Glucose tolerance and mortality from ischemic heart disease in an elderly population

Glucose Tolerance and Mortality from lschemic Heart Disease in an Elderly Population Impact of Repeated Glucose Measurements EDITH J. M. FESKENS, PHD, CAREL H. BOWLES, AND DAAN KROMHOUT, PHD, MPH

PHD, MD,

The impact of glucose tolerance, measured repeatedly, on the mortality from ischemic heart disease (1HD) was assessed in a cohort of 202 elderly patients, aged 64 to 84 years in 1971, from a general practice. During the period from 1971 to 1975 the participants were examined annually. The area under the glucose tolerance curve (AUC) was used as a summary index, and for every subject the mean AUC ower the 5-year period was calculated. This index was most strongly correlated with the mean 60-minute glucose level (r = 0.96). Between 1975 and 1987, 125 participants died, 28.8% of whom died from IHD. No association between a single measurement of glucose tolerance and IHD mortality was obserwed. However, using the mean AUC over the 5-year period, a positive association was observed, independent of age, sex, and other potential confounders (I’ = 0.04). These results indicate that glucose tolerance independently predicts mortality from coronary heart disease in an elderly cohort, provided that information on repeated measurements is taken into account. A continuous tisk gradient is suggested. Ann Epidemiol 1993;3:336-342. Aged, non-insulin-dependent diabetes mellitus, glucose tolerance test, gerontology, ischemic heart disease, longitudinal studies, myocardial infarction, prospective studies. KEY WORDS:

hyperinsulinemia,

INTRODUCTION It is well known that the presence of non-insulin-dependent diabetes mellitus (NIDDM)

is associated with an increased

mortality, especially from ischemic heart disease (1, 2). The relative risk is generally found to range from 2 to 4, and is probably higher among women than among men (3-6). The prevalence

of NIDDM

increases with age, and amounted

to 17% among people 65 years and older in a US population (7). However,

there

is evidence

of some cardiovascular consequences (8-10).

Results

cumseh

Study

heart

disease

risk factors

for preventive

associated

heart

disease

(IHD)

the predictive

declines

strategies

of the Framingham (12) indicate

with

regarding

Study

diabetes

risk of coronary

decreases

with

age,

by others (13). the adverse effects on ischemic

are mainly

of syndrome

the elderly

(11) and the Te-

limited

to subjects

range of blood glucose levels. The recently

sized existence

power

with age, having

that the relative

but this was not confirmed It is also not clear whether highest

that

‘IX,” relating

insulin

in the

hypotheresistance,

NIDDM,

and glucose tolerance

to the onset of

coronary heart disease, and hypertension

suggests the presence of a more continuous According

to this hypothesis,

(14, 15),

relationship.

subjects with impaired glu-

cose tolerance as well as those with diabetes mellitus would experience

an increased risk of heart disease.

Until now, several epidemiologic between glucose tolerance

studies on associations

and ischemic heart disease have

been carried out, and the results are not clear (16). In most studies a threshold phenomenon

was observed (12, 16-22),

but in some studies a continuous

risk gradient was noticed

(23-25).

Part of these differences may be due to differences

in the glucose measurements

used: fasting, as well as l-hour

or 2-hour postload levels were investigated.

Also, the relia-

bility of the glucose tolerance measurements

probably plays

a role (26,27). Due to intraindividual

variation, associations

with other biologic variables as well as with disease outcomes are attenuated

(26-29).

To overcome this problem, the use

of repeated measurements

is recommended

to obtain a bet-

ter estimate of an individual’s risk factor level (28, 29). Regarding glucose tolerance, no study using repeated measure-

From the Department of Epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands. Address reprint requests to: Edith J. M. Feskens, PhD, Department of Epidemiology, National Institute of Public Health and Environmental Protection, P.O. Box 1, 3720 BA Bilthoven, The Netherlands. Received June 19, 1992; revised December 0

1993 by Elsevim Science Publuhrng

Co.,

Inc

15, 1992.

ments has been reported to date. From 1971 until 1975, a longitudinal

health survey was

carried out among elderly patients of a Rotterdam practice. The participants

were examined

annually,

complete oral glucose tolerance test (OGTT)

general and a

was included 1047-2797/93/$06.00

AEP Vol. 3, No. 4 July 1993: 336-342

GLUCOSE

in every examination. From these repeated measurements of glucose tolerance, the mean level over the examination period was derived as an estimate of “true” exposure, reducing the nondifferential measurement error (28, 29). This estimate was related to all-cause and IHD mortality during 12 years of follow-up. In addition, the impact of changes in glucose tolerance over time was examined.

METHODS Population From 1971 until 1975 a longitudinal health survey was carried out among patients of one (C. H. B.) of the authors, who had a general practice in Rotterdam, The Netherlands. All noninstitutionalized men and women born before 1907, and able to participate, were invited to take part in the study (30). Of the 394 eligible subjects, 340 (86%) agreed to enter the study. Due to limitations of laboratory facilities, eventually 292 subjects were medically examined in 1971. Weight, height, and dietary habits were comparable with those reported for other free-living Dutch elderly studied in that period (30). Annual examinations took place until 1975. Subjects were included only if complete information about their cardiovascular risk factor status at baseline was available. So for these analyses designed to investigate glucose tolerance over the period from 1971 to 1975 in relation to the subsequent 12-year mortality, this resulted in a study population of 202 subjects. These persons were alive in December 1975 and had participated in the 1971 survey as well as in at least two follow-up examinations in the period from 1972 to 1975. Eighty-two percent of these subjects participated in all four follow-up examinations. Examinations During every examination, a complete OGTT was carried out according to the 1965 guidelines of the World Health Organization (WHO) (31). Subjects with clinically diagnosed diabetes were included. The OGTT was done in the morning after an overnight fast. A capillary blood sample was obtained from the subjects in the fasting state, and at 30, 60, and 120 minutes following an oral load of 50 g of glucose. Whole-blood glucose analyses were carried out using the glucose oxidase method (test kit from Boehringer Mannheim). Blood sampling and chemical analyses were carried out at the Rotterdam Ophthalmological Hospital. The methods used were identical at every annual examination. From the glucose measurements, a summarizing index, the area under the curve (AUC), was derived. This area was calculated using the trapezoidal rule: AUC where x, denotes

= Z((x, - x,-I)*(Y,-1 + y1)/2) , the time (minutes)

at measurement

mo-

TOLERANCE

Feskens et al. AND MORTALITY

337

ment i, and y, denotes the glucose value at moment i. Of all the glucose measurements, the 60-minute glucose level was most strongly associated with the AUC (T = 0.96). The physical examinations were carried out by an experienced general practitioner (C. H. B.), the principal investigator of the study. Information about the history of cardiovascular and pulmonary diseases was obtained using the Dutch translation of a questionnaire from the London School of Hygiene and Tropical Medicine (32). The reported cardiovascular diseases included myocardial infarction, angina pectoris, and intermittent claudication. The use of drugs was determined by investigation of the patients’ records. Weight and height were measured, with subjects wearing underwear and socks only. Body mass index (BMI) was calculated by dividing body weight by height squared (kg/m*). Blood pressure measurements were taken on the right arm with subjects in a supine position, using a mercury sphygmomanometer. Measurements were made in triplicate, and the lowest values were recorded. A fasting blood sample was obtained by venipuncture and analyzed for serum total cholesterol and triglycerides by thin-layer chromatography (33). Information about smoking habits was obtained through standardized questions asked by the physician during the medical examination. Information about alcohol use was collected by the cross-check dietary history method (34), taken by one trained dietitian (35). Information on vital status was obtained in 1988, covering the period from 197 1 to December 1987. Information about the causes of death was obtained from the Dutch Central Bureau of Statistics. The causes of death were coded by the International Classification of Diseases, according to the ninth revision. IHD was taken to be ICD codes 410 through 414 denoted either as the primary or as the secondary cause of death, because of well-known multiple pathology in the elderly. The vital status of one subject could not be verified, and of two subjects the cause of death was unknown. These subjects were excluded from the analyses. Statistical Analyses For statistical analyses, the SAS statistical package was used (36). For every eligible subject, mean levels of risk factors over the period from 1971 to 1975 were calculated from information of the annual examinations. From regression analysis of the annual measurements on time, an estimate of the annual change was derived. For analyses of characteristics by sex and mortality, Student’s t test was used. When the risk factor distributions were skewed, the MannWhitney U-test was preferred. For categorical variables the x2 test statistic was calculated. Crude risk ratios and risk differences for IHD mortality were calculated for tertiles of glucose tolerance. To adjust for potential confounders, proportional hazard (Cox) regression analysis was used. For this purpose, measures of glucose tolerance were entered as continuous variables. Adjusted risk ratios for tertiles were

338

Feskens et al. GLUCOSE TOLERANCE AND MORTALITY

AEP Vol. 3, No. 4 luly 1993:336-342

TABLE 1. Prevalence (%) and relative risks of selected characteristics of 202 elderly men and women in 1975 with respect to subsequent 12-year mortality from ischemic heart disease (IHD), Rotterdam, The Netherlands, 1975 to 1987 12-y IHD mortality No (n = 166)

(n = 36)

Relative risk“

Myocardial infarction Angina pectoris Intermittent claudication

5.4 21.1 3.0

16.7 36.1 16.7

Diabetes mellitus (clinical) Antihypertensive medication Smoking Alcohol use (197 I)

9.6 33.7 42.8 52.4

11.1 52.8 50.0 63.9

3.4 (1.4-8.1) 2.1 (1.1-4.2) 5.1 (2.1-12.3) 1.3 (0.5-3.7) 2.3 (1.2-4.6) 1.4 (0.7-2.8) 1.4 (0.7-2.7)

Variable

Yes

’95%confidence intervals are in parentheses. calculated from the resulting regression coefficients to enhance data interpretation. Age (< 70, > 70 years), alcohol intake (no/yes), smoking status (no/yes), prevalence of cardiovascular disease and clinical diabetes, and medication use were entered as categorical variables. The effect of change in AUC on mortality was estimated from two different multivariate regression models conditional on the initial or final level of AUC. Interaction terms between AUC and other risk factors were examined, but since they did not reach statistical significance they were excluded from the final models. All P values were based on two-sided tests of statistical significance.

RESULTS Of the examined persons in 197 1,202 subjects (94 men and 108 women) participated in at least two follow-up examinations in the period from 1972 to 1975, and were alive on

December 31, 1975. At the final examination in 1975, they were 69 to 89 years old, with a mean age of 75.1 -+ 4.5 years. During the mortality follow-up from 1976 to 1987, 125 of the participants died, 28.8% (n = 36) of whom had IHD denoted as the primary or secondary cause of death. The mortality rate of IHD over the 12syear period amounted to 23.7/1000 person-years for men and 18.6/1000 person years for women (P = 0.65). Compared to subjects who remained free of IHD mortality, subjects who later died from IHD had significantly higher baseline prevalence rates of myocardial infarction, angina pectoris, and intermittent claudication, and a higher frequency of antihypertensive drug use (Table 1). No significant differences were observed in the baseline prevalence of clinically diagnosed diabetes mellitus, smoking, and alcohol use. Age and mean levels of repeated measurements of systolic blood pressure, 60- and 120sminute glucose, and AUC were higher among future cases (Table 2). No signifi-

TABLE 2. Mean levels of selected characteristics and glucose tolerance over the period of 1971 to 1975 of 202 elderly men and women by subsequent 1971/1975 to 1987

12-year mortality

from ischemic

heart disease (IHD), Rotterdam,

The Netherlands,

12-y IHD mortality Mean level of risk factor Age in 1975 (y) body mass index (kg/m’) Systolic blood pressure (mm Hg) Serum total cholesterol (mmol/L) Serum triglycerides (mmol/L) Glucose (mm&L) Fasting 30 min 60 min I20 min Area under curve (mmol/L. min) Mean in 1971-1975 Observed in 1975 Change

in 1971-1975

n95%confidence intervals are in parentheses. h P < 0.01. P < 0.05.

No (n = 166)

Yes (n = 36)

Difference”

74.6 26.5 156.3 6.80 1.14

+ + + + +

4.1 3.6 21.3 0.53 0.53

77.5 26.5 171.3 6.90 1.17

+ + f ? +

5.5 3.6 22.2 1.31 0.60

2.9 (0.7-3.8)’ 0.03 (- 1.44-1.5) 15.0 (7.2-22.8)b 0.10 (-0.15-0.25) 0.03 (- 11.9-14.3)

5.11 9.44 9.85 6.96

+ + + +

1.56 2.19 2.90 3.18

5.30 10.04 11.00 7.69

f 2 + f

1.28 2.16 3.00 3.26

0.19 (-0.09-0.54) 0.60 (-0.16-1.12) 1.15 (0.30-2.00)b 0.73 (0.01-1.68)

1011.7 f 297.9 955.5 * 301.0 -17.27

f 59.97

1106.3 + 300.0 1051.0 _+ 260.3 -0.64 T 43.88

94.6 (27.4-185.4)b 95.5 (-10.2-159.1) 16.63 (-4.5-29.2)

Feskens et al.

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July 1993: 336-342

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339

AND MORTALITY

TABLE 3. 12-Year mortality from ischemic heart disease by tertiles of different estimates of area under the curve (AUC) among 202 elderly men and women, Rotterdam, The Netherlands, 1971/1975 to 1987 Mortality

comparisonsb Risk ratios

Tertiles” Risk differenced

Crude

Adjustedd,’

32.5

20.0

(18) 22.9

2.67 (1.11-6.37) 2.08

(13) 26.5

(2.8-37.8) 11.9 (-3.3-27.1) 14.7

(14)

(-1.7-31.1)

2.60 (1.03-6.56) 1.70 (0.64-4.50) 2.41’ (1.00-5.80)

AUC

LOW

Middle

High’

Mean in 1971-1975

12.1

18.5

Observed

(7) 11.0

(11) 25.4

(6) 11.8

(14) 24.9

(7)

(15)

Change

in 1975 from 1971-1975

(0.79-5.47) 2.24 (0.91-5.56)

P trend adjusted 0.04 0.29 0.05

’ Mortality/1000 person-y, with number of cases in parentheses. b Comparing highest and lowest tertiles. ‘Cutoff points-for mean AUC in 1971-1975: 892.2, 1035.0 mmol/L~min; for observed AUC in 1975: 877.5, 1021.5 mmol/L.min; and for change AUC in 1971-1975: -27.60, 6.15 mmol/L~min/y. d 95% confidence intervals are in parentheses. ’Adjusted for age, sex, clinical diabetes, cardiovascular disease, body mass index, serum total cholesterol, serum triglycerides, systolic blood pressure, smoking, alcohol use, and antihypertensive medication. ’Adjusted for initial level of AUC, and initial levels of and changes in body mass index, serum total cholesterol, serum triglycerides, and systolic blood pressure.

cant difference was observed in mean values of repeated measurements of serum lipids and fasting and 300minute glucose. The difference was of borderline significance (P < 0.15) for the single AUC measurement in 1975 and the yearly change of AUC. The levels of mean AUC from 197 1 to 1975 were significantly higher among women than among men (P < 0.01). The mean AUC was also positively associated with age (P < O.OOl), presence of cardiovascular disease (P < 0.05), use of antihypertensive medication (P < 0.05), presence of clinically diagnosed diabetes (P< O.OOl), and mean systolic blood pressure (I = 0.24, P < 0.01). Inverse associations were observed with smoking and alcohol use (P< 0.05). After adjustment for age and sex by regression analysis, only the association with presence of cardiovascular disease (P < 0.05) and diabetes mellitus (P < 0.001) remained statistically significant. The correlation of the mean AUC with the single AUC measurement in 1975 amounted to 0.84. The correlations of the change in AUC with the initial, mean, and final AUC level amounted to -0.39, -0.03, and 0.37, respectively. With each increasing tertile of mean AUC, an increase in subsequent IZyear mortality from IHD was noticed (Table 3). Comparing the highest and the lowest tertile of the distribution, the risk ratio was 2.67 (95% confidence interval (CI): 1.11 to 6.37), and the risk difference was 20.3/1000 person-years. For the single AUC measurement in 1975 and the change in AUC over the period from 197 1 to 1975, the risk ratios and differences were smaller, and not statistically significant. For all-cause mortality, comparing the highest and the lowest tertile of mean AUC, the risk ratio amounted to 1.26 (95% CI: 0.82 to 1.94), whereas the risk difference was 17.2/1000 person-years. After adjustment for age, sex, and other potential confounders, such as mean BMI, systolic blood pressure, serum total cholesterol, serum triglycerides, smoking, alcohol use,

use of antihypertensive medication, and presence of cardiovascular diseases and clinically diagnosed diabetes, mean AUC remained significantly associated with IHD mortality (see Table 3). For the single AUC measurement in 1975, the risk ratios were smaller and not statistically significant. The change in AUC was significantly associated with IHD mortality after adjustment for baseline values of AUC and confounders in 197 1 and for 5-year changes in confounders. However, when adjustments were made for the final values of AUC and confounders in 1975, the association was no longer statistically significant (risk ratio = 1.12, P trend = 0.83). Comparing the predictive values of the four separate glucose measurements obtained by the OGTT, the highest value was observed for the mean level of repeated 60-minute glucose measurements (Table 4). This result was comparable to that for mean AUC. The mean 120-minute glucose level was not related to IHD mortality. The regression coefficients of the mean fasting and 30-minute glucose level were comparable to that for the 60-minute value, but did not reach statistical significance.

TABLE 4. Adjusted” regression coefficients for measurements of glucose tolerance in relation to ischemic heart disease mortality among 202 elderly men and women, Rotterdam, The Netherlands, 1971/1975 to 1987 Results of survival analysis

Glucose*

Regression coefficient

Fasting 30 min 60 min 120 min

0.23 0.21 0.19 0.05

Standard error 0.21 0.11 0.09 0.13

’Adjustments: see Table 3. ‘Mean values of repeated measurements

from 1971-1975.

P value 0.28 0.06 0.03 0.39

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(“X”) suggesting that insulin resistance and glucose tolerance

DISCUSSION The results of the present study show that glucose tolerance is associated

with mortality

from IHD in a small cohort

of elderly men and women, provided that information repeated glucose measurements results were also independent

is taken into account. The

of potential confounding

tors such as age, sex, presence of cardiovascular of antihypertensive risk factors.

on

medication,

fac-

disease, use

and classic cardiovascular

The number of subjects in this study was relatively small. It was therefore decided not to exclude subjects with cardiovascular disease and clinically diagnosed diabetes mellitus, but to take these effects into account in multivariate

analy-

sis. The risk ratios were not affected, whereas the power of the analysis was increased. As another consequence

of the

limited sample size, it was not feasible to analyze the effect of OGTT

on mortality for men and women separately. In

several studies the relative risk of diabetes mellitus associated with coronary

heart disease mortality

was higher among

women than among men (3-6). Despite the relatively low power of this study, the mean AUC level was significantly associated with IHD mortality. Comparing the highest with the lowest tertile of the distribution, an adjusted risk ratio of 2.6 was observed, and the risk difference was 20/1000 person-years. measurement

For the single AUC

the effects were smaller, the risk ratio being

1.7 and the risk difference being only 12/1000 person-years. It is well known that the presence of intraindividual tion in an exposure measurement outcome

variables.

affects relationships

Due to this random

observed effect estimates are attenuated of repeated measurements

variawith

are underlying

factors for the development

well as coronary Several

other

suggestions

have been put forward by

may affect coronary

mortality independently

of the classic risk factors considered

heart disease

in the present study. Glucose may play a direct as well as an indirect role. Elevated

glucose levels may give rise to

endothelial

injury or may detrimentally

lipoprotein

(37-39).

other cardiovascular

Glucose

modify low-density

may also be associated with

risk factors that were not investigated

in the present study, such as high-density-lipoprotein lesterol or fibrinogen (37,40).

cho-

It should be noted that these

variables were partly adjusted for by taking BMI and serum triglycerides

into account.

that these factors cannot atherosclerotic

Also, in general it is assumed completely

explain the elevated

risk of diabetic patients (37). Thus, the etio-

logic process is not yet completely elucidated. The clinical significance of the cutoff points used in the present study may be difficult to assess. The postload glucose levels were measured after a glucose load of 50 g, whereas currently a dose of 75 g is recommended

(2). However, atten-

tion should be pain to the fact that the predictive value of the 120-minute

glucose level was much less than the

predictive value of the 60-minute value. Modan and coworkers (41) showed that during a OGTT the 60-minute

using 100 g of glucose,

glucose level in particular discerns subjects

with diabetes mellitus or impaired glucose tolerance normoglycemic

from

persons. Subjects with impaired glucose tol-

erance were less well discerned using the 120-minute glucose level. Although

(26-29).

also apply to the present study population,

will reduce the intraindividual

as

which glucose tolerance

misclassification, The use

of NIDDM

heart disease (14, 15).

a different glucose load was used, this may and explain the

variation, as is confirmed for glucose tolerance in the present

predictive value of the 60-minute glucose level. Using the information on five annual glucose tolerance

study. This observed difference between the use of a single

tests, the change in glucose levels could also be determined.

or of repeated measurements

also suggests that part of the

As discussed by Hofman (42), the effect of changes in risk

reason for the conflicting results seen in previous studies of

factors on morbidity

glucose tolerance

from various points of view. The effect of change conditional

and IHD mortality

the presence of intraindividual

(12, 16-25)

may be

variation. All former studies

used single measurements.

and mortality risk may be of interest

on the initial level is of importance

concerning

measures and public health. In contrast,

It should be noted that in the present study, elevated

preventive

regarding clinical

practice as well as the etiology of the disease, the effect of

mortality was noticed with relatively low blood glucose lev-

change is of special interest when it is independent

els. The

attained level. In the present study, the annual change in

amounted

cutoff

points

to 892 and

for the

tertiles

of mean

1035 mmol/L*min,

which agree with 60-minute

whole-blood

8.8 and 10.4 mmol/L. For AUC glucose levels, a continuous

AUC

respectively,

glucose levels of

as well as for 60-minute

relation

with IHD mortality

was observed, and the results were independent

of the pres-

of the

AUC was an additional risk factor when the baseline value was taken into account, but no clear association was found when the final value was adjusted for. This indicates that the change in blood glucose level is mainly of importance because it results in generally higher levels, but probably provides no clear additional

risk by itself. However,

creased risk for IHD is not only confined to diabetic patients

result stresses the importance

of monitoring

but also experienced by subjects with only moderately elevated glucose levels. The observed continuous risk gradient

over time, and suggests that prevention of an increase in serum glucose levels may act beneficially on IHD risk. Di-

is in accord with the findings of three other studies (23-

etary measures could be useful in this respect (35, 43, 44). The present study population consisted of men and

ence of clinically diagnosed

diabetes.

Apparently,

the in-

25), and agrees with the hypothesis of a metabolic syndrome

this

glucose levels

AEP Vol. 3, No. 4 My 1993: 336-342

GLUCOSE

women aged 64 years and over. In several studies the effect of diabetes on mortality

among different

compared. In the Framingham

Study (IZ), the relative risk for diabetes coronary

age groups was

Study (11) and the Tecumseh associated

with

heart disease mortality decreased with age. How-

TOLERANCE

Feskens et al. AND MORTALITY

341

team; the Laboratory ofthe Rotterdam Ophthalmological Hospital (former head Dr. A. J. Houtsmuller) for glucose analyses; the Gaubius Institute/ TNO, Leiden (head Dr. P. Brakman) for lipid detL+ninations; Dr. J. F. de Wijn; Ms. A. J. van Hall-Ferwerda, RD, Ms. A. M. Jansen, RD, and M. A. van Oostrom, MSc, for collecting, coding, and processing the dietary data; and M. P. Merkus for assistance in data analyses.

ever, this was not observed in the first US National Health and Nutrition remained

Examination

a predictor

in the Honolulu

Survey (13), and serum glucose

of late-onset

coronary

heart disease

Heart program (45). In addition,

be noted that in the Framingham

it must

Study no decline was

observed in the risk difference between diabetics and nondiabetics (11). For higher mortality populations,

rates, such as in elderly

the risk difference may be a better measure of

effect than the risk ratio (46). Furthermore,

the risk differ-

ence may give a direct estimate of the public health problem (47). Finally, more recent analysis of the Framingham

data

showed that blood glucose remained predictive of cardiovascular disease incidence

in men and women aged 65 to 94

years (48). This is confirmed by the present study. Regarding the impact on public health, all-cause mortality may even be a more important cause-specific nificant

mortality,

health outcome

than

especially in old age (49). No sig-

effect of glucose tolerance

on all-cause mortality

was noticed in the present study. This may be partly due to the long follow-up period: The mortality rate amounted to 72.5/1000

person-years,

and at the end of mortality fol-

low-up in 1987, only 38.1% of the subjects were still alive. Furthermore,

although the risk ratio for all-cause mortality

for mean AUC in 1975 was not statistically significant, the associated risk difference amounted 1000 person-years,

to a considerable

comparable to the risk difference for IHD

mortality. In the present study no information on other health

outcomes

general morbidity,

17/

important

disability,

was available

at old age, such as

and quality of life (49, 50).

Serum glucose was an independent

predictor of health in

an aging cohort of Japanese Americans

(5 1). This suggests

that in the elderly, glucose intolerance

and diabetes affect

chronic disease status rather than mortality only, and this is an important

area to be studied more extensively in the

future. In summary, the results of the present study show that glucose tolerance is an independent

risk factor for mortality

from IHD among an elderly population, provided that information on repeated measurements Furthermore, threshold

a continuous

is taken into account.

risk gradient

effect was shown. Prevention

rather

than

a

of increases in glu-

cose levels, for example, by reduction of obesity and changes in diet, may have a beneficial impact.

This work was supported by grants from the Netherlands Organization for Scientific Research, the Netherlands Praeventiefonds, and the Netherlands Nutrition Council. The authors thank the participants in the surveys and the fieldwork

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