Impact of Glucose Tolerance Status on Development of Ischemic Stroke and Coronary Heart Disease in a General Japanese Population
The Hisayama Study
Background and Purpose—Few studies have shown the association between glucose tolerance status defined by a 75-g oral glucose tolerance test and the development of different types of cardiovascular disease.
Methods—A total of 2421 community-dwelling Japanese subjects aged 40 to 79 years who underwent the oral glucose tolerance test were followed up for 14 years.
Results—In multivariable analysis, the risks of ischemic stroke in both sexes and coronary heart disease (CHD) in women were significantly higher in subjects with diabetes determined by the World Health Organization criteria than in those with normal glucose tolerance even after adjustment for other confounding factors, but such association was not seen for CHD in men (ischemic stroke: adjusted hazard ratio [HR]=2.54, P=0.002 in men; adjusted HR=2.02, P=0.03 in women; CHD: adjusted HR=1.26, P=0.47 in men; adjusted HR=3.46, P=0.002 in women). Similar associations were observed for fasting plasma glucose levels of ≥7.0 mmol/L (ischemic stroke: adjusted HR=2.15, P=0.03 in men; adjusted HR=2.10, P=0.045 in women; CHD: adjusted HR=1.29, P=0.47 in men; adjusted HR=3.83, P=0.003 in women) and for 2-hour postload glucose levels of ≥11.1 mmol/L (ischemic stroke: adjusted HR=2.71, P=0.003 in men; adjusted HR=2.19, P=0.03 in women; CHD: adjusted HR=1.58, P=0.16 in men; adjusted HR=4.44, P<0.001 in women). The age-adjusted incidences of ischemic stroke and CHD did not significantly increase in subjects with impaired fasting glycemia or impaired glucose tolerance in either sex.
Conclusions—Our findings suggest that diabetes is an independent risk factor for ischemic stroke in both sexes and CHD in women in the Japanese population.
Cardiovascular disease continues to be a major global public health concern. Investigations into glucose tolerance levels and cardiovascular disease have become increasingly important, because the impact of diabetes on cardiovascular disease is considered to be rising due to the rapid increase in the worldwide prevalence of diabetes mellitus in recent years. A number of epidemiological studies have demonstrated that Type 2 diabetic subjects have approximately 2.0 to 4.0 times higher risk of cardiovascular disease compared with nondiabetic subjects.1–13 However, most of these studies had important limitations. In many cohort studies used to investigate this issue, the outcomes were evaluated using mortality data.3–9,11,12 Because nonfatal events were not included in these studies, the results may not have represented the true association between glucose tolerance levels and cardiovascular disease. Thus, prospective studies using incidence data would provide further information for predicting cardiovascular disease. In addition, the methods used to define diabetes have varied among the epidemiological studies, ranging from administration of questionnaires to measurement of casual blood glucose levels or fasting plasma glucose (FPG) alone.1,2,11,12 Furthermore, many investigators have evaluated cardiovascular generally, rather than by type, and did not separately evaluate sex, although it is well known that the effects of each risk factor are different for each type of cardiovascular disease and sex. Thus, there have been few cohort studies investigating the associations between glucose tolerance levels, defined by a 75-g glucose tolerance test (OGTT), and the risks of developing stroke and coronary heart disease (CHD) in each sex in Asian populations.
The purpose of the present study was to address the association between glucose tolerance levels and the development of ischemic stroke and CHD in a prospective study of a defined community-dwelling Japanese population, all members of which underwent the OGTT.
Materials and Methods
In 1988, a screening survey for the present study was performed in the town of Hisayama, a suburb of the Fukuoka metropolitan area in southern Japan.14 Of a total 3227 residents aged 40 to 79 years on the town registry, 2587 (participation rate, 80.2%) consented to participate in the examination and underwent a comprehensive assessment. After excluding 82 subjects who had already had breakfast, 10 who were on insulin therapy and 15 due to nausea or general fatigue during the ingestion of glucose, a total of 2480 subjects completed the OGTT. From a total of 2490 subjects including 10 on insulin therapy, 68 who had a history of stroke or CHD based on questionnaires and medical records, and one who died before follow-up was started, were excluded. The remaining 2421 (1037 men and 1384 women) were enrolled in this study.
The subjects were followed up prospectively for 14 years, from December 1988 to November 2002, by repeated health examinations. The health status was checked yearly by mail or telephone for subjects who did not undergo a regular examination or who had moved from town. We also established a daily monitoring system among the study team, local physicians, and members of the town’s health and welfare office. Using this system, we gathered information on new events of cardiovascular disease, including suspected cases. When stroke or CHD occurred or was suspected, physicians in the study team examined the subject and evaluated his or her detailed clinical information. The clinical diagnosis of stroke or CHD was based on the patient’s history, physical and neurological examinations, and ancillary laboratory examinations. Additionally, when a subject died, an autopsy was performed at the Departments of Pathology of Kyushu University. During the follow-up period, one subject was lost to follow-up and 418 subjects died, of whom 312 (74.6%) underwent autopsy.
Definition of Cardiovascular Events
In principle, stroke was defined as a sudden onset of nonconvulsive and focal neurological deficit persisting for ≥24 hours. The diagnosis and classification of stroke were determined on the basis of clinical information, including brain CT and MRI, cerebral angiography, echocardiography, carotid duplex imaging, or autopsy findings. Ischemic stroke was classified as either lacunar or nonlacunar infarction based on the Classification of Cerebrovascular Disease III criteria proposed by the National Institute of Neurological Disorders and Stroke.15 In brief, lacunar infarction was diagnosed as the presence of a relevant brain stem, basal ganglia, or subcortical hemispheric lesion with a diameter <1.5 cm demonstrated on brain imaging and no evidence of cerebral cortical or cerebellar impairment. Patients who had typical clinical findings of lacunar infarction and a negative imaging were also categorized as cases of lacunar infarction. The other ischemic strokes were defined as cases of nonlacunar infarction.
CHD included acute myocardial infarction, silent myocardial infarction, sudden cardiac death within 1 hour after the onset of acute illness, and coronary artery disease treated by coronary artery bypass surgery or angioplasty. Acute myocardial infarction was diagnosed when a subject met at least 2 of the following criteria: (1) typical symptoms, including prolonged severe anterior chest pain; (2) evolving diagnostic electrocardiographic changes; (3) cardiac enzyme levels more than twice the upper limit of normal range; and (4) morphological changes, including local asynergy of cardiac wall motion on echocardiography, persistent perfusion defect on cardiac scintigraphy, or myocardial necrosis or scars ≥1 cm long accompanied by coronary atherosclerosis at autopsy. Silent myocardial infarction was defined as myocardial scarring without any historical indication of clinical symptoms or abnormal cardiac enzyme changes.
During the follow-up, we identified 132 cases of ischemic stroke (for men, 61 total, or 27 lacunar and 34 nonlacunar infarctions; for women, 71 total, or 42 lacunar and 29 nonlacunar infarctions) and 112 CHD events (75 men and 37 women). All of the ischemic stroke cases underwent brain imaging.
At the baseline examination, we performed the OGTT after at least a 12-hour overnight fast. Plasma glucose levels were determined by the glucose-oxidase method. FPG and 2-hour postload glucose (PG) levels were divided into 4 categories: for FPG: <5.6, 5.6 to 6.0, 6.1 to 6.9, and ≥7.0 mmol/L; for 2-hour PG: <6.7, 6.7 to 7.7, 7.8 to 11.0, and ≥11.1 mmol/L. Glucose tolerance status was also defined by the 1998 World Health Organization criteria16; namely, for normal glucose tolerance (NGT), FPG <6.1 and 2-hour PG <7.8; for hyperglycemia, FPG ≥6.1 and/or 2-hour PG ≥7.8; for impaired fasting glycemia (IFG), FPG 6.1 to 6.9 and 2-hour PG <7.8; for impaired glucose tolerance (IGT), FPG <7.0 and 2-hour PG 7.8 to 11.0; and for diabetes mellitus, FPG ≥7.0 mmol/L and/or 2-hour PG ≥11.1 mmol/L. Total and high-density lipoprotein cholesterol levels were determined enzymatically.
Blood pressure was measured 3 times using a sphygmomanometer after at least 5 minutes of rest; the average of 3 measurements was used for the analysis. Hypertension was defined as blood pressure levels of ≥140/90 mm Hg or current treatment with antihypertensive agents. Body mass index (kg/m2) was used as an indicator of obesity. Electrocardiographic abnormalities were defined as left ventricular hypertrophy (Minnesota Code 3 to 1) or ST depression (4 to 1, 4 to 2, or 4 to 3). Each participant completed a self-administered questionnaire covering medical history, antidiabetic and antihypertensive treatments, smoking habits, alcohol intake, and leisure time activity. Smoking habits and alcohol intake were classified as either current use or not. Those subjects engaging in sports or other forms of exertion ≥3 times a week during their leisure time made up a regular exercise group.
The SAS software package Version 9.2 (SAS Institute Inc, Cary, NC) was used to perform all statistical analyses. Incidence was calculated by a person-year method and was adjusted for age by the direct method using 10-year age groupings. The age- and multivariable-adjusted hazard ratios (HRs) and their 95% CIs were estimated using the Cox proportional hazards model.
This study was conducted with the approval of the Ethics Committee of Kyushu University, and written informed consent was obtained from the participants.
The baseline characteristics of the subjects are summarized by sex in Table 1. Mean values of age and body mass index did not differ between the sexes. The means of FPG, 2-hour PG, and systolic and diastolic blood pressures and frequencies of diabetes, hypertension, electrocardiographic abnormalities, smoking habits, alcohol intake, and regular exercise were higher in men than in women, whereas women had higher concentrations of total and high-density lipoprotein cholesterol.
The age-adjusted incidences and age-adjusted and multivariable-adjusted HRs of ischemic stroke and CHD according to FPG levels are shown in Table 2. The age-adjusted incidences of ischemic stroke and CHD did not differ between subjects with FPG levels of <5.6 mmol/L and those with FPG levels of 5.6 to 6.0 mmol/L in either sex. In women, the age-adjusted incidence and HR of ischemic stroke were significantly higher in subjects with FPG levels of 6.1 to 6.9 mmol/L than in those with the FPG levels of <5.6 mmol/L; however, this association was attenuated after adjustment for the following confounding factors: age, systolic blood pressure, electrocardiographic abnormalities, body mass index, total and high-density lipoprotein cholesterol, smoking habits, alcohol intake, and regular exercise. An FPG level of ≥7.0 mmol/L was a significant risk factor for ischemic stroke in both sexes and for CHD in women, even after adjustment for the previously mentioned confounding factors (ischemic stroke: multivariable-adjusted HR=2.15, 95% CI, 1.07 to 4.31, P=0.03 in men; multivariable-adjusted HR=2.10, 95% CI, 1.02 to 4.35, P=0.045 in women; CHD: multivariable-adjusted HR=3.83, 95% CI, 1.59 to 9.25, P=0.003 in women).
Table 3 presents data of the analyses for ischemic stroke and CHD according to 2-hour PG levels. Compared with subjects with 2-hour PG levels of <6.7 mmol/L, the age-adjusted incidences and multivariable-adjusted HRs of ischemic stroke in both sexes and CHD in women were significantly higher in those with glucose levels of ≥11.1 mmol/L (ischemic stroke: multivariable-adjusted HR=2.71, 95% CI, 1.41 to 5.20, P=0.003 in men; multivariable-adjusted HR=2.19, 95% CI, 1.07 to 4.48, P=0.03 in women; CHD: multivariable-adjusted HR=4.44, 95% CI, 1.85 to 10.6, P<0.001 in women). Subjects with a prediabetic range of 2-hour PG levels did not have an increased risk of either ischemic stroke or CHD.
Finally, the relationships between glucose tolerance levels defined by the World Health Organization criteria and the risks of ischemic stroke and CHD are displayed in Table 4. Compared with those in women with NGT, the age-adjusted incidences and HRs of ischemic stroke and CHD were significantly increased in women with hyperglycemia, but these associations disappeared after adjustment for other confounding factors. In regard to subtypes of hyperglycemia, the age-adjusted incidences and HRs of ischemic stroke and CHD did not significantly increase in those with IFG or IGT in either sex. Diabetes was a significant risk factor for ischemic stroke in both sexes and for CHD in women. These significant associations also remained robust even after adjustment for the previously mentioned confounding factors (ischemic stroke: multivariable-adjusted HR=2.54, 95% CI, 1.40 to 4.63, P=0.002 in men; multivariable-adjusted HR=2.02, 95% CI, 1.07 to 3.81, P=0.03 in women; CHD: multivariable-adjusted HR=3.46, 95% CI, 1.59 to 7.54, P=0.002 in women). When ischemic stroke was classified as either lacunar or nonlacunar infarction, diabetes was an independent risk factor for lacunar infarction in women (multivariable-adjusted HR=2.65, 95% CI, 1.19 to 5.93, P=0.02) and nonlacunar infarction in men (HR=3.78, 95% CI, 1.74 to 8.19, P=0.001) after adjustment for other confounding factors (Table 5).
Using data from a 14-year follow-up study of a defined general Japanese population, we demonstrated that diabetes defined by the OGTT is an independent risk factor for the development of ischemic stroke in both sexes and CHD in women after adjustment for other confounding factors. Furthermore, we found that diabetes significantly increased the risk of lacunar infarction in women and nonlacunar infarction in men. By contrast, an FPG level of 5.6 to 6.0 mmol/L, a newly extended range from the American Diabetes Association, was not associated with ischemic stroke or CHD in either sex. In women with the FPG levels of 6.1 to 6.9 mmol/L, the age-adjusted incidence of ischemic stroke increased significantly; however, this association was attenuated after multivariable adjustment.
Very few prospective studies have provided evidence of the associations between glucose tolerance levels defined by the OGTT and the incidence of stroke and CHD. Only investigators of the Strong Heart Study of American Indians have evaluated the association of glucose tolerance status defined by the 1998 World Health Organization criteria with the risk of developing stroke. The results showed that, compared with the subjects with NGT, subjects with diabetes had a 2-fold higher risk of stroke, but subjects with IFG or IGT did not have a higher risk.13 In a follow-up examination of a Finnish population who was free of diabetes at baseline, diabetes that developed during the follow-up was a significant risk factor for CHD, but baseline IGT was not.17 These findings are in accordance with those of the present study. In our study, diabetes was significantly associated with the development of ischemic stroke in both sexes as well as CHD in women, but such an association was not observed for CHD in men. Although the precise reasons for this sex difference in the CHD risk conferred by diabetes are unknown, the higher prevalence of smoking in men may be responsible for this phenomenon; a smoking habit, which is a major risk factor for CHD, is considered to increase the risk of CHD in subjects with normal glucose levels, which would weaken the association of diabetes with CHD in men. Several cohort studies indicated that elevated 2-hour PG levels of 7.8 to 11.0 mmol/L, a category of IGT, was associated with an increased mortality from cardiovascular disease.6–8,18,19 However, there have been some epidemiological studies in which IGT was not a risk factor for cardiovascular death.3,5,9 In the present study, IGT was not associated with the development of ischemic stroke or CHD. However, our previous study of a 5-year follow-up of the same cohort showed that IGT was an independent risk factor for the occurrence of cardiovascular disease.4 During a long follow-up period, a potential change in the glucose tolerance of participants may occur, which would induce some misclassification and weaken the relationship between 2-hour PG levels and cardiovascular disease. Thus, the association between the prediabetic range of 2-hour PG and cardiovascular events would attenuate over time.
The American Diabetes Association lowered the FPG cutoff point from 6.1 to 5.6 mmol/L in 2003.20 This decision was prompted partly by population-based studies showing that the cutoff point of 5.6 mmol/L would increase the sensitivity of predicting future diabetes. In addition, this change was also intended to improve the selection of individuals at risk for cardiovascular diseases.20 Two major organizations recently adopted the cutoff point of 5.6 mmol/L in the diagnostic criteria of metabolic syndrome.21,22 Thus, it is very important to appropriately determine the FPG cutoff value for the prediction of cardiovascular disease. However, there is less evidence concerning the positive association between FPG levels of 5.6 to 6.0 mmol/L and the risk of cardiovascular disease. A recent study of a community-based medical center in the United States found that individuals with glucose of 5.6 to 6.0 mmol/L had lower prevalence of most CHD risk factors compared with individuals with glucose of 6.1 to 6.9 mg/dL.23 Furthermore, some epidemiological studies have shown that the mortality and incidence of cardiovascular disease did not increase in those with FPG levels of 5.6 to 6.0 mmol/L.11,12,19,24 These findings, together with those of the present study, suggest that FPG levels of 5.6 to 6.0 mmol/L are not associated with the risk of cardiovascular disease.
Conflicting data for FPG levels of 6.1 to 6.9 mmol/L as a risk factor for cardiovascular disease also exist. At least 4 studies have shown no significantly increased risk of cardiovascular disease in those with FPG levels of 6.1 to 6.9 mmol/L,6,8,18,19 although others have found that this glucose range is a significant risk factor for cardiovascular disease.7,11,12,24 In our study, the age-adjusted incidence of ischemic stroke was significantly higher in women with FPG levels of 6.1 to 6.9 mmol/L than in those with normal FPG levels, but after controlling for confounding risk factors, the risk was no longer statistically significant. Other known cardiovascular risk factors such as hypertension, obesity, and dyslipidemia tend to accumulate at this glucose level.23 Thus, FPG levels of 6.1 to 6.9 mmol/L seem to have increased the risk of ischemic stroke through other coexisting risk factors in our population.
The strengths of our study include its longitudinal population-based design, long duration of follow-up, perfect follow-up of subjects, sufficient number of cardiovascular events, and accuracy of diagnosis of cardiovascular disease. One limitation of our study is that the diagnosis of glucose tolerance status was based on a single measurement of glucose levels at baseline as was the case in most other epidemiological studies. During the follow-up, risk factor levels were changed due to modifications in lifestyle or medication, and misclassification of glucose tolerance categories was possible. This could have weakened the association found in this study, biasing the results toward the null hypothesis. Therefore, the true association may be stronger than that shown in our study.
In conclusion, diabetes defined by an OGTT was an independent risk factor for cardiovascular disease, except for CHD in men. Notably, the new range in the 2003 American Diabetes Association criteria for IFG (FPG of 5.6 to 6.0 mmol/L) was not associated with ischemic stroke or CHD in either sex. The IFG category of the 1997 criteria (FPG of 6.1 to 6.9 mmol/L) increased the risk of ischemic stroke in women, although this association was not independent of other known risk factors. Because the risks of stroke and CHD and the prevalence of diabetes differ among races, further investigations are required to clarify the relationship between hyperglycemia and type of cardiovascular disease in other ethnic populations.
Sources of Funding
This study was supported in part by Grants-in-Aid for Scientific Research A (No. 18209024) and C (No. 20591063) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a Health and Labour Sciences Research Grant of the Ministry of Health, Labour and Welfare of Japan (Comprehensive Research on Aging and Health: H20-Chouju-004).
- Received August 4, 2009.
- Revision received October 14, 2009.
- Accepted October 20, 2009.
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