Pharmacotherapy for diabetic retinopathy

Review

Pharmacotherapy for diabetic retinopathy Stephen G Schwartz†, Harry W Flynn Jr & Ingrid U Scott 1. Introduction 2. Local (ocular) agents 3. Systemic agents 4. Conclusion 5. Expert opinion

†Bascom

Palmer Eye Institute at Naples, 311 9th Street North, #100, Naples, FL 34102, USA

Background: Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) continue to cause significant visual loss among patients with diabetes mellitus. In some patients unresponsive to standard laser techniques, as well as improved control of blood pressure and blood sugar, pharmacologic treatment may be beneficial. Although no agent is now approved by the FDA for this purpose, many agents are now being studied in randomized clinical trials (RCTs). Objective: To review concisely the chief pharmacotherapies for diabetic retinopathy available at present. Methods: Literature review and synopsis. Results: Used alone, intravitreal triamcinolone acetonide (IVTA) seems to have some short-term efficacy against DME, but longer-term outcomes (≤ 3 years) using IVTA monotherapy showed a lesser benefit than focal/grid laser treatment in a prospective RCT done by the Diabetic Retinopathy Clinical Research Network. Intravitreal anti-VEGF agents have demonstrated some short-term efficacy against DME, and continuing RCTs will evaluate combination therapies (anti-VEGF and laser) for both DME and PDR. Other agents are being evaluated in pilot studies and Phase II RCTs. Conclusion: Pharmacotherapies for DME and PDR have potential for vision stabilization or improvement. Continuing RCTs will provide evidence-based data on their role in clinical practice. A potential role for pharmacotherapy in the prevention of DME and PDR is also emerging. Keywords: diabetic macular edema, nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, randomized clinical trial, vascular endothelial growth factor Expert Opin. Pharmacother. (2009) 10(7):1123-1131

1. Introduction

Diabetic retinopathy is an important cause of moderate and severe visual loss [1]. Intensive control of systemic factors, including blood sugar, blood pressure, and serum lipids, is beneficial in patients with type 1 [2] or type 2 [3] diabetes mellitus. Although acutely improving metabolic control may cause ‘early worsening’ and exacerbation of retinopathy in some patients, the long-term benefits generally outweigh these risks, especially when control is improved early in the course of the disease [4]. Photocoagulation for diabetic macular edema (DME) [5] and proliferative diabetic retinopathy (PDR) [6] has shown safety and efficacy in large, multicenter, prospective randomized clinical trials (RCTs). Because many patients with diabetic retinopathy continue to lose vision despite photocoagulation, pharmacologic treatments for diabetic retinopathy have been investigated [7]. Many pharmacologic agents are now being studied for the treatment of diabetic retinopathy. These include local (ocular) (Table 1) and systemic agents (Table 2). In general, ocular agents have little or no systemic toxicity, but ocular morbidity may be significant (endophthalmitis, glaucoma, cataract) and bilateral disease requires bilateral treatment, often over an extended period of time. In contrast, systemic agents

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Pharmacotherapy for diabetic retinopathy

2. Local

Table 1. Local (ocular) therapies for diabetic retinopathy. Agent

Current status

Corticosteroids Intravitreal triamcinolone acetonide Published RCTs [8-13,18,19] Triamcinolone intravitreal implant

Completed Phase I RCT

Fluocinolone acetonide intravitreal implant

Completed Phase III RCT [32]

Bioerodable dexamethasone implant

Continuing Phase III RCT

VEGF antagonists Bevacizumab

Published RCTs [35-38]

Ranibizumab

Continuing Phase III RCTs

Pegaptanib

Published Phase II RCT [50]

Aflibercept (VEGF Trap)

Published Phase I RCT [57]

Sirolimus (rapamycin)

Continuing Phase II RCT

Bevasiranib

Completed Phase II RCT

Vitreolytic agents Hyaluronidase


Microplasmin

Continuing Phase III RCT [71]

Other anti-inflammatory agents Nepafenac

Published case series [74]

Etanercept

Published pilot study [76]

Infliximab

Continuing RCT

RCT: Randomized clinical trial.

Table 2. Systemic therapies for diabetic retinopathy. Agent

Current status

Infliximab

Published pilot series [78]

Ruboxistaurin


Fenofibrate

Published RCT [86]

Rosiglitazone

Published case series [91]

Octreotide

Published RCT [94-95]

RCT: Randomized clinical trial.

generally have little or no ocular toxicity, and can provide bilateral treatment, but may cause systemic morbidity. At this time, no pharmacologic agent is approved by the US FDA for the treatment of diabetic retinopathy. The Diabetic Retinopathy Clinical Research (DRCR) Network includes almost 200 participating sites and is evaluating monotherapies and combination treatments for both DME and PDR at present. 1124

(ocular) agents

2.1 Corticosteroids

Intravitreal triamcinolone acetonide (IVTA) is associated with short-term anatomic and visual improvement of DME in several RCTs [8-12]. In the US, there are at least four commercially available preparations of IVTA at present: • Kenalog-40, Bristol-Myers Squibb, Princeton, New Jersey, US • Preservative-free triamcinolone acetonide from compounding pharmacies • Triesence, Alcon, Fort Worth, Texas, US • Trivaris, Allergan, Irvine, California, US In a small, single-center RCT, IVTA was associated with a reduced rate of recurrent vitreous hemorrhage following pars plana vitrectomy [13]. Intravitreal triamcinolone acetonide may be a beneficial adjunct for patients undergoing photocoagulation for PDR, perhaps by decreasing the risk of DME exacerbation [14-16], although no data from RCTs regarding this treatment indication are available at present. The DRCR Network completed a large, multicenter RCT comparing two doses (1 and 4 mg) of IVTA versus photocoagulation for DME [17]. After 2 years of follow-up, treatment with photocoagulation was associated with better visual outcomes and reduced rates of complications compared with IVTA. No patient developed endophthalmitis during this trial. Elevated intraocular pressure was more common in patients treated with 4 mg IVTA (40%) than in patients treated with 1 mg of it (20%) or treated with photocoagulation (10%). Similarly, cataract surgery was more commonly performed within 2 years in patients treated with 4 mg IVTA (51%) than in patients treated with 1 mg of it (23%) or treated with photocoagulation (13%) [18]. Three-year follow-up data were presented on some of these patients, which demonstrated persistent benefits for photocoagulation over IVTA [19]. The most common complication of IVTA is cataract formation [20], which may become visually significant in ∼ 50% of treated eyes within 1 year [21]. Similarly, ∼ 50% of treated eyes develop increased intraocular pressure (IOP) by ≥ 30% or more [22], typically within ∼ 90 days [23]. The etiology of the steroid response is unknown, although it may have a genetic determinant [24]. A pharmacogenomics study found no association between the magnitude of IOP elevation following IVTA and six glucocorticoid receptor polymorphisms [25]. In an analysis of two large RCTs (the DRCR Network and the Standard Care Versus Corticosteroid for Retinal Vein Occlusion [SCORE] trials), the rate of endophthalmitis following IVTA was 0.05% [26]. However, the risk of pseudoendophthalmitis, owing to migration of triamcinolone crystals into the anterior chamber, or possibly secondary to an inflammatory reaction to a preservative or phagocytic response to the crystals, may be higher than that of true infection [27,28]. In an attempt to reduce the risk of these complications, many investigators have studied the use of peribulbar rather

Expert Opin. Pharmacother. (2009) 10(7)

Schwartz, Flynn & Scott

than intravitreal triamcinolone. In a comparative, single-center, prospective RCT, IVTA demonstrated greater efficacy than peribulbar triamcinolone [29]. In a recent prospective, multicenter RCT, the DRCR Network reported that peribulbar triamcinolone did not significantly benefit patients with mild DME and visual acuity of 20/40 or better [30]. To facilitate the long-term treatment of DME, various extended-release corticosteroids have been investigated. Several manufacturers are investigating sustained-release intravitreal or subretinal delivery systems. A triamcinolone-eluting intravitreal implant (I-vation, SurModics, Inc., Eden Prairie, Minnesota, US) has been studied for DME, and a Phase II RCT is planned (Figure 1). A fluocinolone acetonide intravitreal implant (Retisert, Bausch & Lomb, Rochester, New York, US) is FDA-approved for treating chronic, non-infectious posterior segment inflammation [31]. A Phase III RCT done in patients with DME reported high rates of serious adverse events, including cataract and glaucoma [32]. A smaller fluocinolone acetonide intravitreal implant, which may be injected in an office setting (Iluvien, Alimera Sciences, Alpharetta, Georgia, United States), is in a Phase III RCT at present. A bioerodable, extended-release dexamethasone implant in a biodegradable polymer (Posurdex, Allergan, Irvine, California, US) has demonstrated efficacy in the treatment of macular edema owing to various etiologies, including DME, in a recent Phase II study [33]. A Phase III RCT is continuing. 2.2 VEGF

antagonists

Bevacizumab (Avastin, Genentech, Inc., South San Francisco, California, US) is a full-length recombinant humanized antibody against all isoforms of VEGF-A. Bevacizumab is approved by the FDA for the treatment of metastatic colorectal cancer, metastatic breast cancer and non-small cell lung cancer [34]. In several prospective RCTs, including a Phase II study from the DRCR Network, bevacizumab demonstrated favorable short-term anatomic and visual outcomes in patients with DME [35-37]. In a recent comparative RCT, similar treatment outcomes were observed with the intravitreal injection(s) of 1.25 and 2.5 mg bevacizumab, repeated at 3-monthly intervals [38]. In small comparative trials, IVTA seems relatively more effective than bevacizumab for the treatment of DME [39,40], but further studies of anti-VEGF therapies are underway. Bevacizumab also seems to have activity against PDR. A clinical example is shown in Figure 2. A single RCT reported that bevacizumab demonstrated short-term efficacy as an adjunct to photocoagulation in patients with PDR [41]. However, some patients with PDR experience traction retinal detachment following treatment with bevacizumab [42]. Ranibizumab (Lucentis, Genentech, Inc., South San Francisco, California, US) is a recombinant humanized antibody fragment against all isoforms of VEGF-A. Ranibizumab received FDA approval for the treatment of exudative age-related macular degeneration [43,44]. Two pilot studies with

ranibizumab demonstrated favorable outcomes in the treatment of DME [45,46]. The DRCR network is now recruiting patients with DME, and with PDR and DME, for two RCTs comparing ranibizumab, triamcinolone and photocoagulation. A Phase I/II RCT, RESOLVE, compared two doses of ranibizumab with observation in patients with DME, although no results have yet been published in the peer-reviewed literature [47]. A Phase III RCT, RESTORE, will randomize patients with DME into three groups: photocoagulation plus ranibizumab, photocoagulation plus sham injection and ranibizumab plus sham photocoagulation [48]. Pegaptanib (Macugen, Eyetech, New York, NY, US) is a pegylated aptamer with efficacy against the VEGF-A 165 isoform. Pegaptanib received FDA approval for the treatment of exudative age-related macular degeneration [49]. In a Phase II RCT, pegaptanib showed some efficacy in patients with DME [50]. Subsequent analysis of data from this study revealed that, in patients with PDR, treatment with pegaptanib was associated with regression of retinal neovascularization [51]. Phase III trials of pegaptanib for DME are now being done. Similar to bevacizumab, progression of traction retinal detachment following pegaptanib treatment has been reported [52]. In contrast to intravitreal corticosteroids, the risks of IOP elevation and cataract progression associated with intravitreal VEGF antagonists have not been identified. Major RCTs of pegaptanib and ranibizumab reported rates of endophthalmitis in the general range of 1% per eye over 12 – 24 months of injections [43,44,49,53]. However, in these RCTs, most eyes underwent a series of monthly injections, so the risk of endophthalmitis per injection is lower. The use of a standard aseptic protocol for intravitreal injections seems to decrease this risk [54]. For example, in one RCT of pegaptanib for exudative age-related macular degeneration, most of the cases of endophthalmitis occurred following a protocol deviation, such as omitting the use of an eyelid speculum [49]. An observational case series of bevacizumab injections for various etiologies, including DME, reported an incidence of 0.014% per injection [55]. Several other compounds with activity against VEGF are being studied as potential treatments for diabetic retinopathy. Aflibercept, also known as VEGF Trap-Eye (Regeneron, Tarrytown, New York, US), is a recombinant fusion protein active against all VEGF-A isoforms and placental growth factor [56]. It has demonstrated some short-term efficacy for DME in a Phase I trial [57]. Sirolimus, also known as rapamycin (Rapamune, Wyeth, Madison, New Jersey, US), is a macrolide antifungal with pleiotropic effects. It is FDA-approved for several non-ophthalmologic indications. Sirolimus seems to have anti-VEGF properties and shows activity against retinal and choroidal neovascularization in an animal model [58]. Bevasiranib, previously known as Cand5 (OPKO, Miami, Florida, US), is a small interfering RNA agent with activity against VEGF [59].


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is a pro-drug that is converted to amfenac in the anterior chamber [72]. In one animal model [73] and one small case series [74], nepafenac demonstrated some short-term evidence of efficacy against DME and other features of diabetic retinopathy. Etanercept (Enbrel, Amgen, Inc., Thousand Oaks, California, US and Wyeth, Madison, New Jersey, US), a recombinant fusion protein with activity against TNF-α, is FDA-approved for the treatment of psoriatic disease [75]. A pilot study of intravitreal etanercept reported some evidence of efficacy against refractory DME, although statistical significance was not reached in any outcome measure [76]. Infliximab (Remicade, Centocor, Horsham, PA, US), another TNF-α antagonist, is FDA-approved for the treatment of Crohn’s disease and other disorders [77]. On the basis of a pilot study of systemic infliximab used to treat DME [78], a pilot study of intravitreal infliximab is continuing. Figure 1. Triamcinolone-eluting intravitreal implant (I-vation). Image courtesy of SurModics, Inc. (Eden Prairie, Minnesota, US).

2.3 Vitreolytic

agents

Intravitreal purified ovine hyaluronidase (Vitrase, ISTA Pharmaceuticals, Irvine, California, US) was studied to promote the clearance of vitreous hemorrhage from various etiologies, including PDR. A Phase III RCT reported some evidence of efficacy [60] and safety [61]. Subsequent analyses of these data produced a quantitative model to predict clearance of diabetic vitreous hemorrhage following hylauronidase injection [62]. Induction of a posterior vitreous detachment (PVD) is considered to be possibly beneficial in the treatment of DME and PDR [63]. Enzymes that may have efficacy in creating a PVD include hyaluronidase, plasmin, chondroitinase and dispase [64]. In various pilot series, autologous plasmin has been used as a surgical adjunct to pars plana vitrectomy (PPV) techniques in PDR [65,66] and DME [67,68]. In one pilot study, autologous plasmin was used without PPV to treat DME [69]. In an animal model, intravitreal injection of microplasmin, but not hyaluronidase, increases vitreous oxygenation levels [70]. At this time, no data from RCTs have been published regarding plasmin or microplasmin. The Trial of Microplasmin Intravitreal Injection for Non-Surgical Treatment of Focal Vitreomacular Adhesion (MIVI-TRUST) is a Phase III RCT that is actively recruiting patients. Patients will be randomized to receive intravitreal microplasmin or placebo. The primary outcome measure will be anatomic resolution of focal vitreomacular traction at 28 days following injection [71]. 2.4 Other

anti-inflammatory agents

Various anti-inflammatory agents, other than corticosteroids, have been investigated in the treatment of diabetic retinopathy. No data from RCTs are now available with regard to these agents. Nepafenac (Nevanac, Alcon, Fort Worth, Texas, US) is an FDA-approved topical non-steroidal anti-inflammatory drug. It 1126

3. Systemic

agents

3.1 Ruboxistaurin

The beta subunit of Protein kinase C (PKC) may be important in the pathogenesis of diabetic retinopathy [79,80]. Ruboxistaurin (Arxxant, Eli Lilly and Company, Indianapolis, Indiana, US) is an oral antagonist of PKC-β. In large, multicenter RCTs, treatment with ruboxistaurin was associated with a decrease in the incidence of moderate visual loss, defined as a doubling of the visual angle [81], and with a decrease in the incidence of sustained moderate visual loss, defined as moderate visual loss for 6 months [82]. Treatment with ruboxistaurin may be associated with a reduction in the progression of DME [83] and a reduction in the rate of visual loss in patients with DME [84]. At the present time, ruboxistaurin is not FDA-approved for the treatment of diabetic retinopathy. 3.2 Fenofibrate

Fenofibrate (multiple brand names, multiple manufacturers), a fibric acid derivative with pleiotropic effects, is used as a lipid-modifying agent [85]. A large RCT, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, enrolled almost 10,000 patients and reported that patients treated with fenofibrate required less photocoagulation for PDR and DME than did control patients [86]. There were no clinically important differences in the serum lipid profiles between the two groups of patients, implying that the mechanism of action is unrelated to measurable changes in serum lipid levels [87]. The lack of association between serum lipid levels and clinical course of DME is notable, because an earlier case-control study did not find a correlation between the use of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) and the incidence of diabetic retinopathy [88]. 3.3 Rosiglitazone

Rosiglitazone (Avandia, GlaxoSmithKlein, Research Triangle Park, North Carolina, US), a peroxisome proliferator-activated γ ligand, is used commonly in the treatment of type 2 diabetes



A.

B.

Figure 2. A. 25-year-old female with type 1 diabetes mellitus presented with preretinal neovascularization despite prior panretinal photocoagulation. B. The patient was treated with intravitreal bevacizumab. Approximately 1 month later, there was significant improvement in the neovascularization.

mellitus [89]. Peroxisome proliferator-activated γ ligands seem to have antiangiogenic properties [90]. A recent case-control series reported that treatment with rosiglitazone was associated with a reduced rate of progression to PDR [91]. However, in some patients, the use of glitazones is associated with an increased risk of DME and peripheral edema [92]. 3.4 Somatostatin

analogues

Somatostatin, a naturally occurring growth hormone inhibitor, has antiangiogenic effects and is considered to be possibly beneficial against diabetic retinopathy [93]. In various small RCTs, the somatostatin analogue octreotide (Sandostatin, Novartis, Basel, Switzerland) has been associated with decreased rates of progression to high-risk PDR [94], vitreous hemorrhage and the need for vitrectomy [95] in patients with at least severe nonproliferative diabetic retinopathy (NPDR). The benefits of octreotide in patients with earlier stages of NPDR are not as apparent [96]. 4. Conclusion

According to evidence-based medicine, photocoagulation, as well as improved control of hypertension and hyperglycemia, remain standard treatments for DME and PDR. For some patients unresponsive to standard treatments, off-label pharmacologic therapy may be beneficial. Many RCTs are being performed to investigate the safety and efficacy of various pharmacologic agents for the treatment of diabetic retinopathy. As clinical trial data accumulate, the precise roles of these agents will continue to evolve.

5. Expert

opinion

Prevention of sight-threatening DME and PDR is preferable to treatment of established disease. Therefore, intervention may be most effective if instituted earlier in the disease course, before significant retinopathy develops. The FIELD study [86], for example, suggests that early treatment with fenofibrate may reduce the incidence of DME and PDR [97]. Similarly, although ruboxistaurin was not studied in patients with early-stage disease, its mechanism of action may make it suitable for preventative therapy. In patients who develop vision-threatening DME or PDR not responsive to standard treatments, off-label pharmacologic therapy may be considered. The two most widely used agents, because of their availability and relatively low cost, are triamcinolone and bevacizumab. Direct comparative data between bevacizumab and ranibizumab are lacking at present, and bevacizumab is used more widely than ranibizumab for diabetic retinopathy because of its significantly lower cost. Most of the other agents are typically used within the context of a formal clinical trial. Fenofibrate and rosiglitazone are typically prescribed by internists or endocrinologists, rather than by ophthalmologists. In patients with DME not responsive to repeated sessions of photocoagulation, either triamcinolone or bevacizumab may be considered. Triamcinolone may be more efficacious and is less expensive than bevacizumab, but it is associated with risks of cataract and IOP elevation. One reasonable approach for a patient with DME unresponsive to standard treatment is to offer bevacizumab as a second-line therapy. In


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patients unresponsive to bevacizumab as well, triamcinolone may be considered as a third-line option. In patients with PDR and significant media opacity, bevacizumab may provide short-term improvement, although panretinal photocoagulation will eventually be needed for most patients [98]. Bevacizumab may be especially helpful for patients with corneal edema, poor pupillary dilation or dense vitreous hemorrhage precluding photocoagulation. B-scan echography is frequently helpful to rule out retinal detachment before intravitreal injection. In addition, preoperative treatment with bevacizumab may reduce the risk of intraoperative hemorrhage during pars plana vitrectomy. Future avenues of research will include a more thorough understanding of the agents available at present, especially when combined with photocoagulation techniques. For example, the DRCR is now recruiting patients for multiple RCTs. In one trial, patients with DME are randomized into four groups: sham injection plus photocoagulation; ranibizumab plus photocoagulation; ranibizumab plus deferred photocoagulation; or IVTA plus photocoagulation. In the second trial, patients

Bibliography Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1.

2.

3.

4.

5.

6.

Congdon N, O’Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004;122:477-85 Diabetes Control and Complication 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 UK Prospective Diabetes Study 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 Rodriguez-Fontal M, Kerrison JB, Alfaro DV, Jablon EP. Metabolic control and diabetic retinopathy. Curr Diabetes Rev 2009;5:3-7 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 The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8.

1128

with PDR and DME are randomized into three groups: ranibizumab at baseline and at 4 weeks; IVTA at baseline and sham injection at 4 weeks; or sham injection at baseline and at 4 weeks. In this second trial, all patients are treated with focal and panretinal photocoagulation as well. In addition, intravitreal injection is a delivery modality with many disadvantages, including the need for a skilled injector, as well as risks of endophthalmitis, glaucoma, cataract, and so on. Either a depot administration or an alternative delivery route (such as topical administration) may be preferable.

Declaration of interest Partially supported by NIH center grant P30-EY014801 and by an unrestricted grant to the University of Miami from Research to Prevent Blindness, New York, US. SGS has previously received research funding from Genentech, owns equity in Pfizer and is co-holder of a patent pending entitled ‘Molecular targets for modulating intraocular pressure and differentiation of steroid responders versus non-responders’.

The Diabetic Retinopathy Study Research Group. Ophthalmology 1981;88:583-600 7.

Furlani BA, Meyer CH, Rodrigues EB, et al. Emerging pharmacotherapies for diabetic macular edema. Expert Opin Emerg Drugs 2007;12:591-603

8.

Gillies MC, Sutter FK, Simpson JM, et al. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology 2006;113:1533-8

9.

Lam DS, Chan CK, Mohamed S, et al. A prospective randomized trial of different doses of intravitreal triamcinolone for diabetic macular oedema. Br J Ophthalmol 2007;91:199-203

10. Kim JE, Pollack JS, Miller DG, et al.; Isis Study Group. ISIS-DME: a prospective, randomized, dose-escalation intravitreal steroid injection study for refractory diabetic macular edema. Retina 2008;28:735-40 11. Dehghan MH, Ahmadieh H, Ramezani A, et al. A randomized, placebo-controlled clinical trial of intravitreal triamcinolone for refractory diabetic macular edema. Int Ophthalmol 2008;28:7-17 12. Lam DS, Chan CK, Mohamed S, 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


13. Faghihi H, Taheri A, Farahvash MS, et al. Intravitreal triamcinolone acetonide injection at the end of vitrectomy for diabetic vitreous hemorrhage: a randomized, clinical trial. Retina 2008 [Epub ahead of print] 14. Bandello F, Polito A, Pognuz DR, et al. Triamcinolone as adjunctive treatment to laser panretinal photocoagulation for proliferative diabetic retinopathy. Arch Ophthalmol 2006;124:643-50 15. Zacks DN, Johnson MW. Combined intravitreal injection of triamcinolone acetonide and panretinal photocoagulation for concomitant diabetic macular edema and proliferative diabetic retinopathy. Retina 2005;25:135-40 16. Margolis R, Singh RP, Bhatnagar P, Kaiser PK. Intravitreal triamcinolone as adjunctive treatment to laser panretinal photocoagulation for concomitant proliferative diabetic retinopathy and clinically significant macular oedema. Acta Ophthalmol 2008;86:105-10 17. Ip MS, Bressler SB, Antoszyk AN, et al. A randomized trial comparing intravitreal triamcinolone and focal/grid photocoagulation for diabetic macular edema: baseline features. Retina 2008;28:919-30 18. 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 A large, prospective, multicenter randomized clinical trial, done by the Diabetic Retinopathy Clinical Research Network, comparing two doses of intravitreal triamcinolone acetonide to photocoagulation in patients with diabetic macular edema.

19. Beck RW, Edwards AR, et al. Diabetic Retinopathy Clinical Research Network (DRCR.net), 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

preservative-free triamcinolone acetonide. Retin Cases Brief Rep 2008;2:247-9 29. Bonini-Filho MA, Jorge R, Barbosa JC, et al. Intravitreal injection versus sub-Tenon’s infusion of triamcinolone acetonide for refractory diabetic macular edema: a randomized clinical trial. Invest Ophthalmol Vis Sci 2005;46:3845-9 30. Chew E, Strauber S, et al. Diabetic Retinopathy Clinical Research Network, Randomized trial of peribulbar triamcinolone acetonide with and without focal photocoagulation for mild diabetic macular edema: a pilot study. Ophthalmology 2007;114:1190-6

20. Chu YK, Chung EJ, Kwon OW, et al. Objective evaluation of cataract progression associated with a high dose intravitreal triamcinolone injection. Eye 2007 [Epub ahead of print]

31. Jaffe GJ, Martin D, Callanan D, et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology 2006;113:1020-7

21. Thompson JT. Cataract formation and other complications of intravitreal triamcinolone for macular edema. Am J Ophthalmol 2006;141:629-37

32. Fluocinolone acetonide ophthalmic – Bausch & Lomb: fluocinolone acetonide Envision TD implant. Drugs R D 2005;6:116-9

22. Rhee DJ, Peck RE, Belmont J, et al. Intraocular pressure alterations following intravitreal triamcinolone acetonide. Br J Ophthalmol 2006;90:999-1003

33. Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol 2007;125:309-17

23. Smithen LM, Ober MD, Maranan L, Spaide RF. Intravitreal triamcinolone acetonide and intraocular pressure. Am J Ophthalmol 2004;138:740-3 24. Becker B. Intraocular pressure response to topical corticosteroids. Invest Ophthalmol 1965;4:198-205 25. Gerzenstein SM, Pletcher MT, Cervino ACL, et al. Glucocorticoid receptor polymorphisms and intraocular pressure response to intravitreal triamcinolone acetonide. Ophthalmic Genet 2008;29:166-70 26. Bhavsar AR, Ip MS, Glassman AR, DRCRnet and the SCORE Study Groups. The risk of endophthalmitis following intravitreal triamcinolone acetonide injection in the DRCRnet and SCORE clinical trials. Am J Ophthalmol 2007;144:454-6 27. Moshfeghi DM, Kaiser PK, Bakri SJ, et al. Presumed sterile endophthalmitis following intravitreal triamcinolone acetonide injection. Ophthalmic Surg Lasers Imaging 2005;36:24-9 28. Roth DB, Prenner JL, Krajnyk O. Incidence of noninfectious endophthalmitis after intravitreal injection of

34. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427-34 35. Ahmadieh H, Ramezani A, Shoeibi N, et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol 2008;246:483-9 36. Scott IU, Edwards AR, et al. Diabetic Retinopathy Clinical Research Network, A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology 2007;114:186-7 37. Soheilian M, Ramezani A, Bijanzadeh B, et al. Intravitreal bevacizumab (Avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina 2007;27:1187-95


38. Lam DSC, Lai TYY, Lee VYW, et al. Efficacy of 1.25 mg versus 2.5 mg intravitreal bevacizumab for diabetic macular edema: six-month results of a randomized clinical trial. Retina 2009;29:292-9 39. Paccola L, Costa RA, Folgosa MS, et al. Intravitreal triamcinolone versus bevacizumab for treatment of refractory diabetic macular oedema (IBEME study). Br J Ophthalmol 2008;92:76-80 40. Shimura M, Nakazawa T, Yasuda K, et al. Comparative therapy evaluation of intravitreal bevacizumab and triamcinolone acetonide on persistent diffuse diabetic macular edema. Am J Ophthalmol 2008;145:854-61 41. Mirshahi A, Roohipoor R, Lashay A, et al. Bevacizumab-augmented retinal laser photocoagulation in proliferative diabetic retinopathy: a randomized double-masked clinical trial. Eur J Ophthalmol 2008;18:263-9 42. Arevalo JF, Maia M, Flynn HW Jr, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol 2008;92:213-6 43. Rosenfeld PR, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31 44. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-44 45. Chun DW, Heier JS, Topping TM, et al. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 2006;113:1706-12 46. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 2006;142:961-9 47. Available from: http://www.clinicaltrials. gov/ct2/show/NCT00284050?term=ranibi zumab+resolve&rank;1 [Accessed 19 October 2008] 48. Available from: http://www.clinicaltrials. gov/ct2/show/NCT00687804?term+ranibi zumab&rank+4 [Accessed 19 October 2008]

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49. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351(27):2805-16 50. Cunningham ET Jr, Adamis AP, Altaweel M, et al. 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 51. Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113:23-8 52. Krishnan R, Goverdhan S, Lochhead J. Intravitreal pegaptanib in severe proliferative diabetic retinopathy leading to the progression of tractional retinal detachment. Eye 2008 [Epub ahead of print] 53. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology 2006;113:633-42 54. Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections. Retina 2004;24(5 Suppl):S3-19 55. Fung AE, Rosenfeld PJ, Reichel E. The international intravitreal bevacizumab safety survey: using the internet to assess drug safety worldwide. Br J Ophthalmol 2006;90:1344-9 56. Aflibercept: AVE 0005, AVE 005, AVE0005, VEGF Trap – Regeneron, VEGF Trap (R1R2), VEGF Trap-Eye. Drugs R D 2008;9:261-9 57. Do DV, Nguyen QD, Browning DJ, et al. An exploratory study of the safety, tolerability and biological effect of a single intravitreal administration of vascular endothelial growth factor trap-eye in patients with diabetic macular oedema. Br J Ophthalmol 2009;93:144-9 • A Phase I clinical trial of VEGF Trap-Eye in patients with diabetic macular edema. 58. Dejneka NS, Kuroki AM, Fosnot J, et al. Systemic rapamycin inhibits retinal and choroidal neovascularization in mice. Mol Vis 2004;10:964-72 59. Dejneka NS, Wan S, Bond OS, et al. Ocular biodistribution of bevasiranib following a single intravitreal injection to rabbit eyes. Mol Vis 2008;14:997-1005 60. Kuppermann BD, Thomas EL, de Smet MD, Grillone LR. Vitrase for Vitreous

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Hemorrhage Study Groups. 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 61. Kuppermann BD, Thomas EL, de Smet MD, Grillone LR. Vitrase for Vitreous Hemorrhage Study Groups. 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 62. Bhavsar A, Grillone L, McNamara T, et al. Predicting response of vitreous hemorrhage and outcome of photocoagulation after intravitreous injection of highly purified ovine hyaluronidase in patients with diabetes. Invest Ophthalmol Vis Sci 2008 [Epub ahead of print] 63. Lopez-Lopez F, Rodriguez-Blanco M, Gomez-Ulla F, Marticorena J. Enzymatic vitreolysis. Curr Diabetes Rev 2009;5:57-62 64. Gandorfer A. Enzymatic vitreous disruption. Eye 2008;22:1273-7 65. Williams JG, Trese MT, Williams GA, Hartzer MK. Autologous plasmin enzyme in the surgical management of diabetic retinopathy. Ophthalmology 2001;108:1902-5 66. Hirata A, Takano A, Inomata Y, et al. Plasmin-assisted vitrectomy for management of proliferative membrane in proliferative diabetic retinopathy: a pilot study. Retina 2007;27(8):1074-8 67. Azzolini C, D’Angelo A, Maestranzi G, et al. Intrasurgical plasmin enzyme in diabetic macular edema. Am J Ophthalmol 2004;138:560-6 68. Sakuma T, Tanaka M, Inoue J, et al. Use of autologous plasmin during vitrectomy for diabetic maculopathy. Eur J Ophthalmol 2006;16:138-40 69. Diaz-Llopis M, Udaondo P, Garcia-Delpech S, et al. Enzymatic vitrectomy by intravitreal autologous plasmin injection, as initial treatment for diffuse diabetic macular edema. Arch Soc Esp Oftalmol 2008;83:77-84 70. Quiram PA, Leverenz VR, Baker RM, et al. Microplasmin-induced posterior vitreous detachment affects vitreous oxygen levels. Retina 2007;27:1090-6


71. Available from: http://clinicaltrials.gov/ct2/ show/NCT00798317?term+microplasmin+ vitrectomy&rank=3 [Accessed 16/3/09] 72. Gamache DA, Graff G, Brady MT, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I. assessment of anti-inflammatory efficacy. Inflammation 2000;24:357-70 73. Kern TS, Miller CM, Du Y, et al. Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology. Diabetes 2007;56:373-9 74. Hariprasad SM, Callanan D, Gainey S, et al. Cystoid and diabetic macular edema treated with nepafenac 0.1%. J Ocul Pharmacol Ther 2007;23:585-90 75. Ducharme E, Weinberg JM. Etanercept. Expert Opin Biol Ther 2008;8:491-502 76. Tsilimbaris MK, Panagiotoglou TD, Charisis SK, et al. The use of intravitreal etanercept in diabetic macular edema. Semin Ophthalmol 2007;22:75-9 77. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029-35 78. Sfikais PP, Markomichelakis N, Theodossiadis PG, et al. Regression of sight-threatening macular edema in type 2 diabetes following treatment with the anti-tumor necrosis factor monoclonal antibody infliximab. Diabetes Care 2005;28:445-7 79. Aiello LP. The potential role of PKC β in diabetic retinopathy and macular edema. Surv Ophthalmol 2002;47(Suppl 2):S263-9 80. Donnelly R, Idris I, Forrester JV. Protein kinase C inhibition and diabetic retinopathy: a shot in the dark at translational research. Br J Ophthalmol 2004;88:145-51 81. The PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes 2005;54:2188-97 82. PKC-DRS2 Group. Effect of ruboxistaurin on visual loss in patients with diabetic


retinopathy. Ophthalmology 2006;113:2221-30 83. 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 • A large, multicenter, prospective, randomized clinical trial of ruboxistaurin in patients with diabetic macular edema. 84. Davis MD, Sheetz MJ, Aiello LP, et al. Effect of ruboxistaurin on the visual acuity decline associated with long-standing diabetic macular edema. Invest Ophthalmol Vis Sci 2009;50:1-4 85. Keating GM, Croom KF. Fenofibrate: a review of its use in primary dyslipidaemia, the metabolic syndrome and type 2 diabetes mellitus. Drugs 2007;67:121-53 86. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97 • A large, prospective, multicenter, randomized clinical trial of fenofibrate in patients with diabetic retinopathy.

89. Nolan JJ, Jones NP, Patwardhan R, Deacon LF. Rosiglitazone taken once daily provides effective glycaemic control in patients with type 2 diabetes mellitus. Diab Med 2000;17:287-94 90. Xin X, Yang S, Kowalski J, Gerritsen ME. Peroxisome proliferator-activated receptor γ ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 1999;274:9116-21

97. Ansquer JC, Foucher C, Aubonnet P, Le Malicot K. Fibrates and microvascular complications in diabetes – insight from the FIELD study. Curr Pharm Des 2009;15:537-52

91. Shen LQ, Child A, Weber GM, et al. Rosiglitazone and delayed onset of proliferative diabetic retinopathy. Arch Ophthalmol 2008;126:793-9

98. Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006;26:275-8

92. Ryan EH Jr, Han DP, Ramsay RC, et al. Diabetic macular edema associated with glitazone use. Retina 2006;26:562-70 93. Boehm BO. Use of long-acting somatostatin analogue treatment in diabetic retinopathy. Dev Ophthalmol 2007;39:111-21 94. Grant MB, Mames RN, Fitzgerald C, et al. The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy: a randomized controlled study. Diabetes Care 2000;23:504-9

87. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61

95. Boehm BO, Lang GK, Jehle PM, et al. Octreotide reduces vitreous hemorrhage and loss of visual acuity risk in patients with high-risk proliferative diabetic retinopathy. Horm Metab Res 2001;33:300-6

88. Zhang J, Mcgwin G Jr. Association of statin use with the risk of developing diabetic retinopathy. Arch Ophthalmol 2007;125:1096-9

96. Kierkegaard C, Norgaard K, Snorgaard O, et al. Effect of one year continuous subcutaneous infusion of a somatostatin

analogue, octreotide, on early retinopathy, metabolic control and thyroid function in Type I (insulin-dependent) diabetes mellitus. Acta Endocrinol (Copenh) 1990;122:766-72


Affiliation Stephen G Schwartz†1 MD MBA, Harry W Flynn Jr2 MD & Ingrid U Scott3 MD MPH †Author for correspondence 1Assistant Professor of Clinical Ophthalmology University of Miami Miller School of Medicine, Bascom Palmer Eye Institute, 311 9th Street North, #100, Naples, FL 34102, USA Tel: +1 239 659 3937; Fax: +1 239 659 3982; E-mail: [email protected] 2Professor of Ophthalmology University of Miami Miller School of Medicine, Bascom Palmer Eye Institute, 900 Northwest 17th Street, Miami, FL 33136, USA 3Professor of Ophthalmology and Public Health Sciences, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA

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