Implications of Using Hemoglobin A1C for Diagnosing Diabetes Mellitus

doi:10.1016/j.amjmed.2010.11.025

The American Journal of Medicine

Volume 124, Issue 5, May 2011, Pages 395-401

https://doi.org/10.1016/j.amjmed.2010.11.025 Get rights and content

Abstract

Until 2010, the diagnosis of diabetes mellitus was based solely on glucose concentration, but the American Diabetes Association (ADA) recommendations now include a new criterion: hemoglobin A1C ≥6.5%. Because this change may have significant implications for diabetes diagnosis, we conducted a comprehensive literature review including peer-reviewed articles not referenced in the ADA report. We conclude that A1C and plasma glucose tests are frequently discordant for diagnosing diabetes. A1C ≥6.5% identifies fewer individuals as having diabetes than glucose-based criteria. Convenience of A1C test might increase the number of patients diagnosed, but this is unproven. Diagnostic cut-points for both glucose and A1C are based on consensus judgments regarding optimal sensitivity and specificity for the complications of hyperglycemia. A1C may not accurately reflect levels of glycemia in some situations, but in comparison with glucose measurements, it has greater analytic stability and less temporal variability. When choosing a diagnostic test for diabetes, the limitations of each choice must be understood. Clinical judgment and consideration of patient preference are required to appropriately select among the diagnostic alternatives.

Section snippets

Evolution of Diagnostic Criteria for Diabetes

The first widely accepted laboratory standard for diagnosing diabetes was proposed by the World Health Organization (WHO) in 1965.⁸ It stated that the disease was present if a venous whole-blood glucose concentration was ≥130 mg/dL (plasma glucose ≥150 mg/dL) 2 hours after a 50- or 100-gram oral glucose challenge.

In 1979, the National Diabetes Data Group proposed new diagnostic criteria.⁹ These were based on the midpoints of bimodal curves observed in certain populations tested for FPG and for

Correlation With Microvascular Complications

A1C is accepted as the best single measure of average glucose concentration,16, 17 and it is used routinely to guide adjustments to therapy. A1C has been shown to correlate with likelihood of diabetic retinopathy,18, 19, 20 and in some studies this correlation was found to be stronger than that for fasting glucose.¹⁹ In large clinical trials of both type 1 and type 2 diabetes, A1C also correlates with the probability of developing other microvascular complications.21, 22

Technical Considerations

With the adoption of the

Who Gets the Diagnosis of Diabetes: A1C ≥6.5% Compared to FPG ≥126 And 2-Hour PG ≥200?

The ADA report on the new diagnostic criteria states that based on data from the NHANES, the A1C cut-point of ≥6.5% will identify one-third fewer individuals than a FPG cut-point of ≥126 mg/dL.¹ Other studies confirm this viewpoint. A report comparing the 1999 WHO criteria (2-hour PG) and the 2003 ADA criterion of FPG ≥126 mg/dL with an A1C of ≥6.5% found that A1C categorized the fewest individuals as having diabetes.³⁸ A1C identified 5.2% of individuals in this study as diabetic, compared to

Special Considerations that Apply to the AIC Assay

Multiple factors affect the accuracy of the A1C as an indicator of average glucose concentration (Table 2). Appropriate use of the A1C for diabetes diagnosis requires that clinicians be aware of these factors. For comparison, some factors that affect glucose concentration are listed in Table 3.

When using A1C as a diagnostic tool, it is important that the test be performed in a laboratory that uses a method certified by the NGSP. This program allows clinical laboratories to relate their A1C

Conclusions and Recommendations

The A1C obtained from appropriately selected patients and performed in a qualified laboratory provides an accurate measure of the individual's mean glucose concentration. It correlates well with the probability of microvascular complications, and it offers significant technical and practical advantages over laboratory glucose measurement. There are confounding factors (Table 2) that can interfere with A1C assay accuracy, and clinicians need to be aware of these. The ADA diagnostic threshold of

Acknowledgment

The authors thank David Harlan, MD, for his critical reading of the manuscript.

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Data from the 2015–2017 China Nutrition and Health Surveillance (n=176,223) and the 2015–2018 U.S. National Health and Nutrition Examination Survey (n=4,464) were used. Diagnosed diabetes was self-reported. Undiagnosed diabetes was no report of diagnosed diabetes and fasting plasma glucose ≥126 mg/dL or HbA1c ≥6.5%. Predicted age-adjusted prevalence estimates by BMI were produced using sex- and country-specific logistic regression models.
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In our dataset, there were approximately 21 million deaths during 0·5 billion person-years of follow-up among people with diagnosed diabetes. 17 of 19 data sources showed decreases in the age-standardised and sex-standardised mortality in people with diabetes, among which the annual percentage change in mortality ranged from –0·5% (95% CI –0·7 to –0·3) in Hungary to –4·2% (−4·3 to –4·1) in Hong Kong. The largest decreases in mortality were observed in east and southeast Asia, with a change of –4·2% (95% CI –4·3 to –4·1) in Hong Kong, –4·0% (−4·8 to –3·2) in South Korea, –3·5% (−4·0 to –3·0) in Taiwan, and –3·6% (−4·2 to –2·9) in Singapore. The annual estimated change in SMR between people with and without diabetes ranged from –3·0% (95% CI –3·0 to –2·9; US Medicare) to 1·6% (1·4 to 1·7; Lombardy, Italy). Among the 17 data sources with decreasing mortality among people with diabetes, we found a significant SMR increase in five data sources, no significant SMR change in four data sources, and a significant SMR decrease in eight data sources.
All-cause mortality in diabetes has decreased in most of the high-income countries we assessed. In eight of 19 data sources analysed, mortality decreased more rapidly in people with diabetes than in those without diabetes. Further longevity gains will require continued improvement in prevention and management of diabetes.
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Portable liquid chromatography for point-of-care testing of glycated haemoglobin
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Liquid chromatography (LC) coupled with absorption detection plays an important role in the analytical field. However, the miniaturisation of the whole system is still a challenging problem. Here we developed a compact and lightweight LC system with overall size of 20 cm × 16 cm × 16 cm and weight of 1.8 kg for the fast and accurate measurement of glycated haemoglobin (HbA_1c). The system mainly comprises a battery-operated electrolysis micropump (EMP), a highly integrated LC microchip and an LED-based absorbance detector. The good linearity (R² = 0.9860) and low limit of detection (LOD) (about nine times lower than the commercial detector) of the LED detector were measured to meet the requirement of the on-chip determination. The inaccuracy (≤ 4.3 %) and repeatability (≤ 2.8 %) of the LC system were successfully verified by measuring the HbA_1c levels of patients with diabetes and comparing the results with those from a commercial LC instrument. Thus, the developed LC system showed great potential for accurate and point-of-care diabetes diagnostics.
The Screening and Prevention of Diabetes Mellitus
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: Funding: Supported in part by Center Grant DK32520 from the National Institutes of Health and by grant 7-08-RA-106 from the American Diabetes Association (Dr. Mordes). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

: Conflict of Interest: All authors declare that there are no conflicts of interest.

: Authorship: All authors had access to the data and a role in writing the manuscript.

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ReviewImplications of Using Hemoglobin A1C for Diagnosing Diabetes Mellitus

Abstract

Section snippets

Evolution of Diagnostic Criteria for Diabetes

Correlation With Microvascular Complications

Technical Considerations

Who Gets the Diagnosis of Diabetes: A1C ≥6.5% Compared to FPG ≥126 And 2-Hour PG ≥200?

Special Considerations that Apply to the AIC Assay

Conclusions and Recommendations

Acknowledgment

Lancet

Metabolism

Diagnosis and classification of diabetes mellitus

Diab Care

International Expert Committee Report on the role of the A1C assay in the diagnosis of diabetes

Diab Care

National Glycohemoglobin Standardization Program

Translating the A1C assay into estimated average glucose values

Diab Care

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Lancet

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus

N Engl J Med

Screening for diabetes and prediabetes with proposed A1c-based diagnostic criteria

Diab Care

Diabetes mellitus

Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance

Diabetes

Diabetes mellitus: second report

Report of the expert committee on the diagnosis and classification of diabetes mellitus

Diab Care

Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes

BMJ

Comparison of fasting and 2-hour glucose and HbA1c levels for diagnosing diabetesDiagnostic criteria and performance revisited

Diab Care

Definition, diagnosis and classification of diabetes mellitus and its complications

Report of the expert committee on the diagnosis and classification of diabetes mellitus

Diab Care

Hemoglobin A1c determination in the A1C-Derived Average Glucose (ADAG) study

Clin Chem Lab Med

Photography or ophthalmoscopy for detection of diabetic retinopathy?

Diab Care

Risk factors for incident retinopathy in a diabetic and nondiabetic population: the Hoorn study

Arch Ophthalmol

Longitudinal association of glucose metabolism with retinopathy: results from the Australian Diabetes Obesity and Lifestyle (AusDiab) study

Diab Care

Relationship between glycated haemoglobin and microvascular complications: is there a natural cut-off point for the diagnosis of diabetes?

Diabetologia

The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial

Diabetes

Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study

BMJ

Review
Implications of Using Hemoglobin A1C for Diagnosing Diabetes Mellitus