Published date: Jan 21 2022

Journal Title: Journal of Ophthalmic and Vision Research

Issue title: January–March 2022, Volume 17, Issue 1

Pages: 108–117

DOI: 10.18502/jovr.v17i1.10175

Amir ArabiOphthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Ramin TadayoniUniversité de Paris, Ophthalmology Department, AP-HP, Lariboisière, Saint Louis and Fondation Adolphe de Rothschild Hospitals, Paris, France

Hamid AhmadiehOphthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Toktam ShahrakiOphthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Homayoun Nikkhahh.nikkhah52@gmail.comOphthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Diabetic retinopathy (DR) is the major cause of visual impairment and blindness in the working-age population. Conventional management for nonproliferative diabetic retinopathy (NPDR) without diabetic macular edema (DME) is derived from the findings of the Early Treatment Diabetic Retinopathy Study (ETDRS). Although the ETDRS protocol basically includes observation, selected cases of severe NPDR may undergo scatter laser photocoagulation. Post-hoc analysis of recent trials has shown that patients with NPDR receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) for DME would experience improvement in the DR severity scale (DRSS). In addition, recent randomized trials (PANORAMA and Protocol W) have revealed that early intervention with intravitreal aflibercept in eyes with moderately severe to severe NPDR is associated with significant improvement in DRSS and reduced vision-threatening complications of DR. Based on recent studies, it seems that the therapeutic approach to NPDR may undergo a substantial change and a paradigm shift toward considering early intervention with the administration of intravitreal anti-VEGF injections. However, the long-term results and the duration of adherence to anti-VEGF therapy for eyes with NPDR are not yet defined. It is also not apparent whether improvement in DRSS is a true disease modification. Studies showed that DRSS improvement is not associated with retinal reperfusion. In addition, DRCR.net Protocol W showed no visual acuity benefit with the early intravitreal aflibercept injection in moderate to severe NPDR as compared with performing observation plus intravitreal aflibercept applied only after progression to proliferative DR or vision-impairing DME. The cost–benefit ratio is also a challenge. Herein, we look at different aspects of early anti-VEGF application and discuss its pros and cons in the process of treating NPDR.

1. Gao HX, Regier EE, Close KL. International Diabetes Federation World Diabetes Congress 2015. J Diabetes 2016;8:300–302.

2. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87:4–14.

3. Klein R, Lee KE, Knudtson MD, Gangnon RE, Klein BE. Changes in visual impairment prevalence by period of diagnosis of diabetes: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Ophthalmology 2009;116:1937–1942.

4. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology 1991;98:766–785.

5. Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol 2012;130:1145–1152.

6. Mitchell P, McAllister I, Larsen M, Staurenghi G, Korobelnik JF, Boyer DS, et al. Evaluating the impact of intravitreal aflibercept on diabetic retinopathy progression in the VIVID-DME and VISTA-DME studies. Ophthalmol Retina 2018;2:988–996.

7. Brown DM, Wykoff CC, Boyer D, Heier JS, Clark WL, Emanuelli A, et al. Evaluation of intravitreal aflibercept for the treatment of severe nonproliferative diabetic retinopathy: results from the PANORAMA randomized clinical trial. JAMA Ophthalmol 2021;139:1–10.

8. Maturi RK, Glassman AR, Josic K, Antoszyk AN, Blodi BA, Jampol LM, et al. Effect of intravitreous antivascular endothelial growth factor vs sham treatment for prevention of vision-threatening complications of diabetic retinopathy: the protocol W randomized clinical trial. JAMA Ophthalmol 2021;139:701–712.

9. Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr 1994;125:177–188.

10. Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman RR, Manley SE, et al. UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia 2001;44:156–163.

11. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23:B21–B29.

12. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes. Lancet 1993;341:1306–1309.

13. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103–117.

14. Drzewoski J, Kasznicki J, Trojanowski Z. The role of ”metabolic memory” in the natural history of diabetes mellitus. Pol Arch Med Wewn 2009;119:493–500.

15. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–1589.

16. American Diabetes Association. Standards of medical care in diabetes-2014. Diabetes Care 2014;37:S14–S80.

17. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703–713.

18. Schrier RW, Estacio RO, Jeffers B. Appropriate blood pressure control in NIDDM (ABCD) trial. Diabetologia 1996;39:1646–1654.

19. Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology 1998;105:1801–1815.

20. Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000;23:B54–B64.

21. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351:1755–1762.

22. Raum P, Lamparter J, Ponto KA, Peto T, Hoehn R, Schulz A, et al. Prevalence and cardiovascular associations of diabetic retinopathy and maculopathy: results from the Gutenberg Health Study. PLoS One 2015;10:e0127188.

23. Do DV, Wang X, Vedula SS, Marrone M, Sleilati G, Hawkins BS, et al. Blood pressure control for diabetic retinopathy. Cochrane Database Syst Rev 2015;1:CD006127.

24. Zhou Y, Wang C, Shi K, Yin X. Relationship between dyslipidemia and diabetic retinopathy: a systematic review and meta-analysis. Medicine 2018;97:e12283.

25. Srinivasan S, Raman R, Kulothungan V, Swaminathan G, Sharma T. Influence of serum lipids on the incidence and progression of diabetic retinopathy and macular oedema: Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular genetics Study-II. Clin Exp Ophthalmol 2017;45:894–900.

26. Chew EY, Davis MD, Danis RP, Lovato JF, Perdue LH, Greven C, et al. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology 2014;121:2443–2451.

27. Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TM, Moffitt MS, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687–1697.

28. Mandala A, Armstrong A, Girresch B, Zhu J, Chilakala A, Chavalmane S, et al. Fenofibrate prevents iron induced activation of canonical Wnt/ß-catenin and oxidative stress signaling in the retina. NPJ Aging Mech Dis 2020;6:12.

29. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685–696.

30. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005–2016.

31. Hosseini MS, Rostami Z, Saadat A, Saadatmand SM, Naeimi E. Anemia and microvascular complications in patients with type 2 diabetes mellitus. Nephrourol Mon 2014;6:e19976.

32. Thomas M, Tsalamandris C, MacIsaac R, Jerums G. Anaemia in diabetes: an emerging complication of microvascular disease. Curr Diabetes Rev 2005;1:107–126.

33. Traveset A, Rubinat E, Ortega E, Alcubierre N, Vazquez B, Hernandez M, et al. Lower hemoglobin concentration is associated with retinal ischemia and the severity of diabetic retinopathy in type 2 diabetes. J Diabetes Res 2016;2016:3674946.

34. Ranil PK, Raman R, Rachepalli SR, Pal SS, Kulothungan V, Lakshmipathy P, et al. Anemia and diabetic retinopathy in type 2 diabetes mellitus. J Assoc Physicians India 2010;58:91–94.

35. Idiculla J, Nithyanandam S, Joseph M, Christeena J. Anemia as a risk factor for diabetic retinopathy (dr) with special reference to nutritional etiology. Diabetes 2018;67:591.

36. Luo BA, Gao F, Qin LL. The association between vitamin D deficiency and diabetic retinopathy in type 2 diabetes: a meta-analysis of observational studies. Nutrients 2017;9:307.

37. Lu L, Lu Q, Chen W, Li J, Li C, Zheng Z. Vitamin D3 protects against diabetic retinopathy by inhibiting high-glucose-induced activation of the ROS/TXNIP/NLRP3 inflammasome pathway. J Diabetes Res 2018;2018:8193523.

38. Cai X, Chen Y, Yang W, Gao X, Han X, Ji L. The association of smoking and risk of diabetic retinopathy in patients with type 1 and type 2 diabetes: a meta-analysis. Endocrine 2018;62:299–306.

39. Moss SE, Klein R, Klein BE. Cigarette smoking and tenyear progression of diabetic retinopathy. Ophthalmology 1996;103:1438–1442.

40. Moutray T, Evans JR, Lois N, Armstrong DJ, Peto T, Azuara-Blanco A. Different lasers and techniques for proliferative diabetic retinopathy. Cochrane Database Syst Rev 2018;3:Cd012314.

41. The Diabetic Retinopathy Study Research Group. Indications for photocoagulation treatment of diabetic retinopathy: Diabetic Retinopathy Study Report no. 14. Int Ophthalmol Clin 1987;27:239–253.

42. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Ophthalmology 1991;98:823–833.

43. Mistry H, Auguste P, Lois N, Waugh N. Diabetic retinopathy and the use of laser photocoagulation: is it cost-effective to treat early? BMJ Open Ophthalmol 2017;2:e000021.

44. Royle P, Mistry H, Auguste P, Shyangdan D, Freeman K, Lois N, et al. Pan-retinal photocoagulation and other forms of laser treatment and drug therapies for nonproliferative diabetic retinopathy: systematic review and economic evaluation. Health Technol Assess 2015;19:v– xxviii, 1–247.

45. El Rami H, Barham R, Sun JK, Silva PS. Evidence-based treatment of diabetic retinopathy. Semin Ophthalmol 2017;32:67–74.

46. Fong DS, Girach A, Boney A. Visual side effects of successful scatter laser photocoagulation surgery for proliferative diabetic retinopathy: a literature review. Retina 2007;27:816–824.

47. Iwase T, Kobayashi M, Yamamoto K, Ra E, Terasaki H. Effects of photocoagulation on ocular blood flow in patients with severe non-proliferative diabetic retinopathy. PLoS One 2017;12:e0174427.

48. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480–1487.

49. Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994;118:445–450.

50. Zhao Y, Singh RP. The role of anti-vascular endothelial growth factor (anti-VEGF) in the management of proliferative diabetic retinopathy. Drugs Context 2018;7:212532.

51. Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology 2014;121:1783–1789.

52. Mitchell P, McAllister I, Larsen M, Staurenghi G, Korobelnik JF, Boyer DS, et al. Evaluating the impact of intravitreal aflibercept on diabetic retinopathy progression in the VIVID-DME and VISTA-DME studies. Ophthalmol Retina 2018;2:988–996.

53. Bressler SB, Liu D, Glassman AR, Blodi BA, Castellarin AA, Jampol LM, et al. Change in diabetic retinopathy through 2 years: secondary analysis of a randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab. JAMA Ophthalmol 2017;135:558–568.

54. Lim JI. Long-term clinical impact of intravitreal anti- VEGF therapy for severe non-proliferative diabetic retinopathy (NPDR): analyses through a discrete event simulation model. Association for Research in Vision and Ophthalmology Annual Meeting; May 6, 2021; virtual meeting.

55. Sahni J, Patel SS, Dugel PU, Khanani AM, Jhaveri CD, Wykoff CC, et al. Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-A with faricimab in diabetic macular edema: BOULEVARD phase 2 randomized trial. Ophthalmology 2019;126:1155–1170.

56. Bonnin S, Dupas B, Lavia C, Erginay A, Dhundass M, Couturier A, et al. Anti-vascular endothelial growth factor therapy can improve diabetic retinopathy score without change in retinal perfusion. Retina 2019;39:426–434.

57. Yadav P, Singh SV, Nada M, Dahiya M. Impact of severity of diabetic retinopathy on quality of life in type 2 Indian diabetic patients. Int J Community Med Public Health 2021;8:207–211.

58. Willis JR, Doan QV, Gleeson M, Haskova Z, Ramulu P, Morse L, et al. Vision-related functional burden of diabetic retinopathy across severity levels in the United States. JAMA Ophthalmol 2017;135:926–932.

59. Wykoff CC, Khurana RN, Nguyen QD, Kelly SP, Lum F, Hall R, et al. Risk of blindness among patients with diabetes and newly diagnosed diabetic retinopathy. Diabetes Care 2021;44:748–756.

60. Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, Arevalo JF, Berrocal MH, Farah ME, et al. Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol 2008;246:81–87.

61. Shikari H, Silva PS, Sun JK. Complications of intravitreal injections in patients with diabetes. Semin Ophthalmol 2014;29:276–289.

62. Menchini F, Toneatto G, Miele A, Donati S, Lanzetta P, Virgili G. Antibiotic prophylaxis for preventing endophthalmitis after intravitreal injection: a systematic review. Eye 2018;32:1423–1431.

63. Goldberg RA. What happens to diabetic retinopathy severity scores with less aggressive treatment? A post hoc analysis of the RISE and RIDE open label extension study. Paper presented at: the American Society of Retina Specialists Annual Meeting; July 29, 2019; Chicago, IL.

64. Couturier A, Rey PA, Erginay A, Lavia C, Bonnin S, Dupas B, et al. Widefield oct-angiography and fluorescein angiography assessments of nonperfusion in diabetic retinopathy and edema treated with anti-vascular endothelial growth factor. Ophthalmology 2019;126:1685–1694.

65. Bonnin S, Dupas B, Lavia C, Erginay A, Dhundass M, Couturier A, et al. Anti-vascular endothelial growth factor therapy can improve diabetic retinopathy score without change in retinal perfusion. Retina 2019;39:426–434.

66. Arita R, Hata Y, Nakao S, Kita T, Miura M, Kawahara S, et al. Rho kinase inhibition by fasudil ameliorates diabetesinduced microvascular damage. Diabetes 2009;58:215–226.

67. Rothschild PR, Salah S, Berdugo M, Gélizé E, Delaunay K, Naud MC, et al. ROCK-1 mediates diabetes-induced retinal pigment epithelial and endothelial cell blebbing: contribution to diabetic retinopathy. Sci Rep 2017;7:8834.

68. Hida Y, Nakamura S, Nishinaka A, Inoue Y, Shimazawa M, Hara H. Effects of ripasudil, a ROCK inhibitor, on retinal edema and nonperfusion area in a retinal vein occlusion murine model. J Pharmacol Sci 2018;137:129–136.

69. Ahmadieh H, Nourinia R, Hafezi-Moghadam A, Sabbaghi H, Nakao S, Zandi S, et al. Intravitreal injection of a Rho-kinase inhibitor (fasudil) combined with bevacizumab versus bevacizumab monotherapy for diabetic macular oedema: a pilot randomized clinical trial. Br J Ophthalmol 2019;103:922–927.