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Consensus Statement on the Worldwide Standardization of the Hemoglobin A1C Measurement

The American Diabetes Association, European Association for the Study of Diabetes, International Federation of Clinical Chemistry and Laboratory Medicine, and the International Diabetes Federation

Address correspondence and reprint requests to Richard Kahn, PhD, American Diabetes Association, 1701 N. Beauregard St., Alexandria, VA 22311. E-mail: rkahn{at}diabetes.org

Abbreviations: ADAG, A1C-derived average glucose • IFCC, International Federation of Clinical Chemistry and Laboratory Medicine • NGSP, National Glycohemoglobin Standardization Program

	INTRODUCTION

TOP INTRODUCTION What are the implications... APPENDIX References

 
The hemoglobin A1C (A1C) assay has become the gold-standard measurement of chronic glycemia for over two decades. Anchored in the knowledge that elevated A1C values increase the likelihood of the microvascular complications of diabetes (and perhaps macrovascular complications as well), clinicians have used A1C test results to guide treatment decisions, and the assay has become the cornerstone for the assessment of diabetes care.

The clinical world has assumed that the A1C assay reflects average glycemia over the preceding few months. However, the data supporting that premise are not exceptionally robust (1–5); glucose concentrations were not measured frequently enough to compute a true "average." To gain a better understanding of the relationship between A1C and average blood glucose, an international study has been initiated to document this relationship, using frequent capillary measurements and continuous glucose monitoring. The results of this study will be known around September 2007. Although some clinicians are already providing patients with their "average blood glucose," by simply converting the current A1C test results (6) to a term more relevant to the values obtained from patient self-monitoring, the results of the study will hopefully provide a more accurate conversion algorithm.

Based on the work of the National Glycohemoglobin Standardization Program (NGSP) in the U.S. and other similar programs in other parts of the world, the current A1C assay has been harmonized on reference methods that measure a mixture of glycated hemoglobins (7–9). However, to achieve a more uniform standardization of A1C measurements, it is desirable to have a reference method that measures only a well-defined analyte. Accordingly, after several years of work, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) developed a new reference method that specifically measures the concentration of only one molecular species of glycated A1C (10,11). Results by the new reference method have also been compared with the results obtained by current methodologies (12), and the relation between the assays can be expressed by simple regression equations ("master equations"). Of note, the new reference method is only used to standardize the A1C assay and cannot be used by clinical laboratories in their measurement of A1C.

In keeping with the measurement of other analytes, the IFCC has also suggested that the test results be provided in scientifically correct units, i.e., mmol/mol (13). The impact of both changes proposed by the IFCC would be to significantly change the numeric results provided to clinicians. For example, an A1C value of 5% would become 33 mmol/mol and an 8% would be 65 mmol/mol.

	What are the implications of the above activities?

TOP INTRODUCTION What are the implications... APPENDIX References

 
The advent of a new reference method to standardize the A1C results, along with the anticipated documentation that the assay does indeed indicate average blood glucose, has led to a variety of proposed changes in the reporting of A1C test results worldwide. To reach an agreement on a course of action, a meeting was held in Milan, Italy, on 4 May 2007, at which a consensus agreement emerged. The following statements have been approved by the American Diabetes Association, the European Association for the Study of Diabetes, the International Diabetes Federation, and the IFCC:

1. A1C test results should be standardized worldwide, including the reference system and results reporting.
   
2. The new IFCC reference system for A1C represents the only valid anchor to implement standardization of the measurement.
   
3. A1C results are to be reported worldwide in IFCC units (mmol/mol) and derived NGSP units (%), using the IFCC-NGSP master equation.
   
4. If the ongoing "average plasma glucose study" fulfills its a priori–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.
   
5. Glycemic goals appearing in clinical guidelines should be expressed in IFCC units, derived NGSP units, and as ADAG.
   

	APPENDIX

TOP INTRODUCTION What are the implications... APPENDIX References

 
Consensus Committee
For the IFCC: Jocelyn Hicks, PhD; Mathias Muller, MD; Mauro Panteghini, MD, PhD; and Garry John, PhD. For the American Diabetes Association: Larry Deeb, MD; John Buse, MD, PhD; David M. Nathan, MD; and Richard Kahn, PhD. For the European Association for the Study of Diabetes: Ele Ferrannini, MD, and Robert Heine, MD. For the International Diabetes Federation: Martin Silink, MD, and Jean-Claude Mbanya, MD.

	Footnotes

 
^* A list of the Consensus Committee members can be found in the APPENDIX.

This article is being simultaneously published in 2007 in Diabetes Care and Diabetologia by the American Diabetes Association and the European Association for the Study of Diabetes. Copyright 2007 by the American Diabetes Association, Inc., and Springer-Verlag. Copying with attribution allowed for any noncommercial use of the work.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

	References

TOP INTRODUCTION What are the implications... APPENDIX References

 

1. Koenig BS, Peterson CM, Kilo C, Cerami A, Williamson JR: Hemoglobin A1C as an indicator of the degree of glucose intolerance in diabetes. Diabetes 25:230–232, 1976[Abstract]
   
2. Svendsen PA, Lauritzen T, Soegaard U, Nerup J: Glycosylated hemoglobin and steady-state mean blood glucose concentration in type I (insulin-dependent) diabetes. Diabetologia 23:403–405, 1982[Medline]
   
3. Nathan DM, Singer DE, Hurxthal K, Goodson JD: The clinical information value of the glycosylated hemoglobin assay. N Engl J Med 310:341–346, 1984[Abstract]
   
4. Rohlfing CL, Wiedmeyer HM, Little RR, England JD, Tennill A, Goldstein DE: Defining the relationship between plasma glucose and HbA_1c: analysis of glucose profiles and HbA_1c in the Diabetes Control and Complications Trial. Diabetes Care 25:275–278, 2002[Abstract/Free Full Text]
   
5. Murata GH, Hoffman RM, Duckworth WC, Wendel CS, Shah JH: Contributions of weekly mean blood glucose values to hemoglobin in A1C in insulin-treated type 2 diabetes: the diabetes outcomes in veterans study (DOVES). Am J Med Sci 327:319–323, 2004[Medline]
   
6. American Diabetes Association: Standards of medical care– 2007. Diabetes Care30(Suppl. 1): S10, 2007
   
7. Goldstein DE, Little R, Lorenz RA, Malone JI, Nathan DM, Peterson CM, Sacks DB: Tests of glycemia in diabetes. Diabetes Care 27:1761–1773, 2004[Free Full Text]
   
8. Little RR, Rohlfing CL, Wiedmeyer HM, Myers GL, Sacks DB, Goldstein DE: The National Glycohemoglobin Standardization Program (NGSP): a five-year progress report. Clin Chem 47:1985–1992, 2001[Abstract/Free Full Text]
   
9. Mosca A, Paleari R: Standardization schemes for hemoglobin A1c determination. In Monitoring Glycaemic Control in the Diabetic Patient. John WG, Ed. London, Harcourt Health Communications, Mosby International, 2001, p. 137–150
   
10. Kobold U, Jeppsson J, Dulffer T, Finke A, Hoelzel W, Miedema K: Candidate reference methods for hemoglobin A1C based on peptide mapping. Clin Chem 43:1944–1951, 1997[Abstract/Free Full Text]
    
11. Jeppsson JO, Kobold U, Barr J, Finke A, Hoelzel W, Hoshino T, Miedema K, Mosca A, Mauri P, Paroni R, Thienpont L, Umemoto M, Weykamp C; International Federation of Clinical Chemistry and Laboratory Medicine (IFCC): Approved IFCC reference method for the measurement of HbA1c in human blood. Clin Chem Lab Med 40:78–89, 2002[Medline]
    
12. Hoelzel W, Weykamp C, Jeppsson JO, Miedema K, Barr JR, Goodall I, Hoshino T, John WG, Kobold U, Little R, Mosca A, Mauri P, Paroni R, Susanto F, Takei I, Thienpont L, Umemoto M, Wiedmeyer HM; IFCC Working Group on HbA1c Standardization: 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[Abstract/Free Full Text]
    
13. Nordin G, Dybkaer R: Recommendation for term and measurement unit for "HbA1c." Clin Chem Lab Med. In press
    

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