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- DCCT, Diabetes Control and Complications Trial
- IFCC, International Federation of Clinical Chemistry
- HbA1c, glycated haemoglobin
- UKPDS, United Kingdom Prospective Diabetes Study
As methods improve, inherent limitations become more apparent
It is difficult to overestimate the contribution made by glycated haemoglobin measurement (usually in the form of HbA1c) to the management of patients with diabetes mellitus and the reliance now placed on the test by clinicians. Before its introduction as a routine test in the late 1970s and early 1980s, objectively assessing glycaemic control relied on measures such as 24 hour urine glucose excretions1 and daily blood glucose profiles.2 By comparison, measurement of HbA1c gave a much more reliable measure of glucose control over the prolonged period of the previous six to eight weeks.3 The clinical usefulness of the test was cemented by major trials, such as the Diabetes Control and Complications Trial (DCCT) in type 1 diabetes4 and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetes.5 Both showed that improved glycaemic control, as assessed by HbA1c, could lead to substantial reductions in the risk of developing the microvascular complication of diabetes such as retinopathy, nephropathy, and neuropathy. The UKPDS findings also suggested that the risk of myocardial infarction (the main cause of premature death in diabetes) could be improved by reducing HbA1c values.6
“The importance that is now placed on HbA1c is demonstrated by the new contract for general practitioners in the UK, which sets glycaemic control targets for diabetes patients”
Based on the publication of these and other studies, target values for HbA1c have evolved over recent years. Currently, in the UK it is recommended that a patient’s HbA1c should be between 6.5% and 7.5%, aiming for the lower end of this range if macrovascular complications are present.7 In the USA, an HbA1c of < 7.0% is strived for, with values > 8% requiring major treatment changes in most cases.8 The importance that is now placed on HbA1c is demonstrated by the new contract for general practitioners in the UK, which sets glycaemic control targets for patients with diabetes.9 These targets are based entirely on the HbA1c values that general practitioners obtain in their patients and so, for the first time, there will be an element of “performance related pay” for these doctors based solely on this particular measurement.
Until recently, the possibility of introducing such national targets would have been impossible because of the differences between HbA1c assays and other methodological problems.10 These issues are steadily being dealt with. For example, inclusion of fetal haemoglobin as part of the HbA1c result used to be commonplace, leading to spuriously high HbA1c results in some patients,11 but with contemporary assays this problem is now historical. Most importantly, however, the lack of assay standardisation is now being tackled. Whereas previously the HbA1c value measured differed depending on the assay used, it has now been recommended that laboratories harmonise these results to report a “DCCT equivalent” number.7,12 This is seen as the first step to true standardisation, where the recently published International Federation of Clinical Chemistry (IFCC) reference method13 will be used either to define true HbA1c values (which will be 1.5–2% lower than DCCT equivalent values) or to “anchor” current DCCT/UKPDS numbers to this IFCC “gold standard”.
Now that most of the assay problems have or are currently being dealt with, the greatest source of concern with HbA1c measurement has become the inherent limitations of the test itself. All the targets mentioned previously are an incentive to try and ensure that the risk of diabetes complications is minimised. However, these targets are based on data for an average patient found in the DCCT and UKPDS studies. This raises two potential issues. The first is how applicable the targets from these studies are to all the patients who participated, and the second is how applicable the findings from these studies are to patients from parts of the world outside the USA and the UK where they were performed. The first concern stems from the fact that there is compelling evidence that patients with the same mean blood glucose can have greatly different HbA1c values, as demonstrated by the DCCT study itself, which showed that patients with a mean plasma glucose of 10 mmol/litre could have an HbA1c value anywhere between 6% and 11%.14 Some of this variability is undoubtedly caused by limitations in the study, such as the use of a single seven point day plasma glucose profile (converted from laboratory measured whole blood measurements) to compare with the subsequent HbA1c value, but this is partially offset by the power of averaging 18 such comparisons in the 1439 participants throughout the study period. The findings also corroborate those from biological variation studies, which suggest that although “within individual” changes in glycated haemoglobin are small, differences between non-diabetic individuals can be as much as 2% HbA1c.15 The inference from these data is that by slavishly aiming for the same HbA1c in all patients, for some the target is probably unrealistically low (with a high risk of hypoglycaemia if it is attempted to be reached), whereas for others it can be achieved with apparent ease, thereby leaving the patient and clinician falsely reassured.
In their paper in this issue of the Journal of Clinical Pathology, Camargo and Gross have investigated this last group of patients by looking for causes of spuriously low HbA1c values in their Brazilian patients with diabetes.16 They found that the presence of haemoglobin variants and undiagnosed anaemia accounted for most of these cases. The cosmopolitan nature of their population (certainly in comparison with those in DCCT and UKPDS) probably contributed to the prevalence of haemoglobinopathy, and although the number of affected samples was small (130 patients from 29 657 samples) this is certain to be just the tip of the iceberg because they defined a very low HbA1c as being below their non-diabetic lower reference limit of just 4.7%. Thus, there may have been many other cases where the effect on the HbA1c value was much more subtle but still clinically relevant.
“There is compelling evidence that patients with the same mean blood glucose can have greatly different HbA1c values”
The findings of their study add to the other known intrinsic problems with HbA1c. These include the spurious values that can be found in patients with renal failure17 and in those who appear to glycate at unusual rates.18 Even when patients have none of these abnormalities, the fact that HbA1c measures average glycaemia and says nothing about swings in blood glucose can result in some individuals only achieving their treatment goal at the expense of a poor quality of life, as a result of frequent, disabling, and unpredictable hypoglycaemia.
Taken together, it means that in a health care culture that is being driven increasingly by targets it is important not to lose sight of the fact that patients still need to be assessed as individuals.
As methods improve, inherent limitations become more apparent