Retinopathy

Canadian Diabetes Association Clinical Practice Guideline Expert Committee

Shelley R. Boyd MD, FRCSC Andrew Advani MB ChB, PhD, FRCP(UK) Filiberto Altomare MD, FRCSC Frank Stockl MD, FRCSC

  • Key Messages
  • Recommendations
  • Figures
  • Full Text
  • References

Key Messages

  • Screening is important for early detection of treatable disease. Screening intervals for diabetic retinopathy vary according to the individual's age and type of diabetes.
  • Tight glycemic control reduces the onset and progression of sight-threatening diabetic retinopathy.
  • Laser therapy, local intraocular pharmacological therapy and surgery reduce the risk of significant visual loss.

Introduction

Diabetic retinopathy is the most common cause of new cases of legal blindness in people of working age (1). The Eye Diseases Prevalence Research Group determined the crude prevalence rate of retinopathy in the adult population with diabetes of the United States to be 40.3%; sight-threatening retinopathy occurred at a rate of 8.2% (1). Previous data showed the prevalence rate of proliferative retinopathy to be 23% in people with type 1 diabetes, 14% in people with type 2 diabetes and on insulin therapy, and 3% in people receiving oral antihyperglycemic therapies (2). Macular edema occurs in 11%, 15% and 4% of these groups, respectively (3). Higher prevalence rates were noted in First Nations populations in Canada (4,5).

Visual loss is associated with significant morbidity, including increased falls, hip fracture and a 4-fold increase in mortality (6). Among individuals with type 1 diabetes, limb amputation and visual loss due to diabetic retinopathy are the independent predictors of early death (7).

Definition and Pathogenesis

Diabetic retinopathy is clinically defined, diagnosed and treated based on the extent of retinal vascular disease exclusively. Three distinct forms of diabetic retinopathy are described: 1) macular edema, which includes diffuse or focal vascular leakage at the macula; 2) progressive accumulation of blood vessel change that includes microaneurysms, intraretinal hemorrhage, vascular tortuosity and vascular malformation (together known as nonproliferative diabetic retinopathy) that ultimately leads to abnormal vessel growth (proliferative diabetic retinopathy); and 3) retinal capillary closure, a form of vascular change detected on fluorescein angiography, which is also well recognized as a potentially blinding complication of diabetes but currently has no treatment options.

Screening

Because laser therapy for sight-threatening diabetic retinopathy reduces the risk of blindness, ophthalmic screening strategies are intended to detect disease treatable by this modality (8–11). Sight-threatening diabetic retinopathy includes severe nonproliferative diabetic retinopathy, proliferative diabetic retinopathy or clinically significant macular edema (CSME) (8), a strictly defined form of diabetic macular edema (DME) that relies on the clinical assessment of retinal thickening based on subjective assessment of area and distance from the fovea (the centre of the macula responsible for high-acuity vision), with or without so-called hard exudates. Since the introduction of new treatments based on intravitreal (intraocular) injection of pharmacological agents and use of Optical Coherence Tomography (OCT) to quantify macular thickness, the more general term DME, or “centre-involving” DME has come to describe patients who could benefit from this treatment over laser, the latter of which cannot be applied to the fovea. Despite the change in treatment modalities, screening programs remain unchanged and consider the differences in incidence and prevalence of retinopathy observed in type 1 and type 2 diabetes, and distinguish between children and adults ( Table 1 ) (12–17).

Table 1
Screening for retinopathy
BP, blood pressure.
See “Other Relevant Guidelines”.
When to initiate screening
  • Five years after diagnosis of type 1 diabetes in all individuals ≥15 years
  • In all individuals at diagnosis of type 2 diabetes
Screening methods
  • Seven-standard field, stereoscopic-colour fundus photography with interpretation by a trained reader (gold standard)
  • Direct ophthalmoscopy or indirect slit-lamp funduscopy through dilated pupil
  • Digital fundus photography
If retinopathy is present
  • Diagnose retinopathy severity and establish appropriate monitoring intervals (≤1 year)
  • Treat sight-threatening retinopathy with laser, pharmacological or surgical therapy
  • Review glycemic, BP and lipid control, and adjust therapy to reach targets per guidelines
  • Screen for other diabetes complications
If retinopathy is not present
  • Type 1 diabetes: rescreen annually
  • Type 2 diabetes: rescreen every 1–2 years
  • Review glycemic, BP and lipid control, and adjust therapy to reach targets per guidelines
  • Screen for other diabetes complications

Diabetic retinopathy rarely develops in children with type 1 diabetes <10 years of age regardless of the duration of diabetes (16). Among patients <15 years of age, irrespective of age of onset of diabetes, the prevalence of mild nonproliferative retinopathy was 2%, and none had sight-threatening diabetic retinopathy (9,16). However, the prevalence rate increases sharply after 5 years' duration of diabetes in postpubertal individuals with type 1 diabetes (16). In the Wisconsin Epidemiology Study of Diabetic Retinopathy 4-year incidence study, no person <17 years of age developed proliferative retinopathy or macular edema (14,18,19). Conversely, in people with type 2 diabetes, retinopathy may be present in 21% to 39% of patients soon after clinical diagnosis but is sight-threatening in only about 3% (3,15,17,20). In the United Kingdom Prospective Diabetes Study (UKPDS), few patients without retinopathy at diagnosis of diabetes had disease progression to the point of requiring retinal photocoagulation (laser treatment) in the following 3 to 6 years (21). More recently, progression rates of diabetic retinopathy were prospectively evaluated (12,13,22). The Liverpool Diabetic Eye Study reported the 1-year cumulative incidence of sight-threatening diabetic retinopathy in individuals with type 1 or type 2 diabetes who, at baseline, had no diabetic retinopathy, had background retinopathy or had mild preproliferative retinopathy. In people with type 1 diabetes, the incidence in these groups was 0.3%, 3.6% and 13.5%, respectively (12), and in type 2 diabetes individuals it was 0.3%, 5.0% and 15.0%, respectively (13). Although the incidence of sight-threatening diabetic retinopathy in the group without baseline diabetic retinopathy is low (12,13,21,22), there have been no studies comparing various screening intervals in their effectiveness to reduce the risk of vision loss (23).

Telemedicine programs relying on fundus photography are widely used in Canada and internationally for the identification and triage of patients with diabetic retinopathy (24). Programs relying on OCT to evaluate macular edema are under investigation.

Delay of Onset and Progression

Risk factors for the development or progression of diabetic retinopathy are longer duration of diabetes, elevated glycated hemoglobin (A1C), increased blood pressure (BP), dyslipidemia, low hemoglobin level, pregnancy (with type 1 diabetes), proteinuria and severe retinopathy itself (14–17,19,25–31).

Glycemic control

Tight glycemic control, targeting an A1C ≤7%, is recommended to slow the development and progression of diabetic retinopathy. The Diabetes Control and Complications Trial (DCCT) and the UKPDS demonstrated that intensive glycemic control (A1C ≤7%) reduced both the development and progression of retinopathy (32–34), with the beneficial effects of intensive glycemic control persisting for up to 10 years after completion of the initial trials (35,36). Two studies examined the effect of more aggressive blood glucose lowering (A1C ≤6.5%) in patients with established type 2 diabetes (duration 6 to 10 years). In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye study, intensive glycemic control was associated with a lower rate of retinopathy progression than standard therapy (37), while in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Retinal Measurements study (AdRem), intensive glycemic control did not significantly reduce development or progression of retinopathy (38). In type 1 diabetes, rapid improvement of glycemia may be associated with transient early worsening of retinopathy, but this effect is offset by long-term benefits (39).

Blood pressure control

BP control is an important component of risk factor modification in diabetes and reduces the risk of retinopathy progression. The UKPDS showed that, among patients with newly diagnosed type 2 diabetes, BP control (target BP <150/85 mm Hg, actual BP 144/82 mm Hg) resulted in a significant reduction in retinopathy progression as well as a decrease in significant visual loss and requirement for laser therapy compared to less control (target BP <180/105 mm Hg, actual mean BP 154/87 mm Hg) (40). The ACCORD and ADVANCE studies examined more aggressive BP lowering in patients with established type 2 diabetes. In both these studies, where mean BP was <140/80 mm Hg in both the active intervention and control groups, active treatment did not show additional benefit vs. standard therapy.

Although a number of trials have examined the effect of renin-angiotensin system (RAS) blockade on retinopathy progression or development among normotensive patients with diabetes, the results generally have been conflicting or inconclusive. In the Renin-Angiotensin System Study (RASS), involving 223 normotensive, normoalbuminuric participants with type 1 diabetes, either the angiotensin-converting enzyme (ACE) inhibitor, enalapril, or the angiotensin receptor blocker (ARB), losartan, reduced retinopathy progression independent of BP change (41).The Diabetic Retinopathy Candesartan Trials (DIRECT) program, involving 5231 participants, evaluated the effect of the angiotension II type 1 ARB candesartan 32 mg daily on the incidence of new retinopathy in patients with type 1 diabetes (DIRECT-Prevent 1) (42) and on the progression of retinopathy in patients with either type 1 diabetes (DIRECT-Protect 1) (42) or type 2 diabetes (DIRECT-Protect 2) (43). The DIRECT studies did not meet their primary endpoints, although there was an overall change toward less severe retinopathy with candesartan (42,43). Thus, while BP lowering (including use of RAS blockers) reduces retinopathy rates and is an important component of vascular protection, there is insufficient evidence to recommend RAS blockade as primary prevention for retinopathy for all normotensive patients with diabetes.

Lipid-lowering therapy

Dyslipidemia is an independent risk factor for retinal hard exudates and CSME in type 1 diabetes (28,44). While statin-based lipid-lowering therapies are an integral part of vascular protection in diabetes, the role of these agents in preventing the development or progression of retinopathy has not been established (34,45). The role of the peroxisome proliferator-activated receptor-alpha agonist, fenofibrate, has been assessed in 2 large-scale randomized controlled trials. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate 200 mg daily reduced both the requirement for laser therapy (a prespecified tertiary endpoint) and retinopathy progression among patients with pre-existing retinopathy (46). In the ACCORD Eye study, the addition of fenofibrate 160 mg daily to simvastatin was associated with a 40% reduction in the primary outcome of retinopathy progression over 4 years (37). From the study's control and event rates, the number of patients needed to treat with combination statin and fenofibrate therapy to prevent 1 retinopathy progression event is estimated at 27 over the 4-year period. The mechanism for any beneficial effect of fenofibrate in diabetic retinopathy has not been established, with active treatment being associated with an increase in high-density lipoprotein-cholesterol and decrease in serum triglycerides in ACCORD Eye (37) but appearing to be independent of plasma lipid concentrations in FIELD (46). Thus, the addition of fenofibrate to statin therapy could be considered in patients with type 2 diabetes to slow the progression of established retinopathy.

Antiplatelet therapy

Systematic review suggests that acetylsalicylic acid (ASA) therapy neither decreases nor increases the incidence or progression of diabetic retinopathy (47). Correspondingly, ASA use does not appear to be associated with an increase in risk of vitreous hemorrhage or DME (48,49).

Treatment

Treatment modalities for diabetic retinopathy include retinal photocoagulation, intraocular injection of pharmacological agents and vitreoretinal surgery.

Laser therapy

As determined in the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS), laser therapy by panretinal photocoagulation to the retinal periphery reduces severe visual loss and reduces legal blindness by 90% in people with severe nonproliferative or proliferative retinopathy (9–11). As determined by the ETDRS, focal and/or grid laser treatment to the macula for CSME reduces the incidence of moderate visual loss by 50% (8). Long-term follow-up studies to the original laser photocoagulation trials confirm its benefit over several decades (50).

Local (intraocular) pharmacological intervention

In the treatment of DME with centre-involving disease, as defined by OCT or clinical examination, intraocular pharmacotherapy is now available. With the knowledge that the cytokine vascular endothelial growth factor (VEGF) plays a primary role in the development of DME, 2 anti-VEGF drugs are now widely used. Two masked phase III clinical trials, RISE and RIDE, using monthly ranibizumab, a humanized recombinant anti-VEGF antibody fragment, with or without prompt laser, improved visual acuity compared against sham over the 2 years of study (51). In the RISE trial, 44% and 39% of patients receiving 0.3 or 0.5 mg ranibizumab, respectively, gained 15 letters or more (3 lines) of acuity vs. 18% of those in the control arm. In the RIDE study, 33% or 45% of patients gained 15 letters or more at doses of 0.3 or 0.5 mg, respectively. Furthermore, 1-year results of a phase III clinical trial, RESTORE, using an initial loading dose of 3 monthly injections of 0.5 mg ranibizumab, and as-needed treatment thereafter, likewise showed improvement in the primary and secondary outcome measures of best correct visual acuity and reduction in central macular thickness. In all studies, this was true when ranibizumab was used as monotherapy or in conjunction with macular photocoagulation. In the RESTORE study, 37% to 43% of ranibizumab-treated patients improved vision by 10 letters or more compared to 16% with standard laser therapy (52). Two-year results are pending. Similar results were obtained by the Diabetic Retinopathy Clinical Research Network using physician-based flexible treatment algorithms rather than a strict prescribed injection schedule (53). Intravitreal injection with ranibizumab is approved by Health Canada.

A similar outcome was noted when comparing intraocular injection of bevacizumab (a full-length antibody against VEGF) to macular laser. Two-year results of a phase III clinical trial, the BOLT trial, demonstrated a gain of at least 15 letters or more in 32% of patients receiving 1.25 mg bevacizumab compared to 4% in the control arm (54). However, unlike ranibizumab, intraocular injection of bevacizumab in diabetic retinopathy constitutes off-label use of the drug in Canada.

Steroids are an alternate class of drug evaluated in the treatment of DME. Intraocular injection of steroid combined with prompt macular laser was as effective as ranibizumab in a single subgroup of patients characterized by previous cataract surgery (53). However, treatment with intraocular steroid was associated with increased rates of glaucoma. Two phase III clinical trials investigating the implantation of a long-term drug delivery device containing fluocinolone acetonide met their primary and secondary outcomes (visual acuity and OCT) but showed increased rates of glaucoma and cataract progression compared to sham (55,56). The risk-to-benefit ratio was considered unacceptable to the United States Food and Drug Administration (FDA) where the treatment was not approved. By contrast, the fluocinolone insert has received approval in several European countries.

Surgical intervention

The Diabetic Retinopathy Vitrectomy Study (DRVS) Group evaluated the benefit of early vitrectomy (<6 months) in the treatment of severe vitreous hemorrhage (57) and very severe proliferative diabetic retinopathy (58). People with type 1 diabetes of <20 years' duration and severe vitreous hemorrhage were more likely to achieve good vision with early vitrectomy compared to conventional management (57). Similarly, early vitrectomy was associated with higher chance of visual recovery in people with either type 1 or 2 diabetes with very severe proliferative diabetic retinopathy (58). Surgical advances in vitrectomy since the DRVS trials have demonstrated reduced side effects with more consistent favourable visual outcomes, thus supporting vitrectomy in advanced proliferative diabetic retinopathy (59). Furthermore, these advances have expanded surgical indications to include vitrectomy for diffuse macular edema with or without vitreomacular traction (60). It is worth noting that the use of perioperative ASA (49,61,62) and warfarin therapy (63) for persons undergoing ophthalmic surgery does not appear to raise the risk of hemorrhagic complications.

Overall, the last few years have seen significant advances in systemic, local and surgical treatments of diabetic eye disease, with significantly improved visual outcome. Most notably, long-term follow-up to early laser studies confirm their sustained efficacy in preserving vision (50). New therapies, such as intraocular pharmacological treatment, await long-term follow-up but already demonstrate both preservation and recovery of vision in persons with DME. Despite these successes, it is important to encourage patients with even moderate visual loss to seek assistance from community services that provide spectacle correction, enhanced magnification, vision aids and measures to encourage independence and ongoing quality of life (64,65).

Recommendations

  1. 1.In individuals ≥15 years of age with type 1 diabetes, screening and evaluation for retinopathy by an expert professional should be performed annually starting 5 years after the onset of diabetes [Grade A, Level 1 (14,16)].
  2. 2.In individuals with type 2 diabetes, screening and evaluation for diabetic retinopathy by an expert professional should be performed at the time of diagnosis of diabetes [Grade A, Level 1 (15,18) ] and annually thereafter. The interval for follow-up assessments should be tailored to the severity of the retinopathy. In those with no or minimal retinopathy, the recommended interval is 1–2 years [Grade A, Level 1 (15,18)].
  3. 3.Screening for diabetic retinopathy should be performed by experienced professionals, either in person or through interpretation of retinal photographs taken through dilated pupils [Grade A, Level 1 (66)].
  4. 4.To prevent the onset and delay the progression of diabetic retinopathy, people with diabetes should be treated to achieve optimal control of blood glucose [Grade A, Level 1A (32,33) ] and BP [Grade A, Level 1A (40), for type 2 diabetes].
  5. 5.Though not recommended for CVD prevention or treatment, fenofibrate, in addition to statin therapy, may be used in patients with type 2 diabetes to slow the progression of established retinopathy [Grade A, Level 1A (37,46)].
  6. 6.Patients with sight-threatening diabetic retinopathy should be assessed by a general ophthalmologist or retina specialist [Grade D, Consensus]. Laser therapy and/or vitrectomy [Grade A, Level 1A (8,10,57,58) ] and/or pharmacological intervention [Grade A, Level 1A (51,52,55,56) ] should be used.
  7. 7.Visually disabled people should be referred for low-vision evaluation and rehabilitation [Grade D, Consensus].

Abbreviations:
BP , blood pressure; CVD , cardiovascular disease.

References

  1. 1 J.H. Kempen B.J. O'Colmain M.C. Leske The prevalence of diabetic retinopathy among adults in the United States Arch Ophthalmol 122 2004 552 563
  2. 2 R. Klein B.E. Klein S.E. Moss Epidemiology of proliferative diabetic retinopathy Diabetes Care 15 1992 1875 1891
  3. 3 R. Klein B.E. Klein S.E. Moss The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema Ophthalmology 91 1984 1464 1474
  4. 4 H. Kaur D. Maberley A. Chang D. Hay The current status of diabetes care, diabetic retinopathy screening and eye-care in British Columbia's First Nations Communities Int J Circumpolar Health 63 2004 277 285
  5. 5 D. Maberley H. Walker A. Koushik A. Cruess Screening for diabetic retinopathy in James Bay, Ontario: a cost-effectiveness analysis CMAJ 168 2003 160 164
  6. 6 H.T. Vu J.E. Keeffe C.A. McCarty H.R. Taylor Impact of unilateral and bilateral vision loss on quality of life Br J Ophthalmol 89 2005 360 363
  7. 7 M. Cusick A.D. Meleth E. Agron Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: early treatment diabetic retinopathy study report no. 27 Diabetes Care 28 2005 617 625
  8. 8 Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study Research Group Arch Ophthalmol 103 1985 1796 1806
  9. 9 F.L. Ferris 3rd How effective are treatments for diabetic retinopathy? JAMA 269 1993 1290 1291
  10. 10 Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings Ophthalmology 85 1978 82 106
  11. 11 F. Ferris Early photocoagulation in patients with either type I or type II diabetes Trans Am Ophthalmol Soc 94 1996 505 537
  12. 12 N. Younis D.M. Broadbent S.P. Harding J.P. Vora Incidence of sight-threatening retinopathy in Type 1 diabetes in a systematic screening programme Diabet Med 20 2003 758 765
  13. 13 N. Younis D.M. Broadbent J.P. Vora Incidence of sight-threatening retinopathy in patients with type 2 diabetes in the Liverpool Diabetic Eye Study: a cohort study Lancet 361 2003 195 200
  14. 14 R. Klein B.E. Klein S.E. Moss 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 1989 237 243
  15. 15 R. Klein B.E. Klein S.E. Moss 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 1989 244 249
  16. 16 R. Klein B.E. Klein S.E. Moss The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years Arch Ophthalmol 102 1984 520 526
  17. 17 R. Klein B.E. Klein S.E. Moss The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years Arch Ophthalmol 102 1984 527 532
  18. 18 R. Klein B.E. Klein S.E. Moss The Wisconsin Epidemiologic Study of Diabetic Retinopathy. VII. Diabetic nonproliferative retinal lesions Ophthalmology 94 1987 1389 1400
  19. 19 R. Klein S.E. Moss B.E. Klein The Wisconsin epidemiologic study of diabetic retinopathy. XI. The incidence of macular edema Ophthalmology 96 1989 1501 1510
  20. 20 E.M. Kohner S.J. Aldington I.M. Stratton United Kingdom Prospective Diabetes Study, 30: diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors Arch Ophthalmol 116 1998 297 303
  21. 21 E.M. Kohner I.M. Stratton S.J. Aldington UKPDS Group Relationship between the severity of retinopathy and progression to photocoagulation in patients with Type 2 diabetes mellitus in the UKPDS (UKPDS 52) Diabet Med 18 2001 178 184
  22. 22 A. Maguire A. Chan J. Cusumano The case for biennial retinopathy screening in children and adolescents Diabetes Care 28 2005 509 513
  23. 23 R. Klein Screening interval for retinopathy in type 2 diabetes Lancet 361 2003 190 191
  24. 24 J.D. Whited Accuracy and reliability of teleophthalmology for diagnosing diabetic retinopathy and macular edema: a review of the literature Diabetes Technol Ther 8 2006 102 111
  25. 25 R. Klein B.E. Klein S.E. Moss K.J. Cruickshanks The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes Ophthalmology 105 1998 1801 1815
  26. 26 M.D. Davis M.R. Fisher R.E. Gangnon Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18 Invest Ophthalmol Vis Sci 39 1998 233 252
  27. 27 B.E. Klein S.E. Moss R. Klein Effect of pregnancy on progression of diabetic retinopathy Diabetes Care 13 1990 34 40
  28. 28 E.Y. Chew M.L. Klein F.L. Ferris 3rd Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22 Arch Ophthalmol 114 1996 1079 1084
  29. 29 Q. Qiao S. Keinanen-Kiukaanniemi E. Laara The relationship between hemoglobin levels and diabetic retinopathy J Clin Epidemiol 50 1997 153 158
  30. 30 C. Diabetes Complications Trial Research Group Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group Diabetes Care 23 2000 1084 1091
  31. 31 E.Y. Chew J.L. Mills B.E. Metzger Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study Diabetes Care 18 1995 631 637
  32. 32 The 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 329 1993 977 986
  33. 33 UK Prospective Diabetes Study (UKPDS) 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 352 1998 837 853
  34. 34 Q. Mohamed M.C. Gillies T.Y. Wong Management of diabetic retinopathy: a systematic review JAMA 298 2007 902 916
  35. 35 N.H. White W. Sun P.A. Cleary 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 126 2008 1707 1715
  36. 36 R.R. Holman S.K. Paul M.A. Bethel 10-year follow-up of intensive glucose control in type 2 diabetes N Engl J Med 359 2008 1577 1589
  37. 37 A.S. Group A.E.S. Group E.Y. Chew Effects of medical therapies on retinopathy progression in type 2 diabetes N Engl J Med 363 2010 233 244
  38. 38 J.W. Beulens A. Patel J.R. Vingerling 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 52 2009 2027 2036
  39. 39 Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial Arch Ophthalmol 116 1998 874 886
  40. 40 UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 BMJ 317 1998 703 713
  41. 41 M. Mauer B. Zinman R. Gardiner Renal and retinal effects of enalapril and losartan in type 1 diabetes N Engl J Med 361 2009 40 51
  42. 42 N. Chaturvedi M. Porta R. Klein Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials Lancet 372 2008 1394 1402
  43. 43 A.K. Sjolie R. Klein M. Porta Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial Lancet 372 2008 1385 1393
  44. 44 B. Miljanovic R.J. Glynn D.M. Nathan A prospective study of serum lipids and risk of diabetic macular edema in type 1 diabetes Diabetes 53 2004 2883 2892
  45. 45 H.M. Colhoun D.J. Betteridge P.N. Durrington Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial Lancet 364 2004 685 696
  46. 46 A.C. Keech P. Mitchell P.A. Summanen Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial Lancet 370 2007 1687 1697
  47. 47 K. Bergerhoff C. Clar B. Richter Aspirin in diabetic retinopathy. A systematic review Endocrinol Metab Clin North Am 31 2002 779 793
  48. 48 L.P. Aiello M.T. Cahill J.S. Wong Systemic considerations in the management of diabetic retinopathy Am J Ophthalmol 132 2001 760 776
  49. 49 Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8 Ophthalmology 98 5 Suppl 1991 757 765
  50. 50 E.Y. Chew F.L. Ferris 3rd K.G. Csaky The long-term effects of laser photocoagulation treatment in patients with diabetic retinopathy: the early treatment diabetic retinopathy follow-up study Ophthalmology 110 2003 1683 1689
  51. 51 Q.D. Nguyen D.M. Brown D.M. Marcus Ranibizumab for diabetic macular edema: results from 2 phase iii randomized trials: RISE and RIDE Ophthalmology 119 2012 789 801
  52. 52 P. Mitchell F. Bandello U. Schmidt-Erfurth The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema Ophthalmology 118 2011 615 625
  53. 53 M.J. Elman N.M. Bressler H. Qin Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema Ophthalmology 118 2011 609 614
  54. 54 R. Rajendram S. Fraser-Bell A. Kaines A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema Arch Ophthalmol 130 2012 972 979
  55. 55 P.A. Pearson T.L. Comstock M. Ip Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial Ophthalmology 118 2011 1580 1587
  56. 56 P.A. Campochiaro D.M. Brown A. Pearson Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema Ophthalmology 118 2011 626 635
  57. 57 Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5 Arch Ophthalmol 108 1990 958 964
  58. 58 Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial–Diabetic Retinopathy Vitrectomy Study Report 3. The Diabetic Retinopathy Vitrectomy Study Research Group Ophthalmology 95 1988 1307 1320
  59. 59 W.E. Smiddy H.W. Flynn Jr. Vitrectomy in the management of diabetic retinopathy Surv Ophthalmol 43 1999 491 507
  60. 60 A.M. El-Asrar H.S. Al-Mezaine M.S. Ola Changing paradigms in the treatment of diabetic retinopathy Curr Opin Ophthalmol 20 2009 532 538
  61. 61 E.Y. Chew M.L. Klein R.P. Murphy Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report no. 20 Arch Ophthalmol 113 1995 52 55
  62. 62 E.Y. Chew W.E. Benson N.A. Remaley Results after lens extraction in patients with diabetic retinopathy: early treatment diabetic retinopathy study report number 25 Arch Ophthalmol 117 1999 1600 1606
  63. 63 J.S. Brown T.H. Mahmoud Anticoagulation and clinically significant postoperative vitreous hemorrhage in diabetic vitrectomy Retina 31 2011 1983 1987
  64. 64 G.E. Fonda Optical treatment of residual vision in diabetic retinopathy Ophthalmology 101 1994 84 88
  65. 65 M. Bernbaum S.G. Albert Referring patients with diabetes and vision loss for rehabilitation: who is responsible? Diabetes Care 19 1996 175 177
  66. 66 M.J. Buxton M.J. Sculpher B.A. Ferguson Screening for treatable diabetic retinopathy: a comparison of different methods Diabet Med 8 1991 371 377
 
Reproduced with permission from Canadian Journal of Diabetes © 2013 Canadian Diabetes Association. To cite this article, please refer to For citation.