Judy E Kim, MD Diabetes is highly prevalent among adults, and the incidence of type 2 diabetes among adolescents is increasing. Risk factors for the development of diabetic retinopathy (DR) include duration of diabetes, severity of hyperglycemia, hypertension, and anemia. The progression of DR can accelerate during puberty and pregnancy. DR is diagnosed by careful clinical examination and the use of ancillary diagnostic tests; clinically significant diabetic macular edema (CSME) and proliferative DR (PDR) should be treated. A multidisciplinary approach to metabolic control is the current mainstay of treatment for diabetic retinopathy. This includes intensive control of blood sugar and blood pressure, and optimizing the lipid profile. One drug used for glycemic control, rosiglitazone, has been associated with vision loss due to worsening of diabetic macular edema (DME), but the vision loss is reversible with cessation of rosiglitazone treatment. Ancillary testing with modalities such as optical coherence tomography (OCT) and fluorescein angiography (FA) may guide treatment decisions in DR. Phakic or pseudophakic status, glaucoma, pattern and degree of DME on OCT, and extent of capillary nonperfusion on FA are among the factors to consider in treatment selection. OCT is increasing used in the diagnosis and management of DME. It has been used in clinical trials for DME treatments to assess subject eligibility and to determine efficacy secondary endpoints. OCT has revealed that DME has 4 distinct patterns: sponge-like diffuse DME, cystoid changes, serous retinal detachment without posterior hyaloid traction (PHT), and DME due to PHT. Clinical trial evidence supports the use of focal/grid laser photocoagulation for CSME. Experience has revealed that DME due to PHT does not respond well to laser treatment, but pars plana vitrectomy (PPV) with removal of vitreous and associated traction may improve DME and visual acuity. Treatment options for PDR include PRP, which inhibits neovascular growth and reduces the risk of severe vision loss. Vitrectomy restores and preserves vision in patients with PDR complicated by severe vitreous hemorrhage. Steroid medications have a number of properties which suggest they would be useful as DME treatments. Steroids are potent anti-inflammatory agents, inhibiting both inflammatory cytokines and the expression of VEGF. They directly affect retinal endothelial cell barrier properties, resulting in decreased vascular permeability. Triamcinolone acetonide (TA) may be a useful adjunctive treatment in select patients with diffuse DME without a taut posterior hyaloid. TA may be administered by intravitreal injection or posterior sub-Tenon’s injection. Resolution of DME with intravitreal TA appears to be dose-dependent, but the effect diminishes with time. Various approaches using combination or sequential treatments are under investigation to determine whether the treatment benefit can be extended, including intravitreal TA followed by laser photocoagulation, sub-Tenon’s injection of TA followed by laser photocoagulation, laser followed by steroid, and preoperatively administered anti-VEGF agents followed by panretinal photocoagulation (PRP). Long-acting steroid therapy may also be delivered via miniature intravitreally implanted devices that slowly release a medication over an extended period of time, eliminating the need for repeated injections. Three such devices are currently being investigated. Retisert is a nonbiodegradable, surgically implanted device that delivers fluocinolone acetonide for up to 3 years. Posurdex is a biodegradable device that delivers dexamethasone for up to 35 days; Posurdex may be implanted in an in-office procedure using an applicator with a 23 gauge needle. Medidur is a partially biodegradable device that delivers fluocinolone acetonide for 1.5-3 years; Medidur may be implanted in an in-office procedure with a 25 gauge needle injection. All currently available steroid therapies carry a significant risk of cataract development or progression and glaucoma. Nearly all phakic patients will develop cataract with steroid therapy over time, while 30-40% develop glaucoma following intravitreal injection; sometimes the glaucoma is severe and persistent, necessitating surgical intervention. Retinal tears, vitreous hemorrhage, and endophthalmitis occur less frequently. Ptosis has also been noted, mainly with peribulbar injection. Hyperglycemia upregulates a number of growth factors and cytokines which lead to increased vascular permeability, angiogenesis, and vascular occlusion, among other effects. These growth factors and cytokines make attractive therapeutic targets, as their inhibition has the potential to directly treat the underlying causes of retinal tissue damage in DR. Among these factors are protein kinase C (PKC) and VEGF. PKC appears to play a central role in mediating diabetic complications. The β isoform has been most closely linked to the development of diabetic microvascular complications. Ruboxistaurin (RBX) is an orally active β-isoform–specific PKC inhibitor. A recent clinical trial of 32 mg/day RBX administered for 3-4 years showed that RBX was well tolerated by patients, reduced the risk of moderate visual loss (doubling of the visual angle) in moderately sever to very severe NPDR, and reduced the risk of progression of DME within 100 microns of the fovea, but did not prevent DR progression. VEGF has been conclusively linked to the development of PDR in diabetes. It has been known for some time that increased VEGF levels are found in the vitreous of eyes with PDR. Less well known is that patients with DR also have higher VEGF levels in the aqueous. There are at least 4 anti-VEGF treatments in development: pegaptanib, ranibizumab, bevacizumab, and VEGF trap. Recently, it was reported that eyes with DME treated with pegaptinib were more likely to gain 3 lines of vision than controls (18% vs 7%). Clinical trial results for ranibizumab, bevacizumab, and VEGF trap have not yet been reported. Pharmacological treatment options for PDR currently under investigation include purified ovine hyaluronidase (Vitrase), a dispersant agent that may be helpful in the treatment of vitreous hemorrhage. The anti-VEGF agents pegaptanib and bevacizumab are also being considered for use in PDR. Short-term PDR regression has been reported in some patients treated with either pegaptanib or bevacizumab. Bevacizumab has also been reported to promote clearance of vitreous hemorrhage, reverse neovascular glaucoma, and provide pharmacological hemostasis when injected 1 week prior to surgery. The National Eye Institute has established a collaborative network to facilitate multicenter clinical research on DR, DME, and associated conditions called the Diabetic Retinopathy Clinical Research Network (DRCR.net). As of August 2005, 155 sites had applied for network membership, with a total of 512 investigators in 43 states. This network is investigating new pharmacological treatments for DR, various drug delivery methods, and the use of combination and sequential treatments for DR.
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