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For more than 20 years, the gold standard measurement of chronic glycemia has been the glycated hemoglobin (A1C) assay. Anchored in the knowledge that elevated A1C values increase the likelihood of microvascular—and possibly macrovascular—complications of diabetes, clinicians regularly use A1C test results to guide treatment decisions. Although the assay has become the cornerstone measurement of quality diabetes care, the progress we've made didn't occur overnight.
It took many years for clinicians and patients to appreciate why the term "glycated hemoglobin" or "hemoglobin A1C" and its units—4–12+%—would be relevant to diabetes, in contrast to the direct measure of blood glucose in mg/dl used in the diagnosis and daily management of the disease. Even patients who regularly receive A1C test results are confused as to the relevance of the A1C name and units. Furthermore, few people understand the underlying biology of the assay. But now that the clinical world is comfortable with the A1C test, everything appears likely to change—and relatively quickly.
TEST MEASURES MORE THAN ONE MOLECULE
What's generally unappreciated about the A1C assay is that the test not only measures the glucose attached to one molecule (HbA1C), but the results also pick up other components with uncertain identity. Although the assay is standardized on a reference method that takes into account this mixture of molecules, laboratory chemists always prefer to measure a single analyte and use a reference method that measures the same analyte.
Accordingly, the International Federation of Clinical Chemistry (IFCC), the organization that establishes global clinical chemistry standards and procedures, several years ago developed a reference method that precisely measures the concentration of A1C.1,2 The new reference method has also been compared with the results obtained by the current reference methodology, and a numeric link between the assays can be expressed by a simple regression equation.3 In fact, results using the new and old methods correlate closely.
An important fact, however, in comparing the two standardization schemes is
that the new IFCC reference numbers are significantly lower
(
1.3–1.9%) than current values—an observation that should not
be surprising given that the new reference method measures only A1C.
Based on these findings, discussions have centered around how to introduce the new standardized reference method. IFCC leadership recommended that, with the introduction of the new reference method, all test results reported to clinicians also should reflect this change (which would result in lower values because the reference method is quantifying pure A1C), even though the actual assays used in laboratories still will be measuring a mixture of A1C and unidentified molecules. IFCC also recommended that the assay name should reflect what is measured in the reference method (in this case, N-[1deoxylfructos-1-yl]) hemoglobin beta chain, abbreviated as DOF hemoglobin. Finally, in keeping with the measurement of other analytes, the units should be notated in scientifically correct values, in this case mmol/mol hemoglobin.
The net effect of their recommendations is that an A1C of 5% would now be about 33 mmol/mol, and an 8% A1C would be about 58 mmol/mol. In other words, clinicians would have a new name and all new numbers to learn and teach.
When the clinical endocrinology world learned of these impending changes we formed an international working group to contact the IFCC and voice our concerns. This resulted in a meeting of representatives from the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), and International Diabetes Federation (IDF), along with IFCC representatives, to discuss how best to go forward.
The compromise worked out in a July 2003 meeting consisted of three actions. First, an international study would commence to document that the A1C assay actually does reflect an average blood glucose over many months. Although the clinical world has always thought that to be true, the belief is based on limited data. Second, if the hypothesis can be supported, the assay name would change to mean or average blood glucose and the units would be in mg/dl (or mmol/l). Third, laboratories could opt to report the results using the metrologically correct term and units—DOF hemoglobin in mmol/mol, reflecting the reference method—but the IFCC proposed terminology and units would not be used clinically.
This agreement has many attributes, among them that we at last would be confident that glycated hemoglobin levels, long linked with a likelihood of complications, truly reflect chronic glycemia. If so, patients and clinicians could use a more relevant term for the problem at hand. Clinicians might say, "Here is your average blood glucose reading," and the units used would be identical to those obtained via self-monitoring. Also, the units (mg/dl) would be larger numbers than current A1C percentages, and a message like, "You need to reduce your average from 180 to <150," is likely to be taken more seriously than if one is told "Your A1C is 8% and it should be less than 7%." Low numbers seem to have less of an impact than higher numbers.4 In keeping with IFCC's interests, recognition of the new reference method would occur.
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INTERNATIONAL STUDY RESULTS WILL BE CRITICAL
So where do we stand? First, the international study is proceeding as
scheduled. Nearly 600 people have been recruited, representing a variety of
ethnic and racial groups, people without diabetes and those with type 1 and 2
diabetes, and encompassing a range of A1C values, 5–12%.
The study is taking place at 11 sites in six countries. Briefly, A1C is being measured monthly for 4 months, along with periodic continuous glucose monitoring and multiple daily finger-sticks. We will compare the sum of the glucose measurements with the A1C values and determine if a mathematical relationship exists between A1C and the average blood glucose. A preliminary analysis of the data supports this assumption, and a forthcoming independently conducted study also indicates that there is a close mathematical relationship.
Assuming the international study is successful, an obvious hurdle will be how and when the clinical world begins using our preferred new name and units. Again, keep in mind that the current A1C assay performed in the laboratory will not change—only how results are reported. Certainly, the change will require extensive coordination and the reprinting of an untold number of patient education materials, and both clinicians and patients will have to become comfortable with this new way of describing chronic glycemia. Similar changes in nomenclature and "units" have been far less disruptive than initially thought—for example, the abrupt change in Europe from >30 different national currencies to one euro.
And if the study doesn't work out as desired? We certainly will still have DOF hemoglobin as the reference method name and its corresponding units. Whether they are the only values reported to clinicians or we continue to use percent A1C as we know it is unclear.
And when will we know which way the wind is blowing? A more recent analysis of the study data will be presented at ADA's Scientific Sessions next month in Chicago. Enough information should exist by then to at least start planning a worldwide conversion to a new name and measurement unit.
Final study data will be presented at the EASD meeting in September. If all
goes well, perhaps we'll have a new name and units by the first half of 2008.
In the meantime, remember: Change is coming. 
Footnotes
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References
2. Kobold U, Jeppsson J, Dulffer T, et al.: Candidate reference
methods for hemoglobin A1C based on peptide mapping. Clin
Chem 43:1944–1951, 1997.
3. Hoelzel W, Weykamp C, Jeppsson J, et al.: IFCC reference system for
measurement of hemoglobin A1C in human blood and the national standardization
schemes in the United States, Japan, and Sweden: A method-comparison study.
Clin Chem 50:166–174, 2004.
4. Hanas R: Psychological impact of changing the scale of reported
HbA(1C) results affects metabolic control. Diabetes
Care 25:2110–2111, 2002.
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