|Consensus statement on the worldwide standardisation of the HbA1c 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. Diabetologia. 2007;50:2042-2043.
In September and October of 2007, the same consensus statement on the worldwide standardisation of HbA1c measurement was published in the journals Diabetes Care and Diabetologia.The document, submitted by the American Diabetes Association, the European Association for the Study of Diabetes, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), and the International Diabetes Federation, has recommended the following: HbA1c results should be reported worldwide in IFCC units (mmol/mol) and derived National Glycohemoglobin Standardization Program (NGSP) units (%) based on an IFCC-NGSP master equation. Also, if the ongoing average plasma glucose study fulfils its a priori criteria, then an HbA1c-derived average glucose, or estimated average glucose (eAG), calculated from the HbA1c will also be reported as an interpretation of the HbA1c result.
So what does this all mean? Clinicians and other diabetes healthcare workers could be forgiven for thinking that standardisation already exists since, with a few notable exceptions, HbA1c is largely reported in NGSP (usually called DCCT [Diabetes Control and Complications Trial]) units in most countries throughout the world. This means that the results reported are directly comparable to the values obtained by patients during the DCCT and the United Kingdom Prospective Diabetes Study which both used the same HbA1c method.
However, the HbA1c results reported by this means are not the ‘true’ HbA1c values but simply the closest that 1980s technology could deliver when the DCCT study was conceived. Strictly speaking, therefore, results are currently ‘harmonised’ to the DCCT rather than traceable to a true standard. In order to rectify this situation, the IFCC developed a reference method for HbA1c (Finke et al, 1998; Kobold et al, 1997) which, because of its high specificity, means results using this technique are between 1.5 % and 2 % HbA1c lower than the NGSP ones which relate to the DCCT (a drop of about 25%) (Hoelzel et al, 2004). This difference has led to concern that there may be confusion between the 2 sets of values (Kahn, 2007), with some evidence that changing these numbers may lead clinicians to either undertreat or overtreat patients because they are still using the older targets (Hanas, 2002).
This concern led to the suggestion that rather than moving to these IFCC values, there could be a wholesale change to expressing HbA1c as a ‘mean plasma glucose equivalent’ (Home et al, 2004), or, as it has recently been coined, ‘estimated average glucose’ (eAG). The main purported reason for making this change is that patients may be able to equate this result more closely to that obtained from their blood glucose meter readings. In order for eAG to be a suitable alternative to HbA1c in the first place, there has to be certainty that HbA1c can truly give an accurate reflection of mean blood glucose in most situations. The ongoing mean blood glucose study has the a priori criteria for acceptable agreement as being at least 90% of patients having a mean glucose which is within 15% of the estimated value.
Since this proposal, the IFCC has taken steps to ensure there is no risk of their results being confused with DCCT values by changing its units from being a percentage to something more closely akin to SI units by expressing the result as mmol HbA1c per mol of HbA0 (IFCC, 2007). The relationship between percent and mmol/mol is one of a 10-fold change meaning that, for example, 7 % equates to 70 mmol/mol.
Are there issues with these proposed changes? In relation to eAG, it could be argued that the a priori acceptance criteria are possibly not sufficiently robust, since 90% of patients within 15% of eAG equates to 99% of patients within ±24%. This means that one patient could have a true mean glucose 63% higher than another yet have the same eAG. Thus, the final results of the study will need to be examined closely to be sure that eAG is not adopted to the detriment of these types of patients. Also, use of eAG inherently means there will not be a single global result as the eAG value will be different depending on whether glucose is expressed as mmol/l or mg/dl. In addition, there is the challenge of ‘re-educating’ healthcare staff and patients in what the results mean.
This is obviously also an issue in adopting the IFCC means of expressing HbA1c with the possibility of even greater upheaval than with eAG due to the lack of familiarity with the units. Added to this is the fact that although IFCC results will no longer be confused by patients as being their glucose result when expressed in SI units, it introduces a problem for those countries that express glucose as mg/dl.
Finke A, Kobold U, Hoelzel W, Weykamp C, Miedema K, Jeppsson J-O. Preparation of a candidate primary reference material for the international standardisation of HbA1c determinations. Clin Chem Lab Med. 1998;36:299-308.
Hanas R. Psychological impact of changing the scale of reported HbA1c results affects metabolic control. Diabetes Care. 2002;25:2110-2111.
Hoelzel W, Weykamp C, Jeppsson J-O, et al, on behalf of the 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. 2004;50:166-174.
Home P, Mbanya J-C, Horton E. Standardisation of glycated haemoglobin. BMJ. 2004;329:1196-1197.
International Federation of Clinical Chemistry and Laboratory Medicine, IFCC Scientific Division, Nordin G, Dybkaer R. Recommendation for term and measurement unit for “HbA1c”. Clin Chem Lab Med. 2007;45:1081-1082.
Kahn R. A new name and numbers game for A1C. DOC News. 2007;4:3.
Kobold U, Jeppsson J-O, Dülffer T, Finke A, Hoelzel W, Miedema K. Candidate reference methods for hemoglobin A1c based on peptide mapping. Clin Chem. 1997;43:1944-1951.