ABSTRACT: Since 2010, A1C, the glycosylated form of hemoglobin, has been recognized by diabetes mellitus (DM) clinical guidelines as a diagnostic tool. Three of the latest clinical guidelines on DM address diagnosis and management. One of the guidelines, the American College of Physicians’ guidance statement, has generated controversy because it has recommended higher target glycemic goals than the other recommendations. Limitations have been identified surrounding the use of A1C as a diagnostic aid in certain patient populations. Patient-specific and assay-specific interferences that exist can potentially result in inaccuracies in A1C readings.A1C results from the nonenzymatic glycation of the amino (N)-terminal valine residue of hemoglobin A. This process is dependent on ambient glucose concentrations and occurs throughout the 120-day lifespan of the red blood cell (RBC). Therefore, A1C is used to measure glycemic control over the previous 3 months.1-3 A1C represents a weighted average, with approximately 50% of the value due to the mean blood glucose (BG) concentrations in the 30 days prior to sampling; BG concentrations from the previous 90 to 120 days make up about 10% of the final total A1C value.2
A1C testing gained acceptance as a diagnostic tool for diabetes mellitus (DM) in 2009, when it was formally endorsed by an International Expert Committee that was examining its role.4 It was later incorporated into American Diabetes Association (ADA) guidelines and was subsequently adopted by the World Health Organization.5,6
This shift in policy happened following the publication of the results of the Diabetes Control and Complications Trial (DCCT) and The United Kingdom Prospective Diabetes Study (UKPDS), which found that reductions in A1C resulted in decreased risk of microvascular complications in type 1 DM (T1DM) and type 2 DM (T2DM) patients, respectively.7,8 In the 1990s, the National Glycohemoglobin Standardization Program (NGSP) was developed to formalize A1C testing. The NGSP’s goal is to standardize A1C results to those of the DCCT trial, a process termed traceability.9 The International Federation of Clinical Chemistry (IFCC) Working Group on Hemoglobin A1C Standardization has developed reference methods to assure the traceability and standardization of values assigned to A1C test calibrators and/or control materials against those used in DCCT.10 The IFCC has also called for the reporting of A1C values as mmoL/moL rather than as a percentage, which is the reporting method used by the NGSP network and the United States. The following formula has been developed for converting between the NGSP and IFCC values10: NGSP = [0.09148*IFCC] + 2.152.
The ADAG (A1C-Derived Average Glucose) study found a strong correlation between the A1C and estimated average glucose concentrations.11,12 A change (either positive or negative) in A1C percentage of 0.5% is considered clinically significant.13 See TABLE 1.14
Three clinical guidelines published in 2018 that have addressed the utilization of A1C in the diagnosis and management of DM include the ADA Standards of Medical Care in Diabetes 2018, the Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) on the Comprehensive T2DM Management Algorithm-—2018 Executive Summary, and the guidance statement update from the American College of Physicians (ACP) on A1C targets for glycemic control with pharmacologic therapy for nonpregnant adults with T2DM.15-17 This article will review these recommendations, as well as limitations and interferences with A1C testing.
Recent A1C Guidelines
American Diabetes Association’s Summary of Revisions: Standards of Medical Care in Diabetes-—2018: In 2018, the ADA guidelines were updated to reflect potential limitations in A1C measurements due to hemoglobin variants, assay interferences, ethnicity, age, and conditions associated with altered RBC turnover, all of which may necessitate the use of an alternative form of diagnostic glucose testing. In the case of assay interference, marked disconcordance between measured A1C and observed plasma glucose concentrations should prompt an investigation into the presence of hemoglobin variants that may interfere with test results.5
The diagnosis of DM is made when the A1C values are >6.5% (48 mmoL/moL) based on an NGSP-certified test. Prediabetes is defined by an A1C of 5.7% to 6.4% (39-47 mmoL/moL). Patients with prediabetes should be tested yearly in order to determine whether they have converted to diabetic status. Plasma glucose concentrations are recommended over A1C testing for diagnosing T1DM patients who have overt symptoms of hyperglycemia, most of whom are pediatric patients. On the other hand, A1C, fasting plasma glucose, and 2-hour plasma glucose values obtained during oral glucose tolerance testing are equally beneficial in diagnosing T2DM in both younger and older patients.18
TABLE 2 identifies patient-specific factors that interfere with A1C testing.2,5,19-38 Plasma glucose concentrations (or other alternative glycemic assessments, such as fructosamine and glycated albumin) may be recommended over A1C testing in these patient populations.18
TABLE 3 lists a few common hemoglobin variants and hemoglobinopathies that interfere with A1C assays.40,41 A genome-wide association study involving approximately 160,000 people of European, African, East Asian, and South Asian ancestry recently found that there are 60 genetic variants that can influence A1C.42
In general, there are five different types of assay methods for measuring A1C: enzymatic, immunoassay, boronate affinity, ion-exchange high-performance liquid chromatography, and capillary electrophoresis.3,43 A current list of FDA-approved immunoassays is available.44 A review of variant hemoglobins interfering with A1C measurement has been published.45
Patient-specific factors that affect A1C concentrations are race and age. African Americans have higher A1C concentrations for any mean glucose concentration compared with non-Hispanic whites.18,46 These higher A1C concentrations may occur in the presence of similar fasting and postglucose load glucose concentrations.18 Glucose concentrations increase as glucose intolerance worsens.33 Similar findings have been observed when fructosamine and glycated albumin, which are alternative methods to assess glycemic status, are employed.18 Elevated A1C concentrations have also been found in other racial groups.47 African Americans’, Hispanics’, and Asians’ A1C concentrations are 0.37%, 0.27%, and 0.33%, respectively—higher compared with those of whites.25
With regard to age, A1C testing is not recommended to diagnose T1DM in pediatric patients.18
The ADA guidelines recommend that A1C testing be performed at least twice yearly in patients who have achieved stable glycemic control. For those patients who are not at goal or for whom therapy recently changed, quarterly A1C testing is recommended. The guidelines also caution that A1C does not measure glycemic variability or hypoglycemic risk, although hypoglycemia is less common among patients with A1C values of <7.0% to 7.5% (53-58 mmoL/moL).12 The ADA offers guidelines for initiating and escalating therapy based on A1C concentrations.48
American Association of Clinical Endocrinologists and American College of Endocrinology Consensus Statement on the Comprehensive Type 2 Diabetes Management Algorithm (2018 Executive Summary): At the same time that the ADA released its guidelines on the management of DM, the AACE/ACE disseminated its recommendations.16 Similar to the ADA, AACE/ACE advises that A1C targets be individualized based on age, life expectancy, comorbid conditions, duration of DM, risk of hypoglycemia, or adverse consequences from hypoglycemia. However, if individualized A1C targets can be achieved safely, AACE/ACE identifies an A1C concentration of <6.5% as the optimal glycemic goal for patients with recent DM onset and no clinically significant cardiovascular disease. It also states that higher glycemic goals (>6.5%) may be appropriate for some patients (TABLE 4). These goals may change for the individual patient over time. Algorithm-based recommendations are provided for treatment options based on the initial A1C value.
American College of Physicians’ Guidance Statement on A1C Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: The most contentious of these diabetic guidelines are those issued by the ACP.17 The ACP reviewed six clinical practice guidelines from other organizations in which A1C goals were used to manage antidiabetic therapy.49-54 The group then released four guidance statements that recommended deintensification of hypoglycemic therapy for nonpregnant adults with T2DM. The ACP advocates that clinicians personalize goals for therapy based on the risk versus benefit of pharmacotherapy, treatment burden, and cost. It also recommends glycemic goals of 7% to 8% in most patients with T2DM. For patients who have achieved A1C concentrations of <6.5%, the guidance advises deintensification of drug therapy. This liberalization of glycemic control is advocated because, according to ACP, such low concentrations have not been associated with improved clinical outcomes but are related to increased cost, patient burden, and adverse events. Lastly, the ACP encourages clinicians to minimize hyperglycemic symptoms rather than target A1C concentrations in patients with a life expectancy of <10 years due to advanced age, nursing home residence, or the presence of chronic diseases (TABLE 4) because harm may outweigh benefit in these patients.
The authors of the guidelines argue that intensive glycemic control is associated with small absolute reductions in the risk of microvascular surrogate events (e.g., retinopathy on ophthalmologic examination or nephropathy defined by the presence of albuminuria) and that A1C concentrations of <7% have not consistently shown reductions in clinical microvascular events, such as loss or impairment of vision, end-stage renal disease, or painful neuropathy.17
Additionally, A1C targets of <7% (compared with 8%) were not associated with decreased deaths (either all-cause or cardiovascular-related deaths) or reductions in macrovascular events over a 5- to 10-year treatment period. Further, the authors point out that in all studies that randomized patients to more intensive therapy to lower the A1C, there were higher rates of adverse events, including death, compared with more liberal treatment goals. They caution that it takes a long time to achieve the benefits associated with more intensive glycemic control, and such restrictive regimens may be best for patients with life expectancy in excess of 15 years. Finally, the authors believe that there was insufficient evidence to evaluate clinical outcomes for A1C concentrations between 6.5% and 7.0%.
The Endocrine Society, ADA, AACE, the American Association of Diabetes Educators, and the Joslin Diabetes Center have openly criticized the loosening of glycemic goals.55-57 They take ACP to task because their recommendations contradict the findings of DCCT, UKPDS, ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), and VADT (Veterans Affairs Diabetes Trial), all of which associated lower A1C concentrations with reduced microvascular complications.7,8,58-60 Further, ACP’s recommendations do not take into account the younger T2DM patient, who may be at greater risk for long-term complications, such as cardiovascular disease, retinopathy, amputations, and kidney disease, if the higher A1C targets are implemented. The ACP has also been faulted for failure to recognize the positive impact that newer classes of hypoglycemics, such as the sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, have had on both improved cardiovascular outcomes and glycemic control while having a low risk of hypoglycemia. There is also concern that these more relaxed glycemic targets may become performance measures for health plans.55-57,61,62
Alternative Glycemic-Control Measures
In situations where measuring A1C may produce inaccurate results, such as in people of African, Mediterranean, or Southeast Asian descent or in any condition that shortens RBC survival or decreases mean RBC age, alternative approaches to assessing long-term glycemia may be preferred.22,63 Clinicians should consider the possibility of a test interference when the A1C is >15% or is at odds with other BG results.64 However, these alternative methods have not been standardized or correlated with long-term complications in DM, as has the A1C.3,65
Fructosamines are nonenzymatically glycated proteins. They represent all of the serum-stable proteins and reflect glycemic control over the previous 2 to 3 weeks.20,25 The fructosamine test is useful in patients with renal disease, but not in those with hypoproteinemic states, such as liver disease, nephrotic syndrome, or nephrosis, or in uremia and lipidemia. Fructosamine results are affected by concentrations of serum proteins and the presence of low-molecular-weight substances in the plasma.20,25
Glycated albumin also represents BG control over the previous 2 to 3 weeks. It may also be useful in assessing glycemic status during pregnancy, for patients on hemodialysis or receiving erythropoietin therapy, those with chronic kidney disease, those with severe hemoglobinopathies, and in patients with altered RBC lifespan or degrees of glycation.1,2,20,66 Similar to fructosamine, glycated albumin is unreliable in hypoproteinemic states, uremia, and lipidemia.20 There may be racial differences in measurements of glycated albumin, with blacks having increased concentrations compared with whites.65 It may be more useful than A1C in assessing postprandial hypoglycemia.25
Another substance, 1,5-anhydroglucitol, is also used to assess glycemic control because higher glucose concentrations competitively inhibit its renal absorption, resulting in an inverse relationship with BG concentrations.1 However, it is not useful in patients with renal failure or chronic liver disease and during pregnancy.20,25 It appears most useful in monitoring postprandial glycemic control.20
Continuous glucose monitoring is superior to A1C testing in assessing the degree of glycemic variability over time, as well as in evaluating episodes of hypoglycemia. It can be used to confirm the validity of A1C testing.25
The pharmacist’s role in improving therapeutic outcomes for diabetic patients is well documented.67-70 Despite the current controversy surrounding the clinical guidelines, the pharmacist can play a major role by individualizing therapy. As drug experts, pharmacists are adept at weighing the risks versus benefits of treatment regimens. The long-term benefits of tight glycemic control need to be balanced against the harmful effects of hypoglycemia, especially in older patients and those with limited life expectancy or with severe comorbidities.71 Greater emphasis is currently being placed on outcomes, including cardiovascular events, not just on surrogate markers, such as the A1C.72 Through medication therapy management and the expanding role of the pharmacist, the clinical pharmacist is at the forefront of optimizing the care of patients with diabetes.
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For additional resources on A1C testing, please visit the NGSP’s links page at www.ngsp.org/links.asp.