Advances in the treatment of diabetic retinopathy

Diabetic retinopathy, the most common long-term complication of diabetes mellitus, remains one of the leading causes of blindness worldwide. Strict metabolic control, tight blood pressure control, laser photocoagulation, and vitrectomy remain the standard care for diabetic retinopathy. Focal/grid photocoagulation is a better treatment than intravitreal triamcinolone acetonide in eyes with diabetic macular edema and should be considered as the first-line therapeutic option. The current evidence suggests that intravitreal triamcinolone acetonide or anti-vascular endothelial growth factor agents result in a temporary improvement of visual acuity and a short-term reduction in central macular thickness in patients with refractory diabetic macular edema and are an effective adjunctive treatments to laser photocoagulation or vitrectomy. However, triamcinolone is associated with risks of elevated intraocular pressure and cataract. Vitrectomy with the removal of the posterior hyaloid without internal limiting membrane peeling seems to be effective in eyes with persistent diffuse diabetic macular edema, particularly in eyes with associated vitreomacular traction. Emerging therapies include islet cell transplantation, fenofibrate, ruboxistaurin, pharmacologic vitreolysis, rennin-angiotensin system blockers, and peroxisome proliferator-activated receptor gamma agonists.     

非诺贝特治疗糖尿病视网膜病变的临床研究进展

非诺贝特是过氧化物酶增殖物激活受体α（PPAR-α）激动剂,在临床上作为调脂药物被广泛使用。它能够降低甘油三酯水平,升高高密度脂蛋白胆固醇（HDL-C）水平,降低冠脉血管事件的风险。最近的临床试验表示,非诺贝特能够延缓增殖期糖尿病视网膜病变的进展,且发现非诺贝特的这种作用与其抗炎作用等有关。现主要就非诺贝特在糖尿病视网膜病变发病中的作用及其机制进行综述。     

Side-Effects and Complications of Laser Treatment in Diabetic Retinal Disease

ABSTRACT

Laser treatment for diabetic retinopathy was the first intraocular treatment to provide a highly effective means for preventing visual loss in patients with diabetes. Although inherently destructive, laser treatment is remarkably effective in preventing visual loss and preserving vision long-term. This review will describe briefly the current techniques and discuss in detail the reported side-effects and potential complications of laser treatment of diabetic retinal disease.     

Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature

Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is increasingly used for the treatment of a wide variety of retinal diseases, including age-related macular degeneration, diabetic retinopathy and retinal vascular occlusions, and retinopathy of prematurity. Despite encouraging results in halting the disease and improving the vision, intravitreal injection of anti-VEGF agents may be associated with systemic adverse events and devastating ocular complications. In this review, we provide an overview of safety data for intravitreal injection of common anti-VEGF agents.     

Medikamentöse Therapie der diabetischen Retinopathie

Chronic overproduction of growth hormone and insulin-like growth factor 1 play an important role in the pathogenesis of diabetic retinopathy. Somatostatin receptors are the targets of somatostatin analogues such as octreotide in the treatment of diabetic retinopathy. Octreotide has shown promise as a safe and effective treatment for advanced diabetic retinopathy and diabetic macular edema. One important pathomechanism in the development of diabetic complications is the activation of protein kinase C induced by high glucose due to an increased diacylglycerol level. The development of a selective PKCss inhibitor enables a new therapeutic approach for the treatment of diabetic retinopathy. Ongoing prospective clinical studies are investigating if treatment with specific PKCss inhibitors can prevent the progression of diabetic retinopathy and diabetic macular edema.The intravitreal injection of triamcinolone acetonide leads to at least temporary improvement of the diffuse diabetic macular edema. Side effects are increase of intraocular pressure, cataract, and endophthalmitis.     

Progressive changes in diabetics and their management

The prevalence of diabetic retinopathy is increasing worldwide due to an increasing number, and prolonged survival, of diabetic patients. Many effective treatments for different types and stages of retinopathy exist. However, there is patchy delivery of care, inconsistent screening, and unresolved questions about several management questions. This article discusses the current state of knowledge about therapeutics in diabetic retinopathy, and highlights areas where further studies and evidence base is required.     

Asymmetric retinopathy in patients with diabetes mellitus

We reviewed retrospectively the records of 57 diabetic patients with asymmetric retinopathy persisting for two years or more (mean, 4.8 years) to identify intraocular risk and protective factors for the development of proliferative retinopathy. For each patient in this series, the more severely affected eye had proliferative retinopathy and the fellow eye had either background diabetic retinopathy or no retinopathy. Branch vein occlusion (P = .016) was identified as a statistically significant risk factor for proliferative retinopathy and chorioretinal scarring (P = .031) was found to be a statistically significant protective intraocular factor. In 34 patients with long-standing asymmetric retinopathy, no intraocular risk or protective factors were identified.     

Intraocular implants in diabetic patients

We conducted a retrospective study of 641 cataract operations performed in our service from January 1982 to January 1986 in order to evaluate the results obtained on diabetic patients who had cataract extraction with intraocular lens implantation. In this general population who underwent cataract surgery, diabetics represent 14% of our cases. In this sub-group, we identified 28 patients (33 eyes) who received an intraocular lens. Among these eyes, 25 (76%) achieved a post-operative visual acuity of 5/10 or better. We found that cataract surgery with intraocular lens implantation in diabetics carries the same risks and the same complications rate as it does for a general population. However, for these patients are found a particular risk of activation of the diabetic retinopathy with early development of diabetic maculopathy in 10% of the cases. The examination and treatment of this retinal complication did not seem to be affected by the presence of an intraocular lens. Therefore, the advantages gained by the introduction of an intraocular lens, justify this type of correction of aphakia in selected diabetic patients.     

Progression of diabetic retinopathy after cataract extraction.

The course of diabetic retinopathy following cataract extraction was studied retrospectively in 89 patients (89 eyes). Cataract extraction was extracapsular in 12 eyes (13.5%), extracapsular with intraocular lens implantation in 37 (41.6%), and intracapsular in 40 (45%). In 55 eyes (61.8%) there was no change in the retinal status after surgery, and in 34 (38.2%) there was progression of diabetic retinopathy. In the eyes showing progression there was appearance or aggravation of non-proliferative changes in 85.3% and development of proliferative diabetic retinopathy in 14.7%. Most of these eyes (91%) deteriorated within six months of surgery. Risk factors for the progression of diabetic retinopathy were the preoperative existence of diabetic retinopathy (p less than 0.005) and the need for antidiabetic agents in addition to dietary control in the management of diabetes (p less than 0.025).     

Changing times for the management of diabetic retinopathy

Laser photocoagulation has led a revolution in the management of diabetic retinopathy. Scatter photocoagulation and focal photocoagulation has been shown to be effective in reducing vision loss. Just as dramatic as laser photocoagulation, medical treatment has led another revolution in the treatment of diabetic retinopathy. Good glycemic, blood pressure, and lipid control have contributed to further reduce vision loss and laser photocoagulation. In the very near future, there will be significant advances in pharmacologic treatment of diabetic retinopathy. Treatment with antioxidants, agents inhibiting hyperglycemia-induced protein kinase activity, and other agents will likely prevent the development/progression of retinopathy. Because pharmacologic agents are aimed at the prevention of retinopathy, patients with retinopathy will need to be examined earlier to diagnose retinopathy at earlier stages. To maximize the opportunity for earlier diagnosis, ophthalmologist may need to adopt screening strategies to identify patients most likely to benefit from these new treatments.     

PPAR-γ对糖尿病视网膜病变的潜在治疗作用

糖尿病视网膜病变(diabetic retinopathy,DR)是致盲的重要原因,炎症反应在其发病过程中发挥着重要作用.过氧化物酶体增生物激活受体-γ (peroxisome proliferator-activated receptor-γ,PPAR-y)不仅具有增加胰岛素敏感性的作用,还可以抑制炎症和细胞增殖等,因而激活PPAR-γ可能对DR发挥一定的治疗作用.本文就PPAR-y的生物学功能、PPAR-γ在DR中的作用机制及对DR的可能治疗作用做一综述.     

VEGF抑制剂在新生血管性青光眼治疗中的应用

新生血管性青光眼(neovascular glaucoma,NVG)是一种常见的继发性青光眼,常继发于糖尿病性视网膜病变、视网膜中央静脉阻塞和视网膜缺血综合征。其发病机制复杂,传统的治疗方式虽然能短暂缓解高眼压、消退虹膜新生血管,但对NVG的长期控制效果并不明显。随着近年来对NVG发病机制的深入研究及VEGF抑制剂在眼科疾病中的使用,NVG的治疗迎来了新的曙光。本文就VEGF抑制剂在新生血管性青光眼治疗中的应用做一综述,以期为NVG的治疗提供新的思路。     

Treatment of proliferative diabetic retinopathy with anti‐VEGF agents

Proliferative diabetic retinopathy (PDR) is the most common cause of severe visual loss in people with diabetes. Although panretinal photocoagulation (PRP) remains the gold standard of care to date, several combinations of new treatment modalities have emerged. These approaches can be used to increase the extent of treatment, expedite the effect of laser treatment and provide alternate measures when laser delivery is difficult or impossible, especially in patients with vitreous haemorrhage. Currently, most of the research in this field is focussed on inhibitors of vascular endothelial growth factor (VEGF), referred to herein as anti‐VEGF agents. Although limited by their short‐lived effects and a lack of established protocols, anti‐VEGF agents are widely available, especially for the treatment of aggressive PDR. This review analyses published studies using anti‐VEGF agents alone or as an adjunct to other therapies in the treatment of PDR.     

Drug delivery methods for posterior segment disease

PURPOSE OF REVIEW: New pharmacotherapies for posterior segment diseases of the eye have been recently introduced which use novel drug delivery methods. The various current and potential future methods will be discussed. RECENT FINDINGS: Drug delivery systems have been developed which can provide controlled release of drug for potentially long periods of time. Ideal candidates for these devices are chronic conditions that require repeated local administration of drug, such as noninfectious intermediate or posterior uveitis, neovascular age-related macular degeneration, and persistent macular edema due to diabetic retinopathy or venous occlusive disease. Recently, Retisert (Bausch & Lomb, Rochester, New York, USA), a nonbiodegradable fluocinolone acetonide implant, was approved for use in noninfectious uveitis affecting the posterior segment and is currently in clinical trials for the treatment of macular edema. A biodegradable dexamethasone implant is currently in clinical trials for the treatment of uveitis and diabetic macular edema. SUMMARY: With the development of therapeutic agents that require repeated administration comes a need for new strategies to improve safety and maximize efficacy. Novel drug delivery systems involving nonbiodegradable or biodegradable implants, microparticulates or nanoparticulates, liposomes, or transscleral iontophoresis may provide the solution.     

早期硅油填充联合曲安奈德治疗增生性糖尿病视网膜病变

目的 观察玻璃体手术中使用曲安奈德和早期硅油填充治疗增生性糖尿病视网膜病变的疗效.方法 增生性糖尿病视网膜病变,52例(52眼),行经平坦部玻璃体切除手术.术中使用曲安奈德标识病变组织,将其彻底切除.玻璃体腔内填充硅油.术前最佳矫正视力为0.05.术后随访8个月,观察视力、眼压、视网膜出血和增生情况,并及时补充激光治疗.治疗和随访期内,要求血糖控制在7.0 mmol/L以下的平稳状态.结果 术后8个月,无继发性青光眼或严重增生性反应.观察期内糖尿病视网膜病变无明显再进展表现.结论 在玻璃体切除手术中使用曲安奈德和早期硅油填充,能够有效减少术后并发症,并为及时补充激光治疗提供有利条件,较好的控制糖尿病视网膜病变的进展.     

DR硅油填充后并发白内障行超声乳化联合硅油取出

目的：探讨糖尿病视网膜病变硅油填充后并发白内障的超声乳化及人工晶状体（IOL）植入联合硅油取出术的临床疗效。 方法：糖尿病视网膜病变患者22例22眼硅油填充后并发白内障行超声乳化及IOL植入联合硅油取出术,均通过角膜透明切口植入软性IOL。 结果：患者19眼视力均在白内障超声乳化手术后视力较术前提高,其中0.1以上者13例,3例同术前视力;手术中后囊膜保持完整,均顺利植入软性可折叠IOL;5例术后不同程度发生角膜水肿,均在术后3~7d内消退。22例硅油均顺利取出。3例术后1mo内发现玻璃体腔积血,其中2例约4wk内玻璃体腔积血自行吸收,1例再行玻璃体手术去除积血联合眼内光凝。22例术后均未发现视网膜再脱离。 结论：糖尿病视网膜病变硅油填充眼并发性白内障的超声乳化IOL植入术联合硅油取出手术效果满意,可减少患者多次手术的痛苦。     

Midterm visual outcome and progression of diabetic retinopathy following cataract surgery. Midterm outcome of cataract surgery in diabetes

OBJECTIVE: To assess the influence of cataract surgery on progression of diabetic retinopathy and visual acuity. METHODS: 37 patient eyes with mild to moderate diabetic retinopathy at baseline underwent phacoemulsification and intraocular posterior chamber lens implantation. They were examined 3.3 +/- (SD) 0.7 years after surgery. RESULTS: 83.8% of the eyes showed a better final visual acuity, and 67.6% achieved a final visual acuity of 0.5 or better. The retinopathy remained unchanged in 83.8% and progressed in 16.2% of the eyes. No eye progressed to proliferative retinopathy. CONCLUSION: Phacoemulsification and implantation of a posterior chamber intraocular lens is a safe procedure for patients with mild to moderate diabetic retinopathy.     

Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway

Fenofibrate, a widely used hypolipidemic drug, has anti-inflammatory and anti-atherosclerotic effects in the vessel wall. In the present study, we report an anti-apoptotic property of fenofibrate in human retinal endothelial cells (HRECs) and describe an underlying molecular mechanism. Treatment with fenofibrate protected HRECs from apoptosis in response to serum deprivation in a dose-dependent manner. This inhibition of apoptosis by fenofibrate was not altered by peroxisome proliferator-activated receptor alpha (PPARalpha) antagonist MK 886, and selective agonist for PPARalpha, WY-14643 had no beneficial effects on serum deprivation-induced cell death. Fenofibrate potently induced a sustained activation of AMP-activated protein kinase (AMPK) and vascular endothelial growth factor (VEGF) mRNA expression. Furthermore, compound C, a specific AMPK inhibitor, almost completely blocked the fenofibrate-induced survival effect as well as VEGF mRNA expression. Taken together, these results suggest that fenofibrate prevents apoptotic cell death induced by serum deprivation through PPARalpha-independent, but AMPK-dependent pathway. Thus fenofibrate may have a novel therapeutic property that can control unwanted cell death found in diabetic retinopathy.     

Vascular endothelial growth factor and diabetic complications

Intraocular delivery of anti-vascular endothelial growth factor (VEGF) therapies is now used widely to treat age-related macular degeneration, and is currently undergoing evaluation in clinical trials for treatment of diabetic retinopathy. An important aspect of anti-VEGF treatment is that while the agents are injected into the vitreous cavity, they may be absorbed systemically, thus potentially affecting systemic VEGF levels. Systemic VEGF-A and the interplay between membrane-bound VEGF receptors and the soluble form of VEGF-R1 are key to angiogenesis, vasculogenesis, neurogenesis and hemodynamics. These cellular processes are regulated by complicated negative and positive feedback loops, many of which are disrupted and altered in diabetes. The VEGF protein, mRNA, as well as the actual VEGF receptor levels, appear to be impaired in diabetes in microvascular and macrovascular vessel beds. What is not clear is the exact role and influence that these levels have on an organ's function. In some organ systems, elevated VEGF levels act as a pathologic angiogenic stimulus (i.e., ocular neovascularization) whereas in others, low levels of VEGF activity leads to pathology (i.e., cardiomyopathy, wound healing and peripheral neuropathy). Diabetic patients have a higher risk of hypertension and proteinuria, two surrogate markers of systemic VEGF inhibition. Certain intraocular anti-VEGF treatments could therefore have an adverse effect in this population by possibly affecting circulating and organ-specific VEGF and VEGF receptor levels.