Evidence of the Month

Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.

António Castanheira-Dinis
Institute of Ophthalmology Gama Pinto
Visual Sciences Research Center
Faculty of Medicine – Lisbon University
Lisbon, Portugal

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Background
Long-term microvascular and neurological complications cause considerable morbidity and mortality in patients with diabetes mellitus. Diabetic retinopathy (DR) is a disorder of the retinal vasculature that eventually develops to some degree in nearly all patients with long-standing diabetes, constituting one of the leading causes of blindness in the Western world. For purposes of both prognosis and treatment, it is useful to divide DR into non-proliferative and proliferative categories. Vision loss results mainly from macular oedema, macular capillary non-perfusion, vitreous haemorrhage, and tractional detachment of the retina. The disease is often best treated before symptoms develop, making DR screening important.

The natural history of DR as well as the benefits of early intervention with laser therapy to prevent visual loss is well established. Additionally, several case reports and prospective randomized trials have recently brought forward new drugs for the local and systemic treatment of DR.

Methods and Key Results
A systematic review of all English-language articles on randomized controlled trials (RCTs) of DR from 1966 through May 2007 was performed. Further selection was made using the Delphi consensus criteria list to assess the quality of the RCTs. The final number of studies selected for analysis was 44, including 3 meta-analyses.

Primary interventions, including glycaemic control, blood pressure control, and lipid-lowering therapy, were assessed in terms of the influence of each intervention on the incidence and progression of DR. According to 2 large multicenter RCTs, the DCCT (Diabetes Control and Complications Trial) and the UKPDS (UK Prospective Diabetes Study), patients with either Type 1 or Type 2 diabetes benefitted from tight glycaemic control. The effect of anti-hypertensive therapy was also demonstrated in the reduction of the incidence and progression of retinopathy. However, it was less clear whether treating normotensive patients or using angiotensin-converting enzyme inhibitors in particular was beneficial. Some observational studies suggest that dyslipidaemia increases the risk of DR, particularly of macular oedema, but no RCTs establishing solid evidence on this subject were found.

Two cornerstone studies on laser therapy as secondary intervention for DR showed clear benefits regarding the prevention of visual loss in patients with macular oedema and proliferative or pre-proliferative DR: the ETDRS (Early Treatment Diabetic Retinopathy Study) and the DRS (Diabetic Retinopathy Study). The advantage of early vitrectomy has also been established for eyes with advanced proliferative DR complicated by haemorrhage into the vitreous, especially in Type 1 diabetes.

New interventions for DR, made public in recent years and showing promising results, have a solid scientific foundation and involve injecting locally acting drugs into the eye, thus limiting their effects to the site where they are beneficial and avoiding deleterious systemic effects. The list includes triamcinolone (a steroid derivative) and pegaptanib, ranibizumab, and bevacizumab (synthetic anti-vascular endothelial growth factor [VEGF] agents). However, the efficacy and safety of these novel treatments have not yet been established because the RCTs are ongoing or more data are needed.

There seems to be little evidence for the benefits of anti-platelet agents or aldose reductase inhibitors in reducing DR progression. Ruboxistaurin, a protein kinase C (PKC) inhibitor, has shown promising results in various RCTs, but the evidence is insufficient at this time.

Clinical Implications
A couple of decades have passed since the classic studies on DR (DCCT, UKPDS, ETDRS, DRS). In recent years, there has been new evidence that a number of steps in the pathophysiology of DR could be addressed. New pharmacological interventions at the molecular level are showing promising results in the treatment of vision-disabling conditions such as diabetic macular oedema and proliferative DR. Steroids, PKC inhibitors, and anti-VEGF agents are arguably interesting new approaches to the management of macular oedema and advanced DR and its complications, and the early results of these clinical trials are encouraging.

Although scientific papers have been focusing mainly on these new therapies, we should not underestimate the evidence from years ago of the benefits of tight glycaemic and blood pressure control in preventing and slowing the progression of DR, as well as the value of laser therapy in the management of the disease and prevention of severe vision loss. As there is currently insufficient evidence to recommend routine use of other treatments, diabetic patients should have their DR status assessed regularly; appropriate and well-timed management includes laser photocoagulation treatment directed at the stages of macular oedema and proliferative retinopathy, reserving surgical vitrectomy for severe end-stage situations. DR is today a leading cause of new cases of legal blindness among working-age citizens of developed countries. The dramatic increase in the worldwide prevalence of diabetes, primarily due to an increase in Type 2 diabetes in developing countries, should be indicative of the importance of proper screening and management for DR, one of the more devastating complications of diabetes.

This Website Feature is funded by an unrestricted educational grant from Pfizer Inc.