Hemoglobin A1c to diagnose diabetes: why the controversy over adding a new tool?

Perhaps diabetes is a bit like obscenity: We know it when we see obvious cases, but it is difficult to develop one definition that encompasses the entire spectrum of disease. Hyperglycemia exists on a continuum, and persons destined to develop type 2 diabetes progress along this continuum over time, from having blood glucose concentrations that are physiologic, to those in some intermediate but asymptomatic range, to glucose concentrations that are frankly increased and often associated with acute symptoms and chronic complications of the disease. But at what point does an individual have blood glucose concentrations, or other measures of glycemia, that cross the line from no diabetes to diabetes? Several decades ago, the National Diabetes Data Group (NDDG) developed consensus diagnostic criteria for diabetes that were based on population distributions of glucose concentrations (even though for most populations there is not a bimodal distribution for glucose clearly dividing diseased from nondiseased individuals) and based on the relative risk of decompensation to overt or symptomatic diabetes. These criteria, including a fasting plasma glucose (FPG) concentration of 140 mg/dL (7.8 mmol/L) or greater and a 2-h plasma glucose concentration during a 75-g oral glucose tolerance test (OGTT) of 200 mg/dL (11.1 mmol/L) or greater, became the worldwide standard for diagnosing diabetes. Even in 1979, however, the NDDG noted that “there is no clear division between [those with diabetes] and [those without diabetes] in the FPG concentration or their response to an oral glucose load” and acknowledged that the cutpoints chosen were arbitrary (1 ). In 1997, the Expert Committee on Diagnosis and Classification of Diabetes Mellitus was convened to revisit the criteria for diagnosing diabetes. This group examined population data for retinopathy in 3 distinct populations and noted that for FPG, 2-h postload glucose (PG), and hemoglobin A1c (Hb A1c), the relatively specific diabetes complication of retinopathy was absent at lower levels of the glycemic measures and that its prevalence increased linearly above a certain cutpoint. The group verified that the 2-h PG cutpoint of 200 mg/dL (11.1 mmol/L) appeared to be appropriate for determining the emergence of retinopathy but recognized that the NDDG FPG cutpoint of 140 mg/dL (7.8 mmol/L) was less sensitive— diagnosing far fewer people—than the 2-h PG cutpoint. The FPG cutpoint of 140 mg/dL (7.8 mmol/L) was also clearly above the point at which retinopathy prevalence was observed to increase. This group recommended 126 mg/dL (7.0 mmol/L) as the FPG cutpoint to diagnose diabetes, and this concentration subsequently became the worldwide FPG standard for a diagnosis of diabetes (2 ). Neither the 1997 expert committee nor a subsequent group in 2003 recommended the use of the Hb A1c test to diagnose diabetes, in part because of the lack of standardization and also because of a lack of consensus on the appropriate diagnostic cutpoint for identifying diabetes. In 2009, however, another international expert committee was convened, and it recommended that Hb A1c with a cutpoint of 6.5% or greater be used to diagnose diabetes (3). The American Diabetes Association, in its 2010 Clinical Practice Recommendations, added an Hb A1c cutpoint of 6.5% or greater to the glucose-based criteria as an option for diagnosing diabetes (4). Why the change to the inclusion of Hb A1c as appropriate for the diagnosis of diabetes? The expert committee of 2009 examined data on retinopathy prevalence and glycemic measures from 9 populations (including the 3 examined in 1997) and determined that an Hb A1c value of 6.5% appears to identify the cutpoint at which any retinopathy, or the even more specific moderate diabetic retinopathy, begins to occur at increasing frequency in populations (3). Hb A1c appears to be at least as good as FPG or 2-h PG for showing a cutpoint for retinopathy. The Hb A1c assay is now almost universally standardized and traceable to the Diabetes Control and Complications Trial assay in the US and many other countries, thanks to the work of the National Glycohemoglobin Standardization Program, the manufacturers, and the laboratories. Worldwide standardization efforts are moving forward with the development of a common standard. On the 1 American Diabetes Association, Alexandria, VA. * Address correspondence to this author at: American Diabetes Association, 1701 N. Beauregard St., Alexandria, VA 22311. Fax 703-253-4358; e-mail [email protected]. Received July 16, 2010; accepted August 16, 2010. Previously published online at DOI: 10.1373/clinchem.2010.148213 2 Nonstandard abbreviations: NDDG, National Diabetes Data Group; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; PG, postload glucose; Hb A1c, hemoglobin A1c; NHANES, National Health and Nutrition Examination Survey. Clinical Chemistry 57:2 255–257 (2011) Opinions