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HbA1c refers to a minor population of HbA that has been modified by attachment of glucose to the terminal amino acid of the beta globin chain. The rate of formation of HbA1c is directly proportional to the plasma glucose concentration. Since erythrocytes are freely permeable to glucose, HbA1c levels provide a glycemic history during the average erythrocyte lifespan, which is approximately 120 days. There is broad consensus that HbA1c levels should be used for routine care of all patients with diabetes mellitus. HbA1c levels can be used not only to assess long-term glycemia, but also to predict risk of developing chronic complications. Baseline HbA1c levels are strongly related to the incidence and/or progression of retinopathy, gross proteinuria, and loss of tactile sensation or temperature sensitivity. The Diabetes Control and Complications Trial (DCCT), which was completed in 1993, demonstrated that the risks for development and progression of the chronic complications of type 1 diabetes are closely related to the degree of glycemic control, as measured by serial glycohemoglobin determinations. The U.K. Prospective Diabetes Study (UKPDS), which was completed in 1998, showed similar results in patients with type 2 diabetes. Based on these studies, the American Diabetes Association (ADA) now recommends the following goals for glycemic control in patients with IDDM and NIDDM. [Diabetes Care 1996; 19 (suppl 1): S8-14]). American Diabetes Association Goals
Optimal frequency of HbA1c testing has not been well established. Currently, it is recommended that testing be performed during initial patient assessment and at least quarterly thereafter in patients with insulin dependent diabetes mellitus (IDDM) and as frequently as necessary to assess achievement of glycemic goals in non-insulin treated patients. Monthly HbA1c levels have been recommended for pregnant women with diabetes, but little scientific data is available to support this recommendation. The laboratory frequently receives questions about the relationship between HbA1c and plasma glucose levels. HbA1c is a weighted average of blood glucose levels during the preceding 4 months, which is the average life span of red blood cells. A large change in mean blood glucose can increase HbA1c levels within 1-2 weeks. Sudden changes in HbA1c occur because recent changes in blood glucose levels contribute relatively more to the final HbA1c levels than earlier events. For instance, mean blood glucose levels in the 30 days immediately preceding blood sampling contribute 50% to the HbA1c level, whereas glucose levels in the preceding 90-120 day period contribute only 10%. Thus, it does not take 120 days to detect a clinically meaningful change in HbA1c following a significant change in mean plasma glucose level. The Diabetes Control and Complications Trial (DCCT) has published data relating HbA1c to plasma glucose levels (Diabetes Care 2002; 25:275-78). Mean glucose levels were calculated from 7 point capillary glucose measurements made at home before meals, 90 minutes after meals and at bedtime. Glucose meters were calibrated to measure plasma rather than whole blood glucose. The following table summarizes the relationship.
Results showed a linear relationship between HbA1c and mean plasma glucose [MPG = ( 35.6 x HbA1c ) - 77] with a Pearson correlation coefficient (r) of 0.82. Each 1% change in HbA1c represents a change of approximately 35 mg/dl in plasma glucose. It is important to realize that this data is based on overall averages and may vary slightly in individual patients. Further analysis of this data demonstrated that among single time point measurements, post-lunch and bedtime plasma glucose levels showed relationships to HbA1c that were most similar to the full 7 point glucose profile. Fasting glucose levels correlated less well and underestimated HbA1c at higher HbA1c concentrations. Fasting plasma glucose levels should be used cautiously as a surrogate measure of mean plasma glucose. Understanding the relationship between HbA1c and mean plasma glucose concentration is helpful in setting day to day plasma glucose targets for patients based on the HbA1c goals set by the American Diabetes Association. Unless a patient's plasma glucose levels are very stable month after month, quarterly HbA1c measurements are needed to insure that a patient's glycemic control remains within the target range. Results generated in different laboratories using the same method may differ by as much as 20%, while results generated by different methods may vary by 40%. If individual patients have HbA1c results performed in more than one laboratory, the results should not be compared or trended. Results are expressed as the percent of total hemoglobin. Reference range is 4.4 - 6.0%. Specimen requirement is one lavender top (EDTA) tube of blood. HbA1c for Diagnosis of Diabetes The clinical use of HbA1c levels has been largely restricted to monitoring diabetic patients. A recent meta analysis of 18 investigations involving 11,276 patients suggested that HbA1c levels are also useful in the initial diagnosis of diabetes [JAMA 1996; 276:1246-52]. This study recommended substituting HbA1c for oral glucose tolerance tests in patients with intermediate fasting plasma glucose levels falling between 115 and 140 mg/dL. The authors stated that HbA1c is more reproducible, informative, and convenient. In this setting, HbA1c levels of 7% or greater were indicative of diabetes. Hemoglobin A1c as a CV Risk Factor in Nondiabetic Individuals Macrovascular disease is the most important cause of mortality and morbidity in individuals with type 2 diabetes. Even when adjusted for conventional risk factors, diabetic individuals still exhibit a two to four fold increased risk of cardiovascular disease in comparison to nondiabetic people. Therefore, hyperglycemia is strongly suspected of promoting atherogenesis. Excess glucose is transformed into advanced glycation endproducts (AGEs) that not only make blood vessels inelastic and stenotic but also activates chronic inflammation. Hemoglobin A1c concentration is an indicator of average blood glucose concentration over the previous three months and is the most widely used test to monitor diabetes. Recent studies have demonstrated that HbA1c is also a predictor of all-cause, cardiovascular and ischemic heart disease mortality even at concentrations below the accepted threshold for diabetes (British Med J 2001; 322:15-18). The following table lists the relative risk of death for each quartile of HbA1c concentration. HbA1c Concentration
Individuals with HbA1c concentrations above 5% had greater risk than individuals with concentrations below 5%. Approximately 25% of population had HbA1c levels below 5% and 70% of the population had levels between 5 and 6.9%. HbA1c appears to resemble blood pressure and cholesterol in terms of its continuous relationship with cardiovascular risk. Two recent studies in the Annals of Internal Medicine have also validated that HbA1c is a progressive risk factor for CV disease in individuals with and without diabetes (Ann Intern Med 2004; 141:413-20 & 421-31). Every 1% absolute increase in HbA1c above the nonglycemic level of 5% predicts a 20% relative increase in the incidence of CV events even after adjustment for systolic blood pressure, cholesterol level, body mass index, waist to hip ratio, smoking and previous myocardial infarction or stroke. A similar relationship exists for total mortality. |
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