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Epidemiology/Health Services/Psychosocial Research
O R I G I N A L
A R T I C L E
Postchallenge Hyperglycemia in a
National Sample of U.S. Adults With
Type 2 Diabetes
THOMAS P. ERLINGER, MD, MPH1
FREDERICK L. BRANCATI, MD, MHS1,2
OBJECTIVE — Postchallenge hyperglycemia (PCH) is known to contribute to suboptimal
glycemic control in adults with non–insulin-requiring type 2 diabetes. The objective of this study
was to estimate the prevalence of PCH among individuals with diabetes.
RESEARCH DESIGN AND METHODS — We conducted a cross-sectional analysis of
data from the Third National Health and Nutrition Examination Survey (1988 –1994) in adults
aged 40 –74 years with diabetes who were not using insulin (i.e., they used oral hypoglycemics
or received no pharmacological therapy). Each respondent underwent a standard 75-g oral
glucose tolerance test. PCH was defined as a 2-h glucose level ⱖ200 mg/dl.
RESULTS — Overall, PCH was present in 74% of those with diagnosed diabetes. Although it
was present in virtually all (99%) of the diabetic adults under suboptimal glycemic control
(HbA1c ⱖ7.0%), PCH was also common (39%) among those under optimal control (HbA1c
⬍7.0%). Likewise, among sulfonylurea users, PCH was present in 99% of those under suboptimal control and in 63% of those under good control. Similar patterns were observed in those
with undiagnosed diabetes. Isolated PCH (2-h glucose ⱖ200 mg/dl and fasting glucose ⬍126
mg/dl) was present in 9.8% of the adults with diagnosed diabetes.
CONCLUSIONS — These data suggest that PCH is common among diabetic adults in the
U.S., even in the setting of “optimal” glycemic control and sulfonylurea use. Interventions
designed to lower postprandial glucose excursions may help improve overall glycemic control in
the general population of U.S. adults with diabetes.
Diabetes Care 24:1734 –1738, 2001
H
yperglycemia is a major modifiable
risk factor for morbidity and mortality in diabetes (1,2). Improvements in glycemic control have been
shown to reduce the risk of these complications in type 1 and type 2 diabetes (3,4).
PCH contributes to poor glycemic control, and agents that modify PCH reduce
HbA1c levels (5,6). PCH also appears to be
an independent risk factor for the devel-
opment of atherosclerosis and fatal coronary heart disease (7,8). Moreover, recent
findings suggest that with regard to
deaths from all causes and cardiovascular
disease, 2-h glucose is a better predictor
than fasting blood glucose (9).
Thus, PCH might represent an attractive target in the primary care of adults
with diabetes. However, PCH appears to
receive relatively little attention in pri-
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
From the 1Department of Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of
Hygiene and Public Health, Baltimore; and the 1Department of Epidemiology, Johns Hopkins University
School of Hygiene and Public Health, Baltimore, Maryland.
Address correspondence and reprint requests to Thomas P. Erlinger, Welch Center for Prevention,
Epidemiology and Clinical Research, 2024 E. Monument Ave., Suite 2-602, Baltimore, MD 21205. E-mail:
terlinge@jhmi.edu.
Received for publication 15 December 2000 and accepted in revised form 5 April 2001.
This study was commissioned by Novartis under an agreement with Johns Hopkins Medicine Health Care
Consulting. T.P.E. and F.L.B. have received consulting fees from Novartis.
Abbreviations: FPG, fasting plasma glucose; NHANES III, Third National Health and Nutrition Examination Survey; OGTT, oral glucose tolerance test; PCH, postchallenge hyperglycemia.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
1734
mary care. Most treatment guidelines recommend monitoring of HbA1c and/or
fasting glucose levels (10). Patients who
self-monitor overwhelmingly report
monitoring before meals (11).
One possible explanation for the lack
of attention paid to PCH is uncertainty
about its prevalence in adults with previously diagnosed diabetes. However, if
common, it would be a logical target for
interventions to improve glycemic control in the U.S. We therefore analyzed
data from a nationally representative cohort of diabetic adults in the U.S. who
participated in the Third National Health
and Nutrition Examination Survey
(NHANES III) and underwent an oral glucose tolerance test (OGTT). We hypothesized that PCH would be common,
especially in those with suboptimal glycemic control. We paid particular attention
to the influence of sulfonylureas, the most
commonly used class of oral hypoglycemic agents.
RESEARCH DESIGN AND
METHODS
Data source
We used data from NHANES III, which
was conducted between October 1988
and October 1994 by the National Center
for Health Statistics in two equal 3-year
phases (1988 –1991 and 1991–1994). A
stratified multistage sample design was
used to select a study sample representative of the entire civilian noninstitutionalized U.S. population. The survey included a
physical examination, laboratory tests,
and questionnaires on health and nutrition-related topics. A detailed description
of the survey design, response rates, and
procedures for blood collection and processing have been previously published
elsewhere (12,13).
Study sample selection
A total of 18,825 adults who were 20
years of age and older completed the
household interview, in which information was obtained about demographic
characteristics, race, and medical history
DIABETES CARE, VOLUME 24, NUMBER 10, OCTOBER 2001
Erlinger and Brancati
of diabetes. Participants were defined as
having previously diagnosed diabetes if
they answered “yes” to the following
question: “Have you ever been told by a
doctor that you have diabetes or sugar diabetes?” Of the 1,605 individuals over age
20 years with a history of physiciandiagnosed diabetes, 105 women were diagnosed only during pregnancy and were
excluded from this analysis. A subsample
aged 40 –74 years were selected to receive
an OGTT. We excluded those who did
not fast 9 –24 h before the OGTT and
those who were missing data with respect
to relevant glycemic indexes. In the end,
218 individuals with a history of previously diagnosed type 2 diabetes were included in our analyses. Of these, 134 used
oral hypoglycemic agents and 84 reported
receiving nonpharmacological management for their diabetes. Cases of previously undiagnosed diabetes were identified
according to American Diabetes Association diagnostic criteria: either fasting
plasma glucose (FPG) ⱖ126 mg/dl or
2-h glucose ⱖ200 mg/dl (14).
Data collection
Procedures of physical examination,
blood collection, and processing have
been described in detail elsewhere (13).
HbA1c was measured at the University of
Missouri Diabetes Diagnostic Laboratory
using high-performance liquid chromatography. Plasma glucose was measured
using a modified hexokinase enzymatic
method. BMI was calculated as the weight
in kilograms divided by the square of
height in meters. Current smokers were
those who gave a history of current smoking or had a serum cotinine level ⬎10
ng/ml. Race and ethnicity were determined by self-report. Blood pressure was
the average of measurements obtained at
the household interview (maximum of
three measurements) and the mobile examination center (maximum of three
measurements). Serum cholesterol was
measured enzymatically (Hitachi 704 analyzer; Boehringer Mannheim).
For the OGTT, a 75-g glucoseequivalent oral glucose (Dextol or Trutol)
test was given to a morning subsample of
participants. Data were used from those
participants who were fasting from 9 to
24 h and who had plasma collected after
120 min ⫾ 15 min. Insulin users were
excluded from the morning subsample.
Individuals with a history of diabetes who
were using oral hypoglycemic agents
were asked not to take them on the morning of the test.
Guidelines from the American Diabetes Association for the management of diabetes were followed to estimate the
proportion of adults with diabetes under
optimal, fair, and poor glycemic control
(HbA1c ⬍7.0, 7.0 – 8.0, and ⬎8.0%, respectively) (15), by level of fasting (⬍126,
126 –140, and 140 mg/dl, respectively)
and 2-h glucose levels (⬍140, 140 –200,
and 200 mg/dl, respectively) (14). Isolated PCH was considered present if 2-h
glucose was ⱖ200 mg/dl and fasting glucose was ⬍126 mg/dl.
Analysis
We used sample weights in calculating
means and proportions to account for the
complex, stratified probability sampling
design and to make estimates that were
representative of the U.S. population. To
test for differences between adults with
diabetes who were treated with oral
agents and those not receiving pharmacological therapy with respect to baseline
characteristics, we used analysis of variance for continuous variables (age, systolic blood pressure, diastolic blood
pressure, total cholesterol, HDL cholesterol, BMI, FPG, 2-h postchallenge
plasma glucose, and HbA1c) and logistic
regression for dichotomous outcomes
(sex and smoking). Logistic regression
was used to test for differences in the proportion of diabetic adults with hyperglycemia who were taking oral agents and
those not taking oral agents who had an
HbA1c level ⬍7.0 and were adjusted for
age, race, sex, BMI, and smoking status.
Linear correlation between fasting and
2-h glucose levels was determined by taking the square root of the variance from
the weighted linear regression model that
incorporated 2-h glucose as a function of
FPG.
As a subsidiary analysis, we calculated the prevalence of fasting and 2-h
hyperglycemia in individuals with previously undiagnosed diabetes in order to
confirm patterns observed in previously
diagnosed individuals. All analyses were
conducted using survey commands in
STATA statistical software version 6.0
(College Station, TX).
RESULTS
Baseline characteristics
Table 1 shows selected characteristics of
U.S. adults with diabetes who were not
DIABETES CARE, VOLUME 24, NUMBER 10, OCTOBER 2001
using insulin. Compared with those taking oral hypoglycemic agents, diabetic
adults on no pharmacological therapy
were slightly older, and a greater proportion of that group was female and nonHispanic white. Additionally, those not
treated had a lower BMI than those receiving treatment. As expected, untreated
adults with diabetes were generally under
better glycemic control than treated individuals and had lower fasting and 2-h
plasma glucose levels.
Prevalence of hyperglycemia
PCH was common in this national sample
of adults with previously diagnosed diabetes, its prevalence rising from 39% in
those under “optimal” control (HbA1c
⬍7.0%) to ⬎99% in those under “fair”
and “poor” control (HbA1c 7.0 –7.9 and
8.0%, respectively) (Table 2). This corresponds to mean 2-h glucose levels of 325
and 402 mg/dl in those with fair and poor
control, respectively. As expected, mean
levels of fasting glucose and the prevalence of fasting hyperglycemia (FPG 140
mg/dl) also rose across categories of
HbA1c. Nonetheless, isolated PCH (FPG
⬍126 mg/dl and 2-h glucose 200 mg/dl)
was present in 9.8% of the adults with
diagnosed diabetes (data not shown).
Postprandial hyperglycemia and
medication use
The use of oral antidiabetic medication
(sulfonylureas) was not associated with
lesser degrees of hyperglycemia (Fig. 1).
On the contrary, both fasting and PCH
were equally or more common in those
taking sulfonylureas than in those not
taking them. This difference reached statistical significance among those under
optimal control (P ⬍0.001).
Correlation between fasting and 2-h
glucose levels
To investigate the correlation between
fasting and 2-h glucose levels in adults
with diagnosed diabetes, we plotted mean
plasma glucose levels against HbA1c levels
(Fig. 2). As expected, there were strong
associations of HbA1c with FPG (␤ ⫽
0.024, 95% CI 0.021– 0.027) and 2-h
glucose (0.012, 0.011– 0.013). Consequently, the correlation between FPG and
2-h glucose was high (r2 ⫽ 0.72, P ⬍
0.001).
1735
Postprandial hyperglycemia in adults with diabetes
Table 1—Selected characteristics of non–insulin-using diabetic adults in the U.S. aged 40 –74 years by oral agent status
Characteristic
On oral agents
(sample n ⫽ 134,
weighted N ⫽ 2,090,271)
Not on oral agents
(sample n ⫽ 84,
weighted N ⫽ 1,571,692)
P
58.8 (1.3)
40.3 (5.0)
60.1 (1.2)
47.3 (8.3)
0.45
0.49
75.7 (4.3)
11.8 (2.5)
8.1 (1.8)
4.4 (2.8)
134.2 (2.1)
76.2 (1.1)
225.2 (5.8)
44.3 (3.5)
32.1 (0.6)
17.7 (4.6)
189.2 (9.2)
333.1 (15.4)
8.0 (0.2)
84.8 (3.7)
8.2 (2.5)
7.0 (2.0)
—
133.4 (2.6)
73.6 (1.4)
233.5 (7.1)
47.3 (2.0)
29.1 (0.7)
41.2 (10.2)
148.4 (12.1)
244.1 (27.8)
6.6 (0.3)
0.12
0.12
0.12
Age (years)
Women (%)
Race-ethnicity (%)
Non-Hispanic White
Non-Hispanic Black
Hispanic
Other
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Total cholesterol (mmol/dl)
HDL cholesterol (mmol/dl)
BMI (kg/m2)
Current smokers (%)
FPG (mg/dl)
2-h plasma glucose (mg/dl)
HbA1c (%)
0.80
0.14
0.41
0.46
0.002
0.03
0.02
0.01
0.002
Values are means (SEM) or proportions (SEM), weighted to reflect the U.S. population.
Prevalence of PCH among adults
with previously undiagnosed
diabetes
PCH was also common among adults
with previously undiagnosed diabetes,
whose diabetes was identified by OGTT.
Among those with an HbA1c ⬍7.0, 80%
had a 2-h plasma glucose level of 200 mg/
dl, and 17% had an FPG level of 126 mg/
dl. Corresponding prevalence estimates
for those with HbA1c values of 7.0 –7.9
and 8.0, respectively, were 88 and 100%
for elevated 2-h plasma glucose and 84
and 99% for elevated FPG. Of course,
these estimates may have been inflated
because the same OGTT data were used to
both identify diabetes and determine hyperglycemia.
CONCLUSIONS — These data demonstrate a high prevalence of PCH among
adults with previously diagnosed diabe-
tes, even among those being treated with
oral hypoglycemic agents. In fact, even
among individuals under optimal glycemic control with oral agents, almost
two-thirds have 2-h postchallenge hyperglycemia. Moreover, ⬃10% of adults with
previously diagnosed diabetes who have
an FPG ⬍126 mg/dl have PCH.
The main strength of this study is that
it draws on a nationally representative
sample and is therefore generalizable to
the U.S. population. Nevertheless, several
limitations should be kept in mind. Because of the cross-sectional study design,
we are not able to determine cause-andeffect relationships, especially in regard to
medication use. In particular, we cannot
exclude the possibility that preferential
prescription of sulfonylureas to adults
with PCH might explain the observed associations between PCH and sulfonylurea
use. Second, because our study was lim-
ited to diabetic individuals aged 40 –74
years who were not taking insulin, we
cannot comment on the prevalence of
PCH among younger or older age groups.
However, diabetes prevalence has sharply
increased in younger and older age
groups; thus, our estimates of the total
number of diabetic individuals with PCH
are likely conservative (16). Third, our estimates of elevated 2-h plasma glucose
levels could be artificially inflated because
of skipped morning doses of oral hypoglycemic agents before the glucose challenge in diagnosed diabetic patients.
However, we observed similar patterns in
FPG levels, which are not likely to be affected by skipped medication doses.
Treatment with oral hypoglycemic agents
could theoretically result in an underestimation of the prevalence of PCH. However, the prevalence of PCH is nearly
ubiquitous, except in individuals with an
Table 2—Distribution of FPG and 2-h postchallenge glucose by HbA1c levels in U.S. adults with diagnosed diabetes
HbA1c
n
(Weighted N)
FPG
Mean
⬍126
126–140
Overall 218 (3,661,964) 172.5 (6.8) 28.1% [n ⫽ 70] 14.9% [n ⫽ 27]
⬍7
104 (1,572,903) 118.9 (3.0) 59.9% [n ⫽ 66] 27.4% [n ⫽ 19]
7–7.9
41 (744,515) 169.4 (6.8) 10.2% [n ⫽ 3] 10.2% [n ⫽ 7]
ⱖ8.0
73 (1,344,546) 235.9 (8.6) 0.7% [n ⫽ 1]
3.0% [n ⫽ 1]
2-h postchallenge glucose
ⱖ140
57.0% [n ⫽ 121]
12.7% [n ⫽ 19]
79.5% [n ⫽ 31]
96.4% [n ⫽ 72]
Mean
⬍140
140–200
294.7 (14.6) 16.1% [n ⫽ 26] 10.4% [n ⫽ 32]
184.7 (10.1) 36.8% [n ⫽ 24] 24.2% [n ⫽ 32]
325.1 (11.5) 0.01% [n ⫽ 1]
0% [n ⫽ 0]
402.4 (12.8) 0.7% [n ⫽ 1]
0% [n ⫽ 0]
ⱖ200
73.5% [n ⫽ 160]
39.0% [n ⫽ 48]
99.9% [n ⫽ 40]
99.3% [n ⫽ 73]
Results shown as weighted proportions and means (SEM). Numbers in brackets indicate the number of individuals from the NHANES III sample on which these
estimates are based.
1736
DIABETES CARE, VOLUME 24, NUMBER 10, OCTOBER 2001
Erlinger and Brancati
Figure 1—Percentage of adults with diabetes
with elevated fasting (A) and 2-h (B) plasma
glucose. Columns represent the percentage of
U.S. adults, aged 40 –74 years, with diagnosed
diabetes not using insulin with fasting (A) hyperglycemia (defined as FPG ⱖ126 mg/dl) and
postprandial (B) hyperglycemia (defined as
2-h plasma glucose ⱖ200 mg/dl) by level of
HbA1c. f, Diabetic patients taking oral agents;
u, diabetic patients not taking oral agents. P ⬍
0.001 for difference at HbA1c ⬍7.0%. Error
bars indicate SEM.
edge, no previous studies have examined
the prevalence of elevated postchallenge
glucose levels among adults with diabetes.
The loss of early phase insulin secretion may be a key factor in postprandial
hyperglycemia as well (23,24). Additionally, insulin resistance within muscles and
impaired suppression of hepatic glucose
production may also contribute to postprandial hyperglycemia (25). PCH has
been shown to increase the risk of microvascular and macrovascular complications in individuals with diabetes (7,26),
and the increased prevalence of PCH
demonstrated in this study suggests that it
could be an important target for interventions aimed at reducing glycemia among
individuals with diabetes.
The differences between the prevalence of PCH among those treated with
oral agents and those not treated with oral
agents are likely due to more severe hyperglycemia among treated individuals.
However, because the data in this study
were collected when sulfonylureas were
the only oral hypoglycemic agents available for the treatment of type 2 diabetes
(1988 –1994), it is not clear whether
newer agents designed to specifically reduce PCH would reduce the prevalence
beyond that achieved with sulfonylureas,
given the same level of long-term glycemic control.
HbA1c level ⬍7%. Therefore, this is the
group for which these comments are relevant. Consequently, our estimates are
potentially conservative in this group. Finally, although the prevalence of PCH in
this study was high among individuals
with diabetes, post–mixed-meal glucose
levels would be expected to be lower than
2-h glucose levels (17). Nevertheless, 2-h
glucose levels above normal but ⬍200
mg/dl are still associated with an increased risk of mortality (9). Current recommendations for postmeal glycemic
control are 100 –150 mg/dl (15).
Previous analyses from NHANES III
have shown a similar magnitude of poor
glycemic control among diagnosed diabetic patients with respect to FPG levels
(18). Data from NHANES III and other
populations have also documented a high
prevalence of PCH in adults with previously undiagnosed diabetes, identified
based on elevations in FPG or HbA1c
(5,12,19 –22). However, to our knowl-
Figure 2—Mean levels of fasting and 2-h plasma glucose in U.S. adults aged 40 –74 years with
diagnosed diabetes who were not using insulin, by HbA1c level. Error bars indicate 95% CIs.
DIABETES CARE, VOLUME 24, NUMBER 10, OCTOBER 2001
It would be impractical for most providers seeking to optimize glycemic control among adults with type 2 diabetes to
routinely order OGTTs. One alternative
would be for primary care providers to
recommend the monitoring of postprandial glucose in addition to fasting or preprandial. Another alternative would be to
rely on FPG as an indirect indicator of
PCH, as is currently the standard of practice, because the two are highly correlated.
Such correlation raises an important
question: Does it make sense to focus on
PCH per se, when it is so often accompanied by fasting hyperglycemia? Three
lines of reasoning suggest a tentative answer of “yes.” First, PCH is a strong predictor of cardiovascular disease, even in
the absence of fasting hyperglycemia (7).
Second, specific pharmacotherapy is
available to modify PCH preferentially.
Third, compared with sulfonylureas,
such agents offer a theoretical advantage
in terms of hypoglycemic risk, in so far
as they modify glucose peaks but leave
troughs unaffected (27). Long-term
studies are needed to determine whether
agents that specifically target PCH reduce
the risk of vascular complications among
diabetic patients compared with other
agents. In the meantime, this study underscores that PCH is common enough to
1737
Postprandial hyperglycemia in adults with diabetes
warrant clinical attention, even in the setting of reasonably good glycemic control.
9.
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