of the most common health concerns disturbing people within working years globally is diabetes mellitus (DM). One well-known consequence of DM is vascular damage, which can manifest as macro- and microangiopathy affecting the ocular retina. Therefore, Diabetic macular edema (DME) is a major sight-threatening complication of diabetic retinopathy (DR) worldwide. It is the most prevalent cause of significant vision impairment in diabetic patients. Long-term vision loss can be avoided by following early DME treatment guidelines in everyday life. Hence, there are various therapeutic approaches for DME management. Currently, the first-line treatment for DME is anti-VEGF family drugs, such as ranibizumab, brolucizumab, bevacizumab, and aflibercept. Nevertheless, relapses of the disease, inadequate response, and resistance during anti-VEGF therapy are still seen because of the intricate pathophysiological foundation of the disease. Consequently, there is an excellent requirement for therapeutic approaches to advance and become better at controlling diseases more satisfactorily and require fewer treatments overall. We conducted a thorough literature search in the current review to present a comprehensive overview of the primary data about the current DME therapeutic agents. We also covered the novel advances in DME management and probable future treatments being investigated and developed. This review recommended that Large clinical trials should afford sufficient evidence to support these innovative treatment modalities.

To evaluate the anatomical and functional results of the "3+PRN" protocol in the treatment of diabetic macular edema (DME), determine the predictive factors for good final visual acuity, and compare it to other protocols.

We conducted a retrospective, descriptive, comparative, cross-sectional study of patients with DME, which we dubbed HTSM. All patients were treated with three monthly initial intravitreal injections (IVT) of 1.25mg bevacizumab and followed according to the pro re nata (PRN) protocol for a period of 3years. The protocol was based on a monthly monitoring schedule for the first 3months, then increasingly spaced out over time. "On-demand" treatment was indicated with resumption of bevacizumab IVT in the event of worsening of DME.

A total of 52 patients were included. The mean age was 65years. Type 2 was the most frequently observed type of diabetes. The mean duration of the PRN protocol was 6months, and the mean number of injections was 6. The mean visual acuity (VA), initially 1/10, improved to 3/10 by the conclusion of the 3+PRN protocol, with an improvement of more than 5 letters in 77.6% of cases. The mean initial central macular thickness (CMT) was 451.5μm. The final mean EMC decreased to 298.5μm, which corresponds to a reduction of 153μm compared to the initial value. The mean subfoveal choroidal thickness, initially 304.2μm, decreased to a mean of 284.5μm at completion. Comparative analysis of the results before and after the PRN protocol confirmed the existence of a statistically significant correlation between VA and CMT (P<0.05). No correlation was observed between age and visual acuity or between initial and final VA. The analysis of the various tomographic parameters and VA revealed a significantly better visual improvement in the group in whom the external limiting membrane (MLE) and ellipsoid zone (ZE) were intact (P=0.04), as well as in the group in whom serous retinal detachment (SRD) was absent (P<0.001). Posterior vitreous detachment (PVD) was the most frequently observed vitreomacular anomaly. The final VA was similar in the groups with and without PVD (P=0.04).

The 3+PRN protocol is effective both functionally and tomographically in the treatment of DME. Various tomographic parameters might influence therapeutic efficacy. However, further in-depth studies are needed to better investigate these parameters.

To explore visual acuity (VA) outcomes of anti-vascular endothelial growth factor (VEGF) intravitreal injections in treatment-naive eyes with diabetic macular edema (DME), with bevacizumab as first-line treatment.

Retrospective single-center cohort study over a three-year follow-up. Overall, 1765 eyes from 1179 patients treated with intravitreal injections were evaluated. The cohort was divided according to the treatment given: (1) bevacizumab monotherapy, (2) eyes switched to a second-line agent, and (3) eyes switched to a third-line agent.

In total, 644 eyes of 444 patients met inclusion criteria. The mean age at presentation was 64.0 ± 11.1 years. The mean follow-up period was 24.6 ± 12.4 months. Furthermore, 67.1% of eyes were treated with bevacizumab monotherapy, 25.45% switched to a second-line agent, and 7.45% were switched to a third-line agent. The mean number of injections decreased significantly during each treatment year in the total cohort and within each treatment group ( P < 0.001). Mean VA for the total cohort and within each treatment group improved significantly throughout follow-up ( P < 0.001). No significant difference in VA was found between the groups ( P = 0.373).

This real-world study demonstrates robust and consistent VA gains over long-term follow-up in eyes with DME treated with either bevacizumab monotherapy or switching to alternative anti-VEGF agents in cases of suboptimal response.

The present study evaluated the efficacy of suprachoroidal injection of Triamcinolone Acetonide (SCTA) in diabetic macular edema (DME) following pars plana vitrectomy (PPV) using a modified microneedle.

A prospective interventional study was conducted on 60 eyes of 60 patients with centrally involved diabetic macular edema following pars plana vitrectomy (PPV). SCTA was performed at the baseline and repeated after 3 months in case of persistent subretinal or intraretinal fluid, central macular thickness (CMT) more than 300 µm or visual loss by more than one line of the Snellen chart.

The present study detected significant reduction of the CMT from 498.3 ± 94.8 µm at the baseline to 212.3 ± 11.9 µm after 12 months of injection with p < 0.001 and a significant improvement of best corrected visual acuity (BCVA) from 1 (0.9-1.2) at the baseline to 0.5 (0.3-0.7) after 12 months of injection with p < 0.001. The intraocular pressure (IOP) increased significantly after 3 months of injection with p < 0.001 and then gradually declined to its normal level after 6 months. Inner segment/outer segment (IS/OS) disruption was the only significant predictor of the final CMT; however, the number of injections, IS/OS disruption, baseline BCVA and the HbA1C level were the significant predictors of the final BCVA after injection.

Suprachoroidal injection of TA using this microneedle resulted in significant anatomical and functional improvement in previously vitrectomized diabetic macular edema patients with no recorded ocular or systemic adverse events.

To conduct a multicenter survey of visually impaired patients with diabetes mellitus (DM) and to identify the physical and ocular characteristics that lead to blindness in Japan.

Visually impaired patients with diabetes mellitus in Japan were divided into blind and low-vision groups according to the World Health Organization classification. Data on parameters related to diabetes mellitus and ocular complications in the right and left eyes were collected from 19 highly advanced medical facilities and compared between the two groups.

Among 408 visually impaired persons (blind group: 257, low-vision group: 151), 72.1% were under 70 years of age. The rates of neovascular glaucoma (NVG) (right eye, P = 0.041; left eye, P = 0.0031) or proliferative diabetic retinopathy (PDR) (right eye: P = 0.014, left eye: P = 0.0047) and the rate of proliferative membrane beyond half of the retinal area (right eye: P = 0.0263, left eye: P = 0.037) were significantly higher in the blind group. The direct cause of visual impairment was retinal atrophy, common in both groups. Neovascular glaucoma and diabetic macular edema were equally prevalent in the blind and low-vision groups, respectively.

In Japan, blind patients with diabetes mellitus are characterized by severe conditions such as neovascular glaucoma and progressive proliferative diabetic retinopathy upon their initial visit to an advanced care facility. These results highlight the importance of monitoring retinopathy through regular ophthalmological examinations, internal medicine, and appropriate therapeutic intervention.

Diabetic Macular Edema (DME) significantly impairs vision in diabetics, with varied patient responses to current treatments like anti-vascular endothelial growth factor (VEGF) therapy underscoring the necessity for continued research into more effective strategies. This study aims to evaluate global research trends and identify emerging frontiers in DME to guide future research and clinical management.

A qualitative and quantitative analysis of publications related to diabetic macular edema retrieved from the Web of Science Core Collection (WoSCC) between its inception and September 4, 2023, was conducted. Microsoft Excel, CiteSpace, VOSviewer, Bibliometrix Package, and Tableau were used for the bibliometric analysis and visualization. This encompasses an examination of the overall distribution of annual output, major countries, regions, institutions, authors, core journals, co-cited references, and keyword analyses.

Overall, 5624 publications were analyzed, indicating an increasing trend in DME research. The United States was identified as the leading country in DME research, with the highest h-index of 135 and 91,841 citations. Francesco Bandello emerged as the most prolific author with 97 publications. Neil M. Bressler has the highest h-index and highest total citation count of 46 and 9692, respectively. The journals "Retina - the Journal of Retinal and Vitreous Diseases" and "Ophthalmology" were highlighted as the most prominent in this field. "Retina" leads with 354 publications, a citation count of 11,872, and an h-index of 59. Meanwhile, "Ophthalmology" stands out with the highest overall citation count of 31,558 and the highest h-index of 90. The primary research focal points in diabetic macular edema included "prevalence and risk factors," "pathological mechanisms," "imaging modalities," "treatment strategies," and "clinical trials." Emerging research areas encompassed "deep learning and artificial intelligence," "novel treatment modalities," and "biomarkers."

Our bibliometric analysis delineates the leading role of the United States in DME research. We identified current research hotspots, including epidemiological studies, pathophysiological mechanisms, imaging advancements, and treatment innovations. Emerging trends, such as the integration of artificial intelligence and novel therapeutic approaches, highlight future directions. These insights underscore the importance of collaborative and interdisciplinary approaches in advancing DME research and clinical management.

Diabetic retinopathy (DR) stands as a prevalent complication in the eye resulting from diabetes mellitus, predominantly associated with high blood sugar levels and hypertension as individuals age. DR is a severe microvascular complication of both type I and type II diabetes mellitus and the leading cause of vision impairment. The critical approach to combatting and halting the advancement of DR lies in effectively managing blood glucose and blood pressure levels in diabetic patients; however, this is seldom achieved. Both human and animal studies have revealed the intricate nature of this condition involving various cell types and molecules. Aside from photocoagulation, the sole therapy targeting VEGF molecules in the retina to prevent abnormal blood vessel growth is intravitreal anti-VEGF therapy. However, a substantial portion of cases, approximately 30-40%, do not respond to this treatment. This review explores distinctive pathophysiological phenomena of DR and identifiable cell types and molecules that could be targeted to mitigate the chronic changes occurring in the retina due to diabetes mellitus. Addressing the significant research gap in this domain is imperative to broaden the treatment options available for managing DR effectively.

Among working-age people, diabetic retinopathy and diabetic macular edema are currently considered the main causes of blindness. Nowadays, intravitreal injections are widely acknowledged as a significant milestone in ophthalmology, especially for the treatment of several retinal diseases, including diabetic macular edema. In particular, anti-vascular endothelial growth factor (VEGF) agents are typically the first line of treatment; however, monthly injections are required, at least, during the loading dosage. Notably, an intravitreal 0.7 mg dexamethasone (DEX) implant (Ozurdex®, AbbVie Inc., North Chicago, IL, USA) is considered a legitimate substitute treatment for diabetic eyes that have not responded to anti-VEGF treatment. In fact, clinical trials and real-life studies have demonstrated the effectiveness and safety of an intravitreal DEX implant in treating such conditions over a period of three to six months. For this reason, wisely selecting diabetic patients might be crucial to decreasing the load of injections in clinics and hospitals. The purpose of this review is to analyze the available scientific literature to highlight the benefits, efficacy, and clinical criteria for choosing whether to switch from intravitreal anti-VEGF therapy to an intravitreal DEX implant in diabetic macular edema.

Anti-vascular endothelial growth factor (VEGF) injections are often administered less frequently in real-world treatment of diabetic macular oedema (DMO) than what was studied in clinical trials. This study aims to characterise real-world DMO treatment patterns and the effect of treatment intervals on patient outcomes.

This was a retrospective study of 291 patients with DMO treated with anti-VEGF therapy. 12- and 24-month best visual acuity (BVA) and central subfield thickness (CST) were compared between injection interval groups, which were determined by averaging the two most recent injection intervals. Multiple linear regressions were performed to identify factors associated with injection interval, BVA, and CST.

48.8% of patients received injections less than or equal to every 8 weeks (≤ q8w), 27.5% between every 8 to 12 weeks (q8-12w), and 23.7% greater than every 12 weeks (> q12w). Baseline CST was similar (p = 0.32), but BVA differed significantly in q8-12w patients (p = 0.0095). BVA and CST at 12 months were similar, but q8-12w patients experienced greater 12-month BVA improvement (7.36 ± 12.4 letters) than > q12w patients (1.26 ± 12.3 letters; p = 0.0056). 24-month BVA and CST changes were similar between groups (p = 0.30 and 0.87). Baseline BVA, HbA1c, and sex were associated with 12-month BVA, and baseline BVA and CST were associated with 12-month CST.

Many patients experienced improvements in BVA and CST over 12 months of treatment despite receiving less frequent anti-VEGF therapy than recommended in the pivotal trials. The present study showed that extended treatment intervals with bevacizumab were effective in preserving vision of many individuals with high baseline BVA.

The aim of this study is to evaluate near and distance visual acuity (VA) and their correlation with the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) outcomes in patients with diabetic macular edema (DME) and macular edema due to retinal vein occlusion (RVO) treated with aflibercept.

In this prospective study, we included 87 eyes of patients diagnosed with DME (n = 61) and RVO (n = 26), who received aflibercept treatment and were followed until the 8th injection. Near VA was examined on the 1st, 2nd, 3rd, 4th, 6th, and 8th injection, and patients completed the NEI VFQ-25 on the 1st, 4th, and 8th aflibercept injection.

The mean near VA at baseline in all eyes was 0.89 ± 0.12 logMAR. With every administration, there was a statistically significant improvement; on the 4th (0.70 ± 0.19; p = 0.000) and the 8th application (0.60 ± 0.19; p = 0.000). At baseline, the mean NEI VFQ-25 total score was 71 ± 14%, and improved to 81 ± 13% (p = 0.000) on the 8th injection. The most significant score gain was recorded in the near VA subscale (+ 20 ± 14%, p = 0.000). There was no statistically significant difference between DME and RVO group in the questionnaire or near VA outcomes.

Aflibercept treatment resulted in a remarkable improvement of near vision by 4 lines of logMAR optotype after the 8th application. The near vision questionnaire subscale, initially scoring the lowest, exhibited the greatest gain during the treatment period. This underscores the importance of near vision and reading ability for patients with DME and RVO.

To evaluate the effectiveness and safety of intravitreal brolucizumab (IVB) and intravitreal aflibercept (IVA) injections in the management of naive central involved diabetic macular edema (CIDME).

This study included 45 treatment-naive eyes with CIDME. A complete ophthalmic examination, including BCVA and SD-OCT was performed. Patients were randomized to (IVB) or (IVA) groups. All participants received a loading phase of three consecutive intravitreal injections, then followed by a personalized treat and extend (T&E) regimen.

At 12-month follow-up, the mean numbers of injections in IVA and IVB groups were 7.25  ±  0.53 and 6.3  ±  0.45, respectively (P < 0.0001). The IVA group showed a significant increase of the mean BCVA from 0.66  ±  0.15 logMAR (50.9  ±  7.7 letters) to 0.41  ±  0.19 logMAR (63.7  ±  10.8 letters). Mean CFT decreased significantly from 441.2  ±  35.7 μm to 281.3  ±  18.4 μm. The IVB group showed a significant increase of mean BCVA from 0.65  ±  0.16 logMAR (52.1  ±  7.9 letters) to 0.39  ±  0.17 logMAR (65.3  ±  8.7 letters). Mean CFT decreased significantly from 437.2  ±  41.9 μm to 275.5  ±  21.7 μm.No significant difference between both groups in terms of the vision improvement and the reduction of CFT was reported, whereas a statistical difference was observed in terms of intravitreal injections (IVI) numbers. No ocular complications were reported.

This case series highlights the effectiveness of both brolucizumab and aflibercept in the treatment of CIDME with a lower frequency of injection in brolucizumab group lowering the burden of IVI in this cohort.

Despite advances in systemic care, diabetic disease of the eye (DDE) remains the leading cause of blindness worldwide. There is a critical gap of up-to-date, evidence-based guidance for ophthalmologists in Canada that includes evidence from recent randomized controlled trials. Previous guidance has not always given special consideration to applying treatments and managing DDE in the context of the healthcare system. This consensus statement aims to assist practitioners in the field by providing a spectrum of acceptable opinions on DDE treatment and management from recognized experts in the field. In compiling evidence and generating consensus, a working group of retinal specialists in Canada addressed clinical questions surrounding the four themes of disease, patient, management, and collaboration. The working group reviewed literature representing the highest level of evidence on DDE and shared their opinions on topics surrounding the epidemiology and pathophysiology of diabetic retinopathy and diabetic macular edema; diagnosis and monitoring; considerations around diabetes medication use; strategic considerations for management given systemic comorbidities, ocular comorbidities, and pregnancy; treatment goals and modalities for diabetic macular edema, non-proliferative and proliferative diabetic retinopathy, and retinal detachment; and interdisciplinary collaboration. Ultimately, this work highlighted that the retinal examination in DDE not only informs the treating ophthalmologist but can serve as a global index for disease progression across many tissues of the body. It highlighted further that DDE can be treated regardless of diabetic control, that a systemic approach to patient care will result in the best health outcomes, and prevention of visual complications requires a multidisciplinary management approach. Ophthalmologists must tailor their clinical approach to the needs and circumstances of individual patients and work within the realities of their healthcare setting.

To evaluate disorganization of retinal inner layers (DRIL), as detected on spectral-domain optical coherence tomography (OCT) images, as a biomarker for diabetic macular edema (DME) activity, visual function, and prognosis in eyes with DME.

Longitudinal prospective.

Post hoc correlation analyses were performed on data from a phase 2 clinical trial. Seventy-one eyes of 71 patients with treatment-naive DME received either suprachoroidally administered CLS-TA (proprietary formulation of a triamcinolone acetonide injectable suspension) combined with intravitreal aflibercept or intravitreal aflibercept with a sham suprachoroidal injection procedure. DRIL area, maximum horizontal extent of DRIL, ellipsoid zone (EZ) integrity, and the presence and location of subretinal (SRF) and intraretinal fluid (IRF) were evaluated at baseline and week 24 by certified reading centre graders.

At baseline, the area and maximum horizontal extent of DRIL were negatively correlated with best-corrected visual acuity (BCVA; r = -0.25, p = 0.05 and r = -0.32, p =0.01, respectively). Mean baseline BCVA progressively worsened with each ordinal drop in EZ integrity, improved with the presence of SRF, and was invariant to the presence of IRF. DRIL area and maximum extent were significantly decreased at week 24 (-3.0 mm2 [p < 0.001] and -775.8 mm [p < 0.001], respectively. At week 24, decreases in the area and maximum horizontal extent of DRIL were positively correlated with increases in BCVA (r = -0.40, p = 0.003 and r = -0.30, p = 0.04). Improvements in BCVA at week 24 were no different between patients showing improvement in EZ, SRF, or IRF and those showing no improvement or worsening from baseline.

DRIL area and DRIL maximum horizontal extent were demonstrated to be novel biomarkers for macular edema status, visual function, and prognosis in eyes with treatment-naive DME.

Intravitreal aflibercept injection (IAI) is a treatment for diabetic macular edema (DME), but its mechanism of action (MoA) has not been completely elucidated. Here, we aimed to explore IAI's MoA and its multi-target nature in DME pathophysiology with an in silico (computer simulation) disease model. We used the Therapeutic Performance Mapping System (Anaxomics Biotech property) to generate mathematical models based on the available scientific knowledge at the time of the study, describing the relationship between the modulation of vascular endothelial growth factor receptors (VEGFRs) by IAI and DME pathophysiological processes. We also undertook an enrichment analysis to explore the processes modulated by IAI, visualized the effectors' predicted protein activity, and specifically evaluated the role of VEGFR1 pathway inhibition on DME treatment. The models simulated the potential pathophysiology of DME and the likely IAI's MoA by inhibiting VEGFR1 and VEGFR2 signaling. The action of IAI through both signaling pathways modulated the identified pathophysiological processes associated with DME, with the strongest effects in angiogenesis, blood-retinal barrier alteration and permeability, and inflammation. VEGFR1 inhibition was essential to modulate inflammatory protein effectors. Given the role of VEGFR1 signaling on the modulation of inflammatory-related pathways, IAI may offer therapeutic advantages for DME through sustained VEGFR1 pathway inhibition.

Diabetic macular edema (DME) is a common complication of diabetes mellitus and a leading cause of visual impairment worldwide. It is defined as the diabetes-related accumulation of fluid, proteins, and lipids, with retinal thickening, within the macular area. DME affects a significant proportion of individuals with diabetes, with the prevalence increasing with disease duration and severity. It is estimated that approximately 25-30% of diabetic patients will develop DME during their lifetime. Poor glycemic control, hypertension, hyperlipidemia, diabetes duration, and genetic predisposition are recognized as risk factors for the development and progression of DME. Although the exact pathophysiology is still not completely understood, it has been demonstrated that chronic hyperglycemia triggers a cascade of biochemical processes, including increased oxidative stress, inflammation, activation of vascular endothelial growth factor (VEGF), cellular dysfunction, and apoptosis, with breakdown of the blood-retinal barriers and fluid accumulation within the macular area. Early diagnosis and appropriate management of DME are crucial for improving visual outcomes. Although the control of systemic risk factors still remains the most important strategy in DME treatment, intravitreal pharmacotherapy with anti-VEGF molecules or steroids is currently considered the first-line approach in DME patients, whereas macular laser photocoagulation and pars plana vitrectomy may be useful in selected cases. Available intravitreal steroids, including triamcinolone acetonide injections and dexamethasone and fluocinolone acetonide implants, exert their therapeutic effect by reducing inflammation, inhibiting VEGF expression, stabilizing the blood-retinal barrier and thus reducing vascular permeability. They have been demonstrated to be effective in reducing macular edema and improving visual outcomes in DME patients but are associated with a high risk of intraocular pressure elevation and cataract development, so their use requires an accurate patient selection. This manuscript aims to provide a comprehensive overview of the pathology, epidemiology, risk factors, physiopathology, clinical features, treatment mechanisms of actions, treatment options, prognosis, and ongoing clinical studies related to the treatment of DME, with particular consideration of intravitreal steroids therapy.

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .

Diabetic retinopathy is a complex and progressive ocular complication of diabetes mellitus and is a leading cause of blindness in people of working age worldwide. The pathophysiology of diabetic retinopathy involves multifactorial processes, including oxidative stress, inflammation and vascular abnormalities. Understanding the underlying molecular mechanisms involved in its pathogenesis is essential for the development of effective therapeutic interventions. One of the pathways receiving increasing attention is the Keap1-Nrf2 signaling pathway, which regulates the cellular response to oxidative stress by activating Nrf2. In this review, we analyze the current evidence linking Keap1-Nrf2 signaling pathway dysregulation to diabetic retinopathy. In addition, we explore the potential therapeutic implications and the challenges of targeting this pathway for disease management. A comprehensive understanding of the molecular mechanisms of diabetic retinopathy and the therapeutic potential of the Keap1-Nrf2 pathway may pave the way for innovative and effective interventions to combat this vision-threatening disease.