IMPACT OF RECENT CHANGES IN DIAGNOSTIC CRITERIA ON THE APPARENT NATURAL HISTORY OF DIABETES MELLITUS

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1 AMERICAN JOURNAL OF EPIDIMIOLOCY Copyright 1983 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 117, No. 6 Fruited in U.SA. IMPACT OF RECENT CHANGES IN DIAGNOSTIC CRITERIA ON THE APPARENT NATURAL HISTORY OF DIABETES MELLITUS L. JOSEPH MELTON, IH, 1 PASQUALE J. PALUMBO,' MARK S. DWYER' AND CHU-PIN CHIP Melton, L. J., Ill (Dept of Medical Statistics and Epidemiology, Mayo Clinic, Rochester, MN 55905), P. J. Palumbo, M. S. Dwyer and C. P. Chu. Impact of recent changes in diagnostic criteria on the apparent natural history of diabetes mellitus. Am J Epidemiol 1983;117: The effect of changing from the original to the new National Diabetes Data Group diagnostic criteria for diabetes mellltus was to delete 16.5% of the original diabetes Incidence cohort described among Rochester, Minnesota, residents in , to shift the clinical spectrum at diagnosis toward more severe disease, to reduce relative survival, and to increase the risk of developing macro- or microvascular complications. The changes In apparent natural history were unexpectedly modest in magnitude, however, and should have little practical effect on comparisons of diabetes prognosis under the two different sets of diagnostic criteria. classification; diabetes mellltus; diagnosis; prognosis The apparent natural history of diabetes mellitus, or any other disease for that matter, can be modified by altering the criteria for diagnosis. Davidson (1) reviewed the history of changes in the definition of diabetes and the effect these have had on our understanding of the disorder and concluded with the observation that data do not exist which permit assessment of the impact of the most recent changes in diagnostic criteria. The new criteria of the National Diabetes Data Group exclude certain patients who were formerly considered by many to have diabetes, such as individuals with fasting Received for publication August 30, 1982, and in final form December 27, ' Department of Medical Statistics and Epidemiology, Mayo Clinic, Rochester, MN (Reprint requests to Dr. Melton.) 1 Division of Endocrinology, Department of Internal Medicine, Mayo Clinic. * Mayo Medical School, Rochester, MN. This investigation was supported in part by research grants from the National Institutes of Health (AM-30582) and the American Diabetes Association. The authors thank MTB. Lois Bartz for help in abstracting medical records and Mrs. Janet R. King for assistance in preparing the manuscript. venous whole blood glucose levels between 110 and 120 mg/dl (2). The authors of the new criteria note that the status of these patients has not been fully assessed (2). Nevertheless, it is clear that these patients generally occupy the "mildly affected" end of the clinical spectrum of diabetes mellitus. Their deletion, then, should shift the clinical spectrum at diagnosis toward more severe disease and should cause subsequent prognosis to appear worse under the National Diabetes Data Group criteria than with the previous definition of diabetes. Consequently, it is important to learn what proportion of previously diabetic patients are affected by the changes in diagnostic criteria and what effect their removal has on the apparent natural history of diabetes. A large population-based study of diabetes mellitus had been conducted in Rochester, Minnesota, over the 25-year period, , utilizing the earlier diagnostic criteria (3). By applying the new Diabetes Data Group criteria to these data, it was possible (a) to estimate the proportion of incidence cases deleted by the change; 559

2 560 MELTON ET AL. (b) to describe the clinical characteristics of the patients removed, as well as the characteristics of the entire incidence cohort under the two different sets of criteria; and (c) to document the changes in complication rates and survival which result from systematic elimination of the mildest cases. MATERIALS AND METHODS Rochester, Minnesota, is well suited for studies of the natural history of diabetes mellitus because comprehensive unit medical records for the residents are available and because these records are accessible through a central index of diagnoses made by essentially all medical care providers utilized by the local population. This index includes the diagnoses made among outpatients seen in clinic consultations, emergency room visits, house calls, or nursing home care, as well as diagnoses recorded among hospital inpatients. The potential of this data system for population-based studies has been described previously (4). The original medical records of the patients identified through the index were retrieved and reviewed for an initial diagnosis of diabetes in the 25-year period, The original diagnostic criteria used for diabetes mellitus have been reported in detail previously (3) and required fasting hyperglycemia on two consecutive determinations over 120 mg/dl (Folin-Wu method) for or over 110 mg/dl (Auto-Analyzer ferrocyanide reductase technique) for on whole venous blood. The readings were transformed into their equivalents for purposes of this analysis. Blood glucose values from other institutions where Rochester patients sought medical care were interpreted in light of the method being employed. The fasting blood glucose value used in this report was the first one for each patient that met the stated criteria; and the diagnosis of diabetes was dated from that point even though a second elevated value was required for diagnosis. The fasting blood glucose levels were divided as recommended by West (5) into "mildly elevated" («199 mg/dl whole venous blood), "moderately elevated" ( mg/dl), and "severely elevated" (>300 mg/dl). An oral glucose tolerance test was generally carried out when an equivocal fasting or postprandial blood glucose determination was obtained. At Mayo Clinic, the oral glucose tolerance test was performed by administering 1 g of glucose per kg of body weight and determining blood glucose concentrations at 0, 1, 2, and 3 hours after the loading dose. Only the 1- and 2-hour values were used for the interpretation of the oral glucose tolerance test, and both values had to be elevated in comparison to age-specific standards (table 1) for the diagnosis of diabetes mellitus to be made. For the other institutions providing data in this study, glucose tolerance tests were interpreted by established criteria for the method used. Although these were acceptable criteria at the time the data were originally collected, the National Diabetes Data Group has recently recommended that higher cutoff values be used: namely, 120 mg/dl venous whole blood ( 140 mg/dl plasma glucose) for fasting blood glucose and 180 mg/dl venous whole blood TABLE 1 Diagnostic criteria for oral glucose tolerance tests among Rochester, MN, residents in Blood glucose levels had to exceed the values indicated Age group < *70 Blood glucose value (mg/dl) * t 1 hour 2-hour 1 hour 2-hour * Determined by Folin-Wu method on venous whole blood. t Determined by Auto Analyzer ferrocyanide reductase method on venous whole blood.

3 DIAGNOSTIC CRITERIA FOR DIABETES MELLTTUS 561 ( 200 mg/dl plasma glucose) for the glucose tolerance test (2). Relative weight at diagnosis was calculated using recommended height-weight tables (2), and patients were considered obese whose relative weight was 1.2 or greater. Initial therapeutic regimens were classified as insulin (with or without other therapy), oral agent (with or without diet but without insulin), or diet alone (no insulin or oral agents) as of the time of < discharge after the initial diagnosis and workup. The characterization of specific clinical types of diabetes generally followed National Diabetes Data Group recommendations, although as explained in detail in a separate report some modifications were required in the context of a retrospective study using existing medical records (6). Diabetic "complications" were classified as macrovascular (angina pectoris, myocardial infarction, sudden unexpected death, stroke, transient ischemic attack, or peripheral vascular disease) or microvascular (retinopathy or diabetic renal disease). Complications at diagnosis included a history of any one or more of these. Subsequent complication rates were determined using actuarial methods (7). Relative survival was determined with death rates for West North Central whites in 1960 as the standard. In order to be considered an incident case of diabetes, a patient must have been a resident of Rochester for at least one year before the initial diagnosis. For the calculation of incidence rates, the entire population of Rochester was considered to be at risk, and the denominator age- and sex-specific person-years were derived from decennial census figures. Statistical significance was assessed using 95 per cent confidence intervals around the rates and x 2 tests on the distributions of various characteristics. RESULTS Using the original diagnostic criteria described by Palumbo and coworkers (3), 1135 new cases of diabetes mellitus were diagnosed among the residents of Rochester, Minnesota, during the 25-year study period, (6). However, had the National Diabetes Data Group criteria (2) been used instead, 187 of these patients (16.5 per cent) would have been deleted from the incidence cohort. Of these, 142 would have been removed from the study entirely since they have not yet met the more stringent Data Group criteria. The other 45 would have fallen outside the time limits of the study since they met the National Diabetes Data Group criteria only after The effect of the change in diagnostic criteria on the incidence rates for the most recent decade, , is shown in table 2. The incidence rates were lowered for both sexes and in practically every age group by use of the new Data Group criteria. The total crude incidence among men was reduced from per 100,000 person-years (95 per cent confidence interval ) to per 100,000 person-years (95 per cent confidence interval ). The total crude incidence among women was reduced from per 100,000 person-years (95 per cent confidence interval ) to per 100,000 person-years (95 per cent confidence interval ). Overall, the total age-adjusted incidence was reduced to 81 per cent of its former value, from to per 100,000 person-years (table 2). As anticipated in the introduction, the patients deleted from the study by employing the Data Group criteria were from the mild end of the clinical spectrum of cases (table 3). Less than 1 per cent of the deleted patients were initially placed on insulin therapy and none appeared to represent insulin-dependent diabetes mellitus. Less than 3 per cent of the deleted individuals had one or more of the classical symptoms of diabetes mellitus at onset. The characteristics of the 187 deleted patients were compared with those

4 562 MELTON ET AL. TABLE 2 Incidence of diabetes mellitus among Rochester, UN, residents in under original (3) and revised (2) criteria for diagnosis Age group Males Subtotal Females Subtotal Total (crude)* (adjusted)t (n) Original criteria (3) Rate* National Diabetes Data group criteria (2) (n) Rate* * Incidence per 100,000 person-years. t Incidence per 100,000 person-years directly age- and sex-adjusted to 1970 United States whites. of the remaining 948 incidence cases. The and had a greater prevalence of maclatter were divided into three subgroups: rovascular disease at the time of initial (a) 208 patients with fasting blood glucose diagnosis of diabetes (23.1 versus 10.7 per levels of mg/dl and who just ex- cent). Only the latter difference was ceeded the National Diabetes Data Group statistically significant (p < 0.01), howcutoff level; (b) the remaining 393 pa- ever. Otherwise, the deleted cases and tients who presented with mildly elevated those who just met the Data Group fasting blood glucose levels (=sl99 mg/dl); criteria were much alike. The remaining and (c) the 347 patients who presented 393 patients with mildly elevated fasting with moderately (76 per cent) or severely blood glucose at diagnosis and the 347 (24 per cent) elevated fasting blood glu- with moderately or severely elevated fastcose (5*200 mg/dl) at the time of initial ing blood glucose values were much more diagnosis (table 3). The 208 patients who likely to be on insulin therapy or to have just met the Data Group criteria were insulin-dependent diabetes, were more somewhat more likely than the deleted often symptomatic, and displayed a cases to be symptomatic (5.3 versus 2.7 greater prevalence of macrovascular and per cent), were more often started on oral microvascular disease at the time of iniagent therapy (7.7 versus 3.8 per cent), tial diagnosis (table 3).

5 DIAGNOSTIC CRITERIA FOR DIABETES MELUTUS 563 TABLE 3 Clinical characteristics of various patient groups as of the time of initial diagnosis of diabetes mellitus among Rochester, MN, residents in Age (years): median Sex (%): males Clinical type (%) Insulin dependent Obese noninsulin dependent Nonobese noninsulin dependent Secondary diabetes Initial treatment (%) Insulin Oral agents Diet alone Initial fasting blood glucose (mg/dl): median value Relative weight (%) < *1.2 Classical symptoms (%): *1 Complications at diagnosis (%) Macrovascular Microvascular Deleted cases* (n =187) <130 mg/dl (n =208) Initial fasting blood glucose level mg/dl (n -393) >200 mg/dl (n =347) * Patients who met the original (3) criteria within the time frame of the study but not the more stringent National Diabetes Data Group (2) criteria. If the National Diabetes Data Group nostic criteria in this cohort which had criteria were substituted for the original been followed for over 10,000 personones, the clinical spectrum of cases would years. During this period of observation, be altered by the deletion of the mildly 525 patients died, 306 developed one or affected patients. The magnitude of the more of the macrovascular complications changes is shown in table 4. While the listed above, and 106 were diagnosed with effect of using the new Data Group one or more of the microvascular complicriteria is to make the distribution of clin- cations of diabetes. As shown in figure 1, ical characteristics appear more severe, relative survival was worse under the as expected, none of the changes are Data Group criteria than with the origistatistically significant (p > 0.05), despite nal definition of diabetes. At 20 years the fact that the number of patients in- after the initial diagnosis, survival of the volved in the study is reasonably large. Diabetes Data Group cohort was only 65 The use of the National Diabetes Data per cent of that expected for members of Group criteria should also have had the the general population of like age and sex, effect of worsening the prognosis of diabe- compared with 70 per cent for the original tes patients, compared with the original incidence cohort. Likewise, the actuarcriteria, for the reasons already noted. We ially estimated cumulative incidence of examined the prognosis for survival and macrovascular and microvascular disease for the development of vascular complica- was greater for the cohort defined by the tions under the two different sets of diag- National Diabetes Data Group criteria

6 564 MELTON ET AL. TABLE 4 Clinical characteristics at the time of initial diagnosis of diabetes mellitus among Rochester, MN, residents in under original (3) and revised (2) criteria for diagnosis Age (years): median Sex (%): males Clinical type (%) Insulin dependent Obese noninsulin dependent Nonobese noninsulin dependent Secondary diabetes Initial treatment (%) Insulin Oral agents Diet alone Initial fasting blood glucose Median value (mg/dl) Mild (%) Moderate (%) Severe (%) Relative weight (%) < s=1.2 Classical symptoms (.%): *1 Complications at diagnosis (%) Macrovascular Microvascular (figure 1). However, by 20 years after the initial diagnosis of diabetes the estimated 59.8 per cent incidence of macrovascular disease among the Diabetes Data Group criteria patients was only slightly greater than the 59.6 per cent for the original cohort. The estimated 31 per cent of Data Group criteria patients with microvascular disease after 20 years was only modestly greater than the 27 per cent figure for the original cohort. DISCUSSION It is not our intent to argue that one set of diagnostic criteria is superior to another. With our present state of knowledge, any choice is necessarily arbitrary. Rather, we were concerned about the effect that the introduction of the new National Diabetes Data group criteria would have on the apparent natural history of Original criteria (3) (n ) National Diabetes Data Group criteria (2) (n -948) diabetes. Since about one-sixth of the patients considered diabetic under the original criteria of Palumbo and coworkers (3) would be deleted, the potential for substantial changes in the apparent natural history of the disease seemed very real. As anticipated, our data show that the deleted patients are generally from the mild end of the clinical spectrum. However, the impact of removing them was unexpectedly small. The incidence of diabetes mellitus in our population was reduced by about 20 per cent with the introduction of the National Diabetes Data Group criteria; but the clinical characteristics of the revised incidence cohort, although slightly distorted toward more severely affected diabetic patients, were not significantly different from those under the original criteria. Subsequent prognosis in terms of survival as well as the

7 DIAGNOSTIC CRITERIA FOR DIABETES MELLTTUS 565 Rttatnr* survival Years after initial diagnosis O O is 1 of rr ompll c " o >- ilopm scula Oavc rova FIGURE 1. Actuarially estimated cumulative incidence of macrovascular and microvaacular disease and relative survival after the initial diagnosis of diabetes mellitus among Rochester, MN, residents ( ), using the original diagnostic criteria (3) or those of the National Diabetes Data Group (NDDG) (2). development of macro- and microvascular complications was somewhat worse with the Data Group cohort, but these differences were also modest. Thus, we conclude that adoption of the National Diabetes Data Group diagnostic criteria will distort the previously defined clinical spectrum of diabetes mellitus to a small degree but will have little practical effect. Data concerning the natural history of diabetes which were generated using the earlier criteria should still be reasonably comparable with the data forthcoming from future studies which employ the National Diabetes Data Group criteria. REFERENCES 1. Davidson MB. The continually changing "natural history" of diabetes mellitus. J Chronic Dis 1981;34: National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28: Palumbo PJ, Elveback LR, Chu CP, et al. Diabetes mellitus: incidence, prevalence, survivorship, and causes of death in Rochester, Minnesota, Diabetes 1976;25: Kurland LT, Elveback LR, Nobrega FT. Population studies in Rochester and Olmsted County, Minnesota, In: Kessler II, Levin ML, eds. The community as an epidemiologic laboratory: a casebook of community studies. Baltimore: Johns Hopkins Press, 1970: West KM. Standardization of definition, classification, and reporting in diabetes-related epidemiologic studies. Diabetes Care 1979-^: Melton LJ, Palumbo PJ, Chu CP. Incidence of diabetes mellitus by clinical type. Diabetes Care 1983;6: Elveback LR. Actuarial estimation of survivorship in chronic disease. J Am Statistical Assoc 1958;53: