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de Vegt F, Dekker JM, Jager A, et al. Relation of Impaired Fasting and Postload Glucose With Incident Type 2 Diabetes in a Dutch PopulationThe Hoorn Study. JAMA. 2001;285(16):2109–2113. doi:10.1001/jama.285.16.2109
Context Persons with impaired glucose tolerance (IGT) are known to have an elevated
risk of developing diabetes mellitus. Less is known about diabetes risk among
persons with impaired fasting glucose (IFG) or with normal glucose levels.
Objective To determine the incidence of diabetes in relation to baseline fasting
and postload glucose levels and other risk factors.
Design, Setting, and Participants Population-based cohort study conducted from October 1989 to February
1992 among 1342 nondiabetic white residents of Hoorn, the Netherlands, aged
50 to 75 years at baseline, in whom fasting plasma glucose (FPG) levels and
glucose levels 2 hours after a 75-g oral glucose tolerance test were measured
at baseline and at follow-up in 1996-1998.
Main Outcome Measures Cumulative incidence of diabetes, defined according to the diagnostic
criteria of the World Health Organization (WHO-1985 and WHO-1999) and the
American Diabetes Association (ADA-1997), during a mean follow-up of 6.4 years,
compared among participants with IFG, IGT, and normal glucose levels at baseline.
Results The cumulative incidence of diabetes was 6.1%, 8.3%, and 9.9% according
to the WHO-1985, ADA, and WHO-1999 criteria, respectively. The cumulative
incidence of diabetes (WHO-1999 criteria) for participants with both IFG and
IGT was 64.5% compared with 4.5% for those with normal glucose levels at baseline.
The odds ratios for diabetes (WHO-1999 criteria), adjusted for age, sex, and
follow-up duration, were 10.0 (95% confidence interval [CI], 6.1-16.5), 10.9
(95% CI, 6.0-19.9), and 39.5 (95% CI, 17.0-92.1), respectively, for those
having isolated IFG, isolated IGT, and both IFG and IGT. In addition to FPG
and 2-hour postload glucose levels (P<.001 for
both), the waist-hip ratio also was an important risk factor for developing
diabetes (P = .002).
Conclusion In this study, the cumulative incidence of diabetes was strongly related
to both IFG and IGT at baseline and, in particular, to the combined presence
of IFG and IGT.
Worldwide, the prevalence of type 2 diabetes is very high and increasing.
The World Health Organization (WHO) predicts that between 1995 and 2025, the
worldwide prevalence of diabetes among persons aged 20 years and older will
increase from 4.0% to 5.4%.1 Diabetes is associated
with a high risk for microvascular and macrovascular complications and with
a high risk of premature death.2-4
For prevention purposes, there is great interest in the identification
of persons at high risk for developing diabetes. Therefore, several follow-up
studies have been performed in nonwhite populations with a high prevalence
and among persons with impaired glucose tolerance (IGT).8-10
Edelstein et al11 reported cumulative incidences
ranging from 23% to 62% in 6 prospective studies among persons with IGT, within
2 to 27 years of follow-up. The incidence was higher among the Hispanic, Mexican-American,
Pima, and Nauruan populations compared with the incidence among white populations.
Variables predictive of the development of diabetes in different studies were
fasting and postload glucose,7,11-13
obesity,11,12 and such lifestyle
variables as physical inactivity.14
However, little is known about the conversion from normal glucose tolerance
(NGT) to diabetes in white persons. Furthermore, even less is known about
the incidence of diabetes among persons with impaired fasting glucose (IFG)
and normal fasting glucose (NFG)—relatively new categories defined by
the American Diabetes Association (ADA) in 1997.15
Because the ADA criteria are based on fasting plasma glucose (FPG) values
only, and because the cutoff point for the diagnosis of diabetes has been
lowered to 126 mg/dL (7.0 mmol/L) (the cutoff point of the WHO-1985 criteria
is 140 mg/dL [7.8 mmol/L]),16 it is of importance
to know how this affects the incidence of diabetes. This lower cutoff point
for FPG was adopted by the WHO in 1999. The WHO-1999 criteria differ from
the ADA criteria by still taking into account the postload glucose levels.17
Therefore, in the present study we investigated the cumulative incidence
of diabetes in the white population of the Hoorn Study, which has been followed
up for 6 years. We compared the incidence of diabetes among participants having
normal glucose levels, IFG, IGT, or both IFG and IGT at baseline according
to the WHO-1985, ADA, and WHO-1999 diagnostic criteria. We also determined
which other variables were predictive of the development of diabetes.
The Hoorn Study, begun in 1989, is a population-based cohort study on
glucose intolerance in a general Dutch elderly population. The study population
and design have been described in detail previously.18
In summary, a random sample (n = 3553) of all inhabitants of Hoorn aged 50
to 75 years was invited to take part in the study. A total of 2540 subjects
(71%) agreed to participate. After exclusion of 56 nonwhite participants,
the study cohort consisted of 2484 men and women. The baseline examination
took place between October 1989 and February 1992.
Between January 1996 and December 1998, a follow-up examination was
carried out. Of the initial cohort, 150 persons had died and 108 had moved
out of Hoorn before 1996. One hundred forty other persons were not invited
because of logistic reasons. Of the remaining 2086 persons who were invited
for the follow-up examination, 1513 (72.5%) participated. In the present study
all analyses have been done on 1342 participants, because those who had diabetes
according to any one of the diagnostic criteria at baseline or who had missing
values for glucose were excluded (Figure 1).
All participants gave their written informed consent for participation
in the Hoorn Study. The Ethics Committee of the University Hospital Vrije
Universiteit Amsterdam approved the design of the study.
For the measurement of FPG, a blood sample was taken after an overnight
fast. Subsequently, a 75-g oral glucose tolerance test (OGTT) was administered
and the plasma glucose level was measured 2 hours later (2hPG). The glucose
levels were determined by a glucose dehydrogenase method (Merck, Darmstad,
At both baseline and follow-up, all participants were classified in
categories of glucose intolerance. In the WHO-1985 criteria, diabetes is diagnosed
if FPG is 140 mg/dL (7.8 mmol/L) or greater or if 2hPG is 200 mg/dL (11.1
mmol/L) or greater,16 while by the ADA criteria,
an FPG of 126 (7.0 mmol/L) or greater is sufficient.15
In the WHO-1999 criteria, these are combined and therefore diabetes is defined
by an FPG level of 126 mg/dL (7.0 mmol/L) or greater or a 2hPG level of 200
mg/dL (11.1 mmol/L) or greater.17 Participants
who were already treated for diabetes by insulin, hypoglycemic agents, or
a physician-prescribed diet were categorized as persons with known diabetes,
irrespective of their glucose levels. In case of doubt the medical information
in the hospital or at the general practitioner was checked. In all analyses,
known and newly diagnosed diabetes was taken together.
Impaired fasting glucose is defined as an FPG between 110 mg/dL (6.1
mmol/L) and 126 mg/dL (7.0 mmol/L).15 By WHO-1985
criteria, IGT is diagnosed if FPG is less than 140 mg/dL (7.8 mmol/L) and
2hPG is between 140 mg/dL (7.8 mmol/L) and 200 mg/dL (11.1 mmol/L).16
Weight and height were measured with participants wearing light clothing
only, and the body mass index (BMI) was calculated as weight divided by the
square of the height (kg/m2). Waist and hip circumferences were
measured and the waist-hip ratio (WHR) was defined as waist circumference
divided by hip circumference.
Blood pressure was measured twice on the right arm while sitting and
with a random-zero sphygmomanometer (Hawksley-Gelman, Lancing, England). The
average of these 2 measurements was used for analyses. Participants were considered
hypertensive if their systolic blood pressure was 160 mm Hg or greater, their
diastolic blood pressure was 95 mm Hg or greater, or if they were using antihypertensive
medication. Information on smoking habits (yes or no) and participation in
sports (hours per week) was obtained by questionnaire.18
All statistical analyses were done with SPSS 9.0.19
All P values were based on 2-sided tests, and the
cutoff for statistical significance was .05.
The cumulative incidence of diabetes was calculated as the number of
participants who developed diabetes during the follow-up divided by the total
number of those at risk at baseline. We compared the 6-year cumulative incidence
of diabetes between the WHO-1985, the ADA, and the WHO-1999 diagnostic criteria.
Furthermore, we compared the cumulative incidences for combinations of normal,
impaired fasting, and impaired postload glucose levels.
The follow-up duration was calculated as the time between the baseline
and the follow-up measurements, and the incidence densities were calculated.
Because the mean follow-up duration was not equal in the categories of glucose
intolerance, logistic regression adjusting for follow-up duration was used
to estimate odds ratios (ORs) and 95% confidence intervals (CIs). The ORs
were also adjusted for age and sex. The Hosmer-Lemeshow goodness-of-fit test
was used to assess the overall fit of the logistic regression model.20
The OR is the ratio of the odds of 2 categories and can be interpreted
as an approximation of the relative risk. In this study, odds represent the
chance for conversion to diabetes relative to the chance for nonconversion
to diabetes in 1 particular category. The ORs will overestimate the relative
risk when the disease under study is not rare.21
To investigate which other variables were predictive of the development
of diabetes, the variables WHR (×100), BMI, hypertension, smoking, and
participation in sports were added 1 by 1 into a logistic regression model
including also FPG, 2hPG, age, sex, and follow-up duration as independent
variables. Finally, all statistically significant variables were included
together into 1 logistic regression model.
The study population consisted of 610 men and 732 women with a mean
age of 60.3 (SD, 6.9) years at baseline, who were followed up for 6.4 years
(range, 4.4-8.1 years).
As a consequence of the definitions used, the cumulative incidence of
diabetes was highest according to the WHO-1999 criteria: 9.9% compared with
6.1% and 8.3% according to the WHO-1985 and the ADA criteria, respectively.
Of the 1231 participants with NGT at baseline, 46 (3.7%) had diabetes at follow-up
according to the WHO-1985 criteria. For participants with IGT the cumulative
incidence was 32.4% (WHO-1985 criteria). According to the ADA criteria, the
cumulative incidence was 5.0% for participants with NFG and 38.0% for those
with IFG (Table 1).
The cumulative incidence (WHO-1999 criteria) among participants with
both impaired fasting and impaired postload glucose levels was 64.5%, compared
with 4.5% for those with both normal fasting and normal postload glucose levels.
Among participants with isolated IFG or IGT, the cumulative incidence of diabetes
was similar (33.0% and 33.8%, respectively). However, the mean follow-up durations
were not equal in these categories. The ORs adjusted for follow-up duration,
age, and sex were 10.0 and 10.9 for isolated IFG and IGT, respectively. The
OR for participants with both IFG and IGT relative to those with normal glucose
levels was very high (39.5 [95% CI, 17.0-92.1]) (Table 2).
When the analyses were stratified for men and women, we observed a slightly
higher cumulative incidence of diabetes in men than in women (10.5% vs 9.4%,
respectively; WHO-1999 criteria). For participants with the combined presence
of IFG and IGT the cumulative incidence was more pronounced in women (75.0%)
than in men (53.3%).
In addition to fasting and postload glucose levels, which were the 2
most important predictors for progression to diabetes (both P<.001), the WHR also was highly predictive of incident diabetes
(P = .002). Of less importance, and not statistically
significant, were smoking, hypertension, participation in sports, and BMI.
Including the statistically significant variables into 1 model, the OR expressed
per 1-SD difference was 2.32 (95% CI, 1.85-2.90) for FPG, 1.97 (95% CI, 1.59-2.44)
for 2hPG, and 1.57 (95% CI, 1.19-2.08) for the WHR (Table 3).
In this prospective cohort study of a white population, 64.5% of the
participants who had both impaired fasting and impaired postload glucose levels
at baseline progressed to diabetes (WHO-1999 criteria) during the 6-year follow-up.
Of those with normal fasting and postload glucose levels at baseline, 4.5%
had diabetes at the follow-up examination. To our knowledge, this is the first
large prospective study among whites that reports on the cumulative incidence
of type 2 diabetes according to WHO-1985, ADA, and WHO-1999 diagnostic criteria.
The baseline cohort (n = 2484) of the Hoorn Study was a random sample
of the population of the municipality of Hoorn, aged 50 to 75 years. The present
analyses have been done in 1342 participants who did not have diabetes according
to any 1 of the diagnostic criteria at baseline and who did not have missing
values for glucose. Of the 2086 persons who were invited for the follow-up
examination, 1513 participated and 573 did not. As is frequently observed
in population studies, the participants were more healthy. The participants
were younger (60.6 vs 63.2 years), less hypertensive (28.2% vs 34.8%), had
a lower WHR (0.89 vs 0.90), and a more favorable lipid profile at baseline.
Furthermore, they had lower mean baseline FPG levels (101.8 mg/dL [5.65 mmol/L]
vs 105.5 mg/dL [5.85 mmol/L]), lower 2hPG levels (106.5 mg/dL [5.981 mmol/L]
vs 112.2 mg/dL [6.23 mmol/L]), and lower glycosylated hemoglobin values (5.4%
vs 5.6%). Therefore, we may have underestimated the true cumulative incidence
of diabetes in the general population.
Because of ongoing follow-up studies, persons with IGT were first invited
for the follow-up measurements. This resulted in an unequal distribution over
the categories for the mean follow-up duration, with persons with the highest
risks for progression to diabetes having the shortest follow-up duration.
In a logistic regression model we therefore adjusted for follow-up duration.
The glucose levels were determined only once at baseline and at follow-up.
Because of the known high intraindividual variation in glucose levels, especially
for postload glucose, some misclassification might have occurred when participants
were categorized into glucose tolerance categories.22,23
However, we previously reported that the reproducibility of the classification
in glucose tolerance categories by WHO-1985 and ADA for 1109 persons with
duplicate OGTTs within 6 weeks was very similar, with κ values of 0.59
and 0.61, respectively, which represent fair-to-good reproducibility.24
The incidence of diabetes was highest according to the WHO-1999 combined
criteria and the lowest incidence was observed if using the WHO-1985 criteria,
which is due to the higher cutoff level for FPG. However, the true incidence
according to the WHO-1985 was slightly underestimated, because participants
with FPG levels between 126 mg/dL (7.0 mmol/L) and 140 mg/dL (7.8 mmol/L)
at baseline were excluded in the analyses. If these participants (n = 23)
were included, the cumulative incidence of diabetes according to WHO-1985
criteria was 6.9% instead of 6.1%. For participants with IGT and NGT the incidences
then were 35.5% and 4.1%, respectively. When only the ADA diagnostic criteria
should have been used, the analyses could have been done in 1391 participants
instead of 1342. Then the cumulative incidence of diabetes was 5.5% for participants
with NFG and 40.8% for those with IFG, which is quite similar to the values
in Table 1.
Previous studies on the incidence of diabetes were mainly performed
in persons with IGT only, or in nonwhite populations with a high risk for
diabetes, using the WHO-1985 diagnostic criteria. In South African persons,
the incidence of diabetes was 50.4% within 4 years7
and for Pima Indians the cumulative incidence of diabetes was 62% within 7
years.11 In Kinmen, a series of islands located
in the Pacific Ocean, the cumulative incidence was 8.8% per year.12 We previously reported on the 2-year cumulative incidence
of diabetes in a subsample of participants with IGT in the Hoorn Study. The
cumulative incidence of diabetes was 28.5% when using the mean of duplicate
OGTTs for the classification in glucose tolerance categories.25
Less is known about the cumulative incidence of diabetes of persons
with IFG. In the present study, we observed a 6-year incidence of 38%. Dinneen
et al13 observed a cumulative incidence of
39% within 9 years of follow-up among Olmsted County residents aged 40 years
or older with baseline IFG. In a prospective study in Mauritius among persons
aged 25 to 74 years, 28.9% of the participants with baseline IFG progressed
to diabetes in 5 years, compared with 24.4% with IGT.26
In a study in Italy among 1245 whites who were followed up for 11.5 years,
participants with both IFG and IGT at baseline had an OR of 10.3 for developing
diabetes relative to those with both NFG and NGT. The cumulative incidence
of diabetes among participants with IGT only was higher than the cumulative
incidence for subjects with IFG only (32.5% and 9.1%, respectively).27 These results are therefore only partly in line with
the results of the present study: we observed a 14-fold higher risk for diabetes
in subjects with both IFG and IGT, while the risks of the IFG-only and IGT-only
categories were similar. However, the participants in the Italian study were
younger (40-59 years) and the number of those who progressed to diabetes was
in some categories quite small.27
Impaired fasting glucose and IGT represent different physiologic abnormalities.
The primary cause for fasting hyperglycemia is the elevated rate of basal
hepatic glucose production in the presence of hyperinsulinemia, while IGT
is characterized by defects in both insulin secretion and insulin sensitivity.28,29 Therefore, as demonstrated herein,
when there is a combined presence of these disorders the risk for future diabetes
is very high. Furthermore, we observed that the WHR, not the BMI, was an important
predictor for progression to diabetes. Edelstein et al11
also observed in 4 prospective studies that the WHR was consistently associated
with the development of diabetes. The association between BMI and incident
diabetes differed between the studies reported. Therefore, the body fat distribution
may be a better predictor for progression to diabetes than the BMI.
In this study, the highest cumulative incidence of diabetes was observed
for participants with both IFG and IGT at baseline. Therefore, we conclude
that the cumulative incidence of diabetes among white persons aged 50 to 75
years is strongly related to both impaired fasting and impaired postload glucose
levels at baseline.