Skip to main content
SpringerLink
Log in

Current Approaches to the Management of Diabetic Retinopathy and Diabetic Macular Oedema

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Diabetic retinopathy (DR) is a major cause of blindness in Europe and North America, and the incidence is expected to increase in parallel with the rising incidence of diabetes mellitus. This article reviews the current state of knowledge of the epidemiology, clinical presentation and pathophysiology of DR and its principal associated complications, diabetic macular oedema (DME) and neovascularization, and then proceeds to the primary focus of clinical management. A series of major randomized controlled trials conducted over the past few decades has confirmed that tight glycaemic regulation is the most effective measure to reduce the risk of developing DR and to minimize the likelihood of its progression, and that control of blood pressure is also an important feature of preventive management. Laser-based therapies remain the cornerstone of treatment, with panretinal photocoagulation indicated for proliferative and severe nonproliferative DR and focal photocoagulation indicated for treatment of DME. For patients who do not benefit from these approaches, vitrectomy may provide therapeutic benefits. Medical therapies include two broad classes of agents: anti-inflammatory drugs and agents with molecular targets. The utility of oral anti-inflammatory drugs remains to be established, as dose-finding studies have yet to provide definitive conclusions. Intravitreal corticosteroids may be of value in specific circumstances, although adverse effects include cataract progression and elevated intraocular pressure. However, these complications appear to have been limited with new extended-release technologies. With respect to molecular targets, evidence has been adduced for the roles of vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)-α and protein kinase C (PKC)-β2 in the pathogenesis of DR, and agents targeting these factors are under intense investigation. The role of VEGF in mediating pathological angiogenesis and vascular hyperpermeability has been best defined. Preliminary efficacy of pegaptanib and ranibizumab in the treatment of DME is being confirmed in additional clinical trials with these agents and with the off-label use of bevacizumab, another monoclonal antibody related to ranibizumab. Moreover, other agents targeting VEGF, as well as drugs directed against TNFα and PKC-β2, are under study. Evaluation of the ultimate utility of these approaches will await the efficacy and safety results of properly designed phase III trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Table I
Table II
Table III

Similar content being viewed by others

References

  1. Resnikoff S, Pascolini D, Etya'ale D, et al. Global data on visual impairment in the year 2002. Bull World Health Organ 2004; 82(11): 844–51

    PubMed  Google Scholar 

  2. Mohamed Q, Wong TY. Emerging drugs for diabetic retinopathy. Expert Opin Emerg Drugs 2008; 13(4): 675–94

    Article  PubMed  CAS  Google Scholar 

  3. Masharani U, Rushakoff RJ. Update on systemic management of diabetes. Int Ophthalmol Clin 2009; 49(2): 13–33

    Article  PubMed  Google Scholar 

  4. Nathan DM, Zinman B, Cleary PA, et al., on behalf of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) Research Group. Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005). Arch Intern Med 2009; 169(14): 1307–16

    Article  PubMed  Google Scholar 

  5. Wong TY, Mwamburi M, Klein R, et al. Rates of progression in diabetic retinopathy during different time periods: a systematic review and meta-analysis. Diabetes Care 2009; 32(12): 2307–13

    Article  PubMed  Google Scholar 

  6. Klein R, Lee KE, Knudtson MD, et al. Changes in visual impairment prevalence by period of diagnosis of diabetes: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Ophthalmology 2009; 116(10): 1937–42

    Article  PubMed  Google Scholar 

  7. Romero-Aroca P, Fernández-Balart J, Baget-Bernaldiz M, et al. Changes in the diabetic retinopathy epidemiology after 14 years in a population of type 1 and 2 diabetic patients after the new diabetes mellitus diagnosis criteria and a more strict control of the patients. J Diabetes Complications 2009; 23(4): 229–38

    Article  PubMed  Google Scholar 

  8. Heintz E, Wiréhn AB, Peebo BB, et al. Prevalence and healthcare costs of diabetic retinopathy: a population-based register study in Sweden. Diabetologia 2010 Oct; 53(10): 2147–54

    Article  PubMed  CAS  Google Scholar 

  9. Knudsen LL, Lervang HH, Lundbye-Christensen S, et al. The North Jutland County Diabetic Retinopathy Study: population characteristics. Br J Ophthalmol 2006; 90(11): 1404–9

    Article  PubMed  CAS  Google Scholar 

  10. Hove MN, Kristensen JK, Lauritzen T, et al. The prevalence of retinopathy in an unselected population of type 2 diabetes patients from Arhus County, Denmark. Acta Ophthalmol Scand 2004; 82(4): 443–8

    Article  PubMed  Google Scholar 

  11. Zhang X, Saaddine JB, Chou CF, et al. Prevalence of diabetic retinopathy in the United States, 2005–2008. JAMA 2010; 304(6): 649–56

    Article  PubMed  CAS  Google Scholar 

  12. Klein R, Knudtson MD, Lee KE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXII: the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology 2008; 115(11): 1859–68

    Article  PubMed  Google Scholar 

  13. Saaddine JB, Honeycutt AA, Narayan KM, et al. Projection of diabetic retinopathy and other major eye diseases among people with diabetes mellitus: United States, 2005–2050. Arch Ophthalmol 2008; 126(12): 1740–7

    Article  PubMed  Google Scholar 

  14. Kempen JH, O'Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol 2004; 122(4): 552–63

    Article  PubMed  Google Scholar 

  15. Singh A, Stewart JM. Pathophysiology of diabetic macular edema. Int Ophthalmol Clin 2009; 49(2): 1–11

    Article  PubMed  Google Scholar 

  16. Gardner TW, Antonetti DA. Novel potential mechanisms for diabetic macular edema: leveraging new investigational approaches. Curr Diab Rep 2008; 8(4): 263–9

    Article  PubMed  CAS  Google Scholar 

  17. Bhagat N, Grigorian RA, Tutela A, et al. Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol 2009; 54(1): 1–32

    Article  PubMed  Google Scholar 

  18. Chen E, Looman M, Laouri M, et al. Burden of illness of diabetic macular edema: literature review. Curr Med Res Opin 2010; 26(7): 1587–97

    Article  PubMed  CAS  Google Scholar 

  19. Knudsen LL, Lervang HH, Lundbye-Christensen S, et al. The North Jutland County Diabetic Retinopathy Study (NCDRS) 2: non-ophthalmic parameters and clinically significant macular oedema. Br J Ophthalmol 2007; 91(12): 1593–5

    Article  PubMed  CAS  Google Scholar 

  20. Klein R, Klein BE, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV: the long-term incidence of macular edema. Ophthalmology 1995; 102(1): 7–16

    PubMed  CAS  Google Scholar 

  21. Klein R, Knudtson MD, Lee KE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XXIII: the twenty-five-year incidence of macular edema in persons with type 1 diabetes. Ophthalmology 2009; 116(3): 497–503

    Article  PubMed  Google Scholar 

  22. Shea AM, Curtis LH, Hammill BG, et al. Resource use and costs associated with diabetic macular edema in elderly persons. Arch Ophthalmol 2008; 126(12): 1748–54

    Article  PubMed  Google Scholar 

  23. Fong DS, Aiello LP, Ferris 3rd FL, et al. Diabetic retinopathy. Diabetes Care 2004; 27(10): 2540–53

    Article  PubMed  Google Scholar 

  24. Baskin DE. Optical coherence tomography in diabetic macular edema. Curr Opin Ophthalmol 2010; 21(3): 172–7

    Article  PubMed  Google Scholar 

  25. Chan A, Duker JS. A standardized method for reporting changes in macular thickening using optical coherence tomography. Arch Ophthalmol 2005; 123(7): 939–43

    Article  PubMed  Google Scholar 

  26. Kim BY, Smith SD, Kaiser PK. Optical coherence tomographic patterns of diabetic macular edema. Am J Ophthalmol 2006; 142(3): 406–12

    Article  Google Scholar 

  27. Ophir A, Martinez MR, Mosqueda P, et al. Vitreous traction and epiretinal membranes in diabetic macular oedema using spectral-domain optical coherence tomography. Eye (Lond). Epub 2010 Jun 4

  28. Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol 1999; 127(6): 688–93

    Article  PubMed  CAS  Google Scholar 

  29. Buabbud JC, Al-latayfeh MM, Sun JK. Optical coherence tomography imaging for diabetic retinopathy and macular edema. Curr Diab Rep 2010; 10(4): 264–9

    Article  PubMed  Google Scholar 

  30. Forte R, Cennamo GL, Finelli ML, et al. Comparison of time domain Stratus OCT and spectral domain SLO/OCT for assessment of macular thickness and volume. Eye (Lond) 2009; 23(11): 2071–8

    Article  CAS  Google Scholar 

  31. Wolf-Schnurrbusch UE, Ceklic L, Brinkmann CK, et al. Macular thickness measurements in healthy eyes using six different optical coherence tomography instruments. Invest Ophthalmol Vis Sci 2009; 50(7): 3432–7

    Article  PubMed  Google Scholar 

  32. Pournaras JA, Erginay A, Lazrak Z, et al. Spectral domain optical coherence tomography in diabetic macular edema. Ophthalmic Surg Lasers Imaging 2009; 40(6): 548–53

    Article  PubMed  Google Scholar 

  33. Geitzenauer W, Kiss CG, Durbin MK, et al. Comparing retinal thickness measurements from cirrus spectral domain- and stratus time domain-optical coherence tomography. Retina 2010; 30(4): 596–606

    Article  PubMed  Google Scholar 

  34. Aiello LP, Gardner TW, King GL, et al. Diabetic retinopathy. Diabetes Care 1998; 21(1): 143–56

    PubMed  CAS  Google Scholar 

  35. Kroll P, Rodrigues EB, Hoerle S. Pathogenesis and classification of proliferative diabetic vitreoretinopathy. Ophthalmologica 2007; 221(2): 78–94

    Article  PubMed  Google Scholar 

  36. ETDRS Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report no. 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985; 103(12): 1796–806

    Article  Google Scholar 

  37. Ahmadi MA, Lim JI. Update on laser treatment of diabetic macular edema. Int Ophthalmol Clin 2009; 49(2): 87–94

    Article  PubMed  Google Scholar 

  38. International Council of Ophthalmology. Visual standards: aspects and ranges of vision loss with emphasis on population surveys. Report prepared for the International Council of Ophthalmology at the 29th International Congress of Ophthalmology, Sydney, Australia, April 2002 [online]. Available from URL: http://www.icoph.org/pdf/visualstandardsreport.pdf [Accessed 2010 May 5]

  39. Starita C, Patel M, Katz B, et al. Vascular endothelial growth factor and the potential therapeutic use of pegaptanib (Macugen) in diabetic retinopathy. Dev Ophthalmol 2007; 39: 122–48

    Article  PubMed  CAS  Google Scholar 

  40. Browning DJ, Altaweel MM, Bressler NM, et al. Diabetic macular edema: what is focal and what is diffuse? Am J Ophthalmol 2008; 146(5): 649–55

    Article  PubMed  Google Scholar 

  41. Gardner TW, Antonetti DA, Barber AJ, et al. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 2002; 47 Suppl. 2: S253–62

    Article  PubMed  Google Scholar 

  42. Mortlock KE, Chiti Z, Drasdo N, et al. Silent substitution S-cone electroretinogram in subjects with diabetes mellitus. Ophthalmic Physiol Opt 2005; 25(5): 392–9

    Article  PubMed  Google Scholar 

  43. Georgakopoulos CD, Eliopoulou MI, Exarchou AM, et al. Decreased contrast sensitivity in children and adolescents with type 1 diabetes mellitus. J Pediatr Ophthalmol Strabismus. Epub 2010 Apr 30: 1–6

    Google Scholar 

  44. Parisi V, Uccioli L. Visual electrophysiological responses in persons with type 1 diabetes. Diabetes Metab Res Rev 2001; 17(1): 12–8

    Article  PubMed  CAS  Google Scholar 

  45. Bronson-Castain KW, Bearse Jr MA, Neuville J, et al. Adolescents with type 2 diabetes: early indications of focal retinal neuropathy, retinal thinning, and venular dilation. Retina 2009; 29(5): 618–26

    Article  PubMed  Google Scholar 

  46. Lakhani E, Wright T, Abdolell M, et al. Insufficient long-term glycemic control is associated with multifocal ERG defects in adolescents with type 1 diabetes. Invest Ophthalmol Vis Sci. Epub 2010 May 19

  47. Barber AJ, Lieth E, Khin SA, et al. Neural apoptosis in the retina during experimental and human diabetes: early onset and effect of insulin. J Clin Invest 1998; 102(4): 783–91

    Article  PubMed  CAS  Google Scholar 

  48. van Dijk HW, Kok PH, Garvin M, et al. Selective loss of inner retinal layer thickness in type 1 diabetic patients with minimal diabetic retinopathy. Invest Ophthalmol Vis Sci 2009; 50(7): 3404–9

    Article  PubMed  Google Scholar 

  49. Cabrera DeBuc D, Somfai GM. Early detection of retinal thickness changes in diabetes using optical coherence tomography. Med Sci Monit 2010; 16(3): MT15–21

    Google Scholar 

  50. van Dijk HW, Verbraak FD, Kok PH, et al. Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes. Invest Ophthalmol Vis Sci 2010; 51(7): 3660–5

    Article  PubMed  Google Scholar 

  51. Verma A, Rani PK, Raman R, et al. Is neuronal dysfunction an early sign of diabetic retinopathy? Microperimetry and spectral domain optical coherence tomography (SD-OCT) study in individuals with diabetes, but no diabetic retinopathy. Eye (Lond) 2009; 23(9): 1824–30

    Article  CAS  Google Scholar 

  52. Joussen AM, Murata T, Tsujikawa A, et al. Leukocytemediated endothelial cell injury and death in the diabetic retina. Am J Pathol 2001; 158(1): 147–52

    Article  PubMed  CAS  Google Scholar 

  53. Bursell SE, Clermont AC, Kinsley BT, et al. Retinal blood flow changes in patients with insulin-dependent diabetes mellitus and no diabetic retinopathy. Invest Ophthalmol Vis Sci 1996; 37(5): 886–97

    PubMed  CAS  Google Scholar 

  54. Curtis TM, Gardiner TA, Stitt AW. Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis? Eye (Lond) 2009; 23(7): 1496–508

    Article  CAS  Google Scholar 

  55. Ejaz S, Chekarova I, Ejaz A, et al. Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy. Diabetes Obes Metab 2008; 10(1): 53–63

    PubMed  CAS  Google Scholar 

  56. Caldwell RB, Bartoli M, Behzadian MA, et al. Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev 2003; 19(6): 442–55

    Article  PubMed  CAS  Google Scholar 

  57. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14): 977–86

    Article  Google Scholar 

  58. Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Ophthalmology 1995; 102(4): 647–61

    Google Scholar 

  59. Kalesnykiene V, Sorri I, Voutilainen R, et al. The effect of glycaemic control on the quantitative characteristics of retinopathy lesions in patients with type 2 diabetes mellitus: 10-year follow-up study. Graefes Arch Clin Exp Ophthalmol 2009; 247(3): 335–41

    Article  PubMed  CAS  Google Scholar 

  60. Lorenzi M. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp Diabetes Res 2007; 2007: 61038

    Article  PubMed  CAS  Google Scholar 

  61. Goh SY, Cooper ME. Clinical review: the role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab 2008; 93(4): 1143–52

    Article  PubMed  CAS  Google Scholar 

  62. Kaji Y, Usui T, Ishida S, et al. Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products. Invest Ophthalmol Vis Sci 2007; 48(2): 858–65

    Article  PubMed  Google Scholar 

  63. Pachydaki SI, Tari SR, Lee SE, et al. Upregulation of RAGE and its ligands in proliferative retinal disease. Exp Eye Res 2006; 82(5): 807–15

    Article  PubMed  CAS  Google Scholar 

  64. Zheng L, Du Y, Miller C, et al. Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes. Diabetologia 2007; 50(9): 1987–96

    Article  PubMed  CAS  Google Scholar 

  65. Clarke M, Dodson PM. PKC inhibition and diabetic microvascular complications. Best Pract Res Clin Endocrinol Metab 2007; 21(4): 573–86

    Article  PubMed  CAS  Google Scholar 

  66. Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol 2008; 30(2): 65–84

    Article  PubMed  CAS  Google Scholar 

  67. Wirostko B, Wong TY, Simo R. Vascular endothelial growth factor and diabetic complications. Prog Retin Eye Res 2008; 27(6): 608–21

    Article  PubMed  CAS  Google Scholar 

  68. Kern TS. Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res 2007; 2007: 95103

    Article  PubMed  CAS  Google Scholar 

  69. Joussen AM, Poulaki V, Mitsiades N, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J 2002; 16(3): 438–40

    PubMed  CAS  Google Scholar 

  70. Gao BB, Clermont A, Rook S, et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 2007; 13(2): 181–8

    Article  PubMed  CAS  Google Scholar 

  71. Chen P, Scicli GM, Guo M, et al. Role of angiotensin II in retinal leukostasis in the diabetic rat. Exp Eye Res 2006; 83(5): 1041–51

    Article  PubMed  CAS  Google Scholar 

  72. Nagai N, Izumi-Nagai K, Oike Y, et al. Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kappaB pathway. Invest Ophthalmol Vis Sci 2007; 48(9): 4342–50

    Article  PubMed  Google Scholar 

  73. Kim JH, Kim JH, Yu YS, et al. Blockade of angiotensin II attenuates VEGF-mediated blood-retinal barrier breakdown in diabetic retinopathy. J Cereb Blood Flow Metab 2009; 29(3): 621–8

    Article  PubMed  CAS  Google Scholar 

  74. Diabetes Control and Complications Trial Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000; 342(6): 381–9

    Article  Google Scholar 

  75. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002; 287(19): 2563–9

    Article  Google Scholar 

  76. White NH, Sun W, Cleary PA, et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol 2008; 126(12): 1707–15

    Article  PubMed  Google Scholar 

  77. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131): 837–53

    Article  Google Scholar 

  78. Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA 2007; 298(8): 902–16

    Article  PubMed  CAS  Google Scholar 

  79. 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(7160): 703–13

    Article  Google Scholar 

  80. Schrier RW, Estacio RO, Esler A, et al. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002; 61(3): 1086–97

    Article  PubMed  Google Scholar 

  81. Chaturvedi N, Sjolie AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group: EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998; 351(9095): 28–31

    Article  PubMed  CAS  Google Scholar 

  82. Chaturvedi N, Porta M, Klein R, et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 2008; 372(9647): 1394–402

    Article  PubMed  CAS  Google Scholar 

  83. Sjolie AK, Klein R, Porta M, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 2008; 372(9647): 1385–93

    Article  PubMed  CAS  Google Scholar 

  84. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 370(9600): 1687–97

    Article  PubMed  CAS  Google Scholar 

  85. White NH, Cleary PA, Dahms W, et al. Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT). J Pediatr 2001; 139(6): 804–12

    Article  PubMed  CAS  Google Scholar 

  86. White NH, Sun W, Cleary PA, et al. Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/EDIC: comparison of adults and adolescents. Diabetes 2010; 59(5): 1244–53

    Article  PubMed  CAS  Google Scholar 

  87. Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010; 363(3): 233–44

    Article  PubMed  CAS  Google Scholar 

  88. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358(24): 2545–59

    Article  PubMed  CAS  Google Scholar 

  89. Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998; 116(7): 874–86

    Google Scholar 

  90. Egger M, Davey Smith G, Stettler C, et al. Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis. Diabet Med 1997; 14(11): 919–28

    Article  PubMed  CAS  Google Scholar 

  91. Beulens JW, Patel A, Vingerling JR, et al., on behalf of the AdRem project team and ADVANCE management committee. Effects of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in patients with type 2 diabetes mellitus: a randomised controlled trial. Diabetologia 2009; 52(10): 2027–36

    Article  PubMed  CAS  Google Scholar 

  92. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358(24): 2560–72

    Article  PubMed  CAS  Google Scholar 

  93. Klein R, Klein BE, Moss SE, et al. Is blood pressure a predictor of the incidence or progression of diabetic retinopathy? Arch Intern Med 1989; 149(11): 2427–32

    Article  PubMed  CAS  Google Scholar 

  94. van Leiden HA, Dekker JM, Moll AC, et al. Blood pressure, lipids, and obesity are associated with retinopathy: the Hoorn study. Diabetes Care 2002; 25(8): 1320–5

    Article  PubMed  Google Scholar 

  95. Chatziralli IP, Sergentanis TN, Keryttopoulos P, et al. Risk factors associated with diabetic retinopathy in patients with diabetes mellitus type 2. BMC Res Notes 2010; 3: 153

    Article  PubMed  CAS  Google Scholar 

  96. Estacio RO, Jeffers BW, Gifford N, et al. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000; 23 Suppl. 2: B54–64

    PubMed  Google Scholar 

  97. Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 2009; 361(1): 40–51

    Article  PubMed  CAS  Google Scholar 

  98. Ruggenenti P, Iliev I, Filipponi M, et al. Effect of trandolapril on regression of retinopathy in hypertensive patients with type 2 diabetes: a prespecified analysis of the BENEDICT trial. J Ophthalmol. Epub 2010 Jun 10

  99. Fletcher EL, Phipps JA, Ward MM, et al. The reninangiotensin system in retinal health and disease: its influence on neurons, glia and the vasculature. Prog Retin Eye Res 2010; 29(4): 284–311

    Article  PubMed  CAS  Google Scholar 

  100. Kurihara T, Ozawa Y, Nagai N, et al. Angiotensin II type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina. Diabetes 2008; 57(8): 2191–8

    Article  PubMed  CAS  Google Scholar 

  101. Schupp M, Janke J, Clasen R, et al. Angiotensin type q1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation 2004; 109(17): 2054–7

    Article  PubMed  CAS  Google Scholar 

  102. Dodson P. The effect of statins on diabetic retinopathy. American Diabetes Association 66th Scientific Sessions, Washington, DC, June 9–13, 2006. Webcast [online]. Available from URL: https://www.diabetesconnect.org/Adv_SearchResult.aspx?typ=10&sr=adv&cgr=9&tit=&spk=&ses=&kwd=atorvastatin [Accessed 2009 Nov 18]

  103. Fruchart JC. Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis 2009; 205(1): 1–8

    Article  PubMed  CAS  Google Scholar 

  104. Kim J, Ahn JH, Kim JH, et al. Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway. Exp Eye Res 2007; 84(5): 886–93

    Article  PubMed  CAS  Google Scholar 

  105. Biscetti F, Gaetani E, Flex A, et al. Selective activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPAR gamma induces neoangiogenesis through a vascular endothelial growth factor-dependent mechanism. Diabetes 2008; 57(5): 1394–404

    Article  PubMed  CAS  Google Scholar 

  106. Biscetti F, Straface G, Pitocco D, et al. Peroxisome proliferator-activated receptors and angiogenesis. Nutr Metab Cardiovasc Dis 2009; 19(11): 751–9

    Article  PubMed  CAS  Google Scholar 

  107. Klein BE. Reduction in risk of progression of diabetic retinopathy. N Engl J Med 2010; 363(3): 287–8

    Article  PubMed  CAS  Google Scholar 

  108. Lang GE. Laser treatment of diabetic retinopathy. Dev Ophthalmol 2007; 39: 48–68

    Article  PubMed  Google Scholar 

  109. Diabetic Retinopathy Study Research Group. Indications for photocoagulation treatment of diabetic retinopathy: Diabetic Retinopathy Study Report no. 14. Int Ophthalmol Clin 1987; 27(4): 239–53

    Article  Google Scholar 

  110. Neubauer AS, Ulbig MW. Laser treatment in diabetic retinopathy. Ophthalmologica 2007; 221(2): 95–102

    Article  PubMed  Google Scholar 

  111. 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(7): 816–24

    Article  PubMed  Google Scholar 

  112. Thompson MJ, Ip MS. Diabetic macular edema: a review of past, present, and future therapies. Int Ophthalmol Clin 2004; 44(4): 51–67

    Article  PubMed  Google Scholar 

  113. Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy: the Diabetic Retinopathy Study Research Group. Am J Ophthalmol 1976; 81(4): 383–96

    Google Scholar 

  114. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS report no. 9. Ophthalmology 1991; 98 (5 Suppl.): 766–85

    Google Scholar 

  115. Maeshima K, Utsugi-Sutoh N, Otani T, et al. Progressive enlargement of scattered photocoagulation scars in diabetic retinopathy. Retina 2004; 24(4): 507–11

    Article  PubMed  Google Scholar 

  116. 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(11): 1549–51

    Article  PubMed  CAS  Google Scholar 

  117. Fong DS, Segal PP, Myers F, et al. Subretinal fibrosis in diabetic macular edema: ETDRS report 23. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol 1997; 115(7): 873–7

    Article  PubMed  CAS  Google Scholar 

  118. Luttrull JK, Musch DC, Mainster MA. Subthreshold diode micropulse photocoagulation for the treatment of clinically significant diabetic macular oedema. Br J Ophthalmol 2005; 89(1): 74–80

    Article  PubMed  CAS  Google Scholar 

  119. Moorman CM, Hamilton AM. Clinical applications of the MicroPulse diode laser. Eye 1999; 13 (Pt 2): 145–50

    Article  PubMed  Google Scholar 

  120. Sivaprasad S, Sandhu R, Tandon A, et al. Subthreshold micropulse diode laser photocoagulation for clinically significant diabetic macular oedema: a three-year follow up. Clin Experiment Ophthalmol 2007; 35(7): 640–4

    Article  PubMed  Google Scholar 

  121. Luttrull JK, Musch DC, Spink CA. Subthreshold diode micropulse panretinal photocoagulation for proliferative diabetic retinopathy. Eye (Lond) 2008; 22(5): 607–12

    Article  CAS  Google Scholar 

  122. Fong DS, Strauber SF, Aiello LP, et al. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol 2007; 125(4): 469–80

    Article  PubMed  Google Scholar 

  123. 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(10): 1341–4

    Article  PubMed  CAS  Google Scholar 

  124. 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(6): 908–16

    Article  PubMed  Google Scholar 

  125. Muqit MM, Wakely L, Stanga PE, et al. Effects of conventional argon panretinal laser photocoagulation on retinal nerve fibre layer and driving visual fields in diabetic retinopathy. Eye (Lond) 2010; 24(7): 1136–42

    Article  CAS  Google Scholar 

  126. Nagpal M, Marlecha S, Nagpal K. Comparison of laser photocoagulation for diabetic retinopathy using 532-nm standard laser versus multispot pattern scan laser. Retina 2010; 30(3): 452–8

    Article  PubMed  Google Scholar 

  127. Muqit MM, Marcellino GR, Henson DB, et al. Singlesession vs multiple-session pattern scanning laser panretinal photocoagulation in proliferative diabetic retinopathy: the Manchester Pascal Study. Arch Ophthalmol 2010; 128(5): 525–33

    Article  PubMed  Google Scholar 

  128. Christoforidis JB, D'Amico DJ. Surgical and other treatments of diabetic macular edema: an update. Int Ophthalmol Clin 2004; 44(1): 139–60

    Article  PubMed  Google Scholar 

  129. Ho T, Smiddy WE, Flynn Jr HW. Vitrectomy in the management of diabetic eye disease. Surv Ophthalmol 1992; 37(3): 190–202

    Article  PubMed  CAS  Google Scholar 

  130. Newman DK. Surgical management of the late complications of proliferative diabetic retinopathy. Eye (Lond) 2010; 24(3): 441–9

    Article  CAS  Google Scholar 

  131. Diabetic Retinopathy Vitrectomy Study Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Arch Ophthalmol 1990; 108(7): 958–64

    Article  Google Scholar 

  132. Chang PY, Yang CM, Yang CH, et al. Pars plana vitrectomy for diabetic fibrovascular proliferation with and without internal limiting membrane peeling. Eye (Lond) 2009; 23(4): 960–5

    Article  Google Scholar 

  133. Helbig H. Surgery for diabetic retinopathy. Ophthalmologica 2007; 221(2): 103–11

    Article  PubMed  Google Scholar 

  134. Laidlaw DA. Vitrectomy for diabetic macular oedema. Eye 2008; 22(10): 1337–41

    Article  PubMed  CAS  Google Scholar 

  135. Diabetic Retinopathy Clinical Research Network Writing Committee, on behalf of the DRCR.net. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology 2010; 117(6): 1087–93.e3

    Article  Google Scholar 

  136. Kumagai K, Furukawa M, Ogino N, et al. Long-term follow-up of vitrectomy for diffuse nontractional diabetic macular edema. Retina 2009; 29(4): 464–72

    Article  PubMed  Google Scholar 

  137. Goldenberg DT, Hassan TS. Small gauge, sutureless surgery techniques for diabetic vitrectomy. Int Ophthalmol Clin 2009; 49(2): 141–51

    Article  PubMed  Google Scholar 

  138. Mason III JO, Colagross CT, Vail R. Diabetic vitrectomy: risks, prognosis, future trends. Curr Opin Ophthalmol 2006; 17(3): 281–5

    Article  PubMed  Google Scholar 

  139. Yang SJ, Yoon SY, Kim JG, et al. Transconjunctival sutureless vitrectomy for the treatment of vitreoretinal complications in patients with diabetes mellitus. Ophthalmic Surg Lasers Imaging 2009; 40(5): 461–6

    Article  PubMed  Google Scholar 

  140. Park DH, Shin JP, Kim SY. Comparison of clinical outcomes between 23-gauge and 20-gauge vitrectomy in patients with proliferative diabetic retinopathy. Retina. Epub 2010 Jul 24

  141. Park KH, Woo SJ, Hwang JM, et al. Short-term outcome of bimanual 23-gauge transconjunctival sutureless vitrectomy for patients with complicated vitreoretinopathies. Ophthalmic Surg Lasers Imaging 2010; 41(2): 207–14

    Article  PubMed  Google Scholar 

  142. Cheema RA, Mushtaq J, Cheema MA. Role of residual vitreous cortex removal in prevention of postoperative vitreous hemorrhage in diabetic vitrectomy. Int Ophthalmol 2010; 30(2): 137–42

    Article  PubMed  Google Scholar 

  143. Oshima Y, Shima C, Wakabayashi T, et al. Microincision vitrectomy surgery and intravitreal bevacizumab as a surgical adjunct to treat diabetic traction retinal detachment. Ophthalmology 2009; 116(5): 927–38

    Article  PubMed  Google Scholar 

  144. Modarres M, Nazari H, Falavarjani KG, et al. Intravitreal injection of bevacizumab before vitrectomy for proliferative diabetic retinopathy. Eur J Ophthalmol 2009; 19(5): 848–52

    PubMed  Google Scholar 

  145. da R Lucena D, Ribeiro JA, Costa RA, et al. Intraoperative bleeding during vitrectomy for diabetic tractional retinal detachment with versus without preoperative intravitreal bevacizumab (IBeTra study). Br J Ophthalmol 2009; 93(5): 688–91

    Article  Google Scholar 

  146. Yeh PT, Yang CM, Lin YC, et al. Bevacizumab pretreatment in vitrectomy with silicone oil for severe diabetic retinopathy. Retina 2009; 29(6): 768–74

    Article  PubMed  Google Scholar 

  147. Hattori T, Shimada H, Nakashizuka H, et al. Dose of intravitreal bevacizumab (Avastin) used as preoperative adjunct therapy for proliferative diabetic retinopathy. Retina 2010; 30(5): 761–4

    Article  PubMed  Google Scholar 

  148. Hornan D, Edmeades N, Krishnan R, et al. Use of pegaptanib for recurrent and non-clearing vitreous haemorrhage in proliferative diabetic retinopathy. Eye (Lond). Epub 2010 Mar 12

  149. Ahmadieh H, Shoeibi N, Entezari M, et al. Intravitreal bevacizumab for prevention of early postvitrectomy hemorrhage in diabetic patients. Ophthalmology 2009; 116(10):1943–8

    Article  PubMed  Google Scholar 

  150. di Lauro R, De Ruggiero P, di Lauro R, et al. Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2010; 248(6): 785–91

    Article  PubMed  CAS  Google Scholar 

  151. Hernández-Da Mota SE, Nuñez-Solorio SM. Experience with intravitreal bevacizumab as a preoperative adjunct in 23-G vitrectomy for advanced proliferative diabetic retinopathy. Eur J Ophthalmol. Epub 2010 Apr 23; 20(6): 7

    Google Scholar 

  152. Park DH, Shin JP, Kim SY. Intravitreal injection of bevacizumab and triamcinolone acetonide at the end of vitrectomy for diabetic vitreous hemorrhage: a comparative study. Graefes Arch Clin Exp Ophthalmol 2010; 248(5): 641–50

    Article  PubMed  CAS  Google Scholar 

  153. Lopez-Lopez F, Rodriguez-Blanco M, Gomez-Ulla F, et al. Enzymatic vitreolysis. Curr Diabetes Rev 2009; 5(1): 57–62

    Article  PubMed  CAS  Google Scholar 

  154. Kuppermann BD, Thomas EL, de Smet MD, et al. Pooled efficacy results from two multinational randomized controlled clinical trials of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol 2005; 140(4): 573–84

    Article  PubMed  CAS  Google Scholar 

  155. A safety and efficacy study of Vitreosolve® for non-proliferative diabetic retinopathy subjects [ClinicalTrials.gov identifier NCT00908778]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  156. A multicenter study to compare multiple doses of intravitreal microplasmin versus sham injection for treatment of patients with DME [ClinicalTrials.gov identifier NCT00412451]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  157. A study of the safety and efficacy of microplasmin to induce a posterior vitreous detachment (MIVI III) [ClinicalTrials.gov identifier NCT00412958]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  158. Benz MS, Packo KH, Gonzalez V, et al. A placebocontrolled trial of microplasmin intravitreous injection to facilitate posterior vitreous detachment before vitrectomy. Ophthalmology 2010; 117(4): 791–7

    Article  PubMed  Google Scholar 

  159. Diaz-Llopis M, Udaondo P, Arevalo F, et al. Intravitreal plasmin without associated vitrectomy as a treatment for refractory diabetic macular edema. J Ocul Pharmacol Ther 2009; 25(4): 379–84

    Article  PubMed  CAS  Google Scholar 

  160. Powell ED, Field RA. Diabetic retinopathy and rheumatoid arthritis. Lancet 1964; 41: 17–8

    Article  Google Scholar 

  161. ETDRS Research Group. Effects of aspirin treatment on diabetic retinopathy: ETDRS report number 8. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991; 98 (5 Suppl.): 757–65

    Google Scholar 

  162. DAMAD Study Group. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy: a multi-center randomized controlled clinical trial. Diabetes 1989; 38(4): 491–8

    Article  Google Scholar 

  163. Bergerhoff K, Clar C, Richter B. Aspirin in diabetic retinopathy: a systematic review. Endocrinol Metab Clin North Am 2002; 31(3): 779–93

    Article  PubMed  CAS  Google Scholar 

  164. Hattori Y, Hashizume K, Nakajima K, et al. The effect of long-term treatment with sulindac on the progression of diabetic retinopathy. Curr Med Res Opin 2007; 23(8): 1913–7

    Article  PubMed  CAS  Google Scholar 

  165. Effect of topical nepafenac in macular thickening related to pan-retinal photocoagulation [ClinicalTrials.gov identifier NCT00801905]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  166. Randomized, double blind trial of bromfenac BID (0.09%) as an adjunct to argon laser therapy in the treatment of diabetic macular edema [ClinicalTrials.gov identifier NCT00758628]. US National Institutes of Health, Clinical Trials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  167. A clinical safety and efficacy comparison of NEVANAC 0.1% to vehicle after cataract surgery in diabetic retinopathy patients [ClinicalTrials.gov identifier NCT00782717]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  168. Cunningham MA, Edelman JL, Kaushal S. Intravitreal steroids for macular edema: the past, the present, and the future. Surv Ophthalmol 2008; 53(2): 139–49

    Article  PubMed  Google Scholar 

  169. Grover D, Li TJ, Chong CC. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev 2008; (1): CD005656

  170. Kuo CH, Gillies MC. Role of steroids in the treatment of diabetic macular edema. Int Ophthalmol Clin 2009; 49(2): 121–34

    Article  PubMed  Google Scholar 

  171. Jonas JB. Intravitreal triamcinolone acetonide: a change in a paradigm. Ophthalmic Res 2006; 38(4): 218–45

    Article  PubMed  CAS  Google Scholar 

  172. Blankenship GW. Evaluation of a single intravitreal injection of dexamethasone phosphate in vitrectomy surgery for diabetic retinopathy complications. Graefes Arch Clin Exp Ophthalmol 1991; 229(1): 62–5

    Article  PubMed  CAS  Google Scholar 

  173. Danis RP, Bingaman DP, Yang Y, et al. Inhibition of preretinal and optic nerve head neovascularization in pigs by intravitreal triamcinolone acetonide. Ophthalmology 1996; 103(12): 2099–104

    PubMed  CAS  Google Scholar 

  174. Penfold PL, Wen L, Madigan MC, et al. Modulation of permeability and adhesion molecule expression by human choroidal endothelial cells. Invest Ophthalmol Vis Sci 2002; 43(9): 3125–30

    PubMed  Google Scholar 

  175. Matsuda S, Gomi F, Oshima Y, et al. Vascular endothelial growth factor reduced and connective tissue growth factor induced by triamcinolone in ARPE19 cells under oxidative stress. Invest Ophthalmol Vis Sci 2005; 46(3): 1062–8

    Article  PubMed  Google Scholar 

  176. Brooks Jr HL, Caballero Jr S, Newell CK, et al. Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone. Arch Ophthalmol 2004; 122(12): 1801–7

    Article  PubMed  CAS  Google Scholar 

  177. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet 2010; 376(9735): 124–36

    Article  PubMed  Google Scholar 

  178. Silva PS, Sun JK, Aiello LP. Role of steroids in the management of diabetic macular edema and proliferative diabetic retinopathy. Semin Ophthalmol 2009; 24(2): 93–9

    Article  PubMed  Google Scholar 

  179. 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(5): 902–11

    Article  PubMed  Google Scholar 

  180. Jonas JB. Intravitreal triamcinolone acetonide for diabetic retinopathy. Dev Ophthalmol 2007; 39: 96–110

    Article  PubMed  CAS  Google Scholar 

  181. Gillies MC, Sutter FK, Simpson JM, et al. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology 2006; 113(9): 1533–8

    Article  PubMed  Google Scholar 

  182. Gillies MC, Simpson JM, Gaston C, et al. Five-year results of a randomized trial with open-label extension of triamcinolone acetonide for refractory diabetic macular edema. Ophthalmology 2009; 116(11): 2182–7

    Article  PubMed  Google Scholar 

  183. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008; 115(9): 1447–59

    Article  Google Scholar 

  184. Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009; 127(3): 245–51

    Article  PubMed  Google Scholar 

  185. Bressler NM, Edwards AR, Beck RW, et al. Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation. Arch Ophthalmol 2009; 127(12): 1566–71

    Article  PubMed  CAS  Google Scholar 

  186. Ockrim ZK, Sivaprasad S, Falk S, et al. Intravitreal triamcinolone versus laser photocoagulation for persistent diabetic macular oedema. Br J Ophthalmol 2008; 92(6): 795–9

    Article  PubMed  CAS  Google Scholar 

  187. Gillies MC, Simpson JM, Zhu M, et al. Intravitreal triamcinolone [letter]. Ophthalmology 2009; 116(3): 591

    Article  PubMed  Google Scholar 

  188. Larsson J, Kifley A, Zhu M, et al. Rapid reduction of hard exudates in eyes with diabetic retinopathy after intravitreal triamcinolone: data from a randomized, placebo-controlled, clinical trial. Acta Ophthalmol 2009; 87(3): 275–80

    Article  PubMed  CAS  Google Scholar 

  189. Bandello F, Polito A, Pognuz DR, et al. Triamcinolone as adjunctive treatment to laser panretinal photocoagulation for proliferative diabetic retinopathy. Arch Ophthalmol 2006; 124(5): 643–50

    Article  PubMed  CAS  Google Scholar 

  190. 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(12): 2162–7

    Article  PubMed  Google Scholar 

  191. Maia Jr OO, Takahashi BS, Costa RA, et al. Combined laser and intravitreal triamcinolone for proliferative diabetic retinopathy and macular edema: one-year results of a randomized clinical trial. Am J Ophthalmol 2009; 147(2): 291–7

    Article  PubMed  CAS  Google Scholar 

  192. Lee HY, Lee SY, Park JS. Comparison of photocoagulation with combined intravitreal triamcinolone for diabetic macular edema. Korean J Ophthalmol 2009; 23(3): 153–8

    Article  PubMed  CAS  Google Scholar 

  193. 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(2): 254–9

    Article  PubMed  Google Scholar 

  194. 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(4): 449–54

    Article  PubMed  Google Scholar 

  195. Chung EJ, Freeman WR, Azen SP, et al. Comparison of combination posterior sub-tenon triamcinolone and modified grid laser treatment with intravitreal triamcinolone treatment in patients with diffuse diabetic macular edema. Yonsei Med J 2008; 49(6): 955–64

    Article  PubMed  CAS  Google Scholar 

  196. Unoki N, Nishijima K, Kita M, et al. Randomised controlled trial of posterior sub-Tenon triamcinolone as adjunct to panretinal photocoagulation for treatment of diabetic retinopathy. Br J Ophthalmol 2009; 93(6): 765–70

    Article  PubMed  CAS  Google Scholar 

  197. Gillies MC, McAllister IL, Zhu M, et al. Pretreatment with intravitreal triamcinolone prior to laser for diabetic macular edema: 6-month results of a randomized, placebo-controlled trial. Invest Ophthalmol Vis Sci 2010; 51: 2322–8

    Article  PubMed  Google Scholar 

  198. Kim Y, Kang S, Yi C-H. Three-year follow-up of intravitreal triamcinolone acetonide injection and macular laser photocoagulation for diffuse diabetic macular edema. Invest Ophthalmol Vis Sci 2010; 51: E-Abstract 4260

  199. Efficacy study of triamcinolone associated with nepafenac for treatment of diabetic macular edema [Clinical Trials.gov identifier NCT00780780]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  200. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ [Accessed 2010 May 5]

  201. Mansoor S, Kuppermann BD, Kenney MC. Intraocular sustained-release delivery system for triamcinolone acetonide. Pharm Res 2009; 26(4): 770–84

    Article  PubMed  CAS  Google Scholar 

  202. A study of the safety and efficacy of a new treatment for diabetic macular edema [ClinicalTrials.gov identifier NCT00168389]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  203. A study of the safety and efficacy of a new treatment for diabetic macular edema [ClinicalTrials.gov identifier NCT00168337]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  204. 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(3): 309–17

    Article  PubMed  CAS  Google Scholar 

  205. 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(3): 289–96

    Article  PubMed  CAS  Google Scholar 

  206. Kuppermann BD, Chou C, Weinberg DV, et al. Intravitreous dexamethasone effects on different patterns of diabetic macular edema [letter]. Arch Ophthalmol 2010; 128(5): 642–3

    Article  PubMed  Google Scholar 

  207. Pharmacokinetic and efficacy study of fluocinolone acetonide inserts in patients with diabetic macular edema [ClinicalTrials.gov identifier NCT00490815]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  208. Fluocinolone acetonide implant compared to sham injection in patients with diabetic macular edema [Clinical Trials.gov identifier NCT00344968]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  209. Campochiaro PA, Hafiz G, Shah SM, et al. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology 2010; 117(7): 1393–9.e3

    Article  PubMed  Google Scholar 

  210. Prospective, randomized, multi-center, comparator study evaluating efficacy and safety of PF-04523655 versus laser in subjects with diabetic macular edema [ClinicalTrials. gov identifier NCT00701181]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  211. Campochiaro PA, Shah SM, Hafiz G, et al. Topical mecamylamine for diabetic macular edema. Am J Ophthalmol 2010; 149(5): 839–51

    Article  PubMed  CAS  Google Scholar 

  212. Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246(4935): 1306–9

    Article  PubMed  CAS  Google Scholar 

  213. Csaky KG, Baffi JZ, Byrnes GA, et al. Recruitment of marrow-derived endothelial cells to experimental choroidal neovascularization by local expression of vascular endothelial growth factor. Exp Eye Res 2004; 78(6): 1107–16

    Article  PubMed  CAS  Google Scholar 

  214. Alon T, Hemo I, Itin A, et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995; 1(10): 1024–8

    Article  PubMed  CAS  Google Scholar 

  215. Senger DR, Connolly DT, Van De Water L, et al. Purification and NH2 terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 1990; 50(6): 1774–8

    PubMed  CAS  Google Scholar 

  216. Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 1995; 108 (Pt 6): 2369–79

    PubMed  CAS  Google Scholar 

  217. Antonetti DA, Khin S, Lieth E, et al., and the Penn State Retina Research Group. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Diabetes 1998; 47(12): 1953–9

    Article  PubMed  CAS  Google Scholar 

  218. Antonetti DA, Barber AJ, Hollinger LA, et al. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1: a potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 1999; 274(33): 23463–7

    Article  PubMed  CAS  Google Scholar 

  219. Ishida S, Usui T, Yamashiro K, et al. VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 2003; 44(5): 2155–62

    Article  PubMed  Google Scholar 

  220. Miyamoto K, Hiroshiba N, Tsujikawa A, et al. In vivo demonstration of increased leukocyte entrapment in retinal microcirculation of diabetic rats. Invest Ophthalmol Vis Sci 1998; 39(11): 2190–4

    PubMed  CAS  Google Scholar 

  221. Joussen AM, Poulaki V, Le ML, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J 2004; 18(12): 1450–2

    PubMed  CAS  Google Scholar 

  222. Joussen AM, Poulaki V, Mitsiades N, et al. Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes. FASEB J 2003; 17(1): 76–8

    PubMed  CAS  Google Scholar 

  223. Clauss M, Gerlach M, Gerlach H, et al. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med 1990; 172(6): 1535–45

    Article  PubMed  CAS  Google Scholar 

  224. Barleon B, Sozzani S, Zhou D, et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 1996; 87(8): 3336–43

    PubMed  CAS  Google Scholar 

  225. Ishida S, Usui T, Yamashiro K, et al. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 2003; 198(3): 483–9

    Article  PubMed  CAS  Google Scholar 

  226. Aiello LP, Northrup JM, Keyt BA, et al. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 1995; 113(12): 1538–44

    Article  PubMed  CAS  Google Scholar 

  227. 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 U S A 1999; 96(19): 10836–41

    Article  PubMed  CAS  Google Scholar 

  228. 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): 1480–7

    Article  PubMed  CAS  Google Scholar 

  229. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994; 118(4): 445–50

    PubMed  CAS  Google Scholar 

  230. Joussen AM, Smyth N, Niessen C. Pathophysiology of diabetic macular edema. Dev Ophthalmol 2007; 39: 1–12

    Article  PubMed  CAS  Google Scholar 

  231. Tolentino MJ, McLeod DS, Taomoto M, et al. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol 2002; 133(3): 373–85

    Article  PubMed  CAS  Google Scholar 

  232. Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996; 103(11): 1820–8

    PubMed  CAS  Google Scholar 

  233. Ng EW, Shima DT, Calias P, et al. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 2006; 5(2): 123–32

    Article  PubMed  CAS  Google Scholar 

  234. Ferrara N, Damico L, Shams N, et al. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006; 26(8): 859–70

    Article  PubMed  Google Scholar 

  235. Gragoudas ES, Adamis AP, Cunningham Jr ET, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004; 351(27): 2805–16

    Article  PubMed  CAS  Google Scholar 

  236. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355(14): 1432–44

    Article  PubMed  CAS  Google Scholar 

  237. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355(14): 1419–31

    Article  PubMed  CAS  Google Scholar 

  238. Lynch SS, Cheng CM. Bevacizumab for neovascular ocular diseases. Ann Pharmacother 2007; 41(4): 614–25

    Article  PubMed  CAS  Google Scholar 

  239. DME and VEGF Trap-Eye: investigation of clinical impact [ClinicalTrials.gov identifier NCT00789477]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  240. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002; 99(17): 11393–8

    Article  PubMed  CAS  Google Scholar 

  241. Do DV, Nguyen QD, Shah SM, et al. An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema. Br J Ophthalmol 2009; 93(2): 144–9

    Article  PubMed  CAS  Google Scholar 

  242. Safety and efficacy study of small interfering RNA molecule (Cand5) to treat diabetic macular edema [ClinicalTrials. gov identifier NCT00306904]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  243. Stahl A, Paschek L, Martin G, et al. Rapamycin reduces VEGF expression in retinal pigment epithelium (RPE) and inhibits RPE-induced sprouting angiogenesis in vitro. FEBS Lett 2008; 582(20): 3097–102

    Article  PubMed  CAS  Google Scholar 

  244. Kim DD, Kleinman D, Kanetaka T, et al. Rapamycin inhibits VEGF-induced microvascular hyperpermeability. Microcirculation 2010; 17(2): 128–36

    Article  PubMed  CAS  Google Scholar 

  245. Dose ranging study of an ocular sirolimus (rapamycin) formulation in patients with diabetic macular edema [ClinicalTrials.gov identifier NCT00656643]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  246. Cunningham Jr ET, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005; 112(10): 1747–57

    Article  PubMed  Google Scholar 

  247. Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006; 113(1): 23–8

    Article  PubMed  Google Scholar 

  248. Chun DW, Heier JS, Topping TM, et al. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 2006; 113(10): 1706–12

    Article  PubMed  Google Scholar 

  249. Goodart R, Faber DW, Mehr DS, et al. Lucentis in the treatment of macular edema (LIME): a phase II study evaluating the safety and efficacy of ranibizumab versus focal laser treatment in patients with diabetic macular edema [abstract]. Invest Ophthalmol Vis Sci 2007; 48: E-Abstract 1431

    Google Scholar 

  250. 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(6): 961–9

    Article  PubMed  CAS  Google Scholar 

  251. Wolf S, Massin P, Bandello F, et al. Safety and efficacy of ranibizumab treatment in patients with diabetic macular edema: 12-months results of the Resolve study [abstract]. Invest Ophthalmol Vis Sci 2009; 50: E-Abstract 4331

  252. Arevalo JF, Sanchez JG, Lasave AF, The Pan-American Collaborative Retina Study Group (PACORES). Intravitreal bevacizumab (Avastin®) for diabetic retinopathy at 24-months: the 2008 Juan Verdaguer-Planas Lecture. Curr Diabetes Rev. Epub 2010 Jul 1

  253. Tonello M, Costa RA, Almeida FP, et al. Panretinal photocoagulation versus PRP plus intravitreal bevacizumab for high-risk proliferative diabetic retinopathy (IBeHi study). Acta Ophthalmol 2008; 86(4): 385–9

    Article  PubMed  CAS  Google Scholar 

  254. Mirshahi A, Roohipoor R, Lashay A, et al. Bevacizumabaugmented retinal laser photocoagulation in proliferative diabetic retinopathy: a randomized double-masked clinical trial. Eur J Ophthalmol 2008; 18(2): 263–9

    PubMed  CAS  Google Scholar 

  255. 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(6): 941–8

    PubMed  CAS  Google Scholar 

  256. Nicholson BP, Schachat AP. A review of clinical trials of anti-VEGF agents for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2010; 248(7): 915–30

    Article  PubMed  CAS  Google Scholar 

  257. Ergun E, Macugen Diabetic Retinopathy Study Group. Pegaptanib therapy for diabetic macular edema (DME): two year follow-up. 16th Congress of the European Society of Ophthalmology; 2007 Jun 9–15; Vienna

  258. A multi-center trial to evaluate the safety and efficacy of pegaptanib sodium (Macugen) injected into the eye every 6 weeks for up to 2 years for macular swelling associated with diabetes, with an open-label Macugen year extension [ClinicalTrials.gov identifier NCT00605280]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  259. Gonzalez VH, Giuliari GP, Banda RM, et al. Intravitreal injection of pegaptanib sodium for proliferative diabetic retinopathy. Br J Ophthalmol 2009; 93(11): 1474–8

    Article  PubMed  CAS  Google Scholar 

  260. Morilla Gomez Y, Giuliari GP, Guel DA, et al. Pegaptanib sodium (Macugen) as an adjunct in proliferative diabetic retinopathy refractory to laser treatment [abstract]. Invest Ophthalmol Vis Sci 2008: E-Abstract 2761

  261. Bevacizumab versus ranibizumab for diabetic retinopathy [ClinicalTrials.gov identifier NCT00545870]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  262. 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(11): 2175–81.e1

    Article  PubMed  Google Scholar 

  263. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117(6): 1064–77.e35

    Article  PubMed  Google Scholar 

  264. Laser-ranibizumab-triamcinolone for proliferative diabetic retinopathy [ClinicalTrials.gov identifier NCT00445003]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

  265. Goyal S, Lavalley M, Subramanian ML. Meta-analysis and review on the effect of bevacizumab in diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. Epub 2010 Jul 28

  266. Cho WB, Oh SB, Moon JW, et al. Panretinal photocoagulation combined with intravitreal bevacizumab in high-risk proliferative diabetic retinopathy. Retina 2009; 29(4): 516–22

    Article  PubMed  Google Scholar 

  267. 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(6): 1078–86.e2

    Article  PubMed  Google Scholar 

  268. 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(6): 1142–50

    Article  PubMed  Google Scholar 

  269. Cho WB, Moon JW, Kim HC. Intravitreal triamcinolone and bevacizumab as adjunctive treatments to panretinal photocoagulation in diabetic retinopathy. Br J Ophthalmol 2010; 94(7): 858–63

    Article  PubMed  Google Scholar 

  270. Takamura Y, Kubo E, Akagi Y. Analysis of the effect of intravitreal bevacizumab injection on diabetic macular edema after cataract surgery. Ophthalmology 2009; 116(6): 1151–7

    Article  PubMed  Google Scholar 

  271. Simo R, Hernandez C. Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy. Diabetologia 2008; 51(9): 1574–80

    Article  PubMed  CAS  Google Scholar 

  272. Sang DN, D'Amore PA. Is blockade of vascular endothelial growth factor beneficial for all types of diabetic retinopathy? Diabetologia 2008; 51(9): 1570–3

    Article  PubMed  CAS  Google Scholar 

  273. Storkebaum E, Lambrechts D, Carmeliet P. VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 2004; 26(9): 943–54

    Article  PubMed  CAS  Google Scholar 

  274. Nishijima K, Ng YS, Zhong L, et al. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol 2007; 171(1): 53–67

    Article  PubMed  CAS  Google Scholar 

  275. Saint-Geniez M, Maharaj AS, Walshe TE, et al. Endogenous VEGF is required for visual function: evidence for a survival role on Muller cells and photoreceptors. PLoS One2008;3(11):e3554

    Article  PubMed  CAS  Google Scholar 

  276. Kamba T, Tam BY, Hashizume H, et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 2006; 290(2): H560–76

    Article  PubMed  CAS  Google Scholar 

  277. Gerber HP, Vu TH, Ryan AM, et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999; 5(6): 623–8

    Article  PubMed  CAS  Google Scholar 

  278. Eremina V, Sood M, Haigh J, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003; 111(5): 707–16

    PubMed  CAS  Google Scholar 

  279. Gordon MS, Cunningham D. Managing patients treated with bevacizumab combination therapy. Oncology 2005; 69 Suppl. 3: 25–33

    Article  PubMed  CAS  Google Scholar 

  280. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007; 99(16): 1232–9

    Article  PubMed  Google Scholar 

  281. van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: promises and potential problems. JAMA 2005; 293(12): 1509–13

    Article  PubMed  Google Scholar 

  282. Matsuyama K, Ogata N, Matsuoka M, et al. Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab. Br J Ophthalmol 2010; 94(9): 1215–8

    Article  PubMed  CAS  Google Scholar 

  283. Blaauwgeers HG, Holtkamp GM, Rutten H, et al. Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris: evidence for a trophic paracrine relation. Am JPathol 1999; 155(2): 421–8

    Article  CAS  Google Scholar 

  284. Apte RS, Modi M, Masonson H, et al. Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degeneration. Ophthalmology 2007; 114(9): 1702–12

    Article  PubMed  Google Scholar 

  285. Singerman LJ, Masonson H, Patel M, et al. Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial. Br J Ophthalmol 2008; 92(12): 1606–11

    Article  PubMed  CAS  Google Scholar 

  286. Marcus DM, VEGF Inhibition Study Ocular Neovascularization Clinical Trial Group. Four-year safety of pegaptanib sodium in neovascular age-related macular degeneration (AMD): results of the V.I.S.I.O.N. trial [abstract]. Invest Ophthalmol Vis Sci 2008; 49: E-Abstract 5069

    Google Scholar 

  287. Boyer DS, Heier JS, Brown DM, et al. A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 2009; 116(9): 1731–9

    Article  PubMed  Google Scholar 

  288. Ueta T, Yanagi Y, Tamaki Y, et al. Cerebrovascular accidents in ranibizumab [letter]. Ophthalmology 2009; 116(2): 362

    Article  PubMed  Google Scholar 

  289. Gillies MC, Wong TY. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2007; 356(7): 748–9; author reply 749-50

    PubMed  CAS  Google Scholar 

  290. Moradian S, Ahmadich H, Malihi M, et al. Intravitreal bevacizumab in active progressive proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2008; 246(12): 1699–705

    Article  PubMed  CAS  Google Scholar 

  291. Gordon-Angelozzi M, Velez-Montoya R, Quiroz-Mercado H, et al. Bevacizumab local complications [letter]. Ophthalmology 2009; 116(11): 2264.e1-3

    Article  PubMed  Google Scholar 

  292. Jonas JB, Schmidbauer M, Rensch F. Progression of tractional retinal detachment following intravitreal bevacizumab. Acta Ophthalmol 2009; 87(5): 571–2

    Article  PubMed  Google Scholar 

  293. Arevalo JF, Maia M, Flynn Jr HW, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol 2008; 92(2): 213–6

    Article  PubMed  CAS  Google Scholar 

  294. Krishnan R, Goverdhan S, Lochhead J. Intravitreal pegaptanib in severe proliferative diabetic retinopathy leading to the progression of tractional retinal detachment. Eye (Lond) 2009; 23(5): 1238–9

    Article  CAS  Google Scholar 

  295. Batman C, Ozdamar Y. The relation between bevacizumab injection and the formation of subretinal fibrosis in diabetic patients with panretinal photocoagulation. Ophthalmic Surg Lasers Imaging 2010; 41(2): 190–5

    Article  PubMed  Google Scholar 

  296. Bradley JR. TNF-mediated inflammatory disease. J Pathol 2008; 214(2): 149–60

    Article  PubMed  CAS  Google Scholar 

  297. Kim KA, Lee MS. Recent progress in research on beta-cell apoptosis by cytokines. Front Biosci 2009; 14: 657–64

    Article  PubMed  CAS  Google Scholar 

  298. Ortis F, Pirot P, Naamane N, et al. Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells. Diabetologia 2008; 51(7): 1213–25

    Article  PubMed  CAS  Google Scholar 

  299. Ruan H, Lodish HF. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev 2003; 14(5): 447–55

    Article  PubMed  CAS  Google Scholar 

  300. Demircan N, Safran BG, Soylu M, et al. Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye 2006; 20(12): 1366–9

    Article  PubMed  CAS  Google Scholar 

  301. Adamiec-Mroczek J, Oficjalska-Młyńczak J, Misiuk-Hojło M. Roles of endothelin-1 and selected proinflammatory cytokines in the pathogenesis of proliferative diabetic retinopathy: analysis of vitreous samples. Cytokine 2010; 49(3): 269–74

    Article  PubMed  CAS  Google Scholar 

  302. Yuuki T, Kanda T, Kimura Y, et al. Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. J Diabetes Complications 2001; 15(5): 257–9

    Article  PubMed  CAS  Google Scholar 

  303. Behl Y, Krothapalli P, Desta T, et al. Diabetes-enhanced tumor necrosis factor-alpha production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy. Am J Pathol 2008; 172(5): 1411–8

    Article  PubMed  Google Scholar 

  304. Shi X, Semkova I, Muther PS, et al. Inhibition of TNF-alpha reduces laser-induced choroidal neovascularization. Exp Eye Res 2006; 83(6): 1325–34

    Article  PubMed  CAS  Google Scholar 

  305. Olson JL, Courtney RJ, Mandava N. Intravitreal infliximab and choroidal neovascularization in an animal model. Arch Ophthalmol 2007; 125(9): 1221–4

    Article  PubMed  CAS  Google Scholar 

  306. Hangai M, He S, Hoffmann S, et al. Sequential induction of angiogenic growth factors by TNF-alpha in choroidal endothelial cells. J Neuroimmunol 2006; 171(1–2): 45–56

    Article  PubMed  CAS  Google Scholar 

  307. Sfikakis PP, Markomichelakis N, Theodossiadis GP, et al. Regression of sight-threatening macular edema in type 2 diabetes following treatment with the anti-tumor necrosis factor monoclonal antibody infliximab. Diabetes Care 2005; 28(2): 445–7

    Article  PubMed  Google Scholar 

  308. Markomichelakis NN, Theodossiadis PG, Sfikakis PP. Regression of neovascular age-related macular degeneration following infliximab therapy. Am J Ophthalmol 2005; 139(3): 537–40

    Article  PubMed  Google Scholar 

  309. Theodossiadis PG, Liarakos VS, Sfikakis PP, et al. Intravitreal administration of the anti-tumor necrosis factor agent infliximab for neovascular age-related macular degeneration. Am J Ophthalmol 2009; 147(5): 825–30

    Article  PubMed  CAS  Google Scholar 

  310. Sfikakis PP, Grigoropoulos V, Emfietzoglou I, et al. Infliximab for diabetic macular edema refractory to laser photocoagulation: a randomized, double-blind, placebocontrolled, crossover, 32 weeks study. Diabetes Care 2010; 33(7): 1523–8

    Article  PubMed  CAS  Google Scholar 

  311. Suhler EB, Smith JR, Wertheim MS, et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol 2005; 123(7): 903–12

    Article  PubMed  CAS  Google Scholar 

  312. Giganti M, Beer PM, Lemanski N, et al. Adverse events after intravitreal infliximab (Remicade). Retina 2010; 30(1): 71–80

    Article  PubMed  Google Scholar 

  313. Danis RP, Sheetz MJ. Ruboxistaurin: PKC-beta inhibition for complications of diabetes. Expert Opin Pharmacother 2009; 10(17): 2913–25

    Article  PubMed  CAS  Google Scholar 

  314. Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997; 46(9): 1473–80

    Article  PubMed  CAS  Google Scholar 

  315. Harhaj NS, Felinski EA, Wolpert EB, et al. VEGF activation of protein kinase C stimulates occludin phosphorylation and contributes to endothelial permeability. Invest Ophthalmol Vis Sci 2006; 47(11): 5106–15

    Article  PubMed  Google Scholar 

  316. PKC-DMES 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(7): 2188–97

    Article  Google Scholar 

  317. Aiello LP, Davis MD, Girach A, et al. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology 2006; 113(12): 2221–30

    Article  PubMed  Google Scholar 

  318. 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(3): 318–24

    Article  Google Scholar 

  319. Effect of ruboxistaurin on clinically significant macular edema [ClinicalTrials.gov identifier NCT00133952]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Aug 17]

Download references

Acknowledgements

Editorial support was provided by Lauren Swenarchuk, PhD, of Zola Associates and was funded by Pfizer Inc. Dr Boscia reports no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Ophthalmology and Otolaryngology, University of Bari, Piazza Giulio Cesare, 11, 70100, Bari, Italy

    Francesco Boscia

Authors
  1. Francesco Boscia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Boscia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boscia, F. Current Approaches to the Management of Diabetic Retinopathy and Diabetic Macular Oedema. Drugs 70, 2171–2200 (2010). https://doi.org/10.2165/11538130-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11538130-000000000-00000

Keywords

Search

Navigation