Recent Randomized Controlled Trials on Systemic Therapy for Diabetic Retinopathy* F/U (years) 6.5
Study
Population
Intervention (IT)
Main findings
DCCT1-3
1,441 T1DM
Intensive glycemic control with insulin
HbA1c 7·2% after IT vs. 9·1% after CT IT ↓ risk of DR by 76%, DR progression by 54%, maculopathy by 23%, severe NPDR/PDR by 47%, and laser for ME/PDR by 51%
UKPDS4
3,867 T2DM
Intensive glycemic control with sulphonylurea and/or insulin
HbA1c 7·0% after IT vs. 7·9% after CT IT ↓ risk retinal photocoagulation by 29%, DR progression by 17%, vitreous hemorrhage by 23%, and legal blindness by 16%
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ADVANCE5
11,140 T2DM
Intensive glycemic control with use of glicalzide and other drugs
Baseline HbA1c 7·2% HbA1c 6.5% after IT vs. 7·3% after CT IT did not ↓ risk of DR (6.0% after IT vs. 6·3% after CT) or visual deterioration (54·4% after IT vs. 54·1% after CT)
5
VADT6
1,791 military veterans (97% men) with T2DM
Intensive glycemic control with rosiglitazone + metformin/glimepiride +/insulin
Baseline HbA1c 9·4% HbA1c 6·9% after IT vs. 8·4% after CT IT did not ↓ risk of new DR, progression to PDR or CSMO, or need for laser treatment or vitrectomy. DR progression rate lower in IT than in CT (17·0% vs. 22·1%; p=0·07)
5.5
UKPDS7,8
1,148 T2DM
Tight BP control (<150/85 mmHg) vs. less tight BP control (<180/105 mmHg)
Baseline BP 160/94 mmHg BP 144/82 mmHg after tight control vs. 154/87 mmHg after less tight control IT reduced risk of DR progression by 34%, visual loss by 47%, and laser therapy by 35%
8.4
DIRECT19
1,421 T1DM
Candesartan
DR incidence 25% in IT and 31% in CT DR progression 13% in IT and 13% in CT Post-hoc analysis re-defining DR incidence using more stringent definition (≥3-step increase on ETDRS scale): IT ↓ risk of DR by 35% (26% after adjustments)
5
DIRECT210
1,905 T2DM with mildmoderate NPDR
Candesartan
DR progression 17% in IT and 19% in CT IT ↑ DR regression by 33% IT did not significantly ↓ risk of DR progression
5
RASS11
285 normotensive T1DM
Losartan or enalapril
Losartan ↓ odds of DR progression by 70% Enalapril ↓ odds of DR progression by 65%
5
FIELD12
9,795 T2DM
Fenofibrate
Laser treatment for DR (MO/PDR) was less frequent in IT (3·4%) than in CT (4·9%) IT ↓ risk of laser treatment for DR by 31% DR progression less in IT (3·1%) than in CT (14·6%) in ophthalmology sub-study but no difference in worsening of visual acuity
5
Steno-213
160 T2DM with persistent microalbuminuria
8 years of intensified multifactorial target-driven treatments†
IT included tight glycemic control, renin-angiotensin blockers, aspirin and lipid-lowering agents IT ↓ risk of DR progression by 43% and laser treatment for DR by 55%
13
CALDIRET14
635 T2DM with mildmoderate NPDR
Calcium dobesilate
IT did not ↓ risk of CSMO
5
*Clinical trials before 2007, except for DCCT and UKPDS, are summarised elsewhere.15 1
T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; CT = conventional therapy; NPDR = non-proliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; CSMO = clinically significant macular oedema; F/U = follow-up; ETDRS = Early Treatment Diabetic Retinopathy Study † Targets (achieved): HbA1c <6.5% (7.9), cholesterol <175 (159) mg/dL, triglyceride <150 (115) mg/dL, systolic blood pressure <130 (131) mmHg and diastolic blood pressure <80 (73) mmHg; all patients were given renin-angiotensin inhibitor and low-dose aspirin
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Anti-Vascular Endothelial Growth Factor (VEGF) Agents Used in Diabetic Retinopathy Anti-VEGF agents Pegaptanib (Macugen)
Mechanism of Effect An aptamer against a single isoform (165) of VEGF-A
Ranibizumab (Lucentis)
A modified humanized monoclonal antibody fragment against all VEGF-A isoforms
Bevacizumab (Avastin)
A recombinant humanized antibody that binds all VEGF-A isoforms
VEGF-Trap
A protein composed of extracellular VEGF receptor sequences fused to an immunoglobulin backbone, which selectively binds all VEGF-A isoforms and placental growth factor, with apparently longer biologic activity following intravitreal injection than ranibizumab
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Recent Randomized Controlled Trials on Anti-VEGF Therapy for Diabetic Retinopathy Population
Intervention
Main findings
F/U (months) 24
DRCR.net 854 with DMO16
IVR + laser vs. laser alone
Vision ↑ (gained ≥10 letters) in 47-50% in IVR + laser vs. 28% in laser alone after 1 year Vision ↓ (lost ≥15 letters) in 3-4% in IVR + laser vs. 13% in laser alone after 1 year Visual outcome results similar after 2 years of follow-up
DRCR.net (phase 2) 121 with DMO17
IVB +/- laser vs. laser alone
Vision ↑ slightly (gained 1 line) in IVB vs. laser alone at 12 weeks No difference between 1·25mg vs. 2·5mg DMO ↓ in 37% after IVB vs. 50% after laser alone at 6 weeks No apparent short-term benefit with IVB + laser
3
MDRS (phase 2) 122 with DMO18
IVP vs. no IVP first 12 weeks with follow-up IVP and/or laser for next 18 weeks
Vision ↑ (gained ≥10 letters) in 34% in IVP vs. 10% in no IVP Need for laser 25% in IVP vs. 48% in no IVP
9
MDRS 16 with DMO and PDR19
IVP vs. no IVP (retrospective analysis)
PDR regressed in 62% (8/13 with 1 also treated with PRP) treated with IVP, 0% (0/3) treated with sham, and 0% (0/4) fellow eye. PDR progressed after cessation of IVP.
12
130 with DMO20
IVB +/- IVT vs. laser
Vision unchanged for IVB and laser, with IVB+IVT showing marginal improvement
9
115 with refractory DME21
IVB +/- IVT
Vision and macular thickness significantly better in IVB or IVB + IVT vs. IVT but did not differ significantly between IVB vs. IVB + IVT
4
150 with DMO22
IVB +/- IVT vs. laser
Improvement in visual acuity (>2 lines) greater in IVB (37%) vs. laser (15%) 72% only required 1 IVB injection No adjunctive effect of IVT observed
3
30 with PDR23
PRP + IVB vs. PRP alone
No significant difference in vision but total area of actively leaking new vessels was significantly reduced in the PRP+IVB vs. PRP alone
6
80 with PDR24
PRP + IVB vs. PRP alone
Complete regression of PDR in PRP+IVB (87.5%) vs. PRP alone (25%) at week 6. PDR recurred more frequently in PRP+IVB and complete regression rate became identical between PRP+IVB (25%) vs. PRP alone (25%) HbA1c was the strongest predictor of PDR recurrence.
4
42 with DMO25
IVB x 1 immediately after cataract surgery
Macular thickness ↓ in IVB and ↑ in no IVB Improvement in vision significantly greater in IVB vs. no IVB
4
68 with DR26
IVB x 1 immediately after cataract surgery
DR progression less frequent in IVB (11%) vs. no IVB (45%) Progression of DME less frequent in IVB (6%) vs. no IVB (52%) No significant difference in visual acuity and macular thickness between IVB and no IVB
6
68 with PDR undergoing PPV27
IVB x 1 one week before surgery
Post-PPV hemorrhage significantly lower in IVB vs. control Resolution of VH in 26% of IVB obviating the need for PPV Mean VA improvement greater in IVB vs. control
1
Abbreviations: MDRS = Macugen Diabetic Retinopathy Study; DRCR.net = Diabetic Retinopathy Clinical Research Network; IVR = intravitreal ranibizumab; IVP = intravitreal pegaptanib; IVB = intravitreal bevacizumab; IVT = intravitreal triamcinolone; PDR = proliferative diabetic retinopathy; DMO = diabetic macular oedema; PRP = panretinal retinal photocoagulation; PPV = pars plana vitrectomy 4
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