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      Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies

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          ABSTRACT

          Introduction: Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population of the developed world. DR encompasses a complex pathology, and one that is reflected in the variety of currently available treatments, which include laser photocoagulation, glucocorticoids, vitrectomy and agents which neutralize vascular endothelial growth factor (VEGF). Whilst these options demonstrate modest clinical benefits, none is yet to fully attenuate clinical progression or reverse damage to the retina.

          This has led to an interest in developing novel therapies for the condition, such as mediators of angiopoietin signaling axes, immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), oxidative stress inhibitors and vitriol viscosity inhibitors. Further, preclinical research suggests that gene therapy treatment for DR could provide significant benefits over existing treatments options.

          Areas covered: Here we review the pathophysiology of DR and provide an overview of currently available treatments. We then outline recent advances made towards improved patient outcomes and highlight the potential of the gene therapy paradigm to revolutionize DR management.

          Expert opinion: Whilst significant progress has been made towards our understanding of DR, further research is required to enable the development of a detailed spatiotemporal model of the disease. In addition, we hope that improvements in our knowledge of the condition facilitate therapeutic innovations that continue to address unmet medical need and improve patient outcomes, with a focus on the development of targeted medicines.

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          Most cited references99

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          Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group.

          (1985)
          Data from the Early Treatment Diabetic Retinopathy Study (ETDRS) show that focal photocoagulation of "clinically significant" diabetic macular edema substantially reduces the risk of visual loss. Focal treatment also increases the chance of visual improvement, decreases the frequency of persistent macular edema, and causes only minor visual field losses. In this randomized clinical trial, which was supported by the National Eye Institute, 754 eyes that had macular edema and mild to moderate diabetic retinopathy were randomly assigned to focal argon laser photocoagulation, while 1,490 such eyes were randomly assigned to deferral of photocoagulation. The beneficial effects of treatment demonstrated in this trial suggest that all eyes with clinically significant diabetic macular edema should be considered for focal photocoagulation. Clinically significant macular edema is defined as retinal thickening that involves or threatens the center of the macula (even if visual acuity is not yet reduced) and is assessed by stereo contact lens biomicroscopy or stereo photography. Follow-up of all ETDRS patients continues without other modifications in the study protocol.
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            Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.

            Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50-75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study-was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction 1.5% [0.7-2.3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p=0.004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0.66, 95% CI 0.47-0.94; p=0.022). Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.
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              Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group.

              (1991)
              The Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled 3711 patients with mild-to-severe nonproliferative or early proliferative diabetic retinopathy in both eyes. One eye of each patient was assigned randomly to early photocoagulation and the other to deferral of photocoagulation. Follow-up examinations were scheduled at least every 4 months and photocoagulation was initiated in eyes assigned to deferral as soon as high-risk proliferative retinopathy was detected. Eyes selected for early photocoagulation received one of four different combinations of scatter (panretinal) and focal treatment. This early treatment, compared with deferral of photocoagulation, was associated with a small reduction in the incidence of severe visual loss (visual acuity less than 5/200 at two consecutive visits), but 5-year rates were low in both the early treatment and deferral groups (2.6% and 3.7%, respectively). Adverse effects of scatter photocoagulation on visual acuity and visual field also were observed. These adverse effects were most evident in the months immediately following treatment and were less in eyes assigned to less extensive scatter photocoagulation. Provided careful follow-up can be maintained, scatter photocoagulation is not recommended for eyes with mild or moderate nonproliferative diabetic retinopathy. When retinopathy is more severe, scatter photocoagulation should be considered and usually should not be delayed if the eye has reached the high-risk proliferative stage. The ETDRS results demonstrate that, for eyes with macular edema, focal photocoagulation is effective in reducing the risk of moderate visual loss but that scatter photocoagulation is not. Focal treatment also increases the chance of visual improvement, decreases the frequency of persistent macular edema, and causes only minor visual field losses. Focal treatment should be considered for eyes with macular edema that involves or threatens the center of the macula.
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                Author and article information

                Journal
                Expert Opin Biol Ther
                Expert Opin Biol Ther
                IEBT
                iebt20
                Expert Opinion on Biological Therapy
                Taylor & Francis
                1471-2598
                1744-7682
                2018
                14 November 2018
                : 18
                : 12
                : 1257-1270
                Affiliations
                [a ]John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge , Cambridge, UK
                [b ]Centre for Eye Research Australia, University of Melbourne and Royal Victorian Eye and Ear Hospital , Melbourne, Australia
                [c ]Department of Surgery, University of Melbourne , Melbourne, Australia
                [d ]Eye Department, Addenbrooke’s Hospital , Cambridge, UK
                [e ]Cambridge NIHR Biomedical Research Centre , Cambridge, UK
                [f ]Wellcome Trust – MRC Cambridge Stem Cell Institute, University of Cambridge , Cambridge, UK
                Author notes
                CONTACT Michael Whitehead mw684@ 123456cam.ac.uk John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, E.D. Adrian Building, University of Cambridge Forvie Site , Robinson Way, CambridgeCB2 0PY, UK
                Article
                1545836
                10.1080/14712598.2018.1545836
                6299358
                30408422
                b583e394-fec3-4a88-8b5a-273c5bb71493
                © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 September 2018
                : 05 November 2018
                Page count
                Figures: 2, Tables: 3, References: 152, Pages: 14
                Funding
                Funded by: Medical Research Council 10.13039/501100000265
                Funded by: Cambridge Eye Trust
                Award ID: RRZC/023
                This paper was funded by the Cambridge Eye Trust, Medical Research Council and the Wellcome Trust.
                Categories
                Review

                diabetic retinopathy,diabetic macular edema,neovascularization,vascular endothelial growth factor,neuronal apoptosis

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