Corticosteroid Use for Diabetic Macular Edema: Old Fad or New Trend?

Diabetic retinopathy is the leading cause of blindness in working age individuals in developed countries. Most cases of diabetes related vision loss result from breakdown of the blood-retinal barrier with resultant diabetic macular edema (DME). For over 30 years, laser photocoagulation has been the standard therapy for DME, but most eyes do not experience significant improvements in visual acuity. Intravitreal injections of drugs that inhibit the action of vascular endothelial growth factor (VEGF) lead to gains in vision, but can be expensive and need to be repeated frequently. In addition to VEGF-mediated breakdown of the blood-retinal barrier, recent evidence suggests that inflammation plays an important role in the development of DME. Recognizing this, physicians have injected steroids into the vitreous and developers have created sustained release implants. Intravitreal injections of triamcinolone acetonide lead to rapid resolution of macular edema and significant short-term improvements in visual acuity, but unfortunately, visual acuities diminish when treatment is continued through 2 years. However, intravitreal triamcinolone remains an attractive treatment option for eyes that are pseudophakic, scheduled to undergo cataract surgery, resistant to laser photocoagulation, or require urgent panretinal photocoagulation for proliferative retinopathy. In controlled trials, intraocular implants that slowly release dexamethasone and fluocinolone show promise in reducing macular edema and improving visual acuity. The high incidences of drug related cataracts and glaucoma, however, require that corticosteroids be used cautiously and that patients be selected carefully. The increasing number of patients with DME, the burgeoning cost of medical care and the continuing development of intravitreal steroids suggest that the use of these agents will likely increase in coming years.     

糖尿病性黄斑水肿的发病机制与治疗进展

目前全球糖尿病视网膜病变（DR）患者约9300万,其中增殖性DR（PDR）患者1700万,糖尿病性黄斑水肿（DME）患者2100万,威胁视力的DR患者2800万。随着年龄的增长,DME现已成为糖尿病患者视力损害的主要原因。其发病机制尚未明确,研究显示视网膜内、外屏障的破坏等在DME的发生发展中起到重要作用。目前,DME的治疗方法包括传统的激光光凝、糖皮质激素的应用、抗血管内皮生长因子（VEGF）药物的玻璃体腔注射、蛋白激酶C抑制剂的应用、玻璃体手术等,但每种疗法都有其优点和不足。联合治疗重复次数少、疗效高、安全性强,是未来发展的新趋势。本文对老年性DME治疗的国内外研究现状及发展趋势进行综述。     

Cystic Fibrosis Related Diabetes

Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of diabetic macular edema (DME), the leading cause of vision loss among working-aged individuals. A decade of clinical trials demonstrated that drugs that bind soluble VEGF restore the integrity of the blood-retinal barrier, resolve macular edema, and improve vision in most patients with DME. Four drugs (pegaptanib, ranibizumab, bevacizumab, and aflibercept) effectively treat DME when administered by intravitreal injections. Only ranibizumab has received U.S. Food and Drug Administration (FDA) approval for DME, but bevacizumab is commonly used off-label, and an FDA application for aflibercept is pending. Effective treatment requires repeated injections, although recent data suggest that the treatment burden diminishes after 1 year. Intravitreal therapy is generally safe, although the incidence of systemic thromboembolic events varies among trials.     

Intravitreal steroid versus macular laser for treatment of diabetic macular edema

Diabetic macular edema is a leading cause of vision loss in the United States. Focal/grid laser photocoagulation has been the gold standard for treatment over the past two decades. Intravitreal pharmacologic treatments increasingly have been used over the past 5 years. Various studies have shown the possible benefits of intravitreal corticosteroids and anti-vascular endothelial growth factors in the treatment of diabetic macular edema. However, focal/grid laser photocoagulation continues to be the only proven safe and effective treatment for diabetic macular edema.     

Soluble Mediators of Diabetic Macular Edema: The Diagnostic Role of Aqueous VEGF and Cytokine Levels in Diabetic Macular Edema

Diabetic macular edema (DME) is a significant cause of vision loss and represents an important clinical and public health problem. It is characterized by breakdown of the blood retinal barrier with fluid accumulation in the sub-retinal and intra-retinal spaces. Although several hypotheses exist for the causes of diabetic macular edema, specific molecular mechanisms remain unclear. Current thinking includes the role of vascular endothelial growth factor (VEGF) and inflammatory cytokines in vascular permeability. We review studies showing a relationship between elevated aqueous VEGF, monocyte chemoattractant protein -1, interleukin 6, or interleukin 8 in association with DME and as predictors of DME. The presence of mediators in both the angiogenesis and inflammatory pathways data suggest a multifactorial model for the development of DME. Further studies targeting individual cytokine activity will be important to our understanding of the pathogenesis and treatment.     

Intravitreal triamcinolone for the treatment of diabetic macular edema

Diabetic macular edema is one of the leading causes of visual loss in first world countries and the first cause in diabetic retinopathy. The Early Treatment Diabetic Retinopathy Study showed a significant benefit in using focal laser photocoagulation for the treatment of macular edema, more specifically defined as clinically significant macular edema. Nevertheless, progressive visual loss is found in the 26% of patients with diabetic macular edema treated with photocoagulation. The failure of laser treatment and the destructive nature of the therapy has forced researchers to pursue new alternatives including vitrectomy with or without internal limiting membrane peels, the use of proteinkinase C inhibitors, intravitreal injections of antibodies that inhibit the vascular endothelial growth factor, somatostatin analog, or the intravitreal injection with corticosteroids. Triamcinolone acetonide is glucocoticosteroid with antiangiogenic and antiedematous properties. Publications evaluating the safety and efficacy of intravitreal injection of triamcinolone in the treatment of diabetic macular edema show varying outcomes with respect to the increases of visual acuity and decreases in foveal thickness. Despite this, intravitreal triamcinolone is a treatment that has evolved quickly and is considered increasingly useful.     

Diabetic retinopathy: current and new treatment options

Diabetes mellitus has become a major health concern worldwide and its incidence is projected to increase. Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are considered the most sight-threatening ocular complications in these patients. Pivotal studies, such as the Early Treatment Diabetic Retinopathy Study (ETDRS) and the Diabetic Retinopathy Study (DRS), have established macular and pan-retinal laser as the gold-standard of treatment for these complications. The recent discovery of the vascular endothelial growth factor (VEGF) and its role in the development of proliferative disease, has led to a movement towards treating PDR and DME with anti-angiogenic medications alone or in conjunction with the gold-standard of care. Due to the severity of the diabetic ocular complications and the rising incidence of diabetes worldwide, it is important for the non-ophthalmologist care provider to be informed of the new treatments available for these conditions in an effort to better guide their patients. In this review, I will discuss the importance of these new methods of treatment as well as the significance of systemic glucose control, vitreous surgery and laser photocoagulation.     

Vascular Endothelial Growth Factor Inhibitors for Diabetic Retinopathy

The prevalence of diabetes is growing at epidemic rates in the USA. Diabetic retinopathy develops in a large proportion of patients and is a leading cause of blindness worldwide. Systemic management of diabetic retinopathy has included glycemic, hypertension, and lipid control. Local ophthalmic treatment in the form of focal/grid or panretinal laser photocoagulation has been shown to prevent vision loss in diabetic edema and proliferative diabetic retinopathy, respectively. The introduction of anti-vascular endothelial growth factor for diabetic macular edema and retinopathy has provided clinicians with improved clinical outcomes with potentially less damaging effects than laser.     

Down-regulation of angiogenic inhibitors: a potential pathogenic mechanism for diabetic complications

Diabetic retinopathy (DR) and diabetic nephropathy (DN) are the most common microvascular complications of diabetes. DR is a leading cause of blindness, and DN is a major cause of end-stage renal diseases. Diabetic macular edema (DME) resulting from increased vascular permeability in the retina and retinal neovascularization (NV) represent two major pathological changes in DR and are the primary causes of vision loss in diabetic patients. Previous studies have shown that angiogenic factors such as vascular endothelial growth factor (VEGF) play a key role in the development of DME and retinal NV. Studies in recent years have demonstrated that a number of endogenous angiogenic inhibitors are present in the normal retina and counter act the effect of VEGF in the regulation of angiogenesis and vascular permeability. Decreased levels of angiogenic inhibitors in the vitreous and retina have been found in diabetic patients and diabetic animal models. The decreased levels of angiogenic inhibitors shift the balance between angiogenic factors and angiogenic inhibitors and consequently, lead to the development of DME and retinal NV. Recently, we have found that these angiogenic inhibitors are expressed at high levels in the normal kidney and are down-regulated in diabetes. Moreover, these inhibitors inhibit the activity of VEGF and TGF-beta, two major pathogenic factors of DN. Therefore, decreased levels of these angiogenic inhibitors in diabetes may be associated with pathologies of DN. This review will summarize recent progress in these fields and therapeutic approaches to use angiogenic inhibitors for the treatment of diabetic complications.     

改良糖尿病视网膜病变早期治疗研究组格栅样光凝与轻度黄斑格栅样光凝在治疗糖尿病黄斑水肿中的疗效比较

目的比较改良糖尿病视网膜病变早期治疗研究组（ETDRS）格栅样光凝及轻度格栅样光凝在糖尿病视网膜病变黄斑水肿治疗中的疗效。方法选取2008年1月至2010年1月于我院眼科门诊就诊及内分泌科会诊的伴有糖尿病黄斑水肿（DME）的轻至中度非增殖性糖尿病视网膜病变（NPDR）患者为研究对象,共72例97眼,其中男40例55眼、女32例42眼。入选患者均进行全面眼科检查,采用随机化分组表将患者分为改良ETDRS格栅样光凝组（36例48眼）及轻度格栅样光凝组（36例49眼）进行激光治疗,治疗后随访24个月。观察2组患者治疗前后视力、黄斑中心凹视网膜厚度等变化情况,数据采用SPSS16．0软件进行统计分析。统计学方法采用One．wayANOVA检验,两两比较采用t检验。结果改良ETDRS格栅样光凝组和轻度格栅样光凝组患者治疗后24个月均可见视力明显提高,与治疗前比较差异具有统计学意义（改良ETDRS格栅样光凝组：初始值55．4-21,治疗24个月后59±21;轻度格栅样光凝组：初始值544-11,治疗24个月后584-13,均P〈0．05）,但2组患者视力改善程度在各随访时间点差异均无统计学意义（P〉0．05）。改良ETDRS光凝组和轻度格栅样光凝组患者治疗后24个月内黄斑中心凹视网膜厚度均有所下降,与治疗前比较差异具有统计学意义（改良ETDRS格栅样光凝组：初始值395±174,治疗24个月后2044-16;轻度格栅样光凝组：初始值464±204,治疗24个月后2414-13,均P〈0．05）。但2组在各时间截点黄斑中心凹视网膜厚度改变差异均无统计学意义（均P〉0．05）。结论对轻、中度NPDR合并DME患者采用改良ETDRS光凝或轻度格栅样光凝治疗并随访24个月后发现2种光凝方法均在改善黄斑水肿患者远期视力方面具有一定疗效且无明显差异。     

Diabetic Retinopathy: An Update on Treatment

Diabetic retinopathy is a progressive disease that results from vascular injury due to chronic hyperglycemia. It is the leading cause of blindness in working-age adults in the US and is usually asymptomatic until late stages. Treatment with laser photocoagulation is effective at preventing severe vision loss; thus, diabetic patients should be referred for regular screening by an ophthalmologist. New inhibitors of vascular endothelial growth factor may provide targeted nonsurgical treatment to improve vision in diabetic retinopathy.     

Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema

Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB-9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy.     

Advances in the treatment of diabetic retinopathy

As the diabetes epidemic in the United States continues to worsen, so too does the prevalence of diabetic retinopathy (DR). DR is divided broadly into nonproliferative and proliferative stages, with or without vision-threatening macular edema. Progression to proliferative DR is associated with vision loss that is often irreparable, and a rapid decline in health-related quality of life. Vascular endothelial growth factor (VEGF)-A is upregulated in the diabetic eye, and has been identified as a key driver of DR pathogenesis. With this perspective, we review the published phase III clinical trial data of anti-VEGF therapies approved for the treatment of DR in the United States. Using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale, in which an improvement of ≥2 steps is considered clinically significant, approximately one-third of patients with DR and macular edema experience this level of improvement after 1 year of treatment with either ranibizumab or aflibercept. The rates of clinically significant DR improvement with ranibizumab could be twice that in the subgroup of patients with moderately severe or severe nonproliferative DR and macular edema. These clinical trial data indicate that intraocular inhibition of VEGF is a rational approach for the management of DR.     

微脉冲激光或传统格栅光凝联合康柏西普治疗糖尿病黄斑水肿的临床分析

目的观察微脉冲激光或传统格栅光凝联合康柏西普治疗糖尿病黄斑水肿(DME)的有效性、安全性。方法纳入2017年1月—2019年6月DME患者98眼,577 nm阈值下微脉冲联合治疗(A组)32眼、传统格栅光凝联合治疗(B组)30只眼、单纯康柏西普治疗(C组)36眼。观察最佳矫正视力(BCVA)、黄斑中心凹厚度(CFT)、黄斑容积(MV)及视网膜的微结构变化及注射针数。结果所有患者治疗后3、6、9、12个月的BCVA、CFT、MV均较前改善,差异有统计学意义(F=39.558、62.901、10.078,P<0.001)。组间比较差异无统计学意义(F=0.417、0.085、0.061,P=0.513、0.675、0.823)。A、B组年平均药物注射次数分别为(6.3±0.9)、(6.5±1.1)次低于C组(8.6±2.2)次,差异有统计学意义(F=7.980,P<0.05)。B组可见激光损伤而A组未见。结论激光联合治疗与单纯药物治疗均对DME有效,联合治疗可减少药物注射次数;微脉冲激光较传统格栅光凝更安全。     

Antisense Oligonucleotide Therapy in Diabetic Retinopathy

Diabetic retinopathy is one of the leading causes of blindness in the United States and other parts of the world. Historically, laser photocoagulation and vitrectomy surgery have been used for the treatment of diabetic retinopathy, including diabetic macular edema. Both procedures have proven to be useful under certain conditions but have their limitations. New pathways and processes that promote diabetic retinopathy have been identified, and several new therapeutic approaches are under investigation. These new therapies may be beneficial in the treatment of diabetic retinopathy and include antivascular endothelial growth factor agents, corticosteroids, and therapies that may potentially target a number of additional diabetic retinopathy-related factors and processes, including antisense oligonucleotides. Second-generation antisense oligonucleotides, such as iCo-007, may offer a significant advantage in the treatment of diabetic retinopathy by downregulating the signal pathways of multiple growth factors that seem to play a critical role in the process of ocular angiogenesis and vascular leakage. Benefits of such molecules are expected to include the specificity of the kinase target and an extended half-life, resulting in less frequent intravitreal drug administration, resistance to molecule degradation, and a good safety profile.     

Medikamentöse Therapie der diabetischen Retinopathie und Makulopathie

Although the prognosis in diabetic eye complications has improved as a result of better glycemic and blood pressure control as well as advances in the established therapy options of laser coagulation and vitreoretinal surgery, diabetic retinopathy remains the most common cause of blindness among the working population of the industrial nations. Experimental and clinical data indicate that new pharmacological options for pathophysiologically oriented therapy may be effective. Initial experience with intravitreal injection of the glucocorticoid triamcinolone acetonide or vascular endothelial growth factor (VEGF) inhibitors pegaptanib, ranibizumab and bevacizumab have shown that, in the case of diffuse diabetic macular edema, which has been difficult to treat to date, at least a temporary anatomic and partly functional improvement can be achieved. Furthermore, the application of these intravitreal therapy modalities as adjuvants to/after laser coagulation or surgery can be considered in selected cases of focal diabetic macular edema and proliferative diabetic retinopathy. Further prospective trials are needed to answer questions on duration of effect, the need for repeat injections, as well as on side effects.     

Intravitreal anti-VEGF drugs as adjuvant therapy in diabetic retinopathy surgery

The use of intravitreal anti vascular endothelial growth factor (anti-VEGF) drugs such as pegaptanib, ranibizumab and bevacizumab has been widely reported to treat complications such as macular edema and rubeosis. During the past few years they have also been used as an adjuvant therapy to reduce intraocular bleeding during vitrectomy in eyes with proliferative diabetic retinopathy as well as to reduce the occurrence of vitreous haemorrhages in vitrectomized eyes and facilitate glaucoma surgery. In this paper we review the use of anti VEGF drugs in the surgical management of diabetic retinopathy related complications.     

Diabetic retinopathy,a vascular and inflammatory disease: Therapeutic implications

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in the working-age population in the Western world. Diabetic macular oedema (DME) is one of the major complications of DR. Therapy with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs has become the gold standard treatment for DR and its complications. However, these drugs have no effect on the pathogenesis of DR and must be administered frequently via invasive intravitreal injections over many years. Thus, there is a pressing need to develop new therapeutic strategies to improve the treatment of this devastating disease. Indeed, an increasing volume of data supports the role of the inflammatory process in the pathogenesis of DR itself and its complications, including both increased retinal vascular permeability and neovascularization. Inflammation may also contribute to retinal neurodegeneration. Evidence that low-grade inflammation plays a critical role in the pathogenesis of DME has opened up new pathways and targets for the development of improved treatments. Anti-inflammatory compounds such as intravitreal glucocorticoids, topical non-steroidal anti-inflammatory drugs (NSAIDs), antioxidants, inflammatory molecule inhibitors, renin–angiotensin system (RAS) blockers and natural anti-inflammatory therapies may all be considered to reduce the rate of administration of antineovascularization agents in the treatment of DR. This report describes the current state of knowledge of the potential role of anti-inflammatory drugs in controlling the onset and evolution of DR and DME.     

Anti-VEGF Therapies and Blood Pressure: More Than Meets the Eye

“Wet” (also called neovascular) age-related macular degeneration (AMD) is a chronic progressive disease characterized by leakage of fluid or blood from choroidal neovascularization. It remains the leading cause of blindness in the developed world. Vascular endothelial growth factor (VEGF), which plays a key role in the pathogenesis of retinal neovascularization and vessel leakage leading to central vision loss, has emerged as a potential target in the treatment of wet AMD. Importantly, large-scale clinical trials have demonstrated that intravitreal VEGF antagonism prevents vision loss and may even improve visual acuity in patients with neovascular AMD. Because VEGF and its downstream mediator nitric oxide have a well-established cardioprotective role, however, it can be argued that the beneficial effects of VEGF antagonism in the eye may come at the cost of adverse systemic effects, particularly myocardial infarction and stroke.