The evidence is overwhelming that hyperglycemia is causally associated with the development of microangiopathic complications of diabetes. In the recently published report from the Diabetes Control and Complications Trial (DCCT) [2], the risks for retinopathy, nephropathy, and neuropathy were substantially reduced in the intensively treated group of patients with insulin-dependent diabetes mellitus (IDDM) with good glycemic control compared with the conventionally treated group. Also, cardiovascular events were reduced by 41%, but this decrease was not statistically significant [2]. Therefore, hyperglycemia may play a central role in enhanced atherogenesis in NIDDM. However, the evidence for the hypothesis that hyperglycemia causes the increase in the risk for coronary heart disease in patients with NIDDM is surprisingly limited and, until recently, has been based only on cross-sectional studies. In the World Health Organization Multinational Study of Vascular Disease in Diabetes [3], the relation between the fasting plasma glucose level and the prevalence of different manifestations of atherosclerotic vascular disease was assessed in a pooled population of 3583 diabetic patients from nine different populations. The plasma glucose level failed to show any relation to the prevalence of major Q-wave changes on electrocardiogram. In the cross-sectional study by Welborn and colleagues [4], the casual blood glucose level was positively associated with the occurrence of coronary heart disease. However, none of these studies investigated the exact nature of the relation between glycemic control and the risk for coronary heart disease.

In this article, recent evidence is reviewed from two Finnish prospective, population-based studies on the nature of the association of glycemic control with the risk for coronary heart disease in patients with NIDDM.

Study 1: Middle-Aged Patients Newly Diagnosed with NIDDM

Baseline Study

The baseline examinations were done in Kuopio, Finland, from 1979 to 1981 [5]. The original study population included 133 patients newly diagnosed with NIDDM who were 45 to 64 years old at the time of diagnosis. The diagnosis of definite myocardial infarction was made in patients who had major Q-QS abnormalities or who had had a documented myocardial infarction. All patient records were checked to verify the correct diagnosis of myocardial infarction according to World Health Organization criteria [6]. Blood glucose level was determined by the glucose oxidase method (Glox, KabiAb, Stockholm, Sweden). Glycated hemoglobin A₁ (GHbA₁) was determined by column chromatography (Quick-Sep Fast Hemoglobin Test System, Isolab, Akron, Ohio), with normal values from 5.5% to 8.5%.

Follow-up Study

The follow-up study was done 10 years later [5]. Causes of death were ascertained from patient records and death certificates, and nonfatal events were abstracted from patient records. As at the baseline examination, the definite myocardial infarction group consisted of patients who had new major Q-QS abnormalities or had had a documented myocardial infarction [6].

Association of Glycemic Control with the Risk for Cardiovascular Disease

During the 10-year follow-up, 28 patients with NIDDM died of cardiovascular causes. Cardiovascular mortality was significantly associated with age, elevated total and low-density lipoprotein triglyceride levels, and hyperglycemia (fasting blood glucose level at baseline, plasma glucose level at 5 years, and GHbA₁ level at 5 years). A high fasting blood glucose level significantly predicted cardiovascular mortality in multiple logistic regression analysis independently of other risk factors.

Figure 1 shows the 10-year cardiovascular mortality in patients with NIDDM by tertiles of fasting blood glucose level at baseline in two treatment categories (diet and oral drugs or insulin at the 5-year examination). Cardiovascular mortality was similarly increased in patients with NIDDM who were in the highest blood glucose tertile compared with the lowest blood glucose tertile, regardless of the mode of treatment. Similarly, cardiovascular mortality increased linearly as a function of fasting plasma glucose and GHbA₁ levels determined at the 5-year examination.

View larger version (62K): [in this window] [in a new window]   Figure 1. The 10-year cardiovascular mortality by tertiles of fasting blood glucose level at baseline in diet- and drug-treated patients with diabetes. Low: 8.6 mmol/L or less; middle: 8.7 to 11.8 mmol/L; high: 11.9 mmol/L or more (5; adapted from the original Figure withthe permission of authors and Diabetologia).

Study 2: Elderly Patients with NIDDM

Baseline Study

The baseline examination was done in Kuopio, Finland, from 1986 to 1988 [7]. A total of 1299 patients out of 1827 who were eligible and who were 65 to 74 years of age participated in the baseline examination, giving an overall participation rate of 71%; 229 patients had NIDDM. All medical records of patients who reported that they had been admitted to the hospital because of chest pain or symptoms suggestive of myocardial infarction before the baseline examination were reviewed. World Health Organization criteria for verified definite and possible myocardial infarction based on chest pain symptoms, electrocardiographic changes, and enzyme level determinations were used to ascertain previous myocardial infarction [6]. Non–insulin-dependent diabetes mellitus was defined according to World Health Organization criteria [8]. Plasma glucose levels were determined by the glucose oxidase method (Glucose Auto & Stat HGA-1120 analyzer, Daiichi, Kyoto, Japan). Glycated hemoglobin A_1c levels were determined by a commercial liquid-chromatographic assay (Fast Protein Liquid Chromatography, Pharmacia, Uppsala, Sweden), with normal values from 4.3% to 5.7%.

Follow-up Study

The follow-up study was done approximately 3.5 years after the baseline study [9]. Medical records of those participants who reported hospitalization because of chest pain or other symptoms suggestive of myocardial infarction during the follow-up and medical records of all non-participants and those who died during the follow-up were reviewed. World Health Organization criteria for verified and possible myocardial infarction were used to ascertain new myocardial infarctions during the follow-up period in the same manner as in the baseline study [6]. All deaths were coded according to the 9th revision of the International Classification of Diseases (ICD-9). Coronary heart disease death during follow-up was defined as death resulting from coronary heart disease (ICD-9 codes 410-414). All coronary heart disease events included coronary heart disease deaths and nonfatal myocardial infarctions.

Association of Glycemic Control with the Risk for Coronary Heart Disease

During follow-up, 15 patients with NIDDM died of coronary heart disease, and 33 experienced a severe coronary heart disease event (coronary heart disease death or nonfatal myocardial infarction). Glycated hemoglobin A_1c was the most important single risk factor associated with coronary heart disease death or all coronary heart disease events (P < 0.01). In multiple logistic regression analysis, GHbA (_1c) was significantly associated with coronary heart disease death after adjustment for sex, history of previous myocardial infarction, current smoking, waist-to-hip ratio, systolic blood pressure, high-density lipoprotein cholesterol level, and duration of diabetes. Figure 2 shows the association of coronary heart disease mortality and all coronary heart disease events with GHbA_1c. In the highest GHbA_1c tertile, the coronary heart disease risk was about threefold greater than the risk in the lowest tertile.

View larger version (40K): [in this window] [in a new window]   Figure 2. The 3.5-year incidence of coronary heart disease deaths and all coronary heart disease events (coronary heart disease death or nonfatal myocardial infarction) by tertile of glycated hemoglobin A1c (GHbA1c) level. Low: less than 6.0%; middle: 6.0% to 7.9%; high: greater than 7.9% (9; drawn on the basis of the original figure, with the permission of the authors and Diabetes). CHD equals coronary heart disease; GHbA1c equals glycated hemoglobin A1c.

Discussion

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Many potential mechanisms can be presented to explain why poor glycemic control of diabetes predicts coronary heart disease events. Hyperglycemia hampers the repair of endothelial lesions caused by various factors; increases the proliferation of smooth muscle cells, the glycation of various tissue proteins, the adhesiveness and aggregation of platelets in vitro, and the production of plasminogen activator inhibitor-1; and causes abnormalities in endothelial cell function leading to accelerated thrombogenesis [10, 11]. Furthermore, hyperglycemia causes glycation of lysine residues located in the low-density lipoprotein receptor-binding domain, which impairs the binding of apolipoprotein B-100 to the low-density lipoprotein receptor [10]. Glycated low-density lipoprotein particles are removed more slowly from the circulatory system.

Despite the several mechanisms by which hyper-glycemia could increase the risk for atherothrombosis, prospective studies on the effect of hyperglycemia on the risk for coronary heart disease in patients with and without diabetes are limited. In patients without diabetes, results from prospective population studies of the relation of blood glucose levels after an oral glucose load to coronary heart disease events have been inconsistent [1]. However, in several recent studies, the risks for cardiovascular mortality and morbidity have been shown to relate non-linearly to blood glucose levels, suggesting that the degree of hyperglycemia must exceed a certain limit to increase the risk for coronary heart disease [1]. The data presented here, based on two population studies of patients with NIDDM from eastern Finland, show that the degree of hyperglycemia in frank diabetes linearly increases the risk for coronary heart disease and cardiovascular events. Furthermore, the association of hyperglycemia and the risk for coronary heart disease and cardiovascular disease was independent of the mode of treatment.

These two studies have their limitations. The evaluation of glycemic control was based only on a single measurement of the fasting blood glucose or GHbA (_1c) level. Both of these measurements are subject to short-term variability and may not be relevant to average long-term hyperglycemia. Furthermore, on the basis of epidemiologic data, it is impossible to separate the direct effects of hyperglycemia on the risk for coronary heart disease from its indirect effects on cardiovascular risk factors. Moreover, elevated glucose levels may be a surrogate measure for other metabolic derangements in diabetes that are directly responsible for increased risk of macrovascular disease.

In conclusion, two prospective, population-based studies from Finland give evidence for the linear association of glycemic control with the risk for coronary heart disease in middle-aged and elderly patients with NIDDM. These results suggest that it is reasonable to test the hypothesis that achieving good glycemic control by diet or drug treatment reduces the risk for coronary heart disease in NIDDM. The United Kingdom Prospective Study of Therapies of Maturity Onset Diabetes now in progress may diminish uncertainty in this respect (12; see also "United Kingdom Prospective Diabetes Study 17: A 9-Year Update of a Randomized, Controlled Trial on the Effect of Improved Metabolic Control on Complications in NIDDM").