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Asymptomatic hyperglycemia and cardiovascular risk factors in the elderly
153
Atherosclerosis, 88 (1991) 153-161 0 1991 Elsevier Scientific Publishers Ireland, Ltd. 0021-9150/91/$03.50 ADONIS 0021915091001198
ATHERO 04636
Asymptomatic hyperglycemia and cardiovascular risk factors in the elderly Leena Mykkinen Depmrtments of
‘, Markku
Laakso
‘, Ilkka Penttib
* and Kalevi Py6rSi
’
’Medicine and ’ Clinical Chemistry, Kuopio Unkersity Central Hospital, Kuopio (Finland) (Received 14 September, 1990) (Revised, received 25 January, 1991) (Accepted 28 January, 1991)
Summary We studied the levels of cardiovascular risk factors in a population sample of 511 men and 920 women aged 65-74 years and living in East Finland. Altogether 312 men and 515 women had normal glucose tolerance, 84 men and 158 women impaired glucose tolerance (IGT), 33 men and 59 women newly diagnosed non-insulin-dependent diabetes (NIDDM) detected at the survey, and 82 men and 188 women previously diagnosed NIDDM. Subjects with IGT or newly diagnosed NIDDM had higher levels of total triglycerides and apolipoprotein B and lower levels of HDL cholesterol and apolipoprotein A, than subjects with normal glucose tolerance, similarly as in previously diagnosed NIDDM. Furthermore, subjects with IGT or newly diagnosed NIDDM were more obese, had higher waist-hip ratio, and more frequently hypertension than subjects with normal glucose tolerance. Thlls, asymptomatic hyperglycemia in the elderly is not a benign phenomenon, but is associated with similar adverse changes in cardiovascular risk factors as in middle-aged subjects.
Key words: Aged; Coronary heart disease; Diabetes mellitus, non-insulin-dependent; Lipids; Lipoproteins; Obesity; Hypertension
Introduction Coronary heart disease is found in excess in middle-aged subjects with asymptomatic hyperglycemia, impaired glucose tolerance (IGT) or
Correspondence to: Leena Mykklnen, MD, Department of Medicine, Kuopio University Central Hospital, SF-70210 Kuopio, Finland. Fax: 358-71-173993.
Hyperglycemia;
newly diagnosed non-insulin-dependent diabetes (NIDDM) U-31, similarly as ~II sllbjects with previously diagnosed NIDDM 141. Several studies have reported that middle-aged subjects with IGT or NIDDM are more obese and have more frequently hypertension than subjects with normal glucose tolerance [5-101. Furthermore, elevated total triglyceride levels have been a rather consistent finding in subjects with IGT or NIDDM, but results on the association of reduced HDL
154 cholesterol level with IGT are still controversial [9,11-141. Thus, middle-aged subjecs with asymptomatic hyperglycemia show a similar clustering of cardiovascular risk factors as subjects with previously diagnosed NIDDM [8,9,15]. Although abnormalities of glucose tolerance are frequent in the elderly [16,17], little is known about the association between IGT or newly diagnosed NIDDM and cardiovascular risk factors in older age groups. However, we have recently found in a population survey from East Finland that asymptomatic hyperglycemia is associated with an increased prevalence of coronary heart disease in subjects aged 65-74 years, similarly as in middle-aged subjects [18]. On the basis of that study one would expect to find changes in cardiovascular risk factors favoring atherosclerosis in elderly subjects with asymptomatic hyperglycemia. In this paper, we report our findings on the levels of cardiovascular risk factors by glucose tolerance status based on the same study population of elderly subjects in which we found an increased prevalence of coronary heart disease associated with asymptomatic hyperglycemia [181.
Subjects and methods Subjects
The study was conducted in Kuopio, East Finland, between February 1986 and April 1988. Altogether 1910 subjects born between 1912 and 1921 were randomly selected from the population register including all inhabitants of Kuopio. This random sample covered 35% of all residents in the age group of 65-74 years. In addition, 183 subjects with diabetes born between 1912 and 1921 were selected from the patient registers of general practitioners working at the Kuopio Health Center. This sample was identified from all diabetic subjects aged 65-74 years who visited the Kuopio Health Center during the consecutive 6 months (from 1st January to 30th June, 1985). A postal questionnaire containing questions about diagnosis of diabetes, ability to move, and willingness to participate in the study was sent to these subjects. 262 subjects from the random sample and 20 from the diabetes sample did not respond to the repeated postal questionnaire and 85 sub-
jects from the random sample and 5 from the diabetes sample were originally unwilling to participate. 83 subjects from the random sample and 14 from the diabetes sample were excluded because they were too ill to participate. Of those who were invited, 80 subjects from the random sample and 4 from the diabetes sample died, moved outside of the study area, or became seriously ill before clinical examination. 100 subjects from the random sample and 6 from the diabetes sample refused later on to participate in the examination, giving an overall participation rate of 71%. All patients in Finland needing drug therapy for chronic diseases such as diabetes, hypertension and cardiac failure are provided medication free of charge and registered. Representativeness of the study population was evaluated on the basis of this register. The mean age of subjects who participated (71%) in the study was similar to that of those (29%) who failed to participate (69 vs. 69 years in men, 69 vs. 70 yrs in women). There were no differences in the proportion of subjects receiving drug therapy for diabetes (9.6 vs. 10.6% in men, 11.7 vs. 13.8% in women, NS) or in the duration of diabetes (8 vs. 8 yrs in men, 8 vs. 9 yrs in women) between participants and non-participants. Also the proportion of subjects receiving drug therapy for hypertension was similar among participants and non-participants (27.3 vs. 30. 7% in men, 39.6 vs. 42.2% in women, NS). Male participants did not, however, have drug therapy for heart failure as frequently as non-participants (15.0 vs. 22.5%, P < 0.05), but this difference was not seen among women (24.4 vs. 26.5%, NS). Thus, the study population was a representative sample of subjects aged 65-74 yrs and living in Kuopio. Methods
Standing height and body weight were measured without shoes in light clothes. Body mass index (BMI) was calculated from the formula weight (kg)/height cm>‘. Obesity was defined as BMI 2 27 kg/m2 in men and 2 25 kg/m2 in women [19]. Body fat distribution pattern was measured as waist-hip ratio. Waist circumference was measured to the nearest 1 cm at the level of the umbilicus with the subject standing
155 and breathing normally. Hip circumference was measured to the nearest 1 cm at the level of the greatest hip girth. All anthropometric measurements were performed by the same specially trained nurse. Blood pressure was measured in the supine position after a 5 min rest. Measurements were taken in the right arm with a mercury sphygmomanometer (cuff size 12.5 x 40 cm). Two readings were taken (interval 1.5 min), and the latter one was used in statistical analyses. Systolic and diastolic blood pressure were read to the nearest 2 mm Hg. The disappearance of sounds (Korotkoff’s 5th phase) was recorded as diastolic blood pressure. A subject was defined as having hypertension if systolic blood pressure was 2 160 mm Hg, or diastolic blood pressure 2 95 mm Hg, or if he/she was receiving drug treatment for hypertension. Alcohol consumption was determined according to the subject’s estimate of the average number of glasses of beer, wine, or other alcoholic drinks ingested per week and transformed to absolute alcohol ingested in g/week. In all statistical analyses, subjects were classified as alcohol users or nonusers. The World Health Organization criteria for diabetes mellitus were used in the classification of subjects without previously known diabetes [20]. The criteria are as follows: (1) diabetes mellitus, fasting venous plasma glucose 2 7.8 mM or 2-h venous plasma glucose 2 11.1 mM in an oral glucose tolerance test (75 g glucose); (2) IGT, fasting venous plasma glucose < 7.8 mM and 2-h venous plasma glucose 7.8-l 1.1 mM; and (3) normal glucose tolerance, fasting and 2-h venous plasma glucose < 7.8 mM. Previously known diabetes was considered to be present, if the diagnosis of diabetes had previously been made by a physician. Medical records were checked for those diabetic subjects who had been treated with diet only and who showed normal glucose tolerance test. A subject was considered to have diabetes if his/her fasting venous blood glucose had been 2 6.7 mM on two visits to the health center. Three insulin-treated diabetic subjects whose C-peptide levels 6 min after intravenous glucagon (1 mg) stimulation [21] were < 0.20 nM were regarded as having insulin-de-
pendent diabetes [22] and they were excluded from the study. In this paper IGT and newly diagnosed NIDDM detected at the survey were considered together as a category of “asymptomatic hyperglycemia”. Laboratory methods Blood samples were taken between 7.30 and 9.30 a.m. after a 12-h fast. All subjects, except for those receiving insulin, underwent an oral glucose tolerance test (75 g glucose in 10% solution). Venous blood samples for glucose determinations were taken before and 1 and 2 h after the glucose load. Plasma glucose was determined by the glucose oxidase method (Glucose Auto & Stat HGA-1120 analyzer, Daiici, Kyoto, Japan). Diabetic subjects who used insulin had C-peptide levels measured at fasting and 6 min after intravenous glucagon administration [21]. Plasma Cpeptide was determined from samples stored at -70°C by a commercial radioimmunoassay (Cpeptide of insulin 1255 RIA kit, Incstar Co., Stillwater, MN, U.S.A.) with a detection limit of 0.07 nM and an intra-assay variation < 5.0% [23]. Serum HDL cholesterol was determined after precipitation of low density and very low density lipoproteins with dextran sulphate-MgCl, [24]. Commercial enzymatic methods were used in the determination of cholesterol [24,25] (Monotest, Boehringer Mannheim, F.R.G.) and triglycerides [26] (Peridocrome, Boehringer Mannheim, F.R.G.). Commercial control serums were used to standardize the measurements of cholesterol and triglycerides (Seronorm, Seronorm Lipid, Nycorned, Oslo, Norway). Serum apolipoproteins A, and B were determined from samples stored at - 70°C. The determinations were performed by a commercial immunochemical method (Kone Diagnostics, Espoo, Finland) which was based on the measurement of immunoprecipitation at 340 nm [27]. The standardization of apolipoprotein measurements were carried out utilizing a calibrator. The day-to-day and intra-assay variations in apolipoprotein assays were < 5%. Statistical methods Data analyses were conducted with the SPSSX programs [28]. The results for continuous vari-
156 ables are given as mean t_ SEM. Student’s twotailed t-test for independent samples was used in the assessment of the significance of the differences between two group means. Chi-square test (x2> was used in the assessment of the significance of the differences in prevalence rates of risk factors. Analysis of variance (ANOVA) was used in testing the differences between more than two group means. Adjustment of the risk factors for age, BMI and waist-hip ratio was done by analysis of covariance (ANCOVA). Results Altogether 1431 subjects participated in the study; 312 men and 515 women had normal glucose tolerance, 84 men and 158 women impaired glucose tolerance (IGT), 33 men and 59 women newly diagnosed non-insulin-dependent diabetes
(NIDDM) detected at the survey, and 82 men and 188 women previously diagnosed NIDDM (38% were treated with diet, 56% with oral hypoglycemic drugs and 6% with insulin) (Table 1). Men with normal glucose tolerance, IGT, and newly or previously diagnosed NIDDM were similar with respect to age, but women with previously diagnosed NIDDM were somewhat older than women with normal glucose tolerance. Among both men and women, subjects with IGT or NIDDM had higher mean values of body mass index (BMI, kg/m21 and waist-hip ratio than subjects with normal glucose tolerance. Also the proportion of obese subjects (BMI 2 27 kg/m2 in men and r 25 kg/m2 in women) was higher in men and women with IGT or NIDDM than in subjects with normal glucose tolerance. Tables 2 and 3 show the levels of cardiovascular risk factors in men and women. Subjects with
TABLE 1 CHARACTERISTICS
OF THE STUDY POPULATION
Values are mean f SEM. NIDDM = non-insulin-dependent Sex, variable
BY GLUCOSE TOLERANCE
STATUS AND SEX
diabetes, BMI = body mass index, WHR = waist-hip ratio.
Glucose tolerance status Normal glucose tolerance
Impaired glucose tolerance
Newly diagnosed NIDDM
Previously diagnosed NIDDM
Men Age (yrs) BMI (kg/m*) BMI 2 27 (%I WHR Fasting plasma glucose (mmol/l) 2 h plasma glucose (mmol/lI
(n = 312) 68.9 kO.2 26.0 kO.2 37.8 0.97 + 0.01
(n = 84) 68.9 kO.3 27.9 +0.4 *** 57.1 ** 1.01+ 0.01 * * *
(n = 33) 68.8 *0.4 28.9 +0.8 ** 63.6 ** 1.02-,0.01 ***
(n = 82) 69.3 +0.3 27.1 kO.4 ** 48.8 1.00+0.01 **
5.7 +0.03
6.1 kO.07 ***
8.0 kO.44 ***
5.8 kO.07
8.9 +0.09 ***
Women Age (yr) BMI (kg/m*) BMI 2 25 (%I WHR Fasting plasma glucose (mol/l) 2 h plasma glucose (mmol/lI
(n = 515) 69.1 +O.l 27.1 +0.2 70.4 0.88+0.01
Asymptomatic hyperglycemia a
P-value b
(n = 117) 68.9 +0.3 28.2 +0.4 *** 59.0 *** 1.01* 0.01 * * *
NS < 0.001 < 0.001 < 0.001
11.4 +0.44 ***
6.7 +O.l ***
< 0.001
13.6 +0.72 ***
19.5 kO.84 ***
10.2 +0.3 ***
< 0.001
(n = 158) 68.6 kO.2 29.1 +0.4 *** 842 *** 0:90 + 0.01 * * *
(n = 59) 69.9 i-O.4 30.3 +0.7 *** 89.8 ** 0.93 + 0.01 * * *
(n = 188) 69.7 kO.2 * 29.2 +0.3 *** 77.3 0.92 + 0.01 * * *
(n = 217) 69.0 kO.2 29.4 +0.3 *** 857 *** 0:91+0.01 ***
< < < <
5.5 kO.02
6.0 kO.05 ***
8.0 kO.32 ***
11.5 +0.29 ***
6.6 +0.1 ***
< 0.001
6.0 kO.04
9.0 + 0.07 * * *
13.7 kO.57 ***
20.8 kO.50 ***
10.3 kO.2 ***
< 0.001
0.01 0.001 0.001 0.001
a Impaired glucose tolerance and newly diagnosed NIDDM detected at the survey combined. b P-value for ANOVA and for X*-test over glucose tolerance status groups (normal glucose tolerance, impaired glucose tolerance and NIDDM). * p < 0.05, * * P < 0.01, * * * P < 0.001 (t-test or X2-test; impaired glucose tolerance, NIDDM and asymptomatic hyperglycemia VS. normal glucose tolerance).
157 TABLE
2
CARDIOVASCULAR Values
RISK FACTORS
are mean f SEM. NIDDM
IN MEN BY GLUCOSE
= non-insulin-dependent Glucose
tolerance
Hypertensives (“cl Drug treatment for hypertension Current smokers (%l Alcohol users (%l
diabetes,
46.5 20.8 17.3 59.0
HDL = high density
lipoprotein. Asymptomatic hyperglycemia
Previously diagnosed NIDDM
Newly diagnosed NIDDM
1.57+0.04 1.92+0.08 6.18+0.07 6.29kO.12 1.20_+0.02 1.06kO.03 1.11 kO.01 1.17?0.02 1.34+0.01 1.29+0.02 152.8 ~fr1.3 152.3 k 2.5 x2.2 f 0.7 82.8 & 15 (%)
STATUS
status
Impaired glucose tolerance
Normal glucose tolerance Total triglycerides (mmol/l) Total cholesterol (mmol/l) HDL cholesterol fmmol/l) Apolipoprotein B (g/l) Apolipoprotein A, (g/l) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
TOLERANCE
***
2.44kO.21 *** 2.17kO.19 6.06*0.14 6.23 k 0.26 *** 1.05+0.06 ** 1.04iO.03 1.18+0.03 ** 1.24 f 0.06 * ** 1.29+0.04 1.26kO.02 156.0 k2.8 157.8 k4.6 82.2 k 1.1 86.5 i2.2
53.6 25.0 13.1 50.0
61.0 40.2 4.9 40.2
63.6 42.4 * * 15.2 48.5
TABLE
* * * < 0.001 NS ***
56.4 29.9 * 13.7 49.6
< < < <
* *** ** **
RISK FACTORS
are mean + SEM. NIDDM
Normal glucose tolerance Total triglycerides (mol/l) Total cholesterol (mmol/l) HDL cholesterol fmmol/l) Apolipoprotein B (g/l) Apolipoprotein A, (g/l) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Hypertensives (%) Drug treatment for hypertension smokers (%I users (%)
IN WOMEN
= non-insulin Glucose
f%) Current Alcohol
glucose
tolerance,
NIDDM
impaired
and asymptomatic
glucose
0.05 0.001 0.05 0.05
tolerance
hyperglycemia
vs.
3
CARDIOVASCULAR Values
or X*-test; impaired
’
2.07 i 0.04 6.28+0.11 *** 1.06kO.03 * 1.19kO.02 ** 1.29iO.02 153.9 k2.2 83.8 f1.3 **
’ Impaired glucose tolerance and newly diagnosed NIDDM detected at the survey combined. ” I’-value for ANOVA and for *‘-test over glucose tolerance status groups (normal glucose tolerance. and NIDDM). * P < 0.05, * * P < 0.01, * * * P < 0.001 (/-test normal glucose tolerance).
P-value a
BY GLUCOSE
dependent
tolerance
diabetes,
TOLERANCE
HDL = high density
lipoprotein,
status
Impaired glucose tolerance
Newly diagnosed NIDDM
34.2 * 3.2 9.5 *
Asymptomatic hyperglycemia
Previously diagnosed NIDDM
1.67kO.03 1.96k0.07 *** 2.50?0.17 6.82+0.05 6.64+0.10 6.61 f0.18 1.40+0.01 1.30+0.03 ** 1.17+0.05 l.lh&O.Ol 1.20 * 0.02 1.31+0.04 1.45 f 0.01 1.41+0.02 * 1.38+0.03 157.7 + 1.0 164.0 + 1.7 * * 162.0 +3.1 80.9 + 0.4 81.9 +0.8 82.9 +1.5 56.5 74.7 *** 81.4 *** 24.9 7.0 16.7
STATUS
*** *** ** *
52.5 *** 1.7 8.5
glucose
59.0 *** I.6 *+
39.2 *** 2.8 * 9.2 **
6.4 * * *
tolerance,
h
2.67kO.24 *** 2.11?0.07 ***
” Impaired glucose tolerance and newly diagnosed NIDDM detected at the survey combined, h P-value for ANOVA and for x*-test over glucose tolerance status groups (normal glucose tolerance, and NIDDM). * P < 0.05, * * P < 0.01, * * * P i 0.001, (t-test or X2-test; impaired normal glucose tolerance).
P-value a
NIDDM
impaired
and asymptomatic
< 0.001 < 0.01 < 0.001
glucose
tolerance
hyperglycemia
vs
158
WOMEN
IGT or NIDDM had higher levels of total triglycerides and apolipoprotein B and lower levels of HDL cholesterol and apolipoprotein A 1 than subjects with normal glucose tolerance. Since the frequency of hypertension and drug treatment for hypertension were also higher in subjects with
Total triglycerides ttt
ttt T
*1*-
MEN Total triglycerides mmolll 3,
T Drug
treatment
-
Drug
treatment
.
Total cholesterol mmoltl 6,
Drug treatment
D,“Q
-
,reatment
??
Total cholesterol
Drug
treatment
-
Drug
treatment
+
HDL cholesterol mmolll
1.4 1.2 Drug ,reatment
-
Drug ,rea,men,
1
1 0.8
HDL cholesterol
0.6 0.4 0.2
1.2
??
t
tt 0 Drug
1
treatment
-
Drug
treatment
f
0.6 0.6
n
0.4 0.2 0 Drug treatment
-
b”Q
[3
,Ea,“W”,
.
Newly diagnosed NIDDM prev,oualy diagnosed NIDDM
Fig. 1. Levels of total triglycerides (upper), total cholesterol (middle) and HDL cholesterol (lower) in men with normal glucose tolerance, impaired glucose tolerance (IGT) and newly or previously diagnosed NIDDM receiving and not receiving drug treatment for hypertension. * * * P < 0.001, * * P < 0.01, *P < 0.05; IGT, newly or previously diagnosed NIDDM vs. normal glucose tolerance; Student’s t-test.
Newly diagnosed NIDDM ~rewously diagnosed NIDDM
Fig. 2. Levels of total triglycerides (upper), total cholesterol (middle) and HDL cholesterol (lower) in women with normal glucose tolerance, impaired glucose tolerance (IGT) and newly or previously diagnosed NIDDM receiving and not receiving drug treatment for hypertension. * * * P < 0.001, * * P < 0.01, *P < 0.05; IGT, newly or previously diagnosed NIDDM vs. normal glucose tolerance; Student’s t-test.
IGT or NIDDM (Tables 2 and 3) we analyzed separately the levels of total triglycerides, total cholesterol and HDL cholesterol in men and women receiving no antihypertensive agents and
159 in those having drug treatment for hypertension (Figs. 1 and 2). Similarly as in the total group, subjects with IGT or NIDDM tended to have higher triglyceride and lower HDL cholesterol levels than subjects with normal glucose tolerance independently of the use of antihypertensive medication. There was no difference in the level of total cholesterol between subjects with IGT or NIDDM and subjects with normal glucose tolerance (Tables 2 and 3) and this result was similar in those who were or who were not receiving antihypertensive medication (Figs. 1 and 2). Systolic blood pressure was higher in women with IGT or NIDDM than in women with normal glucose tolerance but men with IGT or NIDDM were not different from men with normal glucose tolerance in this respect (Tables 2 and 3). There was no difference in diastolic blood pressure between glucose tolerance groups. The proportions of current smokers and alcohol users tended to be lower in subjects with IGT or NIDDM than in subjects with normal glucose tolerance, but this difference was statistically significant only between subjects with previously diagnosed NIDDM and normal glucose tolerance. These differences in risk factor levels between glucose tolerance groups persisted after the adjustment for age, BMI and waist-hip ratio in ANCOVA. Asymptomatic hyperglycemia was associated with adverse changes in cardiovascular risk factors similarly as in NIDDM. Levels of total triglycerides and apolipoprotein B were higher and those of HDL cholesterol and apolipoprotein A, lower in subjects with asymptomatic hyperglycemia than in subjects with normal glucose tolerance (Tables 2 and 3). Also hypertension was more frequent in subjects with asymptomatic hyperglycemia than in subjects with normal glucose tolerance. Discussion
Previous studies have indicated that asymptomatic hyperglycemia is associated with a cardiovascular risk factor profile favoring atherosclerosis in middle-aged subjects [8,9]. The findings of this study extended these observations to older age groups and demonstrated that male and female subjects with IGT or newly diagnosed
NIDDM detected at the survey, were more obese, had higher total triglyceride and lower HDL cholesterol levels and higher prevalence of hypertension than corresponding subjects with normal glucose tolerance. The most consistent abnormality in cardiovascular risk factors in this study were unfavorable lipid and lipoprotein changes which were found in both men and women having IGT or NIDDM. The elevated total triglyceride level in subjects with IGT or NIDDM observed in this study is in accordance with previous findings in middle-aged subjects [9,11,12,14] and indicate that even mild abnormalities in glucose metabolism are associated with alterations in triglyceride metabolism also in the elderly. Our findings on decreased HDL cholesterol levels in subjects with asymptomatic hyperglycemia confirmed the results of two large population-based surveys, one in Pima Indians [12] and the other in older adults from Southern California [14]. Other previous studies have, however, not found alterations in HDL cholesterol levels in subjects with IGT [6,9,11,13]. Since the prevalence of hypertension was more frequent in subjects with IGT and NIDDM, the high proportion of drug treatment for hypertension in these subjects could explain their low HDL cholesterol and high triglyceride levels [29.30]. These differences between glucose tolerance groups persisted, however, when analyses were conducted separately in subjects receiving and not receiving drug treatment for hypertension. Thus, the use of antihypertensive agents did not explain lipid changes favoring atherosclerosis in subjects with IGT or NIDDM. In addition to lipid and lipoprotein abnormalities, subjects with IGT or NIDDM were more obese [&lo], had higher waist-hip ratio and more frequently hypertension [5- 101 than subjects with normal glucose tolerance similarly as reported previously in middle-aged subjects. Both obesity and central fat distribution (high waist-hip ratio) have been shown to be associated with high plasma triglyceride and low HDL cholesterol levels and elevated systolic and diastolic blood pressure in middle-aged men and women [31-331. Our results confirmed the findings of Zavaroni et al. [9] that subjects with asymptomatic hyperglycemia have multiple risk factors for cardiovas-
160 cular disease and extended these observations to the elderly population. The differences in lipid and lipoprotein levels and blood pressure between the glucose tolerance groups persisted after the adjustment for age, BMI and waist-hip ratio. Thus, these adverse changes in cardiovascular risk factors were not due to obesity alone. Insulin resistance could be another underlying mechanism explaining this risk factor profile. Subjects with IGT or NIDDM are more insulin resistant than subjects with normal glucose tolerance [34] and recent studies utilizing the glucose clamp technique have indicated that insulin resistance is associated with high total and VLDL triglyceride and low HDL cholesterol levels in subjects with normal glucose tolerance [35,36], IGT and NIDDM [37]. Furthermore, nonobese hypertensive subjects with normal glucose tolerance or NIDDM are more insulin resistant than corresponding normotensive subjects 138,391. Thus, lipid and lipoprotein abnormalities and hypertension in asymptomatic hyperglycemia could partly be due to insulin resistance. In conclusion, elderly subjects with IGT or newly diagnosed NIDDM had multiple cardiovascular risk factor changes, including elevated total triglyceride levels, decreased HDL cholesterol levels and a high occurrence of hypertension and obesity. Thus, asymptomatic hyperglycemia in the elderly is not a benign phenomenon, because it is associated with unfavorable changes in cardiovascular risk factors as in middle-aged subjects. Prospective studies are, however, needed to assess the predictive value of the changes of these risk factors with regard to future coronary heart disease risk in subjects with asymptomatic hyperglycemia. Acknowledgements This study was supported by grants from the Academy of Finland, the Yrjo Jahnsson Foundation, the Foundation of President and Mrs Urho Kekkonen, and the Aarne and Aili Turunen Foundation.
6
7
8
9
10 11
12
13
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161 15 Wingard. D.L., Barrett-Connor, E., Criqui, M.H. and Suarez, L.. Clustering of heart disease risk factors in diabetic compared to nondiabetic adults, Am. J. Epidemiol., 117 (1983) 19. 16 Harris, M.I.. Hadden, W.C., Knowler, W.C. and Bennett, P.H., Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in US. population aged 20-74 yr, Diabetes, 36 (1987) 523. 17 Mykkanen, L., Laakso, M.. Uusitupa, M. and Pyorala, K., Prevalence of diabetes and impaired glucose tolerance in elderly subjects and their association with obesity and family history of diabetes. Diabetes Care, 13 (1990) 1099. IX Mykkanen, L., Uusitupa, M. and Pyorala, K.. Asymptomatic hyperglycemia is associated with an increased prevalence of coronary heart disease in the elderly, Diahetes. 39 (Suppl. 1) (1990) 38A. 19 National Diabetes Data Group, Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes, 28 (1979) 1039. 20 WHO Study Group on Diabetes Mellitus, WHO Techn. Rep. Ser.. 727, WHO, Geneva. 1985. 21 Faber, O.K. and Binder. C.. C-peptide response to glucagon. A test for the residual B-cell function in diabetes mellitus. Diabetes, 26 (1977) 605. 22 Madshad, S.. Alberti, K.G.M.M., Binder, C., Burrin, J.M.. Faber, O.K., Krarup. T. and Regeur, L., Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes, Br. Med. J., 2 (1979) 1257. 23 Kumar, MS., Schumacher, P. and Deodhar, SD.. Measurement of serum C-peptide immunoreactivity by radioimmunoassay in insulin-dependent diabetics, Am. J. Clin. Pathol., 74 (1980) 7X. 24 Penttila. I.M.. Voutilainen. E., Laitinen. P. and Juutilainen. P.. Comparison of different analytic and precipitation methods for direct estimation of serum high-density lipoprotein cholesterol, Stand. J. Clin. Lab. Invest., 41 (1981) 353. 25 Siedel. J.. Hagele. E.O.. Ziegenhorn, J. and Wahlefeld, A.W., Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency, Clin. Chum., 29 (1983) 1075. 26 Wahlefeld. A.W.. Triglycerides determination after enzy matic hydrolysis, In: Bergmeyer, H.V. (Ed.), Methods of Enzymatic Analysis, 2nd edn., Verlag Chemie, Weinheim. and Academic Press. Inc.. New York, 1974, pp. 1831. 27 Fruchart, J-C.. Kora. I., Cachera, C.. Clavey, V.. Duthilleul.
P. and Moschetto, Y.. Simultaneous measurement plasma apolipoproteins A-l and B by electroimmunoassay,
of
Clin. Chem., 28 (1982) 59. 28 SPSSX User’s Guide, 2nd edn., McGraw-Hill, SPSS Inc., New York, 1986. 20 Ames R.P. and Hill P., Improvement of glucose tolerance and lowering of glycohemoglobin and serum lipid concentrations after discontinuation of antihypertensive drug therapy. Circulation, 65 (1982) 899. 30 Ames, R.P., Negative effects of diuretic drugs on metabolic risk factors for coronary heart disease: possible alternative drug therapies, Am. J. Cardiol.. 51 (1983) 632. 31 Krotkiewski, M., Bjorntorp, P.. Sjostrom. L. and Smith, U.. Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution. J. Clin. Invest.. 72 (1983) 1150. 32 Kissebah, A.H. and Peiris, A.N., Biology of regional body fat distribution: Relationship to non-insulin-dependent diabetes mellitus, Diabetes Metab. Rev.. 5 (19891 83. 33 Landin. K., Krotkiewski, M. and Smith. U.. Importance of obesity for the metabolic abnormalities associated with an abdominal fat distribution. Metabolism. 38 (1989) 572. 34 Olefsky. J.M.. Kolterman. O.G. and Scarlett. A., Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus. Am. J. Physiol., 243 (1982) El5. 35 Abbott. W.C.H.. Lillioja, S., Young, A.A.. Zawadzki. J.K.. Yki-Jarvinen. H., Christin. L. and Howard, B.. Relationships between plasma lipoprotein concentrations and insulin action in an obese hyperinsulinemic population, Dia betes, 36 (1987) X97. 36 Garg. A., Helderman. J.H., Koffler. M., Ayuso, R.. Rosenstock, J. and Raskin. P., Relationship between lipoprotein levels and in vivo insulin action in normal young white men, Metabolism, 37 (1988) 982. 37 Laakso. M.. Sarlund. H. and Mykkanen. L.. Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance. Arteriosclerosis, 10 (1990) 223. 38 Ferrannini. E.. Buzzigoli. G.. Bonadonna. R.. Giorico. M.A.. Oleggini. M., Graziadei. L., Pedrinelli, R., Brandi, L. and Bevilacqua. S., Insulin resistance in essential hypertension. New Engl. J. Med., 317 (1987) 350. 39 Laakso. M.. Sarlund, H. and Mykkanen, L., Essential hypertension and insulin resistance in non-insulin-dependent diabetes. Eur. J. Clin. Invest.. I9 (1989) 518.
Atherosclerosis, 88 (1991) 153-161 0 1991 Elsevier Scientific Publishers Ireland, Ltd. 0021-9150/91/$03.50 ADONIS 0021915091001198
ATHERO 04636
Asymptomatic hyperglycemia and cardiovascular risk factors in the elderly Leena Mykkinen Depmrtments of
‘, Markku
Laakso
‘, Ilkka Penttib
* and Kalevi Py6rSi
’
’Medicine and ’ Clinical Chemistry, Kuopio Unkersity Central Hospital, Kuopio (Finland) (Received 14 September, 1990) (Revised, received 25 January, 1991) (Accepted 28 January, 1991)
Summary We studied the levels of cardiovascular risk factors in a population sample of 511 men and 920 women aged 65-74 years and living in East Finland. Altogether 312 men and 515 women had normal glucose tolerance, 84 men and 158 women impaired glucose tolerance (IGT), 33 men and 59 women newly diagnosed non-insulin-dependent diabetes (NIDDM) detected at the survey, and 82 men and 188 women previously diagnosed NIDDM. Subjects with IGT or newly diagnosed NIDDM had higher levels of total triglycerides and apolipoprotein B and lower levels of HDL cholesterol and apolipoprotein A, than subjects with normal glucose tolerance, similarly as in previously diagnosed NIDDM. Furthermore, subjects with IGT or newly diagnosed NIDDM were more obese, had higher waist-hip ratio, and more frequently hypertension than subjects with normal glucose tolerance. Thlls, asymptomatic hyperglycemia in the elderly is not a benign phenomenon, but is associated with similar adverse changes in cardiovascular risk factors as in middle-aged subjects.
Key words: Aged; Coronary heart disease; Diabetes mellitus, non-insulin-dependent; Lipids; Lipoproteins; Obesity; Hypertension
Introduction Coronary heart disease is found in excess in middle-aged subjects with asymptomatic hyperglycemia, impaired glucose tolerance (IGT) or
Correspondence to: Leena Mykklnen, MD, Department of Medicine, Kuopio University Central Hospital, SF-70210 Kuopio, Finland. Fax: 358-71-173993.
Hyperglycemia;
newly diagnosed non-insulin-dependent diabetes (NIDDM) U-31, similarly as ~II sllbjects with previously diagnosed NIDDM 141. Several studies have reported that middle-aged subjects with IGT or NIDDM are more obese and have more frequently hypertension than subjects with normal glucose tolerance [5-101. Furthermore, elevated total triglyceride levels have been a rather consistent finding in subjects with IGT or NIDDM, but results on the association of reduced HDL
154 cholesterol level with IGT are still controversial [9,11-141. Thus, middle-aged subjecs with asymptomatic hyperglycemia show a similar clustering of cardiovascular risk factors as subjects with previously diagnosed NIDDM [8,9,15]. Although abnormalities of glucose tolerance are frequent in the elderly [16,17], little is known about the association between IGT or newly diagnosed NIDDM and cardiovascular risk factors in older age groups. However, we have recently found in a population survey from East Finland that asymptomatic hyperglycemia is associated with an increased prevalence of coronary heart disease in subjects aged 65-74 years, similarly as in middle-aged subjects [18]. On the basis of that study one would expect to find changes in cardiovascular risk factors favoring atherosclerosis in elderly subjects with asymptomatic hyperglycemia. In this paper, we report our findings on the levels of cardiovascular risk factors by glucose tolerance status based on the same study population of elderly subjects in which we found an increased prevalence of coronary heart disease associated with asymptomatic hyperglycemia [181.
Subjects and methods Subjects
The study was conducted in Kuopio, East Finland, between February 1986 and April 1988. Altogether 1910 subjects born between 1912 and 1921 were randomly selected from the population register including all inhabitants of Kuopio. This random sample covered 35% of all residents in the age group of 65-74 years. In addition, 183 subjects with diabetes born between 1912 and 1921 were selected from the patient registers of general practitioners working at the Kuopio Health Center. This sample was identified from all diabetic subjects aged 65-74 years who visited the Kuopio Health Center during the consecutive 6 months (from 1st January to 30th June, 1985). A postal questionnaire containing questions about diagnosis of diabetes, ability to move, and willingness to participate in the study was sent to these subjects. 262 subjects from the random sample and 20 from the diabetes sample did not respond to the repeated postal questionnaire and 85 sub-
jects from the random sample and 5 from the diabetes sample were originally unwilling to participate. 83 subjects from the random sample and 14 from the diabetes sample were excluded because they were too ill to participate. Of those who were invited, 80 subjects from the random sample and 4 from the diabetes sample died, moved outside of the study area, or became seriously ill before clinical examination. 100 subjects from the random sample and 6 from the diabetes sample refused later on to participate in the examination, giving an overall participation rate of 71%. All patients in Finland needing drug therapy for chronic diseases such as diabetes, hypertension and cardiac failure are provided medication free of charge and registered. Representativeness of the study population was evaluated on the basis of this register. The mean age of subjects who participated (71%) in the study was similar to that of those (29%) who failed to participate (69 vs. 69 years in men, 69 vs. 70 yrs in women). There were no differences in the proportion of subjects receiving drug therapy for diabetes (9.6 vs. 10.6% in men, 11.7 vs. 13.8% in women, NS) or in the duration of diabetes (8 vs. 8 yrs in men, 8 vs. 9 yrs in women) between participants and non-participants. Also the proportion of subjects receiving drug therapy for hypertension was similar among participants and non-participants (27.3 vs. 30. 7% in men, 39.6 vs. 42.2% in women, NS). Male participants did not, however, have drug therapy for heart failure as frequently as non-participants (15.0 vs. 22.5%, P < 0.05), but this difference was not seen among women (24.4 vs. 26.5%, NS). Thus, the study population was a representative sample of subjects aged 65-74 yrs and living in Kuopio. Methods
Standing height and body weight were measured without shoes in light clothes. Body mass index (BMI) was calculated from the formula weight (kg)/height cm>‘. Obesity was defined as BMI 2 27 kg/m2 in men and 2 25 kg/m2 in women [19]. Body fat distribution pattern was measured as waist-hip ratio. Waist circumference was measured to the nearest 1 cm at the level of the umbilicus with the subject standing
155 and breathing normally. Hip circumference was measured to the nearest 1 cm at the level of the greatest hip girth. All anthropometric measurements were performed by the same specially trained nurse. Blood pressure was measured in the supine position after a 5 min rest. Measurements were taken in the right arm with a mercury sphygmomanometer (cuff size 12.5 x 40 cm). Two readings were taken (interval 1.5 min), and the latter one was used in statistical analyses. Systolic and diastolic blood pressure were read to the nearest 2 mm Hg. The disappearance of sounds (Korotkoff’s 5th phase) was recorded as diastolic blood pressure. A subject was defined as having hypertension if systolic blood pressure was 2 160 mm Hg, or diastolic blood pressure 2 95 mm Hg, or if he/she was receiving drug treatment for hypertension. Alcohol consumption was determined according to the subject’s estimate of the average number of glasses of beer, wine, or other alcoholic drinks ingested per week and transformed to absolute alcohol ingested in g/week. In all statistical analyses, subjects were classified as alcohol users or nonusers. The World Health Organization criteria for diabetes mellitus were used in the classification of subjects without previously known diabetes [20]. The criteria are as follows: (1) diabetes mellitus, fasting venous plasma glucose 2 7.8 mM or 2-h venous plasma glucose 2 11.1 mM in an oral glucose tolerance test (75 g glucose); (2) IGT, fasting venous plasma glucose < 7.8 mM and 2-h venous plasma glucose 7.8-l 1.1 mM; and (3) normal glucose tolerance, fasting and 2-h venous plasma glucose < 7.8 mM. Previously known diabetes was considered to be present, if the diagnosis of diabetes had previously been made by a physician. Medical records were checked for those diabetic subjects who had been treated with diet only and who showed normal glucose tolerance test. A subject was considered to have diabetes if his/her fasting venous blood glucose had been 2 6.7 mM on two visits to the health center. Three insulin-treated diabetic subjects whose C-peptide levels 6 min after intravenous glucagon (1 mg) stimulation [21] were < 0.20 nM were regarded as having insulin-de-
pendent diabetes [22] and they were excluded from the study. In this paper IGT and newly diagnosed NIDDM detected at the survey were considered together as a category of “asymptomatic hyperglycemia”. Laboratory methods Blood samples were taken between 7.30 and 9.30 a.m. after a 12-h fast. All subjects, except for those receiving insulin, underwent an oral glucose tolerance test (75 g glucose in 10% solution). Venous blood samples for glucose determinations were taken before and 1 and 2 h after the glucose load. Plasma glucose was determined by the glucose oxidase method (Glucose Auto & Stat HGA-1120 analyzer, Daiici, Kyoto, Japan). Diabetic subjects who used insulin had C-peptide levels measured at fasting and 6 min after intravenous glucagon administration [21]. Plasma Cpeptide was determined from samples stored at -70°C by a commercial radioimmunoassay (Cpeptide of insulin 1255 RIA kit, Incstar Co., Stillwater, MN, U.S.A.) with a detection limit of 0.07 nM and an intra-assay variation < 5.0% [23]. Serum HDL cholesterol was determined after precipitation of low density and very low density lipoproteins with dextran sulphate-MgCl, [24]. Commercial enzymatic methods were used in the determination of cholesterol [24,25] (Monotest, Boehringer Mannheim, F.R.G.) and triglycerides [26] (Peridocrome, Boehringer Mannheim, F.R.G.). Commercial control serums were used to standardize the measurements of cholesterol and triglycerides (Seronorm, Seronorm Lipid, Nycorned, Oslo, Norway). Serum apolipoproteins A, and B were determined from samples stored at - 70°C. The determinations were performed by a commercial immunochemical method (Kone Diagnostics, Espoo, Finland) which was based on the measurement of immunoprecipitation at 340 nm [27]. The standardization of apolipoprotein measurements were carried out utilizing a calibrator. The day-to-day and intra-assay variations in apolipoprotein assays were < 5%. Statistical methods Data analyses were conducted with the SPSSX programs [28]. The results for continuous vari-
156 ables are given as mean t_ SEM. Student’s twotailed t-test for independent samples was used in the assessment of the significance of the differences between two group means. Chi-square test (x2> was used in the assessment of the significance of the differences in prevalence rates of risk factors. Analysis of variance (ANOVA) was used in testing the differences between more than two group means. Adjustment of the risk factors for age, BMI and waist-hip ratio was done by analysis of covariance (ANCOVA). Results Altogether 1431 subjects participated in the study; 312 men and 515 women had normal glucose tolerance, 84 men and 158 women impaired glucose tolerance (IGT), 33 men and 59 women newly diagnosed non-insulin-dependent diabetes
(NIDDM) detected at the survey, and 82 men and 188 women previously diagnosed NIDDM (38% were treated with diet, 56% with oral hypoglycemic drugs and 6% with insulin) (Table 1). Men with normal glucose tolerance, IGT, and newly or previously diagnosed NIDDM were similar with respect to age, but women with previously diagnosed NIDDM were somewhat older than women with normal glucose tolerance. Among both men and women, subjects with IGT or NIDDM had higher mean values of body mass index (BMI, kg/m21 and waist-hip ratio than subjects with normal glucose tolerance. Also the proportion of obese subjects (BMI 2 27 kg/m2 in men and r 25 kg/m2 in women) was higher in men and women with IGT or NIDDM than in subjects with normal glucose tolerance. Tables 2 and 3 show the levels of cardiovascular risk factors in men and women. Subjects with
TABLE 1 CHARACTERISTICS
OF THE STUDY POPULATION
Values are mean f SEM. NIDDM = non-insulin-dependent Sex, variable
BY GLUCOSE TOLERANCE
STATUS AND SEX
diabetes, BMI = body mass index, WHR = waist-hip ratio.
Glucose tolerance status Normal glucose tolerance
Impaired glucose tolerance
Newly diagnosed NIDDM
Previously diagnosed NIDDM
Men Age (yrs) BMI (kg/m*) BMI 2 27 (%I WHR Fasting plasma glucose (mmol/l) 2 h plasma glucose (mmol/lI
(n = 312) 68.9 kO.2 26.0 kO.2 37.8 0.97 + 0.01
(n = 84) 68.9 kO.3 27.9 +0.4 *** 57.1 ** 1.01+ 0.01 * * *
(n = 33) 68.8 *0.4 28.9 +0.8 ** 63.6 ** 1.02-,0.01 ***
(n = 82) 69.3 +0.3 27.1 kO.4 ** 48.8 1.00+0.01 **
5.7 +0.03
6.1 kO.07 ***
8.0 kO.44 ***
5.8 kO.07
8.9 +0.09 ***
Women Age (yr) BMI (kg/m*) BMI 2 25 (%I WHR Fasting plasma glucose (mol/l) 2 h plasma glucose (mmol/lI
(n = 515) 69.1 +O.l 27.1 +0.2 70.4 0.88+0.01
Asymptomatic hyperglycemia a
P-value b
(n = 117) 68.9 +0.3 28.2 +0.4 *** 59.0 *** 1.01* 0.01 * * *
NS < 0.001 < 0.001 < 0.001
11.4 +0.44 ***
6.7 +O.l ***
< 0.001
13.6 +0.72 ***
19.5 kO.84 ***
10.2 +0.3 ***
< 0.001
(n = 158) 68.6 kO.2 29.1 +0.4 *** 842 *** 0:90 + 0.01 * * *
(n = 59) 69.9 i-O.4 30.3 +0.7 *** 89.8 ** 0.93 + 0.01 * * *
(n = 188) 69.7 kO.2 * 29.2 +0.3 *** 77.3 0.92 + 0.01 * * *
(n = 217) 69.0 kO.2 29.4 +0.3 *** 857 *** 0:91+0.01 ***
< < < <
5.5 kO.02
6.0 kO.05 ***
8.0 kO.32 ***
11.5 +0.29 ***
6.6 +0.1 ***
< 0.001
6.0 kO.04
9.0 + 0.07 * * *
13.7 kO.57 ***
20.8 kO.50 ***
10.3 kO.2 ***
< 0.001
0.01 0.001 0.001 0.001
a Impaired glucose tolerance and newly diagnosed NIDDM detected at the survey combined. b P-value for ANOVA and for X*-test over glucose tolerance status groups (normal glucose tolerance, impaired glucose tolerance and NIDDM). * p < 0.05, * * P < 0.01, * * * P < 0.001 (t-test or X2-test; impaired glucose tolerance, NIDDM and asymptomatic hyperglycemia VS. normal glucose tolerance).
157 TABLE
2
CARDIOVASCULAR Values
RISK FACTORS
are mean f SEM. NIDDM
IN MEN BY GLUCOSE
= non-insulin-dependent Glucose
tolerance
Hypertensives (“cl Drug treatment for hypertension Current smokers (%l Alcohol users (%l
diabetes,
46.5 20.8 17.3 59.0
HDL = high density
lipoprotein. Asymptomatic hyperglycemia
Previously diagnosed NIDDM
Newly diagnosed NIDDM
1.57+0.04 1.92+0.08 6.18+0.07 6.29kO.12 1.20_+0.02 1.06kO.03 1.11 kO.01 1.17?0.02 1.34+0.01 1.29+0.02 152.8 ~fr1.3 152.3 k 2.5 x2.2 f 0.7 82.8 & 15 (%)
STATUS
status
Impaired glucose tolerance
Normal glucose tolerance Total triglycerides (mmol/l) Total cholesterol (mmol/l) HDL cholesterol fmmol/l) Apolipoprotein B (g/l) Apolipoprotein A, (g/l) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
TOLERANCE
***
2.44kO.21 *** 2.17kO.19 6.06*0.14 6.23 k 0.26 *** 1.05+0.06 ** 1.04iO.03 1.18+0.03 ** 1.24 f 0.06 * ** 1.29+0.04 1.26kO.02 156.0 k2.8 157.8 k4.6 82.2 k 1.1 86.5 i2.2
53.6 25.0 13.1 50.0
61.0 40.2 4.9 40.2
63.6 42.4 * * 15.2 48.5
TABLE
* * * < 0.001 NS ***
56.4 29.9 * 13.7 49.6
< < < <
* *** ** **
RISK FACTORS
are mean + SEM. NIDDM
Normal glucose tolerance Total triglycerides (mol/l) Total cholesterol (mmol/l) HDL cholesterol fmmol/l) Apolipoprotein B (g/l) Apolipoprotein A, (g/l) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Hypertensives (%) Drug treatment for hypertension smokers (%I users (%)
IN WOMEN
= non-insulin Glucose
f%) Current Alcohol
glucose
tolerance,
NIDDM
impaired
and asymptomatic
glucose
0.05 0.001 0.05 0.05
tolerance
hyperglycemia
vs.
3
CARDIOVASCULAR Values
or X*-test; impaired
’
2.07 i 0.04 6.28+0.11 *** 1.06kO.03 * 1.19kO.02 ** 1.29iO.02 153.9 k2.2 83.8 f1.3 **
’ Impaired glucose tolerance and newly diagnosed NIDDM detected at the survey combined. ” I’-value for ANOVA and for *‘-test over glucose tolerance status groups (normal glucose tolerance. and NIDDM). * P < 0.05, * * P < 0.01, * * * P < 0.001 (/-test normal glucose tolerance).
P-value a
BY GLUCOSE
dependent
tolerance
diabetes,
TOLERANCE
HDL = high density
lipoprotein,
status
Impaired glucose tolerance
Newly diagnosed NIDDM
34.2 * 3.2 9.5 *
Asymptomatic hyperglycemia
Previously diagnosed NIDDM
1.67kO.03 1.96k0.07 *** 2.50?0.17 6.82+0.05 6.64+0.10 6.61 f0.18 1.40+0.01 1.30+0.03 ** 1.17+0.05 l.lh&O.Ol 1.20 * 0.02 1.31+0.04 1.45 f 0.01 1.41+0.02 * 1.38+0.03 157.7 + 1.0 164.0 + 1.7 * * 162.0 +3.1 80.9 + 0.4 81.9 +0.8 82.9 +1.5 56.5 74.7 *** 81.4 *** 24.9 7.0 16.7
STATUS
*** *** ** *
52.5 *** 1.7 8.5
glucose
59.0 *** I.6 *+
39.2 *** 2.8 * 9.2 **
6.4 * * *
tolerance,
h
2.67kO.24 *** 2.11?0.07 ***
” Impaired glucose tolerance and newly diagnosed NIDDM detected at the survey combined, h P-value for ANOVA and for x*-test over glucose tolerance status groups (normal glucose tolerance, and NIDDM). * P < 0.05, * * P < 0.01, * * * P i 0.001, (t-test or X2-test; impaired normal glucose tolerance).
P-value a
NIDDM
impaired
and asymptomatic
< 0.001 < 0.01 < 0.001
glucose
tolerance
hyperglycemia
vs
158
WOMEN
IGT or NIDDM had higher levels of total triglycerides and apolipoprotein B and lower levels of HDL cholesterol and apolipoprotein A 1 than subjects with normal glucose tolerance. Since the frequency of hypertension and drug treatment for hypertension were also higher in subjects with
Total triglycerides ttt
ttt T
*1*-
MEN Total triglycerides mmolll 3,
T Drug
treatment
-
Drug
treatment
.
Total cholesterol mmoltl 6,
Drug treatment
D,“Q
-
,reatment
??
Total cholesterol
Drug
treatment
-
Drug
treatment
+
HDL cholesterol mmolll
1.4 1.2 Drug ,reatment
-
Drug ,rea,men,
1
1 0.8
HDL cholesterol
0.6 0.4 0.2
1.2
??
t
tt 0 Drug
1
treatment
-
Drug
treatment
f
0.6 0.6
n
0.4 0.2 0 Drug treatment
-
b”Q
[3
,Ea,“W”,
.
Newly diagnosed NIDDM prev,oualy diagnosed NIDDM
Fig. 1. Levels of total triglycerides (upper), total cholesterol (middle) and HDL cholesterol (lower) in men with normal glucose tolerance, impaired glucose tolerance (IGT) and newly or previously diagnosed NIDDM receiving and not receiving drug treatment for hypertension. * * * P < 0.001, * * P < 0.01, *P < 0.05; IGT, newly or previously diagnosed NIDDM vs. normal glucose tolerance; Student’s t-test.
Newly diagnosed NIDDM ~rewously diagnosed NIDDM
Fig. 2. Levels of total triglycerides (upper), total cholesterol (middle) and HDL cholesterol (lower) in women with normal glucose tolerance, impaired glucose tolerance (IGT) and newly or previously diagnosed NIDDM receiving and not receiving drug treatment for hypertension. * * * P < 0.001, * * P < 0.01, *P < 0.05; IGT, newly or previously diagnosed NIDDM vs. normal glucose tolerance; Student’s t-test.
IGT or NIDDM (Tables 2 and 3) we analyzed separately the levels of total triglycerides, total cholesterol and HDL cholesterol in men and women receiving no antihypertensive agents and
159 in those having drug treatment for hypertension (Figs. 1 and 2). Similarly as in the total group, subjects with IGT or NIDDM tended to have higher triglyceride and lower HDL cholesterol levels than subjects with normal glucose tolerance independently of the use of antihypertensive medication. There was no difference in the level of total cholesterol between subjects with IGT or NIDDM and subjects with normal glucose tolerance (Tables 2 and 3) and this result was similar in those who were or who were not receiving antihypertensive medication (Figs. 1 and 2). Systolic blood pressure was higher in women with IGT or NIDDM than in women with normal glucose tolerance but men with IGT or NIDDM were not different from men with normal glucose tolerance in this respect (Tables 2 and 3). There was no difference in diastolic blood pressure between glucose tolerance groups. The proportions of current smokers and alcohol users tended to be lower in subjects with IGT or NIDDM than in subjects with normal glucose tolerance, but this difference was statistically significant only between subjects with previously diagnosed NIDDM and normal glucose tolerance. These differences in risk factor levels between glucose tolerance groups persisted after the adjustment for age, BMI and waist-hip ratio in ANCOVA. Asymptomatic hyperglycemia was associated with adverse changes in cardiovascular risk factors similarly as in NIDDM. Levels of total triglycerides and apolipoprotein B were higher and those of HDL cholesterol and apolipoprotein A, lower in subjects with asymptomatic hyperglycemia than in subjects with normal glucose tolerance (Tables 2 and 3). Also hypertension was more frequent in subjects with asymptomatic hyperglycemia than in subjects with normal glucose tolerance. Discussion
Previous studies have indicated that asymptomatic hyperglycemia is associated with a cardiovascular risk factor profile favoring atherosclerosis in middle-aged subjects [8,9]. The findings of this study extended these observations to older age groups and demonstrated that male and female subjects with IGT or newly diagnosed
NIDDM detected at the survey, were more obese, had higher total triglyceride and lower HDL cholesterol levels and higher prevalence of hypertension than corresponding subjects with normal glucose tolerance. The most consistent abnormality in cardiovascular risk factors in this study were unfavorable lipid and lipoprotein changes which were found in both men and women having IGT or NIDDM. The elevated total triglyceride level in subjects with IGT or NIDDM observed in this study is in accordance with previous findings in middle-aged subjects [9,11,12,14] and indicate that even mild abnormalities in glucose metabolism are associated with alterations in triglyceride metabolism also in the elderly. Our findings on decreased HDL cholesterol levels in subjects with asymptomatic hyperglycemia confirmed the results of two large population-based surveys, one in Pima Indians [12] and the other in older adults from Southern California [14]. Other previous studies have, however, not found alterations in HDL cholesterol levels in subjects with IGT [6,9,11,13]. Since the prevalence of hypertension was more frequent in subjects with IGT and NIDDM, the high proportion of drug treatment for hypertension in these subjects could explain their low HDL cholesterol and high triglyceride levels [29.30]. These differences between glucose tolerance groups persisted, however, when analyses were conducted separately in subjects receiving and not receiving drug treatment for hypertension. Thus, the use of antihypertensive agents did not explain lipid changes favoring atherosclerosis in subjects with IGT or NIDDM. In addition to lipid and lipoprotein abnormalities, subjects with IGT or NIDDM were more obese [&lo], had higher waist-hip ratio and more frequently hypertension [5- 101 than subjects with normal glucose tolerance similarly as reported previously in middle-aged subjects. Both obesity and central fat distribution (high waist-hip ratio) have been shown to be associated with high plasma triglyceride and low HDL cholesterol levels and elevated systolic and diastolic blood pressure in middle-aged men and women [31-331. Our results confirmed the findings of Zavaroni et al. [9] that subjects with asymptomatic hyperglycemia have multiple risk factors for cardiovas-
160 cular disease and extended these observations to the elderly population. The differences in lipid and lipoprotein levels and blood pressure between the glucose tolerance groups persisted after the adjustment for age, BMI and waist-hip ratio. Thus, these adverse changes in cardiovascular risk factors were not due to obesity alone. Insulin resistance could be another underlying mechanism explaining this risk factor profile. Subjects with IGT or NIDDM are more insulin resistant than subjects with normal glucose tolerance [34] and recent studies utilizing the glucose clamp technique have indicated that insulin resistance is associated with high total and VLDL triglyceride and low HDL cholesterol levels in subjects with normal glucose tolerance [35,36], IGT and NIDDM [37]. Furthermore, nonobese hypertensive subjects with normal glucose tolerance or NIDDM are more insulin resistant than corresponding normotensive subjects 138,391. Thus, lipid and lipoprotein abnormalities and hypertension in asymptomatic hyperglycemia could partly be due to insulin resistance. In conclusion, elderly subjects with IGT or newly diagnosed NIDDM had multiple cardiovascular risk factor changes, including elevated total triglyceride levels, decreased HDL cholesterol levels and a high occurrence of hypertension and obesity. Thus, asymptomatic hyperglycemia in the elderly is not a benign phenomenon, because it is associated with unfavorable changes in cardiovascular risk factors as in middle-aged subjects. Prospective studies are, however, needed to assess the predictive value of the changes of these risk factors with regard to future coronary heart disease risk in subjects with asymptomatic hyperglycemia. Acknowledgements This study was supported by grants from the Academy of Finland, the Yrjo Jahnsson Foundation, the Foundation of President and Mrs Urho Kekkonen, and the Aarne and Aili Turunen Foundation.
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