Pathogenesis Of Diabetic Macular Edema Research Articles

The usefulness of systemic inflammatory markers as diagnostic indicators of the pathogenesis of diabetic macular edema.

To investigate the usefulness of systemic inflammatory markers [i.e., white blood cell and platelet counts, mean platelet volume, and their ratios] as diagnostic markers of the pathogenesis of diabetic macular edema. The study cohort included 80 diabetic macular edema patients (40 with diabetic retinopathy and 40 without) and 40 healthy age- and sex-matched controls. Neutrophil, lymphocyte, monocyte, and platelet counts, and the mean platelet volume were determined from peripheral blood samples, and the monocyte/lymphocyte, platelet/lymphocyte, and mean platelet volume/lymphocyte, and neutrophil/lymphocyte ratios were calculated and compared among groups. The mean neutrophil/lymphocyte ratio of the diabetic macular edema and non-diabetic macular edema groups was higher than that of the control group, and the value of the diabetic macular edema group was higher than that of the non-diabetic macular edema group (p<0.001 in diabetic macular edema vs. control, p=0.04 in non-diabetic macular edema vs. control, and p=0.03 in diabetic macular edema vs. non-diabetic macular edema). A neutrophil/lymphocyte cutoff value of ≥2.26 was identified as an indicator of the pathogenesis of diabetic macular edema with a sensitivity of 85% and specificity of 74%. The mean platelet volume of the diabetic macular edema group was higher than those of the non-diabetic macular edema and control groups, while those of the non-diabetic macular edema and control groups were similar (diabetic macular edema vs. non-diabetic macular edema, p=0.08; diabetic macular edema vs. control, p=0.02; and non- diabetic macular edema vs. control, p=0.78). All other parameters were similar between groups (all p>0.05). The neutrophil/lymphocyte ratio and mean platelet volume of the diabetic macular edema group were higher than those of the non-diabetic macular edema and control groups. A neutrophil/lymphocyte ratio cutoff value of ≥2.26 was identified as an indicator of the pathogenesis of diabetic macular edema with high sensitivity and specificity. Moreover, the neutrophil/ lymphocyte ratio of the non-diabetic macular edema group was higher than that of the control group.

Патогенетические факторы формирования морфологических форм диабетического макулярного отека (обзор литературы)

Diabetic macular edema (DME) is a pathological accumulation of fluid in the subretinal or intraretinal spaces of the macular area in patients with diabetic retinopathy and leads to a significant decrease in Central vision. Various types of technical equipment for retinal imaging have led to significant advances in the study of diabetic macular edema. In particular, optical coherence tomography (OCT) can provide linear and structural analysis of macular layers in great detail. The important role of inflammation in the development of changes in the macular region, based on OCT classification, associated with characteristic changes in the retina, has been studied. In this review, we will describe the pathogenesis of diabetic macular edema and discuss its types based on the results of OCT and identify the relationship of various types of (DME) with inflammation. Inflammation plays an important role in the pathogenesis of diabetic macular edema, but its role differs depending on the type of changes detected on OCT.

Diabetic Macular Edema: State of Art and Intraocular Pharmacological Approaches.

Diabetic macular edema (DME) is the main cause of vision loss in diabetic retinopathy (DR). Although it is one of the main complications of diabetes, the pathogenesis of DME is not completely understood. The hyperglycemic state promotes the activation of multiple interlinked pathways leading to DME. Different classifications have been proposed: based on clinical features, on pathogenesis or on diagnostic tests (optical coherence tomography - OCT and fluorescin angiography - FA). The multimodal imaging allows a better analysis of the morphological features of the DME. Indeed, new inflammatory biomarkers have been identified on OCT. Also, several studies are evaluating the role of the morphological features, identified on multimodal imaging, to find new prognostic factors. Over the past decade, great progresses have been made in the management of DME. Therapeutic alternatives include intraocular injection of anti-vascular endothelial grow factor agents (anti-VEGF) and steroid molecules, focal/grid laser photocoagulation and vitreo-retinal surgery. This review is focused on the description and analysis of the current intravitreal therapeutic pharmacological strategies. Current guidelines recommend anti-VEGF as first line therapy in DME. Corticosteroids are becoming increasingly relevant blocking the inflammatory cascade and indirectly reducing VEGF synthesis.

The role of internal limiting membrane peeling in the treatment of diabetic macular edema

Analysis of the current understanding of the role of internal limiting membrane in the pathogenesis of diabetic macular edema and the feasibility of its surgical removal is based on data from domestic and international literature on pathogenesis, clinical manifestations, outcomes of multicenter studies of treatment and prognosis of this disease. The advantages and disadvantages of both peeling and preservation of the inner limiting membrane are described. The limitations and inconsistencies of data provided by the authors of each theory requires more complete functional studies in the pre- and postoperative periods, increasing the selection of patients, modifying the criteria for inclusion in groups, and microscopic examination of removed membranes. Thus, this issue requires further study due to the ambiguity of the conclusions and the lack of comparative data on the long-term prospects of each of the methods.

Efficacy of Alzer&lt;sup&gt;&amp;#174;&lt;/sup&gt; and Diamel, Nutritional Supplements, in the Prevention of Severe Diabetic Macular Edema

Introduction: Macular edema is the main cause of low vision in diabetic patients. Laser photocoagulation continues to be the treatment of choice in conjunction with the use of steroids and anti-angiogenics, but these treatments include possible ocular complications. The nutritional supplement Alzer (whose primary active ingredient is Ginkgo biloba, a powerful antioxidant that acts on vascular factors and oxidative damage, which are two of the mechanisms implicated in the pathogenesis of diabetic macular edema), which has been used on other non-diabetic macular conditions, along with the Diamel nutritional supplement has been shown to be effective on glycemic control and could represent a treatment alternative for mild to moderate macular edema by reducing the thickness of the macular retina and preventing the progression of other more advanced clinical presentations that are harder to treat. Objective: Identify the effect of Alzer along with Diamel in reduction of the thickness of the macular retina among patients with mild to moderate diabetic macular edema. Materials and Methods: A phase II double-blind clinical trial was conducted in 64 patients with non-severe diabetic macular edema over the course of non-proliferative diabetic retinopathy, who attended the ophthalmology service of the Institute of Endocrinology of Havana from January 2016 to December 2016. The treatment was randomly assigned to two groups: one received Alzer plus Diamel (n = 32) and the other group received Alzer placebo + Diamel placebo (n = 32). All patients were given an initial clinical evaluation, blood testing and ophthalmological evaluation at the start of treatment and after one year of follow-up. Results: There was a clinical improvement in the macular thickness upon the conclusion of the study in the patients treated with Alzer and Diamel. This decrease in thickness was statistically significant in the left eye. There was no decrease in visual acuity one year after treatment. Adverse events were mild and uncommon. Conclusions: Severe macular edema did not evolve in the Alzer and Diamel group. The clinical, but not statistically significant, success obtained in the experimental group proves the protocol hypothesis regarding the efficacy of the product being researched. The positive results in this small sample lead to the suggestion of performing larger-scale studies (Phase III). The clinical trial was registered in Clinical Trials.gov Identifier: NCT03533478.

Role of Inflammation in Classification of Diabetic Macular Edema by Optical Coherence Tomography.

Diabetic macular edema (DME) is the abnormal accumulation of fluid in the subretinal or intraretinal spaces in the macula in patients with diabetic retinopathy and leads to severely impaired central vision. Technical developments in retinal imaging systems have led to many advances in the study of DME. In particular, optical coherence tomography (OCT) can provide longitudinal and microstructural analysis of the macula. A comprehensive review was provided regarding the role of inflammation using OCT-based classification of DME and current and ongoing therapeutic approaches. In this review, we first describe the pathogenesis of DME, then discuss the classification of DME based on OCT findings and the association of different types of DME with inflammation, and finally describe current and ongoing therapeutic approaches using OCT-based classification of DME. Inflammation has an important role in the pathogenesis of DME, but its role appears to differ among the DME phenotypes, as determined by OCT. It is important to determine how the different DME subtypes respond to intravitreal injections of steroids, antivascular endothelial growth factor agents, and other drugs to improve prognosis and responsiveness to treatment.

Clinical Decision Making for Treatment of Diabetic Macular Oedema with DEX Implant: a Consensus Paper

Currently two intravitreally applied corticosteroids (dexamethasone and fluocinolone) are licensed in Germany for treatment of diabetic macular oedema (DME). The use of DEX implant for DME in daily clinical practice has not been defined in detail. Following a Delphi panel survey, a group of retina experts set out to come up with a consensus for use of the DEX implant in DME. International and national treatment recommendations were identified from the literature. A steering group generated a catalogue of 72 statements on the aetiology and pathogenesis of DME, therapy with DEX implant, use of DEX implant in patients previously treated with VEGF-inhibitors, use of DEX implant in combination therapy, safety of DME therapies as well as patients' burden of treatment. Twenty-two ophthalmologists from private practice and 6 hospital ophthalmologists participated in the Delphi panel via Survey Monkey. Consensus was reached if at least 75% of participants agreed or disagreed with a statement. Statements for which consensus was not reached were discussed once more during the expert consensus meeting and a vote was taken. Based on these results a treatment algorithm for foveal DME was proposed. If a patient does not show sufficient response after 3 - 6 months of anti-VEGF treatment (visual acuity gain of < 5ETDRS letters or reduction of central retinal thickness ≤ 20%), a switch to DEX implant should take place. DEX implant is also suitable in eyes with longer presentation of DME, showing e.g. massive lipid exudates. DEX implant is suitable as first-line therapy especially in pseudophakic patients, patients unwilling or able to comply with tight anti-VEGF injection intervals or patients with known vascular diseases. With fixed control visits every 4 - 8 weeks, use of DEX implant is flexible and individual. Decision parameters for repeated use should be visual acuity, retinal thickness and intraocular pressure. Treatment of both eyes on the same day should not take place. The algorithm presented reflects survey as well as expert discussion results and may differ from recommendations issued by the German professional society. The consensus recommendations for the treatment of DME generated during the survey and meeting of retina experts are intended to guide use of DEX implant in daily practice.

Treatment of Diabetic Macular Edema.

Diabetes mellitus is a global epidemic which is growing in prevalence, and diabetic macular edema (DME) is a leading cause of visual impairment among patients affected by this disease. Our objective is to review current and upcoming therapeutic approaches to DME. Once considered the gold standard in treatment of DME, focal/grid laser is now reserved mostly for non-center-involving DME, while anti-vascular endothelial growth factor (anti-VEGF) therapy has become the first-line treatment. However, suboptimal responders to anti-VEGF and the burden of frequent injections have stimulated the development of novel approaches. Corticosteroids can be effective in treating DME, but adverse effects such as intraocular pressure elevation and cataract formation must be considered. Emerging therapeutics and drug delivery systems in the pipeline offer exciting potential solutions to this vision-threatening disease. Multiple types of therapeutics targeting various pathways implicated in the pathogenesis of DME may help lessen the global burden of vision loss from diabetes.

Modulation of the p75 neurotrophin receptor using LM11A-31 prevents diabetes-induced retinal vascular permeability in mice via inhibition of inflammation and the RhoA kinase pathway.

Breakdown of the inner blood-retinal barrier (BRB) is an early event in the pathogenesis of diabetic macular oedema, that eventually leads to vision loss. We have previously shown that diabetes causes an imbalance of nerve growth factor (NGF) isoforms resulting in accumulation of its precursor proNGF and upregulation of the p75 neurotrophin receptor (p75NTR), with consequent increases in the activation of Ras homologue gene family, member A (RhoA). We also showed that genetic deletion of p75NTR in diabetes preserved the BRB and prevented inflammatory mediators in retinas. This study aims to examine the therapeutic potential of LM11A-31, a small-molecule p75NTR modulator and proNGF antagonist, in preventing diabetes-induced BRB breakdown. The study also examined the role of p75NTR/RhoA downstream signalling in mediating cell permeability. Male C57BL/6J mice were rendered diabetic using streptozotocin injection. After 2weeks of diabetes, mice received oral gavage of LM11A-31 (50mgkg-1day-1) or saline (NaCl 154mmol/l) for an additional 4weeks. BRB breakdown was assessed by extravasation of BSA-AlexaFluor-488. Direct effects of proNGF were examined in human retinal endothelial (HRE) cells in the presence or absence of LM11A-31 or the Rho kinase inhibitor Y-27632. Diabetes triggered BRB breakdown and caused significant increases in circulatory and retinal TNF-α and IL-1β levels. These effects coincided with significant decreases in retinal NGF and increases in vascular endothelial growth factor and proNGF expression, as well as activation of RhoA. Interventional modulation of p75NTR activity through treatment of mouse models of diabetes with LM11A-31 significantly mitigated proNGF accumulation and preserved BRB integrity. In HRE cells, treatment with mutant proNGF (10ng/ml) triggered increased cell permeability with marked reduction of expression of tight junction proteins, zona occludens-1 (ZO-1) and claudin-5, compared with control, independent of inflammatory mediators or cell death. Modulating p75NTR significantly inhibited proNGF-mediated RhoA activation, occludin phosphorylation (at serine 490) and cell permeability. ProNGF induced redistribution of ZO-1 in the cell wall and formation of F-actin stress fibres; these effects were mitigated by LM11A-31. Targeting p75NTR signalling using LM11A-31, an orally bioavailable receptor modulator, may offer an effective, safe and non-invasive therapeutic strategy for treating macular oedema, a major cause of blindness in diabetes.

&lt;p&gt;Dexamethasone implant in the management of diabetic macular edema from clinician’s perspective&lt;/p&gt;

The aim of this article is to provide an overview of characteristics and principles of use of dexamethasone implant in patients with diabetic macular edema (DME). The condensed information about patient selection, dosing, and postinjection management is provided to make the clinician’s decisions easier in real-life practice. DME is a common complication of diabetes and the leading cause of visual loss in the working-age population. Inflammation plays an important role in the pathogenesis of DME. The breakdown of the blood–retinal barrier involves the expression of inflammatory cytokines and growth factors, including vascular endothelial growth factor (VEGF). Steroids have proved to be effective in the treatment of DME by blocking the production of VEGF and other inflammatory cytokines, by inhibiting leukostasis, and by enhancing the barrier function of vascular endothelial cell tight junctions. Dexamethasone intravitreal implant has demonstrated efficacy in the treatment of DME resistant to anti-VEGF therapy and in vitrectomized eyes. Data from clinical trials suggest that dexamethasone implant can be considered as first-line treatment in pseudophakic eyes. Dexamethasone implant is also the first-line therapy in patients not suited for anti-VEGF therapy, pregnant women, and patients unable to return for frequent monitoring. It has been shown that the maximum effect of dexamethasone implant on visual gain and retinal thickness occurs approximately 2 months after injection. Various treatment regimens are used in real-life situations, and reported reinjection intervals were usually <6 months. The number of retreatments needed decreased over time. Treatment algorithms should be personalized. Postinjection management and follow-up should consider potential adverse events such as intraocular pressure elevation and cataract.

Lightmasks that prevent dark adaptation for non-central diabetic macular oedema: the CLEOPATRA RCT

Background Hypoxia may contribute to the development and progression of diabetic macular oedema (DMO) and diabetic retinopathy. The photoreceptors are the most metabolically active cells in the retina and the rod photoreceptors consume the maximal amount of oxygen for dark adaptation. Therefore, a lightmask emitting 500- to 505-nm light and worn at night during sleep may prevent rod-related dark adaptation and, thereby, reduce the retinal oxygen consumption and improve or prevent progression of DMO and diabetic retinopathy as evidenced in small short-term studies. Objectives The clinical effectiveness and safety of using a lightmask to prevent dark adaptation as a treatment and preventative option was evaluated for DMO over 24 months. Design A Phase III, multicentre, prospective, single-masked, randomised controlled clinical trial that evaluated the clinical effectiveness and safety of a lightmask that prevents dark adaptation to treat and prevent non-central DMO versus standard care (i.e. non-lightmask arm) at 24 months. A subset of participants also enrolled for a mechanistic substudy that evaluated the role of hypoxia in DMO. Setting Fifteen NHS clinical sites in the UK. Participants Adults with non-centre-involving DMO. Intervention The participants were randomly assigned (1 : 1) to being offered a lightmask (Noctura 400 Sleep Masks, Polyphotonix Medical Ltd, Durham, UK) to wear at night during sleep to prevent dark adaptation or to the non-lightmask arm (standard care) for 24 months. The participants were evaluated every 4 months. Main outcome measure The primary outcome was defined as a change in retinal thickness at the zone of maximum thickness measured by spectral domain optical coherence tomography at 24 months in the study eye, analysed using a linear mixed-effects model that estimated adjusted treatment effects at both 12 and 24 months. Results A total of 308 participants were recruited between April 2014 and May 2015. A total of 155 participants in the lightmask arm and 153 in the control arm contributed to the intention-to-treat strategy. The lightmask arm did not show any difference in effect compared with the non-lightmask arm [adjusted mean difference between arms –0.65 µm, 95% confidence interval –6.90 to 5.59 µm; p = 0.84). The compliance of wearing the lightmask was suboptimal, as recorded electronically, from the returned lightmasks. There were no lightmask-related severe adverse events. The mechanistic study aimed at studying the effect of improving hypoxia by inhaling 100% oxygen or by offering lightmasks to wear during sleep at night over 12 months did not demonstrate any clinically beneficial effect on DMO. Conclusion The lightmask, as offered in this trial to prevent dark adaptation, did not show any treatment or preventative effect in participants with non-central oedema or diabetic retinopathy at 24 months. No effect was seen as early as 4 months when compliance was higher. Future work Future research is needed to evaluate the role of rod-induced hypoxia in the pathogenesis of DMO and diabetic retinopathy. Trial registration Current Controlled Trials ISRCTN85596558. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership. The report will be published in full in Efficacy and Mechanism Evaluation; Vol. 6, No. 2. See the NIHR Journals Library website for further project information. The lightmasks were purchased at a discounted rate from Polyphotonix Medical Ltd.

Correlation of C-reactive protein and glycosylated hemoglobin on severity of diabetic macular edema

Background: Diabetic macular edema (DME) is an important cause of visual impairment in type 2 diabetes. Central macular thickness (CMT) measured using optical coherence tomography (OCT) is a noninvasive method for diagnosis and quantification of DME. OCT not only helps in follow-up and prognosis of macular edema but also aids in early detection of DME, which might not be clinically evident. The study suggests that inflammatory process plays a critical role in retinopathy. C-reactive protein (CRP), an inflammatory marker, is expected to be elevated in patients with poor glycemic control. Furthermore, data on possible association of CRP with diabetic retinopathy are sparse and a limited number of studies reported inconsistent results. The present study is to find the correlation of CRP and glycosylated hemoglobin (HbA1c) on severity of DME. Materials and Methods: This was a case–control study done in a tertiary hospital including 75 cases (type 2 diabetes patients with DME) and 75 controls (diabetics without DME) of diabetic age >5 years. Cases subdivided based on CMT into mild (201–300 μ), moderate (301–400 μ), and severe macular edema (>400 μ). Results: CRP was positive (>0.6 mg/dl) in 32 cases (42.7%) and five controls (6.7%), and positive correlation was obtained between CRP and DME severity. Elevated HbA1c level was associated with increased severity of DME. Conclusion: As inflammation plays a significant role in the pathogenesis of DME, CRP level can be considered as a biomarker to determine the severity of DME along with HbA1c levels.

Phacoemulsification with Posterior Sub-Tenon Triamcinolone Acetonide Injection for Prevention of Progression of Diabetic Macular Edema after Cataract Surgery

Background: diabetic macular edema (DME) is the most common cause of visual loss in diabetic patients. The pathogenesis of DME is multifactorial. It results from multiple biochemical and cellular changes that eventually cause leakage and exudation. A number of patient characteristics such as increasing age, females, duration of DM, poor glycemic control and moderate to severe retinopathy have been found associated with poor prognosis after cataract surgery in diabetic patients. Objective: the aim of this study was to evaluate the efficacy of phacoemulsification with posterior sub-Tenon’s triamcinolone acetonide injection for prevention of progression of diabetic macular edema following uneventful cataract surgery by phacoemulsification. Patients and Methodology: this interventional study included 20 eyes of 20 diabetic patients with visually significant cataract and coexisting DME during the period from December 2017 to October 2018. Preoperative and postoperative best corrected visual acuity (BCVA) using LogMAR and intraocular pressure (IOP) were recorded. Results: statistically significant improvement in BCVA was detected when comparing postoperative values at one week, one month and three months to corresponding preoperative values. In addition, values at one month and three months were significantly improved when compared to values at one week post-operative. On other hand, values at three months revealed non-significant difference when compared to values at one month. Conclusion: this study suggests that posterior sub-Tenon’s triamcinolone acetonide injection can be given safely and easily at the time of phacoemulsification surgery in patients with visually significant cataract and DME.

Diabetic Macular Edema: Current Understanding, Pharmacologic Treatment Options, and Developing Therapies.

Diabetic retinopathy and diabetic macular edema comprise a major source of visual disability throughout the developed world. The etiology and pathogenesis of macular edema is intricate and multifactorial, in which the hyperglycemic state in diabetes induces a microangiopathy. Through several inflammatory and vasogenic mediators, including vascular endothelial growth factor (VEGF) upregulation and inflammatory cytokines and chemokines, pathologic changes are induced in the vascular endothelium triggering breakdown of the blood retinal barrier, causing extravasation of fluid into the extracellular space and manifesting clinically as macular edema, resulting in visual loss. The advent of medications targeting the VEGF pathway has led to great clinical improvements compared with the previous standard of care of laser therapy alone, as shown in studies such as RISE, RIDE, VIVID, VISTA, and DRCR. However, analyses have shown that many patients have inadequate response or are nonresponders to anti-VEGF therapy, demonstrating the need for additional therapies to more comprehensively treat this disease. Although corticosteroid treatments and implants have demonstrated some efficacy in adjunctive and supplemental treatment, the need to more adequately treat macular edema remains. Our knowledge of diabetic macular edema continues to grow, leading to new currently available and emerging pharmacotherapies to further enhance our treatment and restore vision in those affected by diabetic macular edema. This review will discuss the pathogenesis of diabetic macular edema and the pharmacologic therapies available for its treatment, including anti-VEGF, steroids, and newer therapies still in development, such as angiopoietin antagonists, Tie2 agonists, kallikrein inhibitors, interleukin inhibitors, and others.

Management of diabetic macular edema patients in clinical practice in Spain.

Diabetic macular edema is the main cause of blindness in diabetic patients. Vascular endothelial growth factor is involved in diabetic macular edema pathogenesis. Vascular endothelial growth factor inhibitors are an important option in diabetic macular edema therapy. This survey investigates actual clinical practice in diabetic macular edema in Spain. An expert advisory panel of 17 Spanish ophthalmologists developed a 30-item anonymous questionnaire about diagnosis, treatment, and follow-up in diabetic macular edema. A total of 137 ophthalmologists from 10 Spanish regions completed the questionnaire online. Almost all of the respondents (99.3%) record the measured visual acuity and perform biomicroscopic anterior (94.9%) and posterior (91.2%) segment examinations. Similarly, 100% of responding ophthalmologists always/almost always or frequently perform optical coherence tomography. Most respondents (65%) always/almost always or frequently perform a retinography. More than 50% rarely perform fluorescein angiography. Nearly, all (96.4%) of the specialists responded that, in center-involved diabetic macular edema, the first treatment is an anti-vascular endothelial growth factor drug. For corticosteroids, the first choice of most respondents (91.2%) was the dexamethasone implant. In the follow-up, almost all (96.4%) specialists record the measured visual acuity and most also perform biomicroscopic anterior (82.5%) and posterior (83.2%) segment examination. This survey shows the actual clinical practice in diabetic macular edema in Spain, finding that anti-vascular endothelial growth factor therapy is frequently used, and that diagnosis, treatments, and follow-up examinations used by specialists are homogeneous and according to diabetic macular edema guidelines.

Deep Phenotyping of a Spontaneous Nonhuman Primate Model of Diabetic Macular Edema

Diabetic retinopathy (DR) is a diabetic complication involving damages to blood vessels in the retina that, if left untreated, can lead to blindness. It is estimated that over 93 million people suffer from DR worldwide and in fact the disease accounts for 12% of all new cases of blindness each year in the United States. Diabetic macular edema (DME) is one of the manifestations of DR, in which fluids leak from the blood vessels into the centre of the macula, causing pain, swelling, and blurred vision. However, the underlying pathogenesis of DR/DME is complex and not well understood, thus impeding the development of effective treatment. Consequently, the use of animal models of DR is of critical importance for better understanding of the underlying pathogenesis of DME, as well as developing new drugs. Non-human primate (NHP) models of diabetes are known to be the most clinically translatable animal models, where the animals develop major clinical phenotypes along the disease progression, including DR. As such, in this study we phenotyped a cohort of type 2 prediabetes/diabetes NHPs (n=123, weight: 11.5±2.0kg, age: 15.5±2.9years) using clinically relevant circulating and imaging biomarkers. Specifically, spectral domain optical coherence tomography (OCT) was first used to identify a subgroup of the animals with significantly thickened retina (329 ± 6.77µm) with an accumulation of hard exudates and inter-retinal cysts (n= 59). Fundus fluorescein angiography (FA) imaging further confirmed the presence of retinal vascular leakage into the cystoid spaces during the late-phase FA. Levels of vascular endothelial growth factor (VEGF) in both plasma and vitreous fluid were also measured and the results appear to correlate with retina thickness (vs. aged-matched controls). Taken together, our findings demonstrate a clinically translatable NHP model for DR/DME that allows characterization of disease progression in vivo, investigation of co-morbidities, and evaluation of novel therapeutics. Disclosure S. Chia: Employee; Self; Merck Sharp &amp; Dohme Corp.. L. Gong: None. S. Tiu: Employee; Self; Merck &amp; Co., Inc. S. Annamalai: Employee; Self; Merck Sharp &amp; Dohme Corp. N.X. Li: Employee; Self; Merck &amp; Co., Inc.. L. Pan: None. L. Hong: Employee; Self; Merck Sharp &amp; Dohme Corp.. Employee; Spouse/Partner; Illumina, Inc. A. Abu Bakar Ali: Employee; Self; Merck &amp; Co., Inc. C. Chin: Employee; Self; Merck &amp; Co., Inc.. W. Zeng: None.

Aflibercept for the Treatment of Diabetic Retinopathy and Diabetic Macular Edema

Diabetic macular edema (DME) is a common complication of diabetic retinopathy (DR) and is a leading cause of vision loss in developed countries during the working age. Understanding the role of vascular endothelial growth factor (VEGF) in the pathogenesis of DME has emphasized the importance of using anti-VEGF agents in treatment. Anti-VEGF drugs such as pegaptanib, ranibizumab, bevacizumab, and aflibercept have been studied in the treatment of DME. Aflibercept is a recombinant fusion protein with an inhibitory effect on VEGF-A, VEGF-B, placental growth factor (PIGF) 1 and 2. It is believed that this agent has a longer duration of action than other anti-VEGF molecules due to its high-affinity binding to the VEGF molecule. This review summarizes the pharmacological properties of aflibercept in terms of clinical efficacy, use, and tolerability in the treatment of DME.

Aflibercept in the Treatment of Diabetic Macular Edema: A Review and Consensus Paper

To reach a consensus, among experts, on the role of aflibercept in diabetic macular edema (DME) through literature review. Two round tables, involving 12 Italian experts, were organized: in the first one, 6 pharmacologic and clinical questions were selected and analyzed by a systematic literature review, using a population, intervention, control, and outcomes framework; in the second one, the nominal group technique was used to discuss relevant evidence related to each question. The consensus was assessed using the 5-point Delphi score. Agreement on statements was reached on 6/6 questions. The final statements were as follows: 1) High levels of both vascular endothelial growth factor (VEGF) and placental growth factor play an important role in the pathogenesis of DME. 2) The aflibercept pharmacologic profile is notably different from that of other anti-VEGF. 3) Aflibercept significantly improves functional and anatomical outcomes, and rapidly improves best-corrected visual acuity up to its peak; these results remain stable over time. 4) Diabetic macular edema aflibercept treatment requires a 5-monthly injection loading phase. Alternatively, a personalized pro re nata (PRN) regimen based on monthly monitoring and strict retreatment criteria can be used. 5) As an alternative to the bimonthly fixed regimen, in the maintenance phase the treatment schedule may be a PRN regimen with strict retreatment criteria or a treat and extend regimen. 6) No concerns on aflibercept ocular and systemic safety emerged from the literature. Consensus was reached among experts on how to best treat patients with DME with aflibercept.

Intravitreal Aflibercept in Diabetic Macular Edema: Long-Term Outcomes.

For decades, macular laser photocoagulation has been the standard of care in the treatment of diabetic macular edema (DME). With the relatively recent advent of anti-vascular endothelial growth factor (VEGF) agents, DME treatment has entered a new era. VEGF is a well-known pro-angiogenic and pro-permeability factor involved in the pathogenesis of DME. VEGF blockade has proven remarkably effective at reducing DME and improving visual acuity (VA) in eyes with center involved DME causing VA loss in several randomized controlled trials (RCTs). Intravitreal aflibercept, ranibizumab, and bevacizumab (the latter used off-label) are 3 anti-VEGF molecules currently available for DME treatment. Aflibercerpt is a 115-kDA recombinant fusion protein consisting of VEGF binding domains of human VEGF receptors-1 and -2 fused to the Fc domain of human immunoglobulin-G1. The ability to bind placental growth factors 1 and 2 (which is another pro-permeability mediator) and a theoretically long half-life are potential advantages of aflibercept over other anti-VEGF agents. The use of intravitreal aflibercept in DME treatment has been investigated in several RCTs. The aim of this chapter is to briefly report on the current evidence for treating DME with intravitreal aflibercept.

New Insights Into Microaneurysms in the Deep Capillary Plexus Detected by Optical Coherence Tomography Angiography in Diabetic Macular Edema.

To study the association between the distributions of microaneurysms detected by en face optical coherence tomography angiography (OCTA) and diabetic macular edema (DME). The study design was a retrospective chart review of 27 patients (33 eyes) with DME. The eyes were scanned using OCTA (6 × 6 mm) and spectral-domain (SD) OCT macular cube. Each of the images of the capillary plexus was overlaid onto the image of the topographic map, and the densities of the microaneurysms were measured by ImageJ software. The association between the distribution of microaneurysms and macular edema was evaluated. For microaneurysms in areas with and without edema, 77.3 ± 8.1% of these microaneurysms were located in the deep capillary plexuses (DCP). However, in areas of edema where the retinal thickness was more than 400 μm, 91.3 ± 9.1% of the microaneurysms were found in the DCP. This difference was statistically significant (P < 0.001). In the macular edema area, there was a significantly higher density of microaneurysms in the DCP compared to the superficial capillary plexuses (1.71/mm2 vs. 0.17/mm2, P < 0.001). There was also a significant correlation between the macular volume and the density of microaneurysms in the DCP in edema (r = 0.63, P < 0.001). Our study demonstrated a high proportion of microaneurysms in the DCP, as well as a novel association between the distributions of microaneurysms detected by OCTA and DME. Results also indicated that microaneurysms located in the DCP contribute to the pathogenesis of DME.