Diabetic Macular Edema: Treatment Updates 2008

COVER STORY Diabetic Macular Edema: Treatment Updates 2008

BY ALBERTO A. GUARDIOLA, MD; AND MIGUEL A. BUSQUETS MD, FACS

he World Health Organization (WHO) estimates control, as demonstrated by the Diabetes Control and that 15 million people in the United States have Complications Trial (DCCT)2 and the United Kingdom diabetes, with half of these cases undiagnosed. In Prospective Diabetes Study.3 T addition, about 50% of the 8 million patients In the DCCT, intensive glucose control reduced the risk diagnosed with diabetes do not receive appropriate eye of onset of DME by 23% compared with conventional care. Consequently, diabetic retinopathy (DR) continues to treatment. Long-term follow-up of patients in the DCCT be a leading cause of new blindness in the United States. showed a sustained effect of intensive glucose control, Blindness from DR usually results from non-resolving vitre- with a 58% risk reduction in the development of diabetic ous hemorrhage, traction retinal detachment or diabetic macular edema for the DCCT patients followed in the macular edema (DME).1 Epidemiology of Diabetes Interventions and Diabetic macular edema is the result of retinal microvas- Complications Study.4 cular changes that occur in patients with diabetes. Thickening of the basement membrane and reduction in FOCAL/GRID LASER PHOTOCOAGULATION the number of pericytes is believed to lead to increased per- Laser photocoagulation continues to be a well proven meability and incompetence of retinal vasculature. This therapy to reduce the risk of vision loss from DME, as compromise of the blood-retinal barrier leads to the leakage demonstrated by the Early Treatment Diabetic of plasma constituents in the surrounding retina, resulting Retinopathy Study (ETDRS).5 In the ETDRS, laser photo- in retinal edema. The hypoxic state achieved through this coagulation reduced the risk of moderate visual loss from mechanism can also stimulate the production of vascular diabetic macular edema by 50% (from 24 to 12% 3 years endothelial growth factor (VEGF). Macular edema affects after initiation of treatment). Focal laser treatment also approximately 29% of patients with diabetes who have dis- increased the chance for visual improvement, with 16% ease duration of 20 years or longer and constitutes the pri- of patients gaining more than one line of acuity. mary cause of visual impairment in this population. For 30 The Diabetic Retinopathy Clinical Research Network years, the standard of treatment has been glycemic control reported results from a study comparing focal/grid photo- and photocoagulation. Despite this, some patients suffer coagulation and intravitreal triamcinolone for the treat- permanent visual loss even after intensive treatment. ment of DME. They concluded that over a 2 year period New advances in pharmacotherapy and surgical tech- focal/grid photocoagulation is more effective and has fewer niques have shown promise in the treatment of DME. side effects than 1-mg or 4-mg doses of preservative-free The following is a review of the newest and most com- intravitreal triamcinolone for most patients with DME.6 mon treatment options available today. INTRAVITREAL TRIAMCINOLONE MEDICAL CONTROL OF SYSTEMIC ACETONIDE CONDITIONS Intravitreal triamcinolone acetonide (IVTA) has been Currently, the only proven means to reduce the risk of reported widely in the literature for the treatment of dif- vision loss from DME continues to be intense glycemic fuse, refractory DME.7-11 The rationale for the use of cor-

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ticosteroids in this condition stems from the observa- upregulated in diabetic retinopathy and is present in tions that DME may be caused by VEGF, a 45 kda glyco- increased levels in the aqueous and vitreous humors of protein. Antonetti et al11 demonstrated that phosphory- patients with PDR. At least five isoforms of VEGF are lation of tight junction proteins such as occludin and known. Three currently available anti-VEGF agents are zonula occludens was regulated by VEGF-induced vessel pegaptanib, bevacizumab, and ranibizumab.17 permeability. Pegaptanib sodium. Pegaptanib sodium (Macugen, Corticosteroids have been demonstrated to inhibit OSI/Eyetech) is a pegylated aptamer directed against the the expression of the VEGF gene. In a study by Nauck et VEGF-A165 isoform. It was the first US Food and Drug al,12 the platelet-derived growth factor-induced expres- Administration (FDA)-approved ophthalmologic anti- sion of the VEGF gene in cultures of human aortic vas- VEGF agent for the treatment of choroidal neovascular- cular smooth muscle cells was inhibited by corticos- ization (CNV) from age-related macular degeneration teroids in a dose-dependent manner. A separate study (AMD). In a phase 2 prospective clinical trial, pegaptanib by Nauck et al13 demonstrated that corticosteroids appeared to improve anatomic and visual outcomes in downregulate the induction of VEGF by the proinflam- patients with DME. Retrospective analysis of these data matory mediator platelet-derived growth factor and demonstrated some efficacy on retinal neovasculariza- platelet-activating factor in a time- and dose-dependent tion as well. Phase 3 trials of pegaptanib for DME are cur- manner. rently being conducted.17 Martidis et al14 reported results using IVTA injection in Bevacizumab. Bevacizumab (Avastin, Genentech), a 16 eyes with macular edema due to diabetic retinopathy. full-length recombinant humanized antibody, is active All 16 eyes had persistent macular edema after having against all isoforms of VEGF-A. It is FDA-approved as an received multiple sessions of laser photocoagulation. adjunctive systemic treatment for metastatic colorectal Using OCT, it was demonstrated that the mean thickness cancer. Although off-label systemic bevacizumab has of the central macula decreased from 540 µm before demonstrated some efficacy against exudative AMD, the injection (at baseline) to 242 µm after injection (the nor- agent has shown greater promise as an intravitreal med- mal average thickness of the central macula is 175 µm). ication. Case reports and small observational series have Visual acuity improved by 2.4, 2.4, and 1.3 lines from the been reported using off-label intravitreal bevacizumab to baseline value at the 1-, 3-, and 6-month follow-up inter- treat exudative AMD, macular edema from nonischemic vals, respectively. central retinal vein occlusion, iris neovascularization, Jonas et al15 described the results of IVTA injection in pseudophakic cystoid macular edema, and other dis- 26 eyes with macular edema due to DR. These patients eases. Small, nonrandomized pilot studies have docu- showed decreased fluorescein leakage following intravit- mented some efficacy against diffuse DME and various real injection in all patients. Visual acuity improved from complications of PDR. The Diabetic Retinopathy Clinical a mean of 20/165 at baseline to a mean of 20/105 at the Research Network (DRCR.net) has completed enrollment end of follow-up. In comparison, 16 patients followed in in a phase 2, prospective, randomized, multicenter clini- a control group who received laser photocoagulation cal trial to determine the safety and possible benefits of showed no improvement in visual acuity. this agent. Plans for a phase 3 trial of two doses of an intravitreal anti-VEGF agent versus modified ETDRS grid INTRAVITREAL DEXAMETHASONE laser photocoagulation for DME are under discussion.17 Following the same mechanism of action as other cor- Arevalo et al18 reported that primary intravitreal beva- ticosteroids, many physicians favor the use of intravitreal cizumab at doses of 1.25 to 2.5 mg seems to provide sta- dexamethasone (IVD) over IVTA because of the reduced bility or improvement in visual acuity, optical coherence incidence of floaters with this therapy. tomography (OCT), and fluorescein angiography (FA) in Wang et al16reported that dexamethasone may inhibit eyes with DME at 6 months. retinal accumulation, leukostasis accumulation and vas- Ranibizumab. Ranibizumab (Lucentis, Genentech), a cular permeability through its blockage of VEGF and recombinant humanized antibody fragment, is active ICAM-1 expression, thereby exerting the same effects as against all isoforms of VEGF-A. Intravitreal ranibizumab is other corticosteroids. FDA-approved for the treatment of exudative AMD. Two pilot studies of ranibizumab demonstrated some efficacy INTRAVITREAL ANTI-VEGF AGENTS in the treatment of DME. DRCR.net is planning two Vascular endothelial growth factor increases retinal phase 3, prospective, randomized, multicenter trials of vascular permeability, causes breakdown of the blood- ranibizumab for DME. In the first trial, patients with DME retinal barrier, and results in retinal edema. VEGF is and no PDR will be randomized to modified ETDRS grid

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laser photocoagulation; photocoagulation before by thermal laser within 2 weeks. Dexamethasone retreat- ranibizumab; photocoagulation plus IVTA; or ranibizum- ment was based on OCT central thickness >250 µm. At 12 ab before photocoagulation. In the second trial, patients months, mean pre-treatment Snellen (VA) was 20/393; with DME and PDR will be randomized to modified mean final VA was 20/70. Mean VA change was +4.5 lines. ETDRS grid laser photocoagulation plus scatter photoco- Mean reduction in foveal thickness was 103 µm. They con- agulation; modified ETDRS grid laser photocoagulation cluded that therapy with corticosteroids and thermal laser plus scatter photocoagulation plus ranibizumab; or mod- may improve vision in DME patients. ified ETDRS grid photocoagulation plus scatter photocoagulation plus IVTA. FUTURE THERAPIES The RIDE study (A Study of Ranibizumab Injection in PARS PLANA VITRECTOMY Subjects With Clinically Significant Macular Edema It is widely recognized that there have been recent With Center Involvement Secondary to Diabetes advancements in small gauge retinal and macular surgery. The Mellitus) is an ongoing placebo-controlled trial evaluat- advent of better instrumentation, adjuncts to help visualize ing the efficacy and safety of intravitreal ranibizumab the structures of the retina, and decreased surgical times help 0.5 mg injection every 4 weeks for 24 months in explain why diabetic macular edema is now being treated patients with DME. surgically.7-9 These studies suggest that vitreomacular traction, The CAPTURE trial (Combined Approach to or the vitreous itself, may play a role in increased retinal vas- Treatment Using Ranibizumab and Efalizumab for cular permeability. Removal of the vitreous or relief of Diabetic Macular Edema) is studying the combined mechanical traction with vitrectomy may, in some patients, administration of ranibizumab and efalizumab (Raptiva, be followed by substantial resolution of macular edema and Genentech) for DME. It is assessing the role of Raptiva, corresponding visual rehabilitation. However, this treatment which inhibits the binding leukocyte function associat- may be applicable only to a specific subset of eyes with DME. ed antigen-1 (LFA-1) to intercellular adhesion molecule- Another theory involves the removal of the internal lim- 1 (ICAM-1), thereby inhibiting the adhesion of leuko- iting membrane (ILM). Ducournau et al propose that ILM cytes to other cell types. removal would work beyond simply removing adherent VEGF-Trap Eye (Regeneron) is a soluble VEGF receptor collagen fibers (responsible for metamorphopsia and fusion protein that binds all forms of VEGF-A and related edema); it also induces a cellular response at the Muller cell placental growth factor (PGF). When administered as a level (gliosis). This gliosis is believed to play an important single 4.0 mg intravitreal injection in a phase 1 study, a role in the repair and regeneration of injured neural tissue.10 marked decrease in central retinal thickness and mean macular volume was noted. COMBINATION THERAPIES The phase 3 FAME (Fluocinolone Acetonide in DME) Recent studies focus on the combination of two or trial is evaluating the Medidur (Alimera Sciences) fluoci- more of aforementioned discussed treatments. Their nolone-based implant. main objective is to study whether there is a cumulative A phase 3 trial of the Posurdex (Allegan Inc.) effect to these treatments. biodegradable implant (sustained delivery formulation of Intravitreal bevacizumab with triamcinolone. Ahmadieh dexamethasone) for the treatment of DME is currently et al19 reported that three consecutive intravitreal injections under way. Another steroid implant, Retisert (Bausch & of bevacizumab had a beneficial effect on refractory DME in Lomb), was evaluated in patients with DME with good terms of central macular thickness reduction and vision results but a concerning side effect profile (90% of improvement. Addition of triamcinolone in the first injec- patients developed cataracts, and 40% required glauco- tion seemed to induce earlier visual improvement. ma surgery within 3 years). Intravitreal triamcinolone or dexamethasone and focal laser photocoagulation. Kang et al20 concluded CONCLUSION that macular grid laser photocoagulation maintained Multiple therapeutic options are currently available for improved visual acuity and reduced the risk of recurrent the treatment of DME, and many more are on the hori- macular edema after IVTA. This treatment also did not zon. It is up to the clinician to determine which therapies appear to increase the risk of complications. or combinations thereof are most appropriate on a case- Busquets et al21 assessed the effectiveness of intravitreal by-case basis. Optimal patient care will ultimately result dexamethasone with thermal laser photocoagulation for from the evolution of new technologies and effective DME in a 12-month retrospective analysis of 20 eyes with recruitment and enrollment in randomized prospective clinically significant DME. Dexamethasone was followed clinical trials. ■

40 IRETINA TODAYISEPTEMBER/OCTOBER 2008 Alberto A. Guardiola, MD, is a Retina Fellow at the Vitreoretinal Service, Associates in Ophthalmology/Associates Surgery Centers in Pittsburgh, PA, and Miguel A. Busquets MD, FACS, is Partner with the Vitreoretinal Service, Associates in Ophthalmology/ Associates Surgery Centers and is Clinical Instructor, Vitreoretinal Fellowship Director, and Director of Research Division at the University of Pittsburgh. Dr. Busquets states that he is an advisory board member for Genentech and Eyetech phar- maceuticals. Associates in Ophthalmology is a Diabetic Retinopathy Clinical Research Network (DCRCnet) site. Dr. Busquets may be reached via e-mail at [email protected].

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