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Nurse Practitioner:
doi: 10.1097/01.NPR.0000388206.16357.02
Feature: DIABETES CARE: CE Connection

Diagnosing Diabetes with A1C: Implications and considerations for measurement and surrogate markers

Hill, Alethea N. PhDc, MSN, RN, ANP-BC; Appel, Susan J. PhD, ACNP-BC, CCRN, FNP-BC

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Author Information

Alethea N. Hill is a clinical assistant professor at the College of Nursing, University of South Alabama, Mobile, Ala., and a doctoral student in the School of Nursing at the University of Alabama at Birmingham (UAB). Susan J. Appel is an associate professor at the School of Nursing, the University of Alabama at Birmingham.

The authors have disclosed they have no significant relationship with or financial interest in any commercial company that pertains to this educational activity.

According to the CDC, approximately 23.6 million people (7.8% of the population) have diabetes, and an additional 5.7 million people remain undiagnosed.1 In addition, the effects of uncontrolled glucose levels is directly correlated with diabetes-related complications and morbidity.2 The number of diabetes cases has doubled in the last decade, and the disease ranks as the seventh leading cause of death in the United States.1 Finding more efficient means of testing, diagnosing, and managing the disease is crucial to ensure optimum, long-term health for each patient. Every year, studies produce more evidence about diabetes and subsequently change these recommendations, reshaping how physicians, NPs, and other practitioners diagnose, treat, and manage type 2 diabetes mellitus.

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The Summary of Revisions for the American Diabetes Association (ADA) 2010 Clinical Practice Recommendations highlights a number of different areas and focuses on recent evidence supporting new strategies for improving patient care.3 One of the changes affects the way practitioners may diagnose and track the progress of the disease. The ADA recently endorsed assessing the level of a patient's glycated hemoglobin A1C (A1C) as a method for diagnosing diabetes and discussed the value in estimated average glucose (eAG), hemoglobin variants, and the variability of lab testing versus point-of-care (POC) devices.

NPs should understand the meaning of the test values as well as the accuracy level of the tests to make appropriate decisions when interpreting A1C as a diagnostic tool and indicator of glycemic control. As successful glycemic control is achieved in only about one third of all patients,4 NPs are in a key position to use the approved testing to facilitate an increase in successful treatment, which would lead to a reduction in cost and health burden of both microvascular and macrovascular diabetes-related complications. This would reduce preventable complications, injury, and premature death while improving the health and quality of life for individuals.4

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ADA recommendations

The ADA's revisions for 2010 have since sent researchers and clinicians into heavy debate.3,5 One part of the revised recommendation is to perform the A1C assay twice (on separate visits) as a diagnostic tool to ensure that the lab results are similar, making a definitive diagnosis of diabetes. Because chronic hyperglycemia is the antecedent to type 2 diabetes mellitus, it was important to consider measures that support long-term glucohomeostasis, such as A1C. The new diagnostic cut point for diabetes is A1C of 6.5% or greater, and the cut point for categories of increased risk of diabetes is an A1C range of 5.7% to 6.4%.5

The American College of Endocrinology (ACE) and American Association of Clinical Endocrinologists (AACE) support the ADA's recommendation, and they agree that A1C should not be the primary criterion. It should be used in conjunction with fasting plasma glucose (FPG) and/or oral glucose tolerance tests (OGTTs).6

The ACE and AACE released a new algorithm representing a stepwise approach for mono/combination therapy based on A1C measurements taken every 2 to 3 months. This testing, in addition to self-management of blood glucose, will help NPs make decisions when adjusting each patient's diabetic regimen. The ACE/AACE's primary goals are to decrease the risk and severity of hypoglycemic episodes; reduce the possibility of weight gain; use only FDA-approved glycemic medications, such as incretin-based therapies/thiazolidinediones; and design therapies monitored by A1C that will lower A1C. The medications they recommend are prioritized based on safety, risk for hypoglycemic episodes, efficacy, potential patient compliance, and cost-effectiveness. There is also a specific focus on treatment variations based on naivety to medications and risk/benefit of diabetic medication regimens. For reference, see the Summary of Key Benefits and Risks of Medications available at http://www.aace.com/pub/.6 The benefit of A1C measurement has been weighed against traditional methods, such as FPG and 2-hour OGTT, and was found to have more overall clinical use than its predecessors. NPs should keep in mind that FPG, OGTT, and A1C all measure different aspects of beta-cell functioning, insulin sensitivity, and glucose metabolism; therefore, NPs should understand that the tests are intercorrelated, not interchangeable.

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Integrity of sample for glucose and A1C testing

The low success rate of glycemic control may be attributed in part to the way in which clinicians have collected and measured test samples. The recent changes in diagnostic cut points to glucose concentrations may increase the risk of misclassification of individuals at increased risk for diabetes and type 2 diabetes mellitus, if providers do not consider the basic factors involved in correctly collecting and measuring a patient's blood samples.7 NPs should consider that inadequate sample handling in respective clinical settings may also affect the final analysis of blood glucose samples, making A1C measurement an optimal choice when available.8

Subjecting glucose samples to inappropriate temperatures for extended periods facilitates glycolysis, causing the loss of glucose at rates as much as 5% to 7% per hour when exposed for 2 hours or longer. Sodium fluoride (NaF) is used as a reagent to retard glucose degradation, but may not entirely account for a loss incurred 1 to 2 hours before analysis, yielding false low results. Ice can help maintain the integrity of the specimen, but may not be practical in all settings.8,9 NPs should adopt and implement handling procedures that sustain the preanalytic integrity of the specimen from venipuncture to final analysis to minimize errors in the test result. NPs should consider using collection tubes containing acidification reagents and ethylenediaminetetraacetic acid, in addition to NaF.7,8

An alternative to collecting blood glucose samples for assessment in the traditional lab setting are several POC devices, which can make AIC testing easier. NPs should ensure that these devices will evaluate their patient populations properly and that they are National Glycohemoglobin Standardization Program (NGSP) certified. An NP with a large population of African Americans, Asians, or Mediterranean patients could obtain values that reflect hemoglobin variant interference (see Race/ethnicity-specific hemoglobin variants). Not all devices are calibrated such that interference with Hb variants does not occur (see Interference with Hb variants). A compromise might be to use POC devices to monitor long-term glycemic control while using lab analyses as the diagnostic tool.10 Currently, the ADA does not recommend that POC devices be used for diagnosing diabetes.5

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Erythrocyte turnover and glycation

Glycation is a process in which glucose or "sugar" molecules bind to a protein, such as hemoglobin, without the guidance of an enzyme. Glycated hemoglobin is measured by cation-exchange chromatography, electrophoresis, affinity chromatography, and immunoassays.11–14 HbA1C contributes approximately 60% to 80% of the hemoglobin that is glycated. In a hyperglycemic environment, the hemoglobin beta-chain increases glycation substantially, making A1C a useful method of measurement.15

Given that 90% of the protein is hemoglobin—specifically HbA—the life span of an erythrocyte, which is approximately 120 days, directly impacts the clinical significance of A1C values when managing treatment for a patient with diabetes.16,17 Although strong consideration must be given to fluctuations in glycemia during the month before testing, only 50% of the A1C present is a direct result of glycemia during that time, 25% is from 30 to 60 days before measurement, and 25% from 60 to 120 days before measurement.17–19 These percentages may be skewed, however, if there is altered erythrocyte turnover, such as in patients affected by hemolytic anemia, aplastic anemia, or splenectomy. If treatment is based on measurements affected by other conditions, it can result in inappropriate management and misclassification of diabetes.11–20 Biological variation of A1C fluctuations in patients with diabetes reflect changes in mean glycemia caused by the physiology of the disease. Research studies have found that the issue of variation is more interindividual (between subjects) than intraindividual (within subjects).8,13,20

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Standardizing A1C and eAG

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Use of a standardized A1C assay was based on the Diabetes Control and Complications Trial (DCCT).21 As of January 2010, the NGSP ensures standardization for approximately 99% of the labs in the United States (total coefficient of variation at approximately 4%).22 In addition, the A1C-Derived Average Glucose (ADAG) study, which was a large, multisite study involving 11 international centers sponsored by the ADA, European Association for the Study of Diabetes (EASD), and International Diabetes Federation (IDF) demonstrated that the results of an A1C assay can be translated into an eAG for most patients with diabetes.23 The eAG is the unit measured by patients during daily self-monitoring. The study, which included 507 participants with both type 1 and type 2 diabetes, as well as people without diabetes using continuous glucose monitors and traditional glucose monitors, produced a refined mathematical formula that defined the relationship between A1C and eAG (see eAG values).

The ADA's Standards of Care adopted the new eAG measurement. However, the study was not without limitations; while 83% of the cohort were whites; African Americans have demonstrated higher A1C levels than whites, Hispanics, and Asians, after adjusting for factors known to differ among these groups.5,8,23 The exclusion of individuals with unstable diabetes, children, women who were pregnant, and individuals with processes affecting erythrocyte turnover questions whether these findings are applicable to all populations.24 These individual differences will translate into patient-specific glycemic management regimens because race, age, and existing illness or therapies will directly affect how an individual glycates hemoglobin.23–25 A subsequent study that examined whether reporting eAG or A1C resulted in increased knowledge retention among participants revealed that participants did not find eAG easier to understand or recall than A1C.20

NPs should consider whether the sample population for the ADAG study resembles the patients they serve. If there are significant differences specific to race, age, gender, and baseline glycemia in comparison to the patients they treat, it could affect the treatment plan.

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Alternative measures of glycemic control

Successful glycemic control must take into account a significant number of variables as each patient's course of disease and treatment, as well as methods of testing and monitoring, are individualized. NPs need to assess carefully what determines glycemic control in each patient by performing a comprehensive risk assessment and considering existing comorbidities, as well as management that will curtail development and progression of other associated diabetes risks or complications.19

Because the assumption of measuring an A1C is that it indicates the average glucose levels over the preceding 2 to 3 months, it may be an inappropriate measurement for patients who have recently changed dietary habits or received a new antidiabetic medication regimen within 6 weeks, as well as those who experience abnormalities of red blood cell aging or have a mix of hemoglobin subtypes (predominantly HbA in normal adults).19,26 A1C measurements are not appropriate for those who have experienced recent blood loss, hemolytic anemia, hemoglobinopathies, or for women with type 1 diabetes who are pregnant (hormonal changes cause greater short-term fluctuation in glucose concentrations) as it does not account for high turnover of hemoglobin or "high glycators" (see Other conditions that may yield discordant A1C values and Race/ethnicity-specific hemoglobin variants).19,27 An alternative is to test fructosamine, which measures glycemia over 2 to 3 weeks.5,18,26,27 Fructosamine is a general term for glycated protein formed by the nonenzymatic reaction of glucose with the amino groups of proteins. The nonenzymatic glycation of proteins in vivo is proportional to the prevailing glucose concentration during the lifetime of the proteins. Albumin accounts for 80% of the fructosamines.

The glycation gap is another way to understand and examine glycemic control.19 The glycation gap accounts for the difference in A1C (intracellular proteins) as compared to fructosamine levels (extracelluar proteins) as they translate to a predicted level of A1C, which is an independent predictor of which individuals will have adequate glycemic control and which are at increased risk for experiencing associated complications. A high glycation gap is associated with diabetic nephropathy and diabetes-related complications.

The 1,5-anhydroglucitol (1,5-AG) assay may be an additional resource for tracking short-term glucose levels, as it can be administered every 2 weeks. 1,5-AG is a normally occurring monosaccharide. When blood glucose levels rise, 1,5-AG levels decrease, as glucosuria occurs. The assay measures postprandial glucose levels, giving NPs a more comprehensive understanding of the patient's response to current diabetic management. It should be used in conjunction with other tests to provide a complete assessment of the patient's glucohomeostasis. Because this assay measures only 1,5-AG, it can pinpoint fluctuations in glucose levels even if A1C levels are normal. If the patient's postprandial glucose levels are fluctuating, the NP may decide to adjust or add to the patient's regimen of therapeutic agents, which may include short- or rapid-acting insulin analogues or secretagogues, alpha-glucosidase inhibitors, or incretin mimetics.28

For patients with diabetes and chronic renal insufficiency or end-stage kidney disease on hemodialysis who are receiving recombinant erythropoietin, such as epoetin alfa or darbepoetin alfa, an A1C assay may yield false low A1C levels.18 Testing for glycated albumin may be an alternate measure.29–31 Elevated levels of glycated albumin have been correlated with diabetes progression and micro/macrovascular complications associated with diabetes. More specifically, glycated albumin has a strong association with diabetic nephropathy and coronary artery disease.29–31

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A1C, FPG, and diabetes-related conditions

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It was also found that A1C measurements could be used for early diagnosis, prevention, and detection of diabetes-related microvascular complications, such as retinopathy.32–35 Over the years, other test levels have changed to reflect the implications of diabetes-related conditions. For example, FPG cutoffs have changed from 140 to 126 mg/dL after finding glucose levels considerably above levels at which the incidence and prevalence of retinopathy increased.36

The Action to Control Cardiovascular Risk in Diabetes trial and Veterans Affairs Diabetes trials demonstrated that lowering A1C reduced microvascular (retinopathy/neuropathy) and macrovascular cardiovascular disease.5,37–38 The same level of mortality was not observed in individuals with an A1C less than 7%37; the highest risk existed among populations in the intensive arm with the highest A1C levels at baseline assessment and most aggressive reduction in A1C.5 Because of this finding, NPs should consider the rate at which they reduce an individual's A1C evaluating baseline assessment and slowly proceed toward the goal. In addition, NPs should consider how long the patient has been diagnosed with diabetes as aggressive therapy and reduction of A1C in patients diagnosed with diabetes for more than 12 years was contraindicated.5,38

In a recent analysis of 11,092 participants from the Atherosclerosis Risk in Communities study (1990–1992), the prognostic value of A1C and FPG in nondiabetic adults with increased risk of type 2 diabetes mellitus or cardiovascular disease was compared. This analysis adds corroborating evidence that A1C is diagnostic of type 2 diabetes mellitus and more strongly associated with the risk of type 2 diabetes mellitus and cardiovascular disease—as well as mortality associated with cardiovascular disease—than FPG.39

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Conclusion

The NGSP has a standardized A1C assay method for lab analysis in the United States. Germany reports the International Federation of Clinical Chemistry and Laboratory (IFCC) reference measurement. The IFCC reports A1C values 1.5% to 2% lower than the NGSP because the IFCC measurement of A1C is more specific and has a lower margin for error with sample-handling concerns than NGSP. Yet, the IFCC is not practical for routine practice and has cost constraints. The United Kingdom reports both IFCC and NGSP numbers and will report only IFCC numbers in 2 years; several other countries are following Germany and the United Kingdom.

The IDF, EASD, and the ADA have always recommended glycemic control based on A1C. Now that the ADA has officially positioned the assay as a means of diagnosis and monitoring, it is another tool NPs must access properly when helping patients manage diabetes and treatment.

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Other conditions that may yield discordant A1C values

False high17,19,35

* Hypertriglyceridemia

* Hyperbilirubinemia

* Uremia (carbamylated Hb)

* Chronic alcohol abuse

* Chronic ingestion of salicylates

* Opiate addiction

* Iron, vitamin B12, and folate deficiency

* Splenectomy

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False low17,19,35

* Vitamins C and E

* Chronic liver disease

* Medications—Dapsone40, antiretrovirals, methylene blue, phenacetin, benzene derivatives, nitrites

* Hemodialysis

* Post blood transfusion

* Hereditary spherocytosis

* Chronic lymphocytic leukemia

* Hemolysis

* Splenomegaly

* Rheumatoid arthritis

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Web resources

For information regarding patient education on eAG, see http://www.diabetes.org/living-with-diabetes/treatment-and-care/blood-glucose-control/estimated-average-glucose.html.

For information for healthcare professionals who wish to use the eAG calculator, see http://professional.diabetes.org/GlucoseCalculator.aspx.

The American Diabetes Association Standards of Medical Care guidelines may be found at: http://care.diabetesjournals.org/content/33/Supplement_1/S11.full.pdf+html

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© 2010 Lippincott Williams & Wilkins, Inc.

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