New insights into the management of diabetic retinopathy.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and remains one of the leading causes of blindness worldwide among adults aged 20-74 years. DR is characterized by gradual progressive retinal vasculopathy leading to endothelial cell dysfunction, breakdown of the blood-retinal barrier, ischemia-induced retinal neovascularization, and expansion of extracellular matrix resulting in the outgrowth of fibrovascular tissue at vitreoretinal interface. Strong evidence indicates that chronic low-grade inflammation is implicated in the pathogenesis of DR. In addition, recent studies proved that neurodegeneration and impaired visual function are initiated early after the onset of diabetes and progress independently of the vascular lesions.

The two most important visual complications of DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Strict metabolic control and tight blood pressure control represent the cornerstone of medical management of DR and significantly decrease the risk of development as well as the progression of retinopathy. Long-term lipid-lowering therapy with fenofibrate reduces the progression of DR and the need for laser treatment in patients with type 2 diabetes, although the mechanism of this effect does not seem to be related to plasma concentration of lipids.[1] Several studies suggested that renin-angiotensin system blockers might reduce the burden of DR.[2] The peroxisome proliferator-activated receptor gamma agonists such as rosiglitazone are used to improve glycemic control in patients with diabetes mellitus. These medications have potential antiangiogenic therapy and may delay the onset of PDR in patients with severe nonproliferative DR at baseline.[3] Oral administration of the selective protein kinase C β inhibitor roboxistaurin reduced DME progression.[4] Recent studies demonstrated that islet transplantation improved HbA1c and reduced progression of DR.

Panretinal photocoagulation is the standard treatment for PDR. Clinically meaningful differences are unlikely in optical coherence tomography thickness or visual acuity following application in one sitting compared with four sittings.[5] Modified Early Treatment diabetic Retinopathy Study focal/grid laser photocoagulation remains the standard management for DME and is a better treatment than intravitreal triamcinolone acetonide (IVTA). The fact that 4-mg IVTA treatment had a greater positive treatment response on visual acuity and retinal thickening after 4 months of treatment, whereas the photocoagulation treatment had a greater positive response later, raises the possibility that combining focal/grid photocoagulation with IVTA may produce greater benefit for DME than either focal/grid photocoagulation or IVTA alone. However, IVTA is associated with the risks of elevated intraocular pressure and cataract.[6]

Currently, there are four anti-vascular endothelial growth factor (anti-VEGF) agents, which have been used in the management of DR, including pegaptanib (Macugen), ranibizumab (Lucentis), bevacizumab (Avastin), and VEGF Trap-Eye (Aflibercept). Anti-VEGF therapy has been shown to be effective at improving vision in patients with DME. Review of the available literature indicates that anti-VEGF pharmacotherapy, delivered by intravitreal injection, is safe and effective treatment over 2-3 years for DME. Further evidence is required to support long-term safety of these agents and their comparative efficacy. Number of injections required for long-term improvement as well as long-term efficacy is unknown. The available data suggest no difference in effectiveness between bevacizumab and ranibizumab. Blocking VEGF at least in theory could be detrimental to vascular integrity. Therefore, the decision to offer prolonged anti-VEGF treatment in cases of significant coexisting macular ischemia should not be based only on measurements of macular thickness; instead repeat fluorescein angiograms should be performed. Currently, most experts consider combination focal/grid laser therapy and pharmacotherapy with intravitreal anti-VEGF agents in patients with center-involving DME. Combination therapy was shown to reduce the frequency of injections needed to control edema.[78] Vitrectomy with removal of the posterior hyaloid seems to be effective in eyes with persistent diffuse DME, particularly in eyes with associated vitreomacular traction. Preliminary data suggest that pharmacologic vitreolysis without the performance of vitrectomy is effective in eyes with refractory diffuse DME.