The Pros and Cons of Diagnosing Diabetes With A1C

ENZO BONORA PHD 1 JAAKKO TUOMILEHTO MA PHD 0 0 Department of Public Health, University of Helsinki , Helsinki , Finland; South Ostrobothnia Central Hospital , Seinajoki , Finland; and Red RECAVA Grupo RD06/0014/ 0015, Hospital Universitario La Paz , Madrid , Spain 1 Division of Endocrinology and Metabolism, Department of Medicine, University and University Hospital of Verona , Verona , Italy; and the - A was convened in 2008 by the Amern International Expert Committee ican Diabetes Association (ADA), the European Association for the Study of Diabetes, and the International Diabetes Federation to consider the means for diagnosing diabetes in nonpregnant individuals, with particular focus on the possibility to indicate A1C as an alternative if not a better tool (1). After reviewing the available literature and a thorough discussion on the advantages and the limits of previous diagnostic strategies (essentially based on fasting glucose assessment) and the considered alternative approach (based on A1C measurement), a consensus was reached that the latter (i.e., A1C) should be included among diagnostic tools for diabetes and, with the exception of a number of clinical conditions, should even be preferred in diabetes diagnosis in nonpregnant adults. The main conclusion of the International Expert Committee was implemented in the most recent clinical recommendations issued by the ADA. However, in these guidelines, A1C is indicated as a diagnostic tool alternative but not superior to blood glucose, leaving to the health care professional the decision about what test to use in an individual. The World Health Organization is currently examining the proposal made by the International Expert Committee and is carefully addressing the controversial issues still remaining, most of which have been the subject of letters to the editor and articles recently published in the literature. Nevertheless, the use of A1C for diagnosing diabetes is rapidly becoming a reality in many Western countries. In the text that follows, one of us (E.B.) will present the main points supporting A1C (pros) and the other (J.T.) will illustrate the main counterpoints challenging A1C (cons) as the primary tool for diabetes diagnosis. The text has been prepared in full coordination and the final conclusions represent the opinion of both authors. Tables 1 and 2 summarize the pros and cons. A1C captures chronic hyperglycemia better than two assessments of fasting or 2-h oral glucose tolerance test plasma glucose Diabetes has been diagnosed for decades with fasting plasma glucose (FPG) assessment or, much less frequently, with an oral glucose tolerance test (OGTT). Hyperglycemia as the biochemical hallmark of diabetes is unquestionable. However, fasting and 2-h OGTT gauge just a moment of a single day. In addition, the two assessments required to confirm diagnosis might be fallacious in describing a chronic and complex clinical condition. In this respect, there is no doubt that a c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c biochemical or clinical parameter describing the extent of a biological phenomenon over a long period provides a more robust indicator of glycemia than a parameter describing it in the short term or in a given moment only. Accordingly, there are some good examples in medicine: urinary albumin excretion rate provides more reliable information on the presence and the degree of microalbuminuria than spot urinary albumin-to-creatinine ratio; serum IGF-I is definitely more efficacious than serum growth hormone when monitoring patients with acromegaly, etc. Labeling a person with a diagnosis of diabetes has several psychological and legal implications and requires a robust and reliable approach. The measurement of A1C equals the assessment of hundreds (virtually thousands) of fasting glucose levels and also captures postprandial glucose peaks; therefore, it is a more robust and reliable measurement than FPG and/or 2-h OGTT plasma glucose. This is particularly valid when FPG oscillates above and below the cut point of 126 mg/dL or 2-h plasma glucose (PG) oscillates above and below the cut point of 200 mg/dL. Of note, the 2-h PG had poor reproducibility. From a clinical standpoint, having an FPG of 120 or 130 mg/dL or having a 2-h PG of 185 or 215 is virtually the same, but from the patients perspective (perception of having a disease, psychological well-being, health insurance, recognition of particular benefits, or imposition of certain limitations, etc.), it makes a substantial difference. Therefore, a diagnostic tool gauging chronic rather than spot hyperglycemia is certainly preferable. A1C is better associated with chronic complications than FPG Different from National Diabetes Data Group criteria, which were essentially based on distribution of glucose levels within the general population, the 1997 ADA criteria (and the subsequently recommended World Health Organization criteria) established diabetic glycemic levels by means of their association with retinopathy, the most exclusive and specific diabetes complication. Various observational studies documented that an increased prevalence of nonproliferative diabetic retinopathy can be observed with fasting glucose levels around 7.0 mmol/L (126 mg/dL) and 2-h PG around 11.1 mmol/L (200 mg/dL). Interestingly, the same studies documented that retinopathy increased with A1C levels around 6.5% (24). These results were confirmed in a more recent study including almost 30,000 subjects recruited in several countries. Such study clearly showed that prevalent retinopathy started to increase in the A1C category of 6.57.0% (5). Therefore, a cut point of A1C for diagnosing diabetes with an approach similar to the one used with FPG and 2-h PG is available (and indeed already was available in older studies). It is well known that cardiovascular disease (CVD) is the most frequent chronic complication of diabetes, with incidence rates 5- to 10-fold higher than with microvascular disease. For this reason, the association of A1C with CVD can be considered a major issue when discussing the potential use of A1C for diagnosing diabetes. In this regard, it is worth mentioning that, in the general population, FPG is a poor marker of future CVD events, whereas 2-h OGTT and A1C are good predictors (6,7). Fasting is not needed for A1C assessment and no acute perturbations (e.g., stress, diet, exercise) affect A1C Plasma glucose levels are not stable but rather vary throughout the day, mainly in postprandial periods. Although it is believed that fasting glucose levels are reproducible across days, a number of acute perturbations of glucose homeostasis have been described. Acute stress can increase endogenous glucose production substantially and impair glucose utilization. People who are worried about blood sampling or experience a stressful situation in the hours preceding blood sampling can have an increase i (...truncated)