HbA1c testing has been the mainstay of the determination of glycemic control in the management of diabetes since the 1980s and it was at this time that this measurement was introduced into clinical practice. This indicator measures the glycation of haemoglobin molecules in the blood. Hemoglobin is the iron containing protein in the red blood cells that transports oxygen. Glucose attaches to hemoglobin to then form glycated hemoglobin. The HbA1C is measured to identify the percentage of glucose attached to hemoglobin in order to determine the average blood glucose level for the preceding two to three months. Not only is it still the most widely used parameter for glycemic monitoring today, but HbA1c is related to the risk of microvascular (in both type 1 and type 2 diabetes) and macrovascular (at least in type 1 diabetes) complications. More recently, HbA1c determination has been proposed as a criterion for diabetes diagnosis.

However, the correlation between glycemia and HbA1c is not perfect and it has been reported that numerous factors influence the HbA1c concentration. The levels are genetically determined, with heritability accounting for 50% . Other factors such as age, drugs, hemoglobinopathies (which is a group of inherited disorders in which there is abnormal production or structure of the hemoglobin molecule), and some diseases may also affect HbA1c. It also has a limited ability to reflect short-term glycemic changes, and it cannot reveal postprandial hyperglycemia and fasting hyperglycemia separately. These parameters are not to be neglected, as a growing body of evidence suggests that postprandial hyperglycemia and glycemic variability may be independent risk factors for macrovascular complications in patients with diabetes. It therefore has been advised that clinicians consider other glycemic factors beyond HbA1c for the prevention of cardiovascular and microvascular complications and to improve quality of life for those living with diabetes.

While fasting blood glucose provides an acute assessment of glycemia, other measures have also been proposed to provide contrasting measures of glycemic control. These include glycated albumin, fructosamine, and 1,5-anhydroglucitrol (1,5-AG). These methods are of increasing interest in research and clinical practice as alternative measures of hyperglycemia that can be readily measured in serum. As mentioned above, HbA1c yields an estimate of glycemia for the previous 2â€"3 months whereas glycated albumin and fructosamine represent glycemia for 2â€"3 weeks based on the rate of total serum protein and albumin turnover. It has been shown that 1,5-AG summarizes the glycemic response occurring over the previous few days. Both fructosamine and glycated albumin are formed via nonenzymatic glycation reactions and are elevated in the setting of high circulating concentrations of glucose. Therefore fructosamine and 1,5-AG are known as circulating biomarkers that reflect short-term glucose control in diabetes mellitus.

Fructosamine is formed via a nonenzymatic mechanism that involves the binding of blood glucose to serum proteins to form ketoamines. Glycated albumin, formed in a similar reaction as fructosamine, is specific to albumin and both fructosamine and glycated albumin increase in the presence of increased blood glucose. Both of these markers have a half-life of about 17â€"21 days, reflecting exposure to glucose over the preceding 2â€"3weeks. 1,5-AG or fructosamine monitoring may be a convenient method for evaluating short-term glycemic excursion and these biomarkers may be useful for detecting postprandial and glycemic variability in patients with well controlled diabetes mellitus.

Because fructosamine levels correlate best with average glucose levels during the previous 10â€"14 days, it has been used clinically as a complementary marker to detect short-term changes in glucose management. Most commonly, fructosamine refers to a laboratory test for diabetes management that it is rarely used in clinical practice. Similar to the HbA1c testing, fructosamine testing calculates the fraction of total serum proteins that have undergone glycation. Since albumin is the most common protein in blood, fructosamine levels typically reflect albumin glycation and fructosamine determination is the most widely used alternative to HbA1c as it has been shown to correlate rather well with HbA1c. However, in practice, it is rarely measured clinically due to a number of pragmatic concerns. Firstly, diabetes care is rarely changed in short (1-4 week) intervals, since diabetes medications can take months to reach a steady state. Secondly, fructosamine has higher variability than HbA1c tests. Thirdly, the overwhelming majority of studies in diabetes care are based on HbA1c measurements, which can make fructosamine results difficult to interpret. Lastly, the HbA1c test is incredibly well standardized and trusted due to its nearly universal use. There is also no standard reference range available for this test as the reference values depends upon the factors of patient such as age, gender, sample population, and test method. Hence laboratory reports will include the patient’s specific reference range for the test. The way in which Fructosamine is usually calculated is as follows:

Fructosamine = (HbA1c-1.61) x 58.82

Despite the apparent shortfalls in the test there has been an increased interest in the use of Fructosamine in testing for short-term glycemic control in diabetic patients. A study by Juraschek et al. evaluated alternative markers of hyperglycemia and risk of diabetes and it was found that higher baseline quartiles of fructosamine and glycated albumin were associated with a significantly higher risk of diabetes in a doseâ€"response manner, even after adjustment for traditional risk factors and fasting glucose or HbA1C. Fasting glucose was most strongly associated with diagnosed diabetes even after the pattern of association of HbA1C with incident diabetes was similar to that for fructosamine and glycated albumin.
In another study by the same author comparison of the confidence intervals of the markers revealed no statistical difference across quartiles of fructosamine, glycated albumin, 1,5-AG, HbA1C, and fasting glucose in their associations with diabetes risk and it was observed that both fructosamine and glycated albumin were strongly associated with the subsequent risk of diabetes. Glycated albumin, fructosamine, and 1,5-AG were more strongly correlated with HbA1c compared with fasting glucose. When diabetes was defined by an HbA1c≥6.5%, fructosamine and glycated albumin performed comparably to fasting glucose while 1,5-AG performed worse for identifying cases of undiagnosed diabetes. It was thus concluded that Fructosamine and glycated albumin may be useful adjuncts to HbA1c and fasting glucose. They advised that future studies examine these markers in situations where fasting glucose or HbA1c measurements are invalid or not available.
In another study comparing the different biomarkers, 1,5-AG, fructosamine, and glycated albumin it was seen that they were more strongly correlated with HbA1c as compared to fasting glucose overall. Of the alternative glycemic markers, glycated albumin and fructosamine performed comparably to HbA1c and fasting glucose for identifying cases of diabetes in this population, regardless of definition of diabetes used. In conclusion, results suggested that glycated albumin and fructosamine may be useful as adjunct measures of hyperglycemia to HbA1c or in settings where HbA1c (or whole blood samples for its measurement) are not available.

Beck et al evaluated the interrelationships of glycemic control measures of HbA1c, glycated albumin, fructosamine, 1,5-anhydroglucitrol (1,5-AG), and continuous glucose monitoring in children and adolescents with type 1 diabetes .Each of the four measures had a similar correlation with mean glucose and hyperglycemic. 1,5 AG did not correlate with hyperglycemic better than did HbA1c. Some studies have suggested that 1,5-AG reflects hyperglycemia better than HbA1c and may be useful in conjunction with HbA1c to assess glycemic control in patients with moderate or good control. Beck et al also found that each of the four laboratory measures had a similar correlation with mean glucose which was not enhanced when other measures were included in the model. Although they did not find enough evidence to support the use of 1,5-AG as a better marker of long-term glycemic control than HbA1c in their population group, they identified that there may be an important role for 1,5-AG measurements in assessing short-term control.

Zafon et al studied the concept of the Glycation gap (GG), which was initially defined by Cohen et al as the difference between the measured HbA1c and the HbA1c predicted from the measure of fructosamine, based on the HbA1câ€"fructosamine regression equation. Zaqfon et al stipulated that the GG could be useful for identifying the factors accounting for the discrepancy between fructosamine and HbA1c levels.

References:
1. Variables Involved in the Discordance between HbA1c and Fructosamine: The Glycation Gap Revisited, Zafon1 et al.
2. Alternative Markers of Hyperglycemia and Risk of Diabetes , Stephen P. Juraschek et al
3. Associations of Alternative Markers of Glycemia with Hemoglobin A1c and Fasting Glucose by Stephen P. Juraschek,
4. Evaluation of Glycemic Variability in Well-Controlled Type 2 Diabetes Mellitus by Suk Chon et al.
5. The Interrelationships of Glycemic Control Measures: HbA1c, Glycated Albumin, fructosamine, 1,5-Anhydroglucitrol, and Continuous Glucose Monitoring by Roy Beck, M