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DIABETIC RETINOPATHY UPDATE

Advances in the treatment of diabetic retinopathy

Ahmed M. Abu El-Asrar, MD, PhD

*

, Hani S. Al-Mezaine, MD

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

Received 20 January 2011; accepted 22 January 2011 Available online 28 January 2011

KEYWORDS Diabetic retinopathy; Treatment;

Review

Abstract Diabetic retinopathy, the most common long-term complication of diabetes mellitus, remains one of the leading causes of blindness worldwide. Strict metabolic control, tight blood pres-sure control, laser photocoagulation, and vitrectomy remain the standard care for diabetic retinop-athy. Focal/grid photocoagulation is a better treatment than intravitreal triamcinolone acetonide in eyes with diabetic macular edema and should be considered as the first-line therapeutic option. The current evidence suggests that intravitreal triamcinolone acetonide or anti-vascular endothelial growth factor agents result in a temporary improvement of visual acuity and a short-term reduction in central macular thickness in patients with refractory diabetic macular edema and are an effective adjunctive treatments to laser photocoagulation or vitrectomy. However, triamcinolone is associ-ated with risks of elevassoci-ated intraocular pressure and cataract. Vitrectomy with the removal of the posterior hyaloid without internal limiting membrane peeling seems to be effective in eyes with per-sistent diffuse diabetic macular edema, particularly in eyes with associated vitreomacular traction. Emerging therapies include islet cell transplantation, fenofibrate, ruboxistaurin, pharmacologic vit-reolysis, rennin-angiotensin system blockers, and peroxisome proliferator-activated receptor gamma agonists.

ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

* Corresponding author. Address: Department of Ophthalmology, King Abdulaziz University Hospital, Old Airport Road, P.O. Box 245, Riyadh 11411, Saudi Arabia. Tel.: +966 1 4775723; fax: +966 1 4775724.

E-mail address: abuasrar@KSU.edu.sa (A.M. Abu El-Asrar).

1319-4534ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

Peer review under responsibility of King Saud University. doi:10.1016/j.sjopt.2011.01.005

Production and hosting by Elsevier

King Saud University

Saudi Journal of Ophthalmology

www.saudiophthaljournal.com www.ksu.edu.sa

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Contents

1. Introduction . . . 114

2. Evidence-based patient care . . . 114

2.1. The diabetes control and complications trial (DCCT) . . . 114

2.2. The United Kingdom prospective diabetes study (UKPDS) . . . 114

2.3. The diabetic retinopathy study (DRS). . . 115

2.4. The early treatment diabetic retinopathy study (ETDRS) . . . 115

2.5. The diabetic retinopathy vitrectomy study (DRVS) . . . 115

3. Emerging therapies . . . 115

3.1. Intravitreal triamcinolone acetonide . . . 115

3.2. Anti-vascular endothelial growth factor (VEGF) treatment. . . 116

3.2.1. Pegaptanib. . . 116

3.2.2. Ranibizumab . . . 116

3.2.3. Vascular endothelial growth factor Trap-Eye . . . 117

3.2.4. Bevacizumab . . . 117

3.3. Vitrectomy for persistent diffuse diabetic macular edema . . . 117

3.4. Pharmacologic vitreolysis in the management of diabetic retinopathy . . . 118

3.5. Fibrates . . . 118

3.6. Renin-angiotensin system (RAS) blockers . . . 118

3.7. Peroxisome proliferator-activated receptor gamma (PPAR-c) agonists . . . 118

3.8. Ruboxistaurin. . . 119

3.9. Islet cell transplantation . . . 119

Acknowledgments . . . 119

References . . . 119

1. Introduction

Diabetic retinopathy is the most common microvascular com-plication 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 diabetic retinopathy are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). The prevalence of diabetic retinopathy in-creases 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 Epidemiol-ogic Study of Diabetic Retinopathy (WESDR), 3.6% of youn-ger-onset patients (type 1 diabetes) and 1.6% of older-onset patients (type 2 diabetes) were legally blind (Fong et al., 2003). 2. Evidence-based patient care

Five large randomized controlled trials provide the scientific basis for care in the diabetic patient to preserve vision. 2.1. The diabetes control and complications trial (DCCT) The 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 diabetic retinopathy by 76% and progression of diabetic ret-inopathy by 54%, as compared with the conventional treat-ment (DCCT, 1993). Long-term observational DCCT data showed that despite gradual equalization of HbA1c values after study termination, the rate of diabetic retinopathy progression in the former intensively treated group remained significantly lower than in the former conventional group

(‘‘metabolic memory’’) (White et al., 2008), emphasizing the importance of instituting tight glycemic control early in the course of diabetes.

Tight glycemic control has two clinically important adverse effects. First, there is risk of early worsening of diabetic reti-nopathy. 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 18th month, and no case of early worsening resulted in serious visual loss. In the DCCT, the long-term benefits of intensive insulin treatment greatly out-weighted the risks of early worsening of diabetic retinopathy. 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 con-trol, particularly if retinopathy is at or past the moderate non-proliferative stage. In patients whose retinopathy is al-ready approaching the high-risk stage, it may be prudent to de-lay the initiation of intensive treatment until photocoagulation can be completed, particularly if the HbA1c level is high (DCCT, 1998). Second, tight glycemic control was associated with more frequent severe hypoglycemic episodes compared to the conventional group (DCCT, 1993).

2.2. The United Kingdom prospective diabetes study (UKPDS) The 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 diabetic reti-nopathy was reduced by 21% and the need for laser photoco-agulation by 29% in the intensive versus the conventional treatment group (UKPDSGroup 33, 1998). The UKPDS also investigated the influence of tight blood pressure control. A

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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% re-duced risk of deterioration in visual acuity of three lines com-pared with the less tight control group (UKPDSGroup 38, 1998).

2.3. The diabetic retinopathy study (DRS)

The DRS investigated whether scatter (panretinal) photocoag-ulation, 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 ben-efit persisted through the entire duration of follow-up and was greatest among patients whose eyes had high-risk characteris-tics (Anonymous, 1978). Recently, the Diabetic Retinopathy Clinical Research Network compared the effects of single-sitting versus 4-single-sitting panretinal photocoagulation on macular edema in subjects with severe nonproliferative or early prolif-erative diabetic retinopathy 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 fol-lowing application in 1 sitting compared with 4 sittings (

Dia-betic Retinopathy Clinical Research Network, 2009a,b). 2.4. The early treatment diabetic retinopathy study (ETDRS) The ETDRS demonstrated that focal/grid laser photocoagula-tion reduced the risk of moderate vision loss (that is, a dou-bling of the visual angle) from clinically significant macular edema by 50% or more (ETDRS, 1985). 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 prolifera-tive retinopathy (Ferris, 1996).

A recent randomized controlled trial compared modified ETDRS direct/grid photocoagulation technique and mild mac-ular grid (MMG) laser technique in which microaneurysms are not treated directly and small mild burns are placed through-out 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 photocoagula-tion should continue to be a standard approach for treating DME (WritingCommittee for the Diabetic Retinopathy Clin-ical Research Network, 2007). Recently, the Diabetic Retinop-athy Clinical Research Network concluded that focal/grid photocoagulation remains the standard management for dia-betic macular edema (Aiello et al., 2010).

2.5. The diabetic retinopathy vitrectomy study (DRVS) The DRVS randomized 616 eyes with recent vitreous hemor-rhage reducing visual acuity to 5/200 or less for at least one month to undergo early vitrectomy within 6 months or deferral of vitrectomy for one year. After two 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 vi-sual acuity of 10/20 or better (36% versus 12% in the deferral group). No such advantage was found in the type 2 diabetes group (16% in the early group versus 18% in the deferral group) (DRVS, 1985).

The DRS and the ETDRS showed that laser photocoagula-tion for diabetic retinopathy is effective at slowing the progres-sion 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 (Fong et al.,

2003).

3. Emerging therapies

Due to the limitations of the current treatments, new therapeu-tic approaches are being developed.

3.1. 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 which carry risk and are inconvenient for patients (Kang et al., 2006). This early disappearance of the effect of IVTA might be consistent with the results reported byBeer et al. (2003), who calculated that measurable concentrations of triamcinolone could be ex-pected to last no longer than 3 months in nonvitrectomized eyes.

In a prospective randomized controlled trial, eyes with per-sistent 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 P5 mmHg was ob-served 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 trabecu-lectomy. There was one case of infectious endophthalmitis in the treatment group (Gillies et al., 2006).

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 approx-imately three lines of visual acuity was achieved 1 month post injection (Rudnisky et al., 2009; Yilmaz et al., 2009).

The Diabetic Retinopathy Clinical Research Network

(2008) reported 2-year results of a multicenter randomized clinical trial comparing preservative free IVTA and focal/grid

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laser for DME. In this study, 840 eyes were randomized to fo-cal/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 to 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 1-4-mg IVTA group (23%) and the laser group (13%). Increased intraocular pressure from the 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

Dia-betic Retinopathy Clinical Research Network (2009) reported that the 3-year visual outcome results were consistent with the previously published 2-year results. The cumulative probabil-ity of cataract surgery by 3 years was 31%, 46%, and 83% in the laser and 1-mg 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 photocoag-ulation 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 photoco-agulation 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 (Diabetic

Retinop-athy Clinical Research Network, 2008).

More recently, the Diabetic Retinopathy Clinical Research Network reported that IVTA (4 mg) appeared to reduce the risk of progression of diabetic retinopathy. However, the study concluded that use of IVTA to reduce the likelihood of pro-gression 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 (Bressler et al.,

2009).

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 thick-ness and total macular volume when compared with laser photocoagulation alone for the treatment of PDR and macular edema (Lam et al., 2007; Maia et al., 2009). On the other hand, a recent study demonstrated no beneficial effect of combined IVTA plus panretinal photocoagulation and macular photoco-agulation in eyes with coexisting high-risk PDR and clinically significant macular edema as compared with panretinal photo-coagulation and macular photophoto-coagulation as standard treat-ment in those patients (Mirshahi et al., 2010).

Recently, two studies compared the morphological and vi-sual acuity outcomes associated with a single intravitreal injec-tion 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 had the advantage of intraocular pressure stabil-ity compared with the triamcinolone injection (Paccola et al.,

2008; Shimura et al., 2008).

3.2. Anti-vascular endothelial growth factor (VEGF) treatment Currently, there are four anti-VEGF agents which have been used in the management of diabetic retinopathy, including pegaptanib (Macugen; Pfizer, Inc., New York, USA), ranibizumab (Lucentis; Genentech, Inc., South San Francisco, California, USA), bevacizumab (Avastin; Genentech, Inc.), and VEGF Trap-Eye (Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA).

3.2.1. 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 photocoag-ulation therapy (Cunningham et al., 2005). A retrospective analysis of the same study on patients with retinal neovascular-ization at the baseline showed regression of neovascularneovascular-ization after intravitreal pegaptanib administration (Adamis et al.,

2006). Recently,Querques et al. (2009)demonstrated in a ret-rospective study that repeated intravitreal pegaptanib pro-duced significant improvement in best-corrected visual acuity and reduction in mean central macular thickness in patients with diabetic macular edema. In addition, Gonza´lez et al.

(2009) showed that intravitreal pegaptanib produced short-term marked and rapid regression of diabetic retinal neovascu-larization. These data suggest that VEGF blockade may be a safe and efficacious adjuvant treatment to panretinal photoco-agulation in PDR.

3.2.2. Ranibizumab

Ranibizumab is a recombinant humanized monoclonal anti-body fragment with specificity for all isoforms of human VEGF-A. Pilot studies of intravitreal ranibizumab demon-strated reduced foveal thickness and maintained or improved vi-sual acuity in patients with DME (Chun et al., 2006). Recently, Nguyen et al. (2009) demonstrated that during a span of 6 months, repeated intravitreal injections of ranibizumab pro-duced a significantly better visual outcome than focal/grid laser treatment in patients with DME. The Diabetic Retinopathy

Clinical Research Network (2010a) evaluated intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with fo-cal/grid laser compared with fofo-cal/grid laser alone for treatment of diabetic macular edema. The 1-year mean change (±stan-dard deviation) in the visual acuity letter score from the 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 the baseline, visual acuity improvement in the triamcino-lone + prompt laser group appeared comparable to that in the ranibizumab groups. Two-year visual acuity outcomes were similar to 1-year outcomes. Elevated intraocular pressure and cataract surgery were more frequent in the triamcino-lone + prompt laser group and 0.8% had injection-related

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endophthalmitis in the ranibizumabn group. Nguyen et al. (2010), in a randomized study, showed that intraocular injection of ranibizumab provided benefit for diabetic macular edema 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.

3.2.3. Vascular endothelial growth factor Trap-Eye

VEGF Trap is a 115 kDa recombinant fusion protein consist-ing of the VEGF bindconsist-ing domains of human VEGF receptors 1 and 2 fused to the Fc domain of human IgG1. One pilot study showed that a single intravitreal injection of VEGF Trap-Eye was well tolerated and was effective in patients with DME (Do et al., 2009).

3.2.4. Bevacizumab

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

To date, all studies regarding IVB (1.25 mg) for DME ther-apy, have demonstrated transient beneficial effects with a requirement for repeated injections (Arevalo et al., 2009a;

Roh et al., 2008; Fang et al., 2008; Lam et al., 2009). Increased visual acuity with decrease in macular edema with a single injec-tion of IVB lasts for 4 to 6 weeks with deteriorainjec-tion of visual acuity and recurrence of macular edema 8 to 12 weeks later necessitating another injection (Roh et al., 2008; Paccola

et al., 2008).Fang et al. (2008)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. (2007)reported that IVB in DME has no effect on visual acuity and macular edema in previously vitrectomized eyes. Similarly,Lam et al. (2009) dem-onstrated that IVB was more effective in eyes without previous DME treatment, which included focal or grid laser photocoag-ulation. Two recent studies demonstrated that IVB at doses of 1.25 and 2.5 mg seems to have similar treatment efficacy in pa-tients with DME (Lam et al., 2009; Arevalo et al., 2009a). Bonini-Filho et al. (2009) 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. (2009) reported that IVB in patients with DME yielded a better visual outcome 24 weeks later compared with macular photocoagulation.

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 (Arevalo et al., 2009b; Jiang et al., 2008; Wakabayashi

et al., 2008). In addition, IVB injection was demonstrated to be an effective adjunctive treatment to PRP in the treatment of high-risk PDR (Tonello et al., 2008; Cho et al., 2009), and neovascular glaucoma (Wakabayashi et al., 2008). Intravitreal bevacizumab 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 (Tonello et al., 2008; Cho et al., 2009). In addition,Huang et al. (2009)demonstrated that IVB injec-tion 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 complica-tions 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 (Ahmadieh

et al., 2009; di Lauro et al., 2010). However, tractional retinal detachment may occur or progress shortly following adminis-tration of IVB in these patients (Arevalo et al., 2008). Two re-cent studies demonstrated that IVB injection pretreatment for diabetic vitrectomy did not influence rates of postoperative vit-reous hemorrhage or final visual acuity (Romano et al., 2009;

Lo et al., 2009). Several studies determined the clinical effec-tiveness of IVB combined with cataract surgery for the man-agement 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 (Takamura et al., 2009;

Lanzagorta-Aresti et al., 2009).

3.3. Vitrectomy for persistent diffuse diabetic macular edema Vitrectomy with removal of the premacular posterior hyaloid for persistent diffuse macular edema has gained rapid wide-spread acceptance. The large number of series evaluating the efficacy of vitrectomy (with or without internal limiting mem-brane peeling) has yielded conflicting results. In a prospective randomized trial,Stolba et al. (2005)showed that vitrectomy with internal limiting membrane peeling was superior to obser-vation in eyes with persistent diffuse diabetic macular edema 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 with-out internal limiting membrane peeling may provide anatomic and visual benefit in eyes with diffuse nontractional unrespon-sive DME refractory to laser photocoagulation (Kumagai

et al., 2009; Yamamoto et al., 2007). Best corrected visual acuity continued to improve until 1 year postoperatively and is main-tained long term (Kumagai et al., 2009; Yamamoto et al.,

2007). The preoperative best corrected visual acuity was the best prognostic factor for final best corrected visual acuity (Kumagai

et al., 2009; Yamamoto et al., 2007). On the other hand, 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 (Shah et al., 2006; Figueroa

et al., 2008). Macular detachment on optical coherence tomog-raphy was suggested to be an adverse predictive indicator (Shah

et al., 2006). The Diabetic Retinopathy Clinical Research

Network (2010b) evaluated vitrectomy for diabetic macular ede-ma associated with vitreoede-macular traction. At 6 months, med-ian 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 P10 letters in 38% and deteriorated by P10 letters in 22%. The factors associated with favorable outcomes after vitrectomy for diabetic macular edema were also evaluated (Flaxel et al., 2010). Greater visual acuity improvement

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occurred in eyes with worse baseline acuity and in eyes in which an epiretinal membrane was removed. Greater reduction in cen-tral subfield thickness occurred with worse baseline visual acu-ity, 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 out-come after vitrectomy with or without internal limiting mem-brane peeling (Kumagai et al., 2009; Shiba et al., 2009). 3.4. Pharmacologic vitreolysis in the management of diabetic retinopathy

Our enhanced understanding of the role of the vitreous body in diabetic retinopathy has led investigators to use pharmacologic vitreolysis in the management of diabetic retinopathy. 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 (Kuppermann et al., 2005a,b). No serious safety issues were reported (Kuppermann

et al., 2005a,b). In particular, the incidence of retinal detach-ment was not statistically different between treated eyes and control groups.

Quiram et al. (2007)demonstrated that intravitreal injec-tion of microplasmin with inducinjec-tion of the combinainjec-tion of posterior vitreous detachment (PVD) and vitreous liquefaction increased intravitreal oxygen tension. On the other hand, hyal-uronidase-induced vitreous liquefaction without PVD induc-tion 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 to control or hyaluronidase treated eyes. These findings suggest that the beneficial effects of surgical vitrectomy in increasing oxygen tension in the vitre-ous cavity (Stefa´nsson, 2009) may be reproduced with enzy-matic induction of PVD and vitreous liquefaction without the time, risks, and expense of surgery.

It is more difficult to separate the vitreous cortex from the internal limiting membrane in diabetic eyes than in nondia-betic eyes. This is likely due to the effects of diabetes on the macromolecules of vitreous and the structural consequences (Zhi-Liang et al., 2009). In an experimental rat model of diabe-tes, the combination of hyaluronidase causing vitreous lique-faction and plasmin acting as a PVD inducer was more effective than plasmin alone in inducing complete PVD (

Zhi-Liang et al., 2009).

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 the eyes with DME secondary to posterior vitreous cortex contraction (Sakuma et al., 2006;Azzolini et al., 2004; Asami et al., 2004). Plasmin-assisted vitrectomy allowed a more complete and less traumatic posterior vitreous cortex removal with a smooth ret-inal surface. The internal limiting membrane removed during the plasmin-assisted vitrectomy from eyes with diabetic macu-lar edema 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 (Asami et al., 2004). Autologous plas-min enzyme was also beneficial in the surgical management of PDR. The proliferative membranes became softened and were easily peeled without retinal tears (Hirata et al., 2007).

Recently,Diaz-Llopis et al. (2009)demonstrated that intra-vitreal injection of autologous plasmin enzyme without the performance of vitrectomy induced complete PVD and effec-tively reduced macular thickening due to refractory diffuse dia-betic macular edema and improved visual acuity. Therefore, atraumatic pharmacologic separation of the posterior vitreous cortex with clean cleavage between the internal limiting mem-brane and the posterior hyaloids without performing a vitrec-tomy can reduce the risk of intraoperative iatrogenic damage such as retinal tears, and damage to the nerve fibers, and the postoperative sequelae.

3.5. Fibrates

Fibrates are widely prescribed lipid-lowering drugs in the treat-ment 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 triglycer-ides 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 diabetic retinopathy 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 (Keech

et al., 2007). Recently,ACCORD Study Group (2010) demon-strated that fenofibrate for intensive dyslipidemia therapy re-duced the rate of progression of diabetic retinopathy in persons with type 2 diabetes (ACCORDStudy Group, 2010). 3.6. Renin-angiotensin system (RAS) blockers

Several studies suggested that RAS blockers might reduce the burden of diabetic retinopathy. 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 lisin-opril could reduce both incidence and progression of retinop-athy in type 1 diabetes (Chaturvedi et al., 1998). Recently, the Diabetic Retinopathy Candesartan Trials (DIRECT) dem-onstrated that the angiotensin-receptor antagonist candesartan reduced the incidence of retinopathy in patients with type 1 diabetes (Chaturvedi et al., 2008), and might induce improve-ment of retinopathy in type 2 diabetic patients with mild-to-moderate retinopathy (Sjølie et al., 2008).

3.7. Peroxisome proliferator-activated receptor gamma (PPAR-c) agonists

The PPARc agonist rosiglitazone inhibited both the retinal leukostasis and retinal leakage observed in the experimental diabetic rats. In addition, the decreased expression of the endogenous PPARc in mice leads to the aggravation of retinal leukostasis and retinal leakage in diabetic mice (Muranaka

et al., 2006). Rosiglitazone maleate (Avandia; GlaxoSmithK-line, North Carolina, USA) is an orally administered medication used to improve glycemic control in patients with

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diabetes mellitus. This medication activates the PPARc and leads to insulin sensitization in adipose and other tissues, with potential antiangiogenic activity. Recently,Shen et al. (2008)

demonstrated that rosiglitazone may delay the onset of PDR in patients with severe nonproliferative diabetic retinopathy at the baseline. Several studies showed that the use of glitazone class of drugs was associated with DME (Fong and Contreras,

2009). However, another retrospective study concluded that rosiglitazone is not linked to DME (Tatti et al., 2008). 3.8. Ruboxistaurin

Hyperglycemia activates protein kinase C (PKC) by inducing de novo synthesis of diacylglycerol, a physiologic activator of PKC. Substantial data suggest that the b isoform may play an important role in the development of diabetic microvascular complications. Increased PKC b isoform activity induces retinal vascular permeability and neovascularization in animal models. Roboxistaurin (RBX) (LY333531; Lilly Research Laboratories, Indianapolis, Indiana, USA) is a PKC b-selective inhibitor with adequate bioavailability to permit oral administration once dai-ly. In the Protein Kinase C b inhibitor-Diabetic Retinopathy Study 2 (PKC-DRS2), oral administration of RBX (32 mg per day) reduced sustained moderate visual loss, need for laser treat-ment for macular edema, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy (PKC-DRS2 Group, 2006). In the Protein Kinase C b inhibitor Diabetic Macular Edema Study (PKC-DMES), RBX treatment also showed a beneficial effect on DME progression relative to placebo (PKC-DMES Study

Group, 2007). More recently,Davis et al. (2009)demonstrated that RBX treatment appears to ameliorate DME-associated vi-sual decline.

3.9. Islet cell transplantation

Recent studies demonstrated that improved islet transplant outcomes could be observed with enhanced islet isolation, glu-cocorticoid-free immunosuppression, and provision of an ade-quate islet mass of more than 10,000 islet equivalents per kg of body weight. These improvements have resulted in benefits to type 1 diabetic subjects, including long-term c-peptide secre-tion, improved glycemic control, and reduced hypoglycemic episodes. Recently, it was demonstrated that islet transplanta-tion yields improved HbA1c and less progression of retinopa-thy compared with intensive medical therapy during 3 years of follow-up (Warnock et al., 2008; Thompson et al., 2008).

Acknowledgments

The authors thank Ms. Connie B. Unisa-Marfil for secretarial work.

Supported in part by Medical Research Chair funded by Dr. Nasser Al-Rasheed (AMA).

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References

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