The role of hemoglobin A1c in the assessment of diabetes and cardiovascular risk

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ABSTRACTHemoglobin A1c (HbA1c) is a widely used tool for diagnosing, screening, and managing patients with diabetes; however, proper application and interpretation of the HbA1c test is crucial to master for accurate assessment of patients. It also has become the standard test in population-based studies for evaluating the relationship between glycemic control and cardiovascular risk. Results from large clinical trials support the modern perspective that the HbA1c target should be personalized according to the risks and benefits of glycemic control. This likely is most important in patients with diabetes and elevated cardiovascular risk in whom achieving low HbA1c levels early in the natural history may be the most beneficial.


  • An HbA1c level ≥ 6.5% is the diagnostic cutoff used for diabetes diagnosis; patients with prediabetes have HbA1c values of 5.7% to 6.4%.
  • HbA1c is formed by the glycation of hemoglobin, thus HbA1c may be difficult to interpret in patients with medical disorders affecting red blood cell survival or glycosylation.
  • The use of HbA1c monitoring to manage patients with diabetes should include target levels that are tailored according to the risks and benefits of glycemic control, especially cardiovascular risks.
  • Although commonly used by population studies as a risk indicator for diabetes and cardiovascular complications, HbA1c may misrepresent the glycemic “big picture.”



Since its widespread introduction into routine clinical practice nearly 2 decades ago, hemoglobin A1c (HbA1c) measurement has become an integral tool for the diagnosis and management of diabetes mellitus. It is frequently used in both the care of individuals and in landmark population-based clinical trials. It also serves as a surro­gate marker of glycemic control and is a key risk indicator for diabetes-associated microvascular and macrovascular complications and mortality.

With so much importance placed on one labora­tory value, it is imperative to remember that the test is imperfect, with pitfalls both in accuracy and interpretation. The purpose of this review is to provide a broad understanding of HbA1c and how it can be optimally applied to patient management and the assessment of diabetes and cardiovascular (CV) risk.


HbA1c was first discovered in 1955, but elevated HbA1c levels in diabetes patients were not noted until 1968.1 Another 8 years passed before HbA1c was correlated with blood glucose values in hospitalized patients with diabetes and was proposed for monitoring glycemia.2

Biochemically, HbA1c forms through a nonenzymatic reaction in which glucose attaches to the valine amino terminal of one or both beta chains of hemoglobin A. This compound can be separated out from nonglycated hemoglobin and from other glycated hemoglobin molecules through various methods, such as high performance liquid chromatography or immunoassay.3

During the first few years of clinical use, HbA1c measures were inconsistent. The publication of the Diabetes Control and Complications Trial (DCCT) in 19933 made the importance of precise HbA1c measurement apparent. This study found that the approximate 2% difference in HbA1c between standard- and intensive-insulin therapy groups resulted in dramatically reduced risk of microvascular disease in patients with type 1 diabetes. The continuation of the DCCT, the Epidemiology of Diabetes Interventions and Complications trial,4 and a study of patients with type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS),5 further supported the relationship between sustaining a lower average HbA1c over time and improved patient outcomes, including CV events and mortality. Given the implications of small changes in HbA1c on morbidity, the need to reduce error margins in measurement became apparent.

Enhanced reproducibility of hemoglobin A1c over time
FIGURE 1. Enhanced reproducibility of hemoglobin A1c over time.7 Shown as mean (± 2 standard deviations) of methods compared with NGSP/DCCT target in 1993, 1999, 2004, and 2012. DCCT = Diabetes Control and Complications Trial; NGSP = National Glycohemoglobin Standardization Program

The NGSP (formerly the National Glycohemoglobin Standardization Program) was founded in 1996 to regulate HbA1c measurements to DCCT standards.6 This program, now international in scope through involvement with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), calibrates HbA1c measurements by outside laboratories and manufacturers to reference standards. Laboratories and manufacturers that measure HbA1c certify through IFCC/NGSP and participate in yearly surveys to ensure inter-laboratory reproducibility. Through this successful program, standardization and accuracy of HbA1c measurements greatly improved from 1993 to 2012 (Figure 1).1,6,7 Largely owing to this fact, HbA1c was approved as a diagnostic tool by the American Diabetes Association (ADA) in 2009;8 the test has become a key measure for diagnosing, screening, and monitoring diabetes.

The HbA1c level is affected by the blood glucose concentration, the duration of red blood cell (RBC) exposure to varying concentrations, and RBC quantity. HbA1c most accurately reflects the previous 2 to 3 months of glycemic control in the setting of the usual RBC life span of 120 days.9 As a relatively long-term indicator of glycemic control, it may not accurately represent acute improvements or deteriorations in glycemia. Recent factors affecting glycemia must be considered, as HbA1c represents a weighted average glucose with 50% contribution from the preceding month.10

HbA1c must be interpreted with caution. In nonpregnant adults, HbA1c is often falsely low in conditions that reduce the number of glycosylated RBCs, such as hemolysis, splenomegaly, chronic kidney disease, cirrhosis, hemorrhage, blood transfusions, use of erythropoiesis-stimulating agents, and certain hemoglobinopathies (ie, HbS, HbC, HbF). Alternately, HbA1c is elevated in other hemoglobinopathies and in conditions that result in decreased RBC turnover such as iron or vitamin B12-deficiency anemia.11–13

Hemoglobin A1c and corresponding estimated average glucose

The 2008 A1c-Derived Average Glucose study group (507 participants from 10 international centers) used linear regression analysis to correlate HbA1c drawn every 3 months with average blood glucose readings taken during those 3 months. Results from participants without diabetes were compared with patients with type 1 or type 2 diabetes.14 The resulting significant correlation between HbA1c and average blood glucose readings (coefficient of determination 0.84, P <.0001) became the standard for estimating glycemia from HbA1c (Table 1).


HbA1c was accepted by the ADA as a diagnostic test for diabetes in 20094 and the World Health Organization (WHO) in 2011,13 although the WHO recommended alternate methods for diagnosis given concerns about test availability, cost, and accuracy in the developing world.15

Advantages to HbA1c use in diagnosis include standardization of measurement, convenience as a single blood-draw that does not require fasting, minimal day-to-day variability, and preanalytic sample stability. Although point-of-care testing for HbA1c is widely available, it is not recommended for diagnostic use because these assays are generally not IFCC/NGSP certified and do not undergo the same proficiency testing as laboratory samples.12,16

The 1997 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus17 encouraged that diagnosis be based on the glycemic level at which microvascular complications develop. Using fasting plasma glucose (FPG), 2-hour postprandial plasma glucose, and funduscopic data from several large epidemiologic studies, the committee established that increased risk of diabetic retinopathy occurs at FPG levels greater than or equal to 126 mg/dL (7.0 mmol/L). Subsequent studies analyzed sensitivity and specificity correlations between FPG levels above 126 mg/dL and HbA1c in an effort to define cutoffs for HbA1c as a diagnostic tool; however, their results lacked clear clinical relevance.18–20

In 2003, the DETECT-2 trial analyzed HbA1c levels in more than 28,000 participants to determine HbA1c diagnostic definitions based on microvascular complications.21 Evaluating HbA1c in 0.5% increments, investigators found that the incidence of diabetic retinopathy rose above baseline at HbA1c of 6.5%, the now accepted diagnostic value. It is important to note that this cutoff makes HbA1c less sensitive than other diagnostic indicators, which if applied to the same number of individuals, would result in up to one-third more patients diagnosed with diabetes. However, the lower sensitivity is balanced by higher screening rates given HbA1c accessibility.16

Criteria for the diagnosis of diabetes

Diabetes can be diagnosed according to the criteria in Table 2, using venous plasma samples for HbA1c and glucose measurements. FPG assessment, both alone and as part of a 2-hour oral glucose tolerance test (OGTT), requires a minimum 8-hour fast. Although it is more cumbersome for both patients and practitioners, the 2-hour OGTT remains the technical standard diagnostic test for diabetes. It can formally identify patients with impaired fasting glucose and impaired glucose tolerance, which are markers of impaired beta cell function and future progression to frank diabetes mellitus.

In the presence of clear symptoms of hyperglycemia such as blurry vision, polyuria, polydipsia, weight loss, and a random plasma glucose value ≥ 200 mg/dL (11.1 mmol/L), a single laboratory measurement fitting any of the three diagnostic criteria confirms the diagnosis of diabetes. In the absence of these symptoms, one positive test must be repeated and remain positive in order to confirm diabetes. As an alternative to repeating the original diagnostic test, two of the three criteria may be positive at any one time to make the diagnosis.13,16

Diabetes risk criteria for screening nonpregnant adults

Routine screening for diabetes using HbA1c should be based on risk in the absence of symptoms (Table 3). The ADA recommends screening at 3-year intervals if an initial screen is within normal limits or yearly in individuals with prediabetes or a change in risk status.16 Screening also is recommended for patients on medications that increase the risk of hyperglycemia (eg, glucocorticoids, thiazides, and atypical antipsychotics).

Criteria for identifying prediabetes

Individuals with prediabetes are identified as having impaired fasting glucose and impaired glucose tolerance based on 2-hour OGTT, FPG, or HbA1c (Table 4). Those with HbA1c values 6.00% to 6.49% are considered by the ADA and WHO to have the highest risk of developing diabetes.13,15,16 This range is based primarily on a 2010 systematic review22 evaluating the relationship between HbA1c and progression to diabetes in studies involving more than 44,000 participants. Patients with HbA1c of 6.0% or above had a 5-year risk of progression to diabetes between 25% and 50%, 20 times higher than those with HbA1c less than 5%.22 The ADA-defined lower limit for diagnosing prediabetes (HbA1c ≥ 5.7%) is based on a 2011 analysis of National Health and Nutrition Examination Survey data.23 In that study, adults with HbA1c levels at or above 5.7% were at similar risk of developing frank type 2 diabetes and CV disease (41.3% over 7.5 years and 13.3% over 10 years, respectively) as the 3,234 participants in the Diabetes Prevention Program, a prospective, population-based study evaluating the risk of incident diabetes.23,24

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