The primary goals of systemic intervention are to prevent the development of diabetic retinopathy/DME and to reduce vision loss in patients with existing retinopathy/DME. The mainstays of systemic control are blood sugar and blood pressure control. More recently, therapies targeting the renin-angiotensin system (RAS) and lipid-lowering agents have been investigated. Improvement in systemic risk factors alone can significantly decrease the risk of vision loss from DME.

The most effective systemic intervention to prevent the progression of diabetic retinopathy is improved glycemic control seen by a lowering of glycosylated hemoglobin (HbA1c). This was established by the Diabetes Control and Complications Trial (DCCT) in type 1 diabetics and the UK Prospective Diabetes Study (UKPDS) in type 2 diabetics. Both studies showed intensive glycemic control reduced the incidence and progression of diabetic retinopathy.

Not surprisingly, intensive glycemic control is associated with an increased risk of hypoglycemic events. Additionally, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was stopped because an increase in all-cause mortality was identified in patients whose glucose was extremely tightly controlled with insulin and multiple oral agents. The validity of this association has been questioned, but nonetheless it is important to be cognizant of the potential risk.

Optimal metabolic control in both type 1 and type 2 diabetics may be very difficult to achieve. Various interventions to improve patient education such as nurse education and group therapy sessions have been shown to improve HbA1c levels. Since diabetes is a chronic condition, it is imperative that patients have a thorough understanding of their illness which facilitates better compliance with medical therapies.

The American Diabetes Association and the European Association for the Study of Diabetes provided a consensus statement in 2009 which provided guidance for a treatment algorithm for type 2 diabetes. The guidelines emphasized a goal HbA1c <7.0 %, initial therapy with lifestyle modifications and metformin, rapid addition of additional oral agents if glycemic goals are not achieved or sustained, and early addition of insulin therapy in patients who do not meet goals with oral medications. Based on these guidelines and results of clinical studies, it is fundamental for ophthalmologists to review their patients’ HbA1c and emphasize the importance of metabolic control at each visit.

Hypertension has been shown to be a major risk factor for DME in studies such as the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR). The WESDR found that higher diastolic blood pressure increased the risk of progression of diabetic retinopathy over a 4-year period. Furthermore, the UKPDS demonstrated that improved control of systolic blood pressure reduced the need for laser treatment of diabetic retinopathy in patients with type 2 diabetes. Based on these and other studies, the American Diabetes Association recommends a target blood pressure of less than 130/80 mmHg for patients with diabetes.

The renin-angiotensin system (RAS) in the eye is activated by chronic hyperglycemia which leads to overexpression of AII. As mentioned previously, AII induces the release of VEGF as well as increases vascular permeability and promotes vasoconstriction. Clinical trials such as the Renin-Angiotensin System Study (RASS) have evaluated medications that target this system and their effects on diabetic retinopathy. The RASS compared the effect of the angiotensin-converting enzyme inhibitor enalapril, the angiotensin receptor blocker losartan, and placebo on diabetic retinopathy progression over a 5-year period in normotensive patients. Both drugs significantly reduced the progression of diabetic retinopathy independently of glycemic levels and changes in blood pressure. Similar studies such as the Diabetic Retinopathy Candesartan Trials (DIRECT) and the European Controlled Trial of Lisinopril in Insulin-Dependent Diabetes (EUCLID) study have shown favorable effects on diabetic retinopathy progression.

Lipid-lowering therapy is vitally important to decrease the risk of cardiovascular disease in patients with diabetes. Statins and fibrates have been shown to reduce hard exudates, microaneurysms, and the risk of vision loss in diabetic retinopathy. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study showed a decrease in the rate of DME development and need for laser photocoagulation in type 2 diabetic patients. The protective effects of fenofibrate were independent of blood glucose, blood pressure, and baseline lipid levels. Furthermore, the ACCORD study showed that the addition of fenofibrate to statin therapy resulted in a reduction in diabetic retinopathy progression compared to taking a statin alone. These effects of fibrate medications appear to be independent of lipid concentration and have raised questions as to their mechanism of action.

The treatment of DME drastically changed with the advent of intravitreal injections. Intravitreal steroids and anti-VEGF agents are superior to laser photocoagulation with regard to improving visual acuity. This has led to a paradigm shift in the treatment of DME.