Glycosylated Hemoglobin Hbac

The development of the glycosylated hemoglobin assay has become one of the major advances in taking care of patients with diabetes mellitus. The glycohemoglobin measurement correlates with fasting blood glucose, postprandial glucose, the glucose peak during an oral glucose tolerance test and the mean glucose levels over many weeks. Currently most laboratories use the HbA1c measurement but this is not universal. After the results of the DCCT were published the use of the HbA1c level in setting a goal for optimal glucose control was firmly established. However in a consensus statement by Marshall, it was apparent that standardization of the assay was an issue (39). In this consensus statement it was recommended that a DCCT-aligned HbA1c assay should be used since this as well as the UKPDS and Kumamoto study were the best data available on the relationship between control and complications. Furthermore, the availability of a standardized assay will be important for educating patients on the goals of treatment as well for the standards for glycemic control set by national diabetes associations. It will also be important for designing future studies in diabetes where the question of control and complications are studied.

The glycated hemoglobin is a series of stable minor hemoglobin components formed slowly and nonenzymatically from glucose and hemoglobin. The rate of formation of this product is directly related to the level prevailing glucose concentration and is irreversible. Because the red blood cells where the reaction takes place have an average life span of 120 days the test reflects the prior 2 to 3 months of glycemic control. However, most of the reaction takes place over the last 2 to 3 weeks before the measurement. Many types of assay methods are available to the routine laboratory. These methods vary in the glycated components measured, interferences, and the nondiabetic range. It is important for the clinician to know what the laboratory being used measures and what the normal ranges are. In the United States there is the National Glycohemoglobin Standardization Program that is in part sponsored by the ADA. This is an attempt to standardize HbA1c determinations to the DCCT values. Manufacturers of HbA1c assays are given an annual "certificate of traceability to the DCCT reference method" if they pass the criteria for accuracy and precision.

In the United States more than 98% of laboratories use the NGSP certified methods and report results as either HbA1c or HbA1c equivalents. However, changes are on the way. More recently the International Federation of Clinical Chemistry (IFCC) Working Group on HbA1c Standardization has recommended a new reference method that results in a lower normal range (2.8%-3.8%) which is 1.3% to 1.9% lower across the range compared to the NGSP results. An international working group of the ADA/EASD/IDF has recommended that the IFCC reference be adopted as the new global standard for calibration of HbA1c by manufacturers. However the current DCCT/EDIC results will be in place until data linking HbA1c to mean blood glucose can be obtained and public and professional education is done on the new reporting system (52).

According to the ADA position statement testing of the HbA1c should be performed routinely in all patients with diabetes to document the level of their glycemic control. In general the test should be repeated three to four times a year, but the actual frequency will vary based on the individual patient and the goals set. In a study to test the usefulness of HbA1c measurements in type 1 patients, Lytken Larsen and colleagues randomly assigned 240 matched patients with type 1 diabetes mellitus to either a 3 monthly measurement of HbA1c or blood glucose and urine testing to monitor treatment (40). Treatment was modified based on the results of the tests and after one year in the group having the HbA1c measured, the mean HbA1c dropped from 10.1% to 9.5%. In the control group the values were 10.0% and 10.1%, respectively. As a result the proportion of patients in poor control, defined as an HbA1c value above 10% decreased from 46% to 30%. Another interesting study by Chase and colleagues, looked at the issue of severe hypoglycemic episodes in type 1 patients after the introduction of rapid acting lispro insulin in 1996 (41). The DCCT study resulted in an increase in severe hypoglycemia with intensive therapy. They used the DCCT definition of hypoglycemia and studied patients < 5 years of age to > 18 years. They found additional reduction in the HbA1c levels with no increase in the number of severe hypoglycemic episodes. While it is reasonable to measure the HbA1c three to four times a year in type 1 patients the optimal frequency in type 2 diabetes is not clear, especially in stable patients who are diet treated. In the absence of definitive studies, stable patients should have the HbA1c measured twice a year and probably quarterly in those who are not in control or are having therapy changes.

It is extremely important that patients and caregivers understand the basis for the test and how to use the information. Rather than have fixed goals for all patients based on the studies discussed so far, it is better to individualize the approach. The ability of the patient to participate in the treatment program is crucial for optimal control. Focusing only on the HbA1c levels without addressing such issues as, the stresses of adolescence, puberty, the home environment, ageing, depression, and economic issues, will create a counterproductive situation. This is especially important when setting goals in the elderly where comorbidities and many psychosocial and economic issues will determine the goals (42). Caregivers also need to be aware that the glycohemoglobin values we use today to set the goals of treatment come from the DCCT and only assays that are referenced to this method are valid. Other assays cannot be used in the same way since they lack the data showing a relationship of the complications of diabetes to the glycohemoglobin. The ADA suggests an HbA1c goal of < 7% and that the treatment regimen be revaluated if the level is > 8%. It may be argued that based on the data from the UKPDS, where a 0.9% difference is the glycohemoglobin resulted in a 25% reduction in microvascular complications that anything above 7% requires revaluation.

There has also been increased use of point of service AIC assays where a result is obtained during the visit from a finger stick blood sample and changes in treatment made as needed. The advantages to this are obvious as the patient is available to interact with the provider. One issue is the accuracy of these methods compared to the DCCT/EDIC reference assay. In a recent study the DCA 2000 assay was compared to the DCCT/EDIC assay in 200 youth with type 1 diabetes. The DCA 2000 results strongly correlated with the reference test (r = 0.94, p <.001), was slightly higher with a mean difference of + 0.2%. This test therefore can be used in clinical care and results are available in about 6min (53).

Apart from the glycohemoglobin, a glycated serum protein (GSP) and glycated serum albumin (GSA) assay are also available. Because of the much shorter half-life of serum albumin (14-20 days) this assay can reflect an index of glycemia for shorter periods of time. In general the assays correlate well with the HbA1c measurements. These assays can be useful in situations where the HbA1c cannot be measured, as with hemolytic anemia. The fructosamine assay is one such test that is widely used. However, the results can be affected in situations where synthesis or clearance of these proteins is altered such as, systemic illness and liver disease. In general these assays reflect the glycemic control over a 1 to 2 week period whereas the HbA1c provides an index over 2 to 3 months. One area where these shorter tests may be useful is in pregnancy or after major treatment changes. However these tests are not equivalent to the HbA1c in setting the goals of treatment as they have not been shown to be related to the development or progression diabetic complications.

After many decades of questioning the role of glucose control in preventing the long-term complications of diabetes mellitus we now have some data that indicate the benefits of good control. The long-term trials that have been done to date are not many, but the question has been satisfactorily answered and what is needed is to implement the results into clinical practice. We cannot control all our patients equally well but we need to improve all of them. Any decrease in the HbA1c that can be obtained safely is important. The ideal is to keep the patients in the nondiabetic range. Until beta cell transplantation or regeneration becomes widely available for type 1 diabetes the best approach is to use all our current resources optimally. For the global epidemic of type 2 diabetes, it is now apparent that the early treatment of patients with impaired glucose tolerance with lifestyle measures can have a major impact on progression to clinical disease. The situation with regard to macrovascular disease in type 2 diabetes is being addressed by a long-term trial. To improve diabetes care and spread the message of glycemic control will involve a major effort to educate both physicians and patients. AH will need to know about the evidence and the importance of good blood glucose control, and to be aware of the standards of care and goals set out by their national diabetes organizations. It will also require close collaboration between the government and health care providers. There are major human and financial costs from the complications of diabetes and to have evidence that control matters should inspire all involved in diabetes care to improve our efforts. We need to balance our need to control glucose to set goals with the realities of the daily life of our patients and the psychological stresses of living with a chronic disease. While the evidence is very persuasive for controlling diabetes mellitus to glycohemoglobin and fasting and postprandial goals, it is extremely important that the goals be set and adjusted to the individual patient. This situation should serve to foster greater understanding of patients and their problems and the need to continue to build long-term relationships with effective communications and support systems.

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