References for “New ADA Guidelines for Diagnosis, Screening of Diabetes”

Chemistry

In 2010, it got a little easier to diagnose diabetes. Diabetes mellitus is a chronic disorder of glucose metabolism that affects 23.6 million people in the U.S.¹ The four major types of diabetes differ in their causes, but all types have hyperglycemia in common. These are type 1 (formerly called insulin dependent or juvenile diabetes), type 2, gestational diabetes mellitus (GDM) and diabetes due to other causes.

Chronic complications common to all forms include retinopathy, nephropathy, neuropathy and cardiovascular disease. Individuals who are able to keep their blood glucose close to the normal range have the lowest risk of microvascular complications;^2,3 managing lipidemia and hypertension improves macrovascular outcomes as well.⁴ Early diagnosis affords early intervention.

Diagnosis of diabetes has historically been by measuring fasting plasma glucose (FPG) or performing an oral glucose tolerance test (OGTT); specific threshold values are required to categorize an individual as pre-diabetic (increased risk for diabetes) and diabetic (Table 1). For individuals without unequivocal hyperglycemia, positive results must be repeated on a separate day.⁵

Type 2 Diabetes

Type 2 diabetes accounts for 90-95% of the cases in the U.S. Risk factors are obesity and being overweight, race, age, family history, hypertension, gestational diabetes and physical inactivity.⁶ Individuals with symptoms such as blurred vision, polydipsia and polyuria should be tested when they present with these symptoms.⁷ Asymptomatic individuals with risk factors should be screened for diabetes if they are overweight (BMI > 25 kg/m2) and have additional risk factors,⁵ or beginning at age 45 for those without other risk factors. Those with normal results and low risk should be re-tested at three-year intervals.⁵

Type 2 diabetes is also found in children, especially in minority populations. The criteria for testing are a BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight > 120 % of ideal weight for height, plus two of these risk factors: family history, race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander), signs of insulin resistance, or maternal history of diabetes or GDM during child’s gestation. Children should be screened at age 10 or at puberty if it occurs before age 10, with subsequent testing every three years in negative individuals.⁵

In 2010, hemoglobin A1c (A1c) was added as a diagnostic tool for individuals with type 2 diabetes. A1c of 6.5% is the threshold for diagnosis. A1c methods used must be certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial reference assay.⁵

Click to view larger graphic.

Click to view larger graphic.

The A1c result shows the cumulative effect of hyperglycemia over the past 2-3 months. The correlation of average glucose (AG) to A1c% was reported as AG mg/dl = 28.7 X A1c – 46.7.8 As such, A1c provides a long-term analysis of the patient’s average blood glucose. Other advantages to using A1c as the diagnostic test for diabetes are that, unlike plasma glucose and oral glucose tolerance, A1c does not require fasting. A1c values are stable in vitro so tubes can be processed without special handling; in contrast, glucose decreases in unprocessed tubes at a rate sufficient to cause a false-negative diagnosis within 1-2 hours.⁹

Drawbacks to the A1c are cost and availability. Furthermore, A1c is not accurate for individuals who have increased or decreased red blood cell turnover, such as those with hemolytic disease, iron deficiency or pregnancy.^5,10 A1c methods may also be inaccurate in the presence of certain hemoglobinopathies.^11,12 A1c methods are capable of detecting the major hemoglobinopathies, providing a clear advantage when testing populations that have a high incidence of hemoglobin S, C and E.

Type 1 Diabetes

Individuals with type 1 diabetes may have a rapid onset of symptoms, and frequently present with ketoacidosis, obviating the diagnostic need for A1c measurement. Furthermore, due to the short prodromal period, the A1c value may be lower than expected if measured at diagnosis.⁵ Therefore, A1c is not recommended as a diagnostic tool for type 1 diabetes. It is not cost-effective to screen for type 1 diabetes; however, individuals known to be at increased risk based on family history or prior transient hyperglycemia may be tested for presence of islet autoantibodies. The presence of these antibodies confirms an increased risk for development of type 1 diabetes.⁵

Gestational Diabetes

The ADA Standards of Medical Care for 2010 for GDM do not endorse A1c as a diagnostic test during pregnancy, but refer to the Hyperglycemia and Adverse Pregnancy Outcomes Study and conversations the ADA is having with the International Association of Diabetes and Pregnancy Study Groups (IADPSG) about reclassification of GDM. The IADPSG advocates testing pregnant women at their first obstetrics visit for the presence of overt diabetes. This measurement can be done with FPG, A1c or random plasma glucose13 using criteria shown in Table 1. Women who are positive by these criteria are considered to have overt diabetes, not GDM. Women who are particularly at risk are obese, have a personal history of GDM, have glycosuria or a strong family history of diabetes.⁵

The IADPSG has recommended stricter criteria for classification of GDM, but for 2010, the criteria remain those shown in Table 2. These are threshold cutoff glucose values to evaluate pregnant women for GDM. The testing should be done between 24 and 28 weeks gestation. Diagnostic criteria utilize a one- or two-step approach.

The two-step approach includes a screening, followed by a confirmation. The first step measures glucose one hour after a 50-g glucose load. Women with a glucose over 140 mg/dL (7.8 mmol/L) are given an oral glucose tolerance test (OGTT). The OGTT can be done with a 100 g or 75 g glucose load. Fasting, 1-, 2- and 3-hour measurements are taken and compared to specific glucose values for those time points. If two or more of the timed values are higher than the threshold, the diagnosis is made.

As of 2010, an A1c between 5.7% and 6.4% is also considered an increased risk for diabetes. While these individuals are classified as pre-diabetic, the Standards of Medical Care explain that this is not a disease entity, but rather a risk factor for development of diabetes and cardiovascular disease.⁵

The ADA recommends A1c testing 2-4 times per year for patients with diabetes5, and the recommended range is < 7.0% for individuals with diabetes, with an A1c of 8.0% and higher a cause for concern and re-evaluation of the patient’s care.

Patients with diabetes in poor control can have A1c values in excess of 12%. Until now, it has been unusual to have A1c values that are less than 6.0%; lower than expected A1c in a diabetic patient can indicate a hemoglobinopathy, so low values should be scrutinized.^14,15

Dr. Behan is associate professor and director, Clinical Laboratory Sciences Program, School of Allied Health and Life Sciences, University of West Florida, Pensacola.

Click here for a summary recap of the ADA Clinical Practice Guidelines.

References

1. Diabetes Statistics. Available at: http://www.diabetes.org/news-research/research/diabetes-statistics/total-prevelance.html. Accessed December 15, 2010.

2. The Diabetes Control and Complications Trial Research Group. The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. NEJM 1993;329:977-86.

3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or Insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet 1998;352:837-53.

4. G‘de P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial Intervention and Cardiovascular Disease in patients with Type 2 Diabetes. NEJM 2003;348:383-93.

5. American Diabetes Association. Standards of Medical Care in Diabetes – 2010. Diabetes Care 2010:33;S11-61.

6. Diabetes Risk Test. Available at: http://www.diabetes.org/diabetes-basics/prevention/diabetes-risk-test/ (last accessed Dec. 15, 2010).

7. American Diabetes Association. Screening for Type 2 Diabetes. Diabetes Care 2004; 27:S11-14.

8. Nathan DM, Kuenen J, Borg RI, Zheng H, Schoenfeld, D, Heine RJ. Translating the A1c Assay Into Estimated Average Glucose Values. Diabetes Care 2008:31;1473-8.

9. Sidebottom R, Williams PR, Kanarek KS. Glucose Determination in Plasma and Serum: Potential Error Related to Increased Hematocrit. Clin Chem 1982;28:190-2.

10. Coban E, Ozdogan M, Timuragaoglu A. Effect of Iron Deficiency Anemia on the Levels of Hemoglobin A1c in Nondiabetic Patients. Acta Haematologica 2004;112:126-8.

11. Bry, L, Chen, PC, Sacks, BD. Effects of Hemoglobin Variants and Chemically Modified Derivatives on Assays for Glycohemoglobin. Clin Chem 2001;47:153-63.

12. National Glycohemoglobin Standardization Program. Available at: www.ngsp.org (last accessed Dec. 13, 2010).

13. International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International Association of Diabetes and Pregnancy Study Groups Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy. Diabetes Care 2010;33:676-82.

14. Behan K. Improving the Accuracy of Hemoglobin A1c; Your Help is Needed. LabMedicine 2008;39:389-93.

15. Higgins T, Stewart D, Boehr E. Challenges in HbA1c analysis and reporting: An interesting case illustrating the many pitfalls. Clin Biochem 2008;41:1104-6.