Invited critical reviewThe long and winding road to optimal HbA1c measurement
Highlights
► HbA1c is an indicator of both mean glycemia and outcome risks in diabetes. ► Lack of HbA1c standardization made implementation of HbA1c targets difficult. ► The NGSP was established in 1996 to standardize HbA1c results. ► There has been continuous improvement in the quality of HbA1c results since 1993. ► HbA1c is an accurate measure of glycemia for most patients with diabetes.
Introduction
Diabetes mellitus is characterized by chronic hyperglycemia and is a major cause of retinopathy, nephropathy and neuropathy. The burden of diabetes is increasing globally, particularly in developing countries, with over 346 million people diagnosed worldwide [1]. Hemoglobin A1c (HbA1c) is an important measure of glycemic status that has become fundamental to managing patients with diabetes. HbA1c is being used not only to guide diabetes treatment but also to assess quality of care, and to predict risk for development and progression of diabetes complications. More recently, it has also been recommended for use in diagnosis.
There have been many advances in the treatment of diabetes, two of the most important being the development of portable blood glucose meters that can be used for self-monitoring of blood glucose by patients, and the establishment of HbA1c as an important long-term indicator of glycemia. These developments have allowed patients and their healthcare providers to better assess (and therefore better manage) glycemic status. Another important development has been the establishment of a definitive link between glycemia and the risks for diabetes complications. Until the early 1990s there was much debate over whether blood glucose levels in persons with diabetes could be maintained close to normal long-term, and whether doing so would actually prevent or delay the development of complications. However, the results of long-term prospective trials published in the 1990s provided irrefutable proof that diabetes complications are directly related to mean glycemia as measured by HbA1c [2], [3]. This in turn has led to recommendations that patients achieve specific HbA1c target levels in order to minimize risks for complications. However, the initial lack of HbA1c standardization made it difficult to utilize these targets in clinical practice due to substantial variability in results among methods and laboratories [4], [5], [6]. Fortunately, efforts to standardize HbA1c testing have been highly successful, resulting in much improvement in the comparability of results.
The purpose of this report is to review the “long and winding road” to better HbA1c measurements for optimal diabetes care. Along the way there have been “detours” that, while distracting from the end goal of improving the quality of HbA1c measurements, have nonetheless helped to better define the optimal use of HbA1c and set goals for improvement.
Section snippets
Background
In 1955 Kunkel and Wallenuis reported the separation of minor hemoglobin components on starch block electrophoresis [7]. Several investigators subsequently utilized ion-exchange chromatography to separate several minor hemoglobin components which were eventually labeled HbA1a, HbA1b, HbA1c, HbA1d and HbA1e in order of their elution from the column [8], [9], [10]. In 1968 Rahbar and colleagues reported that HbA1c levels were elevated in subjects with diabetes [11]. During the 1970s and early
HbA1c: a link to clinical outcomes in diabetes
Before 1993, HbA1c was used in a general way for estimating the level of glycemic control, e.g. lower HbA1c meant lower average glucose. Studies published in the late 1980s and early 1990s indicated a link between glycemic control and diabetes complications [20], [21], [22], [23], [24], and the European NIDDM Policy Group published a consensus document in 1988 that included targets for blood glucose control [25], but there were no explicit HbA1c target levels (due largely to an acknowledged
The NGSP reference method and standardization
It was recognized that the HbA1c results reported by the DCCT reference method were not “true” values since there was known to be some nonspecificity in the measurement. Nevertheless, expediency, consistency over time, and a direct relationship with clinical outcomes were considered to be most important. The long-term stability of this method is shown in Fig. 1.
Early efforts to standardize HbA1c/GHB results among clinical laboratories by using a “universal calibrator” proved feasible with some
The NGSP network and process
The NGSP HbA1c standardization program began in 1996 to implement the recommendations of the AACC subcommittee. The NGSP approach to HbA1c assay standardization was modeled after the US Cholesterol Reference Method Laboratory Network program [29]. The cholesterol program was based on performing split-sample comparisons with the cholesterol reference method and thus provided a means for manufacturers to establish traceability to the National Reference System for Cholesterol. For HbA1c
Global standardization and the IFCC network
In 1995 the IFCC Working Group on HbA1c Standardization, which included members of the NGSP Steering Committee, was initiated to develop a higher order reference method and reference materials for HbA1c measurement that would fulfill the requirements of the European Directive [32] for HbA1c methods to show traceability to higher order reference methods. Although the NGSP CPRL method is listed as a reference method in the database of the Joint Committee on Traceability in Laboratory Medicine [33]
Use of HbA1c for diagnosis
Historically, every scheme for the diagnosis of diabetes has relied on measurement of blood glucose in timed samples (i.e. fasting or after a glucose load). The use of HbA1c for diabetes diagnosis had been debated for many years [42]. In the past HbA1c was considered but not accepted for use in diagnosis due in part to lack of standardization. However, in 2009, an International Expert Committee recommended HbA1c for diagnosis [43], stating that compared with the measurement of glucose, the
The current status of HbA1c measurement
The NGSP uses data from the CAP HbA1c proficiency testing program to assess the success of standardization and the improvement in HbA1c measurement. Fig. 3 shows CAP data from HbA1c surveys in 1993, 1999, 2004 and 2012. It is clear that despite all of the obstacles on the way to better HbA1c measurement, there has been considerable progress made since 1993 when the DCCT ended. There has been a steady increase in the number of methods and laboratories that have been certified since the NGSP was
Point-of-care (POC) testing
An important issue in efforts to improve the quality of HbA1c testing is the status of point-of-care (POC) HbA1c methods. CAP survey data indicate that POC methods for HbA1c, as a group, do not necessarily perform worse than many laboratory-based HbA1c methods. However, POC methods are CLIA-waived, meaning that laboratories or physicians' offices that use these methods are not required to participate in CAP or other proficiency surveys and the vast majority choose not to do so. We therefore
Limitations of HbA1c testing
For the vast majority of patients with diabetes, HbA1c provides an excellent measure of glycemic control. Similarly, for most people HbA1c can be used for diagnosing diabetes. However, in certain situations HbA1c may be unreliable. These include any condition that alters erythrocyte life span (e.g. renal anemia with erythropoietin use, hemolytic anemia), severe iron-deficiency anemia, and recent blood transfusions; such conditions will affect HbA1c results regardless of assay methodology. In
Conclusions
The availability of more accurate and precise HbA1c methods facilitates better diabetes care. While the test does not substitute for day-to-day testing of blood glucose, it is a useful index of long-term glycemia in most patients with diabetes and offers an alternative to timed glucose testing for diagnosis of diabetes. HbA1c is also a powerful risk predictor. In 1968 when it was discovered that HbA1c was increased in people with diabetes, few could have envisioned that more than 40 years later,
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