Moradi A, Sepah YJ, Sadiq MA, et al.. Vascular endothelial growth factor trap-eye (Aflibercept) for the management of diabetic macular edema

World journal of diabetes 12/2013; 4(6):303-309. DOI: 10.4239/wjd.v4.i6.303
Source: PubMed


Diabetic retinopathy (DR) is the most common cause of visual loss among working age individuals. Diabetic macular edema (DME) is an important complication of DR that affects around one third of the patients with DR. Several treatments have been approved for DME ranging from blood pressure and glycemic control to photocoagulation and more recently the use of vascular endothelial growth factor (VEGF) antagonists. The index review discusses aflibercept (EYLEA(®)-Regeneron Pharmaceuticals, Inc., Tarrytown, New York, NY, and Bayer Healthcare Pharmaceuticals, Berlin, Germany) in the context of other VEGF antagonists currently available for the treatment of DME. A systematic search of literature was conducted on PubMed, Scopus, and Google Scholar with no limitation on language or year of publication. Pre-clinical studies of aflibercept have shown a higher affinity of this molecule for vascular endothelial growth factor A (VEGF-A) along with a longer duration of action as compared to other VEGF antagonists. Recent clinical trials have shown visual outcome results for aflibercept to be similarly favorable as compared to other available agents with the added benefit of fewer required injections and less frequent monitoring. Aflibercept presents a potential exciting new addition to the armamentarium of current VEGF antagonists available for the treatment of DME and other retinal vascular diseases. However, further studies are indicated to confirm the role, safety, and efficacy of aflibercept for DME.

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    ABSTRACT: Background: Currently several anti-angiogenic agents are being widely and successfully used for the treatment of eye diseases like neovascular macular degeneration, retinal vein occlusion and diabetic macular edema. Taking into consideration that these patients may present with a different spectrum of underlying diseases and potentially higher risk profiles, systemic safety data across multiple anti-angiogenic agents should be analyzed critically. Methods: A comprehensive literature search was conducted on Medline, PubMed, and Google Scholar databases in June 2014. Search temporal limits included articles published from 2005 to 2014 with the purpose of providing the most recent evidence. Studies were queried using the following keywords in various combinations: anti-angiogenics in eye diseases, intravitreal pharmacotherapy by anti-VEGF, adverse effects, potential systemic hazards, bevacizumab, pegaptanib sodium, ranibizumab, aflibercept. The articles of high or medium clinical relevance were selected for review. Results: Almost uniformly all trial evaluating systemic safety of anti-angiogenic agents reveal the serious side effects including cardiovascular events, despite the fact that the incidence is low. Systemic safety concern in intraocular pharmacotherapy by anti-angiogenic agents has a strong body of clinical evidence, resulting in plenty of peer reviewed clinical articles. Conclusion Currently available findings obviate the need to raise awareness about cardiovascular risk profile in patients with eye diseases treated by anti-VEGF. Early detection is crucial so that intraocular injections can be stopped before severe accident occurs.
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    ABSTRACT: Diabetic retinopathy (DR) is the leading cause of vision loss of working-age adults, and diabetic macular edema (DME) is the most frequent cause of vision loss related to diabetes. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found the 14-year incidence of DME in type 1 diabetics to be 26%. Similarly the Diabetes Control and Complications Trial reported that 27% of type 1 diabetic patients develop DME within 9 years of onset. The most common type of diabetes, type 2, is strongly associated with obesity and a sedentary lifestyle. An even higher incidence of macular edema has been reported in older patients with type 2 diabetes. Within the last 5 years, the use of intravitreal corticosteroids and intravitreal anti-vascular endothelial growth factor (VEGF) agents have come into clinical practice for the management of DME and several recent randomized clinical trials have shown improved effectiveness of ranibizumab compared to focal/grid laser. In this theme issue, we discuss the classification of DR and the treatment options currently available for the treatment of DME including corticosteroids, anti-VEGF agents, combined therapy, enzymatic vitrectomy (vitreolysis), and new therapies.
    12/2013; 4(6):231-3. DOI:10.4239/wjd.v4.i6.231
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    ABSTRACT: Purpose: Proangiogenic protein VEGF-A contributes significantly to retinal lesions and neovascularization in diabetic retinopathy (DR). In preclinical DR, hyperglycemia can upregulate VEGF-A in retinal cells. The VEGF-A promoter is responsive to the transcription factor specificity protein 1 (Sp1). The O-GlcNAc modification is driven by glucose concentration and has a profound effect on Sp1 activity. This study investigated the effects of hyperglycemia on Sp1-mediated expression of VEGF-A in the retinal endothelium and pigment epithelium. Methods: Hyperglycemia-exposed ARPE-19 (human retinal pigment epithelial cells) and TR-iBRB (rat retinal microendothelial cells) were assayed for levels of VEGF-A by qRT-PCR, Western blot, and ELISA. Small molecule inhibitors of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) were used to manipulate O-GlcNAc levels. Vascular endothelial growth factor-A protein and transcript were measured in cells depleted of OGT or Sp1 by shRNA. The proximal VEGF-A promoter was analyzed for glucose sensitivity by luciferase assay. Chromatin immunoprecipitation (ChIP) was used to assess Sp1 occupancy on the VEGF-A promoter. Results: Hyperglycemia increased VEGF-A promoter activity and upregulated VEGF-A transcript and protein. Elevation of O-GlcNAc by OGA inhibitors was sufficient to increase VEGF-A. O-GlcNAc transferase inhibition abrogated glucose-driven VEGF-A. Cellular depletion of OGT or Sp1 by shRNA significantly abrogated glucose-induced changes in VEGF-A. ChIP analysis showed that hyperglycemia significantly increased binding of Sp1 to the VEGF-A promoter. Conclusions: Hyperglycemia-driven VEGF-A production is mediated by elevated O-GlcNAc modification of the Sp1 transcription factor. This mechanism may be significant in the pathogenesis of preclinical DR through VEGF-A upregulation.
    Investigative Ophthalmology &amp Visual Science 10/2014; 55(12). DOI:10.1167/iovs.14-14048 · 3.40 Impact Factor
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