Vision outcomes in response to anti-vascular endothelial growth factor therapy for diabetic macular edema (DME) may differ between races. This meta-analysis investigated whether vision outcomes differed among racial subgroups treated with ranibizumab for DME in a clinical trial setting.

To assess the impact of race on vision outcomes in participants with DME treated with ranibizumab.

Five randomized clinical trials were preselected for analysis, including the RIDE and RISE trials (Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus); Protocol I (Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination With Laser Photocoagulation for Diabetic Macular Edema), Protocol S (Prompt Panretinal Photocoagulation Versus Intravitreal Ranibizumab With Deferred Panretinal Photocoagulation for Proliferative Diabetic Retinopathy), and Protocol T (A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema).

Targeted meta-analysis of data from 5 trials.

Total enrollment numbers allowed for comparison of Black and White participants with DME who were treated with ranibizumab (0.3 mg or 0.5 mg) and had best-corrected visual acuity (BCVA) data at baseline and month 24. Lower total enrollment of participants of other races precluded statistical analysis. All ranibizumab-treated arms were pooled. Differences in vision outcomes between Black and White participants were evaluated, adjusting for baseline vision. Propensity score-matched models for participants in RIDE/RISE were used to control for differences in baseline and on-study characteristics.

Mean BCVA over time and mean change from baseline at month 24 by race (Black and White).

Among the 1109 participants, the mean age was 60.0 years (95% CI, 59.4-60.7); 621 participants were male and 488 were female; 181 participants were Black and 928 were White. BCVA was better at baseline in Black vs White participants (mean Early Treatment Diabetic Retinopathy Study [ETDRS] letter score, 66.7 [95% CI, 65.0-68.4] vs 62.0 [95% CI, 61.1-62.8], respectively) but similar at month 24 (mean ETDRS letter score, 72.8 [95% CI, 70.2-75.4] vs 72.2 [95% CI, 71.2-73.1]). Mean BCVA change from baseline at month 24 was lower in Black vs White participants (6.1 ETDRS letters [95% CI, 3.6-8.6] vs 10.2 ETDRS letters [95% CI, 9.3-11.1]) and after adjusting for differences in baseline BCVA (7.7 ETDRS letters [95% CI, 5.8-9.7] vs 9.9 ETDRS letters [95% CI, 9.0-10.7]). When groups were propensity score-matched in RIDE/RISE, mean BCVA change from baseline appeared similar between Black vs White participants (10.6 ETDRS letters [95% CI, 7.1-14.1] vs 10.1 ETDRS letters [95% CI, 7.3-12.9]; P = .83).

This meta-analysis evaluating ranibizumab for DME found that baseline BCVA was better in Black vs White participants, and BCVA change from baseline at month 24 was smaller in Black vs White participants. No difference in BCVA was observed in Black vs White participants at 2 years. Smaller enrollment numbers precluded analysis of participants of other races, suggesting lack of robust diversity beyond Black and White participants in these trials.

To report the surgical outcome of fluid aspiration in intraretinal cysts as a novel treatment approach for the refractory cystoid macular edema associated with diabetic retinopathy.

This retrospective consecutive case series examined eight patients with refractory cystoid macular edema who underwent intraretinal cyst fluid aspiration using a 38-gauge subretinal infusion needle during pars plana vitrectomy. This study reviewed changes in central retinal thickness, best-corrected visual acuity, and central sensitivity among patients followed up for 12 months postsurgery.

Central retinal thickness on optical coherence tomography (μm) significantly improved at 12 months after surgery (308 ± 99) compared with before surgery (480 ± 141) ( P < 0.005). During the follow-up period, cystoid macular edema relapsed in one eye. The best-corrected visual acuity (logarithm of the minimal angle of resolution) at 12 months postsurgery (0.23 ± 0.32, Snellen equivalent: 20/50) was significantly better than the preoperative best-corrected visual acuity (0.39 ± 0.29, Snellen equivalent: 20/63) ( P < 0.01). The mean deviation value of central sensitivity did not significantly change between preoperative (-2.5 ± 2.1) and postoperative (-2.2 ± 2.2) assessments ( P = 0.07).

Fluid aspiration in intraretinal cysts may be a treatment option for refractory cystoid macular edema in eyes with diabetes.

This study aimed to evaluate the efficacy and safety of intravitreal injection of aflibercept biosimilar in the treatment of diabetic macular edema (DME).

Clinical data were collected from 33 patients (40 eyes) newly diagnosed with DME in the ophthalmology department of our hospital between February and April 2024, all of whom were treated with the aflibercept biosimilar. Patients were managed according to the 3+ Pro re nata (PRN) regimen and completed a minimum follow-up period of 6 months. The best-corrected visual acuity (BCVA) testing, optical coherence tomography, optical coherence tomography angiography, and multifocal electroretinography were performed before and after treatment. BCVA and central retinal thickness (CRT) were compared at baseline and 1-, 3-, and 6-months post-treatment. Additionally, the changes in the foveal avascular zone area, vascular density (VD) of superficial and deep retinal capillaries in the macular region, and the first positive peak amplitude density in ring 1 were analyzed 6 months post-treatment.

BCVA improved significantly from 0.53 ± 0.12 logMAR at baseline to 0.31 ± 0.12, 0.26 ± 0.10, and 0.26 ± 0.08 logMAR at 1-, 3-, and 6-months post-treatment, respectively, (p < 0.05). CRT decreased significantly from 422.4 ± 63.04 μm at baseline to 294.7 ± 47.89, 272.1 ± 47.43, and 281.0 ± 40.72 μm at 1-, 3-, and 6-months post-treatment, respectively, (p < 0.05). The foveal avascular zone area significantly reduced from 0.40 ± 0.08 mm2 at baseline to 0.35 ± 0.07 mm2 at 6 months post-treatment. Superficial VD increased significantly from 38.90 ± 7.88% at baseline to 41.21 ± 7.98% at 6 months post-treatment, while deep VD significantly increased from 35.67 ± 7.50% at baseline to 38.72 ± 6.90% (p < 0.05). The first positive peak amplitude improved significantly from 55.30 ± 9.45 to 72.90 ± 7.44 nv/deg2 at 6 months post-treatment (p < 0.05).

Intravitreal injections of aflibercept biosimilar can significantly reduce DME, improve BCVA, enhance macular perfusion, and restore macular function.

To compare different doses and dosing regimens of RC28-E, a novel bispecific antibody that simultaneously binds vascular endothelial growth factor-A (VEGF-A) and fibroblast growth factor-2 (FGF-2), with conbercept in patients with diabetic macular edema (DME).

Prospective, randomised, active comparator-controlled, open-label, multicentre, phase 2 clinical trial.cente PARTICIPANTS: The trial enrolled patients aged 18 years or older with centre-involving DME, best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central subfield thickness (CST) of 300 µm or more.

Patients were assigned randomly to one of five treatment regimens: 1.0 mg RC28-E for three initial monthly doses and then every 8 weeks (1.0mgQ8); 1.0 mg RC28-E for five initial monthly doses and then on a pro re nata (PRN) basis (1.0mgPRN); 2.0 mg RC28-E for three initial monthly doses and then every 8 weeks (2.0mgQ8); 2.0 mg RC28-E for five initial monthly doses and then on a PRN basis (2.0mgPRN); or 0.5 mg conbercept for three initial monthly doses and then on a PRN basis. Assessments were made at baseline and every 4 weeks thereafter.

The primary endpoint was the change in BCVA compared with baseline at 24 and 52 weeks. Secondary endpoints included the change in CST from baseline at 52 weeks; the proportion of patients who gained/lost ≥15 letters, ≥10 letters and >0 letter in BCVA; and the number of injections and safety outcomes.

The trial enrolled 156 patients. Mean improvements in BCVA in the RC28-E groups at week 24 were 7.1, 11.0, 7.4 and 10.5 letters for 1.0mgQ8, 1.0mgPRN, 2.0mgQ8 and 2.0mgPRN regimens, respectively, versus 9.7 letters for the conbercept group (p=0.146). By week 52, the RC28-E groups exhibited respective mean BCVA enhancements of 5.5, 9.5, 9.2 and 9.7 letters, compared with 8.4 letters of the conbercept group (p=0.469). Mean reductions in CST in the RC28-E groups at week 52 were -163.2 µm, -136.9 µm, -142.5 µm and -153.6 µm, versus -160.7 µm for the conbercept group (p=0.948). The Per Protocol Set analysis indicated that at 24 weeks, the BCVA improvement in the 2.0mgPRN group was significantly greater than that in the conbercept group (14.0 vs 9.8, p=0.019). In patients with poor baseline glycaemic control (HbA1c ≥7.5%), the 2.0mgPRN group showed greater BCVA improvement than the conbercept group (14.4 vs 4.2, p=0.039) at week 52. During the maintenance phase, the 2.0mgPRN group had fewer injections (2.8, 95% CI 1.8 to 3.7) compared with the conbercept group (4.4, 95% CI 3.5 to 5.2). RC28-E was generally well tolerated. The incidence of ocular adverse events in study eyes was comparable between RC28-E groups (22.6% in 1.0mgQ8 group, 26.7% in 1.0mgPRN group, 34.4% in 2.0mgQ8 group, 25.0% in 2.0 mg PRN group) and conbercept group (32.3%). The number of ocular serious adverse events was 1 (1.0mgQ8), 0 (1.0mgPRN), 1 (2.0mgQ8), 2 (2.0mgPRN) and 0 (conbercept).

Intravitreous RC28-E improved BCVA and CST in eyes with centre-involved DME. Compared with conbercept, the 2.0mgPRN regimen of RC28-E was recommended due to its superior efficacy in improving vision particularly for patients with poor glycaemic control, fewer treatment injections during the maintenance phase and comparable safety profile.

NCT04782115.

Frequent visits and intravitreal anti-vascular endothelial growth factor (VEGF) injections are often required to manage diabetic macular edema (DME), burdening patients and their health care networks. The Port Delivery System (PDS) with ranibizumab is the first continuous anti-VEGF therapy that has the potential to reduce visit and treatment burden without sacrificing vision outcomes for patients with DME.

To evaluate the efficacy and safety through 64 weeks of ranibizumab, 100 mg/mL, via PDS with refill exchanges every 24 weeks (PDS Q24W) in patients with DME vs intravitreal injections of ranibizumab, 0.5 mg, every 4 weeks (monthly ranibizumab).

This randomized clinical trial was a phase 3, multicenter, noninferiority trial conducted across 87 sites in the US. Treatment-naïve patients at least 18 years old with center-involved DME were eligible for study participation. Enrollment was from September 30, 2019, to June 25, 2021; data were analyzed from September 30, 2019, to September 19, 2022.

Participants were randomized 3:2 to receive 4 monthly doses of ranibizumab, 0.5 mg, followed by ranibizumab, 100 mg/mL, via PDS Q24W or monthly ranibizumab.

The primary end point was change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 60 and 64.

A total of 634 participants were randomized (PDS Q24W group, n = 381; monthly ranibizumab, n = 253). The mean (SD) age at baseline was 60.7 (9.6) years; 363 (57.3%) participants were male and 271 (42.7%) female. Adjusted mean BCVA change from baseline averaged over weeks 60 and 64 was an increase of 9.6 letters for PDS Q24W and 9.4 letters for monthly ranibizumab (difference, 0.2; 95% CI, -1.2 to 1.6), meeting the primary end point of PDS noninferiority (margin, -4.5 letters). PDS Q24W participants had a mean (SD) decrease of 6.7 (12.0) letters 4 weeks after PDS insertion; mean BCVA was similar to monthly ranibizumab 16 weeks after implantation. Adverse events of special interest were more common in the PDS Q24W group (88 participants; 27.5%) than the monthly ranibizumab group (28 participants; 8.9%). No cases of endophthalmitis or retinal detachment were reported with PDS Q24W.

This trial found that changes in BCVA from baseline averaged over weeks 60/64 in the PDS Q24W group were comparable to the monthly ranibizumab group. While AESIs were more common with PDS Q24W, there were no instances of endophthalmitis or retinal detachment. Continuous ranibizumab, 100 mg/mL, via PDS was approved in the US for patients with DME in February 2025 and provides effective, durable, and generally well-tolerated treatment for DME with retreatment every 6 months through at least 64 weeks.

ClinicalTrials.gov Identifier: NCT04108156.

To compare the risk of renal adverse events, particularly acute kidney injury (AKI), between intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents.

Meta-analysis.

A systematic literature search was conducted on Ovid Medline, Embase, and the Cochrane Library for randomized controlled trials (RCTs) published from January 2005 to February 2024 involving adult patients receiving anti-VEGF intravitreal injections for age-related macular degeneration, diabetic macular edema, and macular edema secondary to retinal vein occlusion. The primary outcome was the comparative risk of AKI between anti-VEGF agents and sham injections. Secondary outcomes involved other renal adverse events. Subgroup analyses were conducted by specific disease indications. A random-effects model was used for meta-analysis to estimate risk ratios (RRs) and their 95% confidence intervals, with a P value of <.05 representing statistical significance. Risk of bias was assessed using the Cochrane Risk of Bias 2 (ROB2) tool, and the certainty of evidence was evaluated through the Cochrane Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework.

A total of 10,031 eyes from 11 RCTs were included. No significant differences were found in the risk of acute or chronic renal conditions, obstructive uropathies, neoplasia, or infectious processes between anti-VEGF agents and sham therapy. AKI was reported in 5.4% (n = 10/185) of patients treated with bevacizumab, 1.3% (n = 6/456) with sham, 1.0% (n = 48/4724) with aflibercept, 0.8% (n = 15/1929) with faricimab, 0.5% (n = 5/1098) with brolucizumab, and 0.3% (n = 5/1639) with ranibizumab. No significant differences in AKI risk were observed between any of the anti-VEGF agents and sham (P > .05 for all comparisons). However, there was an increased risk of patient-reported symptoms with 1.25 mg bevacizumab compared to 2 mg aflibercept (RR = 3.26, 95% CI = 1.07-9.93, P = .04), driven primarily by reports of hematuria: 4.3% (bevacizumab), 0.7% (sham), 0.2% (aflibercept), 0.1% (faricimab), and 0.1% (ranibizumab).

US Food and Drug Administration (FDA)-approved intravitreal anti-VEGF agents do not significantly increase the risk of AKI compared to sham injections. Nevertheless, variations in patient-reported renal symptoms were observed across different anti-VEGF drugs. These variations were influenced primarily by differences in hematuria events, which may be a result of differential systemic absorption by these agents. These results underscore the importance of continuous monitoring and pharmacovigilance.

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.

While anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized treatment for diabetic macular edema, many patients still manifest refractory disease. This study evaluated rates of diabetic macular edema (DME) refractory to intravitreal bevacizumab in a diverse real-world setting, with the aim of studying demographic and optical coherence tomography (OCT)-based morphological factors associated with refractory disease.

This was a retrospective cohort study of patients receiving treatment. Refractory DME was defined as a gain in visual acuity of < 5 letters after three consecutive injections of bevacizumab or less than 20% reduction in central retinal thickness (CRT) after three consecutive injections of bevacizumab. OCT images from preand post-injection visits were reviewed by two independent image readers. Multivariate logistic regression analysis evaluated for statistical significance between responders and those refractory to bevacizumab, and between Hispanic and non-Hispanic groups.

Ninety-nine patients were included. Of the participants, 42% were Hispanic, 10% were reported as white, 11% were Asian, 11% were Black, and 26% were defined as "not reported." Fifty-four (54.5%) patients were refractory to bevacizumab and 45 were responders. Between responders and refractory patients, race was statistically significant (P = 0.04) with more refractory subjects found to be Hispanic (28/54, 51.9%). OCT morphologic characteristics (CRT, number of hyperreflective foci, disorganization of inner retinal layers, ellipsoid zone discontinuity, and sub-retinal fluid) were not statistically significant between responders and refractory subjects. Multivariate logistic regression demonstrated an odds ratio of 5.7 for refractory disease for Hispanics (CI 1.687 to 19.445, P = 0.01). When comparing Hispanics to non-Hispanics, Hispanics had an average lower baseline visual acuity, lower CSTs, and higher HbA1C.

Our study showed that Hispanics have a nearly 6 times relatively higher likelihood of refractory disease. There is a notable under-representation of these patients in completed clinical trials for diabetic retinopathy and DME. [Ophthalmic Surg Lasers Imaging Retina 2025;56:XX-XX.].

To identify diabetic maculopathy features from photographic screening that are predictive of treatment on referral to a tertiary care centre.

Retrospective review of participants who underwent screening by Singapore Integrated Diabetic Retinopathy Programme from 2015 to 2019. Participants underwent visual acuity (VA) test and non-stereoscopic retinal photographs. Maculopathy features include haemorrhages, microaneurysm and hard exudates (HE), stratified by inner and outer zone (1 and 1-2 disc diameter from fovea respectively) and VA of 6/12. Diabetic macular oedema (DMO) treatment was defined as intravitreal injection or macular photocoagulation up to 540 days from point of referral.

16,712 patients screened had referable eye disease. Out of 3518 maculopathy suspects, 281 (8.0%) received DMO treatment within 540 days. Those treated for DMO had shorter duration of diabetes (6.90 vs. 9.13 years, p < 0.001), higher total cholesterol (4.65 ± 1.20 vs. 4.36 ± 1.13 mmol/L, p = 0.001) and LDL cholesterol (2.59 ± 1.05 vs. 2.37 ± 0.93 mmol/L, p < 0.05) than those without treatment. High-risk features, including inner zone haemorrhages with VA ≤ 6/12 (HR 12.0, 95% CI: 5.5-25.9) and inner zone hard exudates (HR 7.4, 95% CI: 3.4-15.8), significantly increased the likelihood of requiring DMO treatment compared to low-risk features. Higher body mass index is protective of DMO treatment in mild non-proliferative diabetic retinopathy (HR 0.84, 95% CI: 0.73-0.97).

Haemorrhages, microaneurysms and HE within inner zone are important photographic features predictive of DMO treatment. VA is an important stratification for screening especially in patients with only visible haemorrhages.

In recent years, there has been increasing recognition of the importance of diversity in pivotal randomised clinical trials (RCTs). This is vital to ensure the validity and applicability of the results in the clinical setting. In this review, we aim to assess the inclusion of females and minoritized groups in recent RCTs in age-related macular degeneration (AMD) and diabetic macular oedema (DMO) and explore any potential barriers to their enrolment. Overall, a female predominance was observed among the AMD RCTs while less than half of the study population in DMO trials were females. White participants made up the majority of the study population in both AMD and DMO trials. Gender distribution within minoritized groups has only been reported in a few trials but appears lower than in the white population. This disparity may be attributable to the difference in the prevalence of diseases between these subgroups, as well as social and/ or cultural reasons. Nonetheless, there has been an overall increase in representation of minoritized groups over the past two decades. These observations provide important perspectives to consider when applying clinical trial learnings to clinical settings.

This study compared the effects of three induction doses of anti-vascular endothelial growth factor (anti-VEGF) on diabetic macular edema (DME) with that of long-term treatment using biomarkers to find out the predictability potential of early response to anti-VEGF treatment for the long-term restorative effect.

We retrospectively reviewed the clinical and optical coherence tomography (OCT) data of 71 DME eyes treated with three monthly anti-VEGF doses and followed for 1 year. BCVA, central subfield thickness (CST), subretinal fluid (SRF), intraretinal cysts, hyperreflective foci (HF), disorganization of inner retinal layers (DRILs), ellipsoid zone/external limiting membrane (EZ/ELM) integrity, and vitreoretinal relationships were assessed at baseline, 3, 6, and 12 months.

Patients (50.7% male) had a mean follow-up of 12 months. After three anti-VEGF doses, 19 eyes required no additional injections, 25 continued anti-VEGF, 20 switched to dexamethasone implants, and seven received combination therapy. Best corrected visual acuity (BCVA) improved from 0.52 to 0.40 logMAR at 3 months, 0.30 at 6 months, and stabilized at 0.40 at 12 months. CST decreased from 406 µm to 317 µm at 3 months and 307 µm at 12 months. Significant early improvements in BCVA, CST, SRF, and intraretinal cysts were sustained in the long-term follow-up. HF reduction became significant after 6 months, while DRIL and EZ/ELM integrity remained unchanged.

The improvement of OCT biomarkers in DME patients supported that intravitreal anti-VEGF significantly restored the retinal microstructure, which was already evident at 3 months in the control after anti-VEGF induction.

Povidone-iodine (PI) is the gold standard for pre-intravitreal injection ocular antisepsis. Chlorhexidine (CHX) is an emerging alternative with less ocular irritation. This meta-analysis aims to evaluate post-injection endophthalmitis rates with the use of CHX compared to PI. A systematic search of PubMed, Embase, and Scopus was performed for studies published between January 1, 2000 and February 21, 2024. Data on the number of injections and endophthalmitis cases were analyzed. A sample-size weighted mean difference (MD) meta-analysis was performed using RevMan 5.4.1, p < 0.05 was considered statistically significant. Five studies including 230,656 injections were pooled to determine an endophthalmitis rate of 0.0003 [95 % CI, 0.0001-0.0005] with preinjection CHX antisepsis. Three studies included an additional PI branch and thus were used for secondary meta-analysis comparing CHX against PI. The analysis consisted of 185,799 injections in the CHX group and 269,441 injections in the PI group. No significant difference in the weighted relative risk of endophthalmitis with CHX was found (RR = 1.27 [95 %CI 0.50-3.22], p = 0.62). A total of 24 and 31 cases of culture-positivity were recorded in the CHX and PI groups respectively but no significant difference in weighted means was found (RR = 1.42[95 %CI 0.96-2.12], p = 0.08). This meta-analysis disclosed that the rate of post-IVI endophthalmitis while using CHX antisepsis is approximately 1 in 3937 injections, compared to 1 in 3906 with PI. CHX was not associated with a significant difference in the rate of endophthalmitis or culture-positivity compared to PI.

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.

This article provides a comprehensive overview of clinical trial design and regulatory pathways essential for drug development, specifically in the context of retinal diseases. Key concepts include trial structure, efficacy and safety endpoints, and regulatory expectations from agencies like the FDA. It delves into recent regulatory advancements, such as the inclusion of low-luminance vision as a secondary endpoint and analyses case studies from age-related macular degeneration (AMD) trials. Approvals for key retinal drugs, such as ranibizumab and aflibercept, treatments for AMD and diabetic macular oedema, are discussed highlighting criteria like the 15-letter gain/loss in visual acuity as approvable/clinical meaningful efficacy endpoints. Insights into geographic atrophy (GA) and diabetic retinopathy trials showcase the evolving landscape, where anatomical endpoints and new drugs bring fresh challenges and opportunities. It also emphasizes the importance of academic-industry collaboration, citing instances of gene therapy development and innovative endpoint measures like the Multi-Luminance Mobility Test for retinal dystrophies. The overarching aim of this lecture was to demystify the process that spans the design of clinical trials to regulatory approval of drugs so that clinicians understand these complexities. In particular, it is important to understand the reasons behind selection of trial design, inclusion and exclusion criteria, primary and secondary efficacy endpoints and safety endpoints. Since this lecture, there have been important changes in this field including new guidance from the Food and Drug Administration (FDA) as well as lessons learnt from recent drug approvals that are included in this manuscript.

The inherent limitations of traditional treatments for Diabetic Retinopathy (DR) have spurred the development of various nanotechnologies, offering a safer and more efficient approach to managing the disease. Nanomedicine platforms present promising advancements in the diagnosis and treatment of DR by enhancing imaging capabilities, enabling targeted and controlled drug delivery. These innovations ultimately lead to more effective and personalized treatments with fewer side effects. This review highlights the progress, challenges, and opportunities in developing effective diagnostics and therapeutics for DR. Additionally, it explores innovative engineering techniques that leverage our growing understanding of nano-bio interactions to create more potent nanotherapeutics for patients.

To assess the real-world outcome of best-corrected visual acuity after 2-year intervention for treatment-naive diabetic macular edema since the approval of anti-vascular endothelial growth factor therapy.

A total of 1,780 treatment-naive eyes with diabetic macular edema for which intervention was initiated between 2015 and 2019, and which were followed for 2 years, were extracted from the longitudinal medical records of 37 retinal disease institutions in Japan. Interventions included anti-VEGF therapy, topical corticosteroid therapy, macular photocoagulation, and vitrectomy. The baseline and final best-corrected visual acuity, and the number and timing of interventions were recorded. Eyes were classified according to the year in which intervention was initiated.

Over a 2-year period, best-corrected visual acuity improved annually, finally reaching seven letters. The proportion of eyes in which good vision was maintained (best-corrected visual acuity >20/40) increased to 73.3% in the latest period. The administration of anti-VEGF therapy remained stable, accounting for approximately 90% of eyes. Notably, the proportion of eyes receiving anti-VEGF drugs as first-line treatment increased dramatically to approximately 80%.

Anti-VEGF therapy has become the first-line treatment since the approval of anti-VEGF drugs for diabetic macular edema. These findings reflect the evolution of diabetic macular edema treatment and highlight the superiority of anti-VEGF therapy and its increased uptake over time.

To determine if subthreshold micropulse laser (SML) therapy can prevent or delay vision loss in diabetic macular edema (DME) with good visual acuity (VA).

Prospective, single-masked, sham-controlled trial in 27 eyes of 19 adult patients with treatment-naïve, center-involved DME, and VA of 20/25 or better. Measures included best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), contrast sensitivity (CS), average threshold on microperimetry, and central subfield thickness (CST). The primary outcome measure was median time to vision loss of 10 letters at any visit or 5 to 9 letters at two consecutive visits ≤ 28 days apart.

Eight eyes met vision loss criteria during the 2-year study, with similar proportions for SML (n = 5) and sham (n = 3). Median time to vision loss was 5 months for both groups. At 6 months, there were no statistical differences in BCVA, LLVA, CS, microperimetry threshold, and CST between SML and sham arms (P > 0.05 in all measures).

In eyes with center-involved DME and good VA, SML did not prevent or delay the vision loss threshold for initiating anti-VEGF therapy. However, these results may be affected by a high rate of early participant dropout from the study. [Ophthalmic Surg Lasers Imaging Retina 2025;56:86-93.].

To determine how the rates of diabetic retinal disease (DRD) and its vision-threatening components (VTDR), diabetic macular edema (DME), and proliferative diabetic retinopathy (PDR) among patients with diabetes mellitus (DM) have changed over the past 20 years.

Retrospective cohort study.

All DM patients insured by commercial and Medicare Advantage insurance plans in a claims database from 2000 through 2022 and at least 1 full calendar year of data. Cohorts were created using International Classification of Diseases codes to determine the yearly prevalence and incidence of DRD, VTDR, DME, and PDR.

Logistic and Poisson regression models created prevalence and incidence estimates, respectively.

DRD, DME, and PDR prevalence and incidence.

The prevalence of DRD initially decreased from 2001 (13.6%) to 2007 (10.9%), but then increased every year through 2021 (20.8%; P < 0.001, adjusted test for trend [aTT]). Incidence of DRD varied considerably, ranging from 17.7 cases per 1000 patient-years in 2013 to its highest of 32.2 cases per 1000 patient-years in 2022 (P < 0.001, aTT). The prevalence of VTDR and DME trended similarly, with increases from 2007 (VTDR, 5.2%; DME, 3.2%) through 2016 (VTDR, 7.5%; DME, 5.4%), followed by decreases each year through 2021 (VTDR, 6.9%; DME, 4.9%; P < 0.001, aTT). The VTDR and DME incidence rates peaked in 2009 (VTDR, 12.4 cases per 1000 patient-years; DME, 8.6 cases per 1000 patient-years) and decreased through 2022 (VTDR, 6.1 cases per 1000 patient-years; DME, 5.0 cases per 1000 patient-years; P < 0.001, aTT, for both VTDR and DME). Prevalence of PDR varied between 3.2% and 4.0% throughout the 20-year observation period (P < 0.001, aTT). Incidence of PDR decreased over time to 2.6 cases per 1000 patient-years in 2022 (P < 0.001, aTT).

DRD prevalence (through 2007) and incidence (through 2014) initially decreased, but the rate of each has doubled since. Despite increases in DRD, incidence rates of VTDR, DME, and PDR have improved dramatically over the past 20 years.

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

Diabetic retinopathy (DR), the primary retinal vascular consequence of diabetes mellitus (DM) among people of working age worldwide, is the primary cause of vision impairment and blindness. Despite increasing understanding of the prevalence of DM as a significant public health concern in China, the world's most populous developing nation, there is much to discover about the epidemiology of DR.

This work uses a systematic review and meta-analysis to determine the total prevalence of diabetic retinopathy (DR) in China.

Using common keywords, we looked up published research on the prevalence of DR in diabetic patients using Google Scholar, PubMed, and Scopus from their founding until 2023. Using random effects models, pooled estimates of DR prevalence and the associated 95% confidence intervals (CI) were computed. Fifteen articles covering 4837 patients with different forms of diabetes were analyzed. The Egger tests refuted the publication bias assumption for the prevalence of DR (P = 0.825, P = 0.057, respectively). Significant heterogeneity was seen in the prevalence of DR (P < 0.01, I2 = 92% and τ2 = 0.0082), PDR (P < 0.01, I2 = 97% and τ2 = 0.0072), and NPDR (P < 0.01, I2 = 84% and τ2 = 0.0039), according to the results of I2 and τ2 statistics.

The combined prevalence of PDR was 24% (95% CI: 19-28), NPDR was 31% (95% CI: 27-35), and DR was 55% (95% CI: 63-71).

In summary, DR's prevalence appears slightly higher than that of other studies, with a greater incidence of NPDR. This study emphasises the need for DR screening and treatment in individuals with diabetes.

Management of Diabetic Macular edema (DME) requires repeated injections. Therefore newer Anti-VEGFs like Brolucizumab with longer durability have been introduced. We compared two different dosages of Brolucizumab, 6.0 mg and 3.6 mg, for their safety & efficacy in treatment of DME, in treatment naïve patients over 52 weeks.

A prospective, pilot randomised controlled, single centre, double blinded, two arm comparative study was conducted between Dec 2022 to Apr 2024. The study recruited 82 patients of DME who were randomised into two groups of 41 patients each, one group to be treated with Brolucizumab 6.0 mg in 50 μL and the other to receive 3.6 mg in 30 μL. All patients received the first dose of Brolucizumab at 0 week and were then followed up at every 4 weeks for detailed ophthalmic and OCT macula examination. Those who met the pre-defined re-treatment criteria were re-injected with Brolucizumab, the dose being fixed for each group throughout the study. All patient receiving an injection were further followed up on Day 1, Day 7 and Day 28 to look for any adverse reactions. The efficacy parameters included change in best corrected visusal acuity (BCVA), contrast and central macular thickness (CMT) on Optical Coherence Tomography. The average number of injections recd in each group were also calculated.

The change in BCVA from baseline in 6.0 mg group was 0.54 LogMAR units and 3.6 mg group was 0.59 LogMAR units, which was not statistically significant. The reduction in CMT from baseline in 6.0 mg group was 133.2 µm (μ) and 3.6 mg group was 110.6 μ, which was not statistically significant. The improvement in contrast from baseline in 6.0 mg group was 0.74 and 3.6 mg group was 0.95, with p value of 0.0002. The re-injection interval was 14.21 weeks in 6.0 mg group and 15.56 weeks for 3.6 mg subgroup. The total number of adverse events in both groups were similar at 70 in 6.0 mg group and 47 in 3.6 mg group with only one grade 4 adverse event occurring in each group.

The results of present study show that the safety and efficacy of both doses of Brolucizumab, i.e. 6.0 mg and 3.6 mg, for treating diabetic macular edema is similar. Trial registration Study was registered with Clinical trials registry of India (CTRI ref no. CTRI/2023/06/054105), registered on 14 Nov 2022.

 Diabetic retinopathy (DR), a leading cause of vision loss, is driven by inflammation, oxidative stress, and vascular endothelial growth factor (VEGF) production, with elevated blood glucose and advanced glycation end products (AGEs) exacerbating retinal damage. While intravitreal VEGF inhibitors have become the first-line treatment for diabetic macular edema (DME), response to therapy varies due to systemic factors such as HbA1c levels, blood pressure, and diabetes duration.

This study aims to assess the impact of glycosylated hemoglobin (HbA1c) control on the effectiveness of Ranibizumab treatment in patients with DR.

The study included 222 eyes from 222 patients with type 2 diabetes, comprising 60% males and 40% females, with an average age of 60.2 ± 9.32 years. Participants were administered monthly intravitreal injections of Ranibizumab, 0.05 mL of a 6 mg/mL solution, over three months, and an optical coherence tomography (OCT) was done one month after the treatment for the evaluation of the patient's need for further injections. HbA1c, central retinal thickness (CRT), and best-corrected visual acuity (BCVA) were measured at the beginning and end of the study. Patients were then divided into two groups according to their HbA1c level, with a cut-off point of 7% (53 mmol/mol).

At the beginning of the study, the HbA1c mean was 8.16% ± 1.2%, the BCVA mean was 59.7 ± 9.73, and the central macular thickness (CMT) mean was 465.4 ± 132.34 µm. Twelve months later, the 222 patients were separated into two groups based on HbA1c levels: 109 patients had an HbA1c >7% (group A) and 113 patients had an HbA1c ≤7% (group B). The improvement of BCVA was 6.1 ± 7.3 for group A versus 7.9 ± 6.1 for group B (P = 0.0478). The reduction in CMT was 164.2 ± 122.8 μm for group A versus 197.8 ± 125.1 μm for group B (P = 0.0447).

Our study indicates that HbA1c control influences the treatment outcomes of intravitreal Ranibizumab for DME, with better responses observed in patients whose HbA1c is below 7%.

Diabetic macular oedema (DME) is associated with significant loss of visual acuity. Intravitreal VEGF inhibitor injection is the gold standard in treating this disease; second-line treatment consists of intravitreal steroid injections. This treatment has already undergone extensive investigation in large randomised controlled trials. The aim of this study is to evaluate patient population and treatment options in a real-world setting.

A retrospective analysis was conducted on data from 176 eyes in 114 patients diagnosed with diabetic macular oedema who had received at least one intravitreal injection during 2018 at Marburg University Hospital Department of Ophthalmology. The analysis examined demographic characteristics, prior treatment, and treatments performed as well as visual acuity and central retinal thickness development during therapy. Multiple linear regression analyses were used to investigate the influence of different variables on changes in dependent variables in visual acuity (logMAR), changes in retinal thickness (µm), and number of injections, while also taking interactions between the independent variables themselves into account.

Patients were on average 64.45 ± 13.79 years old and predominantly male (61.93%). Most (71.59%) had already been treated for DME. Baseline visual acuity averaged 0.42 logMAR ± 0.34; baseline central retinal thickness averaged 369.1 µm ± 118.81. A total of 688 intravitreal injections were administered at 3.91 ± 2.22 per eye during the study period. Visual acuity improved by 0.04 logMAR ± 0.18 on average; eyes with poorer baseline visual acuity showed a greater increase in visual acuity. CRT values decreased by 44.54 µm ± 133.95 on average. Eyes with higher baseline values showed greater reduction. Using regression analysis, this is the first study to demonstrate that eyes may continue to require additional injections after prior treatment.

This study demonstrated the reality of treatment for patients with diabetic macular oedema at a German university clinic as accurately as possible. We were able to demonstrate the differences from RCTs and the characteristics of the patient cohort.

Introduction Macular edema causes decreased vision in diseases like diabetic retinopathy, uveitis, retinal vein occlusions and post-cataract surgery cystoid macular edema. Steroids in the depot form of triamcinolone acetonide (TA) increase the duration of action, but due to a number of complications, especially raising intraocular pressure (IOP), anti-vascular endothelial growth factor (anti-VEGF) injections are now considered the mainstay of treatment. The suprachoroidal space provides an alternate route for steroid delivery, limiting the drug to the posterior segment, hence preventing the adverse effects on the anterior segment. This study aimed to determine the safety of suprachoroidal steroids with respect to their effect on IOP. Methods This retrospective study involved patients who received suprachoroidal TA injections for macular edema: diabetic retinopathy, retinal vein occlusions, uveitis and cystoid macular edema post-cataract surgery at Layton Rahmatulla Benevolent Trust (LRBT) Free Eye Hospital, Lahore, Pakistan. Manual medical records from two years were accessed and all patients were included in the study. Patients with a history of ocular hypertension, glaucoma and steroid responsiveness had not received the injection. Crystalline steroid particles of 4 mg/0.1 mL, using an intravenous TA (K-Kort; GlaxoSmithKline, Brentford, UK), were injected into the suprachoroidal space through a 30-gauge syringe with a custom plastic sleeve from a 24-gauge branula exposing 0.1 mm of the bevel. IOP was recorded at baseline before the injection and at weeks 2, 4 and 8. Repeated measures multivariate analysis of variance (ANOVA) was used to compare IOP measurements at the different time intervals. Results A total of 61 patients were included, with 70 eyes being assessed, at a mean age of 54.2 ± 10.4 years. Baseline mean IOP was 16.41 ± 2.62 mmHg, 17.04 ± 3.09 mmHg at week 2, 16.30 ± 2.95 mmHg at week 4 and 15.73 ± 1.83 mmHg at week 8. Between baseline IOP and week 2, the mean difference was 1.11 ± 0.66 mmHg (p = 0.59), 0.26 ± 0.43 mmHg from week 2 to week 4 (p = 1.00), and 1.36 ± 0.51 mmHg from week 4 to week 8 (p = 0.51). The mean IOP decreased by 0.50 ± 0.53 mmHg (p = 1.00) from baseline by eight weeks. The differences between IOP, different causes of macular edema and age or gender were not statistically significant. Two patients (1.4%) had a temporary rise in IOP above 24 mmHg requiring ocular medication, with one having a rise above 30 mmHg. Conclusion A single injection of suprachoroidal TA temporarily raises the mean IOP, but the increase is insignificant and settles to baseline by two months. Further studies would be required to establish suprachoroidal triamcinolone as a cost-effective and safe treatment for macular edema.

Diabetic retinopathy is the major cause of vision failure in diabetic patients, and the current treatment involves the practice of glucocorticoids or VEGF antagonists that are "off-label". A few small organic molecules against DR were discovered many years ago. Nutraceuticals are naturally available functional foods that endorse different health benefits, including vitamins, antioxidants, minerals, fatty acids, and amino acids that can defer the development of some diseases.

Numerous studies reported that nutraceuticals encourage multiple therapeutic benefits and provide protection against various diseases. In diabetes, nutraceuticals contribute to improving insulin sensitivity, metabolism regulation, and lower hyperglycemia. The major aim of this study is to discover the most active drug from natural or plant sources. In this work, 42 phytochemical constituents from 4 kinds of plants were docked with the C4 target of diabetic retinopathy by an in silico molecular docking study.

According to the binding energy, all the phytoconstituents possessed good to high attraction towards the target, and 6 phytochemicals, such as terchebulin, punicalagin, chebulagic acid, casuarinin, punicalin, and pedunculagin, disclosed superior binding energy towards the target than standard ruboxistaurin via the interactions of conventional hydrogen bonding, pi-alkyl interactions, etc. Molecular dynamic simulation studies further established the stability of the phytoconstituents, and ADMET studies proved the safety profile of these phytoconstituents.

Hence, the current study suggested that the phytochemicals from various herbs inhibit the C4 target of diabetic retinopathy and can be utilized as lead compounds to develop analogs or repurposed for the treatment of DR.

To objectively assess the immediate response to intravitreal treatment for macular edema and compare it across different agents.

This retrospective, comparative study included patients with macular edema due to diabetic retinopathy (DME) or vein occlusion who were treated with intravitreal injections of either steroids (triamcinolone acetonide or dexamethasone sustained release implant) or anti-vascular endothelial growth factor antibodies (VEGF). The central retinal thickness (CRT) and the best corrected visual acuity (BCVA) were measured 1 day after the injection and compared with immediate pre-injection values.

There were 79 eyes (57 patients) including 51 eyes with DME, 18 with branch retinal vein occlusion edema (BRVO-ME), and 10 eyes with central retinal vein occlusion edema (CRVO-ME). The intravitreal agents were triamcinolone acetonide (TA)(n = 15), dexamethasone sustained release implant (DEX)(n = 22), ranibizumab (n = 19), and bevacizumab (n = 23). Statistically significant improvement in CRT was seen in all injection groups (p < 0.05) while improvement in mean BCVA was significant only in the TA group (p = 0.009). The mean change in CRT was maximum with steroids than with anti-VEGFs; viz. 159.47 µ in TA, 115.45 µ in DEX, 86.10 µ in ranibizumab, and 78.78 µ in bevacizumab group. Least amount of change was noted in the spongy type of macular edema (18.73 µ) while improvement in mean BCVA was statistically significant only in the cystoid group (p = 0.01).

Comparatively, steroid agents showed better immediate response to therapy than anti-VEGFs. Maximum reduction in central retinal thickness was seen following triamcinolone acetonide injection. Cystoid edema showed better immediate response than spongy retinal thickening.

Triamcinolone acetonide (TA) is a corticosteroid, and widely used in the treatment of eye diseases such as macular edema, proliferative vitreoretinopathy, and chronic uveitis. It's also used in diseases such as osteoarthritis and rheumatoid arthritis. Despite the width of its usage, it has toxicity in the eye. Nanogels are advantageous in applying toxic and low bioavailability drugs thanks to their swelling ability and stability. In the presented study, to minimize the disadvantages of TA, and to reach the drug into the back segment of the eye, TA-loaded chitosan (CS) nanogel (CS-TA Nanogel) has been prepared, and in vitro characterized. CS-TA nanogels were prepared by ionic gelation and characterized by SEM, FTIR, and TGA. Drug release profile, and in vitro cytotoxicity was determined to evaluate the efficacy of nanogels for intravitreal eye applications. DNA damage, and oxidative stress caused by nanogels in eye endothelial cells were investigated. CS and CS-TA nanogels were synthesized in the sizes range 200-300 nm with an overall positive charge surface. The loading efficiency of TA on nanogels was determined as 50%. Cells exposed to 250 µg/ml free TA showed 74% viability, while this rate was 90% in cells exposed to CS-TA nanogels. 8-OHdG levels were determined as 54.93 ± 1.118 ng/mL in control cells and 92.47 ± 0.852 ng/mL in cells exposed to 250 µg/ml TA. TA both induces oxidative stress and causes DNA damage in HRMEC cells. However, administration of TA with carrier increased cell viability, total antioxidant capacity, and reduced oxidative DNA damage.

Current treatments for retinal and choroidal neovascular diseases suffer from insufficient durability, including anti-vascular endothelial growth factor-A agents. It is, therefore, of interest to explore alternative methods that could allow for robust improvement in visual acuity with fewer injections required.

Literature review.

Among various preclinical and clinical studies in the literature, a promising approach is the use of suprachoroidal injection with viral and nonviral gene delivery vectors. Compared with other ocular injection methods, suprachoroidal injection has demonstrated wide biodistribution of injected agents and safety as an outpatient procedure. In terms of viral vectors, suprachoroidal injection of an adeno-associated virus 8 vector expressing an anti-vascular endothelial growth factor-A antibody fragment has shown an excellent safety profile and evidence of biological activity. In terms of nonviral vectors, lipid nanoparticles and polymeric nanoparticles both demonstrate strong promise for ocular gene therapy in large animal models. In particular, biodegradable poly(β-amino ester) nanoparticles show excellent biodistribution, safety, and efficacy for gene therapy via the suprachoroidal route. Nonviral nanoparticle approaches can have notable advantages over viral vectors in terms of carrying capacity, redosability, and manufacturing costs. An advantage of gene therapy is that once a delivery vector has been optimized, genetic cargos can be readily tailored without changing the safety, efficacy, and pharmacokinetic properties of the delivery vector.

This review highlights recent progress that has been made and compares viral and nonviral suprachoroidal gene delivery for the treatment of retinal and choroidal vascular diseases. Suprachoroidal gene therapy is an emerging biotechnology that holds substantial potential to make a translational impact in treating these diseases.

Diabetic retinopathy (DR) is a serious microvascular complication of diabetes mellitus and may result in irreversible visual loss. Laser treatment has been the gold standard treatment for diabetic macular edema and proliferative diabetic retinopathy for many years. Of late, intravitreal therapy has emerged as a cornerstone in the management of DR. Among the diverse pharmacotherapeutic options, anti-vascular endothelial growth factor agents have demonstrated remarkable efficacy by attenuating neovascularization and reducing macular edema, thus preserving visual acuity in DR patients.

Where adopted, Autonomous artificial Intelligence (AI) for Diabetic Retinal Disease (DRD) resolves longstanding racial, ethnic, and socioeconomic disparities, but AI adoption bias persists. This preregistered trial determined sensitivity and specificity of a previously FDA authorized AI, improved to compensate for lower contrast and smaller imaged area of a widely adopted, lower cost, handheld fundus camera (RetinaVue700, Baxter Healthcare, Deerfield, IL) to identify DRD in participants with diabetes without known DRD, in primary care. In 626 participants (1252 eyes) 50.8% male, 45.7% Hispanic, 17.3% Black, DRD prevalence was 29.0%, all prespecified non-inferiority endpoints were met and no racial, ethnic or sex bias was identified, against a Wisconsin Reading Center level I prognostic standard using widefield stereoscopic photography and macular Optical Coherence Tomography. Results suggest this improved autonomous AI system can mitigate AI adoption bias, while preserving safety and efficacy, potentially contributing to rapid scaling of health access equity. ClinicalTrials.gov NCT05808699 (3/29/2023).

Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the management of various ocular conditions, including diabetic macular edema (DME), retinal vein occlusion (RVO)-related macular edema (ME), and neovascular age-related macular degeneration (nAMD). However, there remains a need to systematically assess its effectiveness across these distinct conditions.

A systematic review was conducted to identify studies evaluating the efficacy of anti-VEGF therapy in improving ocular outcomes in patients with DME, RVO-related ME, and nAMD. PubMed, Embase, and Cochrane Library databases were searched for relevant articles published up to 2024. Studies meeting the inclusion criteria were critically appraised, and data on the proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in best-corrected visual acuity (BCVA), mean change in BCVA (ETDRS letters), and reduction in central macular thickness (CMT) (μm) were extracted and synthesized.

The systematic review identified 18 studies comprising randomized controlled trials, prospective studies, retrospective analyses, and observational studies. Anti-VEGF therapy demonstrated efficacy across all three conditions, with varying proportions of patients experiencing improvements in BCVA and reductions in CMT. Notably, the proportion of patients gaining ≥15 ETDRS letters ranged from 18.1% to 44.8% in DME, while mean changes in BCVA ranged from +4.2 letters to +21.4 letters in RVO-related ME and nAMD. Reductions in CMT ranged from 183.1 μm to 294 μm in DME and RVO-related ME.

Anti-VEGF therapy represents a cornerstone in the management of DME, RVO-related ME, and nAMD, with significant improvements observed in BCVA and reductions in CMT across diverse patient populations. While our findings support the effectiveness of anti-VEGF therapy in improving ocular outcomes, further research is warranted to compare its efficacy with alternative treatment modalities and to elucidate its long-term safety profile.

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.

In an aging population, the prevalence and burden of diabetes mellitus, diabetic retinopathy, and vision-threatening diabetic macular edema (DME) are only expected to rise around the world. Similarly to other complications of diabetes mellitus, DME requires long-term management. This article aims to review the current challenges associated with the long-term management of DME, opportunities to improve outcomes for patients, and to develop a treat-to-target strategy based on macular morphology. At present, intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for the management of DME; however, best-achievable vision outcomes with treatment are reliant on frequent injections and close monitoring, which are difficult to maintain in current clinical practice because of the burden this imposes on patients. Achieving and maintaining good vision with treatment are the most important factors for patients with DME. Landmark trials have shown that vision gains with anti-VEGF therapy are typically accompanied by anatomical improvements (e.g., reductions in retinal thickness); therefore, multimodal imaging measures of macular morphology are often used in patients with DME to guide real-world treatment decisions. We would like to propose a hypothetical treat-to-target algorithm to guide physicians on treatment strategies for the long-term management of DME. Alternative measures of retinal fluid (e.g., persistence, stability, location) may be stronger predictors of visual acuity in DME, although further research is required to confirm whether alternate quantifiable biomarkers such as subretinal fluid and intraretinal fluid volumes can be used as a biomarker of clinical improvement. Identifying novel biomarkers and treatments that target neuroinflammation and neurodegeneration, improving patient-physician communication around treatment adherence, and using treat-to-target measures may help to ensure that the long-term benefits of treatment are realized.

Intravitreal ranibizumab for diabetic macular oedema (DMO) has been recently shown to modulate levels of aqueous cytokines. This study investigates the associations between changes in aqueous cytokine levels following intravitreal ranibizumab therapy and the corresponding anatomical and functional changes in the eye.

Twenty-five patients comprising 30 eyes diagnosed with DMO were prospectively recruited. All eyes received three loading dose ranibizumab injections at baseline, week 4 and week 8, followed by pro re nata treatment based on best-corrected visual acuity (BCVA) and central macular thickness (CMT) up to week 48. Prior to ranibizumab administration, aqueous samples were collected from all eyes, and subsequent sampling was performed at week 8. Levels of 32 cytokines were assessed at baseline and at week 8.

At baseline, higher aqueous TNF-α levels were associated with poorer BCVA (p = 0.033), greater macular volume (p = 0.017) and worse diabetic retinopathy (p = 0.047). Higher levels of IL-7 were associated with poorer BCVA and greater macular volume (MV). Following treatment with ranibizumab there was a significant correlation with reduction of aqueous TNF-α and improvements in BCVA and MV, both at 6 months (BCVA [r = -0.558, p = 0.001], MV [r = 0.410, p = 0.024]) and 12-months (BCVA [r = -0.413, p = 0.023], MV [r = 0.482, p = 0.008]). The change in VEGF concentration following ranibizumab treatment did not correlate with either BCVA or MV improvements (p > 0.05).

Higher levels of aqueous TNF-α and IL-7 correlated with worse DMO, both anatomically and functionally. Reductions in levels of aqueous TNF-α, but not VEGF, post ranibizumab treatment were associated with improvement in BCVA and MV.

Diabetic retinopathy (DR) is a significant complication of diabetes mellitus that can lead to progressive visual impairment. This study aimed to elucidate the role of fibrinogen, a protein whose serum and intraocular concentrations are elevated in patients with diabetes and DR, in the pathogenesis of DR.

The changes in the protein levels of the neuronal marker tubulin-β3 (TUBB3) and retinal response induced by the intravitreal injections of 1× phosphate-buffered saline, 40 mg/mL of fibrinogen, and 40 mg/mL of fibrinogen in combination with anti-intracellular adhesion molecule-1 (ICAM-1) antibody in normal mice were observed using immunofluorescence, western blotting, and electroretinography.

High concentrations of fibrinogen led to a decrease in the expression of TUBB3 in immunofluorescence and western blotting. The amplitudes of the positive scotopic threshold response and b-wave were notably reduced after the injection of fibrinogen, indicating potential damage to the retinal ganglion cells. The co-administration of anti-ICAM-1 antibody effectively mitigated these fibrinogen-induced changes, indicating that fibrinogen-induced damage is mediated via the ICAM-1 pathway.

The present study underscores the significance of elevated intraocular fibrinogen levels as a pathogenic factor in DR. Involvement of the fibrinogen/ICAM-1 pathway presents new avenues for therapeutic intervention, especially in patients with treatment-resistant conditions.

Despite the wide range of treatment options available for diabetic macular edema (DME), adherence to treatment remains a barrier. Therefore, this study used conjoint analysis to examine the factors that patients with DME prioritize when choosing a course of treatment and investigated differences in quality of life and levels of disease self-management in patients with or without experience of anti-vascular endothelial growth factor (VEGF) treatment.

A cross-sectional study was conducted through an online survey in Japan between May 31, 2022, and June 30, 2022. Questionnaires were sent to 27,236 individuals registered in the diabetes panels, with experience of treatment for DME within the last 10 years. Conjoint analysis was employed to calculate the relative importance, i.e., degree of influence on patients' treatment choices, considering the trade-offs among five factors: cost per treatment, frequency of visits, anticipated post-treatment visual acuity, physician's explanation about disease and treatment, and frequency of treatment-related side effects.

A total of 237 responses were used to assess the relative importance of cost per treatment, frequency of visits, anticipated post-treatment visual acuity, physician's explanation about the disease, treatment, and frequency of treatment-related side effects using conjoint analysis. The importance of each factor was anticipated post-treatment visual acuity at 30.0, frequency of treatment-related side effects at 25.5, treatment frequency at 17.7, cost per treatment at 16.5, and physician explanation about the disease and treatment at 10.4. The average EuroQoL 5 dimension 5 level index value in patients with and without anti-VEGF treatment experience was 0.785 and 0.825, respectively, with no major difference.

Anticipated post-treatment visual acuity was identified as the most important factor in selecting a treatment regardless of the anti-vascular endothelial growth factor treatment experience demonstrating when patients with DME make treatment choices, anticipated post-treatment visual acuity is prioritized over treatment frequency and cost.

This review aims to elucidate the mechanisms and clinical utility of subthreshold micropulse laser (SML) therapy in the context of retinal care. Subthreshold or "nondestructive" laser therapy encompasses treatment modalities that induce minimal or no harm to retinal or choroidal tissue and leave no visible sings post-application, while achieving clinical efficacy.

A comprehensive review of literature sourced from databases including PubMed, Medline, Embase, Cochrane, and Web of Science was conducted, focusing on articles published before February 2024, and discussing the contemporary use of SML therapy in treating diabetic retinopathy (DR).

The review presents evidence from scientific literature supporting SML therapy as a viable therapeutic approach for management of DR. Across numerous studies, SML therapy has demonstrated safety and additional therapeutic efficacy without causing damage to underlying retinal tissue.

Subthreshold laser treatment emerges as a safe strategy for addressing DR. Numerous studies have shown its additional efficacy to anti-VEGF pharmacotherapy, which is the currently approved monotherapy for complications of DR. Ongoing research and clinical investigations aim to further elucidate the mechanisms and optimize the therapeutic advantages of this technology.

Aim of the study was to evaluate the efficacy of dexamethasone (DEX) 0.7 mg intravitreal implant in patients with diabetic macular edema (DME) and serous retinal detachment (SRD), and to study the prognostic factors on a follow up of 12 months.

Forty eyes of twenty- six patients with centre involving DME and SRD, who underwent DEX implant, were enrolled. Best-corrected visual acuity (BCVA), Swept source OCT imaging and intraocular pressure were evaluated. Central macular thickness (CMT), vitreomacular adhesion (VMA), disorganization of retinal inner layers (DRILs), hyperreflective dots (HRD), SRD and ellipsoid zone (EZ) disruption were included in the analysis at baseline and 12 months after implant.

According to our parametric analysis, at 12 months, BVCA improvement from 48.6 ± 23.4 letters to 53.3 ± 24.5 letters was statistically significant (p = 0.04), CMT decreased from 460 ± 99.52 μm to 322.9 ± 117 μm. The presence at baseline of VMA (p = 0.01), EZ disruption (p = 0.03) and DRILs (p = 0.04), were associated with poor BCVA improvement at the end of follow-up.

In conclusion, OCT biomarkers can be considered significant prognostic factors for treatment outcome in patients with DME undergoing DEX intravitreal implant.

To characterize anti-VEGF intravitreal therapy (IVT) patterns and long-term visual outcomes among patients with diabetic macular edema (DME) in routine clinical practice in the United States.

Retrospective analysis of the American Academy of Ophthalmology's IRIS® (Intelligent Research in Sight) Registry.

Treatment-naïve patients with DME (no previous IVT in the past 12 months) initiating anti-VEGF IVT from January 1, 2015, to March 31, 2021.

Baseline characteristics, treatment patterns, and long-term visual acuity (VA) outcomes were reported for up to 6 years of follow-up.

Outcomes included the annualized number of injections, change in VA, and anti-VEGF agents.

A total of 190 345 eyes met the inclusion criteria. After 1 year of anti-VEGF IVT initiation, eyes received a mean of 3.9 (±2.8) injections and gained +3.2 (±16.4) letters of vision. Of the 1236 eyes with year 6 data, eyes received a mean of 2.9 (±2.1) injections in year 6 and gained +0.5 (±19.7) letters from baseline. The number of injections decreased, and injection intervals increased year over year up to 6 years regardless of baseline VA initiation. The average injection interval was 10 weeks in year 1 and increased to 13.2 weeks in year 2 before plateauing in years 3 to 6 (12.6, 12.3, 12.2, and 12.3 weeks, respectively). Improvements in VA from baseline were greatest in eyes that received 5 or more injections each year. At the end of follow-up, eyes with good baseline vision (>20/25) lost vision, whereas those with worse baseline vision (<20/25) gained vision. Although 51.7% of patients with DME discontinued IVT after a mean of 6 months, 32.8% reinitiated anti-VEGF IVT. Worse VA outcomes were associated with patients of Hispanic ethnicity (-1.08; 95% confidence interval: -1.34, -0.83] compared with non-Hispanic), Medicaid insurance (-1.15; 95% confidence interval: -1.48, -0.81 compared with commercial), and older age (-0.06; 95% confidence interval: -0.07, -0.05] each additional year).

Patients with DME in routine clinical settings receive fewer injections than those in clinical trials and fewer than recommended per the label of US Food and Drug Administration-approved anti-VEGF IVT.

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

To determine the correlation between the severity of chronic kidney disease (CKD) and treatment of diabetic macular edema (DME). The retrospective 2-year cohort study included eyes with DME confirmed using spectral-domain optical coherence tomography in Taipei Veterans General Hospital, Taiwan, between 2010 and 2020. All the eyes were treated with an intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) during regular follow-up around 2 years. They were categorized into 3 different groups: an estimated glomerular filtration rate ≥ 60 (mL/min per 1.73 m2) (group A), < 60 (group B), and patients undergoing hemodialysis (group C). The main outcome measures were (1) visual improvement, (2) structural improvement, and (3) the injection frequency of anti-VEGF in the different groups. In this study, 167 eyes from 120 patients were enrolled. Compared with groups B and C, the eyes in group A experienced the only significant visual improvement at month 3, month 6, and month 12 (P = 0.0001, 0.0002, 0.0013, respectively). The presence of subretinal fluid and intraretinal cysts was significantly decreased in groups A and B. In the treatment frequency analysis, the number of injections was the highest in group A and lowest in group C during the study period (P = 0.04). The severity of CKD had an impact on the DME treatment. The less severe CKD was, the greater the visual improvement that could be achieved. In addition, relatively poor renal function required a lower anti-VEGF injection frequency. The active prevention of the progression of CKD may play a key role in DME treatment.

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.

Introduction: To compare the safety and efficacy of antivascular endothelial growth factor (anti-VEGF) monotherapy vs anti-VEGF and steroid combination therapy in treatment-naïve and treatment-resistant patients with diabetic macular edema (DME). Methods: A systematic literature search was conducted from January 2005 to December 2022. Sixteen randomized control trials (RCTs) published in English that reported the efficacy or safety of monotherapy and combination therapy in patients with DME were included. Results: The 16 RCTs included 1166 eyes. Monotherapy was associated with a significantly better best-corrected visual acuity (BCVA) at the final follow-up (weighted mean difference [WMD], -0.04 logMAR; 95% CI, -0.07 to -0.02; P = .002; I 2 = 0%). No significant differences were observed in the change in BCVA between groups at the final observation. Monotherapy was associated with a significantly smaller change in retinal thickness at the final follow-up (WMD, 37.63 μm; 95% CI, 11.67-63.60; P = .005; I 2 = 78%) and with a significantly lower risk for intraocular pressure-related adverse events (AEs) (risk ratio, 0.27; 95% CI, 0.15-0.46; P ≤ .001; I 2 = 0%). The risk for cataract-related AEs was not significantly different between groups (P = .06). The results in treatment-naïve patients were similar. In treatment-resistant patients, the change in retinal thickness at the final follow-up was similar between groups (P = .14) but the risk for cataract-related AEs was significantly lower in the monotherapy group in 2 RCTs (risk ratio, 0.09; 95% CI, 0.01-0.66; P = .02; I 2 = 0%). Conclusions: The changes in BCVA were similar despite combination therapy being associated with greater changes in retinal thickness. However, increased complications were seen with combination therapy. Most results in treatment-naïve patients and treatment-resistant patients were similar.

The modern treatment of chorioretinal vascular diseases follows the recent development and rapid adoption of drugs that inhibit vascular endothelial growth factor (VEGF). All anti-VEGF drugs are delivered intravitreally, with clinical behavior, including efficacy, durability, and safety, largely determined by their pharmacokinetic properties.

Properties of these new drugs include additional binding targets (placental growth factor (PlGF) and angiopoietin 2 (Ang 2)), binding affinity, potency, intravitreal half-life, and increased molar dose. A PubMed search for 'pharmacokinetics of anti-VEGF drugs' was performed from 2000 to 2023. Relevant studies were reviewed and referred to in the manuscript.

Early developers concentrated on improving efficacy, but since maximum efficacy with VEGF inhibition has been reached, development has pivoted to extending the duration of action. Durability strategies include inhibiting additional pathways (faricimab), increasing molar dose (abicipar, brolucizumab, faricimab, and aflibercept 8 mg), and prolonging the intravitreal half-life (abicipar and KSI-301). Recent phase 3 trials demonstrated modest improvements in durability, but failures that might be attributed to these strategies (conjugation and manufacturing processes) have occurred. Future drug development focuses on extending duration of action with implantable reservoirs (ranibizumab port delivery system), sustained release devices (tyrosine kinase inhibitors), and gene therapy.

To investigate the effects of two laser treatment procedures combined, short pulse grid laser (SP) and subthreshold micropulse laser (MP) (the sandwich grid [SWG] technique), plus intravitreal ranibizumab (IVR) on central subfield thickness (CSFT), best-corrected visual acuity (BCVA) and macular sensitivity in patients with diabetic macular edema (DME).

Forty-five eyes (of 33 patients) with center-involving DME were treated with the SWG laser technique plus IVR and followed for 12 months. Laser treatment was performed at baseline: SP laser spots were placed in a grid pattern in the macular area (500 µm from the fovea) according to the extension of DME; subsequently, MP laser was delivered up to the edge of the fovea. MP laser re-treatment sessions could be performed every 3 months if DME was present and CSFT was ≥ 300 μm on SD-OCT. IVR injection was performed at baseline and repeated monthly if CSFT > 300µm. Preoperatively and monthly, ophthalmological examination was performed including measurements of BCVA, CSFT, and macular sensitivity.

One-year follow-up data is available for 37 eyes of 27 patients. Mean ± SE CSFT (µm) was 509.36 ± 25.14 and 325.76 ± 15.34 at baseline and 12 months, respectively. A significant reduction in mean CSFT was observed at all study visits compared to baseline (p < 0.001). Mean ± SE BCVA (logMAR) was 0.62 ± 0.04 and 0.45 ± 0.04 at baseline and 12 months, respectively. A significant improvement in mean BCVA was observed at all study visits compared to baseline (p < 0.001). Mean ± SE macular sensitivity (dB) was 17.85 ± 0.80 and improved to 19.05 ± 0.59 after one year of follow-up (p = 0.006). The mean number of IVR injections was 8.29 ± 0.63. The mean number of MP laser procedures including the initial SWG laser session was 3.67 ± 0.22. No ocular or systemic adverse effects were observed.

The SWG laser technique plus IVR was associated with significant improvement in macular edema, BCVA, and macular sensitivity in patients with center-involving DME.

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