Diabetes Clinic
 
Canadian Diabetes Association Position Statement on the Use of Glycated Hemoglobin (A1C) in the Diagnosis of Diabetes Mellitus
By
Ronald M. Goldenberg, MD, FRCPC, FACE
Alice Y.Y. Cheng, MD, FRCPC
Zubin Punthakee, MD, FRCPC
Maureen Clement, MD, CCFP


The Canadian Diabetes Association (CDA) has reviewed the use of glycated hemoglobin (A1C) in the diagnosis of diabetes mellitus. An International Expert Committee, American Diabetes Association (ADA), American Association of Clinical Endocrinologists/American College of Endocrinology and a World Health Organization (WHO) Consultation have each recommended an A1C of 6.5% or higher as a criterion for the diagnosis of diabetes (1-4).

The relationship between A1C and retinopathy is similar to that of fasting or 2-h plasma glucose with a threshold at around 6.5% (5-8). Although the diagnosis of diabetes is based on an A1C threshold for developing microvascular disease, A1C is also a continuous cardiovascular risk factor and a better predictor of macrovascular events than fasting or 2-h plasma glucose (9,10). While many people identified as having diabetes using A1C will not have diabetes by traditional glucose criteria and vice versa, there are several advantages to using A1C for diabetes diagnosis (4). A1C can be measured at any time of day, and is more convenient than a fasting glucose or 2-h oral glucose tolerance test (OGTT). A1C testing also avoids the problem of day-to-day variability of glucose values, as it reflects the average plasma glucose over the previous 2 to 3 months (2).


In order to use this diagnostic criterion, A1C must be measured using a validated assay standardized to the National Glycohemoglobin Standardization Program - Diabetes Control and Complication Trial reference. It is important to note that A1C may be misleading in individuals with various hemoglobinopathies, iron deficiency, hemolytic anemias, and severe hepatic and renal disease (2,3,11) (see Table 1). In addition, studies of various ethnicities indicate that African-Americans, American-Indians, Hispanics and Asians have A1C values that are up to 0.4% higher than white patients at similar levels of glycemia (12,13). Further research is required to determine if specific ethnic-based A1C cut-points for diabetes diagnosis are warranted. A1C values are also affected by age, rising by up to 0.1% per decade (14-16). More studies may help to determine if age adjusted A1C thresholds are required for diabetes diagnosis in the elderly.


The CDA recommends the addition of A1C as one of the diagnostic criteria to diagnose type 2 diabetes in adults as follows:

  1. A1C can be used as a diagnostic test to diagnose diabetes using a standardized, validated assay when there are no conditions which preclude its accurate measurement.
  2. A1C of 6.5% or more is one of the diagnostic criteria for diabetes which should be confirmed by repeat testing on a subsequent day.
  3. A1C < 6.5% does not exclude diabetes that may be diagnosed using standard glucose tests (see Table 2).
  4. Traditional diagnosis using fasting plasma glucose, random glucose with symptoms or 2-h plasma glucose during an OGTT are still recommended options for diagnosing diabetes (see Table 2).
  5. A1C is not recommended for diagnostic purposes in children, adolescents, pregnant women, or people with type 1 diabetes.
  6. A1C may be misleading and therefore, should not be used as a diagnostic tool in the setting of hemoglobinopathies, hemolytic anemia, thalassemias, iron deficiency, spherocytosis, severe hepatic or renal failure.
  7. A1C may be misleading in certain ethnicities and in the elderly and therefore, its utility as a diagnostic tool in these populations is unclear.
The decision as to which test to use for diabetes diagnosis (see Table 2), is left to clinical judgment. In the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation, a repeat confirmatory laboratory test (FPG, casual PG, 2hPG in a 75-g OGTT, A1C) must be done in all cases on another day. It is preferable that the same test be repeated for confirmation. If results of two different tests are available and both are above the diagnostic cutpoints, the diagnosis of diabetes is confirmed. When results of more than one test are available and the results are discordant, the test whose result is above the diagnostic cut point should be repeated, and the diagnosis is made on the basis of the repeat test.

CDA does not recommend specific A1C criteria for the diagnosis of prediabetes. While there is a continuum of risk for diabetes with A1C levels <6.5%, further research is required to determine whether A1C can be used to identify people at risk for diabetes (currently comprising people with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).


REFERENCES

  1. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327– 1334.
  2. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2011;34:S62-S69.
  3. American Association of Clinical Endocrinologists/American College of Endocrinology Statement on the Use of Hemoglobin A1C for the Diagnosis of Diabetes. Endocrine Practice 2010;16:155-156.
  4. WHO Consultation. Use of glycated haemoglobin (HbA1C) in the diagnosis of diabetes mellitus. http://www.who.int/cardiovascular_diseases/report-hba1c_2011_edited.pdf. Accessed January 15, 2011.
  5. McCance DR, Hanson RL, Charles MA, Ja- cobsson LT, Pettitt DJ, Bennett PH, Knowler WC. Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic meth- ods for diabetes. BMJ 1994;308:1323–1328.
  6. Engelgau MM, Thompson TJ, Herman WH, Boyle JP, Aubert RE, Kenny SJ, Badran A, Sous ES, Ali MA. Comparison of fasting and 2-hour glucose and HbA1c levels for diagnosing diabetes. Diagnostic criteria and performance revisited. Diabetes Care 1997;20:785–791.
  7. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183–1197.
  8. The DETECT-2 Collaboration Writing Group. Glycemic thresholds for diabetes specific retinopathy. Diabetes Care 2011;34:145-150
  9. Sarwar N, Aspelund T, Eiriksdottir G, et al. Markers of dysglycaemia and risk of coronary heart disease in people without diabetes: Reykjavik Prospective Study and systematic review. PLoS Medicine 2010;7(5): e1000278. doi:10.1371/journal.pmed.1000278.
  10. Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010;362:800-11.
  11. Gallagher EJ, Bloomgarden ZT, Roith D. Review of hemoglobin A1c in the management of diabetes. Journal of Diabetes. 2009;1:9-17.
  12. Herman WH, Ma Y, Uwaifo G, et al. Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Pevention Program. Diabetes Care 2007;30:2453-2457.
  13. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-independent, black-white differences in hemoglobin A1c levels. Ann Intern Med 2010;152:770-777.
  14. Davidson MB, Schriger DL. Effect of age and race/ethnicity on HbA1c levels in people without known diabetes mellitus: Implications for the diagnosis of diabetes. Diab Res Clin Pract 2010;87:415-421.
  15. Pani L, Korenda L, Meigs JB, Driver C, Chamany S, Fox CS, et al. Efect of aging on A1C levels in persons without diabetes: evidence from the Framingham Offspring Study and NHANES 2001-2004. Diabetes Care 2008;31:1991-1996.
  16. Lin TT, Pin FJ, Tan E, Chen R, Khoo J, Boon SS, et al. HbA1c may not be a sensitive determinant of diabetic status in the elderly. Diab Res Clin Pract 2011; doi:10.1016/j.diabres.2011.01.003.
  17. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008;32(suppl 1):S1-S201.


Table 1. Factors that can affect A1C. Adapted from Gallagher et al. (9).

Factor Increased A1C Decreased A1C Variable change in A1C
Erythropoiesis

Iron deficiency
B12 deficiency
Decreased erythropoiesis

Use of erythropoietin, iron or B12
Reticulocytosis
Chronic liver disease

 
Altered hemoglobin

 

 

Fetal hemoglobin
Hemoglobinopathies
Methemoglobing
Genetic determinants
Glycation

Alcoholism
Chronic renal failure
Decreased erythrocyte pH

Ingestion of aspirin, vitamin C, vitamin E
Hemoglobinopathies
Increased erythrocyte pH

 
Erythrocyte destruction

Increased erythrocyte lifespan: Splenectomy

Decreased erythrocyte
lifespan:
Chronic renal failure
Hemoglobinopathies
Splenomegaly
Rheumatoid arthritis
Antiretrovirals
Ribavirin

 
Assays

Hyperbilirubinemia
Carbamylated hemoglobin
Alcoholism
Large doses of aspirin
Chronic opiate use

Hypertriglyceridemia

Hemoglobinopathies



Table 2. Diagnostic criteria for diabetes (Updated from reference 17)

FPG > 7.0 mmol/L
Fasting = no caloric intake for at least 8 hours
Or
Casual PG > 11.1 mmol/L + symptoms of diabetes
Casual = any time of the day, without regard to the interval since the last meal
Classic symptoms of diabetes = polyuria, polydipsia and unexplained weight loss
Or
2hPG in a 75-g OGTT > 11.1 mmol/L
Or
A1C > 6.5%
Using a standardized, validated assay, in the absence of conditions that affect the accuracy of the A1C
A repeat confirmatory laboratory test (FPG, casual PG, 2hPG in a 75-g OGTT, A1C) must be done in all cases on another day in the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation. It is preferable that the same test be repeated for confirmation. However, in individuals in whom type 1 diabetes is likely (younger or lean or symptomatic hyperglycemia especially with ketonuria or ketonemia), confirmatory testing should not delay initiation of treatment to avoid rapid deterioration.
FPG = fasting plasma glucose; PG = plasma glucose; 2hPG = 2 hour plasma glucose