Context Diabetic retinopathy (DR) is the leading cause of blindness in the working-aged population in the United States. There are many new interventions for DR, but evidence to support their use is uncertain.
Objective To review the best evidence for primary and secondary intervention in the management of DR, including diabetic macular edema.
Evidence Acquisition Systematic review of all English-language articles, retrieved using a keyword search of MEDLINE (1966 through May 2007), EMBASE, Cochrane Collaboration, the Association for Research in Vision and Ophthalmology database, and the National Institutes of Health Clinical Trials Database, and followed by manual searches of reference lists of selected major review articles. All English-language randomized controlled trials (RCTs) with more than 12 months of follow-up and meta-analyses were included. Delphi consensus criteria were used to identify well-conducted studies.
Evidence Synthesis Forty-four studies (including 3 meta-analyses) met the inclusion criteria. Tight glycemic and blood pressure control reduces the incidence and progression of DR. Pan-retinal laser photocoagulation reduces the risk of moderate and severe visual loss by 50% in patients with severe nonproliferative and proliferative retinopathy. Focal laser photocoagulation reduces the risk of moderate visual loss by 50% to 70% in eyes with macular edema. Early vitrectomy improves visual recovery in patients with proliferative retinopathy and severe vitreous hemorrhage. Intravitreal injections of steroids may be considered in eyes with persistent loss of vision when conventional treatment has failed. There is insufficient evidence for the efficacy or safety of lipid-lowering therapy, medical interventions, or antivascular endothelial growth factors on the incidence or progression of DR.
Conclusions Tight glycemic and blood pressure control remains the cornerstone in the primary prevention of DR. Pan-retinal and focal retinal laser photocoagulation reduces the risk of visual loss in patients with severe DR and macular edema, respectively. There is currently insufficient evidence to recommend routine use of other treatments.
Diabetes mellitus affects 200 million people worldwide,1 including 20 million in the United States alone.2 Diabetic retinopathy (DR), a specific microvascular complication of diabetes, is the leading cause of blindness in working-aged persons in the United States.2 The prevalence of DR increases with duration of diabetes,3 and nearly all persons with type 1 diabetes and more than 60% of those with type 2 have some retinopathy after 20 years. The major risk factors for DR have been reported from epidemiologic studies3,4 and are summarized in the Box.
Box. Summary of Risk Factors for Diabetic Retinopathy Identified in Epidemiologic/Cohort Studies
Consistent Risk Factors
Duration of diabetes3,5,6
Hyperglycemia/glycated hemoglobin value3,5-7
Hypertension3,8-10
Hyperlipidemia8,11-13
Pregnancy14
Nephropathy/renal disease15,16
Less Consistent Risk Factors
Diabetic retinopathy can be classified into 2 stages: nonproliferative and proliferative. The earliest visible signs in nonproliferative DR are microaneurysms and retinal hemorrhages (Figure, A). Progressive capillary nonperfusion is accompanied by development of cotton-wool spots, venous beading, and intraretinal microvascular abnormalities. Proliferative DR occurs with further retinal ischemia and is characterized by the growth of new blood vessels on the surface of the retina or the optic disc (Figure, B). These abnormal vessels may bleed, resulting in vitreous hemorrhage, subsequent fibrosis, and tractional retinal detachment. Quiz Ref IDDiabetic macular edema (DME), which can occur at any stage of DR, is characterized by increased vascular permeability and the deposition of hard exudates at the central retina (Figure, A). Diabetic macular edema is now the principal cause of vision loss in persons with diabetes.
Quiz Ref IDPrimary interventions, such as intensive glycemic and blood pressure control, can reduce the incidence of DR, while secondary interventions, such as laser photocoagulation, may prevent further progression of DR and vision loss. There are many new interventions, but the evidence to support their use is uncertain. This article provides a systematic review of the literature to determine the best evidence for primary and secondary interventions for DR.
We conducted a literature search to identify English-language randomized controlled trials (RCTs) or meta-analyses evaluating interventions for DR. Articles were retrieved using MEDLINE (1966 through May 2007), EMBASE, Cochrane Collaborations, the Association for Research in Vision and Ophthalmology database, and the National Institutes of Health Clinical Trials Database through May 2007. Search terms included variations of keywords for retinopathy, diabetes, DR, DME, retinal neovascularization, controlled clinical trial, and randomized controlled trial (RCT). This was supplemented by hand searching the reference lists of major review articles. As we were primarily interested in longer-term outcomes, we excluded studies with less than 12 months of follow-up and those failing to separate data of different retinal conditions (eg, macular edema from diabetes vs retinal vein occlusion). We also excluded secondary complications of proliferative DR such as rubeotic glaucoma and tractional detachments, as they were beyond the scope of this review.
We used the Delphi consensus criteria list to select well-conducted studies.21 Studies were evaluated on a standardized data extraction form for (1) valid method of randomization, (2) concealed allocation of treatment, (3) similarity of groups at baseline regarding the most important prognostic indicators, (4) clearly specified eligibility criteria, (5) masking of outcome assessor, (6) masking of care provider, (7) masking of patient, (8) reporting of point estimates and measures of variability for outcomes, (9) intention-to-treat analysis, and (10) acceptable loss to follow-up rate unlikely to cause bias. Studies were scored out of a maximum of 10, and studies with a score greater than 5 were considered higher-quality studies. For each intervention, we graded the overall strength of evidence as levels I, II, or III and the ratings for clinical recommendations as levels A, B, and C, using previously reported criteria.22
For primary interventions, outcome measures included incidence of new DR and rate of adverse effects of intervention. For secondary interventions, measures included progression of DR, changes in visual acuity and macular thickness, and rates of legal blindness and adverse effects. Emphasis was given to studies in which best-corrected visual acuity was measured in a masked fashion using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. For some RCTs, both primary (incidence of DR) and secondary (progression of DR) interventions were evaluated.
Studies used different methods to ascertain retinopathy, including clinical ophthalmoscopy, retinal photography, and/or fluorescein angiography.23 Studies also classified DR differently, with most using the Airlie House classification24 with some modifications.25 This gold-standard assessment involves the grading of seven 30° stereoscopic images of the retina (7 standard fields), with each image compared with standard photographs. A score is then assigned to each eye, ranging from 10 (no retinopathy) to 85 (advanced proliferative DR), and the grades for both eyes are combined into a stepped scale. DME was usually classified as absent or present. Definitions for progression of DR also varied. The Diabetes Control and Complications Trial (DCCT)26,27 defined progression as at least 3 steps worsening from baseline, while the United Kingdom Prospective Diabetes Study (UKPDS)28 defined progression as a 2-step change from baseline. Other studies used increases in number of microaneurysms or the need for laser photocoagulation as indicators of progression.
A total of 782 citations were accessed, of which 44 studies (including 3 meta-analyses) of interventions for DR met our inclusion criteria
Glycemic Control. Early epidemiologic studies have shown showed a consistent relationship between glycated hemoglobin (HbA1c) levels and the incidence of DR.5,7 This important observation has been confirmed in large RCTs demonstrating that tight glycemic control reduces both the incidence and progression of DR (Table 1). The DCCT,26,27,29,45 conducted between 1983 and 1993, randomized 1441 patients with type 1 diabetes to receive intensive glycemic or conventional therapy. Over 6.5 years of follow-up, intensive treatment (median HbA1c, 7.2%) reduced the incidence of DR by 76% (95% confidence interval [CI], 62%-85%) and progression of DR by 54% (95% CI, 39%-66%), as compared with conventional treatment (median HbA1c, 9.1%).26,27,29,45
The UKPDS31 reported similar findings in type 2 diabetes. The UKPDS randomized 3867 persons newly diagnosed as having type 2 diabetes to receive intensive or conventional therapy. Intensive therapy reduced microvascular end points by 25% (95% CI, 7%-40%) and the need for laser photocoagulation by 29%. Data from a subgroup of participants' retinal photographic grading showed a similar association.17 These findings have been replicated in other studies,33,46 including a meta-analysis prior to the DCCT34 (Table 1).
Long-term observational DCCT data showed that despite gradual equalization of HbA1c values after study termination, the rate of DR progression in the former intensively treated group remained significantly lower than in the former conventional group,27,30 emphasizing the importance of instituting tight glycemic control early in the course of diabetes. This concept is supported by the results of another RCT,47 in which participants initially assigned to intensive glucose control vs conventional treatment had lower 10-year incidence of severe retinopathy.48
Tight glycemic control has two clinically important adverse effects. First, there is risk of early worsening of DR. In the DCCT, this occurred in 13.1% of the intensive vs 7.6% of the conventional treatment group.49 However, this effect was reversed by 18 months, and no case of early worsening resulted in serious visual loss. Similar adverse event rates were reported in a meta-analysis.35 Participants at risk of this early worsening had higher HbA1c levels at baseline and a more rapid reduction of HbA1c levels in the first 6 months, suggesting that physicians should avoid rapid reductions of HbA1c levels where possible. Quiz Ref IDSecond, tight glycemic control is a known risk factor for hypoglycemic episodes and diabetic ketoacidosis.34 A meta-analysis of 14 RCTs, including the DCCT,50 indicated that intensive treatment is associated with a 3-fold risk of hypoglycemia and 70% higher risk of ketoacidosis as compared with conventional treatment. The risk of ketoacidosis was 7-fold higher among patients exclusively using insulin pumps,50 suggesting that multiple daily insulin injection might be a safer strategy.
Blood Pressure Control. Epidemiologic studies have not found blood pressure to be a consistent risk factor for DR incidence and progression.8,9,51,52 Evidence from RCTs, however, indicates that tight control of blood pressure is a major modifiable factor for the incidence and progression of DR (Table 2). The UKPDS28 randomized 1048 patients with hypertension to receive tight blood pressure control (target systolic/diastolic pressure, <150/<85 mm Hg) or conventional control (target, <180/<105 mm Hg). After 9 years of follow-up, patients having tight control had a 34% reduction (99% CI, 11%-50%) in DR progression, 47% reduction (99% CI, 7%-70%) in visual acuity deterioration, and 35% reduction in laser photocoagulation compared with those having conventional control.
The UKPDS findings contrast with that of the Appropriate Blood Pressure Control in Diabetes (ABCD) trial,54,57 which randomized 470 people with type 2 diabetes and hypertension to receive intensive or moderate blood pressure control. Over 5 years, there was no difference in DR progression between the groups. The lack of efficacy in this study may be related to poorer glycemic control, shorter follow-up, and lower blood pressure levels at baseline as compared with the UKPDS. It is unclear if there is a threshold effect beyond which further blood pressure lowering no longer influences DR progression.
The effects of therapy with antihypertensive agents are also apparent among normotensive persons with diabetes. In another group of the ABCD trial,57 among 480 nonhypertensive patients with type 2 diabetes, intensive blood pressure control significantly reduced DR progression over 5 years as compared with moderate control. The EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID)56 evaluated the effects of the angiotensin-converting enzyme (ACE) inhibitor lisinopril on DR progression in normotensive, normoalbuminuric patients with type 1 diabetes. Over 2 years, lisinopril reduced the progression of DR by 50% (95% CI, 28%-89%) and progression to proliferative DR by 80%.56 EUCLID was limited by differences in baseline glycemic levels between groups (the treatment group had lower HbA1c levels) and a short follow-up of 2 years. This study, along with another smaller RCT,58 suggested that ACE inhibitors may have an additional benefit on DR progression independent of blood pressure lowering. However, data from the UKPDS53 and the ABCD study54,57 did not find ACE inhibitors to be superior to other blood pressure medications.
Whether newer blood pressure medications have additional beneficial effects is unclear. A recent small RCT (n = 24) with short follow-up (4 months) reported a worsening of DME among patients treated with the angiotensin II receptor blocker losartan, compared with controls.59 Two large RCTs are currently ongoing. The Action in Diabetes and Vascular Disease (ADVANCE) study will evaluate the effect of a perindopril-indapamide combination on the incidence of DR,60 while the Diabetic Retinopathy Candesartan Trial (DIRECT) will evaluate the angiotensin II receptor blocker candesartan.61
Lipid-Lowering Therapy. Observational studies suggest that dyslipidemia increases the risk of DR, particularly DME.8,11 A small RCT conducted among 50 patients with DR found a nonsignificant trend in visual acuity improvement in patients receiving simvastatin treatment,62 while another study reported a reduction in hard exudates but no improvement in visual acuity in those with clinically significant DME treated with clofibrate.63
In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (Table 3),64 among 9795 participants with type 2 diabetes, those treated with fenofibrate were less likely than controls to need laser treatment (5.2% vs 3.6%, P < .001). However, the severity of DR, indications for laser treatment, and type of laser treatment (focal or pan-retinal) were not reported.
The Collaborative Atorvastatin Diabetes Study (CARDS), an RCT of 2830 patients with type 2 diabetes, did not find atorvastatin to be effective in reducing DR progression.75,76 The study was limited by substantial missing data (only 65% of patients had retinopathy status recorded at baseline) and lack of photographic grading for DR. Several ongoing RCTs, such as the Atorvastatin Study for Prevention of Coronary Endpoints in NIDDM (ASPEN),77 will also evaluate the effects of atorvastatin on DR.
Medical Interventions.Antiplatelet Agents. The ETDRS showed that aspirin (650 mg/d) had no beneficial effect on DR progression or loss of visual acuity in patients with DME or severe nonproliferative DR during 9 years of follow-up (Table 3).65,66 Aspirin treatment was not associated with an increased rate of vitrectomy.65,66 A smaller RCT evaluating aspirin alone and in combination with dipyridamole reported a reduction in microaneurysms on fluorescein angiograms in both groups as compared with placebo.67 A similar trend was observed in a small RCT68 evaluating ticlopidine, although results were not statistically significant.
Protein Kinase C Inhibitors. Hyperglycemia induces synthesis of diacylglycerol in vascular cells, leading to activation of protein kinase C (PKC) isozymes. Excessive PKC activation may be involved in the pathophysiology of DR. Ruboxistaurin, an orally active PKC inhibitor, was evaluated in the Protein Kinase C Diabetic Retinopathy Study (PKC-DRS) (Table 3),69 which randomized 252 patients with moderate to severe nonproliferative DR to receive ruboxistaurin (8, 16, or 32 mg) or placebo. No significant difference in DR progression was observed after 36 months of follow-up, although patients treated with 32 mg of ruboxistaurin had a significant reduction in the risk of moderate visual loss. Treatment was well tolerated with few adverse events, largely mild gastrointestinal symptoms. A larger study, the PKC-DRS2, which randomized 685 patients, showed similar results.70
The PKC-DMES Study (Table 3) reported no significant reduction in progression of DR or incidence of DME in 686 patients with mild to moderate nonproliferative DR and no prior laser therapy.71,78 There was a trend for a reduction in clinically significant DME among patients treated with 32 mg of ruboxistaurin (P = .04), with a larger effect when patients with HbA1c levels of 10% or greater were excluded (P = .02).
Aldose Reductase Inhibitors. Aldose reductase is the rate-controlling enzyme in the polyol pathway of glucose metabolism and is involved in pathogenesis of DR. Two aldose reductase inhibitors, sorbinil (Pfizer, New York, New York) and tolrestat (Wyeth-Ayerst, St Davids, Pennsylvania), showed no statistically significant effect in reducing DR incidence or progression in RCTs of 3 to 5 years' duration.72
Growth Hormone/Insulinlike Growth Factor Inhibitors. Observations of improvements in DR following surgical hypophysectomy79,80 and of increased serum and ocular levels of insulinlike growth factor in patients with severe DR led to studies investigating the use of agents inhibiting the growth hormone/insulinlike growth factor pathway for prevention of DR.81 A small RCT conducted over 15 months among 23 patients reported reduction in retinopathy severity with octreotide, a synthetic analogue of somatostatin that blocks growth hormone,74 but another RCT conducted over 1 year among 20 patients82 evaluating continuous subcutaneous infusion of octreotide found no significant benefits. Two larger RCTs currently evaluating long-acting–release octreotide injection83,84 have reported inconclusive preliminary results,85 with significant adverse effects (eg, diarrhea, cholelithiasis, hypoglycemic episodes).
Laser and Surgical interventions for Severe Nonproliferative and Proliferative DR.Pan-Retinal Laser Photocoagulation. Pan-retinal laser photocoagulation (PRP), in which laser burns are placed over the entire retina, sparing the central macula, is an established technique for treating severe nonproliferative and proliferative DR86 (Table 4).
Quiz Ref IDThe strongest evidence comes from 2 related RCTs in the 1970s and 1980s, the Diabetic Retinopathy study (DRS)86,88 and the ETDRS.102 The DRS randomized 1758 patients with proliferative DR in least 1 eye or bilateral severe nonproliferative DR to receive PRP or no treatment. At 2 years, severe visual loss (visual acuity <5/200 on 2 successive visits) was observed in 6.4% of treated vs 15.9% of untreated eyes, with the greatest benefit in eyes with high-risk characteristics (new vessels at the optic disc or vitreous hemorrhage with new vessels elsewhere [Figure, B]), in which the risk of severe visual loss was reduced by 50%.86
The ETDRS102 randomized 3711 patients with less severe DR and visual acuity greater than 20/100 to early PRP or deferral (4-month observation and treatment if high-risk proliferative DR developed). Early PRP treatment decreased the risk of high-risk proliferative DR by 50% as compared with deferral, although the incidence of severe visual loss was low in both the early treatment and the deferral groups (2.6% vs 3.7%). Other RCTs91-93 and a meta-analysis with combined data of 2243 patients87 have confirmed the effectiveness of PRP.
Adverse effects of PRP include visual field constriction (with implications for driving103,104), night blindness, color vision changes, inadvertent laser burn, macular edema exacerbation, acute glaucoma, and traction retinal detachment.105 There is also the possibility of visual loss immediately following PRP. The DRS reported vision loss of 2 to 4 lines within 6 weeks of PRP in 10% to 23% of patients vs 6% of controls.106
Surgical Vitrectomy for Vitreous Hemorrhage and Proliferative DR. Vitrectomy has been used for treatment of eyes with advanced DR, including proliferative DR with nonclearing vitreous hemorrhage or fibrosis, areas of traction involving or threatening the macula, and, more recently, persistent DME with vitreous traction (Table 5).115 The Diabetic Retinopathy Vitrectomy Study (DRVS) randomized 616 eyes with recent vitreous hemorrhage and visual acuity of 5/200 or less for at least 1 month to undergo early vitrectomy within 6 months or observation.107,108,116,117 After 2 years’ follow-up, 25% of the early vitrectomy group vs 15% of the observation group had 20/40 or greater vision, with the benefits maintained at 4 years and longer in individuals with type 1 diabetes. Vitreoretinal surgery has advanced considerably since the DVRS. These advances include intraoperative fundal imaging and laser treatment and bimanual instrumentation to manipulate the retina. These have widened the indications of vitrectomy and may improve outcomes.118
Laser and Surgical Interventions for Diabetic Macular Edema.Focal Laser Treatment. Like PRP, there is good evidence that focal laser treatment preserves vision in eyes with DME. The ETDRS96 randomized 1490 eyes with DME to receive focal laser treatment or observation. At 3 years, treatment significantly reduced moderate visual loss as compared with observation,96 with the greatest benefits in eyes with clinically significant DME.119 There is limited evidence that laser type (argon, diode, dye, krypton) or method used influences outcomes.97,120-122 Adverse effects include inadvertent foveal burn, central visual field defect, color vision abnormalities, retinal fibrosis, and spread of laser scars.105,106
Surgical Vitrectomy for Diabetic Macular Edema. Widespread or diffuse DME that is nonresponsive to focal laser treatment may benefit from vitrectomy.123-126 However, the few RCTs to date have had small sample sizes and short follow-up, with inconsistent results (Table 5). An RCT of 28 patients with diffuse DME reported reduced macular thickness and improved visual acuities at 6 months after vitrectomy vs observation.127 Vitrectomy was superior to focal laser treatment in 1 RCT128 but not in others.112,113 Complications of vitrectomy include recurrent vitreous hemorrhage, retinal tears and detachment, cataract formation, and glaucoma. The presence of vitreous traction and macular edema—now readily documented with optical coherence tomography—in association with visual impairment is currently a common indication for vitrectomy.
Intravitreal Corticosteroids. Corticosteroids have potent anti-inflammatory and antiangiogenesis effects. Intravitreal triamcinolone (IVTA)—ie, injection of triamcinolone acetonide into the vitreous cavity129—has been used for treatment of DME,130-132 with a number of RCTs demonstrating significant improvements in DME and visual acuity.133-138 Many of these, however, had small participant numbers and short follow-up. Additionally, there were substantial adverse effects, include infection, glaucoma, and cataract formation.109,139-142
In the largest RCT having the longest follow-up yet reported, eyes with persistent DME were randomized to receive 4 mg of IVTA or sham injection (saline injection into the subconjunctival space).109 After 2 years, 19 of 34 IVTA-treated eyes (56%) had a visual acuity improvement of 5 letters or more compared with 9 of 35 placebo-treated eyes (26%) (P = .007). Overall, IVTA-treated eyes had twice the chance of improved visual acuity and half the risk of further loss. However, many eyes required repeated injections (mean, 2.2), and there was significant intraocular pressure elevation (≥5 mm Hg in 68% of treated eyes vs 10% of controls). Cataract surgery was required in 55% of IVTA-treated eyes. Thus, while this study demonstrated significant efficacy of IVTA in persistent DME, larger RCTs are needed to provide further data on long-term benefits and safety.143 Additionally, the ideal dose of triamcinolone remains unclear.144
More recently, intravitreal or retinal implants have been developed, allowing extended drug delivery. A surgically implanted intravitreal fluocinolone acetonide (Retisert; Bausch & Lomb, Rochester, New York) was evaluated in 97 patients with DME randomized to receive either implantation or standard care (laser treatment or observation).110 At 3 years, 58% of implanted eyes vs 30% of controls had resolution of DME (P < .001) and associated improvement in visual acuity. However, adverse effects included a substantially higher risk of cataract formation and glaucoma than that observed in eyes receiving IVTA, with 5% requiring implant removal to control glaucoma.110 An injectable, biodegradable intravitreal dexamethasone extended-release implant (Posurdex; Allergan, Irvine, California) was evaluated in an RCT, with reported improvements in visual acuity and macular thickness.145 This study, however, also included eyes with macular edema from other causes (retinal vein occlusion, uveitis, and following cataract surgery) and had relatively short follow-up. A larger RCT of Posurdex for DME is currently under way.
Intravitreal Antiangiogenesis Agents. Several RCTs are currently evaluating 3 agents that suppress vascular endothelial growth factor (VEGF) for treatment of DME. Pegaptanib (Macugen; Pfizer, New York, New York) targets the 165 isoform of VEGF for treatment of neovascular age-related macular degeneration (AMD). An RCT of 172 patients with DME randomized to receive repeated intravitreal pegaptanib or sham injections showed that treated eyes were more likely to have improvement in visual acuity of 10 letters or more (34% vs 10%, P = .03), macular thickness (P = .02), and need for focal laser treatment (P = .04) at 36 weeks.146 Serious infection occurred in 1 of 652 injections (0.15%) and was not associated with severe visual loss.146 Retrospective data analysis of 16 eyes with proliferative DR also showed regression of neovascularization.147
Ranibizumab (Lucentis; Genentech, South San Francisco, California) is another anti-VEGF agent used for treatment of neovascular AMD148,149 and may also be useful for DR and DME.150 A phase 2 RCT (the RESOLVE study) is currently evaluating ranibizumab in DME. Finally, bevacizumab (Avastin, Genentech) is an anti-VEGF agent similar to ranibizumab that is approved for the treatment of disseminated colorectal cancer and not licensed for intraocular use. However, bevacizumab appears to show similar efficacy for treatment of neovascular AMD and may also be effective for DME and proliferative DR.151-154 Bevacizumab has attracted interest because of its low cost, but systemic safety is a concern.155 An ongoing RCT sponsored by the US National Eye Institute is comparing the effects of laser treatment, intravitreal bevacizumab, and combined intravitreal bevacizumab and laser or sham injection on DME.156
There is strong evidence that tight glycemic control reduces the incidence and progression of DR (Table 6). For type 1 diabetes, the DCCT showed that each 10% decrease in HbA1c level (eg, 9% to 8%) reduces the risk of DR by 39%, and this beneficial effect persists long after the period of intensive control. In type 2 diabetes, the UKPDS showed that each 10% decrease in HbA1c level reduces the risk of microvascular events, including DR, by 25% (95% CI, 7%-40%).
There also is strong evidence that tight blood pressure control in patients with hypertension and diabetes is beneficial in reducing visual loss from DR. The UKPDS showed that each 10-mm Hg decrease in systolic blood pressure reduces the risk of microvascular complications by 13%, independent of glycemic control. The benefit of blood pressure treatment in normotensive patients with diabetes is less clear.
There remains inconclusive evidence about the benefits of lipid-lowering therapy for DR prevention. There also is little evidence that aspirin, other antiplatelet agents, or aldose reductase inhibitors confer any benefit in reducing progression of DR. The role of PKC and growth hormone inhibitors is currently unclear, and results from ongoing trials are pending.
Proliferative DR. There is strong evidence that PRP significantly reduces the risk of severe vision loss from proliferative DR by at least 50%. The benefits are most marked in those with high-risk proliferative DR, in whom PRP should be commenced without delay.89 Early vitrectomy should be considered in patients with type 1 diabetes and persistent vitreous hemorrhage or when hemorrhage prevents other treatment. The benefits of vitrectomy are less clear for those with type 2 diabetes. With advances in vitreoretinal surgery, vitrectomy may be indicated earlier in eyes with nonclearing hemorrhage.
Nonproliferative DR. Although there is level I evidence that early PRP reduces the risk of severe visual loss in nonproliferative DR, the absolute risk reduction from early PRP treatment is small, and the risks of deferred treatment are low. In mild to moderate nonproliferative DR, systemic factors such as control of glycemia and blood pressure should be gradually optimized and PRP deferred with careful follow-up. The ETDRS and other RCTs95 suggest that PRP should be considered in more severe nonproliferative DR, especially in patients with type 2 diabetes. This benefit for PRP should be balanced against the small risk of vision loss. Early PRP is recommended in these patients if regular follow-up examination is not feasible, if there is significant media opacity or cataract that may affect the ability to apply future laser treatment, or if there are concomitant risk factors (eg, pregnancy) for rapid progression.
Diabetic Macular Edema. There is strong evidence that focal laser photocoagulation reduces the risk of moderate vision loss in DME that poses risk to fixation (or clinically significant DME) by at least 50% and increases the chance of visual improvement. In patients with coexistent proliferative DR and DME, focal laser treatment concurrent with or prior to PRP is recommended.89
There is moderate evidence that IVTA may be useful in eyes with persistent DME and loss of vision despite conventional treatment, including focal laser treatment and attention to systemic risk factors. Patients should be warned of adverse effects and the need for reinjection. Further studies are warranted to determine the ideal dose and longer-term efficacy and safety. Intravitreal anti-VEGF agents are being evaluated in several clinical trials; until results are available, there is currently insufficient evidence recommending their routine use.
There is weak evidence that vitrectomy may be beneficial in some patients with DME, particularly in eyes with associated vitreomacular traction, but well-conducted studies with longer follow-up are needed.
Quiz Ref IDAlthough DR remains the leading cause of preventable blindness in working adults, there are primary and secondary interventions proven effective in limiting visual loss. The indications, efficacy, and safety of newer medical and surgical treatments, however, require further evaluation.
Corresponding Author: Tien Y. Wong, MD, PhD, Centre for Eye Research Australia, University of Melbourne, 32 Gisborne St E, Melbourne Victoria, Australia 3002 (twong@unimelb.edu.au).
Author Contributions: Dr Wong had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Mohamed, Gillies, Wong.
Acquisition of data: Mohamed, Gillies.
Analysis and interpretation of data: Mohamed, Wong.
Drafting of the manuscript: Mohamed, Gillies, Wong.
Critical revision of the manuscript for important intellectual content: Gillies, Wong.
Statistical analysis: Mohamed, Wong.
Obtained funding: Gillies.
Administrative, technical, or material support: Mohamed, Gillies, Wong.
Study supervision: Gillies, Wong.
Financial Disclosures: Dr Gillies reported that he is included as an inventor on patents relating to the formulation of triamcinolone for ocular use and its use for the treatment of retinal neovascularization but not diabetic macular edema. Dr Gillies and Dr Wong reported serving on advisory boards for and as investigators in clinical trials in diabetic retinopathy sponsored by Pfizer, Novartis, and Allergan and receiving grants, honoraria, and traveling fees from these companies. No other disclosures were reported.
Funding/Support: This study was funded by National Health and Medical Research Council of Australia grant 352312.
Role of the Sponsor: The National Health and Medical Research Council of Australia had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
2.US Centers for Disease Control and Prevention. National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2005. Atlanta, GA: Centers for Disease Control and Prevention; 2005
3.Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, XVII: the 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes.
Ophthalmology. 1998;105(10):1801-18159787347
Google ScholarCrossref 4.Wong TY, Klein R, Islam FM.
et al. Diabetic retinopathy in a multi-ethnic cohort in the United States.
Am J Ophthalmol. 2006;141(3):446-45516490489
Google ScholarCrossref 5.Olsen BS, Sjølie A, Hougaard P.
et al. Danish Study Group of Diabetes in Childhood. A 6-year nationwide cohort study of glycaemic control in young people with type 1 diabetes: risk markers for the development of retinopathy, nephropathy and neuropathy.
J Diabetes Complications. 2000;14(6):295-30011120452
Google ScholarCrossref 6.van Leiden HA, Dekker JM, Moll AC.
et al. Risk factors for incident retinopathy in a diabetic and nondiabetic population: the Hoorn study.
Arch Ophthalmol. 2003;121(2):245-25112583792
Google ScholarCrossref 7.Klein R, Palta M, Allen C, Shen G, Han DP, D’Alessio DJ. Incidence of retinopathy and associated risk factors from time of diagnosis of insulin-dependent diabetes.
Arch Ophthalmol. 1997;115(3):351-3569076207
Google ScholarCrossref 8.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):1320-132512145228
Google ScholarCrossref 9.Klein R, Moss SE, Klein BE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy, XI: the incidence of macular edema.
Ophthalmology. 1989;96(10):1501-15102587045
Google Scholar 10.Klein BE, Klein R, Moss SE, Palta M. A cohort study of the relationship of diabetic retinopathy to blood pressure.
Arch Ophthalmol. 1995;113(5):601-6067748130
Google ScholarCrossref 11.Klein R, Sharrett AR, Klein BE.
et al. ARIC Group. The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes: the atherosclerosis risk in communities study.
Ophthalmology. 2002;109(7):1225-123412093643
Google ScholarCrossref 12.Klein R, Klein BE, Moss SE, Linton KL. The Beaver Dam Eye Study: retinopathy in adults with newly discovered and previously diagnosed diabetes mellitus.
Ophthalmology. 1992;99(1):58-621741141
Google Scholar 13.Chew EY, Klein ML, Ferris FL.
et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy: Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22.
Arch Ophthalmol. 1996;114(9):1079-10848790092
Google ScholarCrossref 14.Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy.
Diabetes Care. 1990;13(1):34-402404715
Google ScholarCrossref 15.Cruickshanks KJ, Ritter LL, Klein R, Moss SE. The association of microalbuminuria with diabetic retinopathy: the Wisconsin Epidemiologic Study of Diabetic Retinopathy.
Ophthalmology. 1993;100(6):862-8678510898
Google Scholar 16.Klein R, Moss SE, Klein BE. Is gross proteinuria a risk factor for the incidence of proliferative diabetic retinopathy?
Ophthalmology. 1993;100(8):1140-11468341493
Google Scholar 17.Stratton IM, Kohner EM, Aldington SJ.
et al. UKPDS 50: risk factors for incidence and progression of retinopathy in type II diabetes over 6 years from diagnosis.
Diabetologia. 2001;44(2):156-16311270671
Google ScholarCrossref 18.Moss SE, Klein R, Klein BE. Association of cigarette smoking with diabetic retinopathy.
Diabetes Care. 1991;14(2):119-1262060413
Google ScholarCrossref 19.McKay R, McCarty CA, Taylor HR. Diabetic retinopathy in Victoria, Australia: the Visual Impairment Project.
Br J Ophthalmol. 2000;84(8):865-87010906093
Google ScholarCrossref 20.Kriska AM, LaPorte RE, Patrick SL, Kuller LH, Orchard TJ. The association of physical activity and diabetic complications in individuals with insulin-dependent diabetes mellitus: the Epidemiology of Diabetes Complications Study—VII.
J Clin Epidemiol. 1991;44(11):1207-12141941015
Google ScholarCrossref 21.Verhagen AP, de Vet HC, de Bie RA.
et al. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus.
J Clin Epidemiol. 1998;51(12):1235-124110086815
Google ScholarCrossref 22.Minckler D. Evidence-based ophthalmology series and content based continuing medical education for the journal.
Ophthalmology. 2000;107:9-10
Google ScholarCrossref 23.Early Treatment Diabetic Retinopathy Study Research Group. Classification of diabetic retinopathy from fluorescein angiograms: ETDRS report number 11.
Ophthalmology. 1991;98(5):(suppl)
807-8222062514
Google Scholar 24.Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs—an extension of the modified Airlie House classification: ETDRS report number 10.
Ophthalmology. 1991;98(5):(suppl)
786-8062062513
Google Scholar 25.Aldington SJ, Kohner EM, Meuer S, Klein R, Sjølie AK. Methodology for retinal photography and assessment of diabetic retinopathy: the EURODIAB IDDM complications study.
Diabetologia. 1995;38(4):437-4447796984
Google ScholarCrossref 26.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):647-6617724182
Google Scholar 27.Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy.
N Engl J Med. 2000;342(6):381-38910666428
Google ScholarCrossref 28.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):703-7139732337
Google ScholarCrossref 29. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial.
Diabetes. 1995;44(8):968-9837622004
Google ScholarCrossref 30.Writing Team for the 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):2563-256912020338
Google ScholarCrossref 31.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. 1998;352(9131):837-8539742976
Google ScholarCrossref 32.Kohner EM, Stratton IM, Aldington SJ, Holman RR, Matthews DR.UK Prospective Diabetes Study (IKPDS) 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. 2001;18(3):178-18411318837
Google ScholarCrossref 33.Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients.
Diabetes Care. 2000;23:(suppl 2)
B21-B2910860187
Google Scholar 34.Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes.
Lancet. 1993;341(8856):1306-13098098449
Google ScholarCrossref 35.Wang PH, Lau J, Chalmers TC. Metaanalysis of the effects of intensive glycemic control on late complications of type I diabetes mellitus.
Online J Curr Clin Trials. May 21, 1993;
. Doc No. 608306007
Google Scholar 36.Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T. Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy.
Diabetes. 1985;34:(suppl 3)
74-794018423
Google ScholarCrossref 37.Kroc Collaborative Study Group. Blood glucose control and the evolution of diabetic retinopathy and albuminuria: a preliminary multicenter trial.
N Engl J Med. 1984;311(6):365-3726377076
Google ScholarCrossref 38.Kroc Collaborative Study Group. Diabetic retinopathy after two years of intensified insulin treatment: follow-up of the Kroc Collaborative Study.
JAMA. 1988;260(1):37-412898025
Google ScholarCrossref 39.Beck-Nielsen H, Olesen T, Mogensen CE.
et al. Effect of near normoglycemia for 5 years on progression of early diabetic retinopathy and renal involvement.
Diabetes Res. 1990;15(4):185-1902132407
Google Scholar 40.Olsen T, Richelsen B, Ehlers N, Beck-Nielsen H. Diabetic retinopathy after 3 years' treatment with continuous subcutaneous insulin infusion (CSII).
Acta Ophthalmol (Copenh). 1987;65(2):185-1893300140
Google ScholarCrossref 41.Reichard P, Berglund B, Britz A, Cars I, Nilsson BY, Rosenqvist U. Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years.
J Intern Med. 1991;230(2):101-1081865159
Google ScholarCrossref 42.Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF.
et al. Effect of near normoglycaemia for two years on progression of early diabetic retinopathy, nephropathy, and neuropathy: the Oslo study.
Br Med J (Clin Res Ed). 1986;293:1195-11993096429
Google ScholarCrossref 43.Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O. Rapid tightening of blood glucose control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study.
Br Med J (Clin Res Ed). 1985;290:811-8153919804
Google ScholarCrossref 44.Brinchmann-Hansen O, Dahl-Jørgensen K, Sandvik L, Hanssen KF. Blood glucose concentrations and progression of diabetic retinopathy: the seven year results of the Oslo study.
BMJ. 1992;304(6818):19-221734985
Google ScholarCrossref 45.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):977-9868366922
Google ScholarCrossref 46.Ohkubo Y, Kishikawa H, Araki E.
et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.
Diabetes Res Clin Pract. 1995;28(2):103-1177587918
Google ScholarCrossref 47.Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus.
N Engl J Med. 1993;329(5):304-3098147960
Google ScholarCrossref 48.Reichard P, Pihl M, Rosenqvist U, Sule J. Complications in IDDM are caused by elevated blood glucose level: the Stockholm Diabetes Intervention Study (SDIS) at 10-year follow up.
Diabetologia. 1996;39(12):1483-14888960830
Google ScholarCrossref 49. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial.
Arch Ophthalmol. 1998;116(7):874-8869682700
Google ScholarCrossref 50.Egger M, Davey Smith G, Stettler C, Diem P. Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis.
Diabet Med. 1997;14(11):919-9289400915
Google ScholarCrossref 51.Wong TY, Mitchell P. The eye in hypertension.
Lancet. 2007;369(9559):425-435
[published correction appears in Lancet. 2007;369(9579):2078]17276782
Google ScholarCrossref 52.Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. Is blood pressure a predictor of the incidence or progression of diabetic retinopathy?
Arch Intern Med. 1989;149(11):2427-24322684072
Google ScholarCrossref 53.Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM.UK Prospective Diabetes Study Group. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69.
Arch Ophthalmol. 2004;122(11):1631-164015534123
Google ScholarCrossref 54.Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes.
Diabetes Care. 2000;23:(suppl 2)
B54-B6410860192
Google Scholar 55.Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes.
Kidney Int. 2002;61(3):1086-109711849464
Google ScholarCrossref 56.Chaturvedi N, Sjolie AK, Stephenson JM.
et al. EUCLID Study Group. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes.
Lancet. 1998;351(9095):28-319433426
Google ScholarCrossref 57.Schrier RW, Estacio RO, Jeffers B. Appropriate Blood Pressure Control in NIDDM (ABCD) trial.
Diabetologia. 1996;39(12):1646-16548960857
Google ScholarCrossref 58.Larsen M, Hommel E, Parving HH, Lund-Andersen H. Protective effect of captopril on the blood-retina barrier in normotensive insulin-dependent diabetic patients with nephropathy and background retinopathy.
Graefes Arch Clin Exp Ophthalmol. 1990;228(6):505-5092265765
Google ScholarCrossref 59.Knudsen ST, Bek T, Poulsen PL, Hove MN, Rehling M, Mogensen CE. Effects of losartan on diabetic maculopathy in type 2 diabetic patients: a randomized, double-masked study.
J Intern Med. 2003;254(2):147-15812859696
Google ScholarCrossref 60.ADVANCE Collaborative Group. ADVANCE—Action in Diabetes and Vascular Disease: patient recruitment and characteristics of the study population at baseline.
Diabet Med. 2005;22(7):882-88815975103
Google ScholarCrossref 61.Sjølie AK, Porta M, Parving HH, Bilous R, Klein R.DIRECT Programme Study Group. The DIabetic REtinopathy Candesartan Trials (DIRECT) Programme: baseline characteristics.
J Renin Angiotensin Aldosterone Syst. 2005;6(1):25-3216088848
Google ScholarCrossref 62.Sen K, Misra A, Kumar A, Pandey RM. Simvastatin retards progression of retinopathy in diabetic patients with hypercholesterolemia.
Diabetes Res Clin Pract. 2002;56(1):1-1111879715
Google ScholarCrossref 63.Cullen JF, Town SM, Campbell CJ. Double-blind trial of Atromid-S in exudative diabetic retinopathy.
Trans Ophthalmol Soc U K. 1974;94(2):554-5624619857
Google Scholar 64.Keech A, Simes RJ, Barter P.
et al. FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
Lancet. 2005;366(9500):1849-186116310551
Google ScholarCrossref 65.Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retinopathy: ETDRS report number 8.
Ophthalmology. 1991;98(5):(suppl)
757-7652062511
Google Scholar 66.Chew EY, Klein ML, Murphy RP, Remaley NA, Ferris FL. Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus: Early Treatment Diabetic Retinopathy Study report no. 20.
Arch Ophthalmol. 1995;113(1):52-557826294
Google ScholarCrossref 67.DAMAD Study Group. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy: a multicenter randomized controlled clinical trial.
Diabetes. 1989;38(4):491-4982647556
Google ScholarCrossref 68.TIMAD Study Group. Ticlopidine treatment reduces the progression of nonproliferative diabetic retinopathy.
Arch Ophthalmol. 1990;108(11):1577-15832244843
Google ScholarCrossref 69.PKC-DRS 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):2188-219715983221
Google ScholarCrossref 70.Aiello LP, Davis MD, Girach A.
et al. PKC-DRS2 Group. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy.
Ophthalmology. 2006;113(12):2221-223016989901
Google ScholarCrossref 71.Aiello LP, Davis MD, Girach A.
et al. PKC-DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular edema: thirty-six month results of the randomized PKC-DMES clinical trial.
Arch Ophthalmol. 2007;124:318-32417353401
Google Scholar 72.Sorbinil Retinopathy Trial Research Group. A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy.
Arch Ophthalmol. 1990;108(9):1234-12442119168
Google ScholarCrossref 73.Gardner TW, Sander B, Larsen ML.
et al. An extension of the Early Treatment Diabetic Retinopathy Study (ETDRS) system for grading of diabetic macular edema in the Astemizole Retinopathy Trial.
Curr Eye Res. 2006;31(6):535-54716769613
Google ScholarCrossref 74.Grant MB, Mames RN, Fitzgerald C.
et al. The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy: a randomized controlled study.
Diabetes Care. 2000;23(4):504-50910857943
Google ScholarCrossref 75.Thomason MJ, Colhoun HM, Livingstone SJ.
et al. CARDS Investigators. Baseline characteristics in the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes.
Diabet Med. 2004;21(8):901-90515270795
Google ScholarCrossref 76.Colhoun HM, Betteridge DJ, Durrington PN.
et al. CARDS Investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
Lancet. 2004;364(9435):685-69615325833
Google ScholarCrossref 77.Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN).
Diabetes Care. 2006;29(7):1478-148516801565
Google ScholarCrossref 79.Ray BS, Pazianos AG, Greenberg E, Peretz WL, McLean JM. Pituitary ablation for diabetic retinopathy, I: results of hypophysectomy: (a ten-year evaluation).
JAMA. 1968;203(2):79-845694074
Google ScholarCrossref 80.Hardy J, Ciric IS. Selective anterior hypophysectomy in the treatment of diabetic retinopathy: a transsphenoidal microsurgical technique.
JAMA. 1968;203(2):73-785694073
Google ScholarCrossref 81.Sönksen PH, Russell-Jones D, Jones RH. Growth hormone and diabetes mellitus: a review of sixty-three years of medical research and a glimpse into the future?
Horm Res. 1993;40(1-3):68-798300053
Google ScholarCrossref 82.Kirkegaard C, Nørgaard K, Snorgaard O, Bek T, Larsen M, Lund-Andersen H. 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 (Copenh). 1990;122(6):766-7722197845
Google Scholar 83. 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 Diabetic Retinopathy [NCT00248157].
http://clinicaltrials.gov/ct/show/NCT00248157. Accessibility verified July 19, 2007 84. 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 Diabetic Retinopathy [NCT00248131].
http://clinicaltrials.gov/ct/show/NCT00248131. Accessibility verified July 19, 2007 85. Grant MB. Diabetic retinopathy—diagnostic and treatment novelties. Presented at: American Diabetes Association 66th Scientific Sessions; June 9-13, 2006; Washington, DC
86. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings.
Ophthalmology. 1978;85(1):82-106345173
Google Scholar 87.Rohan TE, Frost CD, Wald NJ. Prevention of blindness by screening for diabetic retinopathy: a quantitative assessment.
BMJ. 1989;299(6709):1198-12012513049
Google ScholarCrossref 88.Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: clinical application of Diabetic Retinopathy Study (DRS) findings: DRS Report Number 8.
Ophthalmology. 1981;88(7):583-6007196564
Google Scholar 89.Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS report number 9.
Ophthalmology. 1991;98(5):(suppl)
766-7852062512
Google Scholar 90.Flynn HW, Chew EY, Simons BD, Barton FB, Remaley NA, Ferris FL.Early Treatment Diabetic Retinopathy Study Research Group. Pars plana vitrectomy in the Early Treatment Diabetic Retinopathy Study: ETDRS report number 17.
Ophthalmology. 1992;99(9):1351-13571407968
Google Scholar 91. Photocoagulation for proliferative diabetic retinopathy: a randomised controlled clinical trial using the xenon-arc.
Diabetologia. 1984;26(2):109-1156201409
Google Scholar 92.British Multicentre Study Group. Photocoagulation for diabetic maculopathy: a randomized controlled clinical trial using the xenon arc.
Diabetes. 1983;32(11):1010-10166357901
Google ScholarCrossref 93.Hercules BL, Gayed II, Lucas SB, Jeacock J. Peripheral retinal ablation in the treatment of proliferative diabetic retinopathy: a three-year interim report of a randomised, controlled study using the argon laser.
Br J Ophthalmol. 1977;61(9):555-563336079
Google ScholarCrossref 94.Patz A, Schatz H, Berkow JW, Gittelsohn AM, Ticho U. Macular edema—an overlooked complication of diabetic retinopathy.
Trans Am Acad Ophthalmol Otolaryngol. 1973;77(1):OP34-OP424738180
Google Scholar 95.Lövestam-Adrian M, Agardh CD, Torffvit O, Agardh E. Type 1 diabetes patients with severe non-proliferative retinopathy may benefit from panretinal photocoagulation.
Acta Ophthalmol Scand. 2003;81(3):221-22512780397
Google ScholarCrossref 96.Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1.
Arch Ophthalmol. 1985;103(12):1796-18062866759
Google ScholarCrossref 97.Fong DS, Strauber SF, Aiello LP.
et al. Writing Committee for the Diabetic Retinopathy Clinical Research Network. 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):469-48017420366
Google ScholarCrossref 98.Blankenship GW. Diabetic macular edema and argon laser photocoagulation: a prospective randomized study.
Ophthalmology. 1979;86(1):69-78530565
Google Scholar 99.Olk RJ. Modified grid argon (blue-green) laser photocoagulation for diffuse diabetic macular edema.
Ophthalmology. 1986;93(7):938-9503763140
Google Scholar 100. Photocoagulation in treatment of diabetic maculopathy: interim report of a multicentre controlled study.
Lancet. 1975;2(7945):1110-111353599
Google Scholar 101.Ladas ID, Theodossiadis GP. Long-term effectiveness of modified grid laser photocoagulation for diffuse diabetic macular edema.
Acta Ophthalmol (Copenh). 1993;71(3):393-3978362641
Google ScholarCrossref 102. Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics: ETDRS report number 7.
Ophthalmology. 1991;98(5):(suppl)
741-7562062510
Google Scholar 103.Pahor D. Visual field loss after argon laser panretinal photocoagulation in diabetic retinopathy: full- versus mild-scatter coagulation.
Int Ophthalmol. 1998;22(5):313-31910826550
Google ScholarCrossref 104.Buckley SA, Jenkins L, Benjamin L. Fields, DVLC and panretinal photocoagulation.
Eye. 1992;6(pt 6):623-6251289141
Google ScholarCrossref 106.Early Treatment Diabetic Retinopathy Study Research Group. Focal photocoagulation treatment of diabetic macular edema: relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19.
Arch Ophthalmol. 1995;113(9):1144-11557661748
Google ScholarCrossref 107.Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy: two-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study report 2.
Arch Ophthalmol. 1985;103(11):1644-16522865943
Google ScholarCrossref 108. 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):958-9642196036
Google ScholarCrossref 109.Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial.
Ophthalmology. 2006;113(9):1533-153816828501
Google ScholarCrossref 110.Pearson , Levy , Comstock .Fluocinolone Acetonide Implant Study Group. Fluocinolone acetonide intravitreal implant to treat diabetic macular edema: 3–year results of a multi-center clinical trial.
Invest Ophthalmol Vis Sci. 2006;(1):16384989
Google Scholar 111.Yanyali A, Horozoglu F, Celik E, Ercalik Y, Nohutcu AF. Pars plana vitrectomy and removal of the internal limiting membrane in diabetic macular edema unresponsive to grid laser photocoagulation.
Eur J Ophthalmol. 2006;16(4):573-58116952097
Google Scholar 112.Thomas D, Bunce C, Moorman C, Laidlaw DA. A randomised controlled feasibility trial of vitrectomy versus laser for diabetic macular oedema.
Br J Ophthalmol. 2005;89(1):81-8615615752
Google ScholarCrossref 113.Dhingra N, Sahni J, Shipley J.
et al. Vitrectomy and internal limiting membrane (ILM) removal for diabetic macular edema in eyes with absent vitreo-macular traction fails to improve visual acuity: results of a 12 months prospective randomized controlled clinical trial [e-abstract 1467].
Invest Ophthalmol Vis Sci. http://abstracts.iovs.org. Accessibility verified August 3, 2007 114.Bahadir M, Ertan A, Mertoğlu O. Visual acuity comparison of vitrectomy with and without internal limiting membrane removal in the treatment of diabetic macular edema.
Int Ophthalmol. 2005;26(1-2):3-816786177
Google ScholarCrossref 115.Ho T, Smiddy WE, Flynn HW. Vitrectomy in the management of diabetic eye disease.
Surv Ophthalmol. 1992;37(3):190-2021475753
Google ScholarCrossref 116.Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision: results of a randomized trial—Diabetic Retinopathy Vitrectomy Study report 3.
Ophthalmology. 1988;95(10):1307-13202465517
Google Scholar 117.Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision: clinical application of results of a randomized trial—Diabetic Retinopathy Vitrectomy Study report 4.
Ophthalmology. 1988;95(10):1321-13342465518
Google Scholar 118.Smiddy WE, Flynn HW. Vitrectomy in the management of diabetic retinopathy.
Surv Ophthalmol. 1999;43(6):491-50710416792
Google ScholarCrossref 119.Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report Number 2.
Ophthalmology. 1987;94(7):761-7743658348
Google Scholar 120.Akduman L, Olk RJ. Diode laser (810 nm) versus argon green (514 nm) modified grid photocoagulation for diffuse diabetic macular edema.
Ophthalmology. 1997;104(9):1433-14419307638
Google ScholarCrossref 121.Canning C, Polkinghorne P, Ariffin A, Gregor Z. Panretinal laser photocoagulation for proliferative diabetic retinopathy: the effect of laser wavelength on macular function.
Br J Ophthalmol. 1991;75(10):608-6101954210
Google ScholarCrossref 122.Akduman L, Olk RJ. Subthreshold (invisible) modified grid diode laser photocoagulation in diffuse diabetic macular edema (DDME)
Ophthalmic Surg Lasers. 1999;30(9):706-71410574491
Google Scholar 123.La Heij EC, Hendrikse F, Kessels AG, Derhaag PJ. Vitrectomy results in diabetic macular oedema without evident vitreomacular traction.
Graefes Arch Clin Exp Ophthalmol. 2001;239(4):264-27011450490
Google ScholarCrossref 124.Dillinger P, Mester U. Vitrectomy with removal of the internal limiting membrane in chronic diabetic macular oedema.
Graefes Arch Clin Exp Ophthalmol. 2004;242(8):630-63715221304
Google ScholarCrossref 125.Yang CM. Surgical treatment for severe diabetic macular edema with massive hard exudates.
Retina. 2000;20(2):121-12510783943
Google ScholarCrossref 126.Kralinger MT, Pedri M, Kralinger F, Troger J, Kieselbach GF. Long-term outcome after vitrectomy for diabetic macular edema.
Ophthalmologica. 2006;220(3):147-15216679787
Google ScholarCrossref 127.Stolba U, Binder S, Gruber D, Krebs I, Aggermann T, Neumaier B. Vitrectomy for persistent diffuse diabetic macular edema.
Am J Ophthalmol. 2005;140(2):295-30116023067
Google ScholarCrossref 128.Yanyali A, Nohutcu AF, Horozoglu F, Celik E. Modified grid laser photocoagulation versus pars plana vitrectomy with internal limiting membrane removal in diabetic macular edema.
Am J Ophthalmol. 2005;139(5):795-80115860282
Google ScholarCrossref 129.Sobrin L, D’Amico DJ. Controversies in intravitreal triamcinolone acetonide use.
Int Ophthalmol Clin. 2005;45(4):133-14116199972
Google ScholarCrossref 130.Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema.
Am J Ophthalmol. 2001;132(3):425-42711530068
Google ScholarCrossref 131.Jonas JB, Kreissig I, Söfker A, Degenring RF. Intravitreal injection of triamcinolone for diffuse diabetic macular edema.
Arch Ophthalmol. 2003;121(1):57-6112523885
Google ScholarCrossref 132.Martidis A, Duker JS, Greenberg PB.
et al. Intravitreal triamcinolone for refractory diabetic macular edema.
Ophthalmology. 2002;109(5):920-92711986098
Google ScholarCrossref 133.Avitabile T, Longo A, Reibaldi A. Intravitreal triamcinolone compared with macular laser grid photocoagulation for the treatment of cystoid macular edema.
Am J Ophthalmol. 2005;140(4):695-70216226521
Google ScholarCrossref 134.Kang SW, Sa HS, Cho HY, Kim JI. Macular grid photocoagulation after intravitreal triamcinolone acetonide for diffuse diabetic macular edema.
Arch Ophthalmol. 2006;124(5):653-65816682586
Google ScholarCrossref 135.Jonas JB, Kamppeter BA, Harder B, Vossmerbaeumer U, Sauder G, Spandau UH. Intravitreal triamcinolone acetonide for diabetic macular edema: a prospective, randomized study.
J Ocul Pharmacol Ther. 2006;22(3):200-20716808682
Google ScholarCrossref 136.Massin P, Audren F, Haouchine B.
et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial.
Ophthalmology. 2004;111(2):218-22415019365
Google ScholarCrossref 137.Audren F, Erginay A, Haouchine B.
et al. Intravitreal triamcinolone acetonide for diffuse diabetic macular oedema: 6-month results of a prospective controlled trial.
Acta Ophthalmol Scand. 2006;84(5):624-63016965492
Google ScholarCrossref 138.Audren F, Lecleire-Collet A, Erginay A.
et al. Intravitreal triamcinolone acetonide for diffuse diabetic macular edema: phase 2 trial comparing 4 mg vs 2 mg.
Am J Ophthalmol. 2006;142(5):794-79916978576
Google ScholarCrossref 139.Jonas JB, Kreissig I, Spandau UH, Harder B. Infectious and noninfectious endophthalmitis after intravitreal high-dosage triamcinolone acetonide.
Am J Ophthalmol. 2006;141(3):579-58016490517
Google ScholarCrossref 140.Jonas JB, Degenring RF, Kreissig I, Akkoyun I, Kamppeter BA. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection.
Ophthalmology. 2005;112(4):593-59815808249
Google ScholarCrossref 141.Gillies MC, Simpson JM, Billson FA.
et al. Safety of an intravitreal injection of triamcinolone: results from a randomized clinical trial.
Arch Ophthalmol. 2004;122(3):336-34015006845
Google ScholarCrossref 142.Westfall AC, Osborn A, Kuhl D, Benz MS, Mieler WF, Holz ER. Acute endophthalmitis incidence: intravitreal triamcinolone.
Arch Ophthalmol. 2005;123(8):1075-107716087840
Google ScholarCrossref 144.Spandau UH, Derse M, Schmitz-Valckenber P, Papoulis C, Jonas JB. Dosage dependency of intravitreal triamcinolone acetonide as treatment for diabetic macular oedema.
Br J Ophthalmol. 2005;89(8):999-100316024853
Google ScholarCrossref 145.Kuppermann BD, Blumenkranz MS, Haller JA, Williams GA.Posurdex Study Group. An intravitreous dexamethasone bioerodible drug delivery system for the treatment of persistent diabetic macular edema [e-abstract 4289].
Invest Ophthalmol Vis Sci. http://abstracts.iovs.org. Accessibility verified August 3, 2007 146.Cunningham ET, Adamis AP, Altaweel M.
et al. Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema.
Ophthalmology. 2005;112(10):1747-175716154196
Google ScholarCrossref 147.Adamis AP, Altaweel M, Bressler NM.
et al. Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals.
Ophthalmology. 2006;113(1):23-2816343627
Google ScholarCrossref 148.Brown DM, Kaiser PK, Michels M.
et al. ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
N Engl J Med. 2006;355(14):1432-144417021319
Google ScholarCrossref 149.Rosenfeld PJ, Brown DM, Heier JS.
et al. MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration.
N Engl J Med. 2006;355(14):1419-143117021318
Google ScholarCrossref 150.Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema.
Ophthalmology. 2006;113(10):1706-171217011952
Google ScholarCrossref 151.Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment.
Retina. 2006;26(3):352-35416508438
Google ScholarCrossref 152.Avery RL, Pearlman J, Pieramici DJ.
et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.
Ophthalmology. 2006;113:169517011951
Google ScholarCrossref 153.Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage.
Retina. 2006;26(3):275-27816508426
Google ScholarCrossref 154.Rosenfeld PJ. Intravitreal Avastin: the low cost alternative to Lucentis?
Am J Ophthalmol. 2006;142(1):141-14316815262
Google ScholarCrossref 155.Gillies MC. What we don't know about Avastin might hurt us.
Arch Ophthalmol. 2006;124(10):1478-147917030717
Google ScholarCrossref