900 Diabetes Care Volume 37, April 2014 Ning Cheung,1,2,3 Ian Y. Wong,1 and Ocular Anti-VEGF Therapy for Tien Y. Wong2,3 BENCH TO CLINIC SYMPOSIA Diabetic Retinopathy: Overview of Clinical Efficacy and Evolving Applications Diabetes Care 2014;37:900–905 | DOI: 10.2337/dc13-1990 Ocular anti-vascular endothelial growth factor (VEGF) therapy represents one of the most significant advances in modern medicine. The introduction and widespread use of ocular anti-VEGF therapy for age-related macular degenera- tion heralded a new era in the treatment of vascular and exudative diseases of the retina. Its expanding indications now include diabetic macular edema and proliferative diabetic retinopathy, two vision-threatening forms of diabetic retinopathy. It is widely anticipated that ocular anti-VEGF therapy could spark a dramatic shift in the treatment paradigm for diabetic retinopathy. However, despite its clear efficacy shown in clinical trials, the dynamic landscape of evolving medical, ethical, and economic issues related to this new treatment suggests significant challenges ahead. In this article, we provide a discussion of this topic as part of this two-part Bench to Clinic narrative. Here, our Clinic contribution provides an overview of the current evidence from clinical trials on anti-VEGF therapy for diabetic retinopathy, and highlights the hopes and fears of this new treatment from clinical and public health standpoints. In the Bench narrative that precedes this contribution, Simo´ et al. provide an overview of the role of VEGF in the pathogenesis of diabetic retinopathy. Ocular anti-vascular endothelial growth factor (VEGF) therapy represents one of the most significant advances in modern medicine. The swift and widespread uptake of this new therapy into clinical practice for treating age-related macular 1 degeneration has saved sight for millions worldwide (1). In fact, national blindness Department of Ophthalmology, The Eye Insti- tute, University of Hong Kong, China Special Ad- registries are already showing declining incidence of blindness related to age- ministrative Region, China related macular degeneration, coinciding with the advent of anti-VEGF therapy 2Singapore Eye Research Institute, Singapore Na- (2). Despite its clear efficacy, however, the safety, cost, and substantial burden tional Eye Centre, National University of Singa- pore, Singapore upon the health care system of this new treatment have generated heated debates 3 in many countries (3). Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Mel- Now, it is widely anticipated that the use of ocular anti-VEGF therapy will be bourne, Melbourne, Australia extended to treat the vision-threatening forms of diabetic retinopathy (4), which Corresponding author: Ning Cheung, affect an estimated 28 million people around the world (5). In this two-part Bench [email protected]. to Clinic narrative, the Bench article by Simo´ et al. (6) reviews the pathophysiological Received 23 August 2013 and accepted 17 role of VEGF in diabetic retinopathy and the molecular characteristics of antiangio- December 2013. genic agents currently used. Here in the Clinic article, we provide an overview of the © 2014 by the American Diabetes Association. current evidence from clinical trials on anti-VEGF therapy for diabetic retinopathy, See http://creativecommons.org/licenses/by- and highlight the hopes and fears of this new treatment from the clinical and public nc-nd/3.0/ for details. health standpoints. See accompanying article, p. 893. care.diabetesjournals.org Cheung, Wong, and Wong 901 EPIDEMIOLOGY AND NATURAL and PDR among patients with recently steroids (e.g., triamcinolone) have dem- HISTORY OF DIABETIC diagnosed diabetes (10). These encour- onstrated ability to reduce DME and RETINOPATHY aging findings reflect improvement in improve vision, these beneficial effects As a global concern, diabetes affects the systemic management of retinopa- appear to be short-lived, and long-term more than 360 million individuals world- thy risk factors over time for a range of visual outcome was generally not better wide. This number is expected to exceed reasons, such as better devices for self- than conventional laser therapy (4). half a billion by 2030 (7). About one in monitoring of glycemic levels and Furthermore, repeated use of intraocu- three individuals with diabetes has administration of insulin, new and lar steroid injections is associated with signs of retinopathy, and among these, effective hypoglycemic medications, significant ocular side effects (e.g., cat- one-third may have diabetic macular and increased public awareness of the aract, glaucoma). Nevertheless, there edema (DME) or proliferative diabetic ret- need for glycemic and blood pressure are certain advantages in using intraoc- inopathy (PDR), two vision-threatening control through educational and ular steroids (e.g., possibly longer-acting forms of diabetic retinopathy (4). A re- screening programs. Despite these and relatively cheap compared with cent pooled analysis of 35 population- advances in diabetes care, it remains most anti-VEGF agents). Its use might fi based studies in developed countries uncertain whether such a declining thereforebebene cial for selected estimated that more than 90 million trend in the incidence of diabetic patients, such as those who have had individuals have diabetic retinopathy, retinopathy will persist in the context previous cataract surgery, or as an ad- with about 21 million having DME and of expanding diabetes epidemic world- junctive therapy prior to laser (12,13). 17 million having PDR (5). wide, particularly in developing countries OCULAR ANTI-VEGF THERAPY FOR In the Wisconsin Epidemiologic Study where intensive diabetes management DIABETIC RETINOPATHY of Diabetic Retinopathy, about three in and public health resources remain four participants developed retinopa- limited (11). The introduction and widespread use of ocular anti-VEGF therapy for age- thy over a 10-year period, and for CURRENT STRATEGIES FOR related macular degeneration, with participants with retinopathy, about MANAGEMENT OF DIABETIC publication of major clinical trials (1), two-thirds developed more severe RETINOPATHY retinopathy and one in five developed heralded a new era in the treatment of Systemic management of hyperglyce- PDR (4). In terms of progression, dia- vascular and exudative diseases of the mia, hypertension, and dyslipidemia betic retinopathy progresses from retina. The expanding indications for remains the most important and nonproliferative to proliferative reti- ocular anti-VEGF therapy, given via an effective strategy for preventing the nopathy in stages. Nonproliferative di- injection into the vitreal cavity, now development and progression of dia- abetic retinopathy (NPDR) is classified include DME and PDR. betic retinopathy (4). For many decades, as mild, moderate, and severe forms. retinal laser photocoagulation has been Efficacy About 5% mild NPDR, 20% moderate the standard ocular treatment for DME AsshownintheaccompanyingBench NPDR, and 50% severe NPDR may and PDR (4,10). The primary goal for article by Simo´ et al. (6), VEGF has progress to PDR within 1 year (4). most patients receiving laser therapy is long been a therapeutic target for dia- In developed countries, DME has now to preserve any useful vision or to pre- betic retinopathy. In recent years, there overtaken PDR as the more common vent adverse sequalae of PDR. Reversal has been a surge of clinical trials vision-threatening form of diabetic reti- of vision loss is uncommon. In addition, investigating the use of anti-VEGF ther- nopathy, particularly among patients laser therapy is associated with signifi- apy for DME (Table 1) (14–16). These with type 2 diabetes. In the National cant ocular side effects due to its inher- trials provide robust evidence that Health and Nutrition Examination ent destructive nature to the retina. intraocular administration of anti- Survey, DME was shown to be twice as Without timely laser therapy, however, VEGF agents is better than laser therapy commonasPDRintheU.S.(8).The patients may develop blinding neovas- both in preserving and in improving vi- 10-year incidence of DME has been cular complications, such as vitreous sion for patients with DME. Among the reported to be 20% in the Wisconsin hemorrhage and tractional retinal de- four anti-VEGF agents (ranibizumab, Epidemiologic Study of Diabetic Reti- tachment, leading to the need for bevacizumab, pegaptanib, and afliber- nopathy (9). Although DME is usually surgical intervention (vitrectomy). cept), ranibizumab has been the one correlated and accompanied with Over the last decade, intraocular most thoroughly tested. In randomized increasing severity of retinopathy, it administration of pharmacological controlled trials that used ranibizumab may also run an independent course agents (e.g., steroid and anti-VEGF injections, up to 46% of patients and develop even at the early stage of agents) has been evaluated as a new improved vision (vs. 18% with laser diabetic retinopathy. treatment modality for DME and PDR alone; by three lines or more on vision There is evidence to suggest a decline (4,10). Delivery of these agents is chart), and only 4% or less lost more in the incidence and risk of progression achieved by direct injection into the vision (vs. up to 20% with laser alone). for diabetic retinopathy over the last vitreal cavity, a procedure that is usually The studies also suggest that, compared three decades (4,10).