Pharmacotherapy for diabetic retinopathy Grant M. Comer a and Thomas A. Ciulla b Purpose of review Diabetic retinopathy (DR) is a potentially visually devastating complication of chronic hyperglycemia and other associated systemic abnormalities. Numerous large, prospective, randomized clinical trials have delineated the current standard prevention and treatment protocols including intensive glycemic and blood pressure control and laser photocoagulation for neovascularization and clinically significant macular edema. However, despite standard intervention, vision loss from DR still occurs at an alarming rate. Thus, more recently, researchers have directed their efforts towards better understanding the microscopic changes occurring in DR to develop more effective pharmacologic prevention and treatment strategies. Recent findings Phase II and III clinical studies involving antivascular endothelial growth factor (VEGF) and protein kinase C (PKC) inhibitors for the management of diabetic macular edema are underway. Researchers recently found elevated pigment endothelium-derived factor (PEDF) associated with active neovascularization, a finding that counteracts prior claims of endogenous anti-angiogenic properties. Other clinical trials are underway to evaluate the efficacy of octreotide, celecoxib, and candesartan on DR. Small clinical studies have suggested beneficial treatment effects for triamcinolone acetonide, interferon -2a, and supplemental oxygen; however, other studies involving losartan, vitamins C and E, and atorvastatin failed to show any benefit. Summary Over the past decade, numerous animal models have led to a more thorough understanding of the early microvascular alterations and later neovascularization and edema observed in DR. These discoveries and subsequent human clinical studies involving direct and indirect growth factor modulation, extracellular matrix alteration, vitreolysis, and alternative DR pathways including dyslipidemia, hypoxia, and sorbitol are reviewed in this manuscript. Keywords proliferative diabetic retinopathy, clinically significant macular edema, vascular endothelial growth factor, protein kinase C, corticosteroid Curr Opin Ophthalmol 15:508–518. © 2004 Lippincott Williams & Wilkins. a Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, USA, and b Vitreoretinal Service, Midwest Eye Institute, Indianapolis, Indiana, USA Correspondence to Thomas A. Ciulla, Vitreoretinal Service, Midwest Eye Institute, 201 Pennsylvania Parkway, Indianapolis, IN 46280, USA Tel: 317 817 1822; fax: 317 817 1898; e-mail: thomasciulla@yahoo.com Dr. Comer does not have a financial interest in any of the products mentioned in the manuscript. Dr. Ciulla is a recipient of a Career Development Award from Research to Prevent Blindness. He serves on the PKC Lilly Advisory Board and has acted as a consultant for Eli Lilly. He serves on the Therasight Theragenics Advisory Board and has acted as a consultant for Theragenics. He has received research funding from Genentech, Eyetech, and Alcon. Current Opinion in Ophthalmology 2004, 15:508–518 Abbreviations CSME clinically significant macular edema PDR proliferative diabetic retinopathy PKC protein kinase C VEGF vascular endothelial growth factor © 2004 Lippincott Williams & Wilkins 1040-8738 Introduction Because diabetic retinopathy affects a large proportion of the population [1], several large, randomized, prospec- tive, clinical trials have molded the current clinical pre- vention and treatment options available today. The Dia- betes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that intensive glycemic control slowed the onset and progression of types I and II diabetes mellitus (DM) retinopathy [2,3]. In addition, the UKPDS dem- onstrated that intensive blood pressure control also re- duced diabetic retinopathy in DM II, independent of glycemic control or the specific type of antihypertensive [4]. Other clinical trials demonstrated that laser photoco- agulation can reduce the risk of visual loss by nearly 50% for patients with proliferative diabetic retinopathy (PDR) and clinically significant diabetic macular edema (CSME) [5–7]. However, despite these valuable treat- ment options, vision loss still occurs at an alarming rate [6,8], and laser photocoagulation is a late, destructive treatment that does not specifically address the under- lying etiology of diabetic retinopathy. Most clinically significant complications of diabetic ret- inopathy (DR), such as neovascularization, which can lead to tractional retinal detachment, vitreous hemor- rhage and neovascular glaucoma, and macular edema are late manifestations of diabetic retinopathy. They occur secondary to the release of growth factors in response to retinal ischemia from alterations in the structure and cel- lular composition of the microvasculature [9–12]. Capil- lary basement membrane thickening and increased col- lagen and fibronectin deposition of the extracellular 508