An International Expert Committee with members appointed by the American Diabetes Association, the European Association for the Study of Diabetes, and the International Diabetes Federation was convened in 2008 to consider the current and future means of diagnosing diabetes in nonpregnant individuals. The report of the International Expert Committee represents the consensus view of its members and not necessarily the view of the organizations that appointed them. The International Expert Committee hopes that its report will serve as a stimulus to the international community and professional organizations to consider the use of the A1C assay for the diagnosis of diabetes. Diabetes is a disease characterized by abnormal metabolism, most notably hyperglycemia, and an associated heightened risk for relatively specific long-term complications affecting the eyes, kidney, and nervous system. Although diabetes also substantially increases the risk for cardiovascular disease, cardiovascular disease is not specific to diabetes and the risk for cardiovascular disease has not been incorporated into previous definitions or classifications of diabetes or of subdiabetic hyperglycemia. Background Diagnosing diabetes based on the distribution of glucose levels Historically, the measurement of glucose has been the means of diagnosing diabetes. Type 1 diabetes has a sufficiently characteristic clinical onset, with relatively acute, extreme elevations in glucose concentrations accompanied by symptoms, such that specific blood glucose cut points are not required for diagnosis in most clinical settings. On the other hand, type 2 diabetes has a more gradual onset, with slowly rising glucose levels over time, and its diagnosis has required specified glucose values to distinguish pathologic glucose concentrations from the distribution of glucose concentrations in the nondiabetic population. Virtually every scheme for the classification and diagnosis of diabetes in modern times has relied on the measurement of plasma (or blood or serum) glucose concentrations in timed samples, such as fasting glucose; in casual samples independent of prandial status; or after a standardized metabolic stress test, such as the 75-g oral glucose tolerance test (OGTT). Early attempts to standardize the definition of diabetes relied on the OGTT, but the performance and interpretation of the test were inconsistent and the number of subjects studied to define abnormal values was very small (1 –6). Studies in the high-risk Pima Indian population that demonstrated a bimodal distribution of glucose levels following the OGTT (7,8) helped establish the 2-h value as the diagnostic value of choice, even though most populations had a unimodal distribution of glucose levels (9). Of note, a bimodal distribution was also seen in the fasting glucose samples in the Pimas and other high-risk populations (10,11). However, a discrete fasting plasma glucose (FPG) or 2-h plasma glucose (2HPG) level that separated the bimodal distributions in the Pimas was difficult to identify, with potential FPG and 2HPG cut points ranging from 120 to 160 mg/dl (6.7–8.9 mmol/l) and from 200 to 250 mg/dl (11.1–13.9 mmol/l), respectively. In 1979, the National Diabetes Data Group (NDDG) provided the diagnostic criteria that would serve as the blueprint for nearly two decades (12). The NDDG relied on distributions of glucose levels, rather than on the relationship of glucose levels with complications, to diagnose diabetes despite emerging evidence that the microvascular complications of diabetes were associated with a higher range of fasting and OGTT glucose values (11,13 –15). The diagnostic glucose values chosen were based on their association with decompensation to “overt” or symptomatic diabetes. When selecting the threshold glucose values, the NDDG acknowledged that “there is no clear division between diabetics and nondiabetics in the FPG concentration or their response to an oral glucose load,” and consequently, “an arbitrary decision has been made as to what level justifies the diagnosis of diabetes.” The diagnosis of diabetes was made when 1) classic symptoms were present; 2) the venous FPG was ≥140 mg/dl (≥7.8 mmol/l); or 3) after a 75-g glucose load, the venous 2HPG and levels from an earlier sample before 2 h were ≥200 mg/dl (≥11.1 mmol/l). An intermediate group was classified as having “impaired glucose tolerance” (IGT) with FPG 12% of patients (35). There are also potential preanalytic errors owing to sample handling and the well-recognized lability of glucose in the collection tube at room temperature (36,37). Even when whole blood samples are collected in sodium fluoride to inhibit in vitro glycolysis, storage at room temperature for as little as 1 to 4 h before analysis may result in decreases in glucose levels by 3–10 mg/dl in nondiabetic individuals (36 –39). By contrast, A1C values are relatively stable after collection (40), and the recent introduction of a new reference method to calibrate all A1C assay instruments should further improve A1C assay standardization in most of the world (41 –43). In addition, between- and within-subject coefficients of variation have been shown to be substantially lower for A1C than for glucose measurements (44). The variability of A1C values is also considerably less than that of FPG levels, with day-to-day within-person variance of 20,000 subjects who had A1C values 200 mg/dl (11.1 mmol/l) despite a nondiagnostic A1C level. Notwithstanding the above limitations of A1C testing, the assay has numerous important advantages compared with the currently used laboratory measurements of glucose (Table 1). The prevalence of diabetes in some populations may not be the same when diagnosis is based on A1C compared with diagnosis with glucose measurements, and one method may identify different individuals than the other. Because the measurements of glucose levels and A1C reflect different aspects of glucose metabolism, this is to be expected. However, establishing identical prevalences should not be the goal in defining a new means of diagnosing diabetes. The ultimate goal is to identify individuals at risk for diabetes complications so that they can be treated. The A1C diagnostic level of 6.5% accomplishes this goal. Can A1C measurements define a specific subdiabetic “high-risk” state? The 2003 International Expert Committee report reduced the lower bound of IFG from 110 mg/dl (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l) on the grounds that the lower level optimized the sensitivity and specificity for predicting future diabetes and also increased the proportion of those with IGT who could be identified with an FPG test (21). While previous studies have shown a powerful effect of IFG and/or IGT on the subsequent development of diabetes diagnosed with glucose values (52 –54), recent reports have demonstrated a graded risk of diabetes development at glycemic levels well within what was previously considered “normal,” i.e., FPG 200 mg/dl (>11.1 mmol/l). Confirmatory testing is also not required to establish risk status in individuals identified as in the highest-risk group for diabetes (A1C of 6.0 to 200 mg/dl. If diabetes is suspected in the absence of those conditions, A1C testing is warranted. Recommendations and conclusions Based on the above discussion, the International Expert Committee has concluded that the best current evidence supports the following recommendations, summarized in Table 2. Table 2 Recommendation of the International Expert Committee For the diagnosis of diabetes: The A1C assay is an accurate, precise measure of chronic glycemic levels and correlates well with the risk of diabetes complications. The A1C assay has several advantages over laboratory measures of glucose. Diabetes should be diagnosed when A1C is ≥6.5%. Diagnosis should be confirmed with a repeat A1C test. Confirmation is not required in symptomatic subjects with plasma glucose levels >200 mg/dl (>11.1 mmol/l). If A1C testing is not possible, previously recommended diagnostic methods (e.g., FPG or 2HPG, with confirmation) are acceptable. A1C testing is indicated in children in whom diabetes is suspected but the classic symptoms and a casual plasma glucose >200 mg/dl (>11.1 mmol/l) are not found. For the identification of those at high risk for diabetes: The risk for diabetes based on levels of glycemia is a continuum; therefore, there is no lower glycemic threshold at which risk clearly begins. The categorical clinical states pre-diabetes, IFG, and IGT fail to capture the continuum of risk and will be phased out of use as A1C measurements replace glucose measurements. As for the diagnosis of diabetes, the A1C assay has several advantages over laboratory measures of glucose in identifying individuals at high risk for developing diabetes. Those with A1C levels below the threshold for diabetes but ≥6.0% should receive demonstrably effective preventive interventions. Those with A1C below this range may still be at risk and, depending on the presence of other diabetes risk factors, may also benefit from prevention efforts. The A1C level at which population-based prevention services begin should be based on the nature of the intervention, the resources available, and the size of the affected population. For the diagnosis of diabetes There is no single assay related to hyperglycemia that can be considered the gold standard, as it relates to the risk for microvascular or macrovascular complications. A measure that captures chronic glucose exposure is more likely to be informative regarding the presence of diabetes than is a single measure of glucose. The A1C assay provides a reliable measure of chronic glycemia and correlates well with the risk of long-term diabetes complications. The A1C assay (standardized and aligned with the Diabetes Control and Complications Trial/UK Prospective Diabetes Study assay) has several technical, including preanalytic and analytic, advantages over the currently used laboratory measurements of glucose. For the reasons above, the A1C assay may be a better means of diagnosing diabetes than measures of glucose levels. The diagnosis of diabetes is made if the A1C level is ≥6.5%. Diagnosis should be confirmed with a repeat A1C test unless clinical symptoms and glucose levels >200 mg/dl (>11.1 mmol/l) are present. If A1C testing is not possible owing to patient factors that preclude its interpretation (e.g., hemoglobinopathy or abnormal erythrocyte turnover) or to unavailability of the assay, previously recommended diagnostic measures (e.g., FPG and 2HPG) and criteria should be used. Mixing different methods to diagnose diabetes should be avoided. In children and adolescents, A1C testing is indicated when diabetes is suspected in the absence of the classical symptoms or a plasma glucose concentration >200 mg/dl (>11.1 mmol/l). The diagnosis of diabetes during pregnancy, when changes in red cell turnover make the A1C assay problematic, will continue to require glucose measurements. For the identification of individuals at high risk for diabetes Individuals with an A1C level ≥6% but <6.5% are likely at the highest risk for progression to diabetes, but this range should not be considered an absolute threshold at which preventative measures are initiated. The classification of subdiabetic hyperglycemia as pre-diabetes is problematic because it suggests that all individuals so classified will develop diabetes and that individuals who do not meet these glycemia-driven criteria (regardless of other risk factor values) are unlikely to develop diabetes—neither of which is the case. Moreover, the categorical classification of individuals as high risk (e.g., IFG or IGT) or low risk, based on any measure of glycemia, is less than ideal because the risk for progression to diabetes appears to be a continuum. The glucose-related terms describing subdiabetic hyperglycemia will be phased out of use as clinical diagnostic states as A1C measurements replace glucose measurements for the diagnosis of diabetes. When assessing risk, implementing prevention strategies, or initiating a population-based prevention program, other diabetes risk factors should be taken into account. In addition, the A1C level at which to begin preventative measures should reflect the resources available, the size of the population affected, and the anticipated degree of success of the intervention. Further analyses of cost-benefit should guide the selection of high-risk groups targeted for intervention within specific populations. Supplementary Material Accompanying Editorial
