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ORIGINAL ARTICLE

Epidemiological Studies on the Effects of Hyperglycemia and Improvement of Glycemic Control on Macrovascular Events in Type 2 Diabetes

Steven M. Haffner, MD

The relation of glycemia to coronary heart disease in subjects with type 2 diabetes is controversial. Recent data have suggested a significant relation of glycemia to cardiovascular disease in both type 2 diabetes and in subjects with impaired glucose tolerance, although the relation of glycemia to cardiovascular disease appears to be weaker than the relation of glycemia to microvascular disease.

Diabetes Care 22 (Suppl. 3):C54–C56, 1999

Although diabetes is characterized by impaired plasma glucose concentrations, the relation of blood glucose to cardiovascular disease remains controversial. The purpose of this review is to examine this topic.

TYPE 2 DIABETES AND CORONARY HEART DISEASE— Subjects with type 2 diabetes have a two- to fourfold increased risk of developing cardiovascular disease (1–3). Unlike the situation with microvascular complications of diabetes (retinopathy and renal disease), in which duration of diabetes and severity of glycemia have been strong and consistent risk factors (4,5), cardiovascular disease has often not been associated with these traditional diabetic risk factors (4,6–8). Definitive resolution of this issue can come only from clinical trials that explicitly examine the issue of glycemic control on cardiovascular disease. The recently reported U.K. Prospective Diabetes Study (8a) showed a significant reduction in diabetes-related end points with improved glycemic control. The reduction in microvascular end points (25%) was statistically significant, while the reduction in myocardial infarction (16%) was not (P = 0.052). In two recent Finnish studies, the duration of diabetes and elevation of glycosylated hemoglobin levels were statistically significant, although fairly weak, predictors of coronary heart disease in type 2 diabetic subjects (9,10). The relatively weak association between duration of diabetes and severity of glycemia and cardiovascular disease suggests that common antecedents might underlie both atherosclerotic heart disease and type 2 diabetes. Hyperinsulinemia and insulin resistance strongly predict the development of diabetes (11–17) in populations that are at high risk and those that are at low risk for the development of type 2 diabetes.

The relation between glycemia and the development of coronary heart disease may be stronger in type 1 diabetes than in type 2 diabetes. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (18), the effect of a 1% rise in glycosylated hemoglobin on coronary heart disease was greater in younger-onset than in older-onset diabetic subjects. Jensen-Urstad et al. (19) showed a cross-sectional correlation between HbA_1c, stiffness of the carotid wall, and endothelial dysfunction in type 1 diabetic subjects followed in the Stockholm Diabetes Intervention Study. In a large study (n = 1,532) of 15- to 34-year-old autopsied young people (who died of external causes), glycosylated hemoglobin was associated with increased fatty streaks and raised lesions in the coronary arteries (20).

Reaven (21) has proposed that insulin resistance may underlie a cluster of disorders, including impaired glucose tolerance, dyslipidemia, hypertension, and cardiovascular disease. This is consistent with the increased blood pressure, increased triglyceride level, and decreased HDL cholesterol level found before the onset of marked hyperglycemia in a number of studies (15,22–24). Increased cardiovascular risk factors were found even in subjects with normal glucose tolerance who later developed type 2 diabetes (22). Moreover, adjustment for fasting insulin concentration abolished the difference between confirmed prediabetic subjects and those who remained normal at follow-up (24). In another study, multiple cardiovascular risk factors predicted the incidence of diabetes, even in subjects who had normal glucose tolerance at baseline (15).

THE PROBLEM OF IMPAIRED GLUCOSE TOLERANCE— The relation of glucose concentrations to atherosclerosis in nondiabetic subjects remains controversial. One way to examine this area is to compare subjects with impaired glucose tolerance to subjects with normal glucose tolerance.

Prevalence of coronary heart disease
In elderly Finnish subjects (10), the prevalence of definite or probable myocardial infarction was not significantly different in either men or women with impaired glucose tolerance compared with subjects with normal glucose tolerance. However, the prevalence of angina was higher in men with impaired glucose tolerance than in men with normal glucose tolerance. No differences were seen in the prevalence of angina between women with normal glucose tolerance and those with impaired glucose tolerance. In the San Luis Valley Study (25), the prevalence of overall coronary heart disease was increased approximately twofold in both non-Hispanic white men and women with impaired glucose tolerance compared with subjects with normal glucose tolerance. However, the prevalence of overall coronary heart disease was very similar in Hispanic men and women with impaired glucose tolerance and normal glucose tolerance.

Prospective studies of impaired glucose tolerance and coronary heart disease
Kuusisto et al. (10) found no differences in the incidence of coronary heart disease over a 3.5-year follow-up in elderly Finnish subjects (women: 3.1% for normal glucose tolerance vs. 4.4% for impaired glucose tolerance; and men: 12.5% for normal glucose tolerance vs. 14.3% for impaired glucose tolerance). However, the number of cases of coronary heart disease was small, especially in subjects with impaired glucose tolerance. In a Japanese study, subjects with impaired glucose tolerance had an increased coronary heart disease relative risk of 1.9 (95% CI 1.2–3.2) compared with subjects with normal glucose tolerance (26). This association was essentially unchanged after adjustment for age, sex, systolic blood pressure, BMI, total and HDL cholesterol, smoking, and alcohol.

Impaired glucose tolerance and atherosclerosis
Few data exist on the association of impaired glucose tolerance and direct measures of atherosclerosis, such as coronary angiography or B-mode ultrasound of the carotid arteries. In a Japanese study (27), impaired glucose tolerance was significantly associated with atherosclerosis as determined by intimal medial wall thickness in the carotid arteries.

CONCLUSIONS— Recent data suggest that glycemia may be related to the incidence of coronary heart disease in type 2 diabetic subjects. Definitive data can only result from clinical trials that examine the relation of glycemic control to coronary heart disease. The positive relation between glucose concentrations and atherosclerosis or coronary heart disease may extend to nondiabetic subjects. It is, however, not certain whether the magnitude of the association between glycemia and coronary heart disease is as strong as the magnitude of the relation between glycemia and microvascular disease.

References
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From the Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Address correspondence and reprint requests to Steven M. Haffner, MD, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284-7873.

Received for publication 6 July 1998 and accepted in revised form 29 October 1998.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

This article is based on a presentation at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company.

Copyright © 1999 American Diabetes Association
Last updated: 3/99
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