2.5New Frontiers

A neural dysfunction has been described at early stages of DR, involving different types of cells related to the neurovascular unit, which contributes to the microcirculatory anomalies. Typical findings of neurodegeneration, such as glial activation and apoptosis, have been identified ex vivo in retinas of diabetics without any biomicroscopic signs of DR [110, 111]. Recent advances in understanding the pathophysiology of DR have highlighted the main role of neuroprotection to prevent or arrest the progression of NPDR. New therapeutic molecules based on neuroprotection are under investigation [112].

Currently, a multicentric, prospective, double-blind, phases II–III randomized controlled trial is recruiting patients to assess the efficacy of two neuroprotective drugs, brimonidine and somatostatin, administered topically, to arrest or slow down the development and progression of NPDR [113]. Brimonidine is an α-2-adrenergic agonist, with intraocular pressure-lowering properties, currently used in the treatment of glaucoma. Several studies showed also an additional neuroprotective activity [114]. Somatostatin is the hypothalamic factor responsible for the inhibition of the pituitary release of the growth hormone. Local beneficial effects of somatostatin I in diabetic retinas have been shown by clinical trials, including neuromodulatory pathways, angiostatic mechanisms, and ion transport systems [115–117].

The role of other agents, including hormones, has been investigated in NPDR, even if the results of these studies showed some controversies or were not published yet.

Octreotide acetate, a synthetic analogue of somatostatin, capable to block the growth hormone, has been investigated in a small, randomized, clinical trial, showing a reduction of the severity of DR [118]. In another small study, subcutaneous administration of octreotide did not reveal any significant benefits [119]. Microspheres of octreotide have been administered every 4 weeks for 2 years in patients with moderately severe or severe NPDR or low-risk PDR during a multicenter randomized clinical trial and its open-label extension [120, 121]. Inconclusive preliminary results have been reported, including a list of side effects, such as diarrhea, hypoglycemic episodes, and cholelithiasis [122].

Two 24-month randomized clinical trials assessed the efficacy of doxycycline, a tetracycline derivative that can promote transgene expression in viral vectors, versus placebo. The study is evaluating the reduction of the deterioration or in the increasing of retinal function among patients with severe NPDR or early PDR [123] and mild to moderate NPDR [124] using different examinations.

Dietary supplementation is currently under investigation, evaluating functional (best corrected visual acuity) and anatomical (using OCT and macular pigment optical density assessments) changes at baseline and after 6 months of therapy [125].

Summary 2.7

Recent advances in understanding the pathophysiology of DR have highlighted the main role of neuroprotection to prevent or arrest the progression of NPDR. New therapeutic molecules are under investigation in the early stages of the disease.

58 F. Bandello et al.

References

1. Speiser P, Gittelsohn AM, Patz A (1968) Studies on diabetic retinopathy: III. Influence of diabetes on intramural pericytes. Arch Ophthalmol 80:332–337

2. Cogan DG, Toussaint D, Kuwabara T (1961) Retinal vascular patterns. IV. Diabetic retinopathy. Arch Ophthalmol 66:366–378

3. Green WR (1996) Retina. In: Spencer W (ed) Ophthalmic pathology. W.B. Saunders, Philadelphia

4. Chew EY, Ferris FL III (2001) Nonproliferative diabetic retinopathy. In: Ryan SJ, Schachat AP (eds) Retina, vol 2, Medical retina. Mosby, St. Louis

5. Ashton N (1969) Pathological and ultrastructural aspect of the cotton-wool spots. Proc R Soc Med 62:1271–1276

6. Laren HW (1960) Diabetic retinopathy. Acta Ophthalmol 60:1–89

7. Hersh PS, Green WR, Thoms JJV (1981) Tractional venous loops in diabetic retinopathy. Am J Ophthalmol 92:661–671

8. Ernest JT, Goldstick TK, Engerman RL (1983) Hyperglycemia impairs retinal oxygen autoregulation in normal and diabetic dogs. Invest Ophthalmol Vis Sci 24:985–989

9. Muraoka K, Shimizu K (1984) Intraretinal neovascularization in diabetic retinopathy. Ophthalmology 91:1440–1446

10. Engerman RL (1989) Pathogenesis of diabetic retinopathy. Diabetes 38:1203–1206

11. Early Treatment Diabetic Retinopathy Study Research Group (1991) Early treatment diabetic retinopathy study. Ophthalmology 98:739–840

12.Diabetic Retinopathy Study Research Group (1981) A modification of the Airlie House classification of diabetic retinopathy. Report 7. Invest Ophthalmol Vis Sci 21:210–226

13.Davis MD, Norton EWD, Myers FL (1969) The Airlie classification of diabetic retinopathy. In: Goldberg MF, Fine SL (eds) Symposium on the treatment of diabetic retinopathy (Public Health Service publication no.1890). US Government Printing Office, Washington, DC

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

15.Fukuda M (1983) Clinical arrangement of classification of diabetic retinopathy. Tohoku J Exp Med 141:331–335

16.Verdaguer TJ (2001) Screening para retinopatia en latin America. Rev Soc Brasil Retina Vitreo 4:14–15

17.National Health and Medical Research Council (1997) Management of diabetic retinopathy: clinical practice guidelines. National Health and Medical Research Council, Canberra

18.Wilkinson CP, Ferris FL III, Klein RE et al (2003) Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 110:1677–1682

19. Klein RE, Klein BE, Moss SE et al (1989) The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 107:237–243

20. Klein RE, Klein BE, Moss SE et al (1989) The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. Arch Ophthalmol 107:244–249

21. Lubow M, Makley TA Jr (1971) Pseudopapilledema of juvenile diabetes mellitus. Arch Ophthalmol 85:417–422

22.Appen RE, Chandra SR, Klein R et al (1980) Diabetic papillopathy. Am J Ophthalmol 90:203–209

23. Pavan PR, Aiello LM, Wafai MZ et al (1980) Optic disc edema in juvenile-onset diabetes. Arch Ophthalmol 98:2193–2195

24. Barr CC, Glaser JS, Blankership G (1980) Acute disc swelling in juvenile diabetes. Clinical profile and natural history of 12 cases. Arch Ophthalmol 98:2185–2192

25. Hayreh SS, Zahoruk RM (1981) Anterior ischemic optic neuropathy. VI. In juvenile diabetics. Ophthalmologica 182:13–28

26.Heller SR, Tattersall RB (1987) Optic disc swelling in young diabetic patients: a diagnostic dilemma. Diabet Med 4:260–264

27.Almog Y, Goldstein M (2003) Visual outcome in eyes with asymptomatic optic disc edema. J Neuroophthalmol 23:204–207

28.Bonnet M, Bensoussan B, Grange JD et al (1982) Acute panendothelial retinal leakage in juvenile diabetes. J Fr Ophtalmol 5:303–316

29.Brancato R, Menchini U, Bandello F (1986) Diabetic papillopathy: fluorangiographic aspects. Metab Pediatr Syst Ophthalmol 9:57–61

30.Bandello F, Menchini F (2004) Diabetic papillopathy as a risk factor for progression of diabetic retinopathy. Retina 24:183–184

31.Henkind P (1967) Radial peripapillary capillaries of the retina. I. Anatomy: human and comparative. Br J Ophthalmol 51:115–123

32.Al-Haddad CE, Jurdi FA, Bashshur ZF (2004) Intravitreal triamcinolone acetonide for the

management of diabetic papillopathy. Am J Ophthalmol 137:1151–1153

33. Mansour AM, El-Dairi MA, Shahab MA (2005) Periocular corticosteroids in diabetic papillopathy. Eye 19:45–51

34.Ornek K, Ogurel T (2010) Intravitreal bevacizumab for diabetic papillopathy. J Ocul Pharmacol Ther 26:217–218

35. Al-Hinai AS (2012) Diabetic papillopathy with macular edema treated with intravitreal bevacizumab. Oman J Ophthalmol 5:138–139

36.The Diabetic Retinopathy Study Research Group (1979) Four risk factors for severe visual loss in diabetic retinopathy. The third report from the Diabetic Retinopathy Study. Arch Ophthalmol 97:654–655

37. Bashshur RL, Mandil SH, Shannon GW (2002) Telemedicine/telehealth: an international perspective. Executive summary. Telemed J E Health 8:95–107

38.Ahmed J, Ward TP, Bursell SE et al (2006) The sensitivity and specificity of non mydriatic digital stereoscopic retinal imaging in detecting diabetic retinopathy. Diabetes Care 29:2205–2209

39.Moss S, Klein R, Kessler S et al (1985) Comparison between ophthalmoscopy and fundus photography in determining severity of diabetic eye disease. Ophthalmology 92:62–67

40. Maguire A, Chan A, Cusumano J et al (2005) The case for biennial retinopathy screening in children and adolescents. Diabetes Care 28:509–513

41. The Diabetic Retinopathy Study Research Group (1976) Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 81:383–396

42. Csutak A, Lengyel I, Jonasson F et al (2010) Agreement between image grading of conventional (45°) and ultra wide-angle (200°) digital images in the macula in the Reykjavik eye study. Eye 24:1568–1575

43. Hellstedt T, Vesti E, Immonen I (1996) Identification of individual microaneurysms: a comparison between fluorescein angiograms and red-free and colour photographs. Graefes Arch Clin Exp Ophthalmol 234:S13–S17

44. Diabetes Control and Complications Trial Research Group (1987) Color photography versus fluorescein angiography in the detection of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 105:1344–1351

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

46.Dimitrova G, Kato S (2010) Color Doppler imaging of retinal diseases. Surv Ophthalmol 55:193–214

47.Wang H, Chhablani J, Freeman WR et al (2012) Characterization of diabetic microaneurysms

by simultaneous fluorescein angiography and spectral-domain optical coherence tomography. Am J Ophthalmol 153:861–867

48. Regatieri CV, Branchini L, Carmody J et al (2012) Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 32: 563–568

49. Querques G, Lattanzio R, Querques L et al (2012) Enhanced depth imaging optical coherence tomography in type 2 diabetes. Invest Ophthalmol Vis Sci 53:6017–6024

50.Tam J, Dhamdhere KP, Tiruveedhula P et al (2012) Subclinical capillary changes in nonproliferative diabetic retinopathy. Optom Vis Sci 89:E692–E703

51. Lung JC, Swann PG, Chan HH (2012) Early local functional changes in the human diabetic retina: a global flash multifocal electroretinogram study. Graefes Arch Clin Exp Ophthalmol 250:1745–1754

52.Heravian J, Ehvaei A, Shoeibi N et al (2012) Pattern visual evoked potentials in patients with type II diabetes mellitus. J Ophthalmic Vis Res 7:225–230

53.Jackson GR, Scott IU, Quillen DA et al (2012) Inner retinal visual dysfunction is a sensitive marker of non-proliferative diabetic retinopathy. Br J Ophthalmol 96:699–703

54.Wild S, Roglic G, Green A et al (2004) Global prevalence of diabetes: estimates for the year 2000 and projection for 2030. Diabetes Care 27:1047–1053

55. Zheng Y, He M, Congdon N (2012) The worldwide epidemic of diabetic retinopathy. Indian J Ophthalmol 60:428–431

56. The Kroc Collaborative Study Group (1984) Blood glucose control and the evolution of diabetic retinopathy and albuminuria. A preliminary multicenter trial. The Kroc Collaborative Study Group. N Engl J Med 311:365–372

57. The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insu- lin-dependent diabetes mellitus. N Engl J Med 329:977–986

58.The Diabetes Control and Complications Trial (1995) The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. Arch Ophthalmol 113:36–51

59.The Diabetes Control and Complications Trial Research Group (1995) Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology 102:647–661

60.The Diabetes Control and Complications Trial Research Group (1995) The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the

diabetes control and complications trial. Diabetes 44:968–983

61. UK Prospective Diabetes Study (UKPDS) Group (1998) 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 352:837–853

62.UK Prospective Diabetes Study (UKPDS) Group (1998) Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 317:703–713

63.The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2000) Retinopathy and nephropathy in patients with type 1

diabetes four years after a trial of intensive therapy. N Engl J Med 342:381–389

64. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2002) Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 287:2563–2569

65.The Diabetes Control and Complications Trial Research Group (1998) Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 116:874–886

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

67.Baruah MP, Kalra S (2012) The novel use of GLP-1 and insulin combination in type 2 diabetes mellitus. Recent Pat Endocr Metab Immune Drug Discov 6:129–135

68.Aiello LP, Avery RL, Arrigg PG et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

69.Sjolie AK, Chaturvedi N (2002) The retinal renin-angiotensin system: implications for therapy in diabetic retinopathy. J Hum Hypertens 16:2–6

70.Wilkinson-Berka JL (2006) Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol 38:752–765

71.Chaturvedi N, Sjolie AK, Stephenson JM et al (1998) 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 351:28–31

72.Chaturvedi N, Porta M, Klein R et al (2008) Effect of candesartan on prevention (DIRECTPrevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 372:1394–1402

73.Sjolie AK, Klein R, Porta M et al (2008) Effect of candesartan on progression and regression

of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 372:1385–1393

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

75.Chew EY, Klein ML, Ferris FL et al (1996) Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol 114:1079–1084

76.Colhoun HM, Bettridge DJ, Durrington PN et al (2004) Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicenter randomised placebo-controlled trial. Lancet 364:685–696

77. Dodson PM (2008) Medical treatment for diabetic retinopathy: do the FIELD microvascular study results support a role for lipid lowering? Pract Diabetes Int 25:76–79

78.Keech A, Simes RJ, Barter P et al (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366:1849–1861

79.Keech AC, Mitchell P, Summanen PA et al (2007) Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD Study): randomized controlled trial. Lancet 370:1687–1697

80.ACCORD Study Group and ACCORD Eye Study Group (2010) Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 363:233–244

81.Cushman WC, Evans GW, Byington RP et al (2010) Effects of intensive blood pressure control

in type 2 diabetes mellitus. N Engl J Med 362:1575–1585

82. Ginsberg HN, Elam MB, Lovato LC et al (2010) Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 362:1563–1574

83.Hiukka A, Maranghi M, Matikaimen N et al (2010) PPARalpha: an emerging therapeutic target in diabetic microvascular damage. Nat Rev Endocrinol 5:454–463

84.Tomizawa A, Hattori Y, Inoue T et al (2011) Fenofibrate suppresses microvascular inflammation and apoptosis through adenosine monophosphate-activated protein kinase. Metabolism

2011:513–522

85. Kim J, Ahn J-H, Kim J-H et al (2007) Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway. Exp Eye Res 84:886–893

86.American Diabetes Association (2013) Standards of medical care in diabetes. Diabetes Care 36:S11–66

87.Sheetz MJ, King GL (2002) Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA 288:2579–2588

88.Mellor H, Parker PJ (1998) The extended protein kinase C superfamily. Biochem J 332:281–292

89.Bullock WH, Magnuson SR, Choi S (2002) Prospects for kinase activity modulators in the treatment of diabetes and diabetic complications. Curr Top Med Chem 2:915–938

90.The PKC-DR Study Group (2005) The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe non proliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes 54:2188–2197

91.PKC-DR2 Study Group (2006) Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology 113:2221–2230

92. McGill JB, King GL, Berg PH et al (2006) Clinical safety of the selective PKC-beta inhibitor, ruboxistaurin. Expert Opin Drug Saf 5:835–845

93. Sheetz MJ, Aiello LP, Shahri N, Mbdv Study Group et al (2011) Effect of ruboxistaurin (RBX) on visual acuity decline over a 6-year period with cessation and reinstitution of therapy: results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2). Retina 31:1053–1059

94. American Academy of Ophthalmology Retina Panel (2008) Preferred practice pattern: diabetic retinopathy. American Academy of Ophthalmology, San Francisco

95. Vijan S, Hofer TP, Hayward RA (2000) Cost-utility analysis of screening intervals for diabetic retinopathy in patients with type 2 diabetes mellitus. JAMA 283:889–896

96. Bonovas S, Peponis V, Filioussi K (2004) Diabetes mellitus as a risk factor for primary openangle glaucoma: a meta-analysis. Diabet Med 21:609–614

97. Javitt JC, Canner JK, Sommer A (1989) Cost effectiveness of current approaches to the control of retinopathy in type 1 diabetes. Ophthalmology 96:255–264

98. Moss SE, Klein R, Klein BE (1995) Factors associated with having eye examinations in persons with diabetes. Arch Fam Med 4:529–534

99. Sprafka JM, Fritsche TL, Baker R et al (1990) Prevalence of undiagnosed eye disease in highrisk diabetic individuals. Arch Intern Med 150:857–861

100.Will JC, German RR, Schuman E et al (1994) Patient adherence to guidelines for diabetes eye care: results from the diabetic eye disease follow-up study. Am J Public Health 84:1669–1671

101.Brink SJ (2001) Complications of pediatric and adolescent type 1 diabetes mellitus. Curr Diab Rep 1:47–55

102.Massin P, Erginay A, Mercat-Caudal I et al (2007) Prevalence of diabetic retinopathy in children and adolescents with type-1 diabetes attending summer camps in France. Diabetes Metab 33:284–289

103.Majaliwa ES, Munubhi E, Ramaiya K et al (2007) Survey on acute and chronic complications in children and adolescents with type 1 diabetes at Muhimbili National Hospital in Dar es Salaam, Tanzania. Diabetes Care 30:2187–2192

104.Sultan MB, Starita C, Huang K (2012) Epidemiology, risk factors and management of paediatric diabetic retinopathy. Br J Ophthalmol 96:312–317

105.Lueder GT, Silverstein J (2005) American Academy of Pediatrics Section on Ophthalmology and Section on Endocrinology. Screening for retinopathy in the pediatric patient with type 1 diabetes mellitus. Pediatrics 116:270–273

106.Kollias AN, Ulbig MW (2010) Diabetic retinopathy. Early diagnosis and effective treatment. Dtsch Arztebl Int 107:75–84

107.Diabetic Retinopathy Study Research Group (1981) Design, methods, and baseline results. DRS report number 6. Invest Ophthalmol Vis Sci 21:149–209

108.Early Treatment Diabetic Retinopathy Study Research Group (1991) Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology 98:741–756

109.Ferris F (1996) Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc 94:505–537

110.Carrasco E, Hernández C, Miralles A et al (2007) Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration. Diabetes Care 30:2902–2908

111.García-Ramírez M, Hernández C, Villarroel M et al (2009) Inter photoreceptor retinoidbinding protein (IRBP) is down regulated at early stages of diabetic retinopathy. Diabetologia 52:2633–2641

112.Imai H, Singh RS, Fort PE et al (2009) Neuroprotection for diabetic retinopathy. Dev Ophthalmol 44:56–68

113.Trial to assess the efficacy of neuroprotective drugs administered topically to prevent or arrest diabetic retinopathy (EUROCONDOR). Available at http://clinicaltrials.gov/ct/show/ NCT01726075. Accessed Jan 2013

114.Saylor M, McLoon LK, Harrison AR et al (2009) Experimental and clinical evidence for brimonidine as an optic nerve and retinal neuroprotective agent: an evidence-based review. Arch Ophthalmol 127:402–406

115.Simó R, Carrasco E, García-Ramírez M et al (2006) Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev 2:71–98

116.Davis MI, Wilson SH, Grant MB et al (2001) The therapeutic problem of proliferative diabetic retinopathy: targeting somatostatin receptors. Horm Metab Res 33:295–299

117.Lambooij AC, Kuijpers RW, van Lichtenauer-Kaligis EG et al (2000) Somatostatin receptor 2A expression in choroidal neovascularization secondary to age-related macular degeneration. Invest Ophthalmol Vis Sci 41:2329–2335

118.Grant MB, Mames RN, Fitzgerald C et al (2000) The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy: a randomized controlled study. Diabetes Care 23:504–509

119.Kirkegaard C, Nørgaard K, Snorgaard O et al (1990) Effect of one year continuous subcutaneous infusion of a somatostatin analogue, octreotide, on early retinopathy, metabolic control and thyroid function in Type I (insulin-dependent) diabetes mellitus. Acta Endocrinol 122:766–772

120.Extension study of the long-term safety and tolerability of octreotide acetate in patients with moderately severe or severe non-proliferative diabetic retinopathy or low risk proliferative diabetic retinopathy. Available at http://clinicaltrials.gov/ct/show/NCT00248157. Accessed Jan 2013

121.Octreotide acetate in microspheres in patients with diabetic retinopathy. Available at http:// clinicaltrials.gov/ct/show/NCT00131144. Accessed Jan 2013

122.Mohamed Q, Wong TY (2008) Emerging drugs for diabetic retinopathy. Expert Opin Emerg Drugs 13:675–694

123.Evaluation of doxycycline versus placebo for the treatment of severe non proliferative or mild or moderate proliferative diabetic retinopathy (POC1). Available at http://clinicaltrials.gov/ ct/show/NCT00511875. Accessed Jan 2013

124.Evaluation of effect of doxycycline versus placebo on retinal function and diabetic retinopathy (POC2). Available at http://clinicaltrials.gov/ct/show/NCT00917553. Accessed Jan 2013

125.Diabetes Visual Function Supplement Study (DiVFuSS). Available at http://clinicaltrials. gov/ct/show/NCT01646047. Accessed Jan 2013