Anti-angiogenic therapy for diabetic macular edema

Cover Page

Cite item

Full Text

Abstract

Diabetic retinopathy remains one of the greatest challenges for healthcare system worldwide despite the fact that the incidence of visual acuity impairment in diabetic population has decreased due to examination quality improvement and dynamic observation of patients. Visual acuity impairment in diabetic patients is often related to diabetic macular edema. Until recently, laser photocoagulation of the retina was regarded as gold standard for diabetic macular edema treatment. Laser photocoagulation of the retina provides visual acuity stabilization rather than improvement. Since early 2000s, pharmacological approach to this severe disease has been established. As vascular endothelial growth factor (VEGF) is one of the crucial factors involved in the pathogenesis of diabetic retinal disorders, VEGF inhibitors are now recognized as a treatment of choice for diabetic macular edema. This article considers results of different clinical trials investigating anti-VEGF therapy efficacy in DME treatment.

About the authors

Fedor E. Shadrichev

Pavlov First Saint Petersburg State Medical University

Author for correspondence.
Email: shadrichev_dr@mail.ru

PhD., Assistant Professor of Pphthalmology Department

Russian Federation, Saint Petersburg

Nyurguyana N. Grigor'eva

Saint Petersburg State University

Email: grinur@mail.ru

PhD, Assistant Professor of Otorhinolaryngology and Ophthalmology Department

Russian Federation, Saint Petersburg

Elizaveta S. Rozhdestvenskaya

Saint Petersburg City Multifield Hospital No 2

Email: shorie48@gmail.com

Ophthalmologist

Russian Federation, Saint Petersburg

References

  1. World Health Organization. Global Report on Diabetes. Geneva: WHO; 2018.
  2. International Diabetes Federation. Atlas of diabetes. 8th ed. Brussels: IDF; 2017.
  3. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015;2:17. doi: 10.1186/s40662-015-0026-2.
  4. Zheng Y, He M, Congdon N. The worldwide epidemic of diabetic retinopathy. Indian J Ophthalmol. 2012;60(5):428-431. doi: 10.4103/0301-4738.100542.
  5. Amoaku WM, Saker S, Stewart EA. A review of therapies for diabetic macular oedema and rationale for combination therapy. Eye (Lond). 2015;29(9):1115-1130. doi: 10.1038/eye.2015.110.
  6. Miller K, Fortun JA. Diabetic Macular Edema: Current Understanding, Pharmacologic Treatment Options, and Developing Therapies. Asia Pac J Ophthalmol (Phila). 2018;7(1):28-35. doi: 10.22608/APO.2017529.
  7. Romero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A, et al. Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory. J Diabetes Res. 2016;2016:2156273. doi: 10.1155/ 2016/2156273.
  8. Beaulieu WT, Bressler NM, Melia M, et al. Panretinal Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Patient-Centered Outcomes from a Randomized Clinical Trial. Am J Ophthalmol. 2016;170:206-213. doi: 10.1016/j.ajo.2016.08.008.
  9. Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. 2017;2(14). doi: 10.1172/jci.insight.93751.
  10. Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica. 2017;237(4):185-222. doi: 10.1159/000458539.
  11. Ogata N, Wang L, Jo N, et al. Pigment epithelium derived factor as a neuroprotective agent against ischemic retinal injury. Curr Eye Res. 2001;22(4):245-252. doi: 10.1076/ceyr.22.4.245.5506.
  12. Simo R, Hernandez C, European Consortium for the Early Treatment of Diabetic R. Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol Metab. 2014;25(1):23-33. doi: 10.1016/j.tem.2013.09.005.
  13. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103(12):1796-1806. doi: 10.1001/archopht.1985.01050120030015.
  14. Romero-Aroca P. Managing diabetic macular edema: The leading cause of diabetes blindness. World J Diabetes. 2011;2(6):98-104. doi: 10.4239/wjd.v2.i6.98.
  15. Bahrami B, Hong T, Gilles MC, et al. Anti-VEGF Therapy for diabetic eye diseases. Asia-Pac J Ophthalmol. 2017;6:535-545.
  16. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380(6573):439-442. doi: 10.1038/380439a0.
  17. Ferrara N. Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int. 1999;56(3):794-814. doi: 10.1046/j.1523-1755.1999.00610.x.
  18. Ferrara N. VEGF-A: a critical regulator of blood vessel growth. Eur Cytokine Netw. 2009;20(4):158-163. doi: 10.1684/ecn.2009.0170.
  19. Freedman SB, Isner JM. Therapeutic angiogenesis for coronary artery disease. Ann Intern Med. 2002;136(1):54-71. doi: 10.7326/0003-4819-136-1-200201010-00011.
  20. Jin K, Zhu Y, Sun Y, et al. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA. 2002;99(18):11946-11950. doi: 10.1073/pnas.182296499.
  21. Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond). 2005;109(3):227-241. doi: 10.1042/CS20040370.
  22. Wang J, Xu X, Elliott MH, et al. Muller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes. 2010;59(9):2297-2305. doi: 10.2337/db09-1420.
  23. Witmer AN, Blaauwgeers HG, Weich HA, et al. Altered expression patterns of VEGF receptors in human diabetic retina and in experimental VEGF-induced retinopathy in monkey. Invest Ophthalmol Vis Sci. 2002;43(3):849-857.
  24. Zhang X, Bao S, Lai D, et al. Intravitreal triamcinolone acetonide inhibits breakdown of the blood-retinal barrier through differential regulation of VEGF-A and its receptors in early diabetic rat retinas. Diabetes. 2008;57(4):1026-1033. doi: 10.2337/db07-0982.
  25. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171-185. doi: 10.1007/s10456-011-9249-6.
  26. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480-1487. doi: 10.1056/NEJM199412013312203.
  27. Funatsu H, Yamashita H, Nakamura S, et al. Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology. 2006;113(2):294-301. doi: 10.1016/j.ophtha.2005.10.030.
  28. Autiero M, Waltenberger J, Communi D, et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med. 2003;9(7):936-943. doi: 10.1038/nm884.
  29. Bry M, Kivela R, Leppanen VM, Alitalo K. Vascular endothelial growth factor-B in physiology and disease. Physiol Rev. 2014;94(3):779-794. doi: 10.1152/physrev.00028.2013.
  30. Nguyen QD, De Falco S, Behar-Cohen F, et al. Placental growth factor and its potential role in diabetic retinopathy and other ocular neovascular diseases. Acta Ophthalmol. 2018;96(1):e1-e9. doi: 10.1111/aos.13325.
  31. Kovacs K, Marra KV, Yu G, et al. Angiogenic and Inflammatory Vitreous Biomarkers Associated With Increasing Levels of Retinal Ischemia. Invest Ophthalmol Vis Sci. 2015;56(11):6523-6530. doi: 10.1167/iovs.15-16793.
  32. Kinoshita S, Noda K, Saito W, et al. Vitreous levels of vascular endothelial growth factor-B in proliferative diabetic retinopathy. Acta Ophthalmol. 2016;94(6): e521-523. doi: 10.1111/aos.12969.
  33. Zhong X, Huang H, Shen J, et al. Vascular endothelial growth factor-B gene transfer exacerbates retinal and choroidal neovascularization and vasopermeability without promoting inflammation. Mol Vis. 2011;17:492-507.
  34. Bressler NM, Beck RW, Ferris FL, 3rd. Panretinal photocoagulation for proliferative diabetic retinopathy. N Engl J Med. 2011;365(16):1520-1526. doi: 10.1056/NEJMct0908432.
  35. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology. 1981;88(7):583-600. doi: 10.1016/S0161-6420(81)34978-1.
  36. Duh EJ, Yang HS, Suzuma I, et al. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci. 2002;43(3):821-829.
  37. Hattenbach LO, Beck KF, Pfeilschifter J, et al. Pigment-epithelium-derived factor is upregulated in photocoagulated human retinal pigment epithelial cells. Ophthalmic Res. 2005;37(6):341-346. doi: 10.1159/000088263.
  38. Ogata N, Ando A, Uyama M, Matsumura M. Expression of cytokines and transcription factors in photocoagulated human retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol. 2001;239(2):87-95. doi: 10.1007/s004170000235.
  39. Freund KB, Korobelnik JF, Devenyi R, et al. Treat-and-extend regimens with anti-VEGF agents in retinal diseases. Retina. 2015;35(8):1489-1506. doi: 10.1097/IAE. 0000000000000627.
  40. Lanzetta P, Loewenstein A, Vision Academy Steering C. Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti-vascular endothelial growth factor therapy of macular diseases. Graefes Arch Clin Exp Ophthalmol. 2017;255(7):1259-1273. doi: 10.1007/s00417-017-3647-4.
  41. 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(11):2399-2405. doi: 10.2337/dc10-0493.
  42. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615-625. doi: 10.1016/j.ophtha. 2011.01.031.
  43. 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(4):789-801. doi: 10.1016/j.ophtha.2011.12.039.
  44. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results from the VISTA and VIVID Studies. Ophthalmology. 2015;122(10):2044-2052. doi: 10.1016/j.ophtha.2015.06.017.
  45. Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies. Ophthalmology. 2016;123(11):2376-2385. doi: 10.1016/j.ophtha.2016.07.032.
  46. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254. doi: 10.1016/j.ophtha.2014.05.006.
  47. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203. doi: 10.1056/NEJMoa1414264.
  48. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016;123(6):1351-1359. doi: 10.1016/j.ophtha.2016.02.022.
  49. Jampol LM, Glassman AR, Bressler NM, et al. Anti-Vascular Endothelial Growth Factor Comparative Effectiveness Trial for Diabetic Macular Edema: Additional Efficacy Post Hoc Analyses of a Randomized Clinical Trial. JAMA Ophthalmol. 2016;134(12). doi: 10.1001/jamaophthalmol.2016.3698.
  50. Bressler SB, Liu D, Glassman AR, et al. Change in Diabetic Retinopathy Through 2 Years: Secondary Analysis of a Randomized Clinical Trial Comparing Aflibercept, Bevacizumab, and Ranibizumab. JAMA Ophthalmol. 2017;135(6):558-568. doi: 10.1001/jamaophthalmol.2017.0821.
  51. Bressler SB, Glassman AR, Almukhtar T, et al. Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema. Am J Ophthalmol. 2016;164:57-68. doi: 10.1016/j.ajo.2015.12.025.
  52. 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(4):609-614. doi: 10.1016/j.ophtha.2010.12.033.
  53. 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(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031.
  54. Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012;119(11):2312-2318. doi: 10.1016/j.ophtha.2012.08.022.
  55. Bressler NM, Beaulieu WT, Glassman AR, et al. Persistent Macular Thickening Following Intravitreous Aflibercept, Bevacizumab, or Ranibizumab for Central-Involved Diabetic Macular Edema with Vision Impairment: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2018;136(3):257-269. doi: 10.1001/jamaophthalmol.2017.6565.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Protocol T DRCRnet. Mean change in visual acuity in groups: a – Overall cohort; b – In cohorts according to baseline visual acuity. Solid lines indicates baseline visual acuity of 20/50 or worse. Dotted lines indicate baseline visual acuity of 20/32 to 20/40. Number of eyes was 195-244 in aflibercept group, 188-218 in ranibizumab and 188-218 bevacizumab groups. Error bars indicated 95% CI. Source: Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema. N Engl J Med. 2015;372(13):1193-1203 [47]

Download (133KB)
Indexing metadata
3. Fig. 2. Protocol T DRCRnet 2 year results. Mean change in visual acuity in groups: a – Overall cohort; b – In cohort with baseline visual acuity of 20/50 or worse; c – In cohort with baseline visual acuity of 20/32 to 20/40. Number of eyes was 195-244 in aflibercept group, 188-218 in ranibizumab and 185-218 bevacizumab groups. Error bars indicated 95% CI. Source: Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016;123:1351-1359 [48]

Download (156KB)
Indexing metadata
4. Fig. 3. Mean change in central retinal subfield thickness according to baseline visual acuity and laser photocoagulation: a – No focal/grid laser treatment and VA of ≤ 20/50; b – Focal/grid laser treatment and VA of ≤ 20/50; c – No focal/grid laser treatment and VA of 20/32 to 20/40; d – Focal/grid laser treatment and VA of 20/32 to 20/40. Source: Jampol LM, Glassman AR, Bressler NM. Anti-Vascular Endothelial Growth Factor Comparative Effectiveness Trial for Diabetic Macular Edema: Additional Efficacy Post Hoc Analyses of a Randomized Clinical Trial. JAMA Ophthalmol. 2016;134(12) [49]

Download (242KB)
Indexing metadata
5. Fig. 4. Mean change in central retinal subfield thickness. Protocol I DRCRnet (2 years follow up). Source: 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(4):609-614 [52]

Download (53KB)
Indexing metadata
6. Fig. 5. Protocol I DRCRnet (3 years follow up). Mean change in visual acuity in cohorts with prompt or deferred laser. Number of eyes was 165-144 in cohort with prompt laser photocoagulation and 173-147 in cohort with deferred laser photocoagulation. Source: Diabetic Retinopathy Clinical Research Network. Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt vs Deferred Laser Treatment: 3-year Randomized Trial Results. Ophthalmology. 2012;119(11):

Download (36KB)
Indexing metadata
7. Fig. 6. Protocol I DRCRnet (3 years follow up). Mean change in central subfield retinal thickening in cohorts with prompt or deferred laser. Number of eyes was 165-131 in cohort with prompt laser photocoagulation and 169-128 in cohort with deferred laser photocoagulation. Source: Diabetic Retinopathy Clinical Research Network. Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt vs Deferred Laser Treatment: 3-year Randomized Trial Results. Ophthalmology. 2012;119(11):2312-2318 [54]

Download (37KB)
Indexing metadata

Copyright (c) 2018 Shadrichev F.E., Grigor'eva N.N., Rozhdestvenskaya E.S.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies