Type 2 diabetes confers high risk for kidney disease, cardiovascular disease, and general mortality. According to the World Health Organization (WHO), the international diabetes rate has nearly doubled in the past 3 decades, mostly due to obesity and unhealthy diets. Meanwhile, an estimated 29.1 million people, or 9.3% of the U.S. population, have the disease, according to the U.S. Centers for Disease Control and Prevention.

Along with the rise in diabetes diagnoses, more people also are at risk for developing this disease. The percentage of prediabetes—the reversible precursor to diabetes—grew almost 10% just between 2010 and 2012, according to the American Diabetes Association (ADA), and about 84 million adults in the U.S. now have the condition. About 70% eventually develop full-blown diabetes, yet 90% of individuals are unaware of being in this vulnerable state.

Screening patients for prediabetes, also known as intermediate hyperglycemia, could be the wake-up call they need to make lifestyle changes or even begin medical interventions to forestall diabetes. This would seem simple enough, but unlike the definition of diabetes, no universal consensus exists for prediabetes. Further, the three methods of measuring glucose control for diagnosis capture different aspects of glucose homeostasis, so an individual deemed to have prediabetes by one method might not be by another.

“Although organizations provide conflicting messages, the goal is to prevent diabetes,” said Jane Reusch, MD, professor of medicine, biochemistry, and bioengineering and associate director of the Center for Women’s Health Research at the University of Colorado School of Medicine in Aurora. “Prediabetes is a risk factor, and the controversial question is how much risk and in whom. The goal is to identify people at risk for diabetes and its complications and introduce lifestyle changes targeting physical activity and weight loss to prevent diabetes.”

Definition Divergence

Three key organizations—ADA, WHO, and the International Expert Committee (IEC)—together have proposed a total of five different criteria for prediabetes based on results of fasting glucose (FG) concentration, 2-hour glucose (2HG) concentration after a 75g glucose load, or HbA1c results (see Table 1). Among these different definitions, ADA and WHO agree on two—FG between 100–125 mg/dL and 2HG between 140–199 mg/dL—while ADA and IEC agree on one, HbA1c, albeit with different thresholds, 5.7–6.4% and 6.0–6.4%, respectively.

prediabetes definitions WHO ADA IEC

The varying definitions cause confusion for patients and physicians and have different sensitivities, specificities, and morbidity and mortality hazard ratios. They also identify different groups of people, said experts.

“A barrier to getting people into prevention programs is a lack of consensus on the optimal definition of prediabetes,” said Elizabeth Selvin, PhD, MPH, professor of epidemiology and medicine at Johns Hopkins Bloomberg School of Public Health and School of Medicine in Baltimore. “We need consensus to develop clear prevention strategies and to determine who is eligible for treatment programs and insurance coverage.”

Different At-Risk Populations, Outcomes

Recent studies have highlighted how the three glucose-related measurements identify different prediabetes populations. For example, a systemic review and meta-analysis of 99 studies found HbA1c is neither sensitive nor specific for detecting prediabetes and that FG is specific but not sensitive (BMJ 2017;356:i6538). The investigators found HbA1c had a mean sensitivity of 0.49 and specificity of 0.79, although studies used different cutoffs. FG had a mean sensitivity of 0.25 and specificity of 0.94. Meanwhile, different measures of glycemia identified different subpopulations. For example, 47% of people with abnormal HbA1c had no other glycemic abnormality.

“As different tests for prediabetes define vastly different populations, large numbers of people will be unnecessarily treated or falsely reassured depending on the test used,” wrote the researchers, noting that many people diagnosed with prediabetes never develop diabetes.

“The most important message from this paper is that each test identifies a different prediabetic population with limited overlap,” said first author Eleanor Barry, MBBS, MRCP, MRCGP, a general practitioner and National Institute for Health Research in Practice fellow at the University of Oxford’s Nuffield Department of Primary Care Sciences in the United Kingdom.

A study Selvin led comparing risk of future outcomes across different prediabetes definitions among more than 10,000 black and white Americans followed for 10 years found that HbA1c-based definitions had stronger associations with long-term outcomes and offered modestly more risk discrimination than glucose-based definitions for many major complications (Lancet Diabetes Endocrinol 2017;5:34–42). HbA1c-related definitions resulted in lower prevalence estimates than WHO and ADA cutoffs for FG and 2HG. Meanwhile, ADA FG and WHO 2HG-based definitions of prediabetes were more sensitive for long-term outcomes. Among the many considerations for settling on a prediabetes definition is long-term risk associations and the populations in question, according to the researchers.

An accompanying editorial emphasizes the extent to which the various definitions differ in whom they identify as having prediabetes. For example, ADA’s FG concentration-based definition had the lowest false positive rate, but missed 38% of participants otherwise identified with prediabetes. More than one-third of this population would be diagnosed with a medical condition by these definitions, despite their relatively low risk of morbidity and mortality, wrote Lydia Makaroff, MPH, PhD, an associate researcher at University of Leuven in Belgium and director of the European Patient Cancer Coalition. ADA and WHO 2HG cutoffs identified 28% of a group of 7,194 participants found to have prediabetes. These criteria were more likely to identify participants who were female, black, and obese than definitions based on FG results, Makaroff wrote.

Meanwhile, participants identified with prediabetes by either ADA’s or IEC’s definitions had higher hazard ratios for chronic kidney disease, cardiovascular disease, peripheral artery disease, and all-cause mortality than those identified by FG, after adjusting for age, sex, race, and testing center. Those diagnosed based on HbA1c levels were more likely to be female and black than those identified by a FG definition, according to Makaroff.

The Way Forward

“Current HbA1c tests identify fewer individuals, but these individuals are at higher risk of complications,” explained Selvin. “Other tests identify a larger, broader group including individuals at lower risk.” A more expansive definition of prediabetes might identify additional individuals, but would be more expensive in the long run if everyone received intensive interventions. HbA1c may be more useful if the goal is to target people at highest risk, she added.

This nuanced picture may not come into sharp relief anytime soon, according to Barry. “For clinicians and laboratorians looking for the best test, easy answers don’t exist. Each test is associated with a different pathological process which leads to diabetes and cardiovascular disease,” she said.

Choice of test necessarily means considering both the logistics of performing each test and of acting on the results, Barry cautioned. “For example, if HbA1c identifies a significant number of people who would have a normal oral glucose challenge test, we must determine if resources are available to monitor, treat, and follow up with those patients,” she explained.

As Reusch sees it, one barrier to a clear, unified definition of and care associated with prediabetes from ADA, WHO, and IEC is that studies on interventions all have had their own investigation-specific guidelines and specific populations. For a strict evidence-based translation into practice, care providers would need to employ the criteria used in a specific trial, she emphasized. But pragmatic interventions needed across the globe to effectively decrease progression to diabetes “can be informed by meta-analyses and will ultimately shape the guidelines.”

When in Doubt, Double Up

With HbA1c and glucose-based tests frequently giving discordant results, Selvin, Barry, and Reusch all suggested using both tests in patients at risk for or suspected of having prediabetes. It’s valuable to figure out what the different information from each test means for an individual patient, Selvin said. Laboratorians who advise clinicians on prediabetes tests should explain their respective strengths and limitations, she added. For example, FG has more preanalytic variability, and anemias sometimes interfere with HbA1c, she noted. “Whatever the test, clinicians should repeat it if it is to be the basis for an intervention,” added Reusch.

Meanwhile, WHO is updating its guidelines on the classification and diagnostic criteria for diabetes mellitus and intermediate hyperglycemia, wrote Gojka Roglic, MD, technical officer in WHO’s Diabetes Unit, in online comments responding to Barry’s meta-analysis. According to Roglic, WHO plans to determine how well various cutoffs for glucose and HbA1C values predict diabetes, related complications, and mortality in people considered at high risk for the disease. This tactic represents a change from current guidelines, which consider tests’ diagnostic accuracy against gold standard FG and HbA1c cutoffs. WHO also will review the impact of lifestyle and treatment interventions on preventing or delaying type 2 diabetes and its associated complications in persons at increased risk, Roglic wrote.

Discussions like those WHO is undertaking “are the way forward,” said Selvin. Input from many stakeholders is necessary “to provide consistent, clear advice to labs and healthcare providers about prediabetes.”

In the meantime, she advised laboratorians and clinicians to consider not only tests’ biochemical aspects, but also wider questions “on what the diagnosis means to people and how they act on it,” stressing the importance of tests’ ability to monitor and support those patients who test positive for prediabetes.

Deborah Levenson is a freelance writer in College Park, Maryland. +Email: [email protected]