The rol of A1c in diabetes diagnosis...

If chronic hyperglycemia sufficient to cause diabetes-specific complications is the hallmark of diabetes, common sense would dictate that laboratory measures that capture long-term glycemic exposure should provide a better marker for the presence and severity of the disease than single measures of glucose concentration. Observational studies that have assessed glycemia with measures that capture longer-term exposure (i.e., A1C) or with single or longitudinal measurements of glucose levels have consistently demonstrated a strong correlation between retinopathy and A1C[24-26] but a less consistent relationship with fasting glucose levels.[27] In one study that measured both FPG and A1C, there was a stronger correlation between A1C and retinopathy than between fasting glucose levels and retinopathy.[25] The correlation between A1C levels and complications has also been shown in the setting of controlled clinical trials in type 1[28] and type 2[29] diabetes, and these findings have been used to establish the widely accepted A1C treatment goals for diabetes care.[30] All of these observations suggest that a reliable measure of chronic glycemic levels such as A1C, which captures the degree of glucose exposure over time[31,32] and which is related more intimately to the risk of complications than single or episodic measures of glucose levels, may serve as a better biochemical marker of diabetes and should be considered a diagnostic tool. Although the 1997 expert committee report considered this option, it recommended against using A1C values for diagnosis in part because of the lack of assay standardization.[17] The 2003 follow-up report noted that, while the National Glycohemoglobin Standardization Program [33] had succeeded in standardizing the vast majority of assays used in the U.S., the use of A1C for diagnosis still had "disadvantages," and it reaffirmed the previous recommendation that A1C not be used to diagnose diabetes.[21] An updated examination of the laboratory measurements of glucose and A1C by the current International Expert Committee indicates that with advances in instrumentation and standardization, the accuracy and precision of A1C assays at least match those of glucose assays. The measurement of glucose itself is less accurate and precise than most clinicians realize.[34] A recent analysis of the performance of a variety of clinical laboratory instruments and methods that measure glucose revealed that 41% of instruments have a significant bias from the reference method that would result in potential misclassification of >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 <2% for A1C but 12-15% for FPG.[45-47] The convenience for the patient and ease of sample collection for A1C testing (which can be obtained at any time, requires no patient preparation, and is relatively stable at room temperature) compared with that of FPG testing (which requires a timed sample after at least an 8-h fast and which is unstable at room temperature) support using the A1C assay to diagnose diabetes.In summary, compared with the measurement of glucose, the A1C assay is at least as good at defining the level of hyperglycemia at which retinopathy prevalence increases; has appreciably superior technical attributes, including less preanalytic instability and less biologic variability; and is more clinically convenient. A1C is a more stable biological index than FPG, as would be expected with a measure of chronic glycemia levels compared with glucose concentrations that are known to fluctuate within and between days