The incidence of diabetes is increasing, but that of diabetic retinopathy is falling, probably owing to better management of glucose levels, lipid abnormalities, and hypertension. Clinical trials of VEGF and PPAR-α inhibitors are improving vision and providing insights into pathogenesis. The latest article in our Mechanisms of Disease review series, “Diabetic Retinopathy,” comes from Drs. David Antonetti and Thomas Gardner of the University of Michigan Medical School, and Dr. Ronald Klein of the University of Wisconsin School of Medicine and Public Health.
Until recently, the treatment for diabetic retinopathy relied almost exclusively on managing the metabolic dysregulation of diabetes mellitus until the severity of the vascular lesions warranted laser surgery. Intensive metabolic control remains a highly effective means of controlling retinopathy and other diabetes-related complications in many patients.
• What is the clinical presentation of diabetic retinopathy?
The features of diabetic retinopathy, as detected by ophthalmoscopy, were described in the 19th century. The involved changes begin with microaneurysms and progress into exudative changes (leakage of lipoproteins [hard exudates] and blood [blot hemorrhages]) that lead to macular edema, ischemic changes (infarcts of the nerve-fiber layer [cotton-wool spots]), collateralization (intraretinal microvascular abnormalities) and dilatation of venules (venous beading), and proliferative changes (abnormal vessels on the optic disk and retina, proliferation of fibroblasts, and vitreous hemorrhage). Persons with mild-to-moderate nonproliferative retinopathy have impaired contrast sensitivity and visual fields that cause difficulty with driving, reading, and managing diabetes, and other activities of daily living. Visual acuity, as determined with the use of Snellen charts, declines when the central macula is affected by edema, ischemia, epiretinal membranes, or retinal detachment.
• How does strict metabolic control impact the incidence and progression of diabetic retinopathy?
Epidemiologic studies have shown the effects of hyperglycemia, hypertension, and dyslipidemia — and, to a lesser extent, a high body-mass index, a low level of physical activity, and insulin resistance — on the incidence and progression of diabetic retinopathy and clinically significant macular edema. The Diabetes Control and Complications Trial (DCCT) showed that intensive metabolic control reduces the incidence and progression of diabetic retinopathy. Although the glycated-hemoglobin level is the standard clinical index for predicting the development and progression of diabetic retinopathy, this index accounted for only 11% of the risk of retinopathy in the DCCT. Similarly, the values for glycated hemoglobin, blood pressure, and total serum cholesterol accounted for only 9 to 10% of the risk of retinopathy in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Proliferative diabetic retinopathy and other complications develop after 30 years in up to 20% of persons with diabetes who have been treated with intensive metabolic control, and ideal metabolic control is difficult to achieve because of the increased risk of hypoglycemia and the nonphysiologic route of insulin administration.
Morning Report Questions
Q: What medical interventions have been shown to be helpful in preventing diabetic retinopathy?
A: Large, randomized trials have revealed that metabolic control, the renin-angiotensin system, peroxisome proliferator-activated receptor alpha (PPAR-alpha), and VEGF contribute to human pathophysiology. Notably, renin- ngiotensin system inhibitors reduce the incidence and risk of progression of diabetic retinopathy in persons with type 1 diabetes and are now standard therapy. The PPAR-alpha agonist, fenofibrate, reduces the risk of progression by up to 40% among patients with nonproliferative retinopathy, as shown in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. The ACCORD study did not show an effect of intensive blood-pressure control on retinopathy progression but did show the benefit of intensive glycemic control in preventing the progression of retinopathy.
Q: What eye-specific treatments are beneficial in patients with diabetic retinopathy?
A: Eye-specific treatments are beneficial in patients whose vision is threatened by macular edema. Use of the VEGF- eutralizing antibodies bevacizumab and ranibizumab improves visual acuity by an average of one to two lines on a Snellen chart, with an improvement of three or more lines in 25 to 30% of patients, and loss of visual acuity decreased by one third. These improvements, which are seen over a period of 2 years after approximately 10 intraocular injections, are significantly better than the results of laser treatment alone. The VEGF aptamer, pegaptanib, improves visual acuity by approximately one line. Sustained intravitreal delivery of fluocinolone yields a similar likelihood of gaining three or more lines of acuity but with a 60% increase in the risk of glaucoma and a 33% increase in the need for cataract surgery. The same implant technology delivering a lower dose of fluocinolone did not increase the risk of cataract or glaucoma. Glucocorticoids such as fluocinolone reduce retinal inflammation and may restore the integrity of the blood-retinal barrier by increasing tight-junction protein expression.