International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes

International Expert Committee Report on
the Role of the A1C Assay in the Diagnosis
of Diabetes
THE INTERNATIONAL EXPERT COMMITTEE*
An International Expert Committee with
members appointed by the American Diabetes
Association, the European Association for
the Study of Diabetes, and the International
Diabetes Federation was convened in 2008 to
consider the current and future means of diagnosing
diabetes in nonpregnant individuals.
The report of the International Expert
Committee represents the consensus view of
its members and not necessarily the view of
the organizations that appointed them. The
International Expert Committee hopes that
its report will serve as a stimulus to the international
community and professional organizations
to consider the use of the A1C assay
for the diagnosis of diabetes.
Diabetes is a disease characterized
by abnormal metabolism, most
notably hyperglycemia, and an
associated heightened risk for relatively
specific long-term complications affecting
the eyes, kidney, and nervous
system. Although diabetes also substantially
increases the risk for cardiovascular
disease, cardiovascular disease is
not specific to diabetes and the risk for
cardiovascular disease has not been incorporated
into previous definitions or
classifications of diabetes or of subdiabetic
hyperglycemia.
BACKGROUND
Diagnosing diabetes based on the
distribution of glucose levels
Historically, the measurement of glucose
has been the means of diagnosing diabetes.
Type 1 diabetes has a sufficiently
characteristic clinical onset, with relatively
acute, extreme elevations in glucose
concentrations accompanied by symptoms,
such that specific blood glucose cut
points are not required for diagnosis in
most clinical settings. On the other hand,
type 2 diabetes has a more gradual onset,
with slowly rising glucose levels over
time, and its diagnosis has required specified
glucose values to distinguish pathologic
glucose concentrations from the
distribution of glucose concentrations in
the nondiabetic population. Virtually every
scheme for the classification and diagnosis
of diabetes in modern times has
relied on the measurement of plasma (or
blood or serum) glucose concentrations
in timed samples, such as fasting glucose;
in casual samples independent of prandial
status; or after a standardized metabolic
stress test, such as the 75-g oral glucose
tolerance test (OGTT).
Early attempts to standardize the definition
of diabetes relied on the OGTT,
but the performance and interpretation of
the test were inconsistent and the number
of subjects studied to define abnormal
values was very small (1– 6). Studies in
the high-risk Pima Indian population that
demonstrated a bimodal distribution of
glucose levels following the OGTT (7,8)
helped establish the 2-h value as the diagnostic
value of choice, even though most
populations had a unimodal distribution
of glucose levels (9). Of note, a bimodal
distribution was also seen in the fasting
glucose samples in the Pimas and other
high-risk populations (10,11). However,
a discrete fasting plasma glucose (FPG) or
2-h plasma glucose (2HPG) level that separated
the bimodal distributions in the Pimas
was difficult to identify, with
potential FPG and 2HPG cut points ranging
from 120 to 160 mg/dl (6.7– 8.9
mmol/l) and from 200 to 250 mg/dl
(11.1–13.9 mmol/l), respectively.
In 1979, the National Diabetes Data
Group (NDDG) provided the diagnostic
criteria that would serve as the blueprint
for nearly two decades (12). The NDDG
relied on distributions of glucose levels,
rather than on the relationship of glucose
levels with complications, to diagnose diabetes
despite emerging evidence that the
microvascular complications of diabetes
were associated with a higher range of
fasting and OGTT glucose values (11,13–
15). The diagnostic glucose values chosen
were based on their association with decompensation
to “overt” or symptomatic
diabetes.
When selecting the threshold glucose
values, the NDDG acknowledged that
“there is no clear division between diabetics
and nondiabetics in the FPG concentration
or their response to an oral glucose
load,” and consequently, “an arbitrary decision
has been made as to what level justifies
the diagnosis of diabetes.” The
diagnosis of diabetes was made when 1)
classic symptoms were present; 2) the venous
FPG was 140 mg/dl ( 7.8 mmol/
l); or 3) after a 75-g glucose load, the
venous 2HPG and levels from an earlier
sample before 2 h were 200 mg/dl
( 11.1 mmol/l). An intermediate group
was classified as having “impaired glucose
tolerance” (IGT) with FPG 140 mg/dl
(7.8 mmol/l) and a 2HPG value between
140 and 200 mg/dl (7.8 –11.1 mmol/l).
IGT was identified on the basis of its relatively
higher risk of progression to diabetes
compared with that of “normal”
glucose tolerance, low frequency of “diabetic
symptoms,” high probability of reverting
to normal glucose tolerance or
continuing to have IGT, and rarity of
“clinically significant” microvascular disease.
The NDDG recommendations were
also promulgated by the contemporaneous
report of the World Health Organization
(WHO) (16).
Diagnosing diabetes based on the
relationship between glucose levels
and long-term complications
In 1997, the Expert Committee on the
Diagnosis and Classification of Diabetes
Mellitus (17) reexamined the basis for diagnosing
diabetes. This committee made
two seminal contributions: First, they refocused
attention on the relationship be-
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Corresponding author: David M. Nathan, dnathan@partners.org.
*A list of members of the International Expert Committee can be found in the APPENDIX.
DOI: 10.2337/dc09-9033
© 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
See accompanying editorial on p. 1344.
R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t s
A D A W O R K G R O U P R E P O R T
DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009 1327
tween glucose levels and the presence of
long-term complications as the basis for
the diagnosis of diabetes. Second, they
summarized data negating the widespread
hypothesis that the 2HPG was the
gold-standard test for diagnosing diabetes.
The committee examined data from
three cross-sectional epidemiological
studies that included an Egyptian
population (n 1,018), Pima Indians
(n 960), and the U.S. National Health
and Nutrition Examination Survey
(NHANES) population (n 2,821). Each
assessed retinopathy with fundus photography
or direct ophthalmoscopy and
measured glycemia as FPG, 2HPG, and
A1C. These studies demonstrated glycemic
levels below which there was little
prevalent retinopathy and above which
the prevalence of retinopathy increased in
an apparently linear fashion (Fig. 1).
When the prevalence of retinopathy was
expressed by deciles of glycemia for each
of the three measures, the deciles at which
retinopathy began to increase were the
same for each measure within each population.
Moreover, the glycemic values
above which retinopathy increased were
similar among the populations. These
data showed a clear relationship between
glycemia and the risk for retinopathy that
would supplant the previous notion of
risk for progression to overt, symptomatic
diabetes as the basis for diagnosing
diabetes.
In comparing the relationship between
FPG and 2HPG values and retinopathy,
it was apparent that the previous
FPG cut point of 140 mg/dl (7.8
mmol/l) was substantially above the glucose
level at which the prevalence of retinopathy
began to increase. As a result,
the committee recommended that the
FPG cut point be lowered to 126 mg/dl
(7.0 mmol/l) so that this cut point would
represent a degree of hyperglycemia that
was “similar” to the 2HPG value and diagnosis
with either measure would result
in a similar prevalence of diabetes in the
population. The 1997 committee report
acknowledged that even at the lower FPG
cut point, the FPG and OGTT (2HPG)
were not perfectly concordant. An individual
could have diabetes using one test
but not the other. This discrepancy has
been confirmed in numerous subsequent
reports and may be due, in part, to the fact
that although both tests are measures of
glycemia, they reflect different physiological
measures of acute glucose metabolism
(18). The debate regarding the relative
roles of FPG and 2HPG in the diagnosis of
diabetes in the nonpregnant adult has
continued (19 –21).
The 1997 report also recommended
that the FPG level, rather than the 2HPG,
be the preferred test to diagnose diabetes
because it was more convenient for patients
and less costly and time consuming
and the repeat-test reproducibility was
superior (17). In addition, the committee
introduced the term “impaired fasting
glucose” (IFG) to differentiate the metabolic
state between a normal state (FPG
110 mg/dl or 6.1 mmol/l) and diabetes
( 126 mg/dl or 7.0 mmol/l) when
the FPG test was used. If an OGTT was
performed, the intermediate glycemic
state continued to be called IGT, with the
2HPG (between 140 and 200 mg/dl [7.8
and 11.1 mmol/l]) the same as that as in
the NDDG report. A WHO consultation
(22) adopted most of the above recommendations
except they concluded that,
Figure 1—Prevalence of retinopathy by deciles of the distribution of FPG, 2HPG, and A1C in
Pima Indians (A), Egyptians (B), and 40- to 74-year-old participants in NHANES III (C). Adapted
with permission from ref. 17.
Role of the A1C assay in the diagnosis of diabetes
1328 DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009
whenever feasible, individuals with IFG
should be given an OGTT to exclude the
presence of diabetes that would otherwise
be missed and that the OGTT should remain
the “gold standard.” A 2003 follow-
up report from the expert committee
refined the fasting glucose value range for
IFG from 110 but 126 mg/dl to 100
but 126 mg/dl ( 6.1 but 7.0 mmol/l
to 5.6 but 7.0 mmol/l) to make it
more comparable with the IGT value
(21). The WHO did not change its previous
recommendations (23).
CAN THE A1C TEST BE USED
TO DIAGNOSE DIABETES?— If
chronic hyperglycemia sufficient to cause
diabetes-specific complications is the
hallmark of diabetes, common sense
would dictate that laboratory measures
that capture long-term glycemic exposure
should provide a better marker for the
presence and severity of the disease than
single measures of glucose concentration.
Observational studies that have assessed
glycemia with measures that capture
longer-term exposure (i.e., A1C) or with
single or longitudinal measurements of
glucose levels have consistently demonstrated
a strong correlation between retinopathy
and A1C (24 –26) but a less
consistent relationship with fasting glucose
levels (27). In one study that measured
both FPG and A1C, there was a
stronger correlation between A1C and
retinopathy than between fasting glucose
levels and retinopathy (25). The correlation
between A1C levels and complications
has also been shown in the setting of
controlled clinical trials in type 1 (28) and
type 2 (29) diabetes, and these findings
have been used to establish the widely accepted
A1C treatment goals for diabetes
care (30).
All of these observations suggest that
a reliable measure of chronic glycemic
levels such as A1C, which captures the
degree of glucose exposure over time
(31,32) and which is related more intimately
to the risk of complications than
single or episodic measures of glucose levels,
may serve as a better biochemical
marker of diabetes and should be considered
a diagnostic tool. Although the 1997
expert committee report considered this
option, it recommended against using
A1C values for diagnosis in part because
of the lack of assay standardization (17).
The 2003 follow-up report noted that,
while the National Glycohemoglobin
Standardization Program (33) had succeeded
in standardizing the vast majority
of assays used in the U.S., the use of A1C
for diagnosis still had “disadvantages,”
and it reaffirmed the previous recommendation
that A1C not be used to diagnose
diabetes (21).
An updated examination of the laboratory
measurements of glucose and A1C
by the current International Expert Committee
indicates that with advances in instrumentation
and standardization, the
accuracy and precision of A1C assays at
least match those of glucose assays. The
measurement of glucose itself is less accurate
and precise than most clinicians realize
(34). A recent analysis of the performance
of a variety of clinical laboratory
instruments and methods that measure
glucose revealed that 41% of instruments
have a significant bias from the reference
method that would result in potential
misclassification of 12% of patients
(35). There are also potential preanalytic
errors owing to sample handling and
the well-recognized lability of glucose in
the collection tube at room temperature
(36,37). Even when whole blood samples
are collected in sodium fluoride to inhibit
in vitro glycolysis, storage at room temperature
for as little as 1 to 4 h before
analysis may result in decreases in glucose
levels by 3–10 mg/dl in nondiabetic individuals
(36 –39).
By contrast, A1C values are relatively
stable after collection (40), and the recent
introduction of a new reference method
to calibrate all A1C assay instruments
should further improve A1C assay standardization
in most of the world (41– 43).
In addition, between- and within-subject
coefficients of variation have been shown
to be substantially lower for A1C than for
glucose measurements (44). The variability
of A1C values is also considerably less
than that of FPG levels, with day-to-day
within-person variance of 2% for A1C
but 12–15% for FPG (45– 47). The convenience
for the patient and ease of sample
collection for A1C testing (which can
be obtained at any time, requires no patient
preparation, and is relatively stable
at room temperature) compared with that
of FPG testing (which requires a timed
sample after at least an 8-h fast and which
is unstable at room temperature) support
using the A1C assay to diagnose diabetes.
In summary, compared with the measurement
of glucose, the A1C assay is at
least as good at defining the level of hyperglycemia
at which retinopathy prevalence
increases; has appreciably superior
technical attributes, including less preanalytic
instability and less biologic variability;
and is more clinically convenient.
A1C is a more stable biological index than
FPG, as would be expected with a measure
of chronic glycemia levels compared
with glucose concentrations that are
known to fluctuate within and between
days (Table 1).
WHAT IS THE MOST
APPROPRIATE A1C CUT
POINT FOR THE DIAGNOSIS
OF DIABETES?— As shown in the
1997 committee report, the prevalence of
retinopathy increases substantially at
A1C values starting between 6.0 and
7.0% (17) (Fig. 1). A recent analysis derived
from DETECT-2 (48) and including
the 3 that were included in the 1997
report examined the association between
A1C and retinopathy, objectively
assessed and graded by fundus photography
(S. Colagiuri, personal communication).
This analysis included 28,000
subjects from nine countries and showed
that the glycemic level at which the prevalence
of “any” retinopathy begins to rise
above background levels (any retinopathy
includes minor changes that can be due to
other conditions, such as hypertension),
and for the more diabetes-specific “moderate”
retinopathy, was 6.5% when the
data were examined in 0.5% increments
(Fig. 2). Among the 20,000 subjects
who had A1C values 6.5%, “moderate”
retinopathy was virtually nonexistent.
The receiver operating characteristic
curve analysis of the same data indicated
that the optimal cut point for detecting at
least moderate retinopathy was an A1C of
6.5%.
In summary, the large volume of data
from diverse populations has now established
an A1C level associated with an increase
in the prevalence of moderate