Current Diabetes Reviews - Volume 5, Issue 1, 2009

This issue of CDR contains a range of interesting and up-to-date articles which review the most recent advances in the Treatment of Diabetic Retinopathy and which are written by highly respected groups of investigators. Although laser photocoagulation is considered to be the standard treatment of Diabetic Retinopathy for both macular edema and for retinal neovascularization, there have recently been important advances in this field, in particular with respect to the treatment of both diabetic macular edema (DME) and retinal neovascularization in Proliferative Diabetic Retinopathy (PDR), whether it be with intraocular steroids and new devices of sustained liberation or with anti-angiogenics. The first article, by Rodriguez-Fontal et al., reviews the importance of metabolic control and the long-term benefits of improving glycemic control, which reduces the risk of any type of retinopathy. Intensive therapy is most effective when initiated early in the course of diabetes because it has a beneficial effect on the development and progression of retinopathy. The article which follows, by Crawford et al., examines the role of angiogenic factors and the use of anti-VEGF drugs to block them. Hypoxia is a key regulator of VEGF-induced ocular neovascularization. Following the induction of VEGF by hypoxia, angiogenesis can be controlled by angiogenic inducers and inhibitors. The balance between VEGF and angiogenic inhibitors may well determine the proliferation of angiogenesis in diabetic retinopathy and understanding this is crucial in subsequent therapeutic strategies. Lopez reviews the role of human protein kinases. Several compounds have been developed that are specific inhibitors of protein kinase C beta isoforms. Synthetic inhibitors of protein kinases include small molecules that can be easily administered as oral therapeutic compounds. These inhibitors can rapidly and often specifically alter the activation state of a target kinase. So far two protein kinase C inhibitors, Protein Kinase C 412 and Ruboxistaurin, have been tested in clinical investigations to study the reduction of microvascular complications in patients with diabetes. Ruboxistaurin has appeared as a new alternative in the management of ocular complications of diabetes and it is necessary to determine whether it is sufficiently efficacious to be used alone or whether it has to be used in combination with other treatments in order to prevent visual loss in patients with diabetes. Two papers examine the treatment of DME by the use of intraocular steroids. The first, Abraldes et al., makes a comprenhensive review of the mechanism of action of triamcinolone acetonide, its pharmacology and its intraocular use both as treatment for DME refractary to focal photocoagulation and as adjuvant to panretinal photocoagulation. Special emphasis is placed on safety and efficacy data. The second written by Montero and Ruiz-Moreno, looks at intravitreal inserts, steroids, dexamethasone and fluocinolone. Different multicentric clinical trials and their results are examined. They conclude that the advantages of these systems are that they maintain a stable and sustained concentration of the drug with higher therapeutic efficacy thus reducing the number of injections. However, the complications associated with the use of steroids, such as cataracts and high intraocular pressure, are very common. The use of the different anti-VEGFs which are used in ophthalmology is tackled in three different papers. Each one reviews the main indications, published results and the experiences of the authors with the medicine used, as well as an efficacy and safety profile. The mechanism of action for pegaptanib sodium (Macugen, Pfizer), ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech) involves specific neutralization of VEGF. These anti-VEGFs are being evaluated in different studies and partial results, some of which are reviewed in this issue, have already been published. In dealing with Pegaptanib sodium both in the treatment of DME and in the case of PDR, Giuliari et al. conclude that these new pharmacologic therapies will cause a paradigmatic shift in the way we treat patients with ocular diabetic complications.

The Early Treatment Diabetic Retinopathy Study (ETDRS) identified important risk factors for progression to high risk proliferative diabetic retinopathy (PDR) including retinopathy severity, decreased visual acuity, and high levels of hemoglobin A1C (HbA1c). Additional risk factors for progression to PDR are decreased hematocrit and increased serum lipids. The long-term benefit of improving glycemic control was evaluated by three large studies: the Diabetes Control and Complications Trial (DCCT), the Stockholm Interventional Study, and the UK prospective study. Several small studies, notably the Kuwamoto study, also evaluated the relationship between the glycemic control and diabetic retinopathy. Intensive glycemic control reduces the risk of any retinopathy by approximately 27%. Intensive therapy is most effective when initiated early in the course of the diabetes, demonstrating a beneficial effect over the course and progression of retinopathy. The long term benefits of the intensive glycemic control greatly outweigh the risk of “early worsening.” Lowering elevated serum lipid levels has been shown to decrease the risk of cardiovascular morbidity. The ETDRS data suggest that lipid lowering may also decrease the risk of hard exudate formation and associated vision loss in patients with diabetic retinopathy. Preservation of vision may be an additional motivating factor for lowering serum lipid levels in persons with diabetic retinopathy and elevated serum lipid levels.

Diabetic retinopathy, a secondary microvascular complication of diabetes mellitus is the leading cause of blindness in the Unites States amongst individuals age 20 to 64. Two major retinal problems cause most of the diabetesrelated vision loss: diabetic macular edema and complications from abnormal retinal blood vessel growth, angiogenesis. Secondary to angiogenesis, increased retinal blood flow is of pathogenic importance in the progression of diabetic retinopathy. Understanding the role of hyperglycemia seems to be the most critical factor in regulating retinal blood flow, as increased levels of blood glucose are thought to have a structural and physiological effect on retinal capillaries causing them to be both functionally and anatomically incompetent. High blood glucose induces hypoxia in retinal tissues, thus leading to the production of VEGF-A (vascular endothelial growth factor protein). Hypoxia is a key regulator of VEGFinduced ocular neovascularization. Secondary to the induction of VEGF by hypoxia, angiogenesis can be controlled by angiogenic inducers and inhibitors. The balance between VEGF and angiogenic inhibitors may determine the proliferation of angiogenesis in diabetic retinopathy. Since VEGF-A is a powerful angiogenic inducer, utilizing anti-VEGF treatments has proved to be a successful protocol in the treatment of proliferative diabetic retinopathy.

Diabetic retinopathy (DR) and diabetic macular edema (DME) are frequent long term ocular complications in diabetic patients and may produce serious effects on visual acuity (VA), sometimes leading to blindness. The high and increasing prevalence of diabetes worldwide suggests that both complications will continue to be the main cause of vision loss and associated impairment for a long time [1]. The development and progression of DR is related to blood glucose concentration and is slowed by intensive glycemic control [2].

Diabetic macular edema is an important cause of visual loss in the developed world and may frequently lead to irreversible changes in visual acuity. 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. However, some cases of diabetic macular edema are refractory to laser therapy and do not have a good prognosis with such treatment. Triamcinolone acetonide is glucocoticosteroid with antiangiogenic and antiedematous properties. Recently, some promising results, respect to the increases of visual acuity and decreases in foveal thickness, have been shown in different studies for the treatment of refractory diabetic macular edema with intravitreal triamcinolone acetonide.

Diabetic retinopathy is the leading cause of blindness in developed countries. Diabetic macular edema (DME) is the most frequent cause of vision loss in patients with type 2 diabetes. Steroids may reduce the concentration of inflammatory cytokines and growth factors, and have effect on increased vascular permeability. Topical steroids does not reach intraocular therapeutic concentrations and periocular injection requires frequent injections at the risk of complications. Systemic administration of steroids may be useful, but high doses are required and are associated with severe systemic side effects. Intravitreal injection of steroids provides a powerful therapeutic effect, but it is associated with frequent secondary cataracts and increased IOP. The need for repeated injections may increase the risks associated with the injection procedure. Preliminary studies have proved the possibility of implanting sustained release inserts in the vitreous body, allowing for therapeutic levels of steroids in the vitreous cavity and retina for more than six months. The advantages of these systems are to keep a stable and sustained concentration of the drug with higher therapeutic efficacy thus reducing the number of injections. However, the complications associated with the use of steroids such as cataracts and high IOP are very common.

Diabetes mellitus is a growing health concern world-wide. Patients with this disease present with a variety of health conditions, including a number of sight-threatening ocular pathologies. Proliferative diabetic retinopathy (PDR) and diabetic macula edema (DME) are common diseases that cause substantial vision impairment in diabetic patients. There has been a strong focus on studying the epidemiology and treatment of these diseases. The recent discovery of 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 in conjunction with the standard of care. In this review we present a summary of the origination and progression of PDR and DME. This will be followed by a review of clinical data surrounding new anti-angiogenic treatment modalities.

Diabetic retinopathy (DR) remains the major threat to sight in the working age population. Diabetic macular edema (DME) is a manifestation of DR that produces loss of central vision. Macular edema within 1 disk diameter of the fovea is present in 9% of the diabetic population. Proliferative diabetic retinopathy (PDR) is a major cause of visual loss in diabetic patients. In PDR, the growth of new vessels from the retina or optic nerve, is thought to occur as a result of vascular endothelial growth factor (VEGF) release into the vitreous cavity as a response to ischemia. Furthermore, VEGF increases vessel permeability leading to deposition of proteins in the interstitium that facilitate the process of angiogenesis and macular edema. This review demonstrates multiple benefits of intravitreal bevacizumab on DR including DME and PDR. The results indicate that intravitreal bevacizumab injections may have a beneficial effect on macular thickness and visual acuity (VA), independent of the type of macular edema that is present. Therefore, in the future this new treatment modality could replace or complement focal/grid laser photocoagulation in DME. In addition, in PDR, this new option could be an adjuvant agent to PRP so that more selective therapy may be applied.

Ranibizumab (Lucentis®) is a Fab-Antibody with high affinity for VEGF, and is being designed to bind to all VEGF isoforms. This quality makes it a powerful drug for VEGF inhibition. Diseases of retinal and choroidal blood vessels are the most prevalent causes of moderate and severe vision loss in developed countries. Vascular endothelial growth factor plays a critical role in the pathogenesis of many of these diseases. Results of the pilot studies showed that intraocular injections of ranibizumab (Lucentis®) decrease the mean retinal thickness and improve the BCVA in all the subjects. Proliferative diabetic retinopathy, currently treated with destructive laser photocoagulation, represents another potential target for anti-VEGF therapy. The early experience in animal models with proliferative retinopathy and neovascular glaucoma shows that posterior and anterior neovascularizations are very sensitive to anti-VEGF therapy. The outcome of two phase III clinical trials will increase our knowledge of the role of Lucentis® in the treatment of DME.

Anti-VEGF drugs may be employed in the surgical treatment of diabetic retinopathy. 1. Prior to surgery. The intravitreal injection of anti-VEGF drugs leads to a significant reduction of neovascularization, with a reduction in the adherence of the fibrovascular complex to the retina. This simplifies viscodelamination and reduces intraoperative bleeding during delamination and segmentation. To minimize the risk of tractional retinal detachment due to the contraction of fibrovascular tissue, vitrectomy must be performed within one week after the injection. 2. To decrease the risk of postoperative bleeding. Recurrent vitreous hemorrhages after vitrectomy are often due to small bleeding from persistent neovascularization. The injection of anti-VEGF drugs at the end of vitrectomy could prevent bleeding from these vessels by blocking the pro-inflammatory stimulus of the surgical procedure. 3. To treat postoperative vitreous hemorrhage. The intravitreal injection of anti-VEGF drugs in patients with postoperative bleeding leads to resolution of the hemorrhage. 4. To treat rubeosis iridis. In eyes with complete panretinal photocoagulation, the combination of cryotherapy and intravitreal anti-VEGF injection in the same surgical procedure produces a disappearance of iris neovascularization together with a long term effect with no recurrences. In neovascular glaucoma, anti-VEGF drugs can also facilitate filtrating surgery.

In the absence of posterior vitreous detachment, vitreous cortex is adhered to the internal limiting lamina of the inner retina. This junction between the vitreous and the retina is thought to participate in the pathophysiology of diverse retinal diseases, including proliferative diabetic retinopathy and diabetic macular edema. Vitrectomy has been associated with decrease of macular edema and improvement of visual acuity in eyes of diabetic patients. Thus, many pharmacologic agents have been studied with the aim of inducing a posterior vitreous detachment in order to facilitate the surgical procedure and reduce complications of vitrectomy. More recently, different agents such as plasmin and microplasmin have shown to be able to induce a posterior vitreous detachment given as a single intravitreal injection. The aim of this article is to give a scope about the pharmacologic vitreolysis and posterior vitreous detachment studies and describe some ongoing clinical trials that will determine the efficacy and safety of these novel therapies for diabetic retinopathy.

This paper reviews the current experience and trends in 23-gauge transconjunctival sutureless vitrectomy for diabetic retinopathy in those patients that need a surgical intervention for either vitreous hemorrhage, fibrovascular proliferation with traction retinal detachment affecting or threatening the macula, traction-rhegmatogenous retinal detachment, or refractory macular edema with taut posterior hyaloid. Since the instruments in 23-gauge vitrectomy are less flexible and perform in a more similar way to 20-gauge instruments, the vitrectomy is more thorough and for more complex manoeuvres can be done. The 23-gauge transconjuntival sutureless vitrectomy avoids some of the shortcomings of the 25- gauge systems.