Can Renin-angiotensin System Blockade Have a Role in Preventing Diabetic Retinopathy?

If untreated, a large proportion of people who develop proliferative diabetic retinopathy (PDR) will experience severe loss of vision within 5 years….

A renin-angiotensin system (RAS) has been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. 

Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for Type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates to treatment rather than prevention of disease.

Tight glycemic and blood pressure control helps to reduce the risk of retinopathy, but this is not easy to achieve in practice and additional treatments are needed for both primary and secondary prevention of retinopathy.

The recent DIRECT program assessed use of the angiotensin receptor blocker (ARB) candesartan in Type 1 and Type 2 diabetes. Although the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in Type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril.

Diabetic retinopathy is the most common long-term complication of diabetes and the most common cause of blindness in working-age people in developed countries. It is one of the most feared complications in people with diabetes and has marked effects on patients’ quality of life. Quality of life can be affected in people with diabetic retinopathy before they have visual loss, because of anxiety about the future.

At the time of the diagnosis of diabetes, up to 40% of patients with Type 2 disease already have some degree of diabetic retinopathy. In data from the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) collected about 30 years ago, more than 60% of patients with Type 2 diabetes and almost all those with Type 1 diabetes had some retinopathy after 20 years.

There is evidence from the Diabetes Control and Complications Trial (DCCT) and UK Prospective Diabetes Study (UKPDS) and other studies that recent improvements in the treatment of diabetes have led to lower incidence of retinopathy; however, this is offset by the current increase in prevalence of diabetes.

If untreated, a large proportion of people who develop proliferative diabetic retinopathy (PDR) will experience severe loss of vision within 5 years. Panretinal laser photocoagulation (PRP) is the only proven treatment with long-term beneficial effect in preventing severe visual loss once PDR is present. It can induce regression of retinal new vessels, but PRP is not always effective and can itself produce side effects on visual function such as loss of visual field and, in rare cases, accidental scars in the macula. This treatment is usually used for patients in whom sight-threatening retinopathy has developed.

By the time visual symptoms occur, severe and irreversible damage to the retina has already occurred and laser treatment is less effective. Therefore, regular screening for retinal new vessels is recommended, the aim being to detect retinopathy at an asymptomatic stage when treatment is more likely to be successful.

Specific drug treatments for retinopathy are being investigated, but these are mostly used in advanced disease when damage to the retina and visual function has already occurred. The aim of this review was to evaluate the data on prevention of diabetic retinopathy development and progression, specifically considering new clinical trial data on the possible effect of drugs that inhibit the renin-angiotensin system.

Among new approaches to retinopathy prevention, there has been considerable interest in whether drugs that block the renin-angiotensin system (RAS) might have a preventive effect, over and above their blood pressure lowering effect. RAS blockade can slow the progression of diabetic nephropathy and there is growing evidence that the RAS may also play an important role in the pathogenesis of diabetic retinopathy.

A local RAS has been shown to operate in the eye and there is evidence from clinical and experimental models that this system is upregulated in active retinopathy. Angiotensin II has been shown to increase exudation from retinal vessels, as well as stimulate formation of new retinal blood vessels, via upregulation of vascular endothelial growth factor (VEGF) activity and other growth factors and studies in animal models suggest that RAS blockade might be associated with protective effects on the retina.

Small short-term clinical studies have also demonstrated beneficial effect of RAS blockade on retinal permeability. These findings could indicate a long-term beneficial effect on diabetic retinopathy.

Microvascular complications remain important causes of morbidity. They also contribute significantly to the cost of treating diabetes in the long-term and will become more common as the incidence of the disease increases and more people with diabetes survive macrovascular complications.

There is an unmet need in retinopathy prevention and the new data on RAS blockade are encouraging. It is not yet clear whether RAS blockade has direct effects on the eye or whether the effect on retinopathy is largely explained by blood pressure lowering, but this is of little consequence for day-to-day clinical practice. Blood pressure targets in diabetes are getting lower and the DIRECT data add weight to existing evidence to consider use of an RAS blocker as antihypertensive agent in patients with diabetes.

Int J Clin Pract. 2011;65(2):148-153