الفهرس 
Diabetic Retinopathy and Diabetic Macular EdemaOnly 14 pages are availabe for public view
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Abstract
Summary
While DME was often blinding in the past, we now are able to provide many of our patients with good and sustained vision, thereby allowing them to continue to be a part of the workforce. Thanks to advances in our understanding and increased treatment options for DME, we are now able to better manage this condition for affected patients.
Physician and patients are now pursuing gains in VA instead of maintenance or reduction in rate of visual loss from DME.
it must be kept in mind that DM is a systemic disease and optimal glycemic and BP control are of paramount importance in both preventing and delaying the progression of both DR and DME.
There has been an incredible advancement in the local treatment of DME over the past 2 decades with the treatment paradigm changing from observation and macular laser photocoagulation to intravitreal pharmacologic therapies of corticosteroids and anti-VEGF agents.
The future is promising and will likely be comprised of a combination approach utilizing anti-VEGF agents, laser, and corticosteroids designed to address the multifactorial nature of the disease.
The introduction of anti-vascular endothelial growth factor (anti-VEGF) drugs to ophthalmology over the past 7 years has revolutionised the treatment of exudative AMD and holds great promise for DME.
In terms of drug development and molecular characteristics, a number of important findings emerge.
Firstly, the aptamer pegaptanib, while offering low immunogenicity, excellent safety profiles, and the prospect of selective VEGF inhibition, does not provide the extent of VEGF blockade necessary for optimal clinical outcomes in a variety of ocular diseases.
Secondly, the antibody fragment ranibizumab, by blocking all VEGF isoforms, has proven to be highly effective not only in reducing macular edema and preventing further vision loss, but also in producing clinically meaningful improvements in vision in significant numbers of patients but at a high cost.
Conversely, bevacizumab, a full-length antibody, offers a low-cost alternative to ranibizumab that has recently been validated in large clinical trials. However, some concerns regarding its use include the longer systemic half-life of a full-length antibody, with the potential for increased systemic adverse events, the potential to trigger inflammatory processes, the need for precise compounding of the drug for intraocular administration, and the decreased affinity of bevacizumab for VEGF relative to that of ranibizumab. bevacizumab is also currently used off-label to treat AMD by intravitreal administration while the comparative safety and efficacy have not yet been definitively established.
Each of the three available drugs (pegaptanib, bevacizumab and ranibizumab) was eagerly embraced by surgeons, but the subsequent clinical results have been mixed particularly those regarding off-label use of bevacizumab, have been challenging. Into this mix enters
aflibercept for which the US Food and Drug Administration granted approval for the treatment of subfoveal choroidal neovascularisation due to AMD on 18 November 2011.
Since pegaptanib use is infrequent, the VEGF Trap Eye enters a clinical environment dominated by the two closely related antibody-based drugs, bevacizumab and ranibizumab. The clinical superiority of ranibizumab over both observation and photodynamic therapy was well documented in both the MARINA4 (7.2 letters vs _10.4 letters) and ANCHOR5 (11.3 letters vs _9.5 letters) studies, thus establishing ranibizumab as the standard against which all subsequent drugs are compared.
VEGF Trap appears to have a higher VEGF binding affinity than bevacizumab and, unlike ranibizumab, can bind other members of the VEGF family. VEGF Trap may, thus, offer a longer duration between doses when compared to ranibizumab and bevacizumab.
Since DME is a multifactorial process, it involves many factors beyond VEGF. Many clinical trials in DME have shown that in spite of repeated anti-VEGF drug injections, more than 50% of the patients with DME still have persistent macular edema (> 250 microns in thickness) at the end of a one-year study (DRCR Protocol I).
inflammation may be involved in the pathophysiology of BRB breakdown in diabetic retinopathy. The VEGF inhibition itself may not achieve neutralization of other inflammatory molecules involved in the cascade of the breakdown of BRB. Injectable corticosteroids have also shown efficacy in recalcitrant cases, but the trials to date do not demonstrate that they are an improvement over FLT.
Given the risk of endophthalmitis, cataract, and IOP elevations without demonstrated superiority to laser, no corticosteroid, be it fluocinolone, triamcinolone, or dexamethasone, should be a first-line therapy for DME. However, with the dexamethasone and fluocinolone devices, long-term control of DME is possible, if the potential effects on the pressure and lens status are monitored.
The appropriate use of intravitreal Flucinolone Acetonide device still remains to be defined. However, this remains a viable second-line therapy, especially in pseudophakic patients who have been unresponsive to anti-VEGF and laser therapy for greater than 3 years. If intravitreal FAc levels can be optimized to the benefits of treatment with the adverse events, FA devices may reach a higher clinical acceptance.
The novel selective inhibitors of the inflammatory cascade, including those for molecules like Ang-2, TNF-α, proteinases, and CCL2 may be useful therapeutic agents in the treatment of DME in the future, either alone or in combination with the currently used anti-VEGF drugs.
In summary, although laser photocoagulation has been the gold standard of therapy for DME, it is being quickly replaced by intravitreal pharmacotherapy as evidenced by three phase 3 clinical trials supporting the superiority of ranibizumab for center involved edema. The role of other agents such as intravitreal triamcinolone injections, steroid implants and aflibercept, as well as that of vitrectomy remains to be determined. While the use of intravitreal triamcinolone and vitrectomy appear to be currently limited
to cases that have failed other available therapeutic options, the former may be effective in pseudophakic patients who have no personal or family history of glaucoma, and the latter in cases with evidence of vitreomacular traction.
Several new treatment modalities for DME are in the horizon of which topical therapy may play a major role in the future with all the advantages the topical route may offer compared to the intravitreal route.