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DIABETIC RETINOPATHY UPDATE
Year : 2013  |  Volume : 20  |  Issue : 4  |  Page : 273-282  

Evolving strategies in the management of diabetic retinopathy


Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Web Publication18-Oct-2013

Correspondence Address:
Ahmed M Abu El-Asrar
Department of Ophthalmology, King Abdulaziz University Hospital, Old Airport Road, P.O. Box 245, Riyadh 11411
Saudi Arabia
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Source of Support: Medical Research Chair funded by Dr. Nasser Al.Rasheed (AMA), Conflict of Interest: None


DOI: 10.4103/0974-9233.119993

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   Abstract 

Diabetic retinopathy (DR), the most common long-term complication of diabetes mellitus, remains one of the leading causes of blindness worldwide. Tight glycemic and blood pressure control has been shown to significantly decrease the risk of development as well as the progression of retinopathy and represents the cornerstone of medical management of DR. The two most threatening complications of DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Focal/grid photocoagulation and panretinal photocoagulation are standard treatments for both DME and PDR, respectively. Focal/grid photocoagulation is a better treatment than intravitreal triamcinolone acetonide in eyes with DME. Currently, most experts consider combination focal/grid laser therapy and pharmacotherapy with intravitreal antivascular endothelial growth factor agents in patients with center-involving DME. Combination therapy reduces the frequency of injections needed to control edema. Vitrectomy with removal of the posterior hyaloid seems to be effective in eyes with persistent diffuse DME, particularly in eyes with associated vitreomacular traction. Emerging therapies include fenofibrate, ruboxistaurin, renin-angiotensin system blockers, peroxisome proliferator-activated receptor gamma agonists, pharmacologic vitreolysis, and islet cell transplantation.

Keywords: Diabetic Retinopathy, Review, Treatment


How to cite this article:
Abu El-Asrar AM. Evolving strategies in the management of diabetic retinopathy. Middle East Afr J Ophthalmol 2013;20:273-82

How to cite this URL:
Abu El-Asrar AM. Evolving strategies in the management of diabetic retinopathy. Middle East Afr J Ophthalmol [serial online] 2013 [cited 2019 Jun 18];20:273-82. Available from: http://www.meajo.org/text.asp?2013/20/4/273/119993


   Introduction Top


Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and remains one of the leading causes of blindness worldwide among adults aged 20-74 years. The two most important visual complications of DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). The prevalence of DR increases with duration of diabetes, and nearly all persons with type 1 diabetes and more than 60% of those with type 2 have some retinopathy after 20 years. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), 3.6% of younger-onset patients (type 1 diabetes) and 1.6% of older-onset patients (type 2 diabetes) were legally blind. [1]


   Evidence-Based Patient Care Top


Five large randomized controlled trials provide the scientific basis for care in the diabetic patient to preserve vision.

The diabetes control and complications trial

The diabetes control and compilations trial (DCCT) randomized 1441 patients with type 1 diabetes to receive intensive glycemic or conventional therapy. Over 6.5 years of follow-up, intensive treatment [median HbA1c (glycosylated hemoglobin A1c), 7.2%] reduced the incidence of DR by 76% and progression of DR by 54%, as compared with conventional treatment. [2] Long-term observational DCCT data showed that despite gradual equalization of HbA1c values after study termination, the rate of DR progression in the former intensively treated group remained significantly lower than in the former conventional group ("metabolic memory"), [3] emphasizing the importance of instituting tight glycemic control early in the course of diabetes.

Tight glycemic control has two clinical important adverse effects. First, there is risk of early worsening of DR. In the DCCT, this occurred in 13.1% of the intensive versus 7.6% of the conventional treatment group. However, this effect was reversed by the 18 th month, and no case of early worsening resulted in serious visual loss. In the DCCT, the long-term benefits of intensive insulin treatment greatly outweighed the risks of early worsening of DR. Therefore, ophthalmoscopic monitoring before initiation of intensive treatment and at 3-month intervals for 6-12 months thereafter seems to be appropriate when intensive treatment is initiated in patients with long-standing poor glycemic control, particularly if retinopathy is at or past moderate nonproliferative stage. In patients whose retinopathy is already approaching the high-risk stage, it may be prudent to delay the initiation of intensive treatment until photocoagulation can be completed, particularly if the HbA1c level is high. [4] Second, tight glycemic control was associated with more frequent severe hypoglycemic episodes compared with the conventional group. [2]

The united kingdom prospective diabetes study

The United Kingdom Prospective Diabetes Study (UKPDS) randomized 3867 patients with newly diagnosed type 2 diabetes to receive intensive or conventional therapy. After 12 years of follow-up, the progression of DR was reduced by 21% and the need for laser photocoagulation by 29% in the intensive versus the conventional treatment group. [5] The UKPDS also investigated the influence of tight blood pressure control. A total of 1148 hypertensive patients with type 2 diabetes were randomized to less tight (<180/105 mmHg) and tight blood pressure control (<150/85 mmHg). With a median follow-up of 8.4 years, patients assigned to the tight control group had a 34% reduction in progression of retinopathy and a 47% reduced risk of deterioration in visual acuity of three lines compared with the less tight control group. [6]

The diabetic retinopathy study

The diabetic retinopathy study (DRS) investigated whether scatter (panretinal) photocoagulation, compared with indefinite deferral, could reduce the risk of vision loss from PDR. After 2 years, photocoagulation was shown to significantly reduce severe visual loss (best-corrected visual acuity of 5/200 or worse) from PDR. The benefit persisted through the entire duration of follow-up and was greatest among patients whose eyes had high-risk characteristics. [7] Recently, the Diabetic Retinopathy Clinical Research Network compared the effects of single-sitting versus 4-sitting panretinal photocoagulation on macular edema in subjects with severe nonproliferative or early PDR with relatively good visual acuity and no or mild center-involved macular edema. The results suggest that clinically meaningful differences are unlikely in optical coherence tomography thickness or visual acuity following application in one sitting compared with four sittings. [8]

The early treatment diabetic retinopathy study

The Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated that focal/grid laser photocoagulation reduced the risk of moderate vision loss (i.e., a doubling of the visual angle) from clinically significant macular edema by 50% or more. [9] ETDRS analyses also indicated that for patients with type 2 diabetes, it is especially important to consider scatter photocoagulation at the time of the development of severe nonproliferative or early proliferative retinopathy. [10]

A recent randomized controlled trial compared modified ETDRS direct/grid photocoagulation technique and mild macular grid (MMG) laser technique in which microaneurysms are not treated directly and small mild burns are placed throughout the macula for DME. Twelve months after treatment, the MMG technique was less effective at reducing optical coherence tomography-measured retinal thickening than the current modified ETDRS laser photocoagulation approach. It was concluded that modified ETDRS focal photocoagulation should continue to be a standard approach for treating DME. [11] Recently, the Diabetic Retinopathy Clinical Research Network concluded that focal/grid photocoagulation remains the standard management for DME. [12]

The diabetic retinopathy vitrectomy study

The Diabetic Retinopathy Vitrectomy Study (DRVS) randomized 616 eyes with recent vitreous hemorrhage reducing visual acuity to 5/200 or less for at least 1 month to undergo early vitrectomy within 6 months or deferral of vitrectomy for one year. After 2 years of follow-up, 25% of the early vitrectomy group had visual acuity of 10/20 or better compared with 15% of the deferral group. In patients with type 1 diabetes, who were on average younger and had more severe PDR, there was a clear-cut advantage for early vitrectomy, as reflected in the percentage of eyes recovering visual acuity of 10/20 or better (36% versus 12% in the deferral group). No such advantage was found in type 2 diabetes group (16% in the early group versus 18% in the deferral group). [13]

The DRS and the ETDRS showed that laser photocoagulation for DR is effective at slowing the progression of retinopathy and reducing visual loss, but the treatment usually does not restore lost vision. Because these treatments are aimed at preventing vision loss and retinopathy can be asymptomatic, it is important to identify and treat patients early in the disease. To achieve this goal, patients with diabetes should be routinely evaluated to detect treatable disease. Guidelines for the frequency of diabetic eye examinations have been largely based on the severity of retinopathy. [1]


   Emerging Therapies Top


Due to the limitations of the current treatments, new therapeutic approaches are being developed.

Sub-threshold diode micropulse photocoagulation for the treatment of clinically significant diabetic macular edema

Sub-threshold diode micropulse laser photocoagulation minimizes chorioretinal damage and demonstrates a beneficial effect on visual acuity and macular edema resolution. The development of the diode laser with micropulsed emission has allowed subthreshold therapy without a visible burn endpoint. This greatly reduces the risk of structural and functional retinal damage, while retaining the therapeutic efficacy of conventional laser treatment. [14],[15],[16],[17]

Intravitreal triamcinolone acetonide

Intravitreal triamcinolone acetonide (IVTA) is reported to generate favorable results in the treatment of diffuse DME. However, the major limitation of IVTA is the recurrence of DME, which develops after a relatively short duration of action necessitating repeated applications of IVTA that carry risk and are inconvenient for patients. [18],[19] This early disappearance of the effect of IVTA might be consistent with the results reported by Beer et al., [20] who calculated that measurable concentrations of triamcinolone could be expected to last no longer than 3 months in nonvitrectomized eyes.

In a prospective randomized controlled trial, eyes with persistent DME after focal/grid photocoagulation received either 4 mg of IVTA or sham injection (saline injection into the sub-conjunctival space). After 2 years, 19 of 34 (56%) eyes treated with repeated IVTA had a visual acuity improvement of five letters or more compared with 9 of 35 (26%) placebo treated eyes. An increase of intraocular pressure of ≥ 5 mmHg was observed in 23 of 34 (68%) treated versus 3 of 30 (10%) untreated eyes. Glaucoma medication was required in 15 of 34 (44%) treated versus 1 of 30 (3%) untreated eyes. Cataract surgery was performed in 15 of 28 (54%) treated versus 0 of 21 (0%) untreated eyes. Two eyes in the IVTA group required trabeculectomy. There was one case of infectious endophthalmitis in the treatment group. [21]

Recent systematic reviews and meta-analysis of randomized controlled trials for IVTA for laser-refractory DME concluded that IVTA is effective in improving visual acuity in patients with refractory DME in the short-term, but the benefits do not seem to persist in the long-term. A peak benefit of approximately three lines of visual acuity was achieved 1 month postinjection. [18],[19]

The Diabetic Retinopathy Clinical Research Network [22] reported 2-year results of a multicenter randomized clinical trial comparing preservative free IVTA and focal/grid laser for DME. In this study, 840 eyes were randomized to focal/grid photocoagulation, 1 mg IVTA, or 4 mg IVTA. Retreatment was given for persistent or new edema at 4-month intervals. After 4 months, mean visual acuity was better in the 4-mg IVTA group than in either the laser group or the 1-mg IVTA group. The mean visual acuity 2 years after starting the treatment was better in the laser group compared with the steroid-injected groups. Optical coherence tomography results generally paralleled the visual acuity results. Cataract surgery performed before the 2-year visit was most frequent in the 4-mg IVTA group (51%) versus the 1-mg IVTA group (23%) and the laser group (13%). Increased intraocular pressure from baseline by 10 mmHg or more at any visit was most frequent in the 4-mg IVTA group (33%) versus the 1-mg IVTA group (16%) and the laser group (4%). More recently, the Diabetic Retinopathy Clinical Research Network [23] reported that the 3-year visual outcome results were consistent with the previously published 2-year results. The cumulative probability of cataract surgery by 3 years was 31%, 46%, and 83% in the laser and 1- and 4-mg IVTA groups, respectively. Intraocular pressure increased by more than 10 mmHg at any visit in 4%, 18%, and 33% of the eyes, respectively. This randomized study indicated clearly that focal/grid photocoagulation is a better treatment than IVTA in eyes with DME involving the center of the macula with visual acuity between 20/40 and 20/320. The fact that the 4-mg IVTA group had a greater positive treatment response on visual acuity and retinal thickening after 4 months of treatment, whereas the photocoagulation group had a greater positive response later, raises the possibility that combining focal/grid photocoagulation with IVTA may produce greater benefit for DME than either focal/grid photocoagulation or IVTA alone. [22]

More recently, the Diabetic Retinopathy Clinical Research Network reported that IVTA (4 mg) appeared to reduce the risk of progression of DR. However, the study concluded that use of IVTA to reduce the likelihood of progression of retinopathy is not warranted at this time because of the increased risk of glaucoma and cataract associated with IVTA and because PDR already can be treated successfully and safely with panretinal photocoagulation. [24]

Several small randomized clinical trials demonstrated that the combination of laser photocoagulation (panretinal and macular) with IVTA was associated with improved best-corrected visual acuity and decreased central macular thickness and total macular volume when compared with laser photocoagulation alone for the treatment of PDR and macular edema. [25],[26] In contrast, a recent study demonstrated no beneficial effect of combined IVTA plus panretinal photocoagulation and macular photocoagulation in eyes with coexisting high-risk PDR and clinically significant macular edema as compared with panretinal photocoagulation and macular photocoagulation as standard treatment in those patients. [27]

Recently, two studies compared the morphological and visual acuity outcomes associated with a single intravitreal injection of triamcinolone acetonide versus bevacizumab for the treatment of DME. These studies concluded that one single intravitreal injection of triamcinolone showed better results in reducing DME and in the improvement of visual acuity than that of bevacizumab in the short-term management of DME. The reduction effect of bevacizumab on DME was weaker and shorter than that by triamcinolone. However, intravitreal bevacizumab (IVB) had the advantage of intraocular pressure stability compared with the triamcinolone injection. [28],[29]

Dexamethasone intravitreal implant

Recent studies demonstrated that the biodegradable dexamethasone 0.7 mg sustained-release intravitreal implant (Ozurdex ® ; Allergan, Inc., Irvine, CA, USA) is a promising new treatment option for patients with persistent DME. [30],[31],[32]

Fluocinolone acetonide intravitreal implant

Fluocinolone acetonide intravitreal implant (Retisert, Bausch and Lomb, Rochester, NY) has been investigated as a treatment for DME. Despite bringing significant improvements in visual acuity and reduced macular edema, fluocinolone devices are associated with cataract formation, increased intraocular pressure, and surgery to lower intraocular pressure. [33],[34]

Antivascular endothelial growth factor treatment

Currently, there are four Antivascular endothelial growth factor (anti-VEGF) agents that have been used in the management of DR, including pegaptanib (Macugen; Pfizer, Inc., NY, USA), ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA, USA), bevacizumab (Avastin; Genentech, Inc.), and VEGF Trap-Eye (Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA).

Pegaptanib

Pegaptanib is a pegylated RNA aptamer directed against the VEGF-A 165 isoform. A phase II clinical trial of intravitreal pegaptanib in patients with DME with 36 weeks of follow-up demonstrated better visual acuity outcomes, reduced central retinal thickness, and reduced need for additional photocoagulation therapy. [35] A retrospective analysis of the same study on patients with retinal neovascularization at baseline showed regression of neovascularization after intravitreal pegaptanib administration. [36] Recently, Querques et al. [37] demonstrated in a retrospective study that repeated intravitreal pegaptanib produced significant improvement in best-corrected visual acuity and reduction in mean central macular thickness in patients with DME. In addition, González et al. [38] showed that intravitreal pegaptanib produced short-term marked and rapid regression of diabetic retinal neovascularization. These data suggest that VEGF blockade may be a safe and efficacious adjuvant treatment to panretinal photocoagulation in PDR.

Ranibizumab

Ranibizumab is a recombinant humanized monoclonal antibody fragment with specificity for all isoforms of human VEGF-A. Pilot studies of intravitreal ranibizumab demonstrated reduced foveal thickness and maintained or improved visual acuity in patients with DME. [39] Recently, Nguyen et al. [40] demonstrated that during a span of 6 months, repeated intravitreal injections of ranibizumab produced a significantly better visual outcome than focal/grid laser treatment in patients with DME. The Diabetic Retinopathy Clinical Research Network [41] evaluated intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of DME. The 1-year mean change (± standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group and ranibizumab + deferred laser group but not in the triamcinolone + prompt laser group compared with the sham + prompt laser group. In the subset of pseudophakic eyes at baseline, visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. Two-year visual acuity outcomes were similar to one-year outcomes. Elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group and 0.8% had injection-related endophthalmitis in the ranibizumabn group. [42] Nguyen et al., [43] in a randomized study, showed that intraocular injection of ranibizumab provided benefit for DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema. The 2- and 3-year results demonstrated the efficacy and safety of repeated intravitreal ranibizumab injections. [42],[44],[45],[46],[47],[48] It was also shown that more extensive focal/grid laser therapy may reduce the need for more frequent ranibizumab injections to control edema. [46]

Vascular endothelial growth factor Trap-Eye

VEGF Trap is a 115 kDa recombinant fusion protein consisting of the VEGF binding domains of human VEGF receptors 1 and 2 fused to the Fc domain of human IgG1. Recent studies showed that intravitreal injection of VEGF Trap-Eye was well tolerated and was effective in patients with DME. [49],[50],[51]

Bevacizumab

Bevacizumab is a full length recombinant humanized antibody active against all isoforms of VEGF-A. It is Food and Drug Administration (FDA)-approved as an adjunctive systemic treatment for metastatic colorectal cancer. Several studies reported the use of the off-label IVB to treat DME, complications of PDR, and iris neovascularization.

To date, all studies regarding IVB (1.25 mg) for DME therapy, have demonstrated transient beneficial effects with a requirement for repeated injections. [52],[53],[54],[55] Increased visual acuity with decrease in macular edema with a single injection of IVB lasts for 4-6 weeks with deterioration of visual acuity and recurrence of macular edema 8-12 weeks later necessitating another injection. [28],[53] Fang et al. [54] reported that the improvement in visual acuity and decrease in macular edema were maintained for 8 weeks in the non-pretreated eyes, and for 2-4 weeks in the pretreated eyes. In addition, Yanyali et al. [56] reported that IVB in DME has no effect on visual acuity and macular edema in previously vitrectomized eyes. Similarly, Lam et al. [55] demonstrated that IVB was more effective in eyes without previous DME treatment, which included focal or grid laser photocoagulation. Two recent studies demonstrated that IVB at doses of 1.25 and 2.5 mg seems to have similar treatment efficacy in patients with DME. [52],[55] Bonini-Filho et al. [57] showed that IVB for DME with severe capillary loss was associated with beneficial effects on vision, central macular thickness, and total macular volume. Soheilian et al. [58] reported that IVB in patients with DME yielded a better visual outcome 24 weeks later compared with macular photocoagulation. The 2-year follow-up demonstrated the beneficial effect of IVB with or without grid laser photocoagulation for diffuse DME. [59],[60]

Several studies demonstrated that IVB injection resulted in marked regression of retinal and iris neovascularization, and rapid resolution of vitreous hemorrhage in patients with PDR. [61],[62],[63] In addition, IVB injection was demonstrated to be an effective adjunctive treatment to PRP in the treatment of high-risk PDR, [64],[65] and neovascular glaucoma. [63] IVB injection before PRP was found to be beneficial in preventing PRP-induced visual dysfunction and foveal thickening and was associated with a greater reduction in the area of active leaking new vessels than PRP alone in patients with high-risk PDR. [64],[65] In addition, Huang et al. [66] demonstrated that IVB injection with PRP was effective in inducing rapid regression of vitreous hemorrhage and may reduce the need for vitrectomy in eyes with PDR complicated with vitreous hemorrhage.

The use of preoperative IVB injection few days before planned pars plana vitrectomy for the treatment of complications of PDR was also found to be efficacious and safe as an adjuvant treatment to facilitate surgery, prevent rebleeding, and accelerate postoperative vitreous clear-up. [67],[68] However, tractional retinal detachment may occur or progress shortly following administration of IVB in these patients. [69] Two recent studies demonstrated that IVB injection pretreatment for diabetic vitrectomy did not influence rates of postoperative vitreous hemorrhage or final visual acuity. [70],[71] Several studies determined the clinical effectiveness of IVB combined with cataract surgery for the management of the postoperative increase of retinal thickness in patients with DME. The short-term results suggest that IVB has the potential not only to prevent the increase in retinal thickness, but also reduce the retinal thickness of eyes with DME after cataract surgery. [72],[73]

Intravitreal bevacizumab versus ranibizumab

Most studies do not provide information about long-term results (i.e., more than 2-3 years of follow-up) on the comparative efficacy of anti-VEGF pharmacotherapies. [74] Further evidence is required to support the long-term safety of these pharmacotherapies and their comparative efficacy. [74] The available data suggest no difference in effectiveness between bavacizumab and ranibizumab. [75],[76]

Vitrectomy for persistent diffuse diabetic macular edema

Vitrectomy with removal of the premacular posterior hyaloid for persistent diffuse macular edema has gained rapid widespread acceptance. The large number of series evaluating the efficacy of vitrectomy (with or without internal limiting membrane peeling) has yielded conflicting results. In a prospective randomized trial, Stolba et al. [77] showed that vitrectomy with internal limiting membrane peeling was superior to observation in eyes with persistent diffuse DME that previously failed to respond to conventional laser treatment and positively influenced distance and reading visual acuity as well as the morphology of the edema. However, they suggested the need for larger follow-up and larger series to confirm these findings. Other studies suggested that vitrectomy with and without internal limiting membrane peeling may provide anatomic and visual benefit in eyes with diffuse nontractional unresponsive DME refractory to laser photocoagulation. [78],[79] Best corrected visual acuity continued to improve until 1 year postoperatively and is maintained long-term. [78],[79] The preoperative best corrected visual acuity was the best prognostic factor for final best corrected visual acuity. [78],[79] In contrast, other studies showed that the benefits of vitrectomy for DME in terms of visual acuity and macular thickness were limited to patients who exhibited signs of macular traction, either clinically and/or on optical coherence tomography. [80],[81] Macular detachment on optical coherence tomography was suggested to be an adverse predictive indicator. [80] The Diabetic Retinopathy Clinical Research Network [82] evaluated vitrectomy for DME associated with vitreomacular traction. At 6 months, median OCT central subfield thickness decreased by 160 microns, with 43% having central subfield thickness < 250 microns and 68% having at least a 50% reduction in thickening. Visual acuity improved by ≥ 10 letters in 38% and deteriorated by ≥ 10 letters in 22%. The factors associated with favorable outcomes after vitrectomy for DME were also evaluated. [83] Greater visual acuity improvement occurred in eyes with worse baseline acuity and in eyes in which an epiretinal membrane was removed. Greater reduction in central subfield thickness occurred with worse baseline visual acuity, greater preoperative retinal thickness, removal of internal limited membrane, and optical coherence tomography evidence of vitreoretinal abnormalities.

The necessity of internal limiting membrane peeling is still unclear. Several studies reported that there was no difference in the absorption rate of macular edema or the functional outcome after vitrectomy with or without internal limiting membrane peeling. [78],[84]

Pharmacologic vitreolysis in the management of diabetic retinopathy

Our enhanced understanding of the role of the vitreous body in DR has led investigators to use pharmacologic vitreolysis in the management of DR. A phase III clinical trial has shown that 55 IU of highly purified ovine hyaluronidase (vitrase) helps to clear vitreous hemorrhage 1 month after intravitreal application. [85] No serious safety issues were reported. [86] In particular, the incidence of retinal detachment was not statistically different between treated eyes and control groups.

Quiram et al. [87] demonstrated that intravitreal injection of microplasmin with induction of the combination of posterior vitreous detachment (PVD) and vitreous liquefaction increased intravitreal oxygen tension. In contrast, hyaluronidase-induced vitreous liquefaction without PVD induction failed to increase intravitreal oxygen tension. Moreover, when microplasmin treated animals were exposed to 100% oxygen, there was an accelerated increase in oxygen levels in the midvitreous cavity compared with control or hyaluronidase treated eyes. These findings suggest that the beneficial effects of surgical vitrectomy in increasing oxygen tension in the vitreous cavity [88] may be reproduced with enzymatic induction of PVD and vitreous liquefaction without the time, risks, and expense of surgery.

It is more difficult to separate vitreous cortex from internal limiting membrane in diabetic eyes than in nondiabetic eyes. This is likely due to the effects of diabetes on the macromolecules of vitreous and the structural consequences. [89] In an experimental rat model of diabetes, the combination of hyaluronidase causing vitreous liquefaction and plasmin acting as a PVD inducer was more effective than plasmin alone in inducing complete PVD. [89]

Pilot clinical studies in diabetic eyes found that autologous plasmin was a safe and effective adjunct to vitrectomy for DME and PDR. Intravitreal injection of autologous plasmin enzyme before surgery was useful in inducing a pharmacologic PVD, and thus mechanical PVD was not necessary in eyes with DME secondary to posterior vitreous cortex contraction. [90],[91],[92] Plasmin-assisted vitrectomy allowed a more complete and less traumatic posterior vitreous cortex removal with a smooth retinal surface. The internal limiting membrane removed during the plasmin-assisted vitrectomy from eyes with DME demonstrated cleaner and flatter surfaces, whereas the internal limiting membrane removed without the use of autologous plasmin enzyme had remnants of the vitreous cortex more frequently. [92] Autologous plasmin enzyme was also beneficial in the surgical management of PDR. The proliferative membranes became softened and were easily peeled without retinal tears. [93]

Recently, Diaz-Llopis et al. [94] demonstrated that intravitreal injection of autologous plasmin enzyme without the performance of vitrectomy induced complete PVD and effectively reduced macular thickening due to refractory diffuse DME and improved visual acuity. Therefore, atraumatic pharmacologic separation of the posterior vitreous cortex with clean cleavage between the internal limiting membrane and the posterior hyaloids without performing a vitrectomy can reduce the risk of intraoperative iatrogenic damage such as retinal tears, and damage to the nerve fibers, and postoperative sequelae.

Fibrates

Fibrates are widely prescribed lipid-lowering drug in the treatment of dyslipidemia. Their main clinical effects, mediated by peroxisome proliferative activated receptor alpha activation, are a moderate reduction in total cholesterol and low-density lipoprotein cholesterol levels, a marked reduction in triglycerides and an increase in high-density lipoprotein cholesterol. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study demonstrated that long-term lipid-lowering therapy with fenofibrate reduced the progression of DR and the need for laser treatment in patients with type 2 diabetes, although the mechanism of this effect does not seem to be related to plasma concentration of lipids. [95] Recently, ACCORD Study Group [96] demonstrated that fenofibrate for intensive dyslipidemia therapy reduced the rate of progression of DR in persons with type 2 diabetes. [96]

Renin-angiotensin system blockers

Several studies suggested that Renin-angiotensin system (RAS) blockers might reduce the burden of DR. The findings of the Eurodiab Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) suggested that blockade of the renin-angiotensin system with the angiotensin-converting enzyme inhibitor lisinopril could reduce both incidence and progression of retinopathy in type 1 diabetes. [97] Recently, the Diabetic Retinopathy Candesartan Trials (DIRECT) demonstrated that the angiotensin-receptor antagonist candesartan reduced the incidence of retinopathy in patients with type 1 diabetes, [98] and might induce improvement of retinopathy in type 2 diabetic patients with mild-to- moderate retinopathy. [99]

Peroxisome proliferator-activated receptor gamma agonists

The Peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone inhibited both the retinal leukostasis and retinal leakage observed in the experimental diabetic rats. In addition, the decreased expression of the endogenous PPARγ in mice leads to the aggravation of retinal leukostasis and retinal leakage in diabetic mice. [100] Rosiglitazone maleate (Avandia; GlaxoSmithKline, NC, USA) is an orally administered medication used to improve glycemic control in patients with diabetes mellitus. This medication activates the PPARγ and leads to insulin sensitization in adipose and other tissues, with potential antiangiogenic activity. Recently, Shen et al. [101] demonstrated that rosiglitazone may delay the onset of PDR in patients with severe nonproliferative DR at baseline. Several studies showed that the use of glitazone class of drugs was associated with DME. [102] However, another retrospective study concluded that rosiglitazone is not linked to DME. [103]

Ruboxistaurin

Hyperglycemia activates protein kinase C (PKC) by inducing de novo synthesis of diacylglycerol, a physiologic activator of PKC. Substantial data suggest that the β isoform may play an important role in the development of diabetic microvascular complications. Increased PKC β isoform activity induces retinal vascular permeability and neovascularization in animal models. Roboxistaurin (RBX) (LY333531; Lilly Research Laboratories, Indianapolis, IN, USA) is a PKC β-selective inhibitor with adequate bioavailability to permit oral administration once daily. In the Protein Kinase C β inhibitor-Diabetic Retinopathy Study 2 (PKC-DRS2), oral administration of RBX (32 mg per day) reduced sustained moderate visual loss, need for laser treatment for macular edema, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy. [104],[105],[106],[107] In the Protein Kinase C β inhibitor Diabetic Macular Edema Study (PKC-DMES), RBX treatment also showed a beneficial effect on DME progression relative to placebo. [108] More recently, Davis et al. [109] demonstrated that RBX treatment appears to ameliorate DME-associated visual decline.

Islet cell transplantation

Recent studies demonstrated that improved islet transplant outcomes could be observed with enhanced islet isolation, glucocorticoid-free immunosuppression, and provision of an adequate islet mass of more than 10,000 islet equivalents per kilogram of body weight. These improvements have resulted in benefits to type 1 diabetic subjects, including long-term c-peptide secretion, improved glycemic control, and reduced hypoglycemic episodes. Recently, it was demonstrated that islet transplantation yields improved HbA1c and less progression of retinopathy compared with intensive medical therapy during 3 years of follow-up. [110],[111],[112]


   Acknowledgments Top


The authors thank Ms. Connie B. Unisa-Marfil for secretarial work. Supported by Medical Research Chair funded by Dr. Nasser Al-Rasheed (AMA).

 
   References Top

1.Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al.; American Diabetes Association. Diabetic retinopathy. Diabetes Care 2003;26 Suppl 1:S99-102.  Back to cited text no. 1
    
2.Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86.  Back to cited text no. 2
    
3.White NH, Sun W, Cleary PA, Danis RP, Davis MD, Hainsworth DP, et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol 2008;126:1707-15.  Back to cited text no. 3
    
4.Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998;116:874-86.  Back to cited text no. 4
    
5.UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.  Back to cited text no. 5
    
6.UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13.  Back to cited text no. 6
    
7.Photocoagulation treatment of proliferative diabetic retinopathy: The second report of diabetic retinopathy study findings. Ophthalmology 1978;85:82-106.  Back to cited text no. 7
    
8.Diabetic Retinopathy Clinical Research Network, Brucker AJ, Qin H, Antoszyk AN, Beck RW, Brassler NM, Browning DJ, et al. Observational study of the development of diabetic macular edema following panretinal (scatter) photocoagulation given in 1 or 4 sittings. Arch Ophthalmol 2009;127:132-40.  Back to cited text no. 8
    
9.Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796-806.  Back to cited text no. 9
    
10.Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc 1996; 94:503-37.  Back to cited text no. 10
    
11.Writing Committee for the Diabetic Retinopathy Clinical Research Network, Fong DS, Strauber SF, Aiello LP, Beck RW, Callanan DG, Danis RP, et al. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol 2007;125:469-80.  Back to cited text no. 11
    
12.Aiello LP, Edwards AR, Beck RW, Bressler NM, Davis MD, Ferris F, et al.; Diabetic Retinopathy Clinical Research Network. Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2010;117:946-53.  Back to cited text no. 12
    
13.Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial. Diabetic Retinopathy Vitrectomy Study report 2. Arch Ophthalmol 1985;103:1644-52.  Back to cited text no. 13
    
14.Figueira J, Khan J, Nunes S, Sivaprasad S, Rosa A, de Abreu JF, et al. Prospective randomized controlled trial comparing sub-threshold micropulse laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema. Br J Ophthalmol 2009;93:1341-4.  Back to cited text no. 14
    
15.Vujosevic S, Bottega E, Casciano M, Pilotto E, Convento E, Midena E. Microperimetry and fundus autofluorescence in diabetic macular edema: Subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina 2010;30:908-16.  Back to cited text no. 15
    
16.Ohkoshi K, Yamaguchi T. Subthreshold micropulse diode laser photocoagulation for diabetic macular edema in Japanese patients. Am J Ophthalmol 2010;149:133-9.  Back to cited text no. 16
    
17.Lavinsky D, Cardillo JA, Melo LA Jr, Dare A, Farah ME, Belfort R Jr. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. Invest Ophthalmol Vis Sci 2011;52:4314-23.  Back to cited text no. 17
    
18.Rudnisky CJ, Lavergne V, Katz D. Visual acuity after intravitreal triamcinolone for diabetic macular edema refractory to laser treatment: A meta-analysis. Can J Ophthalmol 2009;44:587-93.  Back to cited text no. 18
    
19.Yilmaz T, Weaver CD, Gallagher MJ, Cordero-Coma M, Cervantes-Castaneda RA, Klisovic D, et al. Intravitreal triamcinolone acetonide injection for treatment of refractory diabetic macular edema: A systematic review. Ophthalmology 2009;116:902-11.  Back to cited text no. 19
    
20.Beer PM, Bakri SJ, Singh RJ, Liu W, Peters GB 3 rd , Miller M. Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology 2003;110:681-6.  Back to cited text no. 20
    
21.Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: Two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology 2006;113:1533-8.  Back to cited text no. 21
    
22.Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008;115:1447-9.  Back to cited text no. 22
    
23.Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009;127:245-51.  Back to cited text no. 23
    
24.Bressler NM, Edwards AR, Beck RW, Flaxel CJ, Glassman AR, Ip MS, et al.; Diabetic Retinopathy Clinical Research Network. Exploratory analysis or diabetic retinopathy progression through 3 years in randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation. Arch Ophthalmol 2009;127:1566-71.  Back to cited text no. 24
    
25.Lam DS, Chan CK, Mohamed S, Lai TY, Lee VY, Liu DT, et al. Intravitreal triamcinolone plus sequential grid laser versus triamcinolone or laser alone for treating diabetic macular edema: six-month outcomes. Ophthalmology 2007;114:2162-7.  Back to cited text no. 25
    
26.Maia OO Jr, Takahashi BS, Costa RA, Scott IU, Takahashi WY. Combined laser and intravitreal triamcinolone for proliferative diabetic retinopathy and macular edema: One-year results of a randomized clinical trial. Am J Ophthalmol 2009;147:291-7.  Back to cited text no. 26
    
27.Mirshahi A, Shenazandi H, Lashay A, Faghihi H, Alimahmoudi A, Dianat S. Intravitreal triamcinolone as an adjunct to standard laser therapy in coexisting high-risk proliferative diabetic retinopathy and clinically significant macular edema. Retina 2010;30:254-9.  Back to cited text no. 27
    
28.Paccola L, Costa RA, Folgosa MS, Barbosa JC, Scott IU, Jorge R. Intravitreal triamcinolone versus bevacizumab for treatment of refractory diabetic macular oedema (IBEME study). Br J Ophthalmol 2008;92:76-80.  Back to cited text no. 28
    
29.Shimura M, Nakazawa T, Yasuda K, Shiono T, Iida T, Sakamoto T, et al. Comparative therapy evaluation of intravitreal bevacizumab and triamcinolone acetonide on persistent diffuse diabetic macular edema. Am J Ophthalmol 2008;145:854-61.  Back to cited text no. 29
    
30.Zucchiatti I, Lattanzio R, Querques G, Querques L, Del Turco C, Cascavilla ML, et al. Intravitreal dexamethasone implant in patients with persistent diabetic macular edema. Ophthalmologica 2012;228:117-22.  Back to cited text no. 30
    
31.Boyer DS, Faber D, Gupta S, Patel SS, Tabandeh H, Li XY, et al.; Ozurdex CHAMPLAIN Study Group. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 2011;31:915-23.  Back to cited text no. 31
    
32.Callanan DG, Gupta S, Boyer DS, Ciulla TA, Singer MA, Kuppermann BD, et al.; Ozurdex PLACID Study Group. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology 2013. [In press].  Back to cited text no. 32
    
33.Pearson PA, Comstock TL, Ip M, Callanan D, Morse LS, Ashton P, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: A 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 2011;118:1580-7.  Back to cited text no. 33
    
34.Campochiaro PA, Brown DM, Pearson A, Chen S, Boyer D, Ruiz-Moreno J, et al.; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology 2012;119:2125-32.  Back to cited text no. 34
    
35.Cunningham ET Jr, Adamis AP, Altaweel M, Aiello LP, Bressler NM, D'Amico DJ, et al.; Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005;112:1747-57.  Back to cited text no. 35
    
36.Adamis AP, Altaweel M, Bressler NM, Cunningham ET Jr, Davis MD, Goldbaum M, et al.; Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113:23-8.  Back to cited text no. 36
    
37.Querques G, Bux AV, Martinelli D, Iaculli C, Noci ND. Intravitreal pegaptanib sodium (Macugen) for diabetic macular oedema. Acta Ophthalmol 2009;87:623-30.  Back to cited text no. 37
    
38.González VH, Giuliari GP, Banda RM, Guel DA. Intravitreal injection of pegaptanib sodium for proliferative diabetic retinopathy. Br J Ophthalmol 2009;93:1474-8.  Back to cited text no. 38
    
39.Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 2006;113:1706-12.  Back to cited text no. 39
    
40.Nguyen QD, Shah SM, Heier JS, Do DV, Lim J, Boyer D, et al.; READ-2 Study Group. Primary end point (Six Months) results of the Ranibizumab for Edema of the macula in Diabetes (READ-2) study. Ophthalmology 2009;116:2175-81.  Back to cited text no. 40
    
41.Diabetic Retinopathy Clinical Research Network, Elman MJ, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferries FL 3 rd , et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117:1064-77.  Back to cited text no. 41
    
42.Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3 rd , Friedman SM, et al.; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609-14.  Back to cited text no. 42
    
43.Nguyen QD, Shah SM, Khwaja AA, Channa R, Hatef E, Do DV, et al.; READ-2 Study Group. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology 2010;117:2146-51.  Back to cited text no. 43
    
44.Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al.; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789-801.  Back to cited text no. 44
    
45.Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, Aiello LP, Beck RW, Bressler NM, Ferries FL 3 rd , et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: Three-year randomized trial results. Ophthalmology 2012;119:2312-8.  Back to cited text no. 45
    
46.Do DV, Nguyen QD, Khwaja AA, Channa R, Sepah YJ, Sophie R, et al.; READ-2 Study Group. Ranibizumab for edema of the macular in diabetes study: 3-year outcomes and the need for prolonged frequent treatment. JAMA Ophthalmol 2013;131:139-45.  Back to cited text no. 46
    
47.Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al.; RIDE and RISE Research Group. Long-term outcomes of Ranibizumab therapy for diabetic macular edema: The 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013. [In press]  Back to cited text no. 47
    
48.Lang GE, Berta A, Eldem BM, Simader C, Sharp D, Holz FG, et al.; RESTORE Extension Study Group. Two-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema: Interim analysis of the RESTORE Extension Study. Ophthalmology 2013. [In press]  Back to cited text no. 48
    
49.Do DV, Nguyen QD, Shah SM, Browning DJ, Haller JA, Chu K, et al. An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema. Br J Ophthalmol 2009;93:144-9.  Back to cited text no. 49
    
50.Do DV, Schmidt-Erfurth U, Gonzalez VH, Gordon CM, Tolentino M, Berliner AJ, et al. The DA VINCI Study: Phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology 2011;118:1819-26.  Back to cited text no. 50
    
51.Do DV, Nguyen QD, Boyer D, Schmidt-Erfurth U, Brown DM, Vitti R, et al.; DA VINCI Study Group. One-year outcomes of the DA VINCI Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012;119:1658-65.  Back to cited text no. 51
    
52.Arevalo JF, Sanchez JG, Fromow-Guerra J, Wu L, Berrocal MH, Farah ME, et al.; Pan-American Collaborative Retina Study Group (PACORES). Comparison of two doses of primary intravitreal bevacizumab (Avastin) for diffuse diabetic macular edema: Results from the Pan-American Collaborative Retina Study Group (PACORES) at 12-month follow-up. Graefes Arch Clin Exp Ophthalmol 2009;247:735-43.  Back to cited text no. 52
    
53.Roh MI, Byeon SH, Kwon OW. Repeated intravitreal injection of bevacizumab for clinically significant diabetic macular edema. Retina 2008;28:1314-8.  Back to cited text no. 53
    
54.Fang X, Sakaguchi H, Gomi F, Oshima Y, Sawa M, Tsujikawa M, et al. Efficacy and safety of one intravitreal injection of bavacizumab in diabetic macular oedema. Acta Ophthalmol 2008;86:800-5.  Back to cited text no. 54
    
55.Lam DS, Lai TY, Lee VY, Chan CK, Liu DT, Mohamed S, et al. Efficacy of 1.25 MG versus 2.5 MG intravitreal bevacizumab for diabetic macular edema: Six-month results of a randomized controlled trial. Retina 2009;29:292-9.  Back to cited text no. 55
    
56.Yanyali A, Aytug B, Horozoglu F, Nohutcu AF. Bevacizumab (Avastin) for diabetic macular edema in previously vitrectomized eyes. Am J Ophthalmol 2007;144:124-6.  Back to cited text no. 56
    
57.Bonini-Filho M, Costa RA, Calucci D, Jorge R, Melo LA Jr, Scott IU. Intravitreal bevacizumab for diabetic macular edema associated with severe capillary loss: One-year results of a pilot study. Am J Ophthalmol 2009;147:1022-30.  Back to cited text no. 57
    
58.Soheilian M, Ramezani A, Obudi A, Bijanzadeh B, Salehipour M, Yaseri M, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology 2009;116:1142-50.  Back to cited text no. 58
    
59.Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, Hamilton RD, Esposti SD, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: Report 3. Arch Ophthalmol 2012;130:972-9.  Back to cited text no. 59
    
60.Arevalo JF, Lasave AF, Wu L, Diaz-Llopis M, Gallego-Pinazo R, Alezzandrini AA, et al.; Pan-American Collaborative Retina Study Group (PACORES). Intravitreal bevacizumab plus grid laser photocoagulation or intravitreal bavacizumab or grid laser photocoagulation for diffuse diabetic macular edema: Results of the Pan-american Collaborative Retina Study Group at 24 months. Retina 2013;33:403-13.  Back to cited text no. 60
    
61.Arevalo JF, Wu L, Sanchez JG, Maia M, Saravia MJ, Fernandez CF, et al. Intravitreal bevacizumab (Avastin) for proliferative diabetic retinopathy: 6-months follow-up. Eye (Lond) 2009;23:117-23.  Back to cited text no. 61
    
62.Jiang Y, Liang X, Li X, Tao Y, Wang K. Analysis of the clinical efficacy of intravitreal bevacizumab in the treatment of iris neovascularization caused by proliferative diabetic retinopathy. Acta Ophthalmol 2009;87:736-40.  Back to cited text no. 62
    
63.Wakabayashi T, Oshima Y, Sakaguchi H, Ikuno Y, Miki A, Gomi F, et al. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 2008;115:1571-80.  Back to cited text no. 63
    
64.Tonello M, Costa RA, Almeida FP, Barbosa JC, Scott IU, Jorge R. Panretinal photocoagulation versus PRP plus intravitreal bevacizumab for high-risk proliferative diabetic retinopathy (IBeHi study). Acta Ophthalmol 2008;86:385-9.  Back to cited text no. 64
    
65.Cho WB, Oh SB, Moon JW, Kim HC. Panretinal photocoagulation combined with intravitreal bevacizumab in high-risk proliferative diabetic retinopathy. Retina 2009;29:516-22.  Back to cited text no. 65
    
66.Huang YH, Yeh PT, Chen MS, Yang CH, Yang CM. Intravitreal bevacizumab and panretinal photocoagulation for proliferative diabetic retinopathy associated with vitreous hemorrhage. Retina 2009;29:1134-40.  Back to cited text no. 66
    
67.Ahmadieh H, Shoeibi N, Entezari M, Monshizadeh R. Intravitreal bevacizumab for prevention of early postvitrectomy hemorrhage in diabetic patients: A randomized clinical trial. Ophthalmology 2009;116:1943-8.  Back to cited text no. 67
    
68.di Lauro R, De Ruggiero P, di Lauro R, di Lauro MT, Romano MR. Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2010;248:785-91.  Back to cited text no. 68
    
69.Arevalo JF, Maia M, Flynn HW Jr, Saravia M, Avery RL, Wu L, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol 2008;92:213-6.  Back to cited text no. 69
    
70.Romano MR, Gibran SK, Marticorena J, Wong D, Heimann H. Can an intraoperative bevacizumab injection prevent recurrent postvitrectomy diabetic vitreous hemorrhage? Eur J Ophthalmol 2009;19:618-21.  Back to cited text no. 70
    
71.Lo WR, Kim SJ, Aaberg TM Sr, Bergstrom C, Srivastava SK, Yan J, et al. Visual outcomes and incidence of recurrent vitreous hemorrhage after vitrectomy in diabetic eyes pretreated with bavacizumab (avastin). Retina 2009;29:926-31.  Back to cited text no. 71
    
72.Takamura Y, Kubo E, Akagi Y. Analysis of the effect of intravitreal bevacizumab injection on diabetic macular edema after cataract surgery. Ophthalmology 2009;116:1151-7.  Back to cited text no. 72
    
73.Lanzagorta-Aresti A, Palacios-Pozo E, Menezo Rozalen JL, Navea-Tejerina A. Prevention of vision loss after cataract surgery in diabetic macular edema with intravitreal bevacizumab: A pilot study. Retina 2009;29:530-5.  Back to cited text no. 73
    
74.Ho AC, Scott IU, Kim SJ, Brown GC, Brown MM, Ip MS, et al. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: A report by the American Academy of Ophthalmology. Ophthalmology 2012;119:2179-88.  Back to cited text no. 74
    
75.Ford JA, Elders A, Shyangdan D, Royle P, Waugh N. The relative clinical effectiveness of ranibizumab and bavacizumab in diabetic macular oedema: An indirect comparison in a systematic review. BMJ 2012;345:e5182.  Back to cited text no. 75
    
76.Nepomuceno AB, Takaki E, Paes De Almeida FP, Peroni R, Cardillo JA, Siqueira RC, et al. A prospective randomized trial of intravitreal bevacizumab of diabetic macular edema. Am J Ophthalmol 2013. [In press]  Back to cited text no. 76
    
77.Stolba U, Binder S, Gruber D, Krebs I, Aggermann T, Neumaier B. Vitrectomy for persistent diffuse diabetic macular edema. Am J Ophthalmol 2005;140:295-301.  Back to cited text no. 77
    
78.Kumagai K, Furukawa M, Ogino N, Larson E, Iwaki M, Tachi N. Long-term follow-up of vitrectomy for diffuse nontractional diabetic macular edema. Retina 2009;29:464-72.  Back to cited text no. 78
    
79.Yamamoto T, Takeuchi S, Sato Y, Yamashita H. Long-term follow-up results of pars plana vitrectomy for diabetic macular edema. Jpn J Ophthalmol 2007;51:285-91.  Back to cited text no. 79
    
80.Shah SP, Patel M, Thomas D, Aldington S, Laidlaw DA. Factors predicting outcome of vitrectomy for diabetic macular oedema: Results of a prospective study. Br J Ophthalmol 2006;90:33-6.  Back to cited text no. 80
    
81.Figueroa MS, Contreras I, Noval S. Surgical and anatomical outcomes of pars plana vitrectomy for diffuse nontractional diabetic macular edema. Retina 2008;28:420-6.  Back to cited text no. 81
    
82.Diabetic Retinopathy Clinical Research Network Writing Committee, Haller JA, Qin H, Apte RS, Beck RR, Bressler NM, Browning DJ, et al. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology 2010;117:1087-93.  Back to cited text no. 82
    
83.Flaxel CJ, Edwards AR, Aiello LP, Arrigg PG, Beck RW, Bressler NM, et al. Factors associated with visual acuity outcomes after vitrectomy for diabetic macular edema: Diabetic retinopathy clinical research network. Retina 2010;30:1488-95.  Back to cited text no. 83
    
84.Shiba T, Kamura Y, Yagi F, Sato Y. Comparison of surgical procedures for vitreous surgery in diabetic macular edema. Jpn J Ophthalmol 2009;53:120-4.  Back to cited text no. 84
    
85.Kuppermann BD, Thomas EL, de Smet MD, Grillone LR. Pooled efficacy results from two multinational randomized controlled clinical trials of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol 2005;140:573-84.  Back to cited text no. 85
    
86.Kuppermann BD, Thomas EL, de Smet MD, Grillone LR. Safety results of two phase III trials of an intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol 2005;140:585-97.  Back to cited text no. 86
    
87.Quiram PA, Leverenz VR, Baker RM, Dang L, Giblin FJ, Trese MT. Microplasmin-induced posterior vitreous detachment affects vitreous oxygen levels. Retina 2007;27:1090-6.  Back to cited text no. 87
    
88.Stefánsson, E. Physiology of vitreous surgery. Graefes Arch Clin Exp Ophthalmol 2009;247:147-63.  Back to cited text no. 88
    
89.Zhi-Liang W, Wo-Dong S, Min L, Xiao-Ping B, Jin J. Pharmacologic vitreolysis with plasmin and hyaluronidase in diabetic rats. Retina 2009;29:269-74.  Back to cited text no. 89
    
90.Sakuma T, Tanaka M, Inoue J, Mizota A, Souri M, Ichinose A. Use of autologous plasmin during vitrectomy for diabetic maculopathy. Eur J Ophthalmol 2006;16:138-40.  Back to cited text no. 90
    
91.Azzolini C, D'Angelo A, Maestranzi G, Codenotti M, Della Valle P, Prati M, et al. Intrasurgical plasmin enzyme in diabetic macular edema. Am J Ophthalmol 2004;138:560-6.  Back to cited text no. 91
    
92.Asami T, Terasaki H, Kachi S, Nakamura M, Yamamura K, Nabeshima T, et al. Ultrastructure of internal limiting membrane removed during plasmin-assisted vitrectomy from eyes with diabetic macular edema. Ophthalmology 2004;111:231-7.  Back to cited text no. 92
    
93.Hirata A, Takano A, Inomata Y, Yonemura N, Sagara N, Tanihara H. Plasmin-assisted vitrectomy for management of proliferative membrane in proliferative diabetic retinopathy: A pilot study. Retina 2007;27:1074-8.  Back to cited text no. 93
    
94.Diaz-Llopis M, Udaondo P, Arevalo F, Salom D, Garcia-Delpech S, Quijada A, et al. Intravitreal plasmin without associated vitrectomy as a treatment of refractory diabetic macular edema. J Ocul Pharmacol Ther 2009;25:379-84.  Back to cited text no. 94
    
95.Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, et al.; FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): A randomised controlled trial. Lancet 2007;370:1687-97.  Back to cited text no. 95
    
96.ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-44.  Back to cited text no. 96
    
97.Chaturvedi N, Sjølie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998;351:28-31.  Back to cited text no. 97
    
98.Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, et al.; DIRECT Programme Study Group. Effect of Candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: Randomised, placebo-controlled trials. Lancet 2008;372:1394-402.  Back to cited text no. 98
    
99.Sjølie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, et al.; DIRECT Programme Study Group. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): A randomised placebo-controlled trial. Lancet 2008;372:1385-93.  Back to cited text no. 99
    
100.Muranaka K, Yanagi Y, Tamaki Y, Usui T, Kubota N, Iriyama A, et al. Effects of peroxisome proliferator-activated receptor gamma and its ligand on blood-retinal barrier in a streptozotocin-induced diabetic model. Invest Ophthalmol Vis Sci 2006;47:4547-52.  Back to cited text no. 100
    
101.Shen LQ, Child A, Weber GM, Folkman J, Aiello LP. Rosiglitazone and delayed onset of proliferative diabetic retinopathy. Arch Ophthalmol 2008;126:793-9.  Back to cited text no. 101
    
102.Fong DS, Contreras R. Glitazone use associated with diabetic macular edema. Am J Ophthalmol 2009;147:583-6.  Back to cited text no. 102
    
103.Tatti P, Arrigoni F, Longobardi A, Costanza F, Di Blasi P, Merante D. Retrospective analysis of rosiglitazone and macular oedema in patients with type 2 diabetes mellitus. Clin Drug Investig 2008;28:327-32.  Back to cited text no. 103
    
104.PKC-DRS2 Group, Aiello LP, Davis MD, Girach A, Kles KA, Milton RC, Sheetz MJ, et al. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology 2006;113:2221-30.  Back to cited text no. 104
    
105.Aiello LP, Vignati L, Sheetz MJ, Zhi X, Girach A, Davis MD, et al.; PKC-DRS and PCK-DRS2 Study Groups. Oral protein kinase c β inhibition using ruboxistaurin: Efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study and the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study 2. Retina 2011;31:2084-94.  Back to cited text no. 105
    
106.Sheetz MJ, Aiello LP, Shahri N, Davis MD, Kles KA, Danis RP; Mbdv Study Group. Effect of ruboxistaurin (RBX) on visual acuity decline over a 6-year period with cessation and reinstitution of therapy: Results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2). Retina 2011;31:1053-9.  Back to cited text no. 106
    
107.Sheetz MJ, Aiello LP, Davis MD, Danis R, Bek T, Cunha-Vaz J, et al.; MBDL and MBCU Study Groups. The effect of the oral PKC β inhibitor ruboxistaurin on vision loss in two phase 3 studies. Invest Ophthalmol Vis Sci 2013;54:1750-7.  Back to cited text no. 107
    
108.PKC-DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular edema: Thirty-month results of the randomized PKC-DMES clinical trial. Arch Ophthalmol 2007;125:318-24.  Back to cited text no. 108
    
109.Davis MD, Sheetz MJ, Aiello LP, Milton RC, Danis RP, Zhi X, et al.; PKC-DRS2 Study Group. Effect of ruboxistaurin on the visual acuity decline associated with long-standing diabetic macular edema. Invest Ophthalmol Vis Sci 2009;50:1-4.  Back to cited text no. 109
    
110.Warnock GL, Thompson DM, Meloche RM, Shapiro RJ, Ao Z, Keown P, et al. A multi-year analysis of islet transplantation compared with intensive medical therapy on progression of complications in type 1 diabetes. Transplantation 2008;86:1762-6.  Back to cited text no. 110
    
111.Thompson DM, Begg IS, Harris C, Ao Z, Fung MA, Meloche RM, et al. Reduced progression of diabetic retinopathy after islet cell transplantation compared with intensive medical therapy. Transplantation 2008;85:1400-5.  Back to cited text no. 111
    
112.Thompson DM, Meloche M, Ao Z, Paty B, Keown P, Shapiro RJ, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011;91:373-8.  Back to cited text no. 112
    



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