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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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
Published RCTs [60-61]
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
Published RCTs [81-83]
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
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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
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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
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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’.
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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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