Skip to main content
Top

14-02-2017 | Macular edema | Review | Article

Therapeutic Options in Refractory Diabetic Macular Oedema

Journal: Drugs

Authors: Sanket U. Shah, Raj K. Maturi

Publisher: Springer International Publishing

Abstract

Diabetic macular oedema (DMO) results from alterations of several biochemical pathways in diabetic eyes. Centre-involving DMO is an important cause of visual loss in diabetes. Anti-vascular endothelial growth factor agents are now the mainstay of centre-involving DMO treatment. Oedema that does not achieve optimal response to these agents occurs in a sizeable proportion of eyes and is called refractory or persistent DMO. Management of refractory DMO is challenging. In this paper, the pathophysiology of DMO, and the definitions used in various studies are summarised. Therapeutic options for refractory DMO management including corticosteroids, laser, combination therapies, and surgery are explored. Novel agents on the horizon for DMO control that are being investigated at present are discussed as well. A literature review was performed and a summary of the research studies for each of the agents is provided in order to guide the reader regarding the existing evidence for their application in DMO. Importance of early recognition of disease and prompt treatment to achieve best visual outcome is discussed. Utility of optical coherence tomography to guide disease diagnosis and monitoring is highlighted. An algorithmic approach for DMO management is described. Finally, the impact that personalized medicine and genetics might have on DMO management is assessed.
Literature
1.
Ding J, Wong TY. Current epidemiology of diabetic retinopathy and diabetic macular edema. Curr Diab Rep. 2012;12:346–54.CrossRefPubMed
2.
Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609–14.CrossRefPubMedPubMedCentral
3.
Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120:2013–22.CrossRefPubMed
4.
Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the da VINCI study of VEGF trap-eye in eyes with diabetic macular edema. Ophthalmology. 2012;119:1658–65.CrossRefPubMed
5.
Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193–203.
6.
Miyamoto K, Khosrof S, Bursell SE, et al. Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol. 2000;156:1733–9.CrossRefPubMedPubMedCentral
7.
Miyamoto K, Khosrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci USA. 1999;96:10836–41.CrossRefPubMedPubMedCentral
8.
Sohn HJ, Han DH, Kim IT, et al. Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. Am J Ophthalmol. 2011;152:686–94.CrossRefPubMed
9.
Felinski E, Antonetti D. Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy. Curr Eye Res. 2005;30:949–57.CrossRefPubMed
10.
Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol. 2006;142:961–9.CrossRefPubMed
11.
Noma H, Mimura T, Yasuda K, Shimura M. Role of inflammation in diabetic macular edema. Ophthalmologica. 2014;232:127–35.CrossRefPubMed
12.
Funatsu H, Noma H, Mimura T, Eguchi S, Hori S. Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology. 2009;116:73–9.CrossRefPubMed
13.
Jonas JB, Jonas RA, Neumaier M, Findeisen P. Cytokine concentration in aqueous humor of eyes with diabetic macular edema. Retina. 2012;32:2150–7.CrossRefPubMed
14.
Amoaku WMK, Saker S, Stewart EA. A review of therapies for diabetic macular oedema and rationale for combination therapy. Eye. 2015;44:1–16.
15.
Cunha-Vaz J, Ashton P, Iezzi R, et al. Sustained delivery fluocinolone acetonide vitreous implants: long-term benefit in patients with chronic diabetic macular edema. Ophthalmology. 2014;121:1892–903.CrossRefPubMed
16.
Hussain RM, Ciulla TA. Treatment strategies for refractory diabetic macular edema: switching anti-VEGF treatments, adopting corticosteroid-based treatments, and combination therapy. Expert Opin Biol Ther. 2016;2598:1–10.
17.
Kowluru RA, Chan PS. Oxidative stress and diabetic retinopathy. Exp Diabetes Res. 2007;2007:43603.PubMedPubMedCentral
18.
Simó R, Hernández C. Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol Metab. 2014;25:23–33.CrossRefPubMed
19.
Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119:2125–32.CrossRefPubMed
20.
Boyer DS, Yoon YH, Belfort R, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121:1904–14.
21.
Whiting DR, Guariguata L, Weil C, Shaw J. IDF Diabetes Atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94:311–21.CrossRefPubMed
22.
Varma R, Bressler NM, Doan QV, et al. Prevalence of and risk factors for diabetic macular edema in the United States. JAMA Ophthalmol. 2014;132:1334–40.CrossRefPubMedPubMedCentral
23.
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(1064–1077):e35.
24.
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789–801.CrossRefPubMed
25.
Bressler SB, Ayala AR, Bressler NM, et al. Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment. JAMA Ophthalmol. 2016;134:1–8.
26.
Uji A, Murakami T, Nishijima K, et al. Association between hyperreflective foci in the outer retina, status of photoreceptor layer, and visual acuity in diabetic macular edema. Am J Ophthalmol. 2012;153:710–7.CrossRefPubMed
27.
Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology. 2014;121:1045–53.CrossRefPubMed
28.
Agarwal A, Ingham SA, Harkins KA, Do DV, Nguyen QD. The role of pharmacogenetics and advances in gene therapy in the treatment of diabetic retinopathy. Pharmacogenomics. 2016;17:309–20.CrossRefPubMed
29.
Stewart MW. Pharmacokinetics, pharmacodynamics and pre-clinical characteristics of ophthalmic drugs that bind VEGF. Expert Rev Clin Pharmacol. 2014;7:167–80.CrossRefPubMed
30.
Moradi A, Sepah YJ, Sadiq MA, et al. Vascular endothelial growth factor trap-eye (aflibercept) for the management of diabetic macular edema. World J Diabetes. 2013;4:303–9.CrossRefPubMedPubMedCentral
31.
Dhoot DS, Pieramici DJ, Nasir M, et al. Residual edema evaluation with ranibizumab 0.5 mg and 2.0 mg formulations for diabetic macular edema (REEF study). Eye. 2015;29:534–41.CrossRefPubMedPubMedCentral
32.
Katz G, Moisseiev E, Goldenberg D, et al. Ranibizumab for persistent diabetic macular edema after bevacizumab treatment. Eur J Ophthalmol. 2016. doi:10.​5301/​ejo.​5000838.
33.
Ehrlich R, Dan I, Deitch I, Axer-Siegel R, Mimouni K. The effectiveness of intravitreal Ranibizumab in patients with diabetic macular edema who have failed to respond to intravitreal bevacizumab. Ophthalmologica. 2016;235:133–6.CrossRefPubMed
34.
Ciulla TA, Hussain RM, Ciulla LM, Sink B, Harris A. Ranibizumab for diabetic macular edema refractory to multiple prior treatments. Retina. 2016;36:1292–7.CrossRefPubMed
35.
Wood EH, Karth PA, Moshfeghi DM, Leng T. Short-term outcomes of aflibercept therapy for diabetic macular edema in patients with incomplete response to ranibizumab and/or bevacizumab. Ophthalmic Surg Lasers Imaging Retina. 2015;46:950–4.CrossRefPubMed
36.
Lim LS, Ng WY, Mathur R, et al. Conversion to aflibercept for diabetic macular edema unresponsive to ranibizumab or bevacizumab. Clin Ophthalmol. 2015;9:1715–8.CrossRefPubMedPubMedCentral
37.
Rahimy E, Shahlaee A, Khan MA, Ying G-S, Maguire JI, Ho AC, et al. Conversion to aflibercept after prior anti-VEGF therapy for persistent diabetic macular edema. Am J Ophthalmol. 2016;164:118–27.CrossRefPubMed
38.
Wilson CA, Berkowitz BA, Sato Y, Ando N, Handa JT, de Juan E. Treatment with intravitreal steroid reduces blood-retinal barrier breakdown due to retinal photocoagulation. Arch Ophthalmol. 1992;110:1155–9.CrossRefPubMed
39.
Bhisitkul RB, Winn BJ, Lee O-T, et al. Neuroprotective effect of intravitreal triamcinolone acetonide against photoreceptor apoptosis in a rabbit model of subretinal hemorrhage. Investig Ophthalmol Vis Sci. 2008;49:4071–7.CrossRef
40.
Glybina IV, Kennedy A, Ashton P, Abrams GW, Iezzi R. Intravitreous delivery of the corticosteroid fluocinolone acetonide attenuates retinal degeneration in S334ter-4 rats. Investig Ophthalmol Vis Sci. 2010;51:4243–52.CrossRef
41.
Grover D, Li TJ, Chong CCW. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev. 2008;17:CD005656.
42.
Zhioua I, Semoun O, Lalloum F, Souied EH. Intravitreal dexamethasone implant in patients with ranibizumab persistent diabetic macular edema. Retina. 2015;35:11–6.CrossRef
43.
Pacella F, Ferraresi AF, Turchetti P, et al. Intravitreal injection of Ozurdex(®) implant in patients with persistent diabetic macular edema, with six-month follow-up. Ophthalmol Eye Dis. 2016;8:11–6.CrossRefPubMedPubMedCentral
44.
Shah SU, Harless A, Bleau L, Maturi RK. Prospective randomized subject-masked study of intravitreal bevacizumab monotherapy versus dexamethasone implant monotherapy in the treatment of persistent diabetic macular edema. Retina. 2016;36:1986–96.CrossRefPubMed
45.
Ramu J, Yang Y, Menon G, et al. A randomized clinical trial comparing fixed vs pro-re-nata dosing of Ozurdex in refractory diabetic macular oedema (OZDRY study). Eye. 2015;44:1–10.
46.
Scaramuzzi M, Querques G, La Spina C, Lattanzio R, Bandello F. Repeated intravitreal dexamethasone implant (Ozurdex) for diabetic macular edema. Retina. 2015;35:1.CrossRef
47.
Arıkan Yorgun M, Toklu Y, Mutlu M. Comparison of early dexamethasone retreatment versus standard dexamethasone regimen combined with PRN ranibizumab in diabetic macular edema. Int Ophthalmol. 2017;37:185–196.
48.
Malclès A, Dot C, Voirin N, et al. Real-life study in diabetic macular edema treated with dexamethasone implant: the reldex study. Retina. 2016. doi:10.​1097/​IAE.​0000000000001234​.
49.
Shah AR, Xi M, Abbey AM, et al. Short-term efficacy of intravitreal dexamethasone implant in vitrectomized eyes with recalcitrant diabetic macular edema and prior anti-VEGF therapy. J Ophthalmic Vis Res. 2016;11:183–7.CrossRefPubMedPubMedCentral
50.
Lee DH, Kim YJ, Yoon YH. Minimally invasive microincision vitrectomy surgery with an intraoperative dexamethasone implant for refractory diabetic macular edema. Ophthalmologica. 2016;235:150–6.
51.
Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. 2011;31:915–23.CrossRefPubMed
52.
Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment. Ophthalmology. 2012;119:2312–8.CrossRefPubMed
53.
Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122:375–81.CrossRefPubMed
54.
Vujosevic S, Martini F, Longhin E, et al. Subthreshold micropulse yellow laser versus subthreshold micropulse infrared laser in centre-involving diabetic macular edema: morphologic and functional safety. Retina. 2015;35:1594–603.CrossRefPubMed
55.
Chen G, Tzekov R, Li W, et al. Subthreshold micropulse diode laser versus conventional laser photocoagulation for diabetic macular edema: a meta-analysis of randomized controlled trials. Retina. 2016;36:2059–65.
56.
Yolcu Ü, Sobaci G. The effect of combined treatment of bevacizumab and triamcinolone for diabetic macular edema refractory to previous intravitreal mono-injections. Int Ophthalmol. 2015;35:73–9.CrossRefPubMed
57.
Shoeibi N, Ahmadieh H, Entezari M, Yaseri M. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema: long-term results of a clinical trial. J Ophthalmic Vis Res. 2013;8:99–106.PubMedPubMedCentral
58.
Maturi RK, Bleau L, Saunders J, Mubasher M, Stewart MW. A 12-month, single-masked, randomized controlled study of eyes with persistent diabetic macular edema after multiple anti-VEGF injections to assess the efficacy of the dexamethasone-delayed delivery system as an adjunct to bevacizumab compared with continued bevacizumab monotherapy. Retina. 2015;35:1604–14.CrossRefPubMed
59.
Callanan DG, Gupta S, Boyer DS, et al. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology. 2013;120:1843–51.CrossRefPubMed
60.
Chan CKM, Lai TYY, Mohamed S, et al. Combined high-dose sub-tenon triamcinolone, intravitreal bevacizumab, and laser photocoagulation for refractory diabetic macular edema: a pilot study. Retina. 2012;32:672–8.CrossRefPubMed
61.
Kim YT, Kang SW, Kim SJ, Kim SM, Chung SE. Combination of vitrectomy, IVTA, and laser photocoagulation for diabetic macular edema unresponsive to prior treatments; 3-year results. Graefes Arch Clin Exp Ophthalmol. 2012;250:679–84.CrossRefPubMed
62.
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;117:1087–1093.
63.
Flaxel CJ, Edwards AR, Aiello LP, et al. Factors associated with visual acuity outcomes after vitrectomy for diabetic macular edema: diabetic retinopathy clinical research network. Retina. 2010;30:1488–95.CrossRefPubMed
64.
Stefánsson E. Physiology of vitreous surgery. Graefes Arch Clin Exp Ophthalmol. 2009;247:147–63.CrossRefPubMed
65.
Bonnin S, Sandali O, Bonnel S, Monin C, El Sanharawi M. Vitrectomy with internal limiting membrane peeling for tractional and nontractional diabetic macular edema: long-term results of a comparative study. Retina. 2015;35:921–8.CrossRefPubMed
66.
Ahmadieh H, Nourinia R, Hafezi-Moghadam A. Intravitreal fasudil combined with bevacizumab for persistent diabetic macular edema: a novel treatment. JAMA Ophthalmol. 2013;131:923–4.CrossRefPubMed
67.
Isidori AM, Venneri MA, Fiore D. Angiopoietin-1 and Angiopoietin-2 in metabolic disorders: therapeutic strategies to restore the highs and lows of angiogenesis in diabetes. J Endocrinol Investig. 2016;39:1235–46.CrossRef
68.
Campochiaro PA, Sophie R, Tolentino M, et al. Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2. Ophthalmology. 2015;122:545–54.CrossRefPubMed
69.
River Vision Development Corporation. A phase 1, open-label study of teprotumumab in patients with diabetic macular edema (DME) [Internet]. 2014. https://​clinicaltrials.​gov/​ct2/​show/​NCT02103283. Accessed 1 Jan 2016.
70.
Inoue T, Morita M, Tojo T, et al. Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment. Bioorg Med Chem. 2013;21:3873–81.CrossRefPubMed
71.
Dugel PU, Blumenkranz MS, Haller JA, et al. A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema. Ophthalmology. 2012;119:124–31.CrossRefPubMed
72.
Liegl R, Koenig S, Siedlecki J, et al. Temsirolimus inhibits proliferation and migration in retinal pigment epithelial and endothelial cells via mTOR inhibition and decreases VEGF and PDGF expression. PLoS One. 2014;9:e88203.CrossRefPubMedPubMedCentral
73.
Das A, McGuire PG, Monickaraj F. Novel pharmacotherapies in diabetic retinopathy: current status and what’s in the horizon? Indian J Ophthalmol. 2016;64:4–13.CrossRefPubMedPubMedCentral
74.
Campochiaro PA, Channa R, Berger BB, et al. Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am J Ophthalmol. 2013;155:697–704.CrossRefPubMed
75.
Stewart MW, Flynn HW, Schwartz SG, Scott IU. Extended duration strategies for the pharmacologic treatment of diabetic retinopathy: current status and future prospects. Expert Opin Drug Deliv. 2016;5247:1–11.
76.
Cahoon JM, Rai RR, Carroll LS, et al. Intravitreal AAV2.COMP-Ang1 prevents neurovascular degeneration in a murine model of diabetic retinopathy. Diabetes. 2015;64:4247–59.CrossRefPubMedPubMedCentral
77.
Diabetic Retinopathy Clinical Research Network, Browning DJ, Glassman AR, Aiello LP, et al. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology. 2007;114:525–36.
78.
Otani T, Yamaguchi Y, Kishi S. Correlation between visual acuity and foveal microstructural changes in diabetic macular edema. Retina. 2010;30:774–80.CrossRefPubMed
79.
Murakami T, Yoshimura N. Structural changes in individual retinal layers in diabetic macular edema. J Diabetes Res. 2013;2013:920713.CrossRefPubMedPubMedCentral
80.
Sun JK, Lin MM, Lammer J, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with centre-involved diabetic macular edema. JAMA Ophthalmol. 2014;132:1309–16.CrossRefPubMed
81.
Holekamp N. The cost-effectiveness of anti-VEGF treatments for diabetic macular edema. American Society of Retina Specialists. In: 33rd annual meeting, Vienna, Austria. 2015.
82.
Zhang L, Wang W, Gao Y, Lan J, Xie L. The efficacy and safety of current treatments in diabetic macular edema: a systematic review and network meta-analysis. PLoS One. 2016;11:e0159553.CrossRefPubMedPubMedCentral
83.
Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. 2015;314:2137–46.

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform. 

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »