Clinical Laboratory Strategies: September 13, 2007

Coming to a Consensus on HbA1c Measurement
Diabetes Associations, IFCC Release Statement on Worldwide Standardization
By Julie McDowell

Years of negotiation have resulted in an international consensus statement on worldwide hemoglobin A1c (HbA1c) measurement recently released by leading medical associations—including the American Diabetes Association (ADA) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). The statement comes only weeks before the Annual Meeting of the European Association for the Study of Diabetes (EASD), where researchers are expected to present final results from an international study analyzing the relationship between average glucose and HbA1c levels. This issue of Strategies examines the potential impact of both these recent developments, which are likely to lead to changes in the clinical management of the nearly 21 million diabetes patients in the U.S.

For over 20 years, measuring HbA1c has been the gold-standard assay to monitor glycemia and guide treatment decisions for diabetes patients, even though there is not significant data to support the relationship between HbA1c and average blood glucose. As a result, some in the diabetes community have questioned whether the results of the HbA1c assay actually reflect average glycemia over the preceding few months.

Another problem with HbA1c testing is that there are no international standards for reporting results. In the U.S., most labs have been reporting these values as “percent HbA1c” or “percent HbA1c equivalent”, in accordance with the National Glycohemoglobin Standardization Program (NGSP)’s standardization efforts launched in 1996. But there are no standard reporting conventions among the U.S. and other countries that have a different basis for standardization. “Since reporting A1c has always been unstandardized on an international level, patients can go from one country to another, visit different doctors and get their A1c measured, and get conflicting information,” said Larry C. Deeb, MD, ADA’s President, Medicine and Science, and a pediatric endocrinologist based in Tallahassee, Fla.

To confront the problems associated with the lack of international standardization, the IFCC has been pursuing a new reference method for HbA1c, but has often been at odds with clinical societies, such as the ADA. “There were some initial concerns that the IFCC was moving in a direction that was counter to the clinicians view of things, and AACC felt that we needed to support our clinical partners,” said AACC President Gary Myers, PhD, FACB. For example, a previous proposal by the IFCC called for a reference method with new nomenclature and units. While the IFCC members introduced an equation linking this reference method with NGSP results [NGSP-HbA1c = 0.915 (IFCC-HbA1c) + 2.15%], many American clinicians and clinical chemists feared the equation would be disruptive if used in routine testing.

This past spring, however, a compromise was reached among the IFCC, ADA, the EASD, and the International Diabetes Federation, and a consensus statement was published this month in Diabetes Care (2007;30:2399–2400). Based on the IFCC’s previous reference method, the statement is rooted in five key elements:

  • A1c test results should be standardized worldwide, including the reference system and results reporting.
  • The new IFCC reference system for A1c represents the only valid anchor to implement standardization of the measurement.
  • A1c results are to be reported worldwide in IFCC units (mmol/mol) and derived NGSP units (%), using the IFCC-NGSP master equation.
  • If the ongoing “average plasma glucose study” fulfills its specified criteria, an A1c-derived average glucose (ADAG) value calculated from the A1c result will also be reported as an interpretation of the A1c results.
  • Glycemic goals appearing in clinical guidelines should be expressed in IFCC units and derived NGSP units and as ADAG.

Ideally, clinicians and laboratorians should have one name and one unit to describe HbA1c measurement that would be used globally, said Myers, who is also Chief of the Centers for Disease Control and Prevention’s Clinical Chemistry Branch, Division of Laboratory Sciences, National Center for Environmental Health. “But it doesn’t appear that is going to happen, so I think that this consensus statement is a very reasonable convention and compromise on everybody’s part,” he added. “As a new accuracy point, this consensus allows us to use the IFCC reference method as an accuracy base for the different systems that are used around the world. While these systems are different, they are now anchored to this IFCC reference method. So from that standpoint, it’s a good thing, because we now have a common point that all of them can relate back to, as well as a well-documented equation for each of these systems where you can transfer results from the IFCC convention to the NGSP convention and so forth.”

The ADA’s Deeb believes that this consensus statement will translate into better disease management—both by clinicians and patients themselves. “I think some patients don’t have as good of diabetes control as they think because of the current way these HbA1c numbers are communicated—they don’t make a lot of sense,” he explained. “I think we’ve come up with a consensus statement that is clinically accurate and scientifically correct.”

Awaiting International Study Results

In addition to these changes in HbA1c reporting, laboratory medicine leaders are awaiting final results of an ADA-sponsored trial defining the relationship between average glucose levels and A1c. Investigators hope that by comparing these two measures, they can design an equation where A1c levels can be interpreted accurately as an average glucose level. Preliminary results of this study were presented at the ADA’s 67th Annual Scientific Sessions in June, and final results are expected at the EASD’s Annual Meeting held on Sept. 17–21 in Amsterdam, The Netherlands.

The results of this study will likely determine if reporting will go according to the preference of most clinicians—which is average blood glucose, said Myers. “It will be easier for clinicians and patients to understand this value because patients are already measuring their glucose on a regular basis,” he explained. “By going with glucose and mean blood glucose values, the diabetes societies feel that this will be an easier thing for the clinicians and patients to understand.” This might make reporting harder for labs, however, because they would need to know which of the three conventions—HbA1c as a percent, in IFCC units (mmol/mol), and mean blood glucose—to report based on their region or country. “If this international study proves successful, the ADA would opt to use mean blood glucose in the U.S.,” said Myers. “If not, then I’m sure they would recommend sticking with the HbA1c as a percent.”

As the international medical community awaits the results of this study, Myers believes there is an important role for AACC. “But I think there are going to be opportunities for AACC to help educate its members on the do’s and don’ts of implementing these changes. I think AACC will also need to work with clinical societies to help them interpret what the recommendations mean—from the standpoint of not just the clinicians but also of the laboratorians,” he explained. “Right now, we are in a waiting period, until the results of the international study on mean blood glucose and its relation to A1c has been evaluated, the results published, and a decision made as far as what we do in the U.S.

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