Predictors of progression and relationship with incident coronary heart disease. Diabetes Care 23: , 2000

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1 Epidemiology/Health Services/Psychosocial Research O R I G I N A L A R T I C L E Carotid Intima-Media Thickness in Japanese Type 2 Diabetic Subjects Predictors of progression and relationship with incident coronary heart disease YOSHIMITSU YAMASAKI, MD, PHD MINEO KODAMA, MD HIDEKO NISHIZAWA, MD KEN YA SAKAMOTO, MD MUNEHIDE MATSUHISA, MD, PHD OBJECTIVE To examine carotid intima-media thickness (IMT), predictors of its progression, and its relationship with incident coronary heart disease (CHD) in type 2 diabetic Japanese patients. RESEARCH DESIGN AND METHODS Carotid IMT of 287 subjects with type 2 diabetes (mean age 61.6 years) without CHD or cerebrovascular disease was examined at baseline and after a mean follow-up of 3.1 years. RESULTS The annual progression of IMT (means ± SEM) was 0.04 ± mm/year. Stepwise multivariate analysis demonstrated that independent risk factors for progress of IMT were the initial IMT (P 0.001), the average level (P 0.001), and age (P = 0.001). Both the initial IMT (odds ratio [OR] 4.9, 95% CI ) and a low average HDL cholesterol (OR 0.2, ) were identified as predictors of incident nonfatal CHD (angina pectoris or nonfatal myocardial infarction; 3-year incidence 10.1%) after adjusting for age, sex, average, and other risk factors. CONCLUSIONS The predictors of the progression of carotid IMT in Japanese type 2 diabetic subjects were its baseline thickness and the average during the follow-up. Baseline carotid IMT and low HDL cholesterol predicted the incidence of nonfatal CHD. In Westernized countries, more than half of the diabetic subjects die from coronary heart disease (CHD) (1). Another large portion of the patients suffer from cerebral infarction and peripheral vascular disease, mainly due to markedly advanced atherosclerosis. The U.K. Prospective Diabetes Study (2) and Finnish studies (3) have shown an association of the level YOSHITAKA KAJIMOTO, MD, PHD KEISUKE KOSUGI, MD, PHD YASUHISA SHIMIZU, MD, PHD RYUZO KAWAMORI, MD, PHD MASATSUGU HORI, MD, PHD Diabetes Care 23: , 2000 and the risk for CHD in type 2 diabetic patients. However, the Kumamoto Study (4) did not yield results to support strict glycemic control leading to reduced mortality and morbidity of CHD in patients with type 2 diabetes. Thus, the possible contribution of glycemic control to atherosclerosis, in addition to the risk of CHD, needs to be clarified. From the Department of Internal Medicine and Therapeutics (Y.Y., M.K., H.N., K.S., M.M., Y.K., M.H.), Osaka University Graduate School of Medicine; the Osaka Police Hospital (K.K., Y.S.), Osaka; and the Department of Medicine, Metabolism and Endocrinology (R.K.), Juntendo University School of Medicine, Tokyo, Japan. Address correspondence and reprint requests to Yoshimitsu Yamasaki, MD, PhD, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita City, Osaka , Japan. yamasaki@medone.med.asaka-u.ac.jp. Received for publication 22 October 1999 and accepted in revised form 15 May Abbreviations: CHD, coronary heart disease; ECG, electrocardiogram; IMT, intima-medial thickness; OR, odds ratio. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Intima-media thickness (IMT) of the carotid artery has been used as a subclinical index of atherosclerosis (5 15). Several studies have shown an association between increased carotid IMT and new myocardial infarction or stroke in elderly and middleaged subjects (13 15). However, there have been few studies that have evaluated the progression of carotid IMT in subjects with type 2 diabetes. Study of carotid IMT in type 2 diabetic Japanese subjects is of particular interest, because the prevalence and incidence of atherosclerotic vascular disease in the Japanese general population is much lower than that in Western populations. Thus, in the present study, we measured the progression of carotid atherosclerosis in Japanese diabetic patients and evaluated the possibility of increased carotid IMT serving as a predictor of CHD in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS Subjects Subjects with type 2 diabetes were recruited from a group of outpatients at the Osaka University Hospital and the Osaka Police Hospital. The subjects were free from overt symptoms or complaints of cardiovascular disease and were not receiving orally administered antiplatelet drugs. The determination of type 2 diabetes was based on World Health Organization criteria (16). Patients were recruited for the study if they met the following inclusion criteria: 1) no episodes of ketoacidosis and absence of ketonuria, 2) diagnosis of diabetes after 30 years of age, 3) insulin therapy (if any) started after at least 5 years after diagnosis; 4) absence of overt diabetic nephropathy or other renal tract disease, and 5) absence of acute stage or signs and symptoms of CHD, cerebral vascular disease, and peripheral artery disease after careful evaluation of clinical records. Informed consent was obtained from the subjects studied. Patient characteristics at baseline and after the study period are shown in Table DIABETES CARE, VOLUME 23, NUMBER 9, SEPTEMBER 2000

2 Yamasaki and Associates At the time of enrollment, the laboratory data, blood pressure measurements, urinary albumin measurements, resting 12-lead electrocardiogram (ECG) and double-master s 2-step test results (17), and IMT measurements were collected for each patient. During the follow-up period of 3.1 ± 0.02 years, the laboratory data and blood pressure measurements were collected every other month and averaged. IMT was measured annually or biannually according to the severity of IMT. The baseline laboratory data and blood pressure level, were not included in the averaged data during the observation period. At the time of measuring IMT during and after the follow-up period, body weight was measured, smoking habits were monitored, and careful interviews were conducted to detect symptoms of angina pectoris or old myocardial infarction. After termination of the follow-up period, IMT was measured, and the resting 12-lead ECG and double-master s 2-step tests were conducted. Fasting blood was obtained for analyses of serum total cholesterol and HDL cholesterol, serum triglycerides, serum creatinine, urinary creatinine, blood urea nitrogen, serum uric acid, and levels by standard laboratory techniques. LDL cholesterol was estimated by the equation of Friedewald et al. (18). Urinary albumin of a fasting urine specimen and a specimen collected at least 4 weeks later was measured by radioimmunoassay. The level was divided by the urinary creatinine concentration and expressed as milligrams per gram of creatinine (19). The 2 measurements of urinary albumin were averaged. Blood pressure was measured with a mercury sphygmomanometer. After a supine rest of 5 min, 3 measurements in the sitting position were conducted, and the mean value was used. Smoking was estimated as the mean number of cigarettes smoked daily. The same blood samples were sent to Osaka University Hospital and Osaka Police Hospital for laboratory examinations of levels. Fitting equations were calculated from these determinations. Laboratory data obtained from outpatients of Osaka University Hospital were adjusted using the fitting equations. Checking for the occurrence of angina pectoris and old myocardial infarction (major abnormal Q wave or abnormal QS pattern changes) was performed based on the results of the resting 12-lead ECG and double-master s 2-step tests and the existence of previous symptoms of myocardial infarction. During the follow-up period, consistent therapy for diabetes, hyperlipidemia, and hypertension was conducted. Of the diabetic subjects, 31 were controlled with diet only, 113 with sulfonylurea, 46 with insulin injection once or twice daily, and 97 with insulin injections 3 times plus selfmonitoring of blood glucose. Antihypertensive drugs were given to 127 patients (28 received diuretics, 19 received -blockers, 2 received -blockers, 76 received calcium channel blockers, and 53 received angiotensin-converting enzyme inhibitors). Antihyperlipidemic drugs were administered to 140 patients (16 received clofibrates, 55 received probucol, and 79 received 3-hydroxyl-3-methylglutaryl-CoA reductase inhibitors). Antithrombotic drugs were not prescribed. Of the enrolled subjects at baseline, 2 died of causes not related to cardiovascular disease, 2 moved to other districts, and 1 was admitted to another hospital. Assessment of carotid atherosclerosis Ultrasonographic scanning of the carotid arteries was performed using an echotomographic system (EUB-450; Hitachi Medico, Tokyo) with an electrical linear transducer (midfrequency of 7.5 MHz). Scanning of the extracranial common carotid artery, the carotid bulb, and the internal carotid artery in the neck was performed bilaterally from 3 different longitudinal projections (i.e., anterior-oblique, lateral, and posterior-oblique) as well as the transverse projection, as reported in our previous studies (7 9). All of the images were photographed. The scanning session lasted an average of 30 min. The detection limit of this echo system using 7.5 MHz was 0.1 mm. The carotid IMT defined by Pignoli et al. (5,6) was measured as the distance from the leading edge of the first echogenic line to the leading edge of the second echogenic line. The first line represented the lumenintimal interface; the collagen-containing upper layer of the tunica adventitia formed the second line. At each longitudinal projection, the site of the greatest thickness, including plaque, was sought along the arterial walls nearest the skin and farthest from the skin from the common carotid artery to the internal carotid artery. Three determinations of IMT were conducted at the site of the greatest thickness and at 2 other points, 1 cm upstream and 1 cm downstream from this site. These 3 determinations were averaged. The greatest value among the 6 averaged IMTs (3 from the left and 3 from the right) was used as the representative value for each individual. All scans were conducted by physicians (H.N. and K.S.) who were unaware of the clinical characteristics of the subjects. Determination of IMT on the photograph was performed by a physician (M.K.) who was unaware of the clinical characteristics of the subjects. The reproducibility of the IMT measurement was examined by conducting another scan 1 month later on 20 subjects with type 2 diabetes whose IMT values were The mean difference in IMT between these 2 determinations was 0.04 mm, and the standard deviation was 0.09 mm, demonstrating good reproducibility for repeated measurements, as described previously (7 9). Determination of annual change in IMT The enrolled patients were subjected to 974 IMT measurements (average 3.4 measurements of IMT for each diabetic subject). A linear regression line was drawn for sequential determination of IMT as a dependent variable, and its duration was taken as an independent variable. The change in IMT per year (millimeters per year) was calculated as the slope of this regression line for each patient. Data analyses Data are presented as means ± SEM. The laboratory data were compared by Student s paired t test. Statistical significance was evaluated by one-way analysis of variance. Stepwise multivariate analysis was performed to account for the effects and interactions of different variables on the change in IMT per year during the follow-up period in type 2 diabetes. In this analysis, F values for inclusion and exclusion of variables were set at 2.0. To depict the risk factor for angina pectoris or nonfatal myocardial infarction, a multiple logistic model was applied with adjustment for age, sex, average, systolic and diastolic blood pressures, triglycerides, total cholesterol, number of cigarettes smoked per day, serum uric acid, and serum creatinine concentration. These statistical analyses were carried out using the HAL- BAU statistical package (Gendai Sugakusha, Kyoto, Japan) on a personal computer. Statistical significance was determined as P DIABETES CARE, VOLUME 23, NUMBER 9, SEPTEMBER

3 Progression of carotid intima-media thickness Table 1 Patient characteristics before and after the follow-up period Subjects with type 2 diabetes (n = 287) Before follow-up After follow-up P* Age (years) 61.7 ± ± 0.6 Sex (M/F) 124/163 Duration (years) 15.6 ± ± 0.5 BMI (kg/m 2 ) 22.6 ± ± 0.43 (%) 8.66 ± ± Creatinine (µmol/l) 91 ± ± Blood urea nitrogen (mmol/l) 6.17 ± ± 0.22 Uric acid (µmol/l) 308 ± ± 14.8 Total cholesterol (mmol/l) 5.37 ± ± Triglycerides (mmol/l) 1.63 ± ± 0.05 HDL cholesterol (mmol/l) 1.40 ± ± 0.03 LDL cholesterol (mmol/l) 3.22 ± ± 0.05 sbp (mmhg) 133 ± ± dbp (mmhg) 76 ± ± 0.4 Urinary albumin (mg/g creatinine) ± ± 20.5 Data are means ± SEM unless otherwise indicated. *Statistical significance was determined using Student s paired t test. BUN, blood urea nitrogen; dbp, diastolic blood pressure; sbp, systolic blood pressure. RESULTS A total of 287 diabetic patients (124 men, 163 women) aged years at baseline were followed. Subjects with type 2 diabetes showed slight but significant improvement in and total cholesterol (Table 1). However, their serum creatinine and systolic blood pressure worsened significantly (Table 1). On average, the 287 diabetic patients showed an IMT change of ± mm/year. The initial IMT at baseline determination was positively related with the change in IMT per year during the follow-up period (r = 0.45, P 0.001) (Fig. 1). Also, the average during the follow-up period (r = 0.28, P 0.001) (Fig. 2) and the initial at the baseline determination (r = 0.18, P = 0.003) were positively related to the progression of IMT. Average total cholesterol and LDL cholesterol levels were weakly but significantly (r = 0.13, P = 0.025, and r = 0.14, P = 0.021, respectively) related to the progress of IMT (Table 2). Stepwise multivariate analysis demonstrated that the independent risk factors for change in IMT per year in diabetic patients were initial IMT (F = 81.4, P 0.001), average (F = 11.0, P = 0.001), and age (F = 10.6, P = 0.001) (Table 2). Of 287 patients, 73 showed a negative value of change in IMT per year. They had a significantly lower level than those with a positive change in IMT per year (7.9 ± 0.15 vs. 8.4 ± 0.08%, P = 0.002). The other parameters, including percentage of subjects given antihypertensive drugs, antihyperlipidemic drugs, and insulin treatment, led to no significant differences. A total of 55 diabetic subjects who were given probucol showed a significantly higher change in IMT per year (0.066 ± vs ± 0.004, P = 0.029), higher total cholesterol (5.9 ± 0.11 vs. 5.3 ± 0.05, P = 0.013), higher LDL cholesterol (3.6 ± 0.10 vs. 3.1 ± 0.05, P ), and lower HDL cholesterol levels (1.2 ± 0.05 vs. 1.5 ± 0.03, P ) than the other subjects. These probucol-administered subjects also showed a tendency of higher initial IMT and higher BMI but a lower frequency of nonfatal CHD events. Eight subjects showed a negative value of change in IMT per year. Of 287 diabetic subjects, 29 suffered from angina pectoris or nonfatal myocardial infarction during the follow-up period. They had a significantly higher initial IMT and systolic blood pressure and a significantly lower HDL cholesterol level than the remaining diabetic subjects without angina pectoris or nonfatal myocardial infarction. The other parameters, including sex, BMI, duration of diabetes, average, and percentage of subjects given insulin, showed no significant differences. The multiple logistic model showed that both the initial IMT (odds ratio [OR] 4.9, 95% CI ) and the low average HDL cholesterol (OR 0.2, ) were related to the incidence of angina pectoris or nonfatal myocardial infarction with adjustment for age, sex, average, and other risk factors (systolic and diastolic blood pressure, triglycerides, total cholesterol, number of cigarettes smoked per day, serum uric acid, and serum creatinine concentration). However, the average level was not an independent risk factor for incident nonfatal myocardial infarction. CONCLUSIONS In this study, the 287 diabetic subjects showed an IMT change of ± mm/year. Thus, within the observation period of 3 years, the IMT of diabetic patients increased by an average of mm, which is close to the Figure 1 Relationship between the increase in carotid IMT per year during the follow-up period and the initial IMT in 287 subjects with type 2 diabetes. r = 0.450; P DIABETES CARE, VOLUME 23, NUMBER 9, SEPTEMBER 2000

4 Yamasaki and Associates Figure 2 Relationship between the increase in carotid IMT per year and the average in 287 subjects during the follow-up period. r = 0.279; P discrimination limit (0.1 mm) of the 7.5- MHz echo probe used in this study. In a cross-sectional analysis that we previously conducted for 109 control subjects (8), we had obtained mm/year as a partial regression coefficient ( ) for age. Although the design of the 2 studies was quite different, these findings suggest that the IMT of type 2 diabetic subjects with early-stage carotid atherosclerosis might progress remarkably in comparison with nondiabetic control subjects. The diabetic patients had an average LDL level of 3.2 mmol/l and a progression of IMT of 0.04 mm/year for the follow-up period of 3.1 years. The value was comparable with the report of Salonen and Salonen (11), in which the mainly nondiabetic subjects with an LDL cholesterol level of mmol/l showed a mean 2-year increase of carotid IMT of 0.08 mm. Multivariate analysis of possible risk factors for the progression of IMT in the type 2 diabetic subjects pointed out that an initially increased IMT level and the average level could independently account for the progression of carotid atherosclerosis. Salonen and Salonen (11) reported that the progression of IMT was more rapid in men with atherosclerotic lesions at the baseline examination, as defined by the presence of either hard plaques or an IMT of 1.1 mm, compared with men with no lesions at baseline. However, age, serum LDL cholesterol concentration, pack-years of smoking, blood leukocyte count, and platelet aggregability were proven to be the strongest predictors of atherosclerosis progression. The significance of increased level as a predictor of atherosclerosis in subjects with type 2 diabetes has not yet been reported. With respect to the carotid artery of type 1 diabetic patients, Jensen- Urstad et al. (20) reported that patients with lower levels generally had lessstiff arteries and showed no significant change in IMT (20). Our study shows a positive association between carotid artery IMT and the incidence of angina pectoris or nonfatal myocardial infarction, even after adjustment for age, sex, average, and other risk factors. Our results compared well with those of other studies (13 15) that were conducted to explore the possible association between carotid IMT and the incidence of cardiovascular events, despite the difference in the number of subjects enrolled. In a population-based study, Salonen and Salonen (12) showed that the maximum IMT of the common carotid artery was significantly associated with the risk of a CHD event in eastern Finnish men, the population with the highest recorded incidence and mortality from CHD. Taken together, these studies suggest that increased IMT is associated with the risk of CHD in subjects with a risk of coronary heart event. Table 2 Multivariate regression analysis of change in IMT of type 2 diabetes Univariate Multivariate correlation regression analysis Means ± SEM coefficient P F P Baseline data Sex* Age (years) ± Duration (years) ± (%) 8.66 ± Initial IMT (mm) 1.36 ± Average data for follow-up period BMI (kg/m 2 ) ± (%) 8.27 ± Total cholesterol (mmol/l) 5.33 ± Triglycerides (mmol/l) 1.61 ± HDL cholesterol (mmol/l) 1.42 ± LDL cholesterol (mmol/l) 3.18 ± sbp (mmhg) 134 ± dbp (mmhg) 76 ± Smoking habit ± (cigarettes/day) Creatinine (µmol/l) ± Blood urea nitrogen (mmol/l) 6.54 ± Uric acid (mmol/l) 317 ± Change in IMT (mm/year) 0.04 ± 0.00 r Baseline data were obtained at the time of patient enrollment; clinical data were collected every other month and were averaged for the follow-up period. *Men = 1, women = 2. dbp, diastolic blood pressure; sbp, systolic blood pressure. DIABETES CARE, VOLUME 23, NUMBER 9, SEPTEMBER

5 Progression of carotid intima-media thickness Low average HDL cholesterol levels proved to be another risk factor for CHD but not for progression of the carotid artery IMT, as shown in previous studies (21,22). The possible explanation of these observations is that a low average HDL cholesterol may be a risk factor for angina pectoris or acute myocardial infarction rather than a risk factor for carotid artery thickness. The diabetic subjects given probucol showed a significantly higher change in IMT per year accompanied by significantly higher total cholesterol and LDL cholesterol levels and by significantly lower HDL cholesterol levels. Also, they had a tendency of a higher initial IMT and fewer events of CHD. Antihyperlipidemic drugs, including probucol, may be administered to diabetic subjects with hyperlipidemia and a higher IMT, which may in part explain the greater change in IMT per year in diabetic subjects receiving probucol. To explain the discrepancy between the worsening carotid thickening and the improved frequency of nonfatal CHD events after oral administration of probucol requires further follow-up or another prospective study. This study shows that the initially increased IMT can predict the further progression of carotid atherosclerosis in Japanese subjects with type 2 diabetes. In the present study, the initial or average could not significantly predict the incidence of nonfatal CHD in these subjects. The U.K. Prospective Diabetes Study (2) and the Finnish study (3) showed a positive association of during the observation period with a risk for CHD in type 2 diabetic patients. These 2 studies used a large number of subjects and were of longer duration. In the present study, showed a weak but significant association with the progression of IMT, which has been shown to be associated with the incidence of CHD. Extension of the follow-up period might have revealed a significant association of average with the incidence of CHD in subjects with type 2 diabetes. No fatal CHD occurred among the enrolled patients during the follow-up. This finding weakens the predictive value of baseline IMT with regard to the risk of nonfatal CHD, because subjects with the thickest IMT should have the highest risk of dying from cardiovascular causes. Thus, our observations with Japanese type 2 diabetic subjects may not be generalized to other populations with higher atherosclerotic vascular disease rates. Our Japanese patients were relatively thin (mean BMI 22.6 kg/m 2 ) and, in general, diabetic Japanese subjects show a relatively low incidence rate of CHD compared with diabetic Caucasian subjects who are relatively obese and have high LDL cholesterol concentrations. Thus, to evaluate the significance of increased IMT as a predictor of CHD, another study should be conducted with non-japanese subjects with type 2 diabetes. Even with this caveat in mind, our study does suggest that the initial carotid IMT may be a clinically useful predictor of nonfatal CHD in Japanese subjects with type 2 diabetes. Acknowledgments We are deeply indebted to numerous medical doctors and paramedical personnel for their assistance in managing patients with type 2 diabetes at Osaka University Hospital and Osaka Police Hospital. The technical assistance of Hidehiko Waki is also acknowledged. References 1. Chait A, Bierman EL: Pathogenesis of macrovascular disease in diabetes. In Joslin s Diabetes Mellitus. Kahn CR, Weir GC, Eds. 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6 Yamasaki and Associates 20. Jensen-Urstad KJ, Reichard PG, Rosfors JS, Lindblad LE, Jensen-Urstad MT: Early atherosclerosis is retarded by improved longterm blood glucose control in patients with IDDM. Diabetes 45: , Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR: Diabetes, blood lipids, and the role of obesity in coronary heart disease risk for women: the Framingham Study. Ann Intern Med 87: , Reckless JP, Betteridge DJ, Wu P, Payne B, Galton DJ: High-density and low-density lipoproteins and prevalence of vascular disease in diabetes mellitus. Br Med J 8: , 1978 DIABETES CARE, VOLUME 23, NUMBER 9, SEPTEMBER