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Current Treatments of Diabetic Macular Edema
International Journal of Gerontology 5 (2011) 183e188
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International Journal of Gerontology journal homepage: www.ijge-online.com
Review Article
Current Treatments of Diabetic Macular Edemaq Wei-Chun Chan 1, Shawn H. Tsai 1, Ai-Ching Wu 1, Lee-Jen Chen 1 *, Chi-Chun Lai 2 ** 1
Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan, 2 Department of Ophthalmology, Chang Gung Memorial Hospital, Linkuo Medical Center, Taiwan
a r t i c l e i n f o
s u m m a r y
Article history: Received 14 March 2011 Accepted 15 March 2011 Available online 20 January 2012
Diabetic macular edema (DME) is a major cause of visual impairment in diabetic patients. Laser photocoagulation is the standard management strategy for macular edema, but its results remain unsatisfactory. Several clinical trials of new treatment modalities for DME have been conducted over the past 10 years. We performed a literature search of English articles, published between 2000 and 2010, by using the PubMed database. The keywords searched included “diabetic macular edema and treatment” with limits set to include only clinical trials and review articles, over 50 articles were reviewed. Among the newer treatment modalities reviewed, therapy with anti-vascular endothelial growth factor (VEGF) antibodies showed significantly better efficacy, with level I evidence. However, multiple injections were required to maintain its efficacy. Therefore, the associated complications and cost implications are the major limitations of this treatment. Several combinations of different modalities have been evaluated in the literature, but none are more efficacious than monotherapy with anti-VEGF antibodies. Since DME is a multifactorial disease, further studies involving combinations of modalities or new treatments modalities may be needed to reduce the number of injections required or improve the visual outcomes in case of DME. Copyright Ó 2011, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: bevacizumab, diabetes mellitus, laser, macular edema, ranibizumab
1. Introduction Diabetic mellitus is an important issue in public health, especially in the elderly. More than 220 million people worldwide have diabetes (90% type 2 diabetes). Ten percent of these develop severe visual impairment after 15 years of diabetes1. According to a study by Chan et al2, the prevalence of type 2 diabetes in the old age group (> 60 years old) in Taiwan was significantly greater than in the young age group (20 w 40 years old) in both genders. The prevalence in old age groups was 20.5 w 26.3% and that in young
q The authors of this article have no financial interests related to the material in the manuscript. They certify that affiliations with, or financial involvement in, within the past 5 years and foreseeable future, any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript, are completely disclosed (e.g., employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, royalties). * Correspondence to: Dr Lee-Jen Chen, MD, Director of Department of Ophthalmology of Mackay Memorial Hospital, Number 92, Section 2, Chun Shan North Road, Taipei 104, Taiwan. ** Correspondence to: Dr Chi-Chun Lai, MD, Professor & Vice Chairman of Ophthalmology of Chang Gung Memorial Hospital, Linkuo Medical Center, 5. Fu-Hsing St., Kwei-Shan, Taoyuan 333, Taiwan. E-mail addresses: [email protected] (L.-J. Chen), [email protected] (C.-C. Lai).
age groups was 0.6 w 7.6% in 2004. The elderly people have a higher risk of severe visual impairment because of a higher prevalence and longer duration of diabetes. Diabetic macular edema (DME, Fig. 1) is the most common cause of visual impairment in patients with diabetes3. The prevalence of DME was found to be related to the duration of diabetes, as reported in of the Wisconsin Epidemiologic Study of Diabetic Retinopathy4. The prevalence of DME in patients with type 1 diabetes varied from 0% (duration of less than 5 years) to 29% (duration of 20 years or more). The prevalence in patients with type 2 diabetes was similar: 3% in the group with diabetes for less than 5 years and 28% in the group with diabetes for 20 years or more. Approximately 50% of patients with DME will experience a loss of 2 lines of best-corrected visual acuity (BCVA) after 2 years of followup5. It is thus important to treat DME effectively to reduce the possibility of visual loss. Many treatment modalities have been reported, especially in recent years. Here, we review the clinical trials conducted over the past 10 years for the treatment of DME and discuss the results of the comparison studies. 2. Pathogenesis and clinical definition of DME The pathogenesis of DME is complex and involves multiple factors3. It occurs mainly as a result of disruption of the bloodretinal barrier, which leads to increased accumulation of fluid
1873-9598/$ e see front matter Copyright Ó 2011, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.ijge.2011.09.013
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Fig. 1. DME, hard exudate derived from plasma lipoproteins located within 1 disc diameter of the center of the macula.
within the intraretinal layers of the macula. Vasoactive factors such as vascular endothelial growth factor (VEGF), protein kinase C, histamine and others factors that are affected by hypoxia or chronic hyperglycemia may cause breakdown of the blood-retinal barrier. The abnormalities in the structure of the vitreoretinal interface may also play an important role in the pathogenesis of DME. The Early Treatment Diabetic Retinopathy Study (ETDRS) defined DME as retinal thickening or a presence of hard exudates within 1 disc diameter of the center of the macula. The term “clinically significant macular edema” (CSME) is used to characterize the severity of macular edema and for treatment guidelines. CSME is defined by the presence of one or more of the following: retinal thickening at or within 500 mm of the center of the macula, hard exudates at or within 500 mm of the center of the macula if associated with adjacent retinal thickening, or a zone or zones of retinal thickening 1 disc area in size at least part of which is within 1 disc diameter of the center of the macula6. In addition to criteria set by the above definition, fluorescein angiography and optical coherence tomography (OCT) are useful tools to examine the permeability of perimacular vessels and changes in retinal thickness. 3. Current treatment modalities 3.1. Laser photocoagulation for DME The exact mechanism of DME resolution after laser photocoagulation is unknown. One explanation involves laser-induced destruction of oxygen-consuming photoreceptors. Oxygen that normally diffuses from the choriocapillaries into the outer retina can diffuse through the laser scar to the inner retina, thus relieving inner retinal hypoxia. Another hypothesis explains that proliferation of the retinal pigmented epithelium (RPE) induced by laser photocoagulation can produce cytokines to antagonize the permeabilizing effects of VEGF3. Macular laser photocoagulation proposed by ETDRS (Fig. 2) is the standard treatment for DME3. The ETDRS was a prospective, randomized clinical trial to study the effect of laser photocoagulation on DME. The result of ETDRS revealed that patients with mild to moderate nonproliferative diabetic retinopathy (NPDR) with DME, had significantly lower rates of moderate visual loss (defined as a loss of 15 or more letters) in the treated group (12%) than in the deferral group (24%) at the end of 3 years. In the treated group, the risk of moderate visual loss reduced significantly in the patients with CSME, but not in the patients without CSME. The authors
Fig. 2. Examples of laser photocoagulation for DME. (A) focal laser photocoagulations (green spots) are applied on the leaking microaneurysms of focal macular edema; (B) grid laser photocoagulations (green spots) are used to treat diffuse macular edema.
recommended that laser photocoagulation should be considered for all eyes with CSME6. Diffuse DME did not respond well to the grid laser treatment. At a 3-year follow-up study of 302 eyes with diffuse DME, Lee and Olk7 reported 15% of the eyes had visual improvement, 61% remained unchanged, and 24% became worse in visual acuity. Barkmeier et al8 also found the reduction of foveal thickness after laser photocoagulation for CSME was statistically significant in patients with focal parafoveal thickening, but not in patients with diffuse parafoveal thickening. Complications of laser photocoagulation included a visual decrease caused by laser-induced RPE atrophy and subretinal fibrosis involving the central fovea9,10. 3.2. Corticosteroids As described by the above studies, there were many patients with diffuse DME whose condition worsened after grid treatment. Thus, many other modalities of DME treatment were studied. Corticosteroids can suppress activation of the VEGF gene and downregulate the induction of VEGF3. Peribulbar injection (including posterior subtenon injection) alone is not an effective treatment for DME11,12. However, posterior subtenon triamcinolone, as an adjunctive treatment for diffuse DME, can improve the visual outcomes of laser photocoagulation13e15. Intravitreal injection of triamcinolone acetonide (IVTA) as the primary treatment of DME has been studied by the Diabetic Retinopathy Clinical Research Network16. Eight hundred and forty eyes with CSME were randomly assigned into three groups: focal/grid
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laser, IVTA 1 mg, and IVTA 4 mg. In the first year, the mean visual acuity was better in both IVTA groups than in the laser group in the first year. However, after 2 years of treatment, it significantly better in the laser group than in the IVTA groups. There was no significant difference in visual outcome between the two IVTA groups. The main complications of IVTA were glaucoma and cataract formation (Table 1). Although IVTA is less effective than laser photocoagulation for DME as a primary treatment, it may benefit eyes with DME that are refractory to laser treatment. In a prospective, double-masked, placebo-controlled, randomized study of 69 eyes with refractory DME, 55% of treated eyes had visual acuity improvement at 3 months of follow-up compared to only 16% in the placebo group17. Combination therapy using both laser photocoagulation and IVTA for DME has been studied, but the results were not consistent among patients with different severity of diabetic retinopathy. Patients with non-high risk proliferative diabetic retinopathy (PDR) and CSME benefited from combination therapy, but those with NPDR and high risk PDR did not18e21. The therapeutic effect of the triamcinolone is typically seen within 1 week, but in many patients, re-injections are needed every 3 to 6 months as the effect wears out. Repeat intravitreal injections may be needed to maintain the therapeutic effect3,22. Because of the risk and inconvenience of repeat injections, intravitreal sustained- release inserts or implants of dexamethasone and fluocinolone acetonide for persistent DME were studied in randomized, controlled trials23e25. The short-term results were promising and both drugs were well tolerated by patients, but a 3year follow-up of intravitreal dexamethasone implants (Retisert) revealed very high rates of cataracts and glaucoma that required surgical intervention3. 3.3. Anti-VEGF therapy VEGF-A is a major mediator of retinal permeability. Blockage of VEGF can reduce vascular permeability3. There are several drugs against VEGF that have undergone clinical trials for DME treatment in recent years, including protein kinase C (PKC) inhibitors, antiVEGF aptamers, and anti-VEGF antibodies. PKC beta-isoform inhibitors: PKC is activated by hyperglycemia; its b-isoform is an important signaling component for VEGF26. Selective b-isoform PKC inhibitors can suppress VEGF induced retinal permeability27. As such, ruboxistaurin (RBX), has been studied for its effect on DME in a multicenter, double-masked, randomized, placebo-controlled study of 686 patients. The authors concluded that daily oral administration of RBX may delay the progression of DME to a sight-threatening stage28. In another study of 252 patients with moderate to severe NPDR, 32 mg/day RBX significantly reduced the risk of moderate visual loss compared to a placebo29. The effect of RBX on long-standing DME has also been studied; the rate of visual acuity decline was 30% less in the RBX group compared to the placebo group30. The FDA has
Table 1 The 2-year visual outcome and main complications of DME treatment with laser photocoagulation or intravitreal injections of triamcinolone studied by Diabetic Retinopathy Clinical Research Network.
Mean BCVA change BCVA 10 letters improvement BCVA 15 letters worse IOP increased 10 mmHg Cataract surgery
Laser (n ¼ 330)
IVTA 1 mg (n ¼ 256)
IVTA 2 mg (n ¼ 254)
þ1 31% 14% 4% 13%
2 25% 20% 16% 23%
3 28% 20% 33% 51%
IVTA ¼ intravitreal injection of triamcinolone.
requested another phase III trial to determine the efficacy of moderate and severe NPDR before RBX can be approved. Anti-VEGF aptamers: Macugen (pegaptanib) is an aptamer that binds the 165-isoform of VEGF. The efficacy and safety of intravitreal pegaptanib for use in DME treatment were evaluated in a phase II, randomized, double-masked study of 172 patients31. Laser photocoagulation and reinjection of pegaptanib were used as supplemental treatments after the first 3 monthly injections. The results revealed that median visual acuity after 6 months was significantly better in the group with the 0.3 mg intravitreal injections versus the control group (20/50 vs. 20/63). The proportion of patients with visual acuity improving 10 letters or more was larger in the 0.3 mg injection group than in the control group (34% vs. 10%). A solely retrospective study revealed that intravitreal pegaptanib treatment alone may be superior to macular laser photocoagulation for DME; further prospective clinical trials are needed32. Anti-VEGF antibodies: Ranibizumab and bevacizumab are antiVEGF antibodies which have been widely used to treat choroidal neovascular membranes in age-related macular degeneration. Because of the important role of VEGF in the blood-retina barrier breakdown associated with DME, these anti-VEGF antibodies were studied for the treatment of DME. Ranibizumab (Lucentis) is a Fab fragment of an anti-VEGF antibody. Its efficacy, compared to laser photocoagulation, was studied in 126 patients with DME in a prospective, randomized, phase II READ-2 (Ranibizumab for Edema of the mAcula in Diabetes) study33. The 6-month result of this clinical trial revealed that the mean gain in BCVA was significantly greater in the ranibizumab injection group compared with the laser photocoagulation group (þ7.24 vs. e0.43 letters). The rate of BCVA improvement of 3 lines or more was significantly higher in the ranibizumab injection group. After the primary end point (month 6), most patients in the READ-2 study were treated only with intravitreal injections of ranibizumab34. At the end of this 24-month study, the authors concluded that intraocular injections of ranibizumab provided benefits for patients with DME, and when combined with focal or grid laser treatments, the frequency of injections needed to control edema were reduced. The RESOLVE study was a 12-month, multicenter, placebocontrolled, double-masked study with eyes randomly assigned to receive either intravitreal ranibizumab (0.3 or 0.5 mg) or placebo35. The treatment schedule comprised 3 monthly injections, after which treatment could be stopped or reinitiated based on treatment success, disease activity, or safety criteria. Laser photocoagulation could be used as rescue therapy. At month 12, the mean BCVA improvement from baseline was significantly better in the ranibizumab treated group (combination of 0.3 and 0.5 mg groups) than the placebo group (þ10.3 vs. e1.4 letters). A gain in the BCVA of 10 letters over the baseline occurred in 60.8% of eyes in the ranibizumab group and 18.4% of eyes in the control group. The mean numbers of injections administered during 12 months were 10.2 and 8.9 for the ranibizumab and controls, respectively. Severe ocular adverse events (suspected to be drug-related) in the intravitreal ranibizumab group (102 eyes) included vitreous hemorrhage (1 eye), retinal artery occlusion (1 eye), and endophthalmitis (2 eyes). Ocular adverse events which were suspected to be drugrelated included conjunctival hemorrhage (23 eyes) and eye pain (18 eyes). Non-ocular adverse events potentially related to systemic VEGF inhibition included arterial thromboembolic events (3 patients), hypertension (9 patients), and nonocular hemorrhage (2 patients). The Diabetic Retinopathy Clinical Research Network conducted a phase III, randomized, multicenter clinical trial of 854 DME eyes, to evaluate the effects of treatment with intravitreal ranibizumab
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(0.5 mg) or triamcinolone (4 mg) combined with focal/grid laser compared to focal/grid laser alone36. The 1 year mean change in the visual acuity letter score from baseline was significantly better in the ranibizumab þ prompt laser group and the ranibizumab þ deferred laser group (Table 2). In a subset of pseudophakic eyes, visual acuity improvement in the triamcinolone þ prompt laser group appeared comparable to that in the ranibizumab groups. No apparent adverse systemic events attributable to study treatment were noted. The authors concluded that intravitreal ranibizumab combined with prompt or deferred laser treatment is more effective than prompt laser alone for the treatment of DME involving the central macula. Bevacizumab (Avastin) is a complete full-length humanized antibody that binds to all isoforms of VEGF-A. It has been used offlabel for many ocular disorders including age-related macular degeneration, PDR, retinal vein occlusions, and DME3. In a retrospective, non-randomized 24-month study, diffuse DME eyes treated with intravitreal bevacizumab, demonstrated a significant improvement in mean BCVA and a reduction of mean central macular thickness compared to baseline37. There were no significant differences in visual outcomes between groups treated with 1.25 mg or 2.5 mg of bevacizumab. A 6-month, randomized, controlled study also found that doses of 1.25 mg and 2.5 mg seemed to have a similar treatment efficacy38. Michaelides et al conducted a prospective, randomized, masked, clinical trial (BOLT study) to compare the efficacy of intravitreal injections of bevacizumab with that of macular laser therapy in 80 patients with persistent CSME39. The 1-year report revealed that the median visual gain was significantly better in the bevacizumab group than in the laser group (Table 3). The efficacy of combining intravitreal bevacizumab with laser photocoagulation as the primary treatment for diffuse DME was evaluated in a randomized three arm clinical trial40. The authors concluded that a combination of intravitreal bevacizumab and sequential grid laser treatments could be used as an initial treatment for diffuse DME. There were four prospective, randomized, clinical trials conducted to compare the efficacy of combination therapy using bevacizumab and triamcinolone with monotherapy or macular laser photocoagulation41e44. Only one of these studies reported marginal improvements in BCVA using combination therapy42. No further beneficial effects of combination therapy using bevacizumab and triamcinolone were demonstrated in the other studies. 3.4. Vitrectomy It has been hypothesized that the role of the vitreous in DME involves mechanical traction of the vitreoretinal interface and the accumulation of factors altering vascular permeability (e.g. VEGF) in the vitreous3. Vitrectomy, with posterior hyaloid removal or internal limiting membrane (ILM) peeling, can remove these two
Table 3 The 1-year visual outcome and main complications of DME treatment with bevacizumab or laser in the BOLT study.
Median number of treatments BCVA change BCVA 10 letters improvement BCVA 15 letters worse Transient IOP 30 mmHg Cataract surgery a b
IVBa (nv42)
Laserb (n ¼ 38)
9 þ8 31.0% 2.4% 7.1% 14.3%
3 0.5 7.9% 26.3% 0 5.3%
IVB ¼ Intravitreal injection 1.25 mg bevacizumab. Laser ¼ Focal or grid laser treatment alone.
factors from diabetic eyes. The safety and efficacy of these procedures have been studied and are discussed in the literature. Otani and Kishi conducted a nonrandomized trial to compare 7 vitrectomized eyes with untreated fellow to assess the efficacy of vitrectomy for DME45. Among patients undergoing vitrectomy, the BCVA improved in 57% and remained unchanged in 43% of the patients. In the control group, visual acuity improved in 14%, remained unchanged in 43%, and decreased in 43% of eyes. Stolba et al conducted a prospective, randomized study to compare the visual outcomes of eyes treated with vitrectomy and ILM peeling with control eyes46. This study enrolled 56 eyes with persistent DME. They found that the vitrectomy group had significantly better visual acuity and retinal thickness changes at 1, 3, and 6 months. The Diabetic Retinopathy Clinical Research Network conducted a prospective cohort study of 87 eyes, to evaluate vitrectomy for DME with at least moderate vision loss and vitreomacular traction47. At 6 months, they reported that 68% of the vitrectomized eyes had at least a 50% reduction in central retinal thickness. Visual acuity improved by 10 letters or more in 38% and deteriorated by 10 letters or more in 22% of vitrectomized eyes. The comparison of vitrectomy and laser photocoagulation on the treatment of persistent DME has been studied by a pilot randomized trial of 20 eyes48. Patel et al reported that there was little evidence of any difference in foveal thickness between the two treatments at 12 months, but that the laser group showed a slight but significant improvement in ETDRS vision compared to the vitrectomy group. The role of ILM peeling in DME treatment has been evaluated in a prospective, randomized study. Bahadir et al reported that the visual acuity outcomes in eyes with vitrectomy without ILM peeling were just as effective as those in the eyes with both vitrectomy and ILM peeling49. The reported complications of vitrectomy for DME include cataracts (7.5e10%), choroidal detachment (8%), epiretinal membrane (8e10.3%), fibrinoid syndrome (8%), glaucoma (1.7e8%), development of hard exudates (3%), macular ischemia (10%), neovascular glaucoma (3.4e8%), retinal detachment (10%), retinal tear (10e20.7%), tractional rhegmatogenous retinal detachment (1.7%), and vitreous hemorrhage (12.1e16%)3.
Table 2 The 1-year visual outcome and main complications of DME treatment with ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser studied by Diabetic Retinopathy Clinical Research Network.
Median number of injections BCVA change BCVA 10 letters improvement BCVA 15 letters worse IOP increased 10 mmHg Cataract surgery a b c d
IVRa (n ¼ 188)
IVR þ laserb (n ¼ 187)
IVTAc þ laser (n ¼ 186)
Sham þ laserd (n ¼ 293)
9 þ9 47% 2% 3% 6%
8 þ9 50% 2% 5% 5%
3 þ4 33% 8% 38% 15%
5 þ3 28% 8% 5% 6%
IVR ¼ intravitreal injection 0.5 mg ranibizumab. IVR þ laser ¼ intravitreal injection 0.5 mg ranibizumab with prompt laser treatment. IVTA þ laser ¼ intravitreal injection 4 mg triamcinolone with prompt laser treatment. Sham þ laser ¼ sham injection and prompt laser treatment.
Current Treatments of Diabetic Macular Edema
3.5. Subthreshold micropulse diode laser photocoagulation (SMDLP) The mechanism of action of SMDLP is based on the delivery of laser pulses that are shorter in duration than the thermal relaxation time of RPE cells. A micropulse laser produces slight temperature increases, selectively damaging RPE cells but not the adjacent photoreceptors or choriocapillaries. SMDLP may have the potential to eliminate the side effects of paracentral scotoma and scar formation3. The efficacy and safety of SMDLP in treating DME, compared to conventional lasers, were studied in three prospective, randomized clinical trials50e52. The results indicated that the visual outcomes of both types of lasers were equal. Scar formation was less in the SMDLP group, and the central retinal sensitivity was significantly increased in the SMDLP group52. 4. Conclusion DME is the major cause of visual impairment in diabetic patients. Macular laser photocoagulation has been the standard treatment for DME during the past 2 decades. Although it can reduce the risk of moderate visual loss in CSME, only a few patients can experience visual improvement after treatment. Macular laser photocoagulation is not beneficial in patients with diffuse DME. Several prospective clinical trials for new modalities of DME treatments were completed in the past few years. The anti-VEGF antibody, ranibizumab, has shown a greater potential than laser treatment in improving visual outcomes of patients with DME in the phase III trial. The bevacizumab, although it was off-label used, demonstrated similar efficacy in smaller prospective trials. Prospective trials for the comparison of the efficacy and complications of treating DME with these 2 VEGF antibodies may be needed. Patients have to receive multiple injections of the VEGF antibodies to maintain the visual gain. The cost implications and risk associated with of injection-related complications increase with the number of injections. Several trails involving different combinations of treatment modalities for DME have been conducted, including laser therapy, and intravitreal injection of triamcinolone acetonide, bevacizumab, or ranibizumab. However, these combination therapies have not proved more efficacious than monotherapy with anti-VEGF antibodies. Since the pathogenesis of DME involves multiple factors, further investigation of a combination of laser, pharmacological and surgical treatment modalities may be needed to achieve the best outcome of DME treatment. References 1. World Health Organization. Diabetes Fact Sheet No 312 Jan 2011. Available from: http://www.who.int/whr/en/ [accessed 02.11]. 2. Chang CH, Shau WY, Jiang YD, et al. Type 2 diabetes prevalence and incidence among adults in Taiwan during 1999-2004: a national health insurance data set study. Diabet Med. 2010;27:636e643. 3. Bhagat N, Grigorian RA, Tutela A, et al. Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol. 2009;54:1e32. 4. Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy IV. Diabetic macular edema. Ophthalmology. 1984;91:1464e1474. 5. Meyer CH. Current treatment approaches in diabetic macular edema. Ophthalmologica. 2007;221:118e131. 6. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103:1796e1806. 7. Lee CM, Olk RJ. Modified grid laser photocoagulation for diffuse diabetic macular edema. Long-term visual results. Ophthalmology. 1991;98:1594e1602. 8. Barkmeier AJ, Nicholson BP, Akduman L. Effectiveness of laser photocoagulation in clinically significant macular edema with focal versus diffuse parafoveal thickening on optical coherence tomography. Ophthalmic Surg Lasers Imaging. 2009;40:472e479.
187 9. Schatz H, Madeira D, McDonald HR, et al. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol. 1991;109:1549e1551. 10. Rutledge BK, Wallow IH, Poulsen GL. Sub-pigment epithelial membranes after photocoagulation for diabetic macular edema. Arch Ophthalmol. 1993;111: 608e613. 11. Diabetic Retinopathy Clinical Research Network. A Randomized Trial of Peribulbar Triamcinolone Acetonide with and without Focal Photocoagulation for Mild Diabetic Macular Edema: a Pilot Study. Ophthalmology. 2007;114: 1190e1196. 12. Entezari M, Ahmadieh H, Dehghan MH. Posterior sub-tenon triamcinolone for refractory diabetic macular edema: A randomized clinical trial. Eur J Ophthalmol. 2005;15:746e750. 13. Verma LK, Vivek MB, Kumar A, et al. A prospective controlled trial to evaluate the adjunctive role of posterior subtenon triamcinolone in the treatment of diffuse diabetic macular edema. J Ocul Pharmacol Ther. 2004;20:277e284. 14. Shimura M, Nakazawa T, Yasuda K, et al. Pretreatment of posterior subtenon injection of triamcinolone acetonide has beneficial effects for grid pattern photocoagulation against diffuse diabetic macular oedema. Br J Ophthalmol. 2007;91:449e454. 15. Tunc M, Onder HI, Kaya M. Posterior sub-Tenon’s capsule triamcinolone injection combined with focal laser photocoagulation for diabetic macular edema. Ophthalmology. 2005;112:1086e1091. 16. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447e1459. 17. Sutter FKP, Simpson JM, Gillies MC. Intravitreal triamcinolone for diabetic macular edema that persists after laser treatment: three-month efficacy and safety results of a prospective, randomized, double-masked, placebocontrolled clinical trial. Ophthalmology. 2004;111:2044e2049. 18. Maia OO Jr, Takahashi BS, Costa RA, et al. Combined laser and intravitreal triamcinolone for proliferative diabetic retinopathy and macular edema: oneyear results of a randomized clinical trial. Am J Ophthalmol. 2009;147:291e297. 19. Kaderli B, Avci R, Gelisken O, et al. Intravitreal triamcinolone as an adjunct in the treatment of concomitant proliferative diabetic retinopathy and diffuse diabetic macular oedema. Combined IVTA and laser treatment for PDR with CSMO. Int Ophthalmol. 2005;26:207e214. 20. Mirshahi A, Shenazandi H, Lashay A, et al. Intravitreal triamcinolone as an adjunct to standard laser therapy in coexisting high-risk proliferative diabetic retinopathy and clinically significant macular edema. Retina. 2010;30: 254e259. 21. 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;114:2162e2167. 22. Yilmaz T, Weaver CD, Gallagher MJ, et al. Intravitreal triamcinolone acetonide injection for treatment of refractory diabetic macular edema: A systematic review. Ophthalmology. 2009;116:902e913. 23. Haller JA, Kuppermann BD, Blumenkranz MS, et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010;128:289e296. 24. 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;125:309e317. 25. Campochiaro PA, Hafiz G, Shah SM, et al. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology. 2010;117: 1393e1399. 26. Yang XL, Liu K, Xu X. Update on treatments of diabetic macular edema. Chin Med J. 2009;122:2784e2790. 27. Aiello LP, Bursell S-E, Clermont A, et al. Vascular endothelial growth factorinduced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta isoform selective inhibitor. Diabetes. 1997;46:1473e1480. 28. 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;125:318e324. 29. 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: 2188e2197. 30. 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;50:1e4. 31. Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized doublemasked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747e1757. 32. Querques G, Bux AV, Fusco AR, et al. Pegaptanib sodium versus pegaptanib sodium combined with macular laser photocoagulation or laser alone for diabetic macular edema. J Ophthalmol. 2009;2009:672178. 33. Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2009;116:2175e2181. 34. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010; 117:2146e2151.
188 35. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33:2399e2405. 36. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064e1077. 37. Arevalo JF, Sanchez JG, Wu L, et al. Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American collaborative retina study group at 24 months. Ophthalmology. 2009;116:1488e1497. 38. Lam DS, Lai TY, Lee VY, et al. Efficacy of 1.25 MG versus 2.5 MG intravitreal bevacizumab for diabetic macular edema: six-month results of a randomized controlled trial. Retina. 2009;29:292e299. 39. Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010;117:1078e1086. 40. Solaiman KA, Diab MM, Abo-Elenin M. Intravitreal bevacizumab and/or macular photocoagulation as a primary treatment for diffuse diabetic macular edema. Retina. 2010;30:1638e1645. 41. Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology. 2009;116:1142e1150. 42. Faghihi H, Roohipoor R, Mohammadi SF, et al. Intravitreal bevacizumab versus combined bevacizumab-triamcinolone versus macular laser photocoagulation in diabetic macular edema. Eur J Ophthalmol. 2008;18:941e948. 43. Soheilian M, Ramezani A, Bijanzadeh B, et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular
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44.
45. 46. 47.
48.
49.
50. 51.
52.
photocoagulation as primary treatment of diabetic macular edema. Retina. 2007;27:1187e1195. Ahmadieh H, Ramezani A, Shoeibi N, et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebocontrolled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol. 2008; 246:483e489. Otani T, Kishi S. A controlled study of vitrectomy for diabetic macular edema. Am J Ophthalmol. 2002;134:214e219. Stolba U, Binder S, Gruber D, et al. Vitrectomy for persistent diffuse diabetic macular edema. Am J Ophthalmol. 2005;140:295e301. Diabetic Retinopathy Clinical Research Network Writing Committee, Haller JA, Qin H, Apte RS, et al. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology. 2010;117:1087e1093. Patel JI, Hykin PG, Schadt M, et al. Diabetic macular oedema: pilot randomised trial of pars plana vitrectomy vs macular argon photocoagulation. Eye (Lond). 2006;20:873e881. lu O. Visual acuity comparison of vitrectomy with Bahadir M, Ertan A, Mertog and without internal limiting membrane removal in the treatment of diabetic macular edema. Int Ophthalmol. 2005;26:3e8. Laursen ML, Moeller F, Sander B, et al. Subthreshold micropulse diode laser treatment in diabetic macular oedema. Br J Ophthalmol. 2004;88:1173e1179. Figueira J, Khan J, Nunes S, et al. Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema. Br J Ophthalmol. 2009;93:1341e1344. Vujosevic S, Bottega E, Casciano M, et al. Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina. 2010;30:908e916.
Contents lists available at SciVerse ScienceDirect
International Journal of Gerontology journal homepage: www.ijge-online.com
Review Article
Current Treatments of Diabetic Macular Edemaq Wei-Chun Chan 1, Shawn H. Tsai 1, Ai-Ching Wu 1, Lee-Jen Chen 1 *, Chi-Chun Lai 2 ** 1
Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan, 2 Department of Ophthalmology, Chang Gung Memorial Hospital, Linkuo Medical Center, Taiwan
a r t i c l e i n f o
s u m m a r y
Article history: Received 14 March 2011 Accepted 15 March 2011 Available online 20 January 2012
Diabetic macular edema (DME) is a major cause of visual impairment in diabetic patients. Laser photocoagulation is the standard management strategy for macular edema, but its results remain unsatisfactory. Several clinical trials of new treatment modalities for DME have been conducted over the past 10 years. We performed a literature search of English articles, published between 2000 and 2010, by using the PubMed database. The keywords searched included “diabetic macular edema and treatment” with limits set to include only clinical trials and review articles, over 50 articles were reviewed. Among the newer treatment modalities reviewed, therapy with anti-vascular endothelial growth factor (VEGF) antibodies showed significantly better efficacy, with level I evidence. However, multiple injections were required to maintain its efficacy. Therefore, the associated complications and cost implications are the major limitations of this treatment. Several combinations of different modalities have been evaluated in the literature, but none are more efficacious than monotherapy with anti-VEGF antibodies. Since DME is a multifactorial disease, further studies involving combinations of modalities or new treatments modalities may be needed to reduce the number of injections required or improve the visual outcomes in case of DME. Copyright Ó 2011, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: bevacizumab, diabetes mellitus, laser, macular edema, ranibizumab
1. Introduction Diabetic mellitus is an important issue in public health, especially in the elderly. More than 220 million people worldwide have diabetes (90% type 2 diabetes). Ten percent of these develop severe visual impairment after 15 years of diabetes1. According to a study by Chan et al2, the prevalence of type 2 diabetes in the old age group (> 60 years old) in Taiwan was significantly greater than in the young age group (20 w 40 years old) in both genders. The prevalence in old age groups was 20.5 w 26.3% and that in young
q The authors of this article have no financial interests related to the material in the manuscript. They certify that affiliations with, or financial involvement in, within the past 5 years and foreseeable future, any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript, are completely disclosed (e.g., employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, royalties). * Correspondence to: Dr Lee-Jen Chen, MD, Director of Department of Ophthalmology of Mackay Memorial Hospital, Number 92, Section 2, Chun Shan North Road, Taipei 104, Taiwan. ** Correspondence to: Dr Chi-Chun Lai, MD, Professor & Vice Chairman of Ophthalmology of Chang Gung Memorial Hospital, Linkuo Medical Center, 5. Fu-Hsing St., Kwei-Shan, Taoyuan 333, Taiwan. E-mail addresses: [email protected] (L.-J. Chen), [email protected] (C.-C. Lai).
age groups was 0.6 w 7.6% in 2004. The elderly people have a higher risk of severe visual impairment because of a higher prevalence and longer duration of diabetes. Diabetic macular edema (DME, Fig. 1) is the most common cause of visual impairment in patients with diabetes3. The prevalence of DME was found to be related to the duration of diabetes, as reported in of the Wisconsin Epidemiologic Study of Diabetic Retinopathy4. The prevalence of DME in patients with type 1 diabetes varied from 0% (duration of less than 5 years) to 29% (duration of 20 years or more). The prevalence in patients with type 2 diabetes was similar: 3% in the group with diabetes for less than 5 years and 28% in the group with diabetes for 20 years or more. Approximately 50% of patients with DME will experience a loss of 2 lines of best-corrected visual acuity (BCVA) after 2 years of followup5. It is thus important to treat DME effectively to reduce the possibility of visual loss. Many treatment modalities have been reported, especially in recent years. Here, we review the clinical trials conducted over the past 10 years for the treatment of DME and discuss the results of the comparison studies. 2. Pathogenesis and clinical definition of DME The pathogenesis of DME is complex and involves multiple factors3. It occurs mainly as a result of disruption of the bloodretinal barrier, which leads to increased accumulation of fluid
1873-9598/$ e see front matter Copyright Ó 2011, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.ijge.2011.09.013
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Fig. 1. DME, hard exudate derived from plasma lipoproteins located within 1 disc diameter of the center of the macula.
within the intraretinal layers of the macula. Vasoactive factors such as vascular endothelial growth factor (VEGF), protein kinase C, histamine and others factors that are affected by hypoxia or chronic hyperglycemia may cause breakdown of the blood-retinal barrier. The abnormalities in the structure of the vitreoretinal interface may also play an important role in the pathogenesis of DME. The Early Treatment Diabetic Retinopathy Study (ETDRS) defined DME as retinal thickening or a presence of hard exudates within 1 disc diameter of the center of the macula. The term “clinically significant macular edema” (CSME) is used to characterize the severity of macular edema and for treatment guidelines. CSME is defined by the presence of one or more of the following: retinal thickening at or within 500 mm of the center of the macula, hard exudates at or within 500 mm of the center of the macula if associated with adjacent retinal thickening, or a zone or zones of retinal thickening 1 disc area in size at least part of which is within 1 disc diameter of the center of the macula6. In addition to criteria set by the above definition, fluorescein angiography and optical coherence tomography (OCT) are useful tools to examine the permeability of perimacular vessels and changes in retinal thickness. 3. Current treatment modalities 3.1. Laser photocoagulation for DME The exact mechanism of DME resolution after laser photocoagulation is unknown. One explanation involves laser-induced destruction of oxygen-consuming photoreceptors. Oxygen that normally diffuses from the choriocapillaries into the outer retina can diffuse through the laser scar to the inner retina, thus relieving inner retinal hypoxia. Another hypothesis explains that proliferation of the retinal pigmented epithelium (RPE) induced by laser photocoagulation can produce cytokines to antagonize the permeabilizing effects of VEGF3. Macular laser photocoagulation proposed by ETDRS (Fig. 2) is the standard treatment for DME3. The ETDRS was a prospective, randomized clinical trial to study the effect of laser photocoagulation on DME. The result of ETDRS revealed that patients with mild to moderate nonproliferative diabetic retinopathy (NPDR) with DME, had significantly lower rates of moderate visual loss (defined as a loss of 15 or more letters) in the treated group (12%) than in the deferral group (24%) at the end of 3 years. In the treated group, the risk of moderate visual loss reduced significantly in the patients with CSME, but not in the patients without CSME. The authors
Fig. 2. Examples of laser photocoagulation for DME. (A) focal laser photocoagulations (green spots) are applied on the leaking microaneurysms of focal macular edema; (B) grid laser photocoagulations (green spots) are used to treat diffuse macular edema.
recommended that laser photocoagulation should be considered for all eyes with CSME6. Diffuse DME did not respond well to the grid laser treatment. At a 3-year follow-up study of 302 eyes with diffuse DME, Lee and Olk7 reported 15% of the eyes had visual improvement, 61% remained unchanged, and 24% became worse in visual acuity. Barkmeier et al8 also found the reduction of foveal thickness after laser photocoagulation for CSME was statistically significant in patients with focal parafoveal thickening, but not in patients with diffuse parafoveal thickening. Complications of laser photocoagulation included a visual decrease caused by laser-induced RPE atrophy and subretinal fibrosis involving the central fovea9,10. 3.2. Corticosteroids As described by the above studies, there were many patients with diffuse DME whose condition worsened after grid treatment. Thus, many other modalities of DME treatment were studied. Corticosteroids can suppress activation of the VEGF gene and downregulate the induction of VEGF3. Peribulbar injection (including posterior subtenon injection) alone is not an effective treatment for DME11,12. However, posterior subtenon triamcinolone, as an adjunctive treatment for diffuse DME, can improve the visual outcomes of laser photocoagulation13e15. Intravitreal injection of triamcinolone acetonide (IVTA) as the primary treatment of DME has been studied by the Diabetic Retinopathy Clinical Research Network16. Eight hundred and forty eyes with CSME were randomly assigned into three groups: focal/grid
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laser, IVTA 1 mg, and IVTA 4 mg. In the first year, the mean visual acuity was better in both IVTA groups than in the laser group in the first year. However, after 2 years of treatment, it significantly better in the laser group than in the IVTA groups. There was no significant difference in visual outcome between the two IVTA groups. The main complications of IVTA were glaucoma and cataract formation (Table 1). Although IVTA is less effective than laser photocoagulation for DME as a primary treatment, it may benefit eyes with DME that are refractory to laser treatment. In a prospective, double-masked, placebo-controlled, randomized study of 69 eyes with refractory DME, 55% of treated eyes had visual acuity improvement at 3 months of follow-up compared to only 16% in the placebo group17. Combination therapy using both laser photocoagulation and IVTA for DME has been studied, but the results were not consistent among patients with different severity of diabetic retinopathy. Patients with non-high risk proliferative diabetic retinopathy (PDR) and CSME benefited from combination therapy, but those with NPDR and high risk PDR did not18e21. The therapeutic effect of the triamcinolone is typically seen within 1 week, but in many patients, re-injections are needed every 3 to 6 months as the effect wears out. Repeat intravitreal injections may be needed to maintain the therapeutic effect3,22. Because of the risk and inconvenience of repeat injections, intravitreal sustained- release inserts or implants of dexamethasone and fluocinolone acetonide for persistent DME were studied in randomized, controlled trials23e25. The short-term results were promising and both drugs were well tolerated by patients, but a 3year follow-up of intravitreal dexamethasone implants (Retisert) revealed very high rates of cataracts and glaucoma that required surgical intervention3. 3.3. Anti-VEGF therapy VEGF-A is a major mediator of retinal permeability. Blockage of VEGF can reduce vascular permeability3. There are several drugs against VEGF that have undergone clinical trials for DME treatment in recent years, including protein kinase C (PKC) inhibitors, antiVEGF aptamers, and anti-VEGF antibodies. PKC beta-isoform inhibitors: PKC is activated by hyperglycemia; its b-isoform is an important signaling component for VEGF26. Selective b-isoform PKC inhibitors can suppress VEGF induced retinal permeability27. As such, ruboxistaurin (RBX), has been studied for its effect on DME in a multicenter, double-masked, randomized, placebo-controlled study of 686 patients. The authors concluded that daily oral administration of RBX may delay the progression of DME to a sight-threatening stage28. In another study of 252 patients with moderate to severe NPDR, 32 mg/day RBX significantly reduced the risk of moderate visual loss compared to a placebo29. The effect of RBX on long-standing DME has also been studied; the rate of visual acuity decline was 30% less in the RBX group compared to the placebo group30. The FDA has
Table 1 The 2-year visual outcome and main complications of DME treatment with laser photocoagulation or intravitreal injections of triamcinolone studied by Diabetic Retinopathy Clinical Research Network.
Mean BCVA change BCVA 10 letters improvement BCVA 15 letters worse IOP increased 10 mmHg Cataract surgery
Laser (n ¼ 330)
IVTA 1 mg (n ¼ 256)
IVTA 2 mg (n ¼ 254)
þ1 31% 14% 4% 13%
2 25% 20% 16% 23%
3 28% 20% 33% 51%
IVTA ¼ intravitreal injection of triamcinolone.
requested another phase III trial to determine the efficacy of moderate and severe NPDR before RBX can be approved. Anti-VEGF aptamers: Macugen (pegaptanib) is an aptamer that binds the 165-isoform of VEGF. The efficacy and safety of intravitreal pegaptanib for use in DME treatment were evaluated in a phase II, randomized, double-masked study of 172 patients31. Laser photocoagulation and reinjection of pegaptanib were used as supplemental treatments after the first 3 monthly injections. The results revealed that median visual acuity after 6 months was significantly better in the group with the 0.3 mg intravitreal injections versus the control group (20/50 vs. 20/63). The proportion of patients with visual acuity improving 10 letters or more was larger in the 0.3 mg injection group than in the control group (34% vs. 10%). A solely retrospective study revealed that intravitreal pegaptanib treatment alone may be superior to macular laser photocoagulation for DME; further prospective clinical trials are needed32. Anti-VEGF antibodies: Ranibizumab and bevacizumab are antiVEGF antibodies which have been widely used to treat choroidal neovascular membranes in age-related macular degeneration. Because of the important role of VEGF in the blood-retina barrier breakdown associated with DME, these anti-VEGF antibodies were studied for the treatment of DME. Ranibizumab (Lucentis) is a Fab fragment of an anti-VEGF antibody. Its efficacy, compared to laser photocoagulation, was studied in 126 patients with DME in a prospective, randomized, phase II READ-2 (Ranibizumab for Edema of the mAcula in Diabetes) study33. The 6-month result of this clinical trial revealed that the mean gain in BCVA was significantly greater in the ranibizumab injection group compared with the laser photocoagulation group (þ7.24 vs. e0.43 letters). The rate of BCVA improvement of 3 lines or more was significantly higher in the ranibizumab injection group. After the primary end point (month 6), most patients in the READ-2 study were treated only with intravitreal injections of ranibizumab34. At the end of this 24-month study, the authors concluded that intraocular injections of ranibizumab provided benefits for patients with DME, and when combined with focal or grid laser treatments, the frequency of injections needed to control edema were reduced. The RESOLVE study was a 12-month, multicenter, placebocontrolled, double-masked study with eyes randomly assigned to receive either intravitreal ranibizumab (0.3 or 0.5 mg) or placebo35. The treatment schedule comprised 3 monthly injections, after which treatment could be stopped or reinitiated based on treatment success, disease activity, or safety criteria. Laser photocoagulation could be used as rescue therapy. At month 12, the mean BCVA improvement from baseline was significantly better in the ranibizumab treated group (combination of 0.3 and 0.5 mg groups) than the placebo group (þ10.3 vs. e1.4 letters). A gain in the BCVA of 10 letters over the baseline occurred in 60.8% of eyes in the ranibizumab group and 18.4% of eyes in the control group. The mean numbers of injections administered during 12 months were 10.2 and 8.9 for the ranibizumab and controls, respectively. Severe ocular adverse events (suspected to be drug-related) in the intravitreal ranibizumab group (102 eyes) included vitreous hemorrhage (1 eye), retinal artery occlusion (1 eye), and endophthalmitis (2 eyes). Ocular adverse events which were suspected to be drugrelated included conjunctival hemorrhage (23 eyes) and eye pain (18 eyes). Non-ocular adverse events potentially related to systemic VEGF inhibition included arterial thromboembolic events (3 patients), hypertension (9 patients), and nonocular hemorrhage (2 patients). The Diabetic Retinopathy Clinical Research Network conducted a phase III, randomized, multicenter clinical trial of 854 DME eyes, to evaluate the effects of treatment with intravitreal ranibizumab
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(0.5 mg) or triamcinolone (4 mg) combined with focal/grid laser compared to focal/grid laser alone36. The 1 year mean change in the visual acuity letter score from baseline was significantly better in the ranibizumab þ prompt laser group and the ranibizumab þ deferred laser group (Table 2). In a subset of pseudophakic eyes, visual acuity improvement in the triamcinolone þ prompt laser group appeared comparable to that in the ranibizumab groups. No apparent adverse systemic events attributable to study treatment were noted. The authors concluded that intravitreal ranibizumab combined with prompt or deferred laser treatment is more effective than prompt laser alone for the treatment of DME involving the central macula. Bevacizumab (Avastin) is a complete full-length humanized antibody that binds to all isoforms of VEGF-A. It has been used offlabel for many ocular disorders including age-related macular degeneration, PDR, retinal vein occlusions, and DME3. In a retrospective, non-randomized 24-month study, diffuse DME eyes treated with intravitreal bevacizumab, demonstrated a significant improvement in mean BCVA and a reduction of mean central macular thickness compared to baseline37. There were no significant differences in visual outcomes between groups treated with 1.25 mg or 2.5 mg of bevacizumab. A 6-month, randomized, controlled study also found that doses of 1.25 mg and 2.5 mg seemed to have a similar treatment efficacy38. Michaelides et al conducted a prospective, randomized, masked, clinical trial (BOLT study) to compare the efficacy of intravitreal injections of bevacizumab with that of macular laser therapy in 80 patients with persistent CSME39. The 1-year report revealed that the median visual gain was significantly better in the bevacizumab group than in the laser group (Table 3). The efficacy of combining intravitreal bevacizumab with laser photocoagulation as the primary treatment for diffuse DME was evaluated in a randomized three arm clinical trial40. The authors concluded that a combination of intravitreal bevacizumab and sequential grid laser treatments could be used as an initial treatment for diffuse DME. There were four prospective, randomized, clinical trials conducted to compare the efficacy of combination therapy using bevacizumab and triamcinolone with monotherapy or macular laser photocoagulation41e44. Only one of these studies reported marginal improvements in BCVA using combination therapy42. No further beneficial effects of combination therapy using bevacizumab and triamcinolone were demonstrated in the other studies. 3.4. Vitrectomy It has been hypothesized that the role of the vitreous in DME involves mechanical traction of the vitreoretinal interface and the accumulation of factors altering vascular permeability (e.g. VEGF) in the vitreous3. Vitrectomy, with posterior hyaloid removal or internal limiting membrane (ILM) peeling, can remove these two
Table 3 The 1-year visual outcome and main complications of DME treatment with bevacizumab or laser in the BOLT study.
Median number of treatments BCVA change BCVA 10 letters improvement BCVA 15 letters worse Transient IOP 30 mmHg Cataract surgery a b
IVBa (nv42)
Laserb (n ¼ 38)
9 þ8 31.0% 2.4% 7.1% 14.3%
3 0.5 7.9% 26.3% 0 5.3%
IVB ¼ Intravitreal injection 1.25 mg bevacizumab. Laser ¼ Focal or grid laser treatment alone.
factors from diabetic eyes. The safety and efficacy of these procedures have been studied and are discussed in the literature. Otani and Kishi conducted a nonrandomized trial to compare 7 vitrectomized eyes with untreated fellow to assess the efficacy of vitrectomy for DME45. Among patients undergoing vitrectomy, the BCVA improved in 57% and remained unchanged in 43% of the patients. In the control group, visual acuity improved in 14%, remained unchanged in 43%, and decreased in 43% of eyes. Stolba et al conducted a prospective, randomized study to compare the visual outcomes of eyes treated with vitrectomy and ILM peeling with control eyes46. This study enrolled 56 eyes with persistent DME. They found that the vitrectomy group had significantly better visual acuity and retinal thickness changes at 1, 3, and 6 months. The Diabetic Retinopathy Clinical Research Network conducted a prospective cohort study of 87 eyes, to evaluate vitrectomy for DME with at least moderate vision loss and vitreomacular traction47. At 6 months, they reported that 68% of the vitrectomized eyes had at least a 50% reduction in central retinal thickness. Visual acuity improved by 10 letters or more in 38% and deteriorated by 10 letters or more in 22% of vitrectomized eyes. The comparison of vitrectomy and laser photocoagulation on the treatment of persistent DME has been studied by a pilot randomized trial of 20 eyes48. Patel et al reported that there was little evidence of any difference in foveal thickness between the two treatments at 12 months, but that the laser group showed a slight but significant improvement in ETDRS vision compared to the vitrectomy group. The role of ILM peeling in DME treatment has been evaluated in a prospective, randomized study. Bahadir et al reported that the visual acuity outcomes in eyes with vitrectomy without ILM peeling were just as effective as those in the eyes with both vitrectomy and ILM peeling49. The reported complications of vitrectomy for DME include cataracts (7.5e10%), choroidal detachment (8%), epiretinal membrane (8e10.3%), fibrinoid syndrome (8%), glaucoma (1.7e8%), development of hard exudates (3%), macular ischemia (10%), neovascular glaucoma (3.4e8%), retinal detachment (10%), retinal tear (10e20.7%), tractional rhegmatogenous retinal detachment (1.7%), and vitreous hemorrhage (12.1e16%)3.
Table 2 The 1-year visual outcome and main complications of DME treatment with ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser studied by Diabetic Retinopathy Clinical Research Network.
Median number of injections BCVA change BCVA 10 letters improvement BCVA 15 letters worse IOP increased 10 mmHg Cataract surgery a b c d
IVRa (n ¼ 188)
IVR þ laserb (n ¼ 187)
IVTAc þ laser (n ¼ 186)
Sham þ laserd (n ¼ 293)
9 þ9 47% 2% 3% 6%
8 þ9 50% 2% 5% 5%
3 þ4 33% 8% 38% 15%
5 þ3 28% 8% 5% 6%
IVR ¼ intravitreal injection 0.5 mg ranibizumab. IVR þ laser ¼ intravitreal injection 0.5 mg ranibizumab with prompt laser treatment. IVTA þ laser ¼ intravitreal injection 4 mg triamcinolone with prompt laser treatment. Sham þ laser ¼ sham injection and prompt laser treatment.
Current Treatments of Diabetic Macular Edema
3.5. Subthreshold micropulse diode laser photocoagulation (SMDLP) The mechanism of action of SMDLP is based on the delivery of laser pulses that are shorter in duration than the thermal relaxation time of RPE cells. A micropulse laser produces slight temperature increases, selectively damaging RPE cells but not the adjacent photoreceptors or choriocapillaries. SMDLP may have the potential to eliminate the side effects of paracentral scotoma and scar formation3. The efficacy and safety of SMDLP in treating DME, compared to conventional lasers, were studied in three prospective, randomized clinical trials50e52. The results indicated that the visual outcomes of both types of lasers were equal. Scar formation was less in the SMDLP group, and the central retinal sensitivity was significantly increased in the SMDLP group52. 4. Conclusion DME is the major cause of visual impairment in diabetic patients. Macular laser photocoagulation has been the standard treatment for DME during the past 2 decades. Although it can reduce the risk of moderate visual loss in CSME, only a few patients can experience visual improvement after treatment. Macular laser photocoagulation is not beneficial in patients with diffuse DME. Several prospective clinical trials for new modalities of DME treatments were completed in the past few years. The anti-VEGF antibody, ranibizumab, has shown a greater potential than laser treatment in improving visual outcomes of patients with DME in the phase III trial. The bevacizumab, although it was off-label used, demonstrated similar efficacy in smaller prospective trials. Prospective trials for the comparison of the efficacy and complications of treating DME with these 2 VEGF antibodies may be needed. Patients have to receive multiple injections of the VEGF antibodies to maintain the visual gain. The cost implications and risk associated with of injection-related complications increase with the number of injections. Several trails involving different combinations of treatment modalities for DME have been conducted, including laser therapy, and intravitreal injection of triamcinolone acetonide, bevacizumab, or ranibizumab. However, these combination therapies have not proved more efficacious than monotherapy with anti-VEGF antibodies. Since the pathogenesis of DME involves multiple factors, further investigation of a combination of laser, pharmacological and surgical treatment modalities may be needed to achieve the best outcome of DME treatment. References 1. World Health Organization. Diabetes Fact Sheet No 312 Jan 2011. Available from: http://www.who.int/whr/en/ [accessed 02.11]. 2. Chang CH, Shau WY, Jiang YD, et al. Type 2 diabetes prevalence and incidence among adults in Taiwan during 1999-2004: a national health insurance data set study. Diabet Med. 2010;27:636e643. 3. Bhagat N, Grigorian RA, Tutela A, et al. Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol. 2009;54:1e32. 4. Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy IV. Diabetic macular edema. Ophthalmology. 1984;91:1464e1474. 5. Meyer CH. Current treatment approaches in diabetic macular edema. Ophthalmologica. 2007;221:118e131. 6. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103:1796e1806. 7. Lee CM, Olk RJ. Modified grid laser photocoagulation for diffuse diabetic macular edema. Long-term visual results. Ophthalmology. 1991;98:1594e1602. 8. Barkmeier AJ, Nicholson BP, Akduman L. Effectiveness of laser photocoagulation in clinically significant macular edema with focal versus diffuse parafoveal thickening on optical coherence tomography. Ophthalmic Surg Lasers Imaging. 2009;40:472e479.
187 9. Schatz H, Madeira D, McDonald HR, et al. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol. 1991;109:1549e1551. 10. Rutledge BK, Wallow IH, Poulsen GL. Sub-pigment epithelial membranes after photocoagulation for diabetic macular edema. Arch Ophthalmol. 1993;111: 608e613. 11. Diabetic Retinopathy Clinical Research Network. A Randomized Trial of Peribulbar Triamcinolone Acetonide with and without Focal Photocoagulation for Mild Diabetic Macular Edema: a Pilot Study. Ophthalmology. 2007;114: 1190e1196. 12. Entezari M, Ahmadieh H, Dehghan MH. Posterior sub-tenon triamcinolone for refractory diabetic macular edema: A randomized clinical trial. Eur J Ophthalmol. 2005;15:746e750. 13. Verma LK, Vivek MB, Kumar A, et al. A prospective controlled trial to evaluate the adjunctive role of posterior subtenon triamcinolone in the treatment of diffuse diabetic macular edema. J Ocul Pharmacol Ther. 2004;20:277e284. 14. Shimura M, Nakazawa T, Yasuda K, et al. Pretreatment of posterior subtenon injection of triamcinolone acetonide has beneficial effects for grid pattern photocoagulation against diffuse diabetic macular oedema. Br J Ophthalmol. 2007;91:449e454. 15. Tunc M, Onder HI, Kaya M. Posterior sub-Tenon’s capsule triamcinolone injection combined with focal laser photocoagulation for diabetic macular edema. Ophthalmology. 2005;112:1086e1091. 16. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447e1459. 17. Sutter FKP, Simpson JM, Gillies MC. Intravitreal triamcinolone for diabetic macular edema that persists after laser treatment: three-month efficacy and safety results of a prospective, randomized, double-masked, placebocontrolled clinical trial. Ophthalmology. 2004;111:2044e2049. 18. Maia OO Jr, Takahashi BS, Costa RA, et al. Combined laser and intravitreal triamcinolone for proliferative diabetic retinopathy and macular edema: oneyear results of a randomized clinical trial. Am J Ophthalmol. 2009;147:291e297. 19. Kaderli B, Avci R, Gelisken O, et al. Intravitreal triamcinolone as an adjunct in the treatment of concomitant proliferative diabetic retinopathy and diffuse diabetic macular oedema. Combined IVTA and laser treatment for PDR with CSMO. Int Ophthalmol. 2005;26:207e214. 20. Mirshahi A, Shenazandi H, Lashay A, et al. Intravitreal triamcinolone as an adjunct to standard laser therapy in coexisting high-risk proliferative diabetic retinopathy and clinically significant macular edema. Retina. 2010;30: 254e259. 21. 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;114:2162e2167. 22. Yilmaz T, Weaver CD, Gallagher MJ, et al. Intravitreal triamcinolone acetonide injection for treatment of refractory diabetic macular edema: A systematic review. Ophthalmology. 2009;116:902e913. 23. Haller JA, Kuppermann BD, Blumenkranz MS, et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010;128:289e296. 24. 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;125:309e317. 25. Campochiaro PA, Hafiz G, Shah SM, et al. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology. 2010;117: 1393e1399. 26. Yang XL, Liu K, Xu X. Update on treatments of diabetic macular edema. Chin Med J. 2009;122:2784e2790. 27. Aiello LP, Bursell S-E, Clermont A, et al. Vascular endothelial growth factorinduced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta isoform selective inhibitor. Diabetes. 1997;46:1473e1480. 28. 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;125:318e324. 29. 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: 2188e2197. 30. 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;50:1e4. 31. Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized doublemasked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747e1757. 32. Querques G, Bux AV, Fusco AR, et al. Pegaptanib sodium versus pegaptanib sodium combined with macular laser photocoagulation or laser alone for diabetic macular edema. J Ophthalmol. 2009;2009:672178. 33. Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2009;116:2175e2181. 34. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010; 117:2146e2151.
188 35. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33:2399e2405. 36. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064e1077. 37. Arevalo JF, Sanchez JG, Wu L, et al. Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American collaborative retina study group at 24 months. Ophthalmology. 2009;116:1488e1497. 38. Lam DS, Lai TY, Lee VY, et al. Efficacy of 1.25 MG versus 2.5 MG intravitreal bevacizumab for diabetic macular edema: six-month results of a randomized controlled trial. Retina. 2009;29:292e299. 39. Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010;117:1078e1086. 40. Solaiman KA, Diab MM, Abo-Elenin M. Intravitreal bevacizumab and/or macular photocoagulation as a primary treatment for diffuse diabetic macular edema. Retina. 2010;30:1638e1645. 41. Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology. 2009;116:1142e1150. 42. Faghihi H, Roohipoor R, Mohammadi SF, et al. Intravitreal bevacizumab versus combined bevacizumab-triamcinolone versus macular laser photocoagulation in diabetic macular edema. Eur J Ophthalmol. 2008;18:941e948. 43. Soheilian M, Ramezani A, Bijanzadeh B, et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular
W.-C. Chan et al.
44.
45. 46. 47.
48.
49.
50. 51.
52.
photocoagulation as primary treatment of diabetic macular edema. Retina. 2007;27:1187e1195. Ahmadieh H, Ramezani A, Shoeibi N, et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebocontrolled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol. 2008; 246:483e489. Otani T, Kishi S. A controlled study of vitrectomy for diabetic macular edema. Am J Ophthalmol. 2002;134:214e219. Stolba U, Binder S, Gruber D, et al. Vitrectomy for persistent diffuse diabetic macular edema. Am J Ophthalmol. 2005;140:295e301. Diabetic Retinopathy Clinical Research Network Writing Committee, Haller JA, Qin H, Apte RS, et al. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology. 2010;117:1087e1093. Patel JI, Hykin PG, Schadt M, et al. Diabetic macular oedema: pilot randomised trial of pars plana vitrectomy vs macular argon photocoagulation. Eye (Lond). 2006;20:873e881. lu O. Visual acuity comparison of vitrectomy with Bahadir M, Ertan A, Mertog and without internal limiting membrane removal in the treatment of diabetic macular edema. Int Ophthalmol. 2005;26:3e8. Laursen ML, Moeller F, Sander B, et al. Subthreshold micropulse diode laser treatment in diabetic macular oedema. Br J Ophthalmol. 2004;88:1173e1179. Figueira J, Khan J, Nunes S, et al. Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema. Br J Ophthalmol. 2009;93:1341e1344. Vujosevic S, Bottega E, Casciano M, et al. Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina. 2010;30:908e916.