How Do We Diagnose Diabetes and to Practice Research From / Answers Many Three Controversies, Measure Blood Glucose Control? View 1 (Diagnosing) A Clinical Basis for the Diagnosis of Diabetes In Brief In 1979, criteria for the diagnosis of diabetes were selected based on levels of glycemia on the oral glucose tolerance test (OGTT) that were associated with the subsequent development of retinopapthy. Since then, five long-term stud- ies have demonstrated that when HbA1c levels are maintained below 7% (normal 6%), development of retinopathy and microalbuminuria is practical- ly nil. Approximately 60% of people with fasting plasma glucose (FPG) con- centrations of 126–139 mg/dl and 70% of those with 2-h values on the OGTT of 200–239 mg/dl have normal HbA1c levels, with another third hav- ing values between 6 and 7%. This article offers an alternative approach to diagnosis using both FPG and HbA1c values. Except for a few populations in which Table 1 were based on the glucose the prevalence of diabetes is very high concentrations of only 77 individuals and therefore the distribution of blood who did subsequently develop this Mayer B. Davidson, MD glucose concentrations is bimodal,1,2 a complication.8 unimodal distribution is the norm.3,4 Several years ago, the American Thus, there is no clear-cut demarca- Diabetes Association (ADA) con- tion between normal and abnormal vened an Expert Committee to re- blood glucose concentrations. examine the diagnosis and classifica- Before 1979, there were at least six tion of diabetes in light of new infor- sets of criteria upon which to base the mation acquired since the NDDG diagnosis of diabetes. This led to an report.9 One of the goals of the com- untenable situation in which the mittee was to make the fasting plas- prevalence of diabetes in populations ma glucose (FPG) and the 2-h blood differed and diabetes could be either glucose concentrations on the OGTT absent or present in an individual criteria equivalent for the diagnosis of depending on which set of criteria diabetes, i.e., if one of these criteria was used.5 were met, the other would likely be as In 1979, the National Diabetes well. This is not the situation with the Data Group (NDDG) adopted a set of criteria for the diagnosis of diabetes Table 1. Previous World and impaired glucose tolerance (IGT),6 Health Organization Criteria which were slightly modified a year for the Diagnosis of (IGT) and later by the World Health Organiz- Diabetes ation7 (Table 1). An oral glucose toler- ance test (OGTT) was administered to IGT Diabetes 1,277 individuals who were followed FPG <140 mg/dl ≥140 mg/dl for 3–8 years for the subsequent devel- opment of diabetic retinopathy. The and or rationale was that this specific compli- OGTT 140–199 mg/dl ≥200 mg/dl cation of diabetes would identify those (2-h)* subjects whose blood glucose values *2-h plasma glucose concentration fol- were high enough to reliably make the lowing 75 g of oral glucose diagnosis of diabetes. The criteria in 67 Diabetes Spectrum Volume 14, Number 2, 2001 19–24 Table 2. Expert Committee criteria diabetes. All five demonstrated that if the average HbA1c level were for the diagnosis of diabetes <1% above the upper limit of normal (ULN) for the assay used (e.g., <7% 1. Symptoms of diabetes plus casual plasma glucose concentration ≥200 mg/dl. Casual is defined as any time of day without regard to time since last meal. The for the assay used in the Diabetes classic symptoms of diabetes include polyuria, polydipsia, and unexplained Control and Complications Trial, in weight loss. which the ULN was 6.0%), there was or virtually no development or progres- 2. FPG ≥126 mg/dl. Fasting is defined as no caloric intake for at least 8 h. sion of diabetic retinopathy or nephropathy. If the average HbA1c or levels were between 1 and 2 percent- 3. 2-h plasma glucose ≥200 mg/dl during an OGTT. The test should be performed age points above the ULN, there was as described by the World Health Organization7 using a glucose load containing a slight increase in the development the equivalent of 75 g anhydrous glucose dissolved in water. and progression of these complica- In the absence of unequivocal hyperglycemia with acute metabolic decompensation, tions. Average values >2% above the these criteria should be confirmed by repeat testing on a different day. The third ULN were associated with much measure (OGTT) is not recommended for routine clinical use. higher risks for the microvascular complications. two criteria in Table 1. Although ommend for the diagnosis of diabetes My colleagues and I have had the ~95% of individuals with an FPG are shown in Table 2. They also opportunity to examine the relation- ≥ concentration 140 mg/dl had a 2-h defined a normal FPG concentration ship between HbA1c levels and FPG value on the OGTT ≥200 mg/dl,10 as <110 mg/dl and individuals with concentrations25 and 2-h glucose val- only one-fourth to one-half of people FPG concentrations of 110–125 mg/dl ues on an OGTT26 in two large popu- with 2-h values ≥200 mg/dl had FPG as having impaired fasting glucose lations. One cohort of 8,917 individ- levels ≥140 mg/dl.10–12 (IFG). uals was identified from published The committee decided to retain reports of the Meta-Analysis Re- ≥ the 2-h criterion of 200 mg/dl HbA1c Versus OGTT search Group on the Diagnosis of because of the many epidemiological If one accepts the logic that the level Diabetes Using Glycated Hemoglobin studies that used it to define diabetes. of glycemia chosen to diagnose dia- Levels (MRG)10 and therefore was Changing it, the committee noted, betes should be one that is associated not randomly selected. The second “would be very disruptive.”9 The with the specific complication of dia- cohort was the 2,836 randomly FPG concentration that yields an betic retinopathy (and I do), HbA1c selected individuals evaluated in the equivalent prevalence of diabetes levels are a better measure of Third National Health and Nutrition diagnosed by a 2-h value on the glycemia than values on the OGTT Examination Study (NHANES III). ≥ 9 OGTT of 200 mg/dl is 126 mg/dl. for two reasons. First, they reflect The distribution of HbA1c levels The committee also made several months of prevailing glucose concen- and selected intervals of FPG and 2-h other recommendations.9 Because of trations rather than one instance of glucose concentrations are shown in its poor reproducibility13–16 and limited time. Second, there have been five Table 3. Note that 60% of the use in clinical practice,17,18 the OGTT studies in several thousand diabetic patients with FPG concentrations of was not recommended to be used patients carried out over 6–9 years 126–139 mg/dl—the group of diabet- routinely to diagnose diabetes. (Per- relating the average HbA1c level to ic patients diagnosed by the new (but sonally, I agree with that position.) the development and progression of not by the old) FPG criterion—had The criteria the committee did rec- the microvascular complications of normal HbA1c levels in both popula- Table 3. Distribution (%) of HbA1c Levels NHANES III MRG Data Set b d Glucose No. of Subjects HbA1c (%) No. of Subjects HbA1c (%) (mg/dl) (%)a (%)c ≤6.1 6.2–7.0 ≥7.1 ≤6.3 6.4–7.2 ≥7.3 Fasting <110 2,284 (84) 97.3 2.7 0.1 7,908 (89) 96.2 3.63 0.2 110–125 373 (11) 86.7 13.1 0.2 602 (7) 81.4 16.4 2.2 126–139 77 (2) 60.9 35.8 3.4 131 (1) 59.6 16.4 7.6 ≥140 102 (3) 18.6 32.5 48.9 276 (3) 16.7 21.0 62.3 2-h OGTT <140 2,021 (76.2) 97.2 2.7 0.1 7,248 (81.3) 97.1 2.8 0.1 140–199 554 (17.1) 91.4 8.5 0.1 1,109 (12.4) 88.4 11.1 0.8 200–239 111 (2.80) 69.4 29.5 1.1 209 (2.4) 62.2 32.1 5.7 ≥240 150 (3.9) 40.9 24.7 34.4 349 (3.9) 21.8 25.8 52.4 aBased on U.S. population after weighting the surveyed population, which oversampled minorities. bUpper limit of normal = 6.1%. cPercent of MRG population. dUpper limit of normal = 6.3%. 68 Diabetes Spectrum Volume 14, Number 2, 2001 31 19–24 tions. Furthermore, another one-third and 20% already have retinopathy. nephropathy, and neuropathy, to Practice Research From / Answers Many Three Controversies, had HbA1c levels <1% above the In my view, this argument does not but recent reports have also demon- ULN for the assays used, values that hold. These people remain undiag- strated that blocking the production were associated with virtually no nosed because they are not evaluated, of advanced glycosylation end prod- development or progression of the not because the FPG concentration for ucts beyond the formation of HbA1c microvascular complications of dia- diagnosis is too high. (and therefore independent of hyper- betes.19–24 Regarding the 2-h glucose Similarly, the ADA committee glycemia) markedly retards the devel- criterion on the OGTT of ≥200 included macrovascular disease in its opment of these complications.37–40 mg/dl, unchanged by the ADA Expert contention that earlier diagnosis and Given the importance of excessive Committee,9 approximately two- appropriate treatment would decrease glycation of proteins in the pathogen- thirds of individuals with values of the subsequent complications of dia- esis of the diabetic microvascular and 9 200–239 mg/dl had normal HbA1c betes.