Gary Myers, PhD began the session with a discussion of why we measure A1C. A1C is an average measure of chronic glycemia, and it is useful to predict diabetic complications. The ADA established the goal of <7%. In 1993, a survey from the College of American Pathology demonstrated that only 50% were reporting hemoglobin A1C. Additionally, there was a fair amount of variation both across and within laboratories. The use of method-specific calibration can be used to improve the measurement of A1C. The National Glycohemoglobin Standardization Program (NGSP) aimed to standardize A1C and make the results comparable to the DCCT, which demonstrated that elevated A1C increased the risk of diabetic complications. A central primary reference laboratory was developed that used the methodology used during the DCCT. Manufacturers have to go through a calibration process comparing their values to the NGSP anchor, then they must undergo a certification process. Labs using these programs undergo proficiency testing to determine how well the calibration is being implemented in the lab and how well that improves measurement of A1C. By 2006, a majority of labs were reporting hemoglobin A1C and are NGSP certified.
In addition NGSP in US, both Japan and Sweden both have standardization programs. In 1994, the International Federation of Clinical Chemistry (IFCC) established a working group to move toward global harmonization of A1C using a method that is metrologically traceable. In other words, A1C should have units that trace back to the SI units and should establish a hierarchy of analytical measure procedures, known as the traceability chain. In the European Union, traceability is an essential requirement placed on in vitro diagnostic medical devices. The global standardization aimed to define A1C based on its molecular structure, prepare a pure primary standard, and to develop a reference method of higher order. They also established a reference lab network so that manufacturers can determine how reliable their methods are. It is important note that the IFCC is a reference method and not intended for use in routine clinical practice.
The IFCC is accuracy based, and NGSP method is public health based, and they do not compare well. However, there is a reproducible relationship between the 2 and the other 2 standardization programs from Japan and Sweden. In terms of the impact of the IFCC reference method, it may affect how A1C results should be reported. The question that was asked was whether or not we change numbers that are related to patient care needs as we move toward methodologically true values that require new units and a new analyte name. The IFCC reference method a more stable analytical anchor that meets the European IVD directive. Whether or not the IFCC reference method will improve A1C measurement and patient care remains to be seen.
The impact of the IFCC reference method from the laboratory medicine perspective was discussed by Mitchell Scott, PhD. He began by stating that laboratory data leverages 60%-70& of all medical decisions and impacts numerous settings, including academia, clinical practice, and industry. The goal of the laboratory scientist is to assure timely, accurate, and reproducible results for clinical practice. They understand the technology and also the limitations for tests, and they consult on the selection and interpretation of those tests.
Because changing the units of A1C would greatly affect clinical practice, a compromised was reached. It has been recommended that A1C get reported at 3 values: the traditional percentage based on the NGSP, the IFCC value in mmol/mol, and A1C-derived average glucose values. There are several barriers to reporting mean blood glucose values, including 20 years of education and understanding of A1C. However, reporting average glucose may be helpful to patients because it gives them something they can relate to. It emphasizes that they have a glucose problem, not a hemoglobin problem.
Feedback on this topic was solicited from project managers, and feedback from 6 companies was obtained. They unanimously indicated that changing the name or the units of the A1C test would not be in the best interest. Anchoring to IFCC can be accomplished, but it should be reported as percent A1C based on the NGSP standard. Additionally, they felt that instruments should not report average glucose. Instead, average glucose might best be provided as additional information by the lab. Some people felt that too many results may result in confusion and that average glucose is an oversimplification that may not be traceable. Dr Scott stressed that mean glucose values would just be a linear transformation and would be traceable if they are anchored to the IFCC reference values. Dr Scott concluded with his prediction that A1C will continue for some time and that average glucose will also be reported.
David M Nathan, MD delivered the presentation on clinical impact on behalf of Robert J Heine, MD, PhD, who could not attend the meeting. He stated that different measures of glycemia are useful in different setting. A1C is used to assess chronic glycemia, and self monitoring is necessary to prevent acute complications and also to guide therapeutic adjustment. If the standard for A1C was to be changed, there is some evidence to suggest that quality of care will deteriorate. A study of A1C values was conducted in Sweden before a change in A1C reference values, after the change, and then again when the values were reverted to their original. Actual A1C values changed in such a way that suggested people were aiming a the number they were used to and did not account for the change in reference value, a term Dr Heine labeled as A1C illusion. If the reference values were to be dropped by several percentage points, patients will still be aiming for the old values and actual control will deteriorate. Accordingly, the decision was made that A1C will be in %, and it will reported based on the values standardized to the DCCT. Average glucose should be included so both acute and chronic hyperglycemia can be reported on the same unit.
Dr Nathan next reported on the relationship between A1C and average blood glucose. Prior to the development of the A1C test, there was no measure of chronic glycemia. Currently, a standardized measure of chronic glycemia is available and is important to drive treatment decisions. If the treatment goals are based on the IFCC values, there may be panic in the streets.
Because of the previously mentioned benefits of present average blood glucose, the issue of converting a standardized A1C into a mean blood glucose value is being explored. Many studies on this topic in the past have suffered from infrequent glucose monitoring. The DCCT had many subjects, but had infrequent testing. That study collected 7-point glucose profiles once every 3 months. More recent studies have collected between 200 and 300 measurements. The international A1C Derived Average Glucose Evaluation (ADAGE) Study is using a diverse international population determine if we can accurately calculate average glucose from A1C. The study population includes patients with both type 1 and type 2 diabetes, and includes a wide distribution of A1C. Participants collect CGMS for at least 2 days over every month, and frequent self monitoring when not doing CGMS. The study has been going on for over a year. Data for 254 patients (35%) from 9 of 10 centers who have completed study as of June 1 were presented. A total of 2700 measurements per person were collected and used to calculate average glucose values. Although the data are not final, they demonstrated that there is a sufficiently tight correlation to translate A1C into average glucose. This approach has the benefit of providing patients with a measure of chronic glycemia that is reported using the same units as self-monitored blood glucose, which offers the potential to make management better. |
