Pharmacotherapies for Diabetic Retinopathy: Present and Future

Diabetic retinopathy remains a major cause of worldwide preventable blindness. Measures to avoid blindness include medical management (control of blood sugar, blood pressure, and serum lipids) and ocular management (laser photocoagulation and pars plana vitrectomy). Adjunctive pharmacologic therapies (intravitreal triamcinolone acetonide and anti-vascular endothelial growth factor agents) have shown early promise in the treatment of both diabetic macular edema and proliferative diabetic retinopathy. Other medications under investigation include the fluocinolone acetonide implantable device, extended-release dexamethasone implant, oral ruboxistaurin, and intravitreal hyaluronidase.


INTRODUCTION
Despite advancements in the delivery of ophthalmological care, diabetic retinopathy remains a major cause of preventable blindness [1]. The two most important visual complications of diabetic retinopathy are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Glycemic control [2,3] and photocoagulation [4,5] have been standard treatments for both DME and PDR for over 3 decades. Nevertheless, some patients suffer permanent visual loss despite prompt and appropriate therapy.
In recent years, further advances in pharmacotherapy have shown promise in the treatment of diabetic retinopathy. The three major classes of medications currently being studied are corticosteroids, vascular endothelial growth factor (VEGF) antagonists, and miscellaneous agents. Multiple clinical series have been reported (Table 1), and many more are ongoing or being planned ( Table 2).

CORTICOSTEROIDS
Corticosteroids may work through multiple mechanisms of action. In addition to their well-known anti-inflammatory effects, corticosteroids may cause downregulation of VEGF [6,7]. Intravitreal triamcinolone acetonide (IVTA) is commonly used today as an off-label adjunctive treatment of DME ( Figure 1). Other intravitreal corticosteroids under study include a sustained-release device containing fluo-2 Experimental Diabetes Research The rates of injection-related endophthalmitis following IVTA have been reported to be in the range of 0.099%-0.87% per injection [21,22]. The incidence of pseudoendophthalmitis, due to migration of triamcinolone acetonide crystals into the anterior chamber, is probably higher than that of infectious endophthalmitis. Other reported complications of IVTA (and of any intravitreal injection) include retinal detachment, lens trauma, and vitreous hemorrhage.
The use of peribulbar, rather than intravitreal, triamcinolone acetonide offers reduced risks of endophthalmitis and perhaps other complications. Peribulbar triamcinolone acetonide may have some limited efficacy for patients with DME [23,24] although the bulk of the current literature appears to indicate that IVTA is more effective [25,26]. DRCR.net has recently published a phase 2 randomized, prospective, multicenter clinical trial comparing peribulbar triamcinolone acetonide with and without photocoagulation. Peribulbar triamcinolone did not significantly improve vision in patients with mild DME [48]. Neither peribulbar triamcinolone nor IVTA appears to offer long-term efficacy for DME, which has led to the investigation of various extended-release corticosteroids.

Fluocinolone acetonide
The fluocinolone acetonide intravitreal implant (Retisert) is FDA-approved for the treatment of chronic, noninfectious posterior segment uveitis [27]. Although the device was also studied in patients with DME, no specific results has been published in the peer-reviewed literature at this time [28].

Extended-release dexamethasone
A bioerodable, extended-release dexamethasone implant (Posurdex, Allergan, Irvine, Calif) has shown favorable outcomes in the treatment of macular edema due to various etiologies, including DME, in a recent phase 2 study [29]. A phase 3 trial is underway.

VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) INHIBITORS
Vascular endothelial growth factor (VEGF) increases retinal vascular permeability, causes breakdown of the blood-retinal barrier, and results in retinal edema [30]. VEGF is upregulated in diabetic retinopathy [31] and is present in increased levels in the aqueous and vitreous humor of patients with PDR [32,33]. At least 5 isoforms of VEGF are known [34]. Three currently available anti-VEGF agents are pegaptanib, bevacizumab, and ranibizumab.

Pegaptanib
Pegaptanib (Macugen, OSI/Eyetech, Melville, NY) is a pegylated aptamer directed against the VEGF-A 165 isoform. It was the first FDA-approved ophthalmologic anti-VEGF agent, for the treatment of choroidal neovascularization from age-related macular degeneration (AMD) [35]. In a phase 2, prospective clinical trial, pegaptanib appeared to improve anatomic and visual outcomes in patients with DME [36].
Retrospective analysis of these data demonstrated some efficacy on retinal neovascularization as well [37]. Phase 3 trials of pegaptanib for DME are currently being conducted.

Bevacizumab
Bevacizumab (Avastin, Genentech, Inc., South San Francisco, Calif), a full-length recombinant humanized antibody, is active against all isoforms of VEGF-A. It is FDA-approved as an adjunctive systemic treatment for metastatic colorectal cancer [49]. Although off-label systemic bevacizumab has demonstrated some efficacy for exudative AMD [50], the agent has shown greater promise as an intravitreal medication. Case reports and small observational series have been reported using off-label intravitreal bevacizumab to treat exudative AMD [51], macular edema from nonischemic central retinal vein occlusion [52], iris neovascularization [53,54], pseudophakic cystoid macular edema [55], and other diseases. Small, nonrandomized pilot studies have documented some efficacy against diffuse DME [56] and various complications of PDR [38][39][40] (Figure 2). DRCR.net has completed enrollment on a phase 2, prospective, randomized, multicenter clinical trial to determine the safety and possible benefits of this agent. Plans for a phase 3 trial of two doses of an intravitreal anti-VEGF agent versus modified ETDRS grid laser photocoagulation for DME are under discussion.
The risk of injection-related endophthalmitis with the anti-VEGF agents is variable, but appears to be lower in more recent studies. Major prospective clinical trials of pegaptanib and ranibizumab reported rates between 0.7%-1.6% per eye [35,[57][58][59]. Most eyes in these reports received a series of injections, and a recent observational case series reported an incidence of 0.014% per injection for bevacizumab [60].

Ruboxistaurin
The enzyme protein kinase C β (PKC β) is activated by VEGF and appears to increase various systemic complications, in-cluding diabetic retinopathy [61]. Ruboxistaurin (Arxxant, Eli Lilly and Company, Indianapolis, Ind), an orally administered PKC β inhibitor, has shown efficacy against DME in two separate phase 3 trials [43,44], although a recent study reported that treatment did not delay disease progression over Table 3: Guidelines for pharmacologic treatment of advanced diabetic retinopathy.
(A) Clinically significant macular edema (CSME) Experimental Diabetes Research a 30-month followup [45]. A smaller study noted that ruboxistaurin treatment was associated with a reduction in retinal vascular leakage, as measured by vitreous fluorometry, but visual acuity was not affected [46]. Although Lilly received an approvable letter from the FDA on August 18, 2006, the FDA requested an additional, 3-year, Phase 3 clinical trial to collect additional efficacy data in spite of an appeal with additional data.

Hyaluronidase
In an attempt at pharmacologic vitreolysis, intravitreal purified ovine hyaluronidase (Vitrase, ISTA Pharmaceuticals, Irvine, Calif) was proposed to accelerate clearance of vitreous hemorrhage from PDR and other causes. A recent phase 3 prospective clinical trial showed some favorable efficacy [47] and safety [62] outcomes for the clearance of vitreous hemorrhage due to all causes, but this agent is not currently FDAapproved for this indication.

CLINICAL GUIDELINES
Although none of the pharmacologic agents discussed above is FDA-approved for treatment of patients with diabetic retinopathy, off-label treatment can be considered for patients unresponsive to traditional standard care. These guidelines are summarized in Table 3.
In patients with diabetic macular edema not responsive to photocoagulation, either IVTA or an intravitreal anti-VEGF agent may be considered as second-line treatments. At this time, there are no published head-to-head comparisons of IVTA versus the anti-VEGF agents for this disease, although the pending DRCR.net trials may provide useful guidelines in this regard. Triamcinolone may be relatively more efficacious for DME, while the anti-VEGF agents appear more efficacious for PDR. Triamcinolone is considerably less expensive than the anti-VEGF agents, but is associated with risks of elevated IOP, cataract, and pseudoendophthalmitis.
In patients with complications of PDR not amenable to photocoagulation, intravitreal anti-VEGF agents may produce short-term stabilization or regression of iris and/or retinal neovascularization. In most patients, however, photocoagulation will eventually be necessary.
Intravitreal anti-VEGF agents may be helpful in patients with dense vitreous hemorrhage and patients with glaucoma secondary to neovascularization. If B-scan echography shows no evidence of retinal detachment, these agents may provide useful short-term anatomic improvement, until definitive photocoagulation can be given, or to reduce intraoperative bleeding in eyes with neovascular glaucoma.

SUMMARY
Clinical experience with pharmacologic treatment for diabetic retinopathy continues to increase and reported outcomes in observational case series are promising. At this time, improved metabolic control and local ocular treatments (photocoagulation and vitrectomy) remain the proven treatments, through evidence-based medicine. As prospective randomized clinical trials accumulate data, the role of pharmacologic treatments will become clearer.