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Intravitreal Ranibizumab for Diabetic Macular Oedema

European Ophthalmic Review, 2015;9(1):32–6 DOI: http://doi.org/10.17925/EOR.2015.09.01.32

Abstract:

Diabetic macular oedema (DMO) is the most frequent cause of vision loss in patients affected by diabetes mellitus, and has a remarkable effect on public health. The treatment with focal/grid laser photocoagulation was considered in the past decades as the standard of care, but the recent advent of new pharmacological approaches, based on the use of intravitreal anti-vascular endothelial growth factor (anti-VEGF), has completely revolutionised the management of DMO. The most important molecule of this class of drugs is represented by ranibizumab, which has been clinically supported by several randomised clinical trials. The present review aims at providing a comprehensive summary of the most important investigations regarding the ranibizumab treatment of DMO.
Keywords: Diabetic macular oedema, ranibizumab, VEGF, randomised clinical trials
Disclosure: Francesco Bandello is an advisory board member for Alcon, Alimera Sciences, Allergan, Bausch & Lomb, Bayer Schering Pharma, Farmila-Thea, Genentech, Novartis Pharmaceuticals Corporation, Pfizer, Sanofi-Aventis and ThromboGenics. Maria Vittoria Cicinelli and Maurizio Battaglia Parodi have no conflicts of interest to declare. No funding was received in the publication of this article. and reproduction provided the original author(s) and source are given appropriate credit.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation
Received: July 13, 2015 Accepted: July 28, 2015
Correspondence: Maria Vittoria Cicinelli, Department of Ophthalmology, University Vita-Salute, Ospedale San Raffaele, Milan, Italy, Via Olgettina, 60, Milan, Italy. E: cicinelli.mariavittoria@hsr.it

Diabetic retinopathy (DR) is the main cause of vision loss in people between 25 and 74 years old in developed countries, and diabetic macular oedema (DMO) represents the major cause of this visual impairment.1,2

The prevalence of DMO ranges from 0 % to 3 % at the moment of the diagnosis of diabetes to 28 % to 29 % in patients with diabetes duration of over 20 years.3

DMO is the result of blood–retinal barrier disruption and extravascular inflammation and may arise in the setting of both non-proliferative and proliferative DR. DMO has been recently classified in four main forms: vasogenic DMO, as retinal thickening with vascular dilations and hard exudates; non-vasogenic, defined by retinal thickening without identifiable vascular dilations; tractional DMO, due to vitreomacular abnormal adhesion; and mixed DMO, when tractional DMO is associated with vasogenic or non-vasogenic forms.4

Several studies, including the Diabetes Control and Complications Trial (DCCT) for type 1 and the United Kingdom Prospective Diabetes Study (UKPDS) for patients with type 2 diabetes, have shown that primary prevention, including strict blood glucose, blood pressure and serum lipids control, reduces the incidence and severity of DR and DMO.5

Laser photocoagulation is still considered the standard of care for DMO since 1985, and can reduce the risk of moderate visual acuity (VA) loss by about 50 %, although only 3 % of eyes achieve a vision improvement (≥3 lines), and a substantial proportion of treated eyes remain unresponsive.6 Vitreo-retinal surgery, and in particular pars plana vitrectomy and epiretinal membrane peeling, has generally limited efficacy for tractional forms of DMO, being responsible for remarkable side effects.7

Recent advances in understanding DMO pathophysiology have identified the primary role of vascular endothelial growth factor (VEGF) in retinal vasopermeability regulation and extracellular fluid accumulation.8 Hyperglycaemia-related ischaemic changes and lowgrade inflammation at a retinal level induce VEGF genes up-regulation and protein translation; in fact, high levels of VEGF have been found in vitreous samples from the eyes of patients with diabetes.9

VEGF is a pluripotent cell mitogen that causes neo-angiogenesis and disruption of the intercellular tight junctions normally present between retinal endothelial cells, leading to intraretinal leakage.10 Its family includes five molecules: placental growth factor, VEGF-A, VEGF-B, VEGF-C and VEGF-D. VEGF-A, especially the VEGF165 isoform, plays a primary role in the pathogenesis of DMO. For this reason it represents an interesting candidate as a therapeutic target for the treatment of DMO, being the VEGF receptor activation blockage the most targeted therapeutic strategy.

Recent multicentre randomised clinical trials (RCTs) have demonstrated that intravitreal injections of steroids or anti-VEGF molecules result in a significant gain of VA in eyes with DMO, and preserve patients with diabetes from progression towards more advanced forms of DR.11–12 Pegaptanib, ranibizumab, bevacizumab and aflibercept are the most investigated VEGF-inhibitors in recent published literature.13 Pegaptanib is a pegylated 28-nucleotide RNA aptamer that binds to VEGF165 with high specificity; ranibizumab and bevacizumab are a 48 KDa antigen-binding fragment (Fab) and a humanised anti-VEGF antibody, respectively, that inhibit all biologically active isoforms and active proteolytic fragments of VEGF-A. Aflibercept is a 115 kDa fusion protein of portions of VEGF receptor 1 and 2 fused to the constant region of human immunoglobulin (Ig)-G1, functioning as a soluble decoy receptor or all VEGF-A isoforms, with a higher affinity (140 times stronger) and longer half-life in comparison to all the others anti-VEGF substances.

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Keywords: Diabetic macular oedema, ranibizumab, VEGF, randomised clinical trials