Update on Pharmacologic Treatment of Diabetic Macular Edema
Jointly sponsored by The Dulaney Foundation and Retina Today. Release Date: March 2006. Expiration Date: March 31, 2007. This continuing medical education activity is supported by an educational grant from Eli Lilly and Company.
Diabetic macular edema (DME) is a complication of diabetes that affects an estimated 95,000 individuals each year in the United States alone.1 DME has a significant impact on vision and quality of life; thus, new treatments offer the promise of great benefit to a growing patient population.2 Beginning in 2003, the National Eye Institute of the US National Institutes of Health instituted a special program within the Diabetes Research Working Group aimed specifically at DME.3 In order to adequately respond to patient requests for information and evaluate potentially useful treatments progressing through clinical trials, eye care providers specializing in retinal care should be familiar with the current status of research into pharmacologic treatments of DME.
1. Klein R, Moss SE, Klein BEK, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, XI: the incidence of macular edema. Ophthalmology. 1989;96: 1501-1510.
2. Sharma S, Oliver-Fernandez A, Liu W, Buchholz P, Walt J. The impact of diabetic retinopathy on health-related quality of life. Curr Opin Ophthalmol. 2005 Jun;16(3):155-9.
3. National Eye Institute. Congressional Justification for FY 2003. Available at: www.nei.nih.gov/news/congressjust/cj2003.asp. Accessed February 12, 2006.
Medical and surgical retinologists.
Upon successful completion of this learning program, the participant should be able to:
• List and describe pharmacologic treatments for DME that are currently in use or undergoing human clinical trials;
• Describe the indications, prognosis and results of pharmacologic DME treatments; and
• Summarize the most recent studies in the peer-review literature on currently available pharmacologic treatments for DME and new treatments undergoing clinical trials.
METHOD OF INSTRUCTION
Participants should read the learning objectives and CME program in their entirety. After reviewing the material, they must complete the self-assessment test, which consists of a series of multiple-choice questions.
Participants have a choice of completing this activity online by visiting www.RetinaToday.com; getting real-time results at www.CMEToday.net; or by using the print forms following this activity.
Upon completion of the activity and achieving a passing score of ≥70% on the self-assessment test, participants will receive a CME credit letter awarding AMA PRA Category 1 Credit 4 weeks after the registration and evaluation materials are received. The estimated time to complete this activity is 1 hour.
This activity has been planned and implemented in accordance with the essentials and standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The Dulaney Foundation and Retina Today. The Dulaney Foundation designates this educational activity for a maximum of AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.
In accordance with the disclosure policies of The Dulaney Foundation and to conform with ACCME and Food and Drug Administration (FDA) guidelines, all program faculty are required to disclose to the activity participants: 1) the existence of any financial interest or other relationships with the manufacturers of any commercial products/devices, or providers of commercial services that relate to the content of their presentation/material or the commercial contributors of this activity; and 2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.
Glenn J. Jaffe, MD, has received research support from Bausch & Lomb and Control Delivery systems and has a financial interest in pSividia.
Dr. Jaffe is professor of ophthalmology in the Vitreoretinal Service, Duke University Eye Center, Durham, NC. He may be reached at email@example.com
Based on projections of data from the National Health and Nutrition Examination surveys, the American Diabetes Association estimates that there were 20.8 million cases of diagnosed and undiagnosed diabetes in the United States in 2005, representing 7% of the total population.1
DME has long been recognized as an important cause of vision loss.2,3 Clinically significant macular edema (CSME) was defined in the Early Treatment Diabetic Retinopathy Study (ETDRS) as any case in which there is retinal thickening within 500 µm of the center of the fovea; hard yellow exudates within 500 µm of the center of the fovea along with retinal thickening; or >1 disc area of retinal thickening, of which any part lies within 1 disc diameter of the center of the fovea.4
Studies have shown that poor glycemic control and higher levels of HbA1c are among the risk factors for the onset of DME.5,6 The Wisconsin Epidemiologic Study of Diabetic Retinopathy found rates of progression to DME of 26% in patients with diabetes for 14 years and 29% at 20 years or longer after diagnosis.7,8
Based on the results of the ETDRS and subsequent clinical studies, laser photocoagulation has become the standard therapy for DME.9 The ETDRS found that laser photocoagulation reduced the rate of moderate visual acuity loss by 50% in eyes with CSME. The study also revealed some limitations of the treatment. Treated eyes rarely improved to 20/40 or better; only 3% of patients achieved an improvement of >3 lines of visual acuity 36 months after treatment; eyes with advanced retinopathy or diffuse macular edema responded less well; and no benefit was demonstrated in patients with non-CSME.
To prevent the development of DME as well as to treat eyes that are not suitable for laser photocoagulation or have derived the maximum benefit of laser treatment, other modalities have been examined in clinical trials. Results have been reported for pharmacologic treatment of DME with corticosteroids (injected and delivered by implants), protein kinase-C (PKC) inhibitors, and vascular endothelial growth factor (VEGF) inhibitors.
Because they effectively inhibit inflammation, stabilize cell membranes and and enhance blood retinal barrier integrity, corticosteroids have been investigated as a potential treatment for DME.10,11 Oral and topical routes of administration inefficiently deliver corticosteroids to the posterior segment, and there are potentially serious systemic side effects with oral administration. These drawbacks are minimized with intravitreal or sub-Tenon’s injection.
The Intravitreal Steroid Injection StudiesDiabetic Macular Edema (ISIS-DME) trial is a prospective study where patients were randomized to receive intravitreal injection of either a 2- or 4-mg dose of triamcinolone acetonide (Kenalog). The study enrolled 33 patients with CSME who failed to respond to laser photocoagulation and had visual acuity of <20/40. Six-month results were recently reported.12
In the overall group of 24 patients in both the 2- and 4-mg dose groups with 6 months of follow-up, 38% had achieved 3 lines of visual acuity improvement for at least some of the follow-up period. Fluorescein angiography (FA) was used to categorize eyes as having either cystoid or noncystoid foveal edema based on the degree of vessel leakage. There was a statistically significant difference (P=.01) between the subgroups, with 62% (8 of 13) of those with cystoid foveal edema having a >3-line improvement in visual acuity and only 9% (1 of 11) patients with noncystoid foveal edema having a similar improvement. Although DME had completely resolved in 39% of patients 3 months after treatment, by 6 months only 18% of patients were without edema. The need for repeat injections to sustain therapeutic effect, especially in diffuse DME, was noted in the ISIS-DME study and as well as others.13
A retrospective study of 1- or 4-mg intravitreal injection of triamcinolone acetonide in 210 eyes of 174 patients with diffuse CSME found a statistically significant improvement from median visual acuity, from 20/200 to only 20/80 posttreatment.14 Optical coherence tomography (OCT) imaging showed that, in a group of 23 eyes with diffuse DME (including eyes with and without previous laser treatment), visual acuity improved quickly 2 weeks after a 4-mg triamcinolone acetonide injection, remained stable until 3 months posttreatment, then decreased by the 6-month follow-up.15 A prospective study of 53 eyes with diffuse DME receiving a 20-mg dose of intravitreal triamcinolone acetonide found a significant correlation between improvement in BCVA and higher degrees of edema.16 The presence of pronounced macular ischemia or higher levels of preoperative BCVA, however, had a negative correlation to patient outcome.
IOP rise was a common adverse effect in the ISIS-DME study (31% of patients had >10 mm/Hg increase) but was managed without surgery in all cases. Another review of studies in which approximately 20 mg of triamcinolone acetonide was injected intravitreally to treat a variety of posterior segment disorders including DME found postinjection IOP >20 mm/Hg in 68.1% of patients.17 Most of those cases were treated with medical therapy, and only three (1%) were managed with filtration surgery. Another study examining IOP after intravitreal injection of 4 mg (0.1 mL total volume) of triamcinolone found only a moderate and transient pressure rise that did not require paracentesis or other surgical intervention.18 As with any invasive procedure, infection is a serious potential complication and occurs in 0.1% to 0.87% of eyes that have received an intravitreal triamcinolone acetonide injection.19,20 The potential for steroid-induced cataract with higher doses of triamcinolone has also been recognized in other studies, and other complications including vitreous hemorrhage and retinal detachment have been reported.21 The optimal dose for intravitreal injection is still unclear.
Sub-Tenon’s injection/infusion of corticosteroids has been investigated as a way to avoid potential complications of intravitreal injection. However, two recent prospective studies comparing sub-Tenon’s to intravitreal injection of triamcinolone treatment for refractory DME found that both macular thickness (measured by OCT) and visual acuity were significantly better after intravitreal injection.22,23 The treatments were equivalent in terms of IOP rise and other adverse events in both studies. Thus, there seems to be no advantage to the sub-Tenons route of corticosteroid injection. The need for repeat injections of steroids, however, could potentially be avoided if a sustained-release drug-delivery device were available. Several such devices are now being investigated.
Implantable devices to deliver drugs to the posterior segment have been in clinical trials for more than a decade.24 Retisert (fluocinolone acetonide intravitreal implant 0.59 mg; Bausch & Lomb, Rochester, NY) was granted an orphan drug approval by the FDA in April 2005 for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. The implant is composed of an inactive nonbiodegradable polymer substrate designed to release active drug over approximately 30 months (Figure 1).25
Patients usually have a loss of visual acuity immediately after surgical implantation of the device, but this is a temporary phenomenon that resolves from 1 to 4 weeks after surgery. Medical therapy to control IOP was necessary in approximately 60% of patients enrolled in the uveitis study, and 32% of patients were expected to require filtering surgery within 2 years postimplantation. Almost all patients were expected to require cataract surgery by 2 years.26 The implant was effective in controlling inflammation and improving visual acuity in patient with noninfectious uveitis that did not respond to other treatments.27,28
The multicenter clinical trial of Retisert for the treatment of DME completed phase 3 in September 2005.29 A group of 197 patients randomized to receive either the Retisert implant or repeat laser photocoagulation found that 58% of the eyes in the Retisert group had no evidence of DME at the 3-year follow-up point, whereas only 30% of the laser-treated eyes had a resolution of edema. These results were statistically significant
(P< .001).30 Visual acuity improvement of >3 lines was attained by 28% of eyes in the Retisert group versus 15% in the laser group (P<.05). Loss of >3 lines visual acuity was equivalent in both groups (19% with Retisert vs 16% with laser).
Adverse events included cataract in 95% of implanted phakic eyes over the 3-year study period. Of all implanted eyes, IOP rise was noted in 35%, the rate of filtration surgery was 28%, and in 5% of eyes the device was explanted to manage IOP. An analysis of prognostic factors revealed that patients with higher levels of BCVA; shorter duration of diabetes; and less severe DME derived significantly better results from the Retisert implant.31 Less benefit was noted in patients with cardiovascular disease and preoperative vitreomacular attachment. Resolution of DME was associated with better postoperative BCVA, but also with higher levels of postoperative IOP.
A biodegradable anterior-chamber intraocular implant (originally Surodex, later changed to Posurdex after the manufacturer was acquired by Allergan, Irvine, Calif) was developed by Oculex Pharmaceuticals to deliver dexamethasone at constant therapeutic levels.32 A phase 2 randomized, multicenter controlled clinical study of the device to control persistent refractory macular edema by implantation into the posterior segment of the eye followed 306 patients, 165 of whom were affected by DME (Table 1). At the 6-month follow-up point, visual acuity was statistically significantly better in the subgroup receiving the 700-µg implant, and a trend toward better visual acuity outcomes was noted in the 350-µg group as well. Retinal thickness measured by OCT and vessel leakage measured by FA in eyes treated with both implant dosages were significantly better than observation-only eyes.
Adverse effects were usually related to the implantation procedure, in which the device was placed into the vitreous base region through a small pars plana sclerostomy. These included self-limited subconjunctival and vitreous hemorrhage.
Another study evaluated the 700-µg Posurdex device inserted into the pars plana via a preloaded 22-gauge applicator (n=20) compared with incisional placement
(n=10).33 Sutures were not required for patients in the applicator group but were needed to close the wound in all patients in the incisional group. The incidence of adverse ocular events was reported to be lower and the implantation procedure was completed more quickly in the applicator group versus the incisional group.
The Medidur implant, also a nonbiodegradable flucinolone delivery device, was developed by the same manufacturer that created the Retisert implant (Control Delivery Systems, recently acquired by pSivida, Perth, Australia). The current phase 3 US and European clinical trials are underwritten by Alimera Sciences (Atlanta). Medidur is a smaller implant (Figure 2) designed to be injected in an office setting. No clinical study data on results with Medidur were available at press time.
PKC AND VEGF INHIBITORS
Increased levels of VEGF are associated with angiogenesis and increased vascular permeability that cause significant vision loss not only in DME but also in age-related macular edema (AMD). Blocking the action of VEGF has been found to be effective in inhibiting these processes.34 PKC mediates the effects of VEGF, and when activated it will increase VEGF expression. Several agents to inhibit the activity of PKC and VEGF in diabetic vasculopathy are currently in clinical trials for systemic as well as ophthalmic applications.
Ruboxistaurin (Eli Lilly and Company, Indianapolis, Ind), is a selective PKC-beta inhibitor being investigated for treatment of diabetic peripheral neuropathy symptoms and diabetic macular edema. A clinical study found that, compared with placebo, orally administered ruboxistaurin significantly reduced retinal vascular leakage in patients with DME.35 The effect was greater in eyes that had more leakage prior to treatment.
In the Protein Kinase-C Beta Inhibitor Diabetic Retinopathy Study (PKC-DRS), 252 patients with moderately severe to very severe nonproliferative diabetic retinopathy were randomized to receive placebo or
8-, 16-, or 32-mg doses of oral ruboxistaurin per day.36 Patients receiving the 32-mg dosage had a delayed onset of moderate and severe visual acuity loss compared with the placebo group, and this effect was found to be associated with higher levels of DME prior to treatment. Rates of progression to proliferative diabetic retinopathy were equivalent among all groups. There were small but statistically significant differences in the rates of various adverse events among the subgroups, but these did not correlate with drug dosage.
Pegaptanib (Macugen; OSI Eyetech, Melville, NY/Pfizer, New York, NY) has been approved by the FDA for the treatment of AMD. Pegaptanib, administered by repeat intravitreal injection every 6 weeks, selectively binds to the VEGF165 isoform. Results of a phase 2 study of 0.3-, 1-, and 3-mg doses the drug versus placebo injections in 172 patients were recently reported.37
At the 36-week follow-up, patients receiving the 0.3-mg dose of pegaptanib had significantly higher median visual acuity (20/50) compared with the sham-treatment group (20/63). A gain of approximately 2 lines of visual acuity was seen in 34% of the 0.3-mg treatment group versus 10% of the placebo group, which was also statistically significant. Mean central retinal thickness as measured by OCT was found to decrease in the treatment group (by 68 µm) but increase in the sham-treatment group (by 4 µm). Fewer patients who received pegaptanib went on to require laser photocoagulation. Adverse events were associated with the injection rather than the drug (one case of endophthalmitis, retinal detachment and vitreous hemorrhage) and did not have a significant effect on final visual acuity.
Laser photocoagulation has been a powerful tool in the treatment of diabetic eye disease. The growing variety of pharmacologic treatments and preventive agents for DME promise to preserve vision for even more patients at risk from this increasingly prevalent condition.
1. American Diabetes Association. Diabetes statistics. Available at http://www.diabetes.org/diabetes-statistics.jsp. Accessed February 28, 2006.
2. Klein R, Klein BE, Moss SE. Visual impairment in diabetes. Ophthalmology. 1984;91:1-9.
3. Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology. 1998;105:998-1003.
4. Chew EY, Klein ML, Ferris FL 3rd, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol. 1996;114:1079-84.
5. Jeddi Blouza A, Khayati L, Malouche N, Slim B, Azeiz S, Issaoui A, Zouari B. Risk factors for diabetic macular edema. J Fr Ophtalmol. 2005;28:1033-1038.
6. Do DV, Shah SM, Sung JU, Haller JA, Nguyen QD. Persistent diabetic macular edema is associated with elevated hemoglobin A1c. Am J Ophthalmol. 2005;139:620-623.
7. Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology. 1998;105:1801-1815.
8. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984;91:1464-1474.
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10. Speicher MA, Danis RP, Criswell M, Pratt L. Pharmacologic therapy for diabetic retinopathy. Expert Opin Emerg Drugs. 2003;8:239-250.
11. Itakura H, Akiyama H, Hagimura N,et al. Triamcinolone acetonide suppresses interleukin-1 beta-mediated increase in vascular endothelial growth factor expression in cultured rat Muller cells. Graefes Arch Clin Exp Ophthalmol. 2006;244:226-31.
12. Pollock J. Intravitreal steroids for diabetic macular edema: the ISIS trial. Paper presented at the Annual Meeting of the American Academy of Ophthalmology. October 15, 2005; Chicago.
13. Er H, Yilmaz H. Intravitreal cortisone injection for refractory diffuse diabetic macular edema. Ophthalmologica. 2005;219:394-400.
14. Chieh JJ, Roth DB, Liu M, et al. Intravitreal triamcinolone acetonide for diabetic macular edema. Retina. 2005;25:828-834.
15. Patelli F, Fasolino G, Radice P, et al. Time course of changes in retinal thickness and visual acuity after intravitreal triamcinolone acetonide for diffuse diabetic macular edema with and without previous macular laser treatment. Retina. 2005;25:840-845.
16. Jonas JB, Martus P, Degenring RF, Kreissig I, Akkoyun I. Predictive factors for visual acuity after intravitreal triamcinolone treatment for diabetic macular edema. Arch Ophthalmol. 2005;123:1338-1343.
17. Jonas JB, Degenring RF, Kreissig I, Akkoyun I, Kamppeter BA. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection. Ophthalmology. 2005;112:593-598.
18. Dwinger MC, Pieper-Bodeewes I, Eter N, Holz FG. Variations in intraocular pressure (IOP) and necessity for paracentesis following intravitreal triamcinolone injection. Klin Monatsbl Augenheilkd. 2005;222:638-642.
19. Westfall AC, Osborn A, Kuhl D, et al. Acute endophthalmitis incidence: intravitreal triamcinolone. Arch Opthalmol. 2005;123:1075-1077..
20. Moshfeghi DM, Kaiser PK, Scott IU, et al. Acute endophthalmitis following intravitreal acetonide injection. Am J Ophthalmol. 2003;136:791-796.
21. Jonas JB, Degenring R, Vossmerbauemer U, Kamppeter B. Frequency of cataract surgery after intravitreal injection of high-dosage triamcinolone acetonide. Eur J Ophthalmol. 2005;15:462-464.
22. 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;46:3845-3849.
23. Cardillo JA, Melo LA Jr, Costa RA, et al. Comparison of intravitreal versus posterior sub-Tenon’s capsule injection of triamcinolone acetonide for diffuse diabetic macular edema. Ophthalmology. 2005;112:1557-1563.
24. Metrikin DC, Anand R. Intravitreal drug administration with depot devices. Curr Opin Ophthalmol. 1994;5:21-29.
25. Fluocinolone acetonide ophthalmic. Bausch & Lomb: fluocinolone acetonide Envision TD implant. Drugs R D. 2005;6:116-119.
26. Retisert [package insert]. Rochester, NY: Bausch & Lomb; 2005.
27. Jaffe GJ, McCallum RM, Branchaud B, et al. Long-term follow-up results of a pilot trial of a fluocinolone acetonide implant to treat posterior uveitis. Ophthalmology. 2005;112:1192-8.
28. Jaffe GJ, Martin DF, Callanan D, et al. Fluocinolone acetonide intravitreal implant to treat posterior segment uveitis: 3-year results of a multi-center clinical trial. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; May 1, 2006. Ft. Lauderdale, Fla.
29. A multicenter study to evaluate retisert in the treatment of patients with diabetic macular edema. Available at: www.clinicaltrials.gov/ct/show/NCT00031525. Accessed March 10, 2006.
30. Pearson P, Levy B, Comstock T, Fluocinolone Acetonide Implant Study Group. Fluocinolone acetonide intravitreal implant to treat diabetic macular edema: 3-year results of a multi-center clinical trial. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology. May 4, 2006. Ft. Lauderdale, Fla.
31. Ahmad S, Stinnett SS, Jaffe GJ. Pre-treatment prognosticators of response to a fluocinolone acetonide implant for diabetic macular edema. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology. April 30, 2006. Ft. Lauderdale, Fla.
32. Dexamethasone ophthalmic-oculex. Surodex. Drugs R D. 2002;3:152-153.
33. Kuppermann BD, Williams GA, Blumenkranz MS, et al. Efficacy and safety of a novel intravitreous dexamethasone drug-delivery system after applicator or incisional placement in patients with macular edema. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology. May 4, 2006. Ft. Lauderdale, Fla.
34. Ozaki H, Seo MS, Ozaki K, et al. Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am J Pathol. 2000;156:697-707.
35. Strom C, Sander B, Klemp K, et al. Effect of ruboxistaurin on blood-retinal barrier permeability in relation to severity of leakage in diabetic macular edema. Invest Ophthalmol Vis Sci. 2005;46:3855-3858.
36. 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;54:2188-2197.
37. Cunningham ET Jr, Adamis AP, Altaweel M, et al; Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747-1757.