What do we need beyond hemoglobin A1c to get the complete picture of glycemia in people with diabetes?

Abstract

Hemoglobin A1c (HbA1c) is currently the most commonly used marker for the determination of the glycemic status in people with diabetes and it is frequently used to guide therapy and especially medical treatment of people with diabetes. The measurement of HbA1c has reached a high level of analytical quality and, therefore, this biomarker is currently also suggested to be used for the diagnosis of diabetes. Nevertheless, it is crucial for people with diabetes and their treating physicians to be aware of possible interferences during its measurement as well as physiological or pathological factors that contribute to the HbA1c concentration without being related to glycemia, which are discussed in this review. We performed a comprehensive review of the literature based on PubMed searches on HbA1c in the treatment and diagnosis of diabetes including its most relevant limitations, glycemic variability and self-monitoring of blood glucose (SMBG). Although the high analytical quality of the HbA1c test is widely acknowledged, the clinical relevance of this marker regarding risk reduction of cardiovascular morbidity and mortality is still under debate. In this respect, we argue that glycemic variability as a further risk factor should deserve more attention in the treatment of diabetes.

Keywords: Hemoglobin A1C; diabetes complications.; diabetes mellitus; glycemic control; glycemic variability; hemoglobinopathies.

Figure 1

The formation of glycated hemoglobin is a non-enzymatic reaction consisting of two steps of which only the first one is reversible.

Figure 2

Inter-laboratory standard deviations in external quality assessment schemes (here surveys of the American College of Pathologists [CAP]) have decreased over time due to implementation of standardization and decreasing random error of HbA1c measurement devices.

Figure 3

The A1c-Derived Average Glucose (ADAG) Study Group demonstrated that HbA1c correlates well with average glucose (AG) (R2 = 0.84) , however, although 90% of HbA1c concentrations predicted the average measured glucose within ± 15%, significant deviations were observed. The regression equation is: Calculated AG (mg/dL) = 28.7 x HbA1c (%) - 46.7.

Figure 4

The distributions of HbA1c concentrations in non-diabetic non-Hispanic white, non-Hispanic black and Mexican Americans in the National Health and Nutrition Examination Survey-3 (NHANES-3) were different, with non-Hispanic blacks having the highest values .

Figure 5

HPLC chromatogram showing a HbE pattern hemoglobinopathy interfering with the analysis of HbA1c.

Figure 6

In the Structured Testing Program (STeP) study , people with diabetes in the structured testing group showed significant reductions in average, preprandial, postprandial and bedtime blood glucose levels at Month 12 (p<0.01). The degree of glycemic excursions at breakfast, lunch and supper was also significantly improved (intent-to-treat analysis). Abbr.: M1 (Month 1), M12 (Month 12).