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This narrative review examines current and emerging treatment strategies for diabetic macular edema (DME), a complication of diabetic retinopathy characterised by fluid accumulation in the macula, which can lead to vision impairment. The incidence of DME is particularly high in patients with long-standing diabetes and advanced retinopathy. The current treatment options for DME include anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser therapies. Anti-VEGF agents, including bevacizumab, ranibizumab, aflibercept, and the more recently developed brolucizumab and faricimab, have been demonstrated to reduce macular thickness and improve visual acuity. Brolucizumab offers the advantage of fewer injections due to its longer duration of action, although it carries a higher risk of ocular inflammation compared to other anti-VEGF agents. The dual inhibition of the VEGF and angiopoietin-2 (Ang-2) pathways by faricimab may enhance vascular stability and reduce inflammation, potentially improving patient outcomes. Steroid therapies, including dexamethasone, fluocinolone acetonide, and triamcinolone acetonide, represent an alternative for patients who do not respond adequately to anti-VEGF treatment. Laser therapies, including focal, navigated, and subthreshold laser treatments, remain a crucial component in the management of DME, with the ability to seal leaking vessels and reduce fluid accumulation. In order to achieve the best outcomes for patients, it is essential to continue to advance these treatment modalities and adopt a personalised, multifaceted approach.

Introduction and purpose. Diabetes is one of the underlying causes of blindness and other long-term negative consequences that significantly affect patients’ quality of life. The study aimed to determine the indicators characterizing the pathogenetic mechanisms of the development of vascular dysfunction, in particular diabetic retinopathy (DR), and the relationship of these changes with nitric oxide. Material and methods. There were 2114 patients with various surgical diseases under observation (including 1073 patients with purulent-septic soft tissue diseases), among them there were 193 patients with type 2 diabetes mellitus (DM) and 134 patients with Wagner stage 2-5 diabetic foot syndrome (DFS) and diabetic retinopathy in the main group (268 eyes). The comparison group included 59 patients (118 eyes) of the corresponding age with DM without DFS and DR. Both groups were the same in age and gender. Results. The level of the end products of nitric oxide metabolism in peripheral blood was found to be 1.78 times (puperoxide dismutase (SOD) in patients with DR was by 1.56 times (pacid (TBA)-active products in the peripheral blood of patients of the main group exceeded by 1.58 times (p Conclusions. The findings show that the patients with diabetes mellitus complicated by retinopathy and DFS had a significant increase in the content of nitric oxide in the peripheral blood, the cause of which is hyperglycemia. The use of an intercellular mediator (nitric oxide), which contributes to the physiological regulation of the hemodynamics of the eye, protects vascular endothelial cells from pathogenic factors of ischemia, will help clinicians choose an effective pharmacological therapy appropriate for a particular patient and a particular eye.

Diabetic macular edema (DME) is the most common cause of moderate visual loss in diabetic patients. The current treatment of choice for DME is anti-VEGF treatment. Even though recent clinical trials have shown that anti-VEGF treatment is superior to laser photocoagulation there are certain concerns regarding its sustainability over the long term. Most patients that undergo pharmacological inhibition with anti-VEGF agents need multiple monitoring visits that include OCT imaging and multiple injections. There is a theoretical concern regarding systemic thrombo-embolic events with chronic VEGF suppression. Pars plana vitrectomy (PPV) by increasing the vitreous cavity oxygenation, relieving vitreomacular traction and removing cytokines from the vitreous cavity may cause long term resolution of DME without the aforementioned concerns.

Purpose: To provide evidence-based recommendations and guidance for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) based on recently published clinical evidence and clinical experience. Methods: A literature search using PubMed and the Cochrane Library was performed with the terms “diabetic macular edema” or “diabetic retinopathy” to identify studies published from January 2008 to November 2013. This was followed by a manual search of references cited in selected papers published in peer-reviewed journals. The references identified in these literature searches were reviewed and presented by members of the Latin America DME expert panel to the entire group during the 2-day consensus meeting. During this meeting,the experts formulated recommendations with consideration of the health benefits, risks, and adverse effects of interventions. References used to support recommendations were assigned a level of evidence based on the Strength of Recommendation Taxonomy (SORT) evidence rating system. Results: Thirty-one consensus recommendations were formulated. These include the recommendation for early glycemic control in diabetic patients in order to reduce the risk of progression of ocular disease. The expert panel also recommended the collection of epidemiological data to further define the prevalence of DR and DME in Latin America and to establish management and treatment algorithms for various stages of the disease. The need for early screening and development of infrastructure to ensure appropriate followup and treatment of those in need is further emphasized. Both fluorescein angiography (FA) and optical coherence tomography (OCT) are needed for proper assessment of disease progression and response to therapy. Based on available high-level evidence, we recommend ranibizumab as the gold standard for the treatment of DME and panretinal photocoagulation (PRP) as the gold standard for proliferative DR. Vitrectomy should be considered in the presence of macular traction or if edema is not responding to pharmacological therapy. As intravitreal steroids provide a reduction in edema, they can be used to ameliorate the effects of other therapies as well as in pseudophakic eyes. Finally, when selecting a therapy for DR and/or DME, it is of particular importance to consider the general health status of a patient. Conclusion: Although these guidelines are not intended to be a replacement for clinical judgment, they should help to streamline the management of DME across Latin America and ensure that patients receive the best available care in a timely manner.

Resumen El factor de crecimiento vascular endotelial (VEGF) juega un rol protagónico en la patogénesis de la retinopatía diabética. Su inhibición por el Bevacizumab, un anticuerpo monoclonal contra todas las isoformas del VEGF, ha demostrado ser benéfica en el manejo tanto del edema macular diabético (EMD) como de la retinopatía diabética proliferativa (RDP). Nuestro grupo ha previamente demostrado que múltiples inyecciones intravítreas tanto de 1,25 o 2,5 mg de bevacizumab en ojos con EMD resultan en la reducción del edema macular y mejoría en la agudeza visual. No se observó diferencia alguna entre los resultados de los ojos tratados con dosis más bajas o altas del bevacizumab. Se estudió también el efecto del bevacizumab intravítreos en ojos con RDP. El bevacizumab intravítreo es capaz de inducir regresión de la neovascularización de la retina y disco óptico. Sin embargo, esta regresión no es permanente y la fotocoagulación panretiniana o vitrectomía son necesarias para consolidar el tratamiento. Se debe tener cautela en ojos con RDP avanzada debido a que la rápida involución de las proliferaciones fibrovasculares pueden conllevar al desarrollo o progresión de un desprendimiento de retina fraccional. Por lo tanto al utilizar el bevacizumab intravítreo como adyuvante en la vitrectomía de pacientes diabéticos, la cirugía no debe ser programada más de 4 días después de dicha inyección.

Antecedentes: el edema macular es la principal causa de baja visión en personas con retinopatía diabética. Objetivo: revisar los resultados del tratamiento con ruboxistaurin en el edema macular diabético. Desarrollo: la hiperglucemia, entre otras alteraciones metabólicas, activa la proteína quinasa C, lo que contribuye a la disfunción microvascular, trastorno importante en la patogenia del edema macular diabético. Diversos procederes terapéuticos se han utilizado en su tratamiento. En los últimos años el ruboxistaurin ha demostrado su capacidad de inhibir la activación de la proteína quinasa C. Algunos autores opinan que este fármaco es capaz de mejorar el edema macular diabético, y por tanto, la visión. Se ha comunicado que la administración de 32 mg diarios de ruboxistaurin, previene la progresión de la retinopatía diabética y atenúa el riesgo de pérdida visual por edema macular diabético. Otros estudios describen resultados similares, y además, refieren, que el ruboxistaurin disminuye el riesgo de empeoramiento y progresión del edema macular diabético, así como reduce la necesidad de tratamiento con láser. Conclusiones: el uso del ruboxistaurin abre nuevas perspectivas en la prevención y tratamiento del déficit visual por retinopatía diabética y por edema macular diabético, sin embargo, se piensa que los estudios realizados hasta el momento son insuficientes para llegar a conclusiones valederas. Se imponen estudios a más largo plazo para definir su costo/beneficio.Backgrounds: the macular edema is the main cause of low vision in persons with diabetic retinopathy. Objective: to analyze the results of treatment with ruboxistaurin in cases of diabetic macular edema. Development: the hyperglycemia among other metabolic alterations, to active the kinase C protein contributing to microvascular dysfunction, an important disorder in the pathogenesis of the diabetic macular edema. Different therapeutical procedures have been used in its treatment. In past years the ruboxistaurin has showed its ability to inhibit the activation of C kinase protein. Some authors consider that this drug is able to improve the diabetic macular edema and thus, the vision. It has been reported that the administration of 32 mg daily de ruboxistaurin prevents the progression of the diabetic retinopathy and decrease the risk of visual loss from diabetic macular edema. Other studies describe similar results and also, report that this drug decreases the risk or worsening and progression of this type of edema as well as to reduce the need of laser treatment. Conclusions: the use of ruboxistaurin open new perspectives for prevention and treatment of visual deficit due to diabetic retinopathy and from the diabetic macular edema, however, authors consider that the studies conducted until now are insufficient to arrive to valid conclusions. Studies at longer term are necessary to define its cost/benefit.

Objetivo: Describir el comportamiento clínico-epidemiológico de la retinopatía diabética en el municipio Marianao, en el periodo de agosto - noviembre de 2007. Métodos: Se realizó un estudio descriptivo, de corte transversal. El universo estuvo constituido por los 7 693 diabéticos dispensarizados en el municipio Marianao. Se realizó interrogatorio y examen oftalmológico a los 150 pacientes incluidos en la muestra. Además se tomó fotografía de fondo, angiografía fluoresceínica y tomografía de coherencia óptica a aquellos que lo precisaban. Resultados: La prevalencia de retinopatía diabética fue de un 16,0 %. Se encontró con más frecuencia entre los 55 a 64 años de edad (20,0 %), con predominio en los diabéticos tipo 1 (28,6 %). Se evidenció un incremento de la retinopatía diabética con el aumento del tiempo de duración de la diabetes. Se observó tendencia a las formas menos severas y se encontró mayor severidad en ojos de pacientes con 21 años o más de evolución. El 4,7 % de los pacientes presentaban edema macular diabético y el 4,0 % ceguera legal. La retinopatía diabética y la catarata constituyeron las causas más frecuentes de ceguera, 1,3 % respectivamente. Conclusión: La prevalencia de retinopatía diabética y ceguera por esta enfermedad, mostró cifras inferiores a las recogidas en estudios previos. Con el aumento del tiempo de evolución de la diabetes mellitus se observó una mayor severidad de la retinopatía diabética y el edema macular diabético.Objective: To describe the clinical and epidemiological behavior of diabetic retinopathy in Marianao municipality in the period of August to November, 2007 Methods: A single-phase, descriptive and cross-sectional study of 7693 diabetic adults was carried out from August 2007 to November 2007 in Marianao municipality. The sample of 150 adults with diabetes was questioned and examined from the ophthalmological viewpoint. Additionally, funduscopy, fluorescein angiography and optical coherence tomography were performed on those patients who required so. Results: Diabetic retinopathy prevalence was 16,0 % and it was more frequent in patients aged from 55 to 64 years (20,0 %) and in patients suffering from diabetes type 1 (28,6 %). The length of time suffering from diabetes mellitus had an impact on the increased diabetic retinopathy. There was a tendency toward less severe forms of the disease, although more severity was found in patients who had had this disease for 21 years or more. About 4,7 % and 4 % of the patients presented macular diabetic edema and legal blindness respectively. Diabetic retinopathy and cataract were the most frequent causes of blindness (1,3 % both). Conclusions: The prevalence of diabetic retinopathy and blindness caused by this illness showed figures lower than those collected in previous studies. The longer the time of evolution of diabetes, the more severe forms of diabetic retinopathy and diabetic macular edema found.

Introduction: Diabetic macular edema is a frequent pathology that causes gradual deterioration of visual acuity, which does not have a standardized treatment. The anti-vascular endothelial growth factor (anti-VEGF) drugs and corticosteroids are widely used, especially aflibercept and dexamethasone, respectively, but it is unclear which one is best., Methods: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach., Results and Conclusions: No evidence that compared the interventions directly in the population of interest was found, so systematic reviews that provide an estimate of the effect indirectly using network meta-analysis were selected. We identified two systematic reviews that together included four primary studies, all randomized trials. We concluded that we are uncertain whether aflibercept compared to dexamethasone improves visual acuity or is safer, as the certainty of the evidence has been assessed as very low.

Background: Visual improvement after photocoagulation in focal diabetic macular edema is more frequent when temporal perifoveal area is not affected; functional status before treatment could be worse in eyes with perifoveal temporal thickening. The correlation between visual acuity and foveal sensitivity (usually significant), would allow to compare macular function., Objective: To compare the correlation between retinal sensitivity and visual acuity in eyes with diabetic macular edema, with and without temporal perifoveal thickening., Method: Non-experimental, retrospective, comparative, cross-sectional study in type 2 diabetics with macular edema. The correlation between foveal sensitivity and visual acuity was compared in eyes without temporal perifoveal thickening (group 1) and eyes with it (group 2). Multiple regression analysis was used to identify the contribution of foveal sensitivity to the changes of visual acuity; other variables were: center point thickness, center field thickness, temporal perifoveal thickness and macular volume., Results: 60 eyes in group 1, 29 eyes in group 2. Mean sensitivity did no differ between groups (30.0 ± 0.59 vs. 28.4 ± 1.05 dB; p = 0.2), but the correlation between sensitivity and visual acuity did it (group 1, rho: -0.41; group 2, rho: -0.25). In group 1, foveal sensitivity was the only explaining variable of the regression model (beta: -0.52), in group 2 no one explaining variable was included and temporal perifoveal thickness had a negative correlation with foveal sensitivity (rho: -0.60)., Conclusions: Temporal perifoveal thickening reduces the correlation between foveal sensitivity and visual acuity in eyes with diabetic macular edema., (Copyright: © 2019 Permanyer.)

RESUMEN Con este trabajo nos proponemos revisar las evidencias científicas relacionadas con el tratamiento de la retinopatía diabética. Para la investigación documental se examinaron los artículos de la temática indexados en las bases de datos Pubmed, Pubmed Central y Scielo, que correspondieron a los descriptores DeCs-MeSH: retinopatía diabética y tratamiento actual. La evaluación de los datos se realizó mediante el análisis de contenido de tipo directo. El progreso de la retinopatía diabética va desde los estados más benignos hasta los más severos cuando no se aplica una intervención médica apropiada. Es importante reconocer cada estado de la retinopatía diabética para que el tratamiento sea más efectivo. Varias décadas de estudios clínicos han proporcionado excelentes datos sobre el curso natural de la enfermedad y la estrategia de tratamiento que son efectivas en alrededor de un 90 % para prevenir la pérdida visual severa.

Introduction: Vascular endothelial growth factor (VEGF) plays an essential role in development of diabetic macular edema (DME). While there is evidence suggesting that silymarin, a flavonoid extracted from Silybum marianum, could be useful for prevention and treatment of diabetic nephropathy, no studies have been conducted in diabetic retinopathy (DR). The aim of this study was to assess the effect of silymarin on disruption of inner blood retinal barrier (BRB), the primary cause of DME., Materials and Methods: Human retinal endothelial cells (HRECs) were cultured under standard (5.5mM D-glucose) and diabetogenic conditions (25mM D-glucose and 25mM D-glucose + recombinant vascular endothelial growth factor [rVEGF, 25mg/mL]). To assess cell viability, three concentrations of silymarin were tested (2, 4 and 10μg/mL). The effect of silymarin on HREC disruption was determined using a dextran (70kD) permeability asssay., Results: No differences were found in the viability of HRECs treated with 2 or 4μg/mL of silymarin as compared to untreated cells, but viability significantly decreased after using 10μg/mL. The concentration of 4 μg/mL was therefore selected. Silymarin (4μg/mL) caused a significant decrease in VEGF-induced permeability in both media with 5.5nM (422±58 vs. 600±72 ng/mL/cm2; p<0.03) and 25nM of D-glucose (354 ± 28 vs. 567 ± 102 ng/mL/cm2; p<0.04)., Discussion: Our results show that silymarin is effective for preventing hyperpermeability induced by diabetic conditions in HRECs. Further studies are needed to assess whether silymarin could be useful to treat DME., (Copyright © 2018 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

Aflibercept is a new anti-vegf drug that, unlike ranibizumab and bevacizumab blocks both vegf-A and placental growth factor. Moreover, it binds with much greater strength and affinity to human VEGF-A165 than other endogenous vegf receptors, conferring it with a more extended effect and allowing a lower frequency of intravitreal injections. This facilitates the adoption of fixed treatment regimens other than monthly or individual regimens such as "treat and extend". Aflibercept is indicated for the treatment of neovascular (exudative) age-related macular degeneration (ARMD), visual alteration due to macular edema secondary to central retinal vein occlusion (CRVO) and visual alteration due to diabetic macular edema (DME). The present article reviews the management of aflibercept in routine clinical practice, based on the specifications of its new core data sheet, which includes all the therapeutic indications in which its use has been approved and evaluating the distinct alternatives and treatment regimens after the initial loading doses., (Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Angiogenesis is the process through which new blood vessels are formed, based on preexisting vessels, and is the paradigm of diseases such as cancer and exudative ageassociated macular degeneration (ARMD). Several proangiogenic factors have been identified, such as vascular endothelial growth factor (VEGF), especially VEGF-A, which activates endothelial cells and promotes cell proliferation, migration, and an increase in vascular permeability. VEGF is also involved in the etiopathogenesis of other retinal diseases, such as diabetic macular edema and macular edema secondary to retinal vein occlusion. Likewise, there is increasing evidence that placental growth factor (PIGF) acts recepsynergetically with VEGF in promoting these diseases. Currently, the main treatment for these diseases are the anti-VEGF drugs, aflibercept, ranibizumab and bevacizumab. These agents differ in their molecular structure and mechanism of action., (Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

The VISTA and VIVID trials were conducted to compare the safety and efficacy of two intravitreal injection (IVI) regimens of aflibercept versus macular laser photocoagulation for the treatment of diabetic macular edema (DME). These double-masked, phase III clinical trials randomized (461/402) patients with DME to receive either 2mg aflibercept IVI every 4 weeks (2q4) or 2mg aflibercept IVI every 8 weeks (2q8) after 5 initial monthly doses vs macular laser photocoagularion. The primary efficacy endpoint was the mean change in best corrected visual acuity (BCVA) from baseline to week 52. Secondary efficacy endpoints were the change in central retinal thickness (CRT), the proportion of patients who gained ≥10 amd ≥15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and the change in the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) in near and distance vision. The mean BCVA gains in the 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (p<0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (p<0.0001) in VIVID. The proportions of patients gaining ≥ 15 letters and the proportion of patients with an improvement of > 2 levels in the severity of diabetic retinopathy was significant in the treatment groups versus the laser group. Mean reductions in CRT in the 2q4 and 2q8 groups vs the laser group were 185.9 and 183.1 versus 73.3 μm (p<0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 μm (p<0.0001) in VIVID. The incidences of ocular and nonocular adverse events were similar in all groups. In conclusion, IIV aflibercept demonstrated statistically significant superiority in improvement in BCVA and reduction in DME over laser, with similar efficacy in the 2q4 and 2q8 groups in VISTA and VIVID., (Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Focal photocoagulation interrupts vascular leakage in diabetic macular edema, and allows the retinal pigment epithelium to withdraw fluid that thickens the retina; this mechanism could be enhanced by dorzolamida, a topical carbonic anhydrase inhibitor., Objective: To determine the efficacy of dorzolamida compared against placebo, in reducing retinal thickness after focal photocoagulation, in eyes with diabetic macular oedema., Material and Methods: Experimental, comparative, prospective, longitudinal, double blind study in diabetics with focal macular oedema treated with photocoagulation. Treated eyes were randomly assigned three weeks after the procedure to receive dorzolamide (group 1) or placebo (group 2), three times daily during three weeks. Means of visual acuity, center point thickness and macular volume were compared 3 and 6 weeks after photocoagulation within groups (Wilcoxon's t) and between groups (Mann-Whitneys's U)., Results: Sixty-nine eyes form patients aged 58.3 ± 8.3 years; 37 were assigned to group 1 and 42 to group 2. Mean center point thickness changed from 178.4 ± 34μm to 170 ± 29.1μm in group 1 (p = 0.04), and from 179.2 ± 22.4μm to 178.6 ± 20.8μm in group 2 (p = 0.7); mean macular volume changed from 7.63 ± 0.52mm(3) to 7.50 ± 0.50mm(3) in group 1 (p = 0.02) and from 7.82 ± 0.43mm(3) to 7.76 ± 0.42mm(3) in group 2 (p = 0.014)., Conclusions: The efficacy of dorzolamide was higher than that of placebo, to reduce retinal thickness after focal photocoagulation in diabetics with macular oedema., (Copyright © 2015. Published by Masson Doyma México S.A.)

Background: Center point thickness in diabetic macular edema varies after photocoagulation according to its baseline status; it is unknown whether this variation reduces the correlation between anatomic and visual acuity changes., Objective: to identify the contribution of baseline center point thickness to the correlation between anatomic and visual acuity after photocoagulation, in eyes with diabetic macular edema., Methods: non-experimental, prospective, longitudinal, analytical study in diabetics with macular edema treated with photocoagulation, stratified by groups: visual acuity < 0.5 with (group 1) or without central thickening (group 2), and visual acuity = 0.5 with (group 3) or without central thickening (4). The correlations between changes of center point thickness, macular volume, and visual acuity were identified (Spearman)., Results: 79 eyes, 17 in group 1 (21.5%), 21 in group 2 (26.6%), 14 in group 3 (17.7%) and 27 in group 4 (34.2%). Center point thickness increased in groups 2 and 4, visual acuity decreased in group 3 and macular volume in all the groups. The correlations between center point thickness and best corrected visual acuity changes in group 3, and between macular volume and visual acuity in group 1 were negative. The correlations between anatomic variables and visual acuity were low in the sample (r= 0.14)., Conclusion: the increase of center point thickness in eyes without baseline central thickening produced opposite correlations between groups, which reduced the correlations in the samples. Stratification according to baseline center point thickness would make easier to evaluate other variables that modify the functional outcome after photocoagulation.