Roy D Brod, MD
Two landmark studies confirmed the benefit of intensive glycemic control for the reduction of onset and progression of diabetic retinopathy (DR) and other diabetic microvascular complications (DMC). The Diabetes Control and Complications Trial (DCCT) established that intensive insulin therapy reduced the onset and progression of DR in patients with type 1 diabetes. Compared to patients maintained on conventional control, intensive treatment reduced the onset of DR by 76%, reduced the progression of DR by 54%, and reduced the development of proliferative or severe nonproliferative DR by 47%. Intensive glycemic control also reduced the incidence and progression of albuminuria and neuropathy. Patients randomized to intensive control sometimes experienced temporary worsening of DR within the first year of A1C reduction, during which the average A1C declined from 13% to 7.6%. Although recovery was noted by 18 months, this finding suggests patients newly assigned to an intensive insulin regimen should be watched closely for development and progression of DR. The United Kingdom Prospective Diabetes Study (UKPDS) found that intensive glucose control (fasting plasma glucose [FPG] <110 mg/dL) reduced DR progression by 21% compared to conventional control (FPG <270 mg/dL without symptoms of hyperglycemia).
In addition to glycemia, other systemic factors also play a role in the development and progression of DR, including blood pressure, lipid status, renal function, anemia, exercise, and smoking status. The UKPDS demonstrated that maintaining blood pressure <150/85 mm Hg reduced the risk of DMC by 37%, the risk of a 3-line vision loss by 47%, and the risk of DR progression by 34%. Another British study, the Appropriate Blood Pressure Control in Diabetes (ABCD) trial showed that reducing blood pressure reduced the progression of DR even in normotensive patients with type 2 diabetes. Current blood pressure treatment goals are considerably more stringent than those used in the UKPDS; the American Diabetes Association recommends maintaining blood pressure <130/80 mm Hg for all patients with diabetes.
Elevated triglyceride and cholesterol levels are associated with increased development of hard exudates, increasing the risk of vision loss. Patients with hard exudates should be referred to an internist for evaluation for treatment with a statin to reduce lipid levels. There is some evidence suggesting statins may be beneficial in reducing hard exudates.
There is a strong correlation between DR and diabetic nephropathy. Proteinuria is associated with both diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). DME may improve after initiation of dialysis. Independently of nephropathy, anemia (low hematocrit) is a risk factor for DR. The Early Treatment Diabetic Retinopathy Study (ETDRS) found a 2-fold increase in DR risk for hemoglobin <12 g/dL. Anemia treatment improves DR.
Generally, exercise is beneficial for controlling systemic factors related to diabetes such as improving cardiovascular function, reducing blood pressure, increasing high-density lipoprotein (HDL) cholesterol, reducing weight, and improving insulin sensitivity. Because patients with active PDR are at risk for vitreoretinal hemorrhage and retinal detachment, they should not participate in strenuous exercise until the PDR is brought under control. Examples of these sorts of exercises include high-impact sports, maximal exertion, heavy weight training, or isometric exercises with extreme Valsalva maneuvers.
The effects of smoking on DR remain unclear, but should be discouraged because of its clearly deleterious effects on renal, cardiovascular, and respiratory function.
Cardiovascular disease is the leading cause of mortality in diabetes. Encouragingly, treatments to improve cardiovascular risk are not deleterious for DR. The ETDRS demonstrated that daily aspirin (650 mg/d) reduced cardiovascular mortality by 17% but did not affect DR progression, visual outcome following laser photocoagulation, or increase the risk of vitreous hemorrhage. Additionally, DR is not a contraindication for thrombolytic therapy. One study found that thrombolytic therapy reduced 35-day mortality in patients with diabetes with suspected myocardial infarction by 71.7% without evidence of hemorrhagic complications.
A number of pharmacologic treatments for DR are under investigation. These include antioxidants, protein kinase C (PKC) inhibitors, renin-angiotensin system inhibitors, growth hormone inhibitors, steroids, vascular endothelial growth factor (VEGF) inhibitors, minocycline, and vitreolysis agents. Although there is a sound theoretical basis for using antioxidants to treat DR, trials conducted to date using Vitamin E have shown only modest benefits. Clinical trials of ruboxistaurin, a PKC inhibitor, have demonstrated reduced progression of DR and DME. ACE inhibitors, a class of RAS inhibitors currently approved as hypertension medications, may have beneficial effects on the kidney and the eye. Growth hormone inhibition has been shown to decrease the need for laser photocoagulation therapy in severe nonproliferative DR and early PDR. Steroids have shown benefits in the treatment of DME, while VEGF inhibitors have shown benefits in the treatment of DME and neovascularization. Minocycline, a tetracycline used to treat acne, may limit retinal damage caused by microglia (Krady JK, Basu A, Allen CM, et al. Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes. 2005;54:1559-1565.). Agents that promote vitreolysis, such as hyaluronidase, induce posterior vitreous detachment, which arrests the development of PDR.
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