Diabetes Diagnosis and Monitoring

On a variety of lab and POC platforms, HbA1c testing is playing an increasingly important role
By Lindsey Nolen

Diabetes is a widespread epidemic affecting the daily lives of millions of people. According to the US Centers for Disease Control and Prevention (CDC) 30.3 million Americans have diabetes.¹ Out of this population, however, CDC estimates that only about 23.1 million people have been accurately diagnosed—meaning that 23.8% of people with diabetes continue to go without a diagnosis.

As symptoms or concerns present themselves, the American Diabetes Association (ADA) recommends that certain screening, diagnostic, and therapeutic actions be taken to help ensure favorable health outcomes for these patients.² ADA’s standards include the most current evidence-based recommendations for diagnosing and treating children and adults with all forms of diabetes.

Screening Recommendations

According to ADA, risk-based screening for prediabetes or type 2 diabetes should be considered only after a child reaches 10 years of age, or after the onset of puberty. Testing for prediabetes and type 2 diabetes should be considered for asymptomatic adults of any age who are overweight or obese and who have one or more additional risk factors for diabetes. For the rest of the general population, testing is recommended to begin at age 45. If test results are normal, the tests only need to be repeated at a minimum of 3-year intervals.²

If a patient is considered to be at risk of having diabetes, ADA suggests that the patient first undergo a complete medical evaluation. Patients should be evaluated for diabetes complications and potential comorbidities and, for patients with established diabetes, previous treatment and risk factor control.

The ADA guidelines provide the range of screening values corresponding to prediabetes and diabetes, as measured by three different test methods: fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), or an oral glucose tolerance test (OGTT). Values indicative of diabetes are also provided for screening with a random plasma glucose (RPG) test, which ADA notes is “only diagnostic in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis.”²

Although any of the tests listed by ADA can be used for screening of patients considered to be at risk for diabetes, in the first instance clinicians typically order a glucose test—FPG or OGTT—because such tests are easier and faster to perform, more convenient and acceptable to patients, and less expensive. However, as such tests indicate the patient’s glucose level only at the time the test is performed—and therefore may not be reflective of ongoing glucose issues—an HbA1c test may need to be ordered so that the patient’s glucose levels over a longer reference period can be understood. Such information is sometimes critical for assessing a patient’s status and making a diagnosis of diabetes.

Diagnostic Testing

Risk-based screening is meant to identify individuals whose test results indicate that they may have prediabetes or diabetes, even though they are asymptomatic. Such tests are also indicated when an individual exhibits signs or symptoms of diabetes.

“Many people do not seek out or have access to preventive care, so often it is not until a later stage that people are being diagnosed and monitoring can begin,” says Gillian Parker, senior director for cardiometabolic disease, rapid diagnostics, at Abbott. “Even then, when people are presenting to physicians, they often do not follow through to their scheduled laboratory or follow-up appointments.”^3,4

Any of the test methods listed by ADA for screening can also be used to diagnose diabetes. For diagnostic purposes, however, a single test result is not sufficient. According to ADA:

Unless there is a clear clinical diagnosis based on overt signs of hyperglycemia, diagnosis requires two abnormal test results from the same sample or in two separate test samples. If using two separate test samples, it is recommended that the second test, which may be either a repeat of the initial test or a different test, be performed without delay.²

For nearly 20 years, the 2-hour plasma glucose test (2HPG) conducted as part of a 75-g oral glucose tolerance test (OGTT) was considered the gold standard for testing patient glucose levels and thereby diagnosing diabetes. But in 1997 new research called into question the utility of 2HPG testing, and instead recommended that fasting plasma glucose (FPG) be adopted as the standard diagnostic test.⁵ FPG remained the diagnostic standard for more than a decade. For most of this period, HbA1c was a known glucose marker, but was not considered sufficiently standardized for use.

“For quite a while there was disagreement among health professional societies about what should be the gold standard for glucose testing,” says Douglas Borses, director of sales and marketing at Diazyme Laboratories. “But since then, there has been some intense work by the American Association for Clinical Chemistry, the American Association of Bioanalysts, and the American Diabetes Association, to harmonize on HbA1c testing. I would say that thus far their work has been a success.”

In 2009, a new international expert committee reevaluated the evidence in favor of the use of HbA1c as a diagnostic for diabetes, and found a changed landscape. The committee reported that “with advances in instrumentation and standardization, the accuracy and precision of A1C assays at least match those of glucose assays.”⁵ The committee’s report discussed a number of advantages to HbA1c testing, including “the convenience for the patient and ease of sample collection for A1C testing, which can be obtained at any time, requires no patient preparation, and is relatively stable at room temperature” (Table 1).⁵ While acknowledging costs and other obstacles to universal adoption, the committee encouraged clinicians worldwide “to move as quickly as possible to A1C testing using standardized methods and instrumentation.”⁵

Guidelines issued by international healthcare organizations effectively followed the course and timing of revised US guidelines. In 2005, a consultation panel convened by the World Health Organization (WHO) judged that HbA1c should not be adopted as a diagnostic test, because the “challenges of measurement accuracy outweighed the convenience of its use.” But in 2009, WHO convened a new consultation panel, which ultimately issued a report recommending the adoption of HbA1c testing for the diagnosis of diabetes, “providing that stringent quality assurance tests are in place and assays are standardized to criteria aligned to the international reference values, and there are no conditions present which preclude its accurate measurement.”⁶

HbA1c Testing in Practice

Diagnostic testing by means of an HbA1c test is typically recommended for patients who are experiencing symptoms suggestive of diabetes, such as increased thirst, increased urination, blurred vision, fatigue, or a combination of all four of these ailments. Individuals who are physically inactive, overweight, have high blood pressure, or a history of heart disease, are more frequently predisposed to diabetes, and are thus also likely candidates to undergo an HbA1c test.⁷

A patient’s HbA1c level is a unique indicator of average blood glucose status over an extended period. The HbA1c test helps providers and patients come to diagnostic conclusions by quantifying the average amount of glucose attached to hemoglobin within the body over the course of the previous 3 months. As the lifespan of a single red blood cell rarely exceeds this 3-month window, an HbA1c test is able to measure an individual’s average blood glucose level over an extended period, rather than detecting the glucose level only at the time when the test is conducted.

The HbA1c test involves a healthcare professional—typically a phlebotomist, physician, or laboratorian—taking a sample of blood from the individual being tested via a small needle. The venous blood sample, usually retrieved from a vein in the patient’s forearm, is captured in a blood collection tube and assessed. The calculated percentage of glucose is reported back to the provider; the higher the percentage, the higher the individual’s average HbA1c level over the preceding 3 months.

HbA1c testing offers a number of advantages over other alternatives available for either screening or diagnostic testing. Unlike an FPG test, the HbA1c test does not require the patient to fast prior to submitting a blood sample. And unlike a 2HPG test, an HbA1c test does not require the patient to drink a glucose solution, or to wait for hours until the patient’s response can be measured. HbA1c tests can be performed at any time, day or night, without any significant patient preparation or waiting time.

“Laboratory testing is very well regulated, and providers understand that in order to screen patients, their methods must be cleared for diagnosis,” says Shanti Narayanan, marketing manager at Tosoh Bioscience, San Francisco. “The criteria used are very stringent, and those administering HbA1c tests work to closely follow national guidelines and best practices.” Narayanan stresses that tests need to be robust, sensitive, and precise in order to be used for diagnostic purposes. Otherwise, a test simply provides the patient with a number, and the patient won’t be able to determine what to do if that number changes.

In accordance with such standards, a normal HbA1c level rests just below 5.7%. Readings between 5.7% and 6.4% are considered to signify a patient who is prediabetic. HbA1c levels at or above 6.5% are considered to indicate that the patient is diabetic and should therefore undergo confirmatory testing, unless there are indisputably clear symptoms of the disease.⁸ If repeat testing confirms the initial diagnosis, the patient can be guided toward effective interventions to help reduce and manage their blood glucose level.

Monitoring

In line with current understandings about the benefits of glycemic control, ADA guidelines recommend that diabetic patients undergo regular testing to assess their glucose levels.

In the past—prior to the advances that have led to the widespread adoption of HbA1c for both screening and diagnostic applications—such monitoring would likely have been performed exclusively through self-monitoring of blood glucose (SMBG) using fingerstick collection of capillary blood and a handheld glucose monitor.

However, ADA’s current recommendations provide only limited support for SMBG. The guidelines call SMBG “an integral component of effective therapy of patients taking insulin,” and acknowledge that SMBG “may help with self-management and medication adjustment, particularly in individuals taking insulin.”²

But the guidelines also note that “in people with type 2 diabetes not using insulin, routine glucose monitoring may be of limited additional clinical benefit.”²

“Several randomized trials have called into question the clinical utility and cost-effectiveness of routine SMBG in noninsulin-treated patients,” the guidelines observe. “The ongoing need for and frequency of SMBG should be reevaluated at each routine visit to avoid overuse, particularly if SMBG is not being used effectively for self-management.”²

In place of SMBG, ADA now recommends that a patient’s glycemic control should be assessed primarily through the use of the HbA1c test, and that most diabetic patients should seek to keep their HbA1c levels below 7% (see “Staying on Target”). Patients who are able to meet their treatment goals and have stable glycemic control should undergo HbA1c testing at least twice per year, while those who are not meeting their goals should be tested quarterly.⁸

“Generally, when testing happens in adherence to these frequencies, patients do better,” says Parker. “However, adherence to these guideline levels of testing has been shown to be suboptimal.⁹ There is room for improvement, and implementing opportunistic point-of-care testing is one strategy to address that. One study has shown a significant increase in adherence to guideline testing frequency with the implementation of point-of-care testing.”¹⁰

Patient Response

“Patients do not always understand the differing roles played by diagnostic technologies such as the HbA1c test,” says Narayanan. “Patients typically go to a doctor and the doctor will order the HbA1c test. They understand to an extent that the HbA1c test is better—and preferred to an individual testing their glucose levels each day—but that’s about the extent of it.”

“I agree that the lay public understands very little of what is being measured during an HbA1c test,” says John Ryals, the recently retired president and CEO of Metabolon, Morrisville, NC. “Generally speaking, most providers do the best they can to reach results while following ADA guidelines.”

“The majority of people with diabetes are most familiar with the blood glucose and HbA1c tests,” says Borses. “They associate the glucose test with blood sugar, but do not always fully understand what the HbA1c test is for. Conceptually, it’s a bit different from what most people imagine. Most people expect blood testing to determine what’s in the blood right now—not what was in the blood during a preceding 3-month window.”

HbA1c in the Lab

Many healthcare providers and patients continue to associate testing performed in clinical laboratory settings with the achievement of test results that are more accurate than those from testing performed in other settings. Although many types of tests are beginning to be cleared for use in primary care or near-patient settings, says Borses, some physicians still believe that the lab is truly the best environment for performing patient testing.

In the context of a population with a high rate of undiagnosed diabetics, simple and accurate laboratory HbA1c tests continue to play an important role, making opportunistic testing available for patients who would otherwise not be tested (see “Diabetes and the Clinical Laboratory”). By consolidating a patient’s testing into a reduced number of visits to the laboratory, labs can help to overcome the barriers that reduce compliance with ADA recommendations for HbA1c testing (Figure 1).

“Laboratories are constantly trying to make testing easier and more patient-friendly,” says Narayanan. “Testing is so much easier now than what it once was. The amount of blood required is far less, and the overall experience is much more user-friendly.”

Laboratories also have a headstart on how to calibrate test results across sites and platforms. “HbA1c test results are quantitative, so providers must calibrate the results to ensure accuracy,” says Narayanan. “The numbers have to match from one lab to another, and across various platforms. This is the whole point of standardization, so that the patient’s test results remain comparable, regardless of where the tests are done.”

Yet, study comparisons have suggested that such standardization is not always accurate, and that HbA1c values obtained from point-of-care (POC) instruments can sometimes be less than the comparable results obtained using central laboratory instruments.¹¹ “Clinicians should be aware of any discrepancies between POC A1C and central laboratory values and, if necessary, carry out a local audit,” the researchers report. “It should be dangerous to rely only upon POC A1C to evaluate the quality of long-term glucose control in diabetic patients. Measurement of HbA1c by laboratory method should be performed at least once a year.”

HbA1c at the Point of Care

When making its initial recommendation for HbA1c to become the standard for diabetes diagnosis, the 2009 international executive committee stopped short of advocating the use of POC versions of the test for diagnosis. “A1C tests to diagnose diabetes should be performed using clinical laboratory equipment. Point-of-care instruments have not yet been shown to be sufficiently accurate or precise for diagnosing diabetes.”⁵

But since that time, the technologies for and standardization of POC HbA1c testing have advanced considerably, to the point that it is gradually displacing other technologies for diabetes screening, diagnosis, and monitoring. Benefits of POC HbA1c testing for clinicians and patients include near-immediate test results, without extensive instrumentation or wait times (Figure 2). Patients need this knowledge to understand which methods result in the most informative short- and long-term test results, helping them identify optimal treatments if necessary.

“If real-time results can be captured opportunistically, when a patient presents to a physician’s office, this provides an opportunity to lead to timely diagnosis and treatment monitoring,” says Parker. “Clinical lab results have long been critical for informing healthcare practitioner decisionmaking. But now, as testing is moving closer to the patient, the delivery of test results can also become a vehicle for furthering a patient’s education, understanding, and engagement in managing their own health. Using a POC HbA1c test to perform diagnostic testing in a physician office lab can be another beneficial step in this direction.”

“There are some controversies surrounding ADA’s recommendation of HbA1c testing to diagnose diabetes in POC settings,” says Borses. “Some physicians question whether the HbA1c test captures all the people with prediabetes and diabetes. For example, HbA1c tests may respond differently to individuals of certain backgrounds, including some individuals of African descent. Therefore, some physicians have reasoned that including supplemental tests would bring up the capture rate.”

Nevertheless, says Narayanan, “the general trend is heading more toward ‘near-patient’ testing.”

“ADA guidelines recommend the use of POC HbA1c testing for monitoring patients with diabetes because this approach provides opportunities for more timely treatment interventions with patients,” says Parker. “When such test results are available to the patient and the physician during consultation, they can in some cases completely change the visit. Suddenly, the patient’s symptom of a pounding headache has more meaning when the patient’s HbA1c level is found to be very high. Having such results in hand may allow for changes in the patient’s treatment plan, providing a more complete clinical picture. But it also affords a ‘teachable moment’ between the physician and the patient, where patients can gain a greater understanding of what they can do to improve their test results.”

“Today, most clinicians think that POC HbA1c testing is extremely valuable, because it presents the picture of what has been happening over the past 3 months,” agrees Borses. “It’s the type of test that is of greatest value when the patient is right there. It’s not going to change moment-to-moment or day-to-day.”

“As more technologies become available, moving them closer to the patient, where they can inform the patient-physician dialogue, may help patients to develop a better understanding of the technologies, of their own condition, and how best to affect their own health outcomes,” adds Parker.

Conclusion

The International Diabetes Federation estimates that by 2045 the global incidence of diabetes may rise to 629 million people—a 48% increase over current levels.⁷ Such an increase would lead to one in every three people having some degree of the complex disease. Being able to ensure that such an ever-growing diabetic population can be properly identified, diagnosed, and monitored will be critically important for patient management.

Meanwhile, the introduction of new technologies and innovations for diabetes diagnosis and monitoring is expected to continue. In the future, expanded POC testing menus and technology, advances in continuous glucose monitoring, and closed-loop system development will all change the world of diabetes diagnosis and monitoring.

“As more robust information becomes immediately and seamlessly available to patients and clinicians—at more touchpoints across the continuum of care, and for different types of diabetes patients along their journey—technology will become a health enabler,” says Parker. “Technology will not be the solution to the epidemic of diabetes by itself, but it will provide much-needed health insights to enable patients to achieve their optimal health.”

With recent advances in HbA1c testing, specialists are now better assured of obtaining precise test results, regardless of whether the tests are carried out in laboratory or near-patient settings. It will always be necessary to evaluate new versions of the test for possible performance limitations, including the handling of hemoglobinopathies prevalent in certain patient populations. But current generations of HbA1c tests are already making inroads on patient engagement, with POC testing strategies that encourage patients to become more involved in managing their own care.

Lindsey Nolen is a freelance healthcare writer based in Florida. For further information, contact CLP chief editor Steve Halasey via [email protected].

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