Association between Glucose-lowering Treatments and Risk of Diabetic Retinopathy in People with Type 2 Diabetes: A Nationwide Cohort Study.

INTRODUCTION: Glycaemic variability is possibly linked to the development of diabetic retinopathy, and newer second-line glucose-lowering treatments in type 2 diabetes might reduce glycaemic variability. AIM: This study aimed to investigate whether newer second-line glucose-lowering treatments are associated with an alternative risk of developing diabetic retinopathy in people with type 2 diabetes. METHODS: A nationwide cohort of people with type 2 diabetes on second-line glucose-lowering treatment regimens in 2008-2018 was extracted from the Danish National Patient Registry. Adjusted time to diabetic retinopathy was estimated with a Cox Proportional Hazards model. The model was adjusted for age, sex, diabetes duration, alcohol abuse, treatment start year, education, income, history of late-diabetic complications, history of non-fatal major adverse cardiovascular events, history of chronic kidney disease, and history of hypoglycaemic episodes. RESULTS: Treatment regimens of metformin + basal insulin (HR: 3.15, 95% CI: 2.42-4.10) and metformin + glucagon-like peptide-1 receptor agonist (GLP-1-RA, HR: 1.46, 95% CI: 1.09-1.96) were associated with an increased risk of diabetic retinopathy compared with metformin + dipeptidyl peptidase-4 inhibitors (DPP-4i). Treatment with metformin + sodium-glucose cotransporter-2 inhibitor (SGLT2i, HR: 0.77, 95% CI: 0.28-2.11) was associated with the numerically lowest risk of diabetic retinopathy compared with all regimens investigated. CONCLUSION: Findings from this study indicate that basal insulin and GLP-1-RA are suboptimal second- line choices for people with type 2 diabetes at risk of developing diabetic retinopathy. However, many other considerations concerning the choice of second-line glucose-lowering treatment for type 2 diabetes patients should be taken into account.

Risk of Diabetic Retinopathy in Patients With Type 2 Diabetes After SGLT-2 Inhibitors: A Nationwide Population Cohort Study.

Diabetic retinopathy (DR) accounts for 80% of cases of vision loss in patients with type 2 diabetes mellitus (T2DM). Interventional treatments are only indicated in advanced DR and are ineffective in some patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are used to attenuate T2DM-associated cardiovascular complications. We conducted the cohort study to investigate the effect of SGLT2is on DR development. Data (May 2016-December 2018) obtained from the Taiwan National Health Insurance Research Database were analyzed in this nationwide retrospective cohort study. After propensity score matching, a total of 31,764 patients receiving SGLT2is and another 31,764 patients receiving dipeptidyl peptidase 4 inhibitors (DPP4is) were included in this study. Multiple Cox proportional-hazards regression models were used to evaluate DR risk. Overall DR incidence among SGLT2i or DPP4i users was 10.9 or 15.6 per 10,000 patient-years, respectively. After covariate adjustment, DR (both early and late stage) risk was substantially lower in SGLT2i users (adjusted hazard ratio: 0.68, 95% confidence interval: 0.6-0.78) than in DPP4i users. DR risk appears to be considerably lower in SGLT2i users than in DPP4i users. Glycemic control measurement with HbA1C level was unavailable in this claim database.

Effectiveness Differences of Ranibizumab and Aflibercept Action in the Treatment of Diabetic Retinopathy.

Objective: To compare the difference in the effectiveness of ranibizumab (LU) and aflibercept (AF) in the treatment of diabetic retinopathy (DR). Methods: Ninety-four patients with DR admitted to Sunshine Union Hospital from August 2020 to February 2022 were selected for the study and were divided into LU group (n = 47) and AF group (n = 47) according to the random number table method. Both groups underwent 25G vitrectomy in our hospital, with LU injected into the vitreous before surgery in the LU group and AF in the AF group. Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in the pre-and post-injection atrial water were compared between the two groups, and the operative time, intraoperative bleeding, and the occurrence of medically induced fissures were recorded in both groups. In addition, the expression of best corrected visual acuity (BCVA), Central Macular Thickness (CMT), and inflammatory factors were compared before and after surgery. Finally, patients were counted for adverse reactions and prognosis of DR recurrence during treatment. Results: After injection, VEGF decreased and PEDF increased in both groups (P < .001). There were no differences in operative time (P = .604), intraoperative bleeding rate (P = .694), the incidence of medically induced fissure (P = .557), BCVA [P = .665 (T0), P > .999 (T1), P = .727 (T2)], and CMT [P = .688 (T0), P = .065 (T1), P = .148 (T2)] between the two groups, while IL-6, IL-8, and MMP-9 were lower in the AF group than in the LU group at 2 months after surgery (P < .001). Finally, there was no difference between both groups in terms of adverse effects and prognosis of DR recurrence rate (P = 1.000, .478). Conclusion: Both vitreous cavity injections of LU and AF can effectively reduce the expression of vascular-related factors in the atrial fluid of DR patients, but AF has a more significant inhibitory effect on the level of inflammatory factors in patients in the short term after treatment.

Applications of nanomaterials in anti-VEGF treatment for ophthalmic diseases.

Angiogenesis has been determined to be essential in the occurrence and metastasis of diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal vein occlusion (RVO), choroidal neovascularization (CNV), retinopathy of prematurity (ROP), tumor, etc. However, the clinical use of anti-vascular endothelial growth factors (VEGF) drugs is currently limited due to its high cost, potential side effects, and need for repeated injections. In recent years, nanotechnology has shown promising results in inhibiting neovascularization and reducing reactive oxygen species (ROS) or inflammatory factors. Some nanomaterials can also act as vehicles for drug delivery, such as lipid nanoparticles and PLGA. The process of angiogenesis and its molecular mechanism are discussed in this article. At the same time, this study aims to systematically review the research progress of nanotechnology and offer more treatment options for neovascularization-related diseases in clinical ophthalmology.

Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Retinopathy in Patients With Type 2 Diabetes.

Importance: Diabetic nephropathy and diabetic retinopathy share many similarities in pathophysiological processes. Preclinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have a protective role in the risk of diabetic retinopathy. Objective: To compare the risk of sight-threatening retinopathy associated with SGLT2is and other second-line glucose-lowering medications (including pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors [DPP-4is]) in patients with type 2 diabetes (T2D). Design, Setting, and Participants: This cohort study in Taiwan applied a new-user and active-comparator design. Patient demographic and clinical data were obtained from the National Health Insurance Research Database. Adult patients with newly diagnosed T2D from January 1, 2009, to December 31, 2019, were recruited and followed up until December 31, 2020. Propensity score matching was used to identify pairs of patients treated with SGLT2i vs DPP-4i, SGLT2i vs pioglitazone, and SGLT2i vs sulfonylurea from January 1, 2016, to December 31, 2019. Data were analyzed between August 18, 2022, and May 5, 2023. Exposures: Treatment with SGLT2i, DPP-4i, pioglitazone, and sulfonylureas starting on January 1, 2016. Main Outcomes and Measures: The main outcome was sight-threatening retinopathy in participants. Cox proportional hazards regression models were used to assess relative hazards of sight-threatening retinopathy between the matched case and control groups. Results: A total of 3 544 383 patients with newly diagnosed T2D were identified. After 1:1 propensity score matching, 65 930 pairs of patients treated with SGLT2i vs DPP-4i, 93 760 pairs treated with SGLT2i vs pioglitazone, and 42 121 pairs treated with SGLT2i vs sulfonylurea were identified. These matched patients included 236 574 males (58.6%), with a mean (SD) age of 56.9 (11.8) years. In the matched cohorts, SGLT2i had a significantly lower risk of sight-threatening retinopathy than DPP-4i (adjusted hazard ratio [AHR], 0.57; 95% CI, 0.51-0.63), pioglitazone (AHR, 0.75; 95% CI, 0.69-0.81), and sulfonylureas (AHR, 0.62; 95% CI, 0.53-0.71). The Kaplan-Meier curves showed that SGLT2i was associated with a significantly lower cumulative incidence of sight-threatening retinopathy than DPP-4i (3.52 vs 6.13; P < .001), pioglitazone (4.32 vs 5.76; P < .001), and sulfonylureas (2.94 vs 4.67; P < .001). Conclusions and Relevance: This cohort study found that SGLT2i was associated with a lower risk of sight-threatening retinopathy compared with DPP-4i, pioglitazone, and sulfonylureas. This finding suggests that SGLT2i may play a role not only in reduced risk of diabetic nephropathy but also in the slow progression of diabetic retinopathy in patients with T2D.

Modified early intensive and treat-and-extend regimen of anti-vascular endothelial growth factor for diabetic macular edema in Taiwan.

Given the rising prevalence of patients with diabetes and increasing treatment burden for patients with vision-threatening diabetic macular edema (DME), we aimed to explore the efficacy of modified early intensive and treat-and-extend regimen of anti-vascular endothelial growth factor (VEGF) therapy under the Taiwan National Insurance Bureau reimbursement policy. We obtained data on 69 eyes treated with initial 4-monthly intravitreal injections of aflibercept or ranibizumab, plus individualized treat-and-extend regimen. At 12 months, the mean (SD) change in LogMAR best corrected visual acuity from baseline was - 0.28 (0.31) in all eyes, while that in the aflibercept and ranibizumab groups were - 0.30 (0.34) and - 0.25 (0.28), respectively. Central retinal thickness decreased by 137.2 (122.4) in all eyes, 138.1 (134.2) in the aflibercept group, and 136.2 (110.9) in the ranibizumab group. Additionally, the aflibercept group had a lower mean number of injections than the ranibizumab group (8.5 vs. 8.7). The last extended dosing interval of > 12 weeks was 31.0% and 16.7% of the eyes in the aflibercept and ranibizumab groups, respectively. The modified anti-VEGF regimens effectively managed DME in terms of functional and anatomical outcomes, and efficiently reduced the healthcare burden by reducing the number of injections and extending treatment intervals within 12 months.

Acute Kidney Injury from Intravitreal Anti-vascular Endothelial Growth Factor Drugs: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Several observational studies have reported acute kidney injury from intravitreal anti-vascular endothelial growth factor (anti-VEGF) drugs for retinal diseases. However, systematic reviews and meta-analyses of randomized controlled trials on this critical topic are scant. OBJECTIVE: To evaluate acute kidney injury risk associated with intravitreal anti-VEGF drugs in patients with retinal diseases. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials on 12 July, 2023, and included randomized controlled trials reporting acute kidney injury between anti-VEGF drugs (e.g., aflibercept, bevacizumab, brolucizumab, and ranibizumab) and controls for retinal diseases (e.g., age-related macular degeneration, polypoidal choroidal vasculopathy, diabetic retinopathy/diabetic macular edema, retinal vein occlusion, and myopic choroidal neovascularization). Data were synthesized by a fixed-effects model for pooling odds ratios (ORs) using the Peto method. RESULTS: We included 13 randomized controlled trials (four and nine trials for aflibercept and ranibizumab, respectively) with a total of 4282 participants. The meta-analysis indicated intravitreal anti-VEGF drugs did not increase the acute kidney injury risk, compared with controls (odds ratio [OR]: 1.00, 95% confidence interval [CI] 0.49-2.04, I2: 0%), and no differences in the acute kidney injury risk were observed between different anti-VEGF drugs (OR: 1.10, 95% CI 0.27-4.43, I2: 0% for aflibercept; OR: 0.97, 95% CI 0.42-2.22, I2: 0% for ranibizumab) and between different retinal diseases (OR: 4.61, 95% CI 0.07-284.13, I2: not applicable for age-related macular degeneration; OR: 0.90, 95% CI 0.42-1.93, I2: 0% for diabetic retinopathy/diabetic macular edema; OR: 1.57, 95% CI 0.16-15.88, I2: 0% for retinal vein occlusion). CONCLUSIONS: Intravitreal anti-VEGF drugs were not associated with an acute kidney injury risk, regardless of which anti-VEGF drugs (aflibercept or ranibizumab) or retinal diseases (age-related macular degeneration, diabetic retinopathy/diabetic macular edema, or retinal vein occlusion) were involved. SYSTEMATIC REVIEW PROTOCOL REGISTRATION: PROSPERO CRD42021267854.

Evaluating initial responses to brolucizumab in patients undergoing conventional anti-VEGF therapy for diabetic macular edema: a retrospective, single-center, observational study.

Our retrospective, single-center, observational study aimed to evaluate the initial responses to intravitreal injection of brolucizumab (IVBr) in patients undergoing anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). In total, 23 eyes of 20 patients with DME treated with at least one intravitreal injection of ranibizumab or aflibercept within one year and then switched to IVBr were included. Best corrected visual acuity (BCVA), central macular thickness (CMT), and macular volume (MV) on optical coherence tomography images were evaluated just before the most recent conventional anti-VEGF (ranibizumab/aflibercept) injection therapy (V1), one month after the most recent traditional anti-VEGF therapy (V2), just before the first IVBr (V3), and one month after the first IVBr (V4). BCVA, CMT, MV, and presence of intraocular inflammation (IOI) were evaluated at each visit. Anterior chamber flare values were also examined at V3 and V4. BCVA showed significant improvement at V2 (0.30 ± 0.23) than V1 (0.39 ± 0.29) and at V4 (0.34 ± 0.26) than V3 (0.48 ± 0.34) (P = 0.002, P < 0.001). However, no significant difference was observed between V2 and V4 (P = 0.257). CMT was significantly thinner at V2 (346.8 ± 90.2 µm) than V1 (495.5 ± 123.8 µm), and at V4 (322.2 ± 95.7 µm) than V3 (536.5 ± 166.0 µm) (P < 0.001, P < 0.001), but no significant difference was observed between V2 and V4 (P = 0.140). MV was significantly smaller at V2 (11.6 ± 2.0 mm3) than V1 (12.6 ± 1.9 mm3) and at V4 (11.2 ± 2.0 mm3) than V3 (12.6 ± 2.0 mm3) (P < 0.001, P < 0.001), and even significantly smaller at V4 than V2 (P = 0.009). No patient had IOI. No significant changes were observed in anterior chamber flare values between V3 and V4 (25.6 ± 14.6 vs. 24.0 ± 11.5 photon count/ms; P = 0.543). Both CMT and MV significantly reduced without any adverse events one month after switching from conventional anti-VEGF to IVBr therapy for DME, including IOI. MV was significantly lower for IVBr than anti-VEGF therapy after one month of treatment. Therefore, brolucizumab may be a viable treatment option for DME patients considering switching from conventional anti-VEGF agents for various reasons, such as poor response or inability to extend dosing intervals.

Efficacy and safety profile of intravitreal dexamethasone implant versus antivascular endothelial growth factor treatment in diabetic macular edema: a systematic review and meta-analysis.

To better understand the efficacy of intravitreal dexamethasone implant (Ozurdex) versus antivascular endothelial growth factor (anti-VEGF) treatment in patients with diabetic macular edema (DME). A systematic review and meta-analysis. The study included randomized control trials (RCTs) and non-randomized control trials (Non-RCTs) before December 2021 that compare the efficacy of Ozurdex-related therapyand anti-VEGF therapy. We searched PubMed, Cochrane Library, and EMBASE. The quality of the included studies was assessed carefully. 30 studies were included. Regarding BCVA change, the overall result revealed no significant differences between Ozurdex and anti-VEGF therapies in patients with nonresistant DME, but Ozurdex group had significantly more VA improvement than anti-VEGF therapies in patients with resistant DME (MD 0.12, 95% CI 0.02-0.21). In terms of central retinal thickness (CRT) decrease, there was a significant difference between Ozurdex therapy and anti-VEGF therapy in patients with nonresistant DME (MD 48.10, 95% CI 19.06-77.13) and resistant DME (MD 65.37, 95% CI 3.62-127.13). Overall, Ozurdex therapy resulted in significantly greater VA improvement and CRT decrease than anti-VEGF therapy in resistant DME patients. Ozurdex therapy was not inferior to anti-VEGF therapy in patients with nonresistant DME.

Glucagon-like peptide-1 receptor agonists and diabetic retinopathy: nationwide cohort and Mendelian randomization studies.

BACKGROUND: The ability of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to decrease certain microvascular events has called for the investigation of GLP-1 RAs against diabetic retinopathy (DR), but the evidence is limited. By combining data from observational and Mendelian randomization (MR) studies, we aimed to investigate whether GLP-1 RAs decrease the risk of DR. METHODS: We combined data from several Swedish Registers and identified patients with incident type 2 diabetes being treated with GLP-1 RAs between 2006 and 2015, and matched them to diabetic patients who did not use GLP-1 RAs as the comparisons. The Cox proportional hazards models were applied to assess the risk of DR. We further performed the summary-data-based MR (SMR) analyses based on the Genotype-Tissue Expression databases and the Genome-Wide Association Study of DR from the FinnGen consortium. RESULTS: A total of 2390 diabetic patients were treated with GLP-1 RAs and the incidence of DR was 5.97 per 1000 person-years. Compared with diabetic patients who did not use GLP-1 RAs having an incidence of 12.85 per 1000 person-years, the adjusted hazard ratio (HR) of DR was 0.42 [95% confidence interval (CI), 0.29-0.61]. Genetically-predicted GLP1R expression (the target of GLP-1 RAs) showed an inverse association with background [odds ratio (OR)=0.83, 95% CI, 0.71-0.97] and severe nonproliferative DR (OR=0.72, 95% CI, 0.53-0.98), and a non-significant association with overall (OR=0.97, 95% CI, 0.92-1.03) and proliferative DR (OR=0.98, 95% CI, 0.91-1.05). CONCLUSIONS: Both observational and mendelian randomization analyses showed a significantly lower risk of DR for patients treated with GLP-1 RAs, which calls for further studies to validate these findings.

Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes.

AIM: Glucagon-like peptide-1 receptor agonists improve glycaemic control: some are now available as oral and subcutaneous formulations, and some have indications for reducing cardiovascular risk. The expanded scope for these therapies warrants comprehensive safety evaluations. We report the safety/tolerability of subcutaneous and oral semaglutide from the SUSTAIN and PIONEER clinical trial programmes, respectively. MATERIALS AND METHODS: Adverse events (AEs) from 16 randomized placebo- or active-controlled phase IIIa trials in patients with type 2 diabetes (n = 11 159) including once-weekly subcutaneous semaglutide (n = 3150; SUSTAIN trials) or once-daily oral semaglutide (n = 4116; PIONEER trials) were analysed. Data pools were analysed for each programme, with separate analyses of cardiovascular outcomes trials (CVOTs; n = 6480). RESULTS: In the phase IIIa pools, gastrointestinal disorders were reported in 41.9%/39.1% of patients with subcutaneous/oral semaglutide, respectively (most prevalent during initiation/escalation) versus 22.0%/24.8% with comparators. Rates of kidney disorders, acute pancreatitis, malignant neoplasms, hypoglycaemia, diabetic retinopathy, heart failure and other cardiovascular events were similar for semaglutide versus comparators. Cholelithiasis incidence was higher with subcutaneous and oral semaglutide versus placebo. Diabetic retinopathy incidence was higher with subcutaneous semaglutide versus placebo in SUSTAIN 6. Small pulse rate increases occurred with both formulations; there was no increased rate of arrhythmias. Fatal AE incidence was similar between semaglutide and comparators. Versus placebo, CVOTs showed a reduced risk of major adverse cardiovascular events with subcutaneous semaglutide and non-inferiority criteria were met with oral semaglutide. CONCLUSIONS: The most common AEs with semaglutide were gastrointestinal disorders, which decreased with continued therapy. These comprehensive safety/tolerability data may better inform patient selection and guidance in care.

A systematic review and meta-analysis of the effect of intravitreal VEGF inhibitors on cardiorenal outcomes.

BACKGROUND: Vascular endothelial growth factor inhibitors (VEGFis) have transformed the treatment of many retinal diseases, including diabetic maculopathy. Increasing evidence supports systemic absorption of intravitreal VEGFi and development of significant cardiorenal side effects. METHODS: We conducted a systematic review and meta-analysis (PROSPERO: CRD42020189037) of randomised controlled trials of intravitreal VEGFi treatments (bevacizumab, ranibizumab and aflibercept) for any eye disease. Outcomes of interest were cardiorenal side effects (hypertension, proteinuria, kidney function decline and heart failure). Fixed effects meta-analyses were conducted where possible. RESULTS: There were 78 trials (81 comparisons; 13 175 participants) that met the criteria for inclusion: 47% were trials in diabetic eye disease. Hypertension (29 trials; 8570 participants) was equally common in VEGFi and control groups {7.3 versus 5.4%; relative risk [RR] 1.08 [95% confidence interval (CI) 0.91-1.28]}. New or worsening heart failure (10 trials; 3384 participants) had a similar incidence in VEGFi and control groups [RR 1.03 (95% CI 0.70-1.51)]. Proteinuria (5 trials; 1902 participants) was detectable in some VEGFi-treated participants (0.2%) but not controls [0.0%; RR 4.43 (95% CI 0.49-40.0)]. Kidney function decline (9 trials; 3471 participants) was similar in VEGFi and control groups. In participants with diabetic eye disease, the risk of all-cause mortality was higher in VEGFi-treated participants [RR 1.62 (95% CI 1.04-2.46)]. CONCLUSION: In trials of intravitreal VEGFi, we did not identify an increased risk of cardiorenal outcomes, although these outcomes were reported in only a minority of cases. There was an increased risk of death in VEGFi-treated participants with diabetic eye disease. Additional scrutiny of post-licensing observational data may improve the recognition of safety concerns in VEGFi-treated patients.

Antioxidant and anti-apoptotic effects of tocotrienol-rich fraction against streptozotocin-induced diabetic retinopathy in rats.

Oxidative stress, a key player in diabetic retinopathy (DR), is associated with retinal cell apoptosis. This study investigated the effect of tocotrienol-rich fraction (TRF), a potent antioxidant, towards visual behaviour, retinal morphology, cells apoptosis and redox status in streptozotocin (STZ)-induced DR rats. Sprague-Dawley rats were divided into 3 groups: non-diabetic (N), was injected with citrate buffer intraperitoneally, diabetic treated with vehicle (DV), and diabetic treated with TRF (DT), were injected with STZ intraperitoneally (55 mg/kg) to induce diabetes. DT received 100 mg of TRF/kg orally for 12-weeks, whereas DV and N received vehicle. The general and visual-behaviour responses were assessed at week 12 in an open field arena. Rats were then sacrificed, and retinae were processed for haematoxylin and eosin (H&E) and terminal transferase-mediated dUTP nick end-labelling (TUNEL) staining. Retinal antioxidant, lipid peroxidation and anti-apoptotic markers were measured. The general and visual-behaviour responses in DT were comparable to N. Retinal thickness and cell counts were lower in DV and DT compared to N. Lower number of TUNEL-positive cells were observed in DT compared to DV (1.48-fold, p < 0.001) which correlated with retinal caspase-3 expression (2.31-fold, p < 0.001). The retinal oxidative stress in DT was lower than DV as indicated by higher reduced glutathione (2.10-fold, p < 0.05), superoxide dismutase (1.12-fold, p < 0.05) and catalase (1.40-fold, p < 0.001), and lower malondialdehyde (2.54-fold, p < 0.001). In conclusion, oral TRF (100 mg/kg) supplementation for 12-weeks reduces retinal oxidative stress in STZ-induced DR rats, which in turn reduces retinal cell apoptosis and protects retinal morphology. These findings were associated with preservation of the visual-behaviour responses.

Results of intravitreal dexamethasone implant (Ozurdex®) for retinal vascular diseases with macular edema: An observational study of real-life situations.

To evaluate the efficacy of intravitreal dexamethasone implants (Ozurdex®) for the treatment of macular edema (ME) associated with retinal vascular diseases in real-life situations. This retrospective study included patients with ME associated with retinal vascular occlusion (RVO) or diabetic macular edema (DME) treated with dexamethasone implants. Demographic data, best-corrected visual acuity (BCVA), and central retinal thickness (CRT) at baseline and at 1, 3, and 6 months postoperatively were collected and analyzed, and the adverse events were recorded. Forty-four eyes, 42 patients were included in the study. The mean logMAR BCVA improved from 0.79 ± 0.38 at baseline to 0.60 ± 0.34 (P < 0.001), 0.72 ± 0.38 (P = .002), and 0.72 ± 0.37 (P = .002) at 1, 3, and 6 months, respectively. The CRT decreased from 526.70 ± 159.58 µm at baseline to 279 ± 66.23, 422.91 ± 206.99, and 350.23 ± 151.51 µm at 1, 3, and 6 months, respectively (P < 0.001, all visits). The average number of injections was 1.43 ± 0.5. Nineteen eyes (43.18%) received second injections at an interval of 4.20 ± 0.61 months. The mean logMAR BCVA was greater in RVO than in DME patients and in treatment-naïve eyes than in previously treated ones. The baseline CRT of the reinjection group was significantly higher than that of the single-injection group for both the RVO (P < 0.001) and DME groups (P = .002). Nine eyes (20.45%) with increasing intraocular pressure (IOP) were well controlled with medication, and cataract progression was observed in five eyes (21.73%) during follow-up. The dexamethasone implant was effective for the treatment of macular edema secondary to RVO and DME in terms of visual acuity and CRT improvement over 6 months. The visual acuity was greater in the RVO and treatment-naïve eyes. Reinjection may be associated with a high baseline CRT. The increase in the occurrence of IOP and cataract progression was similar to that reported in previous studies.

Interleukin-17A attenuates photoreceptor cell apoptosis in streptozotocin-induced diabetic mouse model.

Diabetic retinopathy (DR) represents an important microvascular complication of diabetes, which is the top etiology of vision impairment worldwide. Although interleukin (IL)-17A is increasingly implicated in DR development, the underlying cellular mechanisms remain poorly defined. This work aims to evaluate IL-17A levels in the retina of streptozotocin (STZ)-induced diabetic mice and elucidate their potential roles. We found IL-17A was upregulated in diabetic retina after intraperitoneal injection of STZ and high-glucose (HG)-cultured primary Müller cells. IL-17A knockout (IL-17A-/-) downregulated glial fibrillary acidic protein (GFAP) and inhibited the conversion of proneurotrophin-3 (proNT-3) to mature NT-3 in retinal specimens from diabetic mice as well as in Müller cells cultured under HG conditions. Induced apoptosis and upregulated Bax and cleaved caspase-3 were observed in retinal specimens from IL-17A-/- diabetic mice and photoreceptor (661 W) cells after co-culture with IL-17A-/- Müller cells. Moreover, RNA interference-induced gene silencing of tyrosine kinase C receptor (TrkC) in 661 W cells reversed the anti-apoptotic effect of IL-17A under HG conditions. Taken together, our findings suggest that IL-17A/NT-3/TrkC axis regulation suppresses apoptosis in photoreceptor cells, providing a new treatment strategy for DR.

Monosodium Glutamate-Induced Mouse Model With Unique Diabetic Retinal Neuropathy Features and Artificial Intelligence Techniques for Quantitative Evaluation.

Objective: To establish an artificial intelligence-based method to quantitatively evaluate subtle pathological changes in retinal nerve cells and synapses in monosodium glutamate (MSG) mice and provide an effective animal model and technique for quantitative evaluation of retinal neurocytopathies. Methods: ICR mice were subcutaneously injected with MSG to establish a model of metabolic syndrome. We then established a mouse model of type 1 diabetes, type 2 diabetes, and KKAy mouse model as control. The HE sections of the retina were visualized using an optical microscope. AI technology was used for quantitative evaluation of the retinal lesions in each group of rats. The surface area custom parameters of the retinal nerve fiber layer (RNFL), inner plexiform layer (IPL), inner nuclear layer (INL), and outer plexiform layer (OPL) were defined as SR, SIPL, SINL, and SOPL, respectively. Their heights were defined as HR, HIPL, HINL, and HOPL, and the number of ganglion cells was defined as A. Then, the attention-augmented fully convolutional Unet network was used to segment the retinal HE images, and AI technology to identify retinal neurocytopathies quantitatively. Results: The attention-augmented fully convolutional Unet network increased PA and IOU parameters for INL, OPL, RNFL, and ganglion cells and was superior in recognizing fine structures. A quantitative AI identification of the height of each layer of the retina showed that the heights of the IPL and INL of the MSG model were significantly less than those of the control groups; the retinas of the other diabetic models did not exhibit this pathological feature. The RNFLs of type 2 diabetes were thinner, and the characteristics of retinopathy were not obvious in the other animal models. The pathological changes seen on HE images were consistent with the results of the quantitative AI evaluation. Immunohistochemistry results showed that NMDAR2A, GluR2, and NRG1 were significantly downregulated in the retina of MSG mice. Conclusions: The MSG retinopathy model is closely associated with neurotransmitter abnormalities and exhibits important characteristics of retinal neurodegeneration, making it suitable for studying retinal neurocytopathies. The AI recognition technology for retinal images established in the present study can be used for the quantitative and objective evaluation of drug efficacy.

Effect Modification by Indication to the Risks of Major Thromboembolic Adverse Events in Patients Receiving Intravitreal Anti-Vascular Endothelial Growth Factor Treatment: A Population-Based Retrospective Cohort Study.

BACKGROUND: The association between intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment and the risk of major thromboembolic adverse events (TAEs) remains under debate. This study aimed to examine associated risks of TAEs in patients receiving intravitreal anti-VEGF treatment, and effect modification by different indications. METHODS: This retrospective cohort study analyzed Taiwan's National Health Insurance Database during 2011-2017 to identify neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) patients newly receiving intravitreal aflibercept or ranibizumab. We followed up patients for 2 years, or until the occurrence of TAEs, including ischemic heart disease, ischemic stroke, transient ischemic attack, deep vein thrombosis, and pulmonary embolism, death, or the end of the study period (i.e., 31 December 2018). We compared the risk of TAEs between patients with aflibercept and ranibizumab using Cox-proportional hazard models. We examined statistical interactions between the anti-VEGF treatment (i.e., ranibizumab and aflibercept) and indications (i.e., nAMD and DME) with regard to the outcome of TAEs. RESULTS: We included 12,215 nAMD and 7532 DME patients. Among nAMD patients, those receiving aflibercept had lower risk of TAEs (adjusted hazard ratio [HR] 0.85; 95% CI 0.77-0.94) compared with those receiving ranibizumab. However, among DME patients, those receiving aflibercept had no differences in the risk of TAEs (1.14; 0.97-1.35) compared with those receiving ranibizumab. Among patients treated with ranibizumab, the DME group had a higher risk of TAEs than the nAMD group (HR 1.15; 95% CI 1.03-1.28); similar results were observed in patients treated with aflibercept (HR 1.53; 95% CI 1.27-1.85). When DME patients were treated with aflibercept, the risk of TAEs was 31% higher than when nAMD patients were treated with ranibizumab (HR 1.31; 95% CI 1.09-1.56; p < 0.05). The p-value for statistical interaction between the anti-VEGF treatment and indications was 0.0033. CONCLUSIONS: Patients treated with aflibercept or ranibizumab for different indications may be associated with varying risk of TAEs. The findings provide evidence to support treatment selection, taking indications and TAE risk into consideration.

Semaglutide and Diabetic Retinopathy Risk in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Semaglutide is a recently approved glucagon-like peptide-1 receptor agonist used to treat patients with type 2 diabetes mellitus (T2DM). The SUSTAIN 6 trial found a significantly higher rate of retinopathy complications in the semaglutide-treated group compared with the placebo group. OBJECTIVE: This study aimed to evaluate the association between semaglutide and the risk of retinopathy in patients with T2DM. METHODS: Electronic databases were systematically searched up to April 2021 to identify randomized controlled trials that reported diabetic retinopathy (DR) events in semaglutide-treated and control groups. A meta-analysis was conducted using Review Manager 5.4 software to calculate the risk ratio (RR) and 95% confidence intervals (CIs). RESULTS: A total of 23 randomized trials involving 22,096 patients with T2DM were included. There were 730 incident DR cases-463 in the semaglutide group and 267 in the control group. Overall, semaglutide was not associated with increased DR risk compared with controls when all trials were combined (RR 1.14, 95% CI 0.98-1.33). Subgroup analysis showed that semaglutide was associated with an increased risk of DR compared with placebo (RR 1.24, 95% CI 1.03-1.50). Moreover, patient age ≥ 60 years and diabetes duration ≥ 10 years were also factors for increased risk of DR when using semaglutide (RR 1.27, 95% CI 1.02-1.59; RR 1.28, 95% CI 1.04-1.58, respectively). CONCLUSIONS: Semaglutide was not associated with an increased risk of DR; however, caution regarding DR risk is needed for older patients or those with long diabetes duration when taking semaglutide.

Early Microglial Changes Associated with Diabetic Retinopathy in Rats with Streptozotocin-Induced Diabetes.

Although morphological changes in microglia have been reported to be associated with diabetic retinopathy, little is known about the early changes in the microglia and macrophages during the progression of this condition. The present study was aimed at characterizing retinal microglial activation in the early stages of experimental diabetic retinopathy. Toward this end, a model of diabetic retinopathy was generated by intraperitoneally injecting male Sprague-Dawley rats with streptozotocin. No apparent histological changes were observed during the early stages of experimental diabetic retinopathy. However, at 4 to 16 weeks after the onset of diabetes, the retinas from diabetic rats exhibited higher density of microglia than those from age-matched normal controls, with microglial density peaking at 12 weeks. In particular, the proportion of the activated microglia increased significantly in the diabetic rats, specifically in the nerve fiber and ganglion cell layers, whereas it decreased in the inner plexiform layer within 12 weeks. Furthermore, the resident retinal microglial cells were activated immediately after diabetes induction, peaked at 12 weeks, and remained for up to 16 weeks after disease onset. Thus, experimental diabetic retinopathy causes gradual hypoxia and neuroinflammation, followed by the activation of microglia and the migration of macrophages. The distribution and density of retinal microglial activation changed typically with the progression of the disease in early-stage diabetic rats.

Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy.

Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial-capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial-vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.