| Clinical Study “Common” Name (formal title) | Study design | Treatment arms | Primary outcomes | Results | Author conclusions | "Real-world" impact |
|---|---|---|---|---|---|---|
| DCCT/EDIC (Diabetic Retinopathy and Other Ocular Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study) | DCCT=controlled clinical trial EDIC=observational study of the DCCT cohort | Total subjects at baseline = 1441 Primary prevention cohort (no DR; n=726) Secondary intervention cohort (mild DR; n=715) | Initial occurrence of a three-step or more progression of diabetic retinopathy from the termination of the DCCT through the EDIC follow-up using the ETDRS grading scale and DCCT methods. | After a mean follow up of 6.5 years: Median hemoglobin A1C, intervention cohort: 7%, reducing the adjusted mean risk for diabetic retinopathy development by 76% and slowing diabetic retinopathy progression by 54% compared with the conventional therapy cohort.. Median hemoglobin A1C, conventional therapy cohort: 9% By year 8, the groups had similar hemoglobin A1Cs (intervention group, 7.98%; conventional therapy group, 8.07%) but continued to have durable effect of assigned therapy with significantly lower diabetic retinopathy progression in the intervention group. | Intensive treatment delayed the onset and slowed the progression of diabetic retinopathy. The early effects of metabolic control continued to accrue despite subsequent comparable glycemic control. | Optimizing glycemic control as early as possible in patients with diabetes can help to delay the onset and reduce the progression of diabetic retinopathy. [Aiello.Diabetes Care.2014] |
| DRCR Retina Network Protocol S (Panretinal Photocoagulation Vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial) | Randomized trial | Study eyes = 394 Ranibizumab 0.5 and panretinal photocoagulation if ranibizumab treatment failed or for diabetic macular edema=191 eyes Panretinal photocoagulation and ranibizumab if needed for diabetic macular edema = 203 eyes | Mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis) | Ranibizumab group, mean visual acuity letter improvement at 2 years, +2.8 Panretinal photocoagulation, mean visual acuity letter improvement at 2 years, +0.2 Mean peripheral visual field sensitivity loss was worse and vitrectomy and diabetic macular edema were more frequent in the panretinal photocoagulation group. | Treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) panretinal photocoagulation treatment at 2 years. | Ranibizumab may be a reasonable treatment alternative, at least for 2 years, in patients with proliferative diabetic retinopathy. [WritingCommittee.JAMA.2015] |
| DRCR Retina Network Protocol T (Change in Diabetic Retinopathy Through 2 YearsSecondary Analysis of a Randomized Clinical Trial Comparing Aflibercept, Bevacizumab, and Ranibizumab) | Preplanned secondary analysis of data from DRCR Retina Network Protocol T, a comparative effectiveness trial for center-involved diabetic macular edema |
Nonproliferative diabetic retinopathy (n=495)
Proliferative diabetic retinopathy (n=155) Participants were randomized to receive aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab 0.3 mg |
Percentages with retinopathy improvement at 1 and 2 years and cumulative probabilities for retinopathy worsening through 2 years without adjustment for multiple outcomes. |
1 year results:
Nonproliferative diabetic retinopathy eyes: 31.2% treated with aflibercept, 22.1% with bevacizumab and 37.7% with ranibizumab had an improvement in diabetic retinopathy severity.
Proliferative diabetic retinopathy eyes:
75.9% treated with aflibercept, 31.4% for bevacizumab, and 55.2% for ranibizumab had diabetic retinopathy improvements.
2 year results: Nonproliferative diabetic retinopathy eyes: 24.8% treated with aflibercept, 22.1% with bevacizumab and 31.0% with ranibizumab had an improvement in diabetic retinopathy severity. Proliferative diabetic retinopathy eyes: 70% of eyes had sustained improvement of diabetic retinopathy, including 70% among the aflibercept group, 77.8% in the bevacizumab group, and 63.6% among the ranibizumab group. |
Eyes with nonproliferative diabetic retinopathy receiving anti-VEGF treatment for diabetic macular edema may have an improvement in diabetic retinopathy severity at 1 and 2 years. | Less improvement was demonstrated with bevacizumab at 1 year than with aflibercept or ranibizumab. Aflibercept was associated with more improvement at 1 and 2 years in the smaller subgroup of participants with proliferative diabetic retinopathy at baseline. All three anti-VEGF treatments were associated with low rates of diabetic retinopathy worsening. These data provide additional outcomes that might be considered when choosing an anti-VEGF agent to treat diabetic macular edema. [Bressler.JAMA Ophthalmol.2017] |
| DRCR Retina Network Protocol AA (Comparison of Early Treatment Diabetic Retinopathy Study Standard 7-Field Imaging With Ultrawide-Field Imaging for Determining Severity of Diabetic Retinopathy) | Prospective, observational, cross-sectional analysis | Ultrawide-field images and fundus photographs were both performed on study participants (764 eyes). Study participants had type 1 or type 2 diabetes and nonproliferative diabetic retinopathy. | Agreement between ultrawide-field images | Among 742 eyes with both ETDRS 7-field images and ultrawide-field masked images graded, 48.4% of eyes had exact agreement; 88.0% agreed within one step. After open adjudication by an independent senior grader of all images with more than a two-step discrepancy, perfect agreement was found in 59.0% of eyes and agreement within one step in 96.9% of eyes. [Aiello.JAMA Ophthalmol.2019] | Imaging by the ETDRS 7-field and ultrawide-field imaging systems have moderate to substantial agreement when determining the severity of diabetic retinopathy within the seven standard fields. | These findings could justify ultrawide-field imaging for assessing diabetic retinopathy severity end points in future studies. The use of ultrawide-field imaging in clinical settings not only increases the frequency of diabetic retinopathy identification nearly 2-fold, but also reduces acquisition time by more than half, ungradable image rate by 71%, and image evaluation time by 28% compared with nonmydriatic fundus photography. The finding of predominantly peripheral hemorrhages confers an increased rate of progression to proliferative diabetic retinopathy. [Aiello.JAMA Ophthalmol.2019] |
| PANORAMA | Phase 3, double-masked, prospective, randomized trial [Singh.AAO.2019] | Aflibercept 2 mg every 8 weeks (n=134) Aflibercept 2 mg every 16 weeks (n=135) Sham injection (n=133) [Singh.AAO.2019] | By week 24: Proportion of eyes improving two or more steps on the Diabetic Retinopathy Severity Scale, all aflibercept injections combined By week 52: Proportion of eyes improving two or more steps on the Diabetic Retinopathy Severity Scale, every 8 and 16 weeks injections versus sham [Singh.AAO.2019] |
At 1 year, 80% and 65% of patients receiving aflibercept on an every 8- and every 16-week interval (after an initial monthly dosing period), respectively, experienced a two-step or greater improvement from baseline on the Diabetic Retinopathy Severity Scale, compared to 15% of patients receiving sham injection.
[Singh.AAO.2019] |
The proportion of eyes with a two-step or greater improvement on the Diabetic Retinopathy Severity Scale was significantly greater with intravitreal aflibercept. [Singh.AAO.2019] | PANORAMA is the first large, prospective trial of eyes with moderately severe to severe nonproliferative diabetic retinopathy in patients without diabetic macular edema since the ETDRS. There is a potential value in early intervention with aflibercept to treat diabetic retinopathy disease. [Singh.AAO.2019] |
| RISE/RIDE (Durability of Diabetic Retinopathy Improvement with As-Needed Ranibizumab: Open-Label Extension of RIDE and RISE Studies) | Pooled analysis of the open-label RIDE and RISE studies | After 24 months, sham injection patients crossed over to ranibizumab 0.5 mg monthly. After 36 months, patients in the open-label extension could receive ranibizumab 0.5 PRN based on predefined diabetic macular edema criteria. Ranibizumab 0.3 mg monthly (n= 121) Ranibizumab 0.5 mg monthly from the core treatment group (n= 125) Ranibizumab crossover after initial sham injections (n= 121) | Changes in diabetic retinopathy severity status from months 36 to 48 by retreatment status |
In the open-label extension, 24% of patients did not require further ranibizumab injections. At months 36 and 48, 367 of 500 patients had evaluable diabetic retinopathy.
Among patients who did not require ranibizumab retreatment from months 36 to 48, 57% to 78%, 0% to 7%, and 22% to 36% experienced diabetic retinopathy severity stability, two step or more improvement, and two step or more worsening, respectively.
[Sun.Ophthalmology.2019] |
Diabetic retinopathy severity improvements with ranibizumab were maintained in more than 70% of open-label extension patients after switching from ranibizumab monthly to ranibizumab 0.5 mg PRN dosing regimen. | Robust diabetic retinopathy improvements with monthly ranibizumab in RIDE and RISE, which can be maintained in many patients with less than monthly dosing, further suggest a paradigm shift in diabetic retinopathy treatment, with a focus on early treatment to improve diabetic retinopathy severity to prevent a vision-threatening complication such as proliferative diabetic retinopathy or diabetic macular edema, rather than a wait-and-watch approach followed by treatment only for advanced diabetic eye disease complications. [Sun.Ophthalmology.2019] |
| UKPDS (United Kingdom Prospective Diabetes Study)Risk Factors for Incidence and Progression of Retinopathy in Type II Diabetes Over 6 Years From Diagnosis | Randomized trial | Retina photographs taken at diagnosis of type 2 diabetes and six years later (n=1919). | Incidence and progression of retinopathy, defined as a two-step ETDRS final scale change. | Among patients, 63% had no retinopathy at diagnosis. By year 6, 22% of those had developed retinopathy. Among the 37% of patients with retinopathy at diagnosis, 29% progressed by two scale steps or more. | Retinopathy onset was strongly associated with baseline glycemia and glycemic exposure over 6 years, with higher blood pressure and inversely with smoking. In those who already had retinopathy, progression was associated with not smoking, older age, male sex, and glycemia as evidenced by a higher hemoglobin A1C. | The findings re-emphasize the need for intensive glycemic control and assiduous treatment of hypertension if diabetic retinopathy is to be controlled and reduced. [Stratton.Diabetologia.2011] |