Key Studies in Diabetes Care: Management of Complications
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- Hemoglobin A1c Predicts Retinopathy:Followed 891 younger- and 987 older-onset persons with diabetes over four years and determined retinopathy using stereoscopic fundus photographs. In younger-onset group, comparing highest versus lowest quartile of A1c, relative risk for developing: any diabetic retinopathy 1.9, proliferative retinopathy 21.8, progression 4.0. Amongst older-onset group taking insulin, corresponding RR were 1.9, 4.0, 2.1. These data, showing the positive relationship between incidence and progression of retinopathy and A1c, remained after controlling for confounders. They were important in planning the power of the DCCT.
- Effects of Glycemic Control, Type 1 Diabetes:DCCT took a more detailed look at effect of intensive glycemic treatment on diabetic retinopathy in 1,441 patients with type 1 diabetes. Intensive therapy reduced risk for the development of retinopathy by 76% and slowed the progression of retinopathy by 54%. Although intensive therapy could not prevent retinopathy completely, it had a beneficial effect that began after 3 years of therapy.
- Effects of Glycemic Control, Type 1 Diabetes: EDIC was the first report describing the long-term follow-up of the DCCT 4 years after the trial ended and found that although hemoglobin A1c equalized in persons with type 1 diabetes treated with intensive or conventional control, the difference in progression of retinopathy (n=1,208) persisted, favoring those who had been intensively treated.
- Effects of Glycemic Control, Type 2 Diabetes: Randomized 110 patients with type 2 diabetes to multiple insulin injection (MIT) or conventional insulin injection therapy for 6 years. In the primary prevention cohort, the MIT group had developed significantly less retinopathy (7.7% versus 32%) and nephropathy (7.7% versus 28.0%) compared to conventional group. In the secondary prevention cohort, the MIT group had significantly less progression of retinopathy (19.2 versus 44.0%) and nephropathy (11.5% versus 32.0%) compared to conventional group. Based on this study, the glycemic threshold at which to prevent onset and progression of diabetic microangiopathy was found to be HbA1c < 6.5%, fasting blood glucose < 110 mg/dl, and 2-hour post-prandial blood glucose < 180 mg/dl.
- Effects of Glycemic Control, Type 2 Diabetes: Followed 1,919 patients from UKPDS who had retinal photographs at diagnosis and 6 years later. 63% had no retinopathy at diagnosis but by 6 years, 22% had developed retinopathy. 37% had retinopathy at diagnosis, with 29% that progressed by two scale steps or more. Incidence of retinopathy associated with baseline glycemia, glycemic exposure over 6 years, higher blood pressure, and not smoking. Hyperglycemia also a risk factor for secondary progression of retinopathy.
- Effects of Blood Pressure Control, Type 1 Diabetes: Losartan and enalopril compared with placebo in 285 normotensive, normoalubminuric patients with type 1 diabetes. There was no effect of either medication on carefully assessed progression of nephropathy. However, there was, however, a surprising and significant reduction of progression of diabetic retinopathy from both losartan (70% reduction) and enalopril (65% reduction).
- Effects of Blood Pressure Control, Type 2 Diabetes: Randomized 1,148 hypertensive patients with type 2 diabetes to tight control (< 150/85 mmHg; n=758) versus less tight control (< 180/105 mmHg; n=390) with median follow-up of 8.4 years and looked at various endpoints including retinopathy, determined using retinal photography. Group assigned to tighter control had 34% reduction in retinopathy by two steps and 47% reduced risk of deterioration in visual acuity by three lines of EDTRS chart.
- Effects of Lipid Control, Type 2 Diabetes:The FIELD study randomized 9,795 participants with type 2 diabetes to fenofibrate versus placebo. After 5 years, the primary outcome of coronary events was not significantly reduced, although it did reduce total cardiovascular events (p=0.035). The fenofibrate group also had less progression of albuminuria (p=0.002) and less retinopathy needing laser treatment (p=0.0003).
- Effects of Medical Treatments, Type 2 Diabetes: Randomized 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive (A1c< 6) or standard treatment (A1c 7-7.9) for glycemia and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin versus placebo plus simvastatin) or for systolic blood-pressure control (< 120 versus < 140 mm Hg). 2,856 participants evaluated for the progression of diabetic retinopathy using ETDRS Severity Scale (as assessed stereoscopic fundus photographs). At 4 years, the rates of progression of diabetic retinopathy reduced significantly by 33% with intensive glycemia treatment, 40% with fenofibrate for intensive dyslipidemia therapy, and no significant effect with intensive blood-pressure therapy.
- Treatment with Panretinal Laser Photocoagulation:The DRS was the first to demonstrate rigorously the beneficial effect of panretinal laser photocoagulation in reducing the risk of severe visual loss by 50% or more, providing the evidence base for treating proliferative diabetic retinopathy and the rationale for screening people with diabetes in order to make a timely diagnosis of proliferative retinopathy. However, decreases of visual acuity of one or more lines and peripheral field constriction were more frequent with the xenon technique. The findings suggest that prompt treatment is advisable if progression to severe retinopathy has occurred.
- Treatment with Focal Laser Photocoagulation: The ETDRS tested whether stages of retinopathy that precede proliferative retinopathy also benefit from laser photocoagulation. 754 eyes with macular edema and mild to moderate diabetic retinopathy were randomly assigned to focal argon laser photocoagulation and 1,490 eyes were randomly assigned to deferral of laser treatment. Major findings of the ETDRS included the fact that macular edema benefits from treatment with focal (not panretinal) photocoagulation, but that the outcome of pre-proliferative retinopathy is not improved by laser treatment.
- Treatment with Vitrectomy: A randomized trial of vitrectomy versus watchful waiting in 375 eyes with proliferative diabetic retinopathy (PDR) and very poor vision. At four years follow-up, 44% of vitrectomized eyes had 10/20 or better vision, versus 28% in conventional group. The value of vitrectomy was proportional to the increasing severity of PDR.
- Treatment with VEGF inhibitors: A trial of 394 adult eyes with proliferative diabetic retinopathy, randomized to panretinal photocoagulation versus intravitrious injection of ranibizumab 0.5mg (as often as every 4 weeks) for the primary outcome of change in visual acuity at the end of 2 years. Ranibizumab was found non-inferior and was associated with less need for vitrectomy (4% vs. 15%; P< 0.001) and less frequent development of diabetic macular edema (9% vs. 28%; P< 0.001).