Diagnostic Criteria For Diabetes Mellitus
The new criteria
The diagnostic criteria for diabetes mellitus have been modified from those previously recommended by the NDDG [1] or WHO [2]. The revised criteria for the diagnosis of diabetes are shown in Table 3 . Three ways to diagnose diabetes are possible, and each must be confirmed, on a subsequent day, by any one of the three methods given in Table 3 . For example, one instance of symptoms with casual plasma glucose >=200 mg/dl (11.1 mmol/l), confirmed on a subsequent day by 1) FPG >=126 mg/dl (7.0 mmol/l), 2) an OGTT with the 2-h postload value >=200 mg/dl (11.1 mmol/l), or 3) symptoms with a casual plasma glucose >=200 mg/dl (11.1 mmol/l), warrants the diagnosis of diabetes.
For epidemiological studies, estimates of diabetes prevalence and incidence should be based on an FPG >=126 mg/dl (7.0 mmol/l). This recommendation is made in the interest of standardization and also to facilitate field work, particularly where the OGTT may be difficult to perform and where the cost and demands on participants' time may be excessive. This approach will lead to slightly lower estimates of prevalence than would be obtained from the combined use of the FPG and OGTT ( Table 4 ).
The Expert Committee recognizes an intermediate group of subjects whose glucose levels, although not meeting criteria for diabetes, are nevertheless too high to be considered altogether normal. This group is defined as having FPG levels >=110 mg/dl (6.1 mmol/l) but <126 mg/dl (7.0 mmol/l) or 2-h values in the OGTT of >=140 mg/dl (7.8 mmol/l) but <200 mg/dl (11.1 mmol/l). Thus, the categories of FPG values are as follows:
FPG <110 mg/dl (6.1 mmol/l) = normal fasting glucose;
FPG >=110 (6.1 mmol/l) and <126 mg/dl (7.0 mmol/l) = IFG;
FPG >=126 mg/dl (7.0 mmol/l) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above).
The corresponding categories when the OGTT is used are the following:
2-h postload glucose (2-h PG) <140 mg/dl (7.8 mmol/l) = normal glucose tolerance;
2-h PG >=140 (7.8 mmol/l) and <200 mg/dl (11.1 mmol/l) = IGT;
2-h PG >=200 mg/dl (11.1 mmol/l) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above).
Since the 2-h OGTT cutoff of 140 mg/dl (7.8 mmol/l) will identify more people as having impaired glucose homeostasis than will the fasting cutoff of 110 mg/dl (6.1 mmol/l), it is essential that investigators always report which test was used.
Rationale for the revised criteria for diagnosing diabetes
The revised criteria are still based on measures of hyperglycemia. Whereas many different diagnostic schemes have been used, all have been based on some measurement of blood or urine glucose, as reviewed by McCance et al. [125]. The metabolic defects underlying hyperglycemia, such as islet cell autoimmunity or insulin resistance, should be referred to independently from the diagnosis of diabetes, i.e., in the classification of the disease. Determining the optimal diagnostic level of hyperglycemia depends on a balance between the medical, social, and economic costs of making a diagnosis in someone who is not truly at substantial risk of the adverse effects of diabetes and those of failing to diagnose someone who is [126]. Unfortunately, not all these data are available, so we relied primarily on medical data.
Plasma glucose concentrations are distributed over a continuum, but there is an approximate threshold separating those subjects who are at substantially increased risk for some adverse outcomes caused by diabetes (e.g., microvascular complications) from those who are not. Based in part on estimates of the thresholds for microvascular disease, the previous WHO criteria defined diabetes by FPG >=140 mg/dl (7.8 mmol/l), 2-h PG >=200 mg/dl (11.1 mmol/l) in the OGTT, or both. These criteria effectively defined diabetes by the 2-h PG alone because the fasting and 2-h cutpoint values are not equivalent. Almost all individuals with FPG >=140 mg/dl (7.8 mmol/l) have 2-h PG >=200 mg/dl (11.1 mmol/l) if given an OGTT, whereas only about one-fourth of those with 2-h PG >=200 mg/dl (11.1 mmol/l) and without previously known diabetes have FPG >=140 mg/dl (7.8 mmol/l) [127]. Thus, the cutpoint of FPG >=140 mg/dl (7.8 mmol/l) defined a greater degree of hyperglycemia than did the cutpoint of 2-h PG >=200 mg/dl (11.1 mmol/l). It is the consensus of the Expert Committee that this discrepancy is unwarranted and that the cutpoint values for both tests should reflect a similar degree of hyperglycemia and risk of adverse outcomes.
Under the previous WHO and the NDDG criteria, the diagnosis of diabetes is largely a function of which test is performed. Many individuals who would have 2-h PG >=200 mg/dl (11.1 mmol/l) in an OGTT are not tested with an OGTT because they lack symptoms or because they have an FPG <140 mg/dl (7.8 mmol/l). Thus, if it is desired that all people with diabetes be diagnosed and the previous criteria are followed, OGTTs must be performed periodically in everyone. However, in ordinary practice, not only is the OGTT performed infrequently, but it is usually not used even to confirm suspected cases [128]. In summary, the diagnostic criteria are now revised to 1) avoid the discrepancy between the FPG and 2-h PG cutpoint values and 2) facilitate and encourage the use of a simpler and equally accurate test—fasting plasma glucose—for diagnosing diabetes.
The cutpoint for the 2-h PG has been justified largely because at approximately that point the prevalence of the microvascular complications considered specific for diabetes (i.e., retinopathy and nephropathy) increases dramatically. This property of the 2-h PG has been compared with the FPG in population studies of the Pima Indians in the U.S., among Egyptians, and in the Third National Health and Nutrition Examination Survey (NHANES III) in the U.S. In other studies, the relationships between glycemia and macrovascular disease have also been examined.
The relationships of FPG and 2-h PG to the development of retinopathy were evaluated in Pima Indians over a wide range of plasma glucose cutpoints (Fig. 2A) [129]. Both variables were similarly associated with retinopathy, indicating that by this criterion, each could work equally well for diagnosing diabetes. The authors concluded that both measures were equivalent in terms of the properties previously used to justify diagnostic criteria.
These findings were confirmed in a similar study in Egypt, in which the FPG and 2-h PG were each strongly and equally associated with retinopathy (Fig. 2B) [130]. For both the FPG and the 2-h PG, the prevalence of retinopathy was markedly higher above the point of intersection of the two components of the bimodal frequency distribution (FPG = 129 mg/dl [7.2 mmol/l] and 2-h PG = 207 mg/dl [11.5 mmol/l]).
In the NHANES III, 2,821 individuals aged 40-74 years received an OGTT, a measurement of HbA1c, and an assessment of retinopathy by fundus photography (K. Flegal, personal communication). Figure 2C shows that all three measures of glycemia (FPG, 2-h PG, and HbA1c) are strongly associated with retinopathy, which is similar to the relationships found in the Pima Indians [129] and Egyptians [130], although the relationship was strongest for 2-h PG. As in other studies, the prevalence rose dramatically in the highest decile of each variable, corresponding to FPG >=120 mg/dl (6.7 mmol/l), 2-h PG >=195 mg/dl (10.8 mmol/l), and HbA1c >=6.2%. As in the Pima Indian [129] and Egyptian [130] studies, estimates of these "thresholds" for retinopathy are somewhat imprecise. More precision cannot easily be obtained by using narrower glycemic intervals (e.g., 20 instead of the 10 shown in Fig. 2) because of the limited numbers of cases of retinopathy in each sample (32 cases in the Pima study, 146 in the Egyptian study, and 111 in NHANES III). There are no absolute thresholds because some retinopathy occurred at all glucose levels, presumably because of measurement or disease variability and because of nondiabetic causes of retinopathy.
The associations between FPG and 2-h PG and macrovascular disease have been examined in adults without known diabetes [131]. The 2-h PG was somewhat more closely associated with major coronary heart disease, but there was no significant difference in the association of the FPG or the 2-h PG with other indexes of macrovascular disease. Similarly, the relationship between glycemia and peripheral arterial disease was studied in 50- to 74-year-old Caucasians [132]. The prevalence of arterial disease was strongly related to the FPG and 2-h PG. The associations appeared to be of the same strength for both variables.
In a recent analysis of the Paris Prospective Study, the incidence of fatal coronary heart disease was related to both FPG and 2-h PG determined at a baseline examination [118]. Incidence rates were markedly increased at FPG >=125 mg/dl (6.9 mmol/l) or 2-h PG >=140 mg/dl (7.8 mmol/l). Similarly, the incidence of coronary artery disease and the all-cause mortality rates were predicted by the FPG in the Baltimore Longitudinal Study of Aging (R. Andres, C. Coleman, D. Elahi, J. Fleg, D.C. Muller, J.D. Sorkin, J.D. Tobin, personal communication). The incidence rates of both these outcomes increased markedly and almost linearly above FPG levels in the range of 110-120 mg/dl (6.1-6.7 mmol/l). In conclusion, both the FPG and 2-h PG provide important information regarding risk of both micro- and macrovascular disease, and the approximate thresholds for increased risk correspond with those for retinopathy and with the revised diagnostic criteria.
Reproducibility is another important property of a diagnostic test, a property for which the FPG appears to be preferable. When OGTTs were repeated in adults during a 2- to 6-week interval, the intra-individual coefficients of variation were 6.4% for the FPG and 16.7% for the 2-h PG [133].
It is important to review the rationale for retaining the diagnostic cutpoint of 200 mg/dl (11.1 mmol/l) for the 2-h PG. This cutpoint was originally adopted for three reasons [1,2]. First, 200 mg/dl (11.1 mmol/l) has been found to approximate the cutpoint separating the two components of the bimodal distribution of 2-h PG. Second, in several studies, the prevalence of microvascular disease sharply increased above 2-h PG levels of ~200 mg/dl (11.1 mmol/l). Third, an enormous body of clinical and epidemiological data has been collected based on the 2-h PG cutpoint of 200 mg/dl (11.1 mmol/l). Thus, this value has been retained for the diagnosis of diabetes because it would be very disruptive, and add little benefit, to alter the well-accepted 2-h PG diagnostic level of >=200 mg/dl (11.1 mmol/l).
Changing the diagnostic cutpoint for the FPG to 126 mg/dl (7.0 mmol/l) is based on the belief that the cutpoints for the FPG and 2-h PG should diagnose similar conditions, given the equivalence of the FPG and the 2-h PG in their associations with vascular complications and their discrimination between two components of a bimodal frequency distribution [129,130]. McCance et al. [129] computed the FPG level equivalent (in sensitivity and specificity for retinopathy) to the 1985 WHO criterion of the 2-h PG >=200 mg/dl (11.1 mmol/l) and found it to be an FPG of >=123 mg/dl (6.8 mmol/l) ( Table 5 ). Finch et al. [134] approached the problem in each of 13 Pacific populations surveyed with OGTTs by determining the value in the FPG that, when used alone as a diagnostic criterion, gave the same prevalence of diabetes as did 2-h PG >=200 mg/dl (11.1 mmol/l). The summary estimate from all these populations was a cutpoint of 126 mg/dl (7.0 mmol/l). The same method was applied to data derived from the Pima Indians and resulted in an FPG cutpoint of 120 mg/dl (6.7 mmol/l). In NHANES III, the corresponding cutpoint was 121 mg/dl (6.7 mmol/l) ( Table 5 ). These values and the 2-h PG cutpoint of 200 mg/dl (11.1 mmol/l) are also quite similar to the values of FPG 129 mg/dl (7.2 mmol/l) and 2-h PG 207 mg/dl (11.5 mmol/l) that separated the components of the bimodal frequency distributions and identified individuals with a high prevalence of retinopathy among Egyptians [130]. Because the standard errors of these estimates are not known, the small differences in the estimates shown in Table 5 may be consistent with sampling variability.
We chose a cutpoint at the upper end of these estimates (FPG >=126 mg/dl, 7.0 mmol/l). This value is slightly higher than most of the estimated cutpoints that would give the same prevalence of diabetes as the criterion of 2-h PG >=200 mg/dl (11.1 mmol/l). That is, slightly fewer people will be diagnosed with diabetes if the new FPG criterion is used alone than if either the FPG or the OGTT is used and interpreted by the previous WHO and NDDG criteria ( Table 4 ).
As noted above, although the OGTT is an acceptable diagnostic test and has been an invaluable tool in research, it is not recommended for routine use. Because of its inconvenience to patients and the perception by many physicians that it is unnecessary, the OGTT is already not widely used for diagnosing diabetes. In addition, it is more costly and time-consuming than the FPG, and the repeat test reproducibility of the 2-h PG is worse than that of the FPG [133]. If the OGTT is used, either for clinical or research purposes, the test procedure methods recommended by the WHO [2] and the diagnostic criterion in Table 3 should be employed.
HbA1c measurement is not currently recommended for diagnosis of diabetes, although some studies have shown that the frequency distributions for HbA1c have characteristics similar to those of the FPG and the 2-h PG. Moreover, these studies have defined an HbA1c level above which the likelihood of having or developing macro- or microvascular disease rises sharply (Fig. 2) [129,130,131,132]. Furthermore, HbA1c and FPG (in type 2 diabetes) have become the measurements of choice in monitoring the treatment of diabetes, and decisions on when and how to implement therapy are often made on the basis of HbA1c. These observations have led some to recommend HbA1c measurement as a diagnostic test [126,135].
On the other hand, there are many different methods for the measurement of HbA1c and other glycosylated proteins, and nationwide standardization of the HbA1c test has just begun [136]. Studies of the utility of the test compared with the FPG and 2-h PG have used different assays, thereby making it difficult to assign an appropriate cutpoint. Also, the FPG, 2-h PG, and HbA1c tests are imperfectly correlated. In most clinical laboratories, a "normal" HbA1c is usually based on a statistical sampling of healthy, presumably nondiabetic individuals. In conclusion, HbA1c remains a valuable tool for monitoring glycemia, but it is not currently recommended for the diagnosis of diabetes.
The revised criteria are for diagnosis and are not treatment criteria or goals of therapy. No change is made in the American Diabetes Association's recommendations of FPG <120 mg/dl (6.7 mmol/l) and HbA1c <7% as treatment goals [137]. The new diagnostic cutpoint (FPG >=126 mg/dl [7.0 mmol/l]) is based on the observation that this degree of hyperglycemia usually reflects a serious metabolic abnormality that has been shown to be associated with serious complications. The treatment of nonpregnant patients with hyperglycemia near the cutpoint should begin with an individualized lifestyle-modification regimen (i.e., meal planning and exercise). Initiation of pharmacological therapy in these patients has not yet been shown to improve prognosis and may lead to an unacceptably high incidence of hypoglycemic reactions with certain drugs (e.g., sulfonylureas, insulin).
The new criteria have implications for estimates of the prevalence of diabetes. Although an FPG >=126 mg/dl (7.0 mmol/l) and a 2-h PG >=200 mg/dl (11.1 mmol/l) have similar predictive value for adverse outcomes, the two tests are not perfectly correlated with each other. A given person may have one glucose value above one cutpoint and another value below the other cutpoint. Thus, simultaneous measurement of both FPG and 2-h PG will inevitably lead to some diagnostic discrepancies and dilemmas. Although diagnosing diabetes by either test will result in a similar number of "cases," different individuals in different hyperglycemic stages may be identified. (This situation would be even more complicated if a third diagnostic test, such as HbA1c, were used.) However, according to the data reviewed above, there is no basis for concluding that the 2-h PG is more reliable than the FPG. Thus, the FPG alone should be used for estimating the comparative prevalence of diabetes in different populations.
Table 4 shows the effect of the new diagnostic criteria on the estimated prevalence of diabetes in the U.S. population aged 40-74 years using data from NHANES III. Diagnosing diabetes in those without a medical history of diabetes by using only the FPG test would result in a lower prevalence of diabetes than would using WHO criteria (4.35 vs. 6.34%). The total prevalence of diabetes (including those with a medical history) would be 12.27%, or 14% lower than the prevalence of 14.26% by the WHO criteria. Of note, these prevalence estimates refer to results of testing on one occasion. The prevalence of diabetes confirmed by a second test will be lower regardless of which criteria are used.
Widespread adoption of the new criteria may, however, have a large impact on the number of people actually diagnosed with diabetes. Presently, about half the adults with diabetes in the U.S. are undiagnosed [127], but many might now be diagnosed if the simpler FPG test were always used.
Diabetes Care. 2000;23(1s) © 2000 American Diabetes Association, Inc.
Cite this: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus - Medscape - Jan 01, 2000.
