Diabetes Intervention Study - Diabetes Care

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Diabetes Intervention Study. Multi-Intervention Trial in Newly. Diagnosed NIDDM. Markolf Hanefeld, DSc. Sabine Fischer, DSc. Harald Schmechel, DSc.
Diabetes Intervention Study Multi-Intervention Trial in Newly Diagnosed NIDDM

Objective: In a randomized 5-yr multi-intervention trial, we tested the efficacy of intensified health education (IHE) in improving metabolic control and reducing the level of coronary risk factors and incidence of ischemic heart disease (IHD). Research Design and Methods: Within the intervention group, the benefit of clofibric acid was evaluated in a double-blind study. One thousand one hundred thirty-nine newly diagnosed middle-aged (30- to 55-yr-old) patients with non-insulindependent diabetes mellitus (NIDDM) entered the study. They were classified as diet controlled after a 6wk screening phase with conventional dietary treatment. During the follow-up, the control group (n = 378) was cared for at different diabetes outpatient clinics with a standardized surveillance. The intervention group (n 761) had a structured IHE that included dietary advice, antismoking and antialcohol education, and ways to enhance physical activity. Results: Randomly, 379 of the IHE patients received 1.6 g clofibric acid/day, and the others received placebo. IHE resulted in improved glucose control (adjusted fasting blood glucose) levels after 5 yr (control subjects 9.27 mM, IHE group 8.71 mM, and IHE plus clofibric acid group 8.60 mM, P < 0.01). The better glycemic control was achieved with fewer antidiabetic drugs. After 5 yr, antidiabetic drugs were prescribed to 47% of the control subjects, 28% of the IHE group, and 34% of the IHE plus clofibric acid group (cutoff limit for drug application was postprandial blood glucose of >13.87 mM). The ratio of polyunsaturated to

From the Department of Metabolic Diseases and Lipid Research Unit, Clinic of Internal Medicine; the Institute of Clinical Chemistry and Laboratory Diagnostics; and the Institute of Biostatistics of the Medical Academy C.G. Cams, Dresden; and the District Hospital, Weimar, Germany. Address correspondence and reprint requests to Markolf Hanefeld, DSc, Department of Metabolic Diseases and Lipid Research Unit, Clinic of Internal Medic inc, Medical Academy C.G. Cams, Fetscherstrasse 74, 8019 Dresden, Germany. Received for publication 15 November 1989 and accepted in revised form 29 November 1990.

Markolf Hanefeld, DSc Sabine Fischer, DSc Harald Schmechel, DSc Gisela Rothe Jan Schulze, DSc Helmut Dude, MA Uta Schwanebeck, MA Ulrich Julius, DSc

saturated fatty acids (0.26 vs. 0.40, P < 0.01) and physical activity (174 vs. 327 scores, P < 0.01) were increased, and blood pressure, tobacco, and alcohol consumption were significantly reduced by IHE. However, IHE had no effect on calorie intake, percentage of fat in the diet (45%), and body weight. The most important finding was the significant increase of blood cholesterol in all three groups ( + 0.47, +0.36, and +0.34 mM, respectively). Clofibric acid only prevented the increase of triglyceride levels ( + 0.56, +0.24, and +0.05 mM, respectively). The incidence rate per 1000 for myocardial infarction was 30.3 for control subjects, 53.6 for the IHE group, and 55.6 for the IHE plus clofibric acid group. The corresponding rates for IHD incidence were 90.9, 97.8, and 98.8, respectively. Men suffered more frequently from myocardial infarction, whereas women developed ECG criteria for IHD more frequently. Among the 35 cases of death, besides cardiovascular diseases, liver cirrhosis and neoplasia were the predominant causes. The death rate per 1000 in control subjects was 46.2, 30.6 in the IHE group, and 27 among patients with IHE plus clofibric acid. Conclusions: IHE was of substantial benefit for the control of glycemia, significantly diminished the need for antidiabetic drugs, and reduced a cluster of risk factors but had no effect on the control of blood lipids. This could be one major reason for the failure of IHE, effective lowering of blood pressure, and clofibric acid to prevent cardiovascular complications. Clofibric acid was only effective in reducing triglycerides. Diabetes Care 14:308-17, 1991

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schemic heart disease (IHD) is the major cause of death in non-insulin-dependent diabetes mellitus (NIDDM) (1,2). An unhealthy life-style deteriorates metabolic control of N I D D M and frequently promotes associated disorders such- as obesity, hyperten-

DIABETES CARE, VOL. 14, NO. 4, APRIL 1991

M. HANEFELD AND ASSOCIATES

sion, and dyslipoproteinemia. Frequently, IHD precedes the manifestation of NIDDM. Therefore, it was hypothesized that both NIDDM and IHD could be related to a common set of risk factors (3). Prospective studies in NIDDM patients have shown a clustering of hypertension, dyslipoproteinemia, and obesity in patients associated with an excess mortality from IHD (3-6). The consequences of hyperglycemia on lipoproteins and the vascular wall become more and more obvious (7). The clustering of risk factors and their interaction with metabolic and hormonal abnormalities in diabetes is supposed to provide the basis for the accelerated and excessive development of IHD (2,8). Intensified dietary advice, correction of overweight, and increased aerobic physical exercise are the accepted basic measures to improve metabolic control in NIDDM. They also represent the primary intervention strategy against common coronary risk factors. Therefore, an integrated approach to ameliorate the fate of diabetes and prevent cardiovascular complications seems to be rational. Large-scale studies (9-12) with nondiabetic patients having a high risk for IHD have proved that the correction of hypercholesterolemia (9,10), hypertension (11), and smoking habits (12) leads to a substantial reduction in the incidence of IHD. Changes in life-style by health education and, if necessary, antihypertensive and lipid-lowering drugs are established and acceptable means to achieve this goal. So far, no intervention studies have been published that evaluate the longterm benefit of these preventive measures in NIDDM. The multiplicity and interdependence of risk factors in NIDDM led us to the concept of a multi-intervention trial with particular emphasis on intensified health education (IHE), which integrated the abovementioned preventive measures, which were successful in nondiabetic patients. Our primary goal was to evaluate the efficacy of IHE on the course of NIDDM and micro- and macroangiopathy. With regard to the importance of dyslipoproteinemia, we included clofibric acid into a randomized double-blind trial. Clofibric acid reduces total cholesterol and triglyceride levels (13,14); beneficial effects of this drug on glucose control have been suggested (15,16). In the Diabetes Intervention Study (DIS), newly diagnosed middle-aged NIDDM patients were investigated who were recruited through a population-based screening survey of geographically defined areas in Germany. With the use of a screening phase with dietary treatment, we identified diabetic patients whose glucose values could be controlled with diet only. After randomization, the control subjects were referred back to their local diabetes clinic for care by trained diabetologists. This study documents the impact of IHE and clofibric acid on metabolic control, the percentage of patients who received insulin or oral antidiabetic drugs, coronary risk factors, and cardiovascular complications after a 5 yr follow-up.

DIABETES CARE, VOL. 14, NO. 4, APRIL 1991

RESEARCH DESIGN AND METHODS DIS is a controlled three-arm clinical trial of IHE versus conventional treatment in specialized diabetes clinics with newly diagnosed NIDDM. In addition, clofibric acid was tested in the IHE group in a double-blind placebo-controlled fashion. For that reason, patients who met the admission criteria were randomly allocated to one of three groups: control subjects, IHE plus placebo, and IHE plus clofibric acid. The primary goal was to improve health behavior. The control group was cared for in the usual way by trained diabetologists. A second goal was to determine whether clofibric acid was of benefit in addition to the use of nondrug treatment. The study protocol was approved by the Medical Council for Diabetes Research of East Germany. The study was coordinated by a scientific committee in Dresden, which was responsible for the training of the staff in the 16 participating clinics, to ensure standardization in diagnostic testing, intervention, and data handling of the common protocol. Sixteen diabetes clinics located in urban and rural areas of Germany cooperated in the DIS. Based on a centralized registration, every subject aged 30-55 yr with a newly detected elevation of fasting blood glucose of >7.21 mM was considered. Thus, the candidates with suspected diabetes represent all geographical areas during the screening period from 15 February 1977 to 31 March 1980. The reasons for fasting blood glucose measurements were casual investigation 55.4%, clinical symptoms 23%, checkup 12.8%, and others 8.8%. If the fasting blood glucose was >8.88 mM, the diagnosis of diabetes was accepted without further diagnostic testing. If fasting blood glucose was between 7.21 and 8.88 mM, a 50-g oral glucose tolerance test was performed to confirm or exclude the diagnosis. The cutoff limits for diabetes were blood glucose values after 60 min of >12.21 mM and after 120 min of >8.32 mM, so that according to the revised European Association for the Study of Diabetes criteria, with a 75-g oral glucose tolerance test, some cases could be classified as impaired glucose tolerance. The examination schedule is shown in Fig. 1. The purpose of the screening phase was to determine the patients who 7) fulfilled the inclusion criteria, 2) met the target levels of blood glucose and urine glucose excretion for those in the diet controlled group, and 3) were willing and able to participate in a 5-yr trial. One thousand eight hundred and forty-six patients with newly diagnosed diabetes were seen in the screening phase (1012 men, 834 women). The DIS inclusion criteria were age 30-55 yr, diabetes controlled by diet according to DIS limits after 6 wk of a conventional diet, and oral consent to take part in the study program. Some participants were excluded from the study due to myocardial infarction before entry (2.5%), stroke (1.3%), gangrene (0.3%), cancer (1.5%), other severe life-lim-

DIABETES INTERVENTION STUDY IN NIDDM

Screening phase: Screened probands:

15.2.1977 - 31.3.1980 Fasting BG > 7.21 mmol/l 3 0 - 5 5 years (incl.)

7.21 < FBG