Additional characteristics would expand its clinical usefulness: a marker informative for an individual patient would facilitate clinical decision making while a marker that reliably measures reversibility of the disease process could become a surrogate end point in drug development and preventative treatment. A biomarker useful in the prevention of a clinical end point (e.g., retinopathy) would 1) noninvasively detect early preclinical disease before the first clinical signs of the end point (e.g., microaneurysms) appear, 2) be causally linked or be an indicator of a causal mechanism that leads to the development of this end point, and 3) be consistently and strongly associated with the end point ( 5). CURRENT STATUS OF EARLY BIOMARKERS FOR DIABETES COMPLICATIONSĪ biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention” ( 5). In this review we will focus on retinal vascular caliber as a potential biomarker for the three major microvascular complications of diabetes: retinopathy, nephropathy, and neuropathy. Thus they fulfill important requirements for being investigated as biomarkers of diabetes complications ( 3). In addition, changes in vascular caliber have implications relevant to the pathophysiology of the vascular and end-organ damage observed in the eye and elsewhere in diabetes. The National Institutes of Health (NIH)/JDRF convened a workshop on 3–4 October 2011, in Bethesda, Maryland, titled “Seeing the Development of Diabetes Complications: Retinal Vessels as Biomarkers.” From the presentations and discussions at the workshop emerged that, to date, changes in retinal vascular caliber appear to be among the earliest changes detected in the retina in diabetes. It seems timely to assess which concepts have emerged and which needs must be met toward fulfilling the expectation that retinal vessels may be able to predict the clinical onset of complications. New measuring techniques have steadily come along, and others are in development. Hence, investigators have attempted over the decades to identify early changes in the retinal vessels in diabetes and determine whether they could inform about the development of retinopathy and other complications. They can be seen, measured, and tested by noninvasive means ( 4). The retinal vessels are early and prevalent targets of diabetic damage. One such approach is to identify biomarkers that will enable systematic patient surveillance and the identification of high-risk patients and also surrogate end points that will accelerate the discovery of new interventions. Thus, new approaches are required to derive further benefit from current interventions at an earlier stage of diabetes and to support the development of new interventions. Drugs such as fenofibrate have reduced the risk of diabetic retinopathy (DR) progression in type 2 diabetic patients, and inhibitors of the renin-angiotensin system (e.g., enalapril, losartan) have reduced the risk of progression in type 1 diabetic patients, but have not reduced the risk of DR incidence. Intensive control of hyperglycemia and blood pressure implemented with the imperfect means available today delays the appearance and reduces the severity of most complications, but does not prevent their development ( 3). In theory, the long preclinical phase should provide a window to apply interventions that preempt progression to clinical disease, but to date no strategy achieves this aim for diabetes complications. Both the macrovascular (coronary artery disease, peripheral artery disease, and stroke) and microvascular (retinopathy, nephropathy, and neuropathy) complications of diabetes are major causes of morbidity and mortality ( 2). Globally, the number of people with diabetes is expected to reach 552 million in 2030 ( 1).
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