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Implications for the use of FPG and HbA1c for cost-effective screening
DAVID R. JESUDASON, MBBS, FRACP1
KERRIE DUNSTAN, RN1 DARRYL LEONG, MBBS1

GARY A. WITTERT, MBBCH, MD, FRACP1,2

OBJECTIVE -- The use of fasting plasma glucose (FPG) level 7.0 mmol/l leads to under-
diagnosis of type 2 diabetes compared with the oral glucose tolerance test (OGTT).The aims of this study were 1) to com-
pare the utility of HbA1c and FPG at dif-
ferent thresholds as screening tests for

diagnosing type 2 diabetes, as defined by

OGTT criteria; 2) to determine the rela-
tionship between HbA1c and FPG and

cardiovascular risk; and 3) to compare
HbA1c measured by HPLC with the result
obtained using a portable device
(DCA2000; Bayer Diagnostics, Mulgrave,
Australia) to assess the potential utility of
the latter in screening for type 2 diabetes. RESEARCH DESIGN AND
METHODS
Subjects
Subjects were recruited for this study by
community advertisement for people
with obesity, family history of diabetes,

history of gestational diabetes, or symp-
toms such as polyuria and polydipsia. All

individuals older than 18 years of age

without a previous diagnosis of type 2 di-
abetes were tested if they responded to the

advertisement with a request for screen-
ing. Pregnant women were excluded from

the study. Patients referred by general

practitioners and other hospital special-
ists for an OGTT were offered the oppor-
tunity to participate in the study. The Ethics Com-
mittee of the Royal Adelaide Hospital

approved the protocol. Informed consent
was obtained from all volunteers. Study design
Subjects fasted from food and fluid from

11:00 P.M. the previous night and at-
tended the Endocrine Test Unit at the

Royal Adelaide Hospital between 8:00
A.M. and 9:00 A.M. Subjects were asked to
complete a questionnaire to document
the presence of ischemic heart disease,
hypertension, and hyperlipidemia and
whether there was a family history of type

2 diabetes. Height, weight, and waist cir-
cumference were measured. A forearm

vein was then cannulated with a 19-g but-
terfly and 5 ml of venous blood was col-
lected for measurement of glucose and

HbA1c. Thereafter, 75 g of glucose was
administered orally and 5 ml of blood was
collected at 120 min for measurement of
plasma glucose. All patients and their

general practitioners were sent a letter in-
forming them of the results, and patients

were advised by telephone and by letter to
seek follow-up whenever either diabetes
or IGT was detected. Assays

Plasma glucose was measured by the hex-
okinase method, which has an interassay

CV of 1.9% at a glucose level of 4.8
mmol/l. HbA1c was measured by HPLC
using a spherical cation exchange gel,
which has an interassay CV of 2% at an
HbA1c level of 6%. HbA1c results from our

laboratory (Institute of Medical and Vet-
erinary Science) were referenced to the

National Glycohemoglobin Standardisa-
tion Program.Table 1--The sensitivity, specificity, and cardiovascular risk ratio at each cutoff of HbA1c (by HPLC), HbA1c (by DCA2000), and FPG
HbA1c by HPLC HbA1c by DCA2000 FPG (mmol/l)
HbA1c (%) Sen (%) Spec (%) CV HbA1c (%) Sen (%) Spec (%) CV FPG Sen (%) Spec (%) CV
3.9 100 0.22 1 4.0 100 0.2 1 3.0 100 0 1.0
4.7 100 10.0 1.3 5.0 100 11.1 1.3 4.7 100 23.1 1.4
5.6 85.2 80.5 1.8 5.8 85.2 77.8 1.6 5.6 79.6 85.8 1.7
6.2 42.6 99.1 2.3 6.8 42.6 99.6 2.1 6.4 59.3 99.1 2.0
6.8 22.2 100 2.8 7.3 20.4 100 2.4 7.7 31.5 100 2.5
Sen, sensitivity; Spec, specificity.More-
over, data from the Diabetes Control and

Complications Trial (DCCT) (21) and

U.K. Prospective Diabetes Study (UK-
PDS) (22) demonstrate that there remains

a significant risk of microvascular disease
with HbA1c levels well below 8%, and
even at an HbA1c of 6%, there is a 75%

Figure 1--ROC curves comparing FPG (F), HbA1c by HPLC (OE), and HbA1c by DCA2000 ()
as diagnostic indicators for diabetes.The World Health Organization
(WHO) and subsequently the Australian
Diabetes Society similarly adopted an
FPG level of 7 mmol/l as the threshold for

diagnosing type 2 diabetes (6,7); how-
ever, these organizations continue to rec-
ommend use of the OGTT, because

patients with type 2 diabetes based on an
OGTT often have a nondiabetic FPG level
(1,8,9).When measured by DCA2000, HbA1c
6.2% (sensitivity 72.2%, specificity
94.7%) was the best predictor of diabetes,

and HbA1c levels 5.0 and 6.8% pre-
dict the absence or presence of diabetes,

respectively, with almost 100% certainty
(Table 1).Macrovascular risk and diagnostic criteria for type 2 diabetes

488 DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2003

used self-reported data to evaluate cardio-
vascular risk, our data relating to cardio-
vascular risk are consistent with the

results of other studies demonstrating an

association between cardiovascular dis-
ease and increasing FPG and HbA1c, even

in the nondiabetic range (18,20,29).Cardiovascular risk increased at least
2.2 times at an HbA1c level 6.2% (by HPLC), 1.8-2.2 times at an HbA1c level of 5.6-6.1% (by
HPLC), 2 times at an FPG level 6.4 mmol/l, and 1.7-1.9 times at an FPG level of 5.6-6.3
mmol/l.Davidson et al. (27) suggested measuring
HbA1c to determine whether diabetes was
present in subjects with borderline FPG
(6.1-7.7 mmol/l) to avoid inappropriate
diagnosis of type 2 diabetes.The American Diabetes Asso-
ciation (ADA) based diagnosis of diabetes

on a fasting plasma glucose (FPG) level of
7.0 mmol/l because this level correlates
with a 2-h (post-75 g glucose) level of
11.1 mmol/l (5).Sensitivity is the

fraction of individuals at or above the
HbA1c cutoff point who have diabetes,

whereas specificity is the fraction of indi-
viduals with an HbA1c level below the cut-
off point who do not have diabetes.Our study has also shown that
when the FPG level is 4.7 mmol/l, type
2 diabetes can be confidently excluded;
73% of all subjects had an FPG level
between 4.7 and 6.3 mmol/l, and 17%
of these individuals had an FPG level of
5.6 - 6.3 mmol/l.Problems with the use of

HbA1c for screening have included vari-
ability and poor standardization of assays,

biological variability of HbA1c levels,

overlap between subjects with and with-
out diabetes as compared with fasting or

2-h glucose levels (5,14-17), and poor
sensitivity (12).Abbreviations: ADA, American Diabetes Association; CV, coefficient of variation; FPG, fasting plasma
glucose; HPLC, high-performance liquid chromatography; IFG, impaired fasting glycemia; IGT, impaired
glucose tolerance; OGTT, oral glucose tolerance test; ROC, receiver operating characteristic; WHO, World
Health Organization.Type 2 diabetes
is diagnosed at HbA1c 6.8%, whereas

HbA1c 5.0% excludes diabetes confi-
dently.The regression data for HbA1c by

DCA2000 versus HPLC reveals a small in-
Macrovascular risk and diagnostic criteria for type 2 diabetes

486 DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2003

tercept of 0.2 but no change in slope.Reproducibility
There was a within-subject CV of 2.2% for
HbA1c by HPLC, 2.7% for HbA1c by
DCA2000, 4.9% for FPG, and 16.0% for
120-min plasma glucose after a 75-g oral
glucose load.Cardiovascular risk
The mean SD for HbA1c by HPLC,
HbA1c by DCA2000, and FPG were 5.3
0.74%, 5.6 0.84%, and 5.3 1.2
mmol/l, respectively.Statistical analysis
Results are presented as means SD. The
receiver operating characteristic (ROC)
was used to describe the ability of HbA1c

(HPLC or DCA2000) and FPG to deter-
mine the presence or absence of type 2

diabetes as defined by the OGTT.Nondiabetic

subjects had a mean HbA1c (HPLC) of
5.2% (range 3.5- 6.6), a mean HbA1c
(DCA2000) of 5.5% (4-6.9), and a mean

FPG of 5.1 mmol/l (3-6.7).The aim of this study was to evaluate the use of HbA1c and FPG as predictors of type 2
diabetes and cardiovascular risk and, accordingly, to develop a rational approach to screening for
abnormalities of glucose tolerance.Diabetic sub-
jects had a mean HbA1c (HPLC) of 6.5%

(4.7-12.2), a mean HbA1c (DCA2000) of
7.0% (5-13.1), and a mean FPG of 7.4

mmol/l (4.7-15.7).RESEARCH DESIGN AND METHODS -- OGTT and measurement of HbA1c and FPG

levels were performed in 505 subjects screened for type 2 diabetes.Wahl PW, Savage PJ, Psaty BM, Orchard
TJ, Robbins JA, Tracey RP: Diabetes in

older adults: comparison of 1997 Ameri-
can Diabetes Association classification of

diabetes mellitus with 1985 WHO classi-
fication.In the study
by Perry et al. (28), an HbA1c 6.1% was
considered specific for type 2 diabetes
and was used to confirm the presence or
absence of the disease in subjects with an
FPG level between 5.5 and 8 mmol/l.The risk ratio (95%
CI) for each SD change in HbA1c by
HPLC, HbA1c by DCA2000, and FPG
were 1.3 (1.1-1.5; P 0.0002), 1.24
(1.1-1.4; P 0.0038), and 1.26 (1.1-

1.4; P 0.0001), respectively.Based on an ROC analysis, the areas
under the curve (predictive values) of
HbA1c as measured by HPLC and
DCA2000 for detecting type 2 diabetes,
compared with OGTT, were 0.893 and
0.911, respectively (2 0.53, df 2,
P 0.77) (Fig.Moreover, although we

Figure 2--An algorithm for diagnosing type 2 diabetes and assigning cardiovascular risk using FPG or HbA1c by HPLC.After

adjustment for these risk factors, the rel-
ative risk of ischemic heart disease for

HbA1c by HPLC, HbA1c by DCA2000, or
FPG was 1.1 (0.9-1.4; P 0.22), 1.1
(0.8-1.4; P 0.64), and 1.2 (0.99-1.4;
P 0.059).Clinicians should target the cardiovascu-
lar risk factors of these subjects and screen

for diabetes with HbA1c or FPG every
12-24 months, depending on previous

results.Perry RC, Shankar RR, Fineberg N, McGill

J, Baron AD: HbA1c measurement im-
proves the detection of type 2 diabetes in

high risk individuals with non-diagnostic
levels of fasting plasma glucose.Taken to-
gether, the data suggest that an FPG level

6.4 mmol/l is the most appropriate level
at which to diagnose type 2 diabetes and

only 40% (rather than 60%) of individ-
uals with type 2 diabetes would be

missed.Using the
Australian Diabetes Society and WHO
criteria, the incidence of type 2 diabetes

was 10.7% (54 subjects) and the inci-
dence of IGT was 24.4% (123 subjects).CONCLUSIONS -- Measurement of FPG and HbA1c levels will diagnose or exclude type 2
diabetes with certainty in a minority (15%) of people.To improve the detection rate of type
2 diabetes, alternative approaches to
screening have been proposed, such as a
lower threshold for FPG (8) or the use of
HbA1c (4,10-12).We have shown that a reduction in
the FPG level at which type 2 diabetes is

diagnosed will lead to a comparable in-
crease in the detection rate of diabetes.In situations in which fasting blood

glucose can be readily obtained, a cutoff
of 6.4 mmol/l results in diagnosis of more
diabetic subjects than HbA1c as well as
identification of those at significant risk

for cardiovascular disease, in whom max-
imal intervention, whether pharmacolog-
ical or nonpharmacological, should be

targeted.Using
high-performance liquid chromatography (HPLC), HbA1c of 4.7 and 6.2% predicted with
certainty the absence or presence of type 2 diabetes as defined by the OGTT.They argued that

HbA1c should be used in screening to re-
duce the number of OGTTs performed

but that the OGTT should continue to be
used to avoid missing subjects with type 2

diabetes.The ADA

also created a new category termed im-
paired fasting glycemia (IFG) to describe

patients with FPG levels of 6.1-6.9

mmol/l (5) to categorize individuals at in-
creased risk for type 2 diabetes and those

who may be at increased cardiovascular
risk.Given
that a major part of the morbidity and
mortality from type 2 diabetes arises from
macrovascular disease such as ischemic
heart disease and not just microvascular
disease, any screening test for diabetes
would be more meaningful if it could also

predict cardiovascular disease.CONCLUSIONS -- These results
show that FPG and HbA1c (by either

method) will diagnose or exclude diabe-
tes with certainty in only a minority

(15%) of subjects when the OGTT, with
currently defined cutoffs, is used as the
gold standard.The relative cardiovas-
cular risk in our group with an HbA1c

(HPLC) 6.1% was at least 2.3, and in
those with an HbA1c of 5.6-6.1%, the
relative cardiovascular risk was 1.8-2.2.The corresponding
cutoffs were 5.0 and 6.8% for HbA1c (DCA2000 HPLC device; Bayer Diagnostics, Mulgrave,
Australia) and 4.7 and 6.4 mmol/l for FPG.When measured by HPLC, HbA1c
5.7% predicted type 2 diabetes with a
sensitivity of 80.0% and a specificity of
86.3%.The current OGTT and FPG thresh-
olds for diagnosis of diabetes are based on

their association with microvascular dis-
ease, the incidence of which increases

sharply above currently defined glycemic

thresholds.Neither HbA1c (HPLC or DCA2000) nor
FPG remained independent risk factors

for cardiovascular disease after adjust-
ment for age, waist circumference, hyper-
tension, and high cholesterol.The Diabetes Control and Complications

Trial Research Group: The effect of inten-
sive treatment of diabetes on the develop-
ment and progression of long term

complications of insulin-dependant dia-
betes mellitus.N Engl J Med 329:977-986,

1993

23.The rela-
tive cardiovascular risks associated with

different cutoffs of HbA1c (HPLC and
DCA2000) and FPG are shown in Table 1.U.K. Prospective Diabetes Study Group:

Intensive blood glucose control with sul-
phonylureas or insulin compared with

conventional treatment and risk of com-
plications in-patients with type 2 diabetes

(UKPDS 33).Diabetes Care 26:485-490, 2003

T

he incidence of type 2 diabetes var-
ies from 3.6 to 14.8%, depending on

the population being screened (1,2)
and the diagnostic criteria used.FPG 6.0
mmol/l (sensitivity 74.1%, specificity
94.5%) was the best predictor of type 2
diabetes as defined by OGTT.HbA1c was also measured

using the DCA2000 (Bayer Diagnostics),

a portable device that uses an immunoas-
say technique with a monoclonal anti-
body directed against a sequence of the

HbA1c molecule (19).The repro-
ducibility of measurements of FPG, 2-h

glucose, and HbA1c by each method was
calculated for the 41 subjects, who were
tested twice, and the intrasubject CV was
determined (15).Rohlfing CL, Little RR, Wiedmeyer HM,
England JD, Madsen R, Harris MI, Flegal
KM, Eberhardt MS, Goldstein DE: Use of

GHb (HbA1c) in screening for undiag-
nosed diabetes in the U.S. population.Interestingly, they acknowl-
edged that if there were a relationship be-
tween HbA1c and complications of type 2

diabetes, then it could replace the OGTT.Measurement of HbA1c
is used to determine average glycemic
control over an 8- to 12-week period, and

HbA1c level has been linked to develop-
ment of microvascular complications

such as neuropathy, nephropathy, and
retinopathy (7).American Diabetes Association: Report of
the Expert Committee on the Diagnosis
and Classification of Diabetes Mellitus.References
1.2). 1).


Original text

Implications for the use of FPG and HbA1c for cost-effective screening
DAVID R. JESUDASON, MBBS, FRACP1
KERRIE DUNSTAN, RN1 DARRYL LEONG, MBBS1

GARY A. WITTERT, MBBCH, MD, FRACP1,2

OBJECTIVE — The use of fasting plasma glucose (FPG) level 7.0 mmol/l leads to under-
diagnosis of type 2 diabetes compared with the oral glucose tolerance test (OGTT). The OGTT

is of limited use for population screening. Most of the increase in cardiovascular risk in relation
to increasing blood glucose occurs before the threshold at which the diagnosis of type 2 diabetes
is made. The aim of this study was to evaluate the use of HbA1c and FPG as predictors of type 2
diabetes and cardiovascular risk and, accordingly, to develop a rational approach to screening for
abnormalities of glucose tolerance.
RESEARCH DESIGN AND METHODS — OGTT and measurement of HbA1c and FPG

levels were performed in 505 subjects screened for type 2 diabetes. Anthropomorphic measure-
ments were obtained. A cardiovascular risk factor questionnaire was completed.

RESULTS — The subjects were aged 19–88 years (mean 53.8). The incidence of type 2
diabetes was 10.4% based on the OGTT and 4% based on an FPG level 7.0 mmol/l. Using
high-performance liquid chromatography (HPLC), HbA1c of 4.7 and 6.2% predicted with
certainty the absence or presence of type 2 diabetes as defined by the OGTT. The corresponding
cutoffs were 5.0 and 6.8% for HbA1c (DCA2000 HPLC device; Bayer Diagnostics, Mulgrave,
Australia) and 4.7 and 6.4 mmol/l for FPG. However, 75–85% of subjects in each case had
intermediate values, which were therefore nondiagnostic. Cardiovascular risk increased at least
2.2 times at an HbA1c level 6.2% (by HPLC), 1.8–2.2 times at an HbA1c level of 5.6–6.1% (by
HPLC), 2 times at an FPG level 6.4 mmol/l, and 1.7–1.9 times at an FPG level of 5.6–6.3
mmol/l.
CONCLUSIONS — Measurement of FPG and HbA1c levels will diagnose or exclude type 2
diabetes with certainty in a minority (15%) of people. There is a continuous relationship between
FPG and HbA1c and cardiovascular risk. Accordingly, we propose that there is a rational basis for
using either FPG and HbA1c for purposes of screening and assigning risk. Individuals with an

HbA1c level of 5.6–6.1% and an FPG level of 5.6–6.3 mmol/l are at greatest risk for cardiovas-
cular disease and should be targeted for further evaluation. An algorithm outlining a cost-
effective approach is presented.

Diabetes Care 26:485–490, 2003

T

he incidence of type 2 diabetes var-
ies from 3.6 to 14.8%, depending on

the population being screened (1,2)
and the diagnostic criteria used. Up to

50% of diabetic subjects remain undetec-
ted. The oral glucose tolerance test

(OGTT) is the gold standard for diagnos-
ing type 2 diabetes. It has limited use for

mass screening, due to the need for fast-
ing, the time-consuming nature of the

test, and poor reproducibility of the re-
sults (3,4). The American Diabetes Asso-
ciation (ADA) based diagnosis of diabetes

on a fasting plasma glucose (FPG) level of
7.0 mmol/l because this level correlates
with a 2-h (post–75 g glucose) level of
11.1 mmol/l (5). It was hoped the better
reproducibility of FPG and its relative
convenience would increase the number
of diabetic subjects diagnosed. The ADA

also created a new category termed im-
paired fasting glycemia (IFG) to describe

patients with FPG levels of 6.1–6.9

mmol/l (5) to categorize individuals at in-
creased risk for type 2 diabetes and those

who may be at increased cardiovascular
risk. The World Health Organization
(WHO) and subsequently the Australian
Diabetes Society similarly adopted an
FPG level of 7 mmol/l as the threshold for

diagnosing type 2 diabetes (6,7); how-
ever, these organizations continue to rec-
ommend use of the OGTT, because

patients with type 2 diabetes based on an
OGTT often have a nondiabetic FPG level
(1,8,9).
To improve the detection rate of type
2 diabetes, alternative approaches to
screening have been proposed, such as a
lower threshold for FPG (8) or the use of
HbA1c (4,10–12). Measurement of HbA1c
is used to determine average glycemic
control over an 8- to 12-week period, and

HbA1c level has been linked to develop-
ment of microvascular complications

such as neuropathy, nephropathy, and
retinopathy (7). Compared with the
OGTT, HbA1c measurement is quicker, is
more convenient, and avoids the need for
fasting (3). Problems with the use of

HbA1c for screening have included vari-
ability and poor standardization of assays,

biological variability of HbA1c levels,

overlap between subjects with and with-
out diabetes as compared with fasting or

2-h glucose levels (5,14–17), and poor
sensitivity (12). When measured using

high-performance liquid chromatogra-
phy (HPLC), however, the test has high

precision (interassay coefficient of varia-
tion [CV] 1–2%). Furthermore, rapid, on-

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
From the 1
Department of Endocrinology and Metabolism, Royal Adelaide Hospital, Adelaide, Australia; and
the 2
Department of Medicine, University of Adelaide, Adelaide, Australia.
Address correspondence and reprint requests to Associate Professor Gary Wittert, University of Adelaide
Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide SA 5000, Australia. E-mail:
[email protected]
Received for publication 3 April 2002 and accepted in revised form 24 October 2002.
Abbreviations: ADA, American Diabetes Association; CV, coefficient of variation; FPG, fasting plasma
glucose; HPLC, high-performance liquid chromatography; IFG, impaired fasting glycemia; IGT, impaired
glucose tolerance; OGTT, oral glucose tolerance test; ROC, receiver operating characteristic; WHO, World
Health Organization.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
Pathophysiology/Complications
ORIGINAL ARTICLE

DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2003 485

the-spot results comparable to those

obtained with HPLC can be obtained us-
ing automated and portable devices (17).

The current OGTT and FPG thresh-
olds for diagnosis of diabetes are based on

their association with microvascular dis-
ease, the incidence of which increases

sharply above currently defined glycemic

thresholds. Macrovascular disease, how-
ever, seems to increase gradually in pre-
diabetic states such as impaired glucose

tolerance (IGT) and IFG (4,18). Given
that a major part of the morbidity and
mortality from type 2 diabetes arises from
macrovascular disease such as ischemic
heart disease and not just microvascular
disease, any screening test for diabetes
would be more meaningful if it could also

predict cardiovascular disease. We hy-
pothesized that levels of HbA1c may in-
crease progressively with increasing

plasma glucose levels, even below con-
ventionally defined diabetic thresholds,

and are associated with the risk of macro-
vascular disease.

The aims of this study were 1) to com-
pare the utility of HbA1c and FPG at dif-
ferent thresholds as screening tests for

diagnosing type 2 diabetes, as defined by

OGTT criteria; 2) to determine the rela-
tionship between HbA1c and FPG and

cardiovascular risk; and 3) to compare
HbA1c measured by HPLC with the result
obtained using a portable device
(DCA2000; Bayer Diagnostics, Mulgrave,
Australia) to assess the potential utility of
the latter in screening for type 2 diabetes.
RESEARCH DESIGN AND
METHODS
Subjects
Subjects were recruited for this study by
community advertisement for people
with obesity, family history of diabetes,

history of gestational diabetes, or symp-
toms such as polyuria and polydipsia. All

individuals older than 18 years of age

without a previous diagnosis of type 2 di-
abetes were tested if they responded to the

advertisement with a request for screen-
ing. Pregnant women were excluded from

the study. Patients referred by general

practitioners and other hospital special-
ists for an OGTT were offered the oppor-
tunity to participate in the study. To

determine reproducibility of the tests

used, 41 subjects were tested on two oc-
casions (1 week apart). The Ethics Com-
mittee of the Royal Adelaide Hospital

approved the protocol. Informed consent
was obtained from all volunteers.
Study design
Subjects fasted from food and fluid from

11:00 P.M. the previous night and at-
tended the Endocrine Test Unit at the

Royal Adelaide Hospital between 8:00
A.M. and 9:00 A.M. Subjects were asked to
complete a questionnaire to document
the presence of ischemic heart disease,
hypertension, and hyperlipidemia and
whether there was a family history of type

2 diabetes. Height, weight, and waist cir-
cumference were measured. A forearm

vein was then cannulated with a 19-g but-
terfly and 5 ml of venous blood was col-
lected for measurement of glucose and

HbA1c. Thereafter, 75 g of glucose was
administered orally and 5 ml of blood was
collected at 120 min for measurement of
plasma glucose. All patients and their

general practitioners were sent a letter in-
forming them of the results, and patients

were advised by telephone and by letter to
seek follow-up whenever either diabetes
or IGT was detected.
Assays

Plasma glucose was measured by the hex-
okinase method, which has an interassay

CV of 1.9% at a glucose level of 4.8
mmol/l. HbA1c was measured by HPLC
using a spherical cation exchange gel,
which has an interassay CV of 2% at an
HbA1c level of 6%. HbA1c results from our

laboratory (Institute of Medical and Vet-
erinary Science) were referenced to the

National Glycohemoglobin Standardisa-
tion Program. HbA1c was also measured

using the DCA2000 (Bayer Diagnostics),

a portable device that uses an immunoas-
say technique with a monoclonal anti-
body directed against a sequence of the

HbA1c molecule (19). A result is available
within 6 min of testing, with a CV of
2.2%.
Statistical analysis
Results are presented as means SD. The
receiver operating characteristic (ROC)
was used to describe the ability of HbA1c

(HPLC or DCA2000) and FPG to deter-
mine the presence or absence of type 2

diabetes as defined by the OGTT. The
ROC describes the diagnostic properties

of a test by plotting sensitivity as a func-
tion of 1-specificity (20). Sensitivity is the

fraction of individuals at or above the
HbA1c cutoff point who have diabetes,

whereas specificity is the fraction of indi-
viduals with an HbA1c level below the cut-
off point who do not have diabetes. The

area under the ROC curve represents the

probability that a subject chosen at ran-
dom from the group with the outcome of

interest (type 2 diabetes) had a higher
value than a subject without. Wald 2

analysis was used to compare the respec-
tive areas under the curve for the different

diabetic screening tests. The relationship
between HbA1c as measured by HPLC
and using the DCA2000 was determined
using linear regression.
Log-binomial regression was used to
determine the risk ratios (and 95% CIs)
for the presence of ischemic heart disease

for each SD increase in HbA1c, as mea-
sured by either HPLC or using the

DCA2000 method and the FPG. A risk of
1 was arbitrarily assigned to a cutoff 2 SD

below the mean for each of the aforemen-
tioned measurements, and risk ratios

were then determined for higher levels.
The risk ratio was also calculated for each
parameter after adjusting for the presence

of the other stated risk factors. The repro-
ducibility of measurements of FPG, 2-h

glucose, and HbA1c by each method was
calculated for the 41 subjects, who were
tested twice, and the intrasubject CV was
determined (15).
RESULTS — A total of 505 subjects
aged 19–88 years (mean age 53.8 years)
were studied. There were 294 (58.2%)
women and 211 (41.8%) men. Using the
Australian Diabetes Society and WHO
criteria, the incidence of type 2 diabetes

was 10.7% (54 subjects) and the inci-
dence of IGT was 24.4% (123 subjects).

Using the ADA criteria, the incidence of
type 2 diabetes was 4.0% (20 subjects)
and the incidence of IFG was 7.1% (36
subjects).
Subjects were divided according to

the presence or absence of diabetes ac-
cording to OGTT criteria. Nondiabetic

subjects had a mean HbA1c (HPLC) of
5.2% (range 3.5– 6.6), a mean HbA1c
(DCA2000) of 5.5% (4–6.9), and a mean

FPG of 5.1 mmol/l (3–6.7). Diabetic sub-
jects had a mean HbA1c (HPLC) of 6.5%

(4.7–12.2), a mean HbA1c (DCA2000) of
7.0% (5–13.1), and a mean FPG of 7.4

mmol/l (4.7–15.7). There was a good cor-
relation between the HbA1c values ob-
tained by HPLC and DCA2000 (R2

0.876). The regression data for HbA1c by

DCA2000 versus HPLC reveals a small in-
Macrovascular risk and diagnostic criteria for type 2 diabetes

486 DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2003

tercept of 0.2 but no change in slope.
Accordingly, there is a constant bias of
0.2 but no evidence of relative bias.

Based on our ROC curves, our cutoff cri-
teria showed higher values for DCA2000

than HPLC.
Based on an ROC analysis, the areas
under the curve (predictive values) of
HbA1c as measured by HPLC and
DCA2000 for detecting type 2 diabetes,
compared with OGTT, were 0.893 and
0.911, respectively (2 0.53, df 2,
P 0.77) (Fig. 1).
When measured by HPLC, HbA1c
5.7% predicted type 2 diabetes with a
sensitivity of 80.0% and a specificity of
86.3%. HbA1c levels 4.7 and 6.2%
have almost 100% accuracy for predicting

the absence and presence of type 2 diabe-
tes, respectively (Table 1).

When measured by DCA2000, HbA1c
6.2% (sensitivity 72.2%, specificity
94.7%) was the best predictor of diabetes,

and HbA1c levels 5.0 and 6.8% pre-
dict the absence or presence of diabetes,

respectively, with almost 100% certainty
(Table 1). Using FPG, the area under the
ROC curve was 0.9065. FPG 6.0
mmol/l (sensitivity 74.1%, specificity
94.5%) was the best predictor of type 2
diabetes as defined by OGTT. FPG levels
4.7 and 6.4 mmol/l had almost 100%
accuracy for detecting the absence or
presence of type 2 diabetes.
Cardiovascular risk
The mean SD for HbA1c by HPLC,
HbA1c by DCA2000, and FPG were 5.3
0.74%, 5.6 0.84%, and 5.3 1.2
mmol/l, respectively. The risk ratio (95%
CI) for each SD change in HbA1c by
HPLC, HbA1c by DCA2000, and FPG
were 1.3 (1.1–1.5; P 0.0002), 1.24
(1.1–1.4; P 0.0038), and 1.26 (1.1–

1.4; P 0.0001), respectively. The rela-
tive cardiovascular risks associated with

different cutoffs of HbA1c (HPLC and
DCA2000) and FPG are shown in Table 1.

Neither HbA1c (HPLC or DCA2000) nor
FPG remained independent risk factors

for cardiovascular disease after adjust-
ment for age, waist circumference, hyper-
tension, and high cholesterol. After

adjustment for these risk factors, the rel-
ative risk of ischemic heart disease for

HbA1c by HPLC, HbA1c by DCA2000, or
FPG was 1.1 (0.9–1.4; P 0.22), 1.1
(0.8–1.4; P 0.64), and 1.2 (0.99–1.4;
P 0.059). Only age and high cholesterol

were independent risk factors for cardio-
vascular disease. For example, when ana-
lyzed with HbA1c (HPLC) the relative risk

of ischemic heart disease for age was 2.0

(1.4–2.9; P 0.0002) and for high cho-
lesterol was 2.2 (1.2–3.9; P 0.01). The

ischemic heart disease risk for waist cir-
cumference was 1.2 (0.9–1.6; P 0.18)

and for hypertension was 1.7 (0.8–3.3;
P 0.14).
Reproducibility
There was a within-subject CV of 2.2% for
HbA1c by HPLC, 2.7% for HbA1c by
DCA2000, 4.9% for FPG, and 16.0% for
120-min plasma glucose after a 75-g oral
glucose load.
CONCLUSIONS — These results
show that FPG and HbA1c (by either

method) will diagnose or exclude diabe-
tes with certainty in only a minority

(15%) of subjects when the OGTT, with
currently defined cutoffs, is used as the
gold standard. Although FPG and HbA1c
do not seem to be independent measures

of cardiovascular risk, there is a continu-
ous relationship between both of these

measures and cardiovascular risk. More-
over, data from the Diabetes Control and

Complications Trial (DCCT) (21) and

U.K. Prospective Diabetes Study (UK-
PDS) (22) demonstrate that there remains

a significant risk of microvascular disease
with HbA1c levels well below 8%, and
even at an HbA1c of 6%, there is a 75%

Figure 1—ROC curves comparing FPG (F), HbA1c by HPLC (Œ), and HbA1c by DCA2000 ()
as diagnostic indicators for diabetes.

Table 1—The sensitivity, specificity, and cardiovascular risk ratio at each cutoff of HbA1c (by HPLC), HbA1c (by DCA2000), and FPG
HbA1c by HPLC HbA1c by DCA2000 FPG (mmol/l)
HbA1c (%) Sen (%) Spec (%) CV HbA1c (%) Sen (%) Spec (%) CV FPG Sen (%) Spec (%) CV
3.9 100 0.22 1 4.0 100 0.2 1 3.0 100 0 1.0
4.7 100 10.0 1.3 5.0 100 11.1 1.3 4.7 100 23.1 1.4
5.6 85.2 80.5 1.8 5.8 85.2 77.8 1.6 5.6 79.6 85.8 1.7
6.2 42.6 99.1 2.3 6.8 42.6 99.6 2.1 6.4 59.3 99.1 2.0
6.8 22.2 100 2.8 7.3 20.4 100 2.4 7.7 31.5 100 2.5
Sen, sensitivity; Spec, specificity.

Jesudason and Associates

DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2003 487

increased risk of microvascular complica-
tions of type 2 diabetes. Gabir et al. (23)

have shown that retinopathy and ne-
phropathy increase at an FPG level of 6.0

mmol/l. Accordingly, we propose that
there is a rational basis for using either
FPG or HbA1c for purposes of screening

and assigning risk and, therefore, target-
ing the most appropriate group of indi-
viduals for further investigation and

intervention.
If an FPG level 7 mmol/l is used, the

incidence of type 2 diabetes is underesti-
mated, as compared with the OGTT

(1,8,9,24). Only 4.0% of our subjects
were diabetic using FPG based on the
ADA criteria, compared with 10.4% using

WHO criteria. The detection of type 2 di-
abetes has been reported by others to

halve when ADA as opposed to WHO cri-
teria are applied (1). Wahl et al. (1)

showed that at an FPG level of 6.38
mmol/l, the prevalence of diabetes by

ADA and 1985 WHO criteria were simi-
lar. In the DECODE study, the FPG level

that predicted a 2-h value of 11.1 mmol/l

was 6.4 mmol/l in men (25). Taken to-
gether, the data suggest that an FPG level

6.4 mmol/l is the most appropriate level
at which to diagnose type 2 diabetes and

only 40% (rather than 60%) of individ-
uals with type 2 diabetes would be

missed. Our study has also shown that
when the FPG level is 4.7 mmol/l, type
2 diabetes can be confidently excluded;
73% of all subjects had an FPG level
between 4.7 and 6.3 mmol/l, and 17%
of these individuals had an FPG level of
5.6 – 6.3 mmol/l. Of this latter group,
13.6% (12 of 88) were diabetic based on
an OGTT.
The relative cardiovascular risk was at
least 2 in the group with FPG 6.3
mmol/l and was 1.7–1.9 in those with an

FPG of 5.6–6.3 mmol/l. Therefore, al-
though an FPG of 5.6–6.3 mmol/l is as-
sociated with a low risk of microvascular

disease, there is a relatively high risk of

macrovascular disease. Aggressive treat-
ment of cardiovascular risk factors and at-
tention to lifestyle issues such as diet and

exercise are indicated. Moreover, we
would argue that lifestyle interventions to
prevent progression to type 2 diabetes
would be most appropriately targeted to
this group (26).

Our data also show that type 2 diabe-
tes is present at an HbA1c (HPLC) 6.2%,

and the detection rate is better than when
the ADA criteria are used. If an OGTT was

performed, however, 57% more of the in-
dividuals would have been diagnosed as

having type 2 diabetes. An HbA1c (HPLC)

4.7% excludes type 2 diabetes. How-
ever, 86% of all subjects had an HbA1c

between 4.7 and 6.1%; 21% of these sub-
jects had an HbA1c of 5.6–6.1%. Of the

latter subjects, 21.5% (23 of 107) were
diabetic on the OGTT.
We did not observe an independent

relationship between HbA1c and cardio-
vascular risk, although such an associa-
tion has previously been reported in a

larger study (20). The relative cardiovas-
cular risk in our group with an HbA1c

(HPLC) 6.1% was at least 2.3, and in
those with an HbA1c of 5.6–6.1%, the
relative cardiovascular risk was 1.8–2.2.
As with FPG, the risk of microvascular
disease is low with an HbA1c 6.1%, but
a relatively high risk of macrovascular

disease remains and accordingly aggres-
sive risk factor reduction is warranted.

The situation with HbA1c as measured us-
ing DCA2000 is analogous, although

the cutoffs were higher. Type 2 diabetes
is diagnosed at HbA1c 6.8%, whereas

HbA1c 5.0% excludes diabetes confi-
dently. The high cardiovascular risk

group were those subjects with an HbA1c
of 5.8–6.7%.
Wiener et al. (12) found that HbA1c

6.2% had 100% specificity for diagnos-
ing type 2 diabetes. They argued that

HbA1c should be used in screening to re-
duce the number of OGTTs performed

but that the OGTT should continue to be
used to avoid missing subjects with type 2

diabetes. Interestingly, they acknowl-
edged that if there were a relationship be-
tween HbA1c and complications of type 2

diabetes, then it could replace the OGTT.
Davidson et al. (27) suggested measuring
HbA1c to determine whether diabetes was
present in subjects with borderline FPG
(6.1–7.7 mmol/l) to avoid inappropriate
diagnosis of type 2 diabetes. In the study
by Perry et al. (28), an HbA1c 6.1% was
considered specific for type 2 diabetes
and was used to confirm the presence or
absence of the disease in subjects with an
FPG level between 5.5 and 8 mmol/l.
We have shown that a reduction in
the FPG level at which type 2 diabetes is

diagnosed will lead to a comparable in-
crease in the detection rate of diabetes. If

we combined FPG and HbA1c, we de-
tected an additional two subjects with di-
abetes (4%). We would argue, however,

that intervention is more logically based
on the risk of complications or associated
diseases rather than a comparison with
arbitrary cutoffs on the OGTT. In a large
meta-analysis, HbA1c was proposed as a

means to identify diabetic subjects requir-
ing pharmacological intervention (3).

There is a relationship between HbA1c

and FPG and the risk of both microvascu-
lar (4) and macrovascular disease (1,20),

although the increased risk of macrovas-
cular disease occurs at lower glycemic

thresholds.
In contrast to other studies that have
evaluated the use of glucose and HbA1c as

screening tests, we studied smaller num-
bers of subjects prospectively rather than

derived data retrospectively but obtained
consistent results. Moreover, although we

Figure 2—An algorithm for diagnosing type 2 diabetes and assigning cardiovascular risk using FPG or HbA1c by HPLC.
Macrovascular risk and diagnostic criteria for type 2 diabetes

488 DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2003

used self-reported data to evaluate cardio-
vascular risk, our data relating to cardio-
vascular risk are consistent with the

results of other studies demonstrating an

association between cardiovascular dis-
ease and increasing FPG and HbA1c, even

in the nondiabetic range (18,20,29).
The OGTT is a time-consuming,
poorly reproducible, inconvenient, and
expensive test that we would argue can
largely be avoided in favor of an HbA1c or
FPG, using lower diagnostic thresholds
and risk factor assessment to provide the
most rational approach to subsequent

management. We have proposed an algo-
rithm for how this may occur (Fig. 2).

Using this algorithm, whether with HbA1c
or with FPG, the population is divided
into four subsets. The first subset should
be considered diabetic because they are at

increased risk for cardiovascular and mi-
crovascular complications; these subjects

should receive standard diabetic assess-
ment (e.g., for retinopathy, neuropathy,

and nephropathy) as well as for cardio-
vascular disease. The second subset is at

high cardiovascular risk and at greatest
risk for future progression to diabetes.

Clinicians should target the cardiovascu-
lar risk factors of these subjects and screen

for diabetes with HbA1c or FPG every
12–24 months, depending on previous

results. The third subset has a cardiovas-
cular risk above baseline although lower

than the first two subsets. In the absence
of any other indications, these subjects do
not require any specific intervention but
could receive general dietary and lifestyle
advice as well as appropriate follow-up.
The fourth subset is at lowest risk and can

be reassured, although it is always appro-
priate to encourage healthy behaviors.

The algorithm in Fig. 2 illustrates this ap-
proach using FPG and HbA1c (HPLC).

Portable devices for measuring HbA1c
are suitable for transport to community

settings and, accordingly, provide the po-
tential for mass screening. Fasting is not

required and there is no need for further

HbA1c measurement in those subse-
quently determined to have type 2 diabe-
tes. In situations in which fasting blood

glucose can be readily obtained, a cutoff
of 6.4 mmol/l results in diagnosis of more
diabetic subjects than HbA1c as well as
identification of those at significant risk

for cardiovascular disease, in whom max-
imal intervention, whether pharmacolog-
ical or nonpharmacological, should be

targeted.

Acknowledgments— This research was sup-
ported by the Royal Adelaide Hospital, the In-
stitute of Medical and Veterinary Science, and

a grant from Bayer Diagnostics.
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