How Do We Diagnose Diabetes and Three Controversies, Many Answers / From Research to Practice 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, Three Controversies, Many Answers / From Research to Practice 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. This reasoning is also suspect neuropathic complications and the levels, and most of the remainder had because the increased risk for coro- principle that the level of glycemia values <1% above the ULN, suggest- nary artery disease extends all the associated with these complications is ing that ≥240 mg/dl may be a more way down to the highest quartile of appropriate for the diagnosis of dia- appropriate cutoff point. normal FPG concentrations.32–34 betes, an alternative approach to (After this article was submitted, a diagnosis, which takes into account The Case for HbA1c new study was published of the 4- these clinical outcomes, is suggested In view of the close relationship year incidence of the age-adjusted in Figure 1. This diagnostic algorithm between HbA1c levels and the micro- rate of ischemic heart disease in 4,662 uses measurements of FPG concentra- vascular and neuropathic complica- men aged 45–79 years. It revealed a tions followed by HbA1c levels in tions of diabetes, and the dictum that marked increase in the relative risk of people whose FPG values are neither ≥ only blood glucose concentrations that those with HbA1c levels 5.0% com- normal (<110 mg/dl) nor meet the are associated with the subsequent pared with individuals with lesser val- older criterion for the diagnosis of 41 ≥ development of retinopathy are suit- ues, confirming the earlier studies diabetes ( 140 mg/dl). The HbA1c able for the diagnosis of diabetes, that utilized glucose concentrations.) level determines whether an individ- what is the justification of making this Furthermore, improved glycemic ual with an FPG concentration of diagnosis in individuals with normal control (unfortunately) has little 110–139 mg/dl has diabetes or a HbA1c values? Not only will ~60% of effect on the morbidity and mortality milder degree of hyperglycemia. An people with FPG concentrations of from cardiovascular disease in people HbA1c level 1 percentage point or 35 126–139 mg/dl have normal HbA1c with diabetes. A number of other more above the ULN for the assay levels, an additional one-third will risk factors need addressing, but their used, if confirmed, makes the diagno- have values that meet the ADA goal prevalences are similar in those with sis of diabetes. A lower value makes (i.e., <7% for assays with a ULN of IFG (FPG concentrations of 110–125 the diagnosis of IFG, which is a high- 6%) before any treatment is initiated. mg/dl) and those in the new cohort of risk category for the future develop- We must balance the advantages of diabetes (FPG concentrations of ment of both diabetes and cardiovas- diagnosing diabetes against its poten- 126–139 mg/dl).36 Thus, from a cular disease and warrants close fol- tial disadvantages in terms of insur- macrovascular perspective, there is no low-up and aggressive treatment of ance (both life and medical), employ- advantage in distinguishing between the risk factors for each. ment, and psychosocial implica- the two groups and labeling people in It has been argued that HbA1c tions.27–29 For instance, people carry- the latter group as having diabetes. assays are not yet standardized ing the diagnosis of diabetes are eight Not only are HbA1c levels so tight- enough to be used in the diagnosis of times more likely to be unable to ly linked to diabetic retinopathy, diabetes.9 However, using an assay obtain medical insurance because of poor health or illness than are those without diabetes.29 It is not clear that it would be helpful to label people with FPG con- centrations of 126–139 mg/dl (or 2-h values on an OGTT of 200–239 mg/dl) but with normal or only slight- ly elevated HbA1c levels as having diabetes. Their treatment would be the same lifestyle therapies of diet and exercise as would be prescribed for individuals with similar HbA1c levels but FPG concentrations of 110–125 mg/dl, which qualifies them for the diagnosis of IFG.9 Some argue that the new, lower FPG concentrations for diagnosis are justified because there are so many individuals with undiagnosed type 2 diabetes, and at diagnosis, ~10% of patients already have nephropathy,30 Figure 1. An approach to the diagnosis of diabetes based on clinical outcomes. 69 Diabetes Spectrum Volume 14, Number 2, 2001 meeting the recent standards of the approach for the diagnosis of diabetes mellitus: hyperglycemia. Diabetes 49:94–100, 2000 an analysis using glycosylated hemoglobin levels. National Glycohemoglobin Program 25 JAMA 276:1246–1252, 1996 Davidson MB, Schriger DL, Peters AL, Lorber to analyze the NHANES III data, B: Relationship between fasting plasma glucose Rohlfing and colleagues41 concluded 11Harris MI, Hadden WC, Knowler WC, Bennett and glycosylated hemoglobin: potential for false- that HbA levels are both sensitive PH: Prevalence of diabetes and impaired glucose positive diagnoses of type 2 diabetes using new 1c tolerance and glucose levels in U.S. population diagnostic criteria. JAMA 281:1203–1210, 1999 and specific for detecting diabetes. aged 20–74 yr. Diabetes 36:523–534, 1987 If the approach outlined in Figure 26Davidson MB, Schriger DL, Peters AL, Lorber 12 1 is followed, diabetes will be diag- Modan M, Harris MI: Fasting plasma glucose B: Revisiting the oral glucose tolerance test crite- in screening for NIDDM in the U.S. and Israel. rion for the diagnosis of diabetes. J Gen Intern nosed in those at clear risk for devel- Diabetes Care 17:436–439, 1994 Med 15:551–555, 2000 oping the microvascular and neuro- 13 pathic complications. Individuals Olefsky JM, Reaven GM: Insulin and glucose 27Tattersall RB, Jackson JGL: Social and emo- responses to identical oral glucose tolerance tests tional complications of diabetes. In with milder degrees of hyperglycemia performed forty-eight hours apart. Diabetes Complications of Diabetes. Keen H, Jarrett J, (who are currently not at risk for 23:449–453, 1974 Eds. Chicago, Year Book Medical Publishers, these complications) will also be iden- 1982, p. 271 14Kosaka K, Mizuno Y, Kuzuga T: Reproduci- tified so that appropriate measures bility of the oral glucose tolerance test and the 28Knowler WC: Screening for NIDDM: opportu- can be instituted to reduce their rice-meal test in mild diabetes. 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Technical report 646. 28:103–117, 1995 Bucala R, Cerami A, Vlassara H: Advanced Geneva, Switzerland, World Health glycosylation end products in diabetic complica- 22Krolewski AS, Laffel LMB, Krolewski M, Organization, 1980 tions. Diabetes Rev 3:258–268, 1995 Quinn M, Warram JH: Glycosylated hemoglobin 38 8Davidson MB, Peters AL, Schriger DL: An alter- and the risk of microalbuminuria in patients with Cohen MP, Sharma K, Jin Y, Hud E, Wu V-Y, native approach to the diagnosis of diabetes with insulin-dependent diabetes mellitus. N Engl J Tomaszewski J, Ziyadeh FN: Prevention of dia- a review of the literature. Diabetes Care Med 332:1251–1255, 1995 betic nephropathy in db/db mice with glycated 18:1065–1071, 1996 albumin antagonists. J Clin Invest 95:2338– 23Tanaka Y, Atsumi Y, Matsuoka K, Onuma T, 2345, 1995 9 Tohjima T, Kawamori R: Role of glycemic con- Expert Committee on the Diagnosis and 39 Classification of Diabetes Mellitus: Report of the trol and blood pressure in the development and Nakamura S, Makita Z, Ishikawa S, Yasamura Expert Committee on the Diagnosis and progression of nephropathy in elderly Japanese K, Fujii W, Yanagisawa K, Kawata T, Koike T: Classification of Diabetes Mellitus. Diabetes NIDDM patients. Diabetes Care 21:116–120, Progression of nephropathy in spontaneous dia- Care 20:1183–1197, 1997 1998 betic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation. Diabetes 10Peters AL, Davidson MB, Schriger DL, 24Warram JH, Scott LJ, Hanna LS, Wantman M, 46:895–899, 1997 Cohen SE, Laffel LMB, Ryan L, Krolewski A: Hasselblad V, for the Meta-Analysis Research 40 Group on the Diagnosis of Diabetes Using Progression of microalbuminuria to proteinuria Clements RS Jr, Robsion WG Jr, Cohen MP: Glycated Hemoglobin Levels: A clinical in type 1 diabetes: nonlinear relatioinship with Anti-glycated albumin therapy ameliorates early 70 Diabetes Spectrum Volume 14, Number 2, 2001 retinal microvascular pathology in db/db mice. J ported by National Institutes of Three Controversies, Many Answers / From Research to Practice Diabetes Complications 12:28–33, 1998 Acknowledgments Health Grant #5 U01 DK54047. I am deeply indebted to all of the 41Rohlfing CL, Little RP, Wiedmeyer H-M, England JD, Madsen R, Harris MI, Flegal KM, investigators who contributed their Mayer B. Davidson, MD, is director Eberhardt MS, Goldstein DE: Use of GHb data to the MRG data set. A com- of the Clinical Trials Unit at Charles (HbA1c) in screening for undiagnosed diabetes in plete list of these investigators has R. Drew University and a professor the U.S. population. Diabetes Care 23:187–191, been previously published (JAMA of medicine at the UCLA School of 2000 276:1246–1252, 1996). I was sup- Medicine in Los Angeles, Calif.

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