Prediabetes: Pre- Does Not Mean Preordained

Although the number of U.S. adults diagnosed with diabetes has decreased in recent years, about 1.4 million new cases of diabetes were diagnosed in Americans aged 18 to 79 in 2014, and that number remains near historic highs. But the prevalence of diagnosed diabetes in the United States is dwarfed by the prevalence of undiagnosed diabetes and prediabetes (Figure 1). As of 2012, about 21 million Americans had diagnosed diabetes. More than 4 times as many—86 million—had prediabetes and an additional 8 million had diabetes that hadn’t been diagnosed (CDC 2014).

Prediabetes is an intermediate stage between normal, healthy glucose tolerance and the more severe glucose intolerance that characterizes type 2 diabetes. Without appropriate lifestyle interventions, about 15% to 30% of U.S. adults with prediabetes will go on to develop full-fledged type 2 diabetes within 5 years; on an annual basis, 11% of prediabetic adults who fail to improve their diet and increase their physical activity will develop type 2 diabetes (CDC 2013).

Prediabetes encompasses impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both. It can also be defined with the results from a glycated hemoglobin (HbA1c) test: prediabetes is 5.7% to 6.4% and diabetes is 6.5% or higher (Table 1). Prediabetes does not always lead to type 2 diabetes, although a majority of people with prediabetes—up to 70%—eventually progress to type 2 diabetes. Over the short term (3 to 5 years), about 25% of people with IFG or IGT progress to diabetes, 25% revert to normal glucose tolerance, and 50% remain in the IFG or IGT category (Nathan 2007).

Prediabetes that does not progress to diabetes is associated with a modestly increased risk for cardiovascular disease (HR, ~1.1–1.4). But the main reason to be concerned about prediabetes is the risk of it developing into diabetes. Among those who develop type 2 diabetes, the risk for cardiovascular disease doubles or even quadruples compared with those in the prediabetes category (Nathan 2007). Furthermore, microvascular complications (retinopathy, neuro­pathy) that develop subclinically while someone is in the prediabetes phase may become more serious and start producing symptoms by the time type 2 diabetes is diagnosed.

In addition to reducing morbidity and mortality and improving patients’ quality of life, an economic argument can be advanced for identifying and treating people with prediabetes, given the prevalence of type 2 diabetes and the high cost of treating episodes of its macrovascular and microvascular complications (Figure 2). In 2012, medical costs associated with diabetes and prediabetes amounted to $244 billion, but medical costs associated only with prediabetes accounted for just 18% of that amount (Figure 3) (Dall 2014).

On the other hand, the prediabetes label may cause undue alarm if physicians and other clinicians fail to help patients understand that prediabetes does not necessarily lead to diabetes. Only in rare cases is treatment with medication warranted, and people can have a positive influence on their chances of progressing to diabetes by improving their diets and becoming more physically active. In the wrong circumstance, categorizing people as having prediabetes could lead to overtreatment and added expense.

Screening and diagnosis

The American Diabetes Association (ADA) recommends glucose screening for all adults aged 45 years and for adults of any age who are overweight or obese and have additional risk factors (Table 2).

In a 2015 update of its 2008 recommendation, the United States Preventive Services Task Force (USPSTF) recommended screening asymptomatic nonpregnant adults, ages 40 to 70, for glucose abnormalities and type 2 diabetes if their body-mass index (BMI) is 25 or greater (Siu 2015). The task force previously recommended screening asymptomatic adults for diabetes if they had sustained blood pressure >135/80 mmHg (treated or untreated) (Selph 2015b).

The ADA today recognizes three blood tests to screen for and diagnose prediabetes and diabetes: the oral glucose tolerance test (OGTT), which is also known as the 2-hour plasma glucose test; fasting plasma glucose (FPG); and HbA1c (Table 1). The FPG test measures the amount of plasma glucose after a fast of at least 8 hours. The OGTT begins with an FPG test, after which the patient ingests 75 g of glucose, which stimulates insulin secretion; plasma glucose is measured 2 hours after the glucose is swallowed. The HbA1c test measures the percentage of hemoglobin A (the predominant form of hemoglobin) to which glucose has bound, forming glycated hemoglobin. Once formed, HbA1c persists in a red blood cell until the cell dies. Because red blood cells live about 2 or 3 months, measuring the percentage of HbA1c provides a long-term picture of glycemic levels, in contrast to snapshots provided by glucose tests taken on a single day. These tests should not be regarded as just different ways to measure the same phenomenon, however.

The ADA notes that each test is equally appropriate but that a given test may fail to detect diabetes or prediabetes in an individual (ADA 2016a). That can happen because the physiologic mechanisms underlying IFG and IGT are different. IFG is characterized by hepatic insulin resistance, while IGT is characterized by insulin resistance in skeletal muscle and greater beta-cell dysfunction (Table 3, Figure 4).

Interventions

The goal for patients with prediabetes is to stave off progression to full-blown diabetes. The ADA recommends intensive counseling about diet and physical activity that aims for losing 7% of body weight. The term physical activity includes but is not restricted to structured exercise. For certain patients (BMI >35, age <60 years, history of gestational diabetes), metformin therapy also should be considered in addition to lifestyle modification (ADA 2016b).

The USPSTF found that a substantial body of evidence supports similar behavioral intervention because at-risk patients tend to have multiple risk factors. Eating healthy foods and becoming more physically active address elevated blood sugar, excessive weight, high blood pressure, and elevated lipid levels all at once, in contrast to drug treatment narrowly focused on individual risk factors (Siu 2015).

Research shows that lifestyle modifications modestly reduce the risk for CVD in populations with multiple risk factors such as excessive weight, hypertension, lipid disorders, and IFG or IGT. But in studies of patients with IFG or IGT, lifestyle interventions were found to decrease the risk of progression to diabetes by 45% (pooled RR, 0.55; CI, 0.43–0.70) (Selph 2015a). The USPSTF notes that while metformin and other drugs are effective in reducing progression to diabetes in patients with glucose abnormalities, lifestyle modifications (dietary changes and increased physical activity) are more effective.

Yet in its review, the USPSTF found little evidence from randomized controlled trials (RCTs) showing that treating IFG, IGT, or diabetes detected via screening results in mortality benefits. The USPSTF said the best (and only) evidence available for such a benefit comes from a Chinese study in which 6 years of lifestyle intervention after 23 years of follow-up resulted in a 29% reduction in risk for all-cause mortality (HR, 0.71 [CI, 0.51–0.99]) and a 41% reduction in risk for cardio­vascular mortality (HR, 0.59 [CI, 0.36–0.96]) compared with usual care (Selph 2015a). After 20 years of follow-up, however, no statistically significant difference in all-cause mortality and cardio­vascular mortality had been observed. This study enrolled overweight adults (mean BMI, 25.8) with IGT. Neither was any mortality benefit found in similar trials with shorter follow-up than the Chinese study.

Trials of drug treatment—with or without lifestyle intervention—in people who are overweight or obese with IFG, IGT, or early diabetes have shown no mortality benefit and few differences in other health outcomes (Selph 2015a). For eight studies of glucose-lowering drugs, the pooled odds ratio for all-cause mortality was 1.1 (CI, 0.87–1.18); for cardiovascular mortality, 1.06 (CI, 0.84–1.35). Because of the high cost, large number of subjects, and lengthy follow-up required, it is doubtful that an RCT ever will be conducted to find out if there is a mortality benefit from screening for prediabetes.

The dearth of evidence from RCTs is offset to some extent by the substantial amount of evidence showing that lifestyle interventions can delay—and possibly prevent—prediabetes from worsening into diabetes. Moreover, there is little, if any chance, of harm from improved diets or greater physical activity. For these reasons, the USPSTF sees a moderate net benefit in screening for abnormal glucose metabolism.

Debate about definitions

Over the past 3 decades, the concept of prediabetes and the appropriate method for identifying it has been the subject of extensive debate and revision. The National Institute of Diabetes and Digestive and Kidney Diseases assembled a small group of diabetes experts in the late 1970s called National Diabetes Data Group (NDDG). In 1979, the NDDG defined diabetes in 3 ways: by the presence of classic symptoms, by FPG ≥140 mg/dL, or by 2-hour plasma glucose ≥200 mg/dL. At the same time the NDDG also introduced impaired glucose tolerance as an intermediate stage between normal glucose tolerance and diabetes. IGT was defined as FPG <140 mg/dL at the start of the OGTT and 2-hour plasma glucose ≥140 to 199 mg/dL. The OGTT was widely regarded as the gold standard for diagnosing diabetes.

An argument supporting the initial range defining IGT was that microvascular complications of diabetes were thought to be relatively rare within the range. In 1997, however, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus challenged this notion by citing studies of diabetic retinopathy in three populations: Pima Indians, Egyptians, and the general U.S. population. Those studies used OGTT, FPG, and HbA1c tests; retinopathy was determined via fundus photography or ophthalmoscopy. In all three populations, similar thresholds for 2-hour plasma glucose, FPG, and HbA1c were identified, below which the prevalence of retinopathy was low and above which it was much higher. The FPG cutpoint in those studies was well below the 140 mg/dL level that triggered a diabetes diagnosis according to the 1979 NDDG definition. As a result, the committee recommended that diabetes be diagnosed at a lower FPG concentration, 126 mg/dL, and this recommendation was adopted by the ADA.

In addition, the committee recommended that impaired fasting glucose, defined as FPG ≥110 mg/dL to 125 mg/dL, be used to describe the intermediate state between normal glucose tolerance and diabetes. The ADA also adopted this recommendation. The previous conventions for OGTT and IGT stayed in place. The World Health Organization, which concurred with the 1979 definitions, went along with most of what the expert committee said in 1997 except for continuing to regard OGTT as the gold standard and recommending that it be used whenever feasible to make sure patients with IFG didn’t have diabetes.

In 2003, the expert committee made a further adjustment, lowering the threshold for IFG from 110 mg/dL to 100 mg/dL so that IFG would be more comparable with IGT, from a numerical perspective, with respect to prevalence.

The most recent change, setting the current testing triad in place, came from a recommendation from a third group, the International Expert Committee (IEC), whose members were appointed by the ADA, the European Association for the Study of Diabetes, and the International Diabetes Federation. The IEC added HbA1c testing as a tool for diagnosing prediabetes and diabetes (IEC 2009), arguing that the correlation between HbA1c and retinopathy was stronger than the correlation between FPG and retino­pathy, and that a measure that captures long-term glucose levels is superior to the measure of a single point. In 1997, the Expert Committee had cited the lack of assay standardization as a reason for not adopting HbA1c as a diagnostic tool. Although this objection had been overcome by 2003, the expert committee still recommended against using HbA1c to diagnose diabetes. The ADA adopted the IEC recommendation, however, and added HbA1c testing to its 2010 standards of medical care (ADA 2010), with HbA1c ≥6.5% designating diabetes and with HbA1c in the range of 5.7% to 6.4% identified as prediabetes.

In its 2009 report, the IEC went beyond simply endorsing HbA1c testing, however. It rejected the notion that any test is the gold standard, with respect to microvascular and macro­vascular complications of diabetes and took issue with the concepts of prediabetes, IFG, and IGT:

While there appears to be an approximate glycemic threshold above which the risk for retinopathy escalates, there does not appear to be a specific level at which risk for diabetes clearly begins. A continuum of risk for the development of diabetes across a wide range of subdiabetic A1c levels may make the classification of individuals into categories similar to IFG and IGT equally problematic for A1c, as it implies that we actually know where risk begins or becomes clinically important. The continuum of risk in the subdiabetic glycemic range argues for the elimination of dichotomous subdiabetic classifications, such as “pre-diabetes,” IFG, and IGT.

But the committee’s prediction that, with the arrival of HbA1c testing, “the categorical clinical states prediabetes, IFG, and IGT ... will be phased out” has not yet happened (and neither has HbA1c testing replaced the fasting glucose test). As of 2016, these terms continue to be prominent in the ADA’s annually revised standard of care for diabetes.

The takeaway

Determining whether a person has prediabetes could be a starting point for helping patients to adopt a healthier lifestyle, but an assessment of the person’s risk for progressing to type 2 diabetes requires identifying the many other risk factors at play. A great advantage of the recommended inter­vention, lifestyle modification, for prediabetes is that it presents little or no drawbacks while addressing multiple risk factors—not just glucose levels but also high blood pressure, high triglycerides, low HDL-cholesterol, and excess weight, all of which are also risk factors for cardiovascular disease. Furthermore, improvements in diet and physical activity provide many benefits not easily captured by data entered into a medical record but which are commonly recognized by people who pursue such changes.

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Jack McCain is a freelance medical writer living in Durham, Conn. He has been writing about health care for almost 30 years.