The diagnosis of diabetes is changing: how implementation of hemoglobin A1c will impact clinical laboratories.

The earliest known description of diabetes mellitus is in the Papyrus of Ebers by Hesy-Ra in 1552 BC. Since then, we have learned that diabetes consists of a group of metabolic disorders, all of which produce hyperglycemia. The relatively specific complications of diabetes (affecting the eyes, kidneys, and nervous system) and the high prevalence (estimated at approximately 40 10 in the US and approximately 250 10 worldwide) combine to make it a substantial public health problem. Our comprehension of the pathophysiology of the disease is limited, however, and no biological marker is known to be unique to diabetes. Diagnosis has been based exclusively on the demonstration of increased glucose concentrations, initially in urine and subsequently in the blood. Therefore, the recent publication of the International Expert Committee report on the diagnosis of diabetes (1 ), which recommends the use of hemoglobin A1c (Hb A1c) 2 rather than glucose for the diagnosis of diabetes, represents a dramatic change that deserves reflection. Hyperglycemia has been the sole diagnostic criterion for diabetes since the development of blood glucose assays 100 years ago. Measurement of the response to a metabolic challenge in the form of the oral glucose tolerance test (OGTT) was initially used. The cutoff was 2 SDs above the mean glucose concentration in healthy individuals. This strategy was limited by a lack of standardization in both the performance and the interpretation of the test and its poor reproducibility. In 1979, the National Diabetes Data Group proposed criteria that were derived from the distribution of glucose concentrations in populations with a high prevalence of diabetes (2 ). The diagnostic criteria were (a) classic symptoms of diabetes with an unequivocal increase in plasma glucose, (b) a venous fasting plasma glucose (FPG) concentration 7.8 mmol/L (140 mg/dL), or (c) a 2-h and an earlier sample during an OGTT with glucose concentrations 11.1 mmol/L (200 mg/dL) (2). The National Diabetes Data Group criteria were adopted widely and were endorsed in 1980 by the WHO. With time, flaws became apparent in these criteria, and they were revised about 20 years later (3, 4 ). The entire focus was altered to a more pragmatic approach, with diagnosis based on the development of complications. Analysis of several epidemiologic studies revealed that the prevalence of retinopathy increased substantially above a glycemic threshold. Remarkably, FPG, 2-h postload glucose (during an OGTT), and Hb A1c values all exhibit a distinct and identifiable threshold (3 ). On the basis of these data, the Expert Committee recommended that the cutoff for diagnosis with FPG measurement be lowered from 7.8 mmol/L (140 mg/dL) to 7.0 mmol/L (126 mg/dL), which is equivalent to a 2-h postload glucose concentration of 11.1 mmol/L (200 mg/dL). Thus, the diagnostic criteria recommended were (a) FPG 7.0 mmol/L (126 mg/dL), (b) 2-h postload glucose concentration 11.1 mmol/L (200 mg/dL) during an OGTT, or (c) symptoms of diabetes plus a casual plasma glucose value 11.1 mmol/L (200 mg/dL), with “casual” indicating that the blood is drawn without regard to the time of the preceding meal. In the absence of unequivocal hyperglycemia, confirmation is required through repeat testing on a subsequent day if any of these criteria is met. The WHO proposed an essentially identical scheme (4 ). The only difference is that the American Diabetes Association recommended analysis of FPG as the preferred test, whereas the WHO favored the OGTT. Despite being the gold standard for diagnosis of diabetes for many years, measurement of blood glucose is subject to several limitations. For example, bias among instruments can misclassify as many as 12% of patients (1). Diurnal variation and the large biological variation in FPG values further contribute to possible misclassification. In addition, preanalytical factors, particularly glycolysis in vitro, further limit the diagnostic value of FPG. Although the incorporation of Hb A1c into diabetes diagnosis is a marked change, it has been considered— and rejected—previously. Lack of assay standardization was the reason Hb A1c was not incorporated by the 1997 1 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. * Address correspondence to this author at: Brigham and Women’s Hospital, Department of Pathology, 75 Francis St., Thorn 530, Boston, MA 02115, USA. Fax 617-278-6921; e-mail [email protected]. Received June 23, 2009; accepted June 26, 2009. Previously published online at DOI: 10.1373/clinchem.2009.132704 2 Nonstandard abbreviations: Hb A1c, hemoglobin A1c; OGTT, oral glucose tolerance test; FPB, fasting plasma glucose. Clinical Chemistry 55:9 1612–1614 (2009) Perspectives