The role of HbA1c in the diagnosis of

diabetes mellitus in Australia

Michael C dEmden, Jonathan E Shaw, Peter G Colman, Stephen Colagiuri, Stephen M Twigg, Graham R D Jones,
Ian Goodall, Hans G Schneider and N Wah Cheung
Med J Aust 2012; 197 (4): 220-221.
doi:
10.5694/mja12.10988
Download PDF

Summary

For many years, the diagnosis of diabetes has been made through the laboratorybased measurement of fasting or random blood glucose levels, or using the oral
glucose tolerance test.

A glycated haemoglobin (HbA1c) level 6.5% (48 mmol/mol) is now also

acceptable for diagnosing diabetes.

Caution is needed in interpreting HbA1c test results in the presence of conditions

affecting red blood cells or their survival time, such as haemoglobinopathies or
anaemia.

A PDF of the abridged version of this article from the print issue can be downloaded
here.
Diabetes mellitus is a major health problem for Australia. It is associated with the
development of a variety of complications that have a significant impact on morbidity and
mortality. The Australian Diabetes, Obesity and Lifestyle (AusDiab) Study found an overall
diabetes prevalence of 7.4% in a national sample of people aged 25 years or older, with
50% of cases being previously undiagnosed.1 The long-term complications of type 1 and
type 2 diabetes include the microvascular complications of retinopathy, nephropathy and
neuropathy, but the major health problem in type 2 diabetes is the increased risk of
macrovascular complications, such as coronary artery disease and peripheral artery disease.
It is important to establish the diagnosis of diabetes early in its development, as effective
management of the disease has been shown in the United Kingdom Prospective Diabetes
Study (UKPDS) to significantly reduce the risk of developing complications. 2 Furthermore,
long-term follow-up of participants during the observational phase of the UKPDS
demonstrated that more effective glycaemic control from the time of diagnosis in people
with type 2 diabetes conferred a long-term legacy benefit that persisted even though
glycaemic control may deteriorate over time.3 This observation implies that strategies that

facilitate early detection of diabetes should result in improved outcomes, with major longterm health and cost benefits for Australia.
Traditionally, we have relied on measurement of blood glucose parameters to make the
diagnosis of diabetes.4,5 The cut-offs used to establish the diagnosis defined elevated blood
glucose levels on the basis of an increased risk of diabetes-related complications. Although
there is a clear and highly significant relationship between blood glucose levels and
cardiovascular disease, there is no threshold level at which cardiovascular disease will
occur.6 However, microvascular complications, and in particular retinopathy, show a much
clearer threshold of glycaemia above which they occur and where glucose-lowering therapy
is clearly effective in preventing them.2 Thus, the diagnosis of diabetes has been based on
blood glucose threshold levels associated with the presence of retinopathy.5
However, measuring blood glucose levels is associated with methodological, procedural and
practical problems. Day-to-day variation of blood glucose levels is considerable, the
concentration ex vivo falls quickly even when the blood sample is collected in a fluorideoxalate tube, and interlaboratory levels can vary by at least 14% in a third of cases. 7,8 The
oral glucose tolerance test (OGTT) requires proper pretest preparation, including an
appropriate diet for 3 days before the test and a satisfactory period of overnight fasting. The
OGTT is also time-consuming, taking at least 2 hours. The glucose load is poorly tolerated
by a significant number of people, with nausea, vomiting, delayed gastric emptying and
issues of venous access all potentially contributing to an invalid test result. The test often
needs to be repeated and has poor patient compliance. A recent study from South Australia
showed that only 27% of patients identified on admission to hospital as potentially having
diabetes presented for a diagnostic OGTT despite consenting to undertake the test. 9
The use of glycated haemoglobin (HbA1c) measurement as an alternative diagnostic test
overcomes many of these concerns. The HbA1c test is attractive as it measures chronic
glycaemia, rather than instantaneous blood glucose levels. HbA 1c has been used as an
objective marker of average glycaemic control for many years, has an accepted place in the
monitoring of patients with diabetes, and is relied on for significant management decisions,
such as initiation of insulin therapy. The strength of its relationship with diabetes-related
complications was demonstrated in an analysis of the combined data from eight studies
conducted between 1988 and 2004, which reported that HbA1c levels were at least as
strongly related to the presence of diabetic retinopathy as were blood glucose levels. 10 It is
also strongly associated with macrovascular outcomes and mortality.11-13 Practically,
HbA1c measurement provides significant advantages over blood glucose measurement for
diagnosis of diabetes. It can be performed at any time of the day, does not require special
pretest preparation such as a diet or fasting, and is stable when collected in the appropriate
specimen tube.

HbA1c has recently been endorsed as a diagnostic test for diabetes by the World Health
Organization, the International Diabetes Federation and the American Diabetes
Association.14,15 The Australian Diabetes Society established an expert committee in 2011,
including invited representatives of the Royal College of Pathologists of Australasia (RCPA)
and the Australasian Association of Clinical Biochemists (AACB), to review the available
evidence and provide this position statement concerning the role of HbA 1c in the diagnostic
pathway. Additionally, the committee sought to ensure that its recommendations otherwise
concur with recently published National Health and Medical Research Council (NHMRC)
guidelines for the detection and diagnosis of type 2 diabetes.16A summary of the
committees recommendations is shown in the Box.
The committee concluded that HbA1c can have an important place in the diagnostic pathway
and can be used to establish the diagnosis of diabetes. An HbA 1c level 6.5%
(48 mmol/mol) is recommended as the cut-off point for diagnosing diabetes. In an
asymptomatic patient with a positive test result, the test should be repeated to confirm the
diagnosis. The use of HbA1c measurement will simplify the diagnostic process and may lead
to earlier diagnosis of more patients with diabetes. However, HbA1c should not be used as a
general screening test for diabetes; initial screening should be on the basis of the Australian
Type 2 Diabetes Risk Assessment Tool (AUSDRISK) score, as recommended in the NHMRC
guidelines.16 Furthermore, it must be noted that the HbA1c assay is not currently funded by
Medicare as a diagnostic or screening test for diabetes, although funding for this purpose is
being sought. Medicare payments for HbA1c testing currently require evidence that the
patient has diabetes, such as a statement to this effect on the request form.
There are some important caveats. If used as a diagnostic test, the HbA 1cassay needs to be
reliable and consistent across Australia. There have been problems in the past with
HbA1c test results varying considerably between laboratories. In the United States, the
National Glycohemoglobin Standardization Program (NGSP) has progressively driven
improvements in assays,18 resulting in better-quality results around the world. The
variability of HbA1c values within Australia is now acceptably low. In a recent Australian
study, whole blood samples were sent to more than 200 laboratories, and more than 90% of
HbA1c results fell within 6% of the median.19 Although the variation between laboratories
remains even lower for blood glucose assays, when the pretest issues (eg, day-to-day
variation in glucose levels, the fall in plasma glucose levels after the sample has been taken)
are also considered, the HbA1c test performs at least as well as glucose testing. Further
improvements in standardisation of HbA1c measurements should be achieved following the
development of a national whole blood external quality control program by the RCPA Quality
Assurance Programs and the AACB.
When applying HbA1c testing for the diagnosis of diabetes, some medical conditions may
affect the test and cause falsely high or low readings. The tests accuracy is affected
principally by conditions that affect red blood cell survival time or non-enzymatic glycation of

haemoglobin. A reduced red blood cell survival time will lower the HbA 1c level and may lead
to a false negative result. Red blood cell survival time is reduced in any haemolytic anaemia,
and it can also be reduced in chronic renal failure, severe liver disease and anaemia of
chronic disease. Vitamin B12 and folic acid deficiencies may shorten red blood cell survival
time. A common clinical situation that shortens red blood cell survival time occurs when
patients undergo regular phlebotomy for medical indications (eg, haemochromatosis) or
because they are regular blood donors. Iron deficiency may also have an impact on red
blood cell survival and the HbA1c level. The congenital variants of the haemoglobin molecule
(haemoglobinopathies), which may be relatively common in certain ethnic communities (eg,
African, Mediterranean) in Australia, affect glycation to a variable amount, principally due to
interference with the laboratory measurement of HbA1c level. Many newer laboratory
methods are reducing this problem. The NGSP provides a summary of the effect of common
haemoglobinopathies on measurement of HbA1c levels using various methods
(http://www.ngsp.org/interf.asp). However, any inexplicably high or low HbA1c test result or
discrepancy between glucose and HbA1c levels should alert the medical practitioner to a
potential problem.
Simplistically, HbA1c may not be the appropriate test to confirm the diagnosis of diabetes in
patients with any significant chronic medical disease, any anaemia or any abnormality of red
blood cell structure.7,8,20If any of these conditions exist, the diagnosis should be based on
measures of blood glucose levels using existing criteria (fasting or random glucose level, and
OGTT). These issues will be addressed in another publication from the Australian Diabetes
Society, as will the place of HbA1c in the clinical pathways for diagnosing diabetes.

Box Recommendations regarding the use of glycated haemoglobin

(HbA1c) testing for the diagnosis of diabetes*

Measurement of HbA1c level can be used as a diagnostic test for diabetes if analysis
is performed in a facility producing acceptable performance in external quality
assurance, assays are standardised to criteria aligned to international reference
values, and if no conditions which preclude its accuracy are present. It is important
to note that HbA1c testing is not currently funded by Medicare for the purpose of
diagnosis of diabetes.

An HbA1c level of 6.5% (48 mmol/mol) is recommended as the cut-off point for
diagnosing diabetes.

An HbA1c level of < 6.5% (48 mmol/mol) does not negate a diagnosis of diabetes
based on elevated glucose parameters. The existing criteria based on fasting and
random glucose levels, and on the oral glucose tolerance test, remain valid, and
are the diagnostic tests of choice for gestational diabetes, type 1 diabetes and in
the presence of conditions that interfere with HbA1cmeasurement.

* Level of evidence according to the Grading of Recommendations Assessment,

Development and Evaluation (GRADE) system: moderate.17

HbA1c as a Diagnostic Test for Diabetes Mellitus Reviewing the Evidence

Chris Florkowski*
Author information Copyright and License information

This article has been cited by other articles in PMC.

Abstract
Go to:

Introduction
HbA1c is now formally endorsed in many countries as a diagnostic test for (type 2) diabetes as well as for
monitoring, although some debate still continues regarding its applicability for diagnosis.15 Pivotal to this
discussion is the evidence base upon which these recommendations have been made. In considering the
diagnosis of diabetes, we are primarily concerned with defining a disease state rather than establishing a
reference interval for health. In particular, the evidence base is focused on predicting a clinical outcome,
considered to be the pinnacle of the Stockholm Hierarchy applied to reference intervals and clinical decision
limits.6 In the case of diabetes, the major outcome of interest is the long-term microvascular complications for
which a large body of data has been accumulated, as discussed below. The debate surrounding the role of
HbA1c as a diagnostic test addresses the relative merits and disadvantages of glucose versus HbA1c and brings
into focus many pre-analytical, analytical and other biological considerations as well as factors such as cost and
accessibility.
Go to:

Background
Type 1 diabetes usually presents with symptoms and unequivocal hyperglycaemia, thus diagnosis is usually
uncomplicated. The onset of type 2 diabetes, however, is slower with a more gradual increase in glucose levels
over time. A continuum exists from health through to diabetes, from low risk through to high risk of
complications.
Effective management of the disease has been shown in the United Kingdom Prospective Diabetes Study
(UKPDS) to significantly reduce the risk of developing complications.7 Furthermore, long-term follow-up of
UKPDS participants demonstrated that more effective glycaemic control from the time of diagnosis in people
with type 2 diabetes conferred a long-term benefit that persisted even though glycaemic control may deteriorate
over time.8 This observation implies that earlier detection of diabetes should result in improved outcomes, with
major long-term health benefits.
Go to:

Glucose Based Criteria for the Diagnosis of Diabetes

Conventionally, blood glucose levels measured either in the fasting state or following a standard glucose load
have formed the basis for diagnosis of diabetes. Some populations with a high prevalence of diabetes, such as
the Pima Indians and the Micronesian population of Nauru, demonstrate a bimodal distribution of glucose
levels.9 Taking this into consideration, the intersect of these two curves has been used to provide an indication of
the level at which individuals should be classified as either having or not having diabetes. In 1979, on the basis
of these and other outcome data, the National Diabetes Data Group (NDDG) in the US and subsequently the
World Health Organization (WHO) Expert Committee on Diabetes Mellitus published recommendations for the
diagnosis of diabetes using both fasting and 2-hour plasma glucose measured during an oral glucose tolerance
test.10,11 It was recommended that diabetes be diagnosed when glucose levels were 7.8 mmol/L in the fasting
state or 11.1 mmol/L following a 75 g glucose load. An intermediate range, termed impaired glucose tolerance
(IGT), was defined by a post-load glucose between 7.8 mmol/L and 11.0 mmol/L.10,11 These criteria formed the
basis for the diagnosis of type 2 diabetes for nearly two decades. In 1997, an expert committee shifted the
emphasis away from the bimodal distribution to focus more on clinical outcomes. They updated the diagnostic
criteria based on the relationship between glycaemia, measured as fasting or 2-hour plasma glucose, and
prevalent retinopathy in three studies.12 These studies were conducted in Pima Indians, Egyptians and
participants from the National Health and Nutrition Examination Survey (NHANES) in the United States. It was
recommended that the fasting glucose cut-off be lowered to 7.0 mmol/L and that a new pre-diabetic category
be introduced, impaired fasting glycaemia (IFG), defined as a fasting glucose between 6.1 mmol/L and 6.9
mmol/L.12 No changes were made to the post-load glucose criteria. These criteria are still recommended by the
WHO.13
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The Case for HbA1c as a Diagnostic Test

Firstly, HbA1c gives an indication of chronic glycaemia rather than being a test of glycaemia at a single point in
time. It gives an integrated index of glycaemia over the entire 120-day lifespan of the red blood cell, but within
this period of 120 days, recent glycaemia has the largest influence on the HbA1c value, with 50% of
HbA1c formed in the month prior to sampling and 25% in the month before that.14 It therefore seems logical that
such a test would be appropriate in diagnosing a disease characterised by chronic hyperglycaemia and a gradual
progression to complications.
Secondly, it is a relatively convenient test, not requiring the patient to fast and only using a single blood sample.
This is an important consideration, in that it may enable improved uptake of testing and improved detection of
diabetes, given the large proportion of diabetes cases that go undiagnosed.15,16
For an oral glucose tolerance test (OGTT), more extensive pre-test preparation is required, including an
appropriate diet for 3 days before the test and a satisfactory period of overnight fasting. The OGTT is also timeconsuming, taking at least 2 hours. The glucose load is poorly tolerated by a significant number of people, with
nausea, vomiting, delayed gastric emptying and issues of venous access all potentially contributing to an invalid
test result. The test often needs to be repeated and has poor patient compliance. A recent study from South
Australia showed that only 27% of patients identified on admission to hospital as potentially having diabetes

presented for a diagnostic OGTT despite consenting to undertake the test.17HbA1c in contrast is not affected by
prandial status and has no diurnal rhythm, allowing measurement at any time of day.
Unlike plasma glucose, HbA1c shows minimal pre-analytical variability. It is very stable after collection with no
change in its concentration in the collection tube. Ideally when measuring plasma glucose, the venous blood
sample should be spun and plasma separated within minutes of taking the sample as red blood cells continue to
consume glucose at about 7% per hour in vitro, leading to a falsely low measured glucose.18Collection of the
sample into a container with a Antiglycolytic preservative (fluoride) is only partially effective.18 Ideally the
sample should also be placed in iced water and processed within 3060 minutes, although most laboratories do
not fulfil these rigorous sample handling requirements. HbA1c in contrast has high pre-analytical stability (one
week at 4 C).
Within-subject biological variation of HbA1c is in the order of 3.6%, compared with 5.7% for fasting plasma
glucose and 16.7% for the 2-hour post-OGTT value.19 Analytical precision for HbA1c now approaches that for
glucose, with intra- and between-laboratory analytic variability in the order of 2.5%.20 Standardisation of
HbA1c measurement is also better than for glucose.
Overall reproducibility of oral glucose tolerance testing is poor, in the order of 66% variability, which can result
in inappropriate labels being given to patients.21 Furthermore no attempt at weight adjusting the dose of glucose
is included in OGTT protocols so a 60 kg person given 75 g glucose receives twice the dose in mg/kg
compared to a 120 kg person. This in part explains the poor correlation of 2-hour post oral glucose levels with
significant prevalent diabetic retinopathy in patients with previously undiagnosed diabetes,22 and it is therefore
somewhat arbitrary that the 2-hour post glucose cut point for diabetes is currently set at 11.1 mmol/L.
Most importantly, with respect to prediction of clinical outcomes (the central tenet of the evidence base),
HbA1c has a similar relationship with prevalent diabetic retinopathy as that of both fasting and 2-hour plasma
glucose, as shown in the recent DETECT-2 analysis.22
This landmark study involved data pooling of nine studies from five countries, with 44623 participants aged
2079 y with gradable retinal photographs. The study examined the relationship between diabetes-specific
retinopathy (defined as moderate or more severe retinopathy) and three glycaemic measures: fasting plasma
glucose (n=41411), 2-hour post oral glucose load plasma glucose (n=21334), and glycated haemoglobin (HbA1c,
n=28010).22 It was found that both fasting plasma glucose and HbA1c have narrow threshold ranges within which
the prevalence of diabetes-specific retinopathy begins to increase significantly (Figure). The prevalence of
retinopathy was low with HbA1c <42 mmol/mol (<6.0%) but increased above this level, with an optimal
threshold of 46 mmol/mol (6.4%) calculated using receiver-operative characteristic curve analysis. These
findings suggest that HbA1c is at least as good at predicting microvascular complications as either fasting or 2hour plasma glucose and that the diagnostic threshold of 48 mmol/mol (6.5%) is appropriate.22 The
relationship between HbA1c and prevalent retinopathy is similar to that of plasma glucose, whether glucose and
HbA1c are plotted in deciles, in vigintiles or as continuous variables (Figure).22

Figure.
Prevalence of retinopathy for fasting plasma glucose (FPG), 2-h post oral glucose load plasma
glucose (2-h PG) and HbA1c, for any retinopathy and diabetes-specific retinopathy ( moderate
non-proliferative diabetic retinopathy) from DETECT-2. ...

Aside from any consideration of the relationship between HbA1c and microvascular complications, it should also
be noted that the relationship between glycaemic parameters (whether glucose or HbA1c) and cardiovascular
outcomes is different from that seen for microvascular disease. This also brings into question the validity of any
single chosen cut-off and whether risk prediction may be expressed in any other way. There is also a
relationship with cardiovascular outcomes associated with lower levels of HbA1c. In the EPIC-Norfolk study, a
prospective population study, cardiovascular disease events increased above HbA1c31 mmol/mol (5%) in both
men and women and independently of age, body mass index (BMI) and other factors.23 The relationship with
HbA1c is therefore different dependent upon the outcome of interest and it could be argued that it might be better
to assign a measure of glycaemia-attributable risk rather than an all or nothing diagnosis based upon an
arbitrary cut-off.
Go to:

Recommendations for HbA1c as a Diagnostic Test

The case for HbA1c for as a diagnostic test was put forward as early as the mid-1980s, but concerns regarding its
availability and poor assay standardisation prevented its uptake.24 It wasnt until 2009 that an international
expert committee recommended HbA1c be introduced into diagnostic criteria at a threshold level of 48
mmol/mol (6.5%).25 This recommendation was adopted by the American Diabetes Association (ADA) the
following year and more recently by the WHO.1,2
American Diabetes Association Recommendations

The ADA endorsed HbA1c as a diagnostic test for diabetes at a cut-off of 48 mmol/mol (6.5%) with the
provision that this be measured in a laboratory using a NGSP-certified assay aligned to the DCCT study, and
that in the absence of unequivocal hyperglycaemia the test should be repeated (Table 1).1 Individuals with an
HbA1c of 3946 mmol/mol (5.76.4%) are considered to be at increased risk for diabetes as well as
cardiovascular disease, and should be counselled about effective strategies, such as weight loss and physical
activity, to lower their risks.1

Table 1
Diagnostic criteria for diabetes; the American Diabetes Association (Ref. 1).

In formulating the WHO recommendations (Table 2), a process of consultation included experts in diabetology,
biochemistry, immunology, genetics, epidemiology and public health. The main question to be answered for the
update was agreed upon by the expert group: how does HbA1c perform in the diagnosis of type 2 diabetes based
on the detection and prediction of microvascular complications? Applying the principles of Evidence Based
Medicine, a search for existing systematic reviews in Embase did not identify any such review. Therefore, a
systematic review to answer this question was conducted by the Boden Institute of Obesity, Nutrition and
Exercise, The University of Sydney, Australia. The recommendation was drafted by the expert group following
the GRADE methodology, and the process outlined in the WHO Handbook for Guideline Development.26 The
decision process took into account the findings of the systematic review and the other advantages and
disadvantages of using HbA1c to diagnose diabetes. The recommendation, quality of evidence and strength of
the recommendation were discussed and consensus was reached. All the experts agreed on the recommendation.

Table 2
World Health Organization recommendations for HbA1c as a diagnostic test for diabetes (Ref. 2).
Australian Recommendations

The Australian Diabetes Society established an expert committee in 2011, including invited representatives of
the Royal College of Pathologists of Australasia (RCPA) and the Australasian Association of Clinical
Biochemists (AACB), to review the available evidence and provide a position statement concerning the role of
HbA1c in the diagnostic pathway. Additionally, the committee sought to ensure that its recommendations
otherwise concur with recently published National Health and Medical Research Council (NHMRC) guidelines
for the detection and diagnosis of type 2 diabetes.27 A summary of the committees recommendations is shown
in Table 3.3

Table 3
Australian recommendations for HbA1c as a diagnostic test for diabetes (Ref. 3).

A HbA1c level of 48 mmol/mol (6.5%) is recommended as the cut-off point for diagnosing diabetes. In an
asymptomatic patient with a positive test result, the test should be repeated to confirm the diagnosis. The use of
HbA1c measurement will simplify the diagnostic process and may lead to earlier diagnosis of more patients with
diabetes. However, HbA1c should not be used as a general screening test for diabetes; initial screening should be
on the basis of the Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK) score, as recommended in
the NHMRC guidelines.27 At the time of writing, the Australian recommendations, although formally endorsed,
are yet to receive funding support, although an application has been made.
New Zealand Recommendations

In New Zealand, HbA1c as a diagnostic test was formally endorsed by the New Zealand Society for the Study of
Diabetes (NZSSD) from 3 October 2011.4 This recommendation was coordinated with the adoption of
exclusively molar units for reporting HbA1c (following a two year period of dual reporting, like the United
Kingdom), with the diagnostic cut-off rounded up to 50 mmol/mol (6.7%), and with repeat testing on a
second occasion in asymptomatic individuals.28 Individuals with HbA1c in the range 4149 mmol/L are
categorised as having dysglycaemia or abnormal glucose tolerance, with the recommendation for re-testing in
612 months and also implementation of cardio-vascular risk management. Part of the NZSSD rationale for
rounding of HbA1c was to make the molar units more memorable, although in addition, to maximise the
specificity for the diagnosis of diabetes.4 It may be argued that sensitivity is being compromised by adoption of
HbA1c as a diagnostic test, and especially at a still higher level, and that cases of diabetes will be missed.
NZSSD would contend, however, that individuals with HbA1c close to the cut-off (4149 mmol/mol) will be retested in 612 months and will enter a lifestyle programme where cardiovascular risk factors will be
appropriately addressed. Although they will not acquire the diagnostic label of diabetes, nor enter an annual
programme of microvascular complications screening at that time, they are not really being missed. In
addition, although glucose-based criteria remain valid, the NZSSD recommendations (Table 4) strongly favour
HbA1c as the diagnostic test in preference to OGTT testing.4

Table 4

New Zealand recommendations for type 2 diabetes screening. (Reproduced from Ref.
permission from the New Zealand Society for the Study of Diabetes.)

with

The New Zealand position is therefore somewhat inconsistent with approaches adopted in other countries,
although the rationale and arguments in support of this variance have been well presented and the approach is
pragmatic and practical.4
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Cautions and Caveats Regarding HbA1c as a Diagnostic Test

There are some important caveats. If used as a diagnostic test, the HbA1c assay needs to be reliable and
consistent across different centres. There have been problems in the past with HbA1c results varying
considerably between laboratories. In a recent Australian study, whole blood samples were sent to more than
200 laboratories, and more than 90% of HbA1c results fell within 6% of the median.29 Further improvements in
standardisation of HbA1c measurements should be achieved following the development of a national whole
blood external quality control program by the RCPA Quality Assurance Programs and the AACB.29
The ADA recommended that Point-of-Care Testing (POCT) HbA1c assays are not sufficiently accurate at this
time to use for diagnostic purposes,1 a view endorsed by other recommendations.4 The WHO stipulated,
however, that the diagnosis should be made by the best technology available, avoiding blood glucose
monitoring meters and single-use HbA1c test kits (except where this is the only option available or where there is
a stringent quality assurance programme in place).2 Although not formally endorsed at the present time, it is
recognised that some POCT devices do perform satisfactorily with correct usage, and may be the only practical
option in remote rural settings.
When applying HbA1c testing for the diagnosis of diabetes, some medical conditions may affect the test and
cause falsely high or low readings (Table 5). The tests accuracy is affected principally by conditions that affect
red blood cell survival time or non-enzymatic glycation of haemoglobin.30 A reduced red blood cell survival
time will lower the HbA1c level and may lead to a false negative result. Red blood cell survival time is reduced
in any haemolytic anaemia, and it can also be reduced in chronic renal failure, severe liver disease and anaemia
of chronic disease. Vitamin B12 and folic acid deficiencies may also shorten red blood cell survival time. A
common clinical situation that shortens red blood cell survival time occurs when patients undergo regular
phlebotomy for medical indications (e.g. haemochromatosis). Iron deficiency may also have an impact on red
blood cell survival and increase the HbA1c level.31 The congenital variants of the haemoglobin molecule
(haemoglobinopathies), which may be relatively common in certain ethnic communities (e.g. African,
Mediterranean) affect the result to a variable amount, principally due to interference with the laboratory
measurement of HbA1c. Many newer laboratory methods have measures in place to reduce this problem. The
NGSP provides a summary of the effect of common haemoglobinopathies on measurement of HbA1c levels
using various methods.32 Any HbA1c result, however, that is not consistent with clinical expectations or the
results of self-monitored capillary blood glucose readings should be regarded with suspicion and should alert
the medical practitioner to a potential problem. Some methodologies for HbA1c measurement (such as boronate
affinity chromatography) are less susceptible to the effects of haemoglobinopathies and such methods may be
favoured for populations where a higher proportion of abnormal haemoglobins may be expected. Otherwise, it

is good to have access to HbA1c measurement by an alternative method when a potential haemoglobin variant is
suspected and to follow up with further investigations such as haemoglobin electrophoresis or mass
spectrometry.

Table 5
Arguments for and against the use of HbA 1c as a diagnostic test.

Simplistically, if a haemoglobin variant is suspected, then HbA1c is not an appropriate diagnostic test and
glucose based criteria should be preferred. HbA1c should also not be regarded as the appropriate test to confirm
the diagnosis of diabetes in patients with any significant chronic medical disease, any anaemia or any
abnormality of red blood cell structure. If any of these conditions exist, the diagnosis of diabetes should be
based on measures of blood glucose levels. It should also be recognised that HbA1c is more expensive than
plasma glucose testing and this may prohibit its use in many countries worldwide. Others, however, have argued
that its practical advantages may, indeed improve access to care in disadvantaged populations (Table 5).33
Go to:

Ethnic Variations in HbA1c

There is also evidence which indicates that HbA1c will detect a different population as having diabetes to that
identified by plasma glucose. For example, in the US, a number of reports have suggested that African
Americans have higher HbA1c than both Mexican Americans and non-Hispanic Whites.34 It may be that the
prevalence of conditions affecting erythrocyte turnover or genetic differences in the physiology of glycation
differ with ethnicity. Alternatively, it may be that HbA1c detects real differences in chronic glycaemia that are
not represented by the fasting and 2-hour plasma glucose levels of the OGTT. If the former explanation is true,
then HbA1c may not be appropriate for diagnosis or else it may be necessary to consider the use of ethnicspecific cut points for HbA1c both in the management and diagnosis of diabetes. Conversely, if the latter
explanation is true, it would argue in favour of using HbA1c to diagnose diabetes, as the observed elevations of
HbA1c are likely to be reflective of increased complication risk at the tissue level. This point also brings into
consideration the presumption that the OGTT is a gold standard for diagnosis which may not necessarily be the
case, and that HbA1c is a more valid marker of tissue glycation. It remains to be determined whether or not these
supposed ethnic differences in HbA1c are clinically consequential, although this is another factor that needs to be
taken into further consideration as we move forward.
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An Intermediate Position for HbA1c in Diagnosis

Another perspective emanates from the studies of Zhong Lu et al.35 who studied two populations: the clinical
population (MP), including all those referred to Melbourne Pathology Services for an OGTT who had a
concomitant HbA1c measured (n=2494) and a validation population from the population based AusDiab study
who also underwent OGTT and had HbA1c measured (n=6014).16 Among those with undiagnosed diabetes
(34.6%) by OGTT criteria in the MP population, HbA1c at the 2.5th percentile was 38 mmol/mol (5.6%) and at
the 97.5th percentile was 52 mmol/mol (6.9%). From these data, HbA1c 37 mmol/mol (5.5%) was chosen to
rule out diabetes and 53 mmol/mol (7.0%) to rule in diabetes. Applying these cut-offs to the AusDiab
population, HbA1c at 37 mmol/mol (5.5%) provided high negative predictive value (99%) and at 53 mmol/mol
(7.0%), 100% positive predictive value. By dropping the cut-off to 48 mmol/mol (6.5%), specificity remained at
99% with positive predictive value near 100%. Other authors, rather than accepting a single cutoff have
advocated for separate rule out and rule in criteria applying the same cut-offs suggested by the Melbourne
studies.36
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Conclusions
The case for HbA1c as a diagnostic test for diabetes has therefore been submitted to a very rigorous examination
based upon the principles of evidence based medicine. In particular, the evidence base is focused mainly on
predicting clinical outcomes (particularly microvascular complications) considered to be the pinnacle of the
Stockholm Hierarchy applied to reference intervals and clinical decision limits.6 In addition, many other factors
need to be taken into consideration, including pre-analytical, analytical and other biological parameters as well
as cost and accessibility. There are clear advantages for HbA1c over glucose (and in particular OGTT) as a
diagnostic test for diabetes, although with an important series of caveats that clinicians need to be aware of. As
always, there is need for educational resources to be widely available and for on-going dialogue between
clinicians and the laboratory.
Go to:

Footnotes
Competing Interests: None declared.

Go to:

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the diagnosis of diabetes in Australia. Med J Aust. 2012;197:2201. [PubMed]

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HbA1cunits for the diagnosis of Type 2 diabetes. N Z Med J. 2012;125:7080. [PubMed]
5. Kilpatrick ES, Winocour PH. ABCD position statement on haemoglobin A1c for the diagnosis of
diabetes. Pract Diab Int. 2010;27:30610.
6. Sikaris K. Application of the stockholm hierarchy to defining the quality of reference intervals
and clinical decision limits. Clin Biochem Rev. 2012;33:1418. [PMC free article] [PubMed]
7. UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with
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patients with type 2 diabetes (UKPDS 33) Lancet. 1998;352:83753. [PubMed]
8. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose
control in type 2 diabetes. N Engl J Med. 2008;359:157789. [PubMed]
9. Zimmet P, Whitehouse S. Bimodality of fasting and two-hour glucose tolerance distributions in
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categories of glucose intolerance. Diabetes. 1979;28:103957. [PubMed]
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12. Report of the Expert Committee on the Diagnosis and Classification of Diabetes
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Hyperglycemia: Report of a WHO/IDF Consultation. Geneva: WHO; 2006.
14. Tahara Y, Shima K. Kinetics of HbA1c, glycated albumin, and fructosamine and analysis of their
weight functions against preceding plasma glucose level. Diabetes Care. 1995;18:440
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prevalence of diabetes and impaired glucose tolerance: the Australian Diabetes, Obesity and
Lifestyle Study.Diabetes Care. 2002;25:82934. [PubMed]
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undiagnosed diabetes using glycated haemoglobin: an automated screening test in hospitalised
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Table 1
Diagnostic criteria for diabetes; the American Diabetes Association (Ref. 1).
1. HbA1c 48 mmol/mol (6.5%). The test should be performed in a laboratory using a method that is
NGSP certified and standardised to the DCCT assay. *
OR
2. FPG 7.0 mmol/L (126 mg/dL). Fasting is defined as no caloric intake for at least 8 h. *
OR
3. 2-h plasma glucose 11,1 mmol/L (200 mg/dL) during an OGTT. The test should be performed as
described by the World Health Organization, using a glucose load containing the equivalent of 75 g
anhydrous glucose dissolved in water.*
OR
4. In a patient with classic symptoms of hyperglycaemia or hyperglycaemic crisis, a random plasma
glucose 11.1 mmol/L (200 mg/dL).

NGSP = National Glycohemoglobin Standardization Program; DCCT = Diabetes Control and Complications
Trial; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test.
In the absence of unequivocal hyperglycaemia, criteria 13 should be confirmed by repeat
testing.
*

Table 2
World Health Organization recommendations for HbA1c as a diagnostic test for diabetes (Ref. 2).
HbA1c can be used as a diagnostic test for diabetes providing that stringent quality assurance tests are in
place and assays are standardised to criteria aligned to the international reference values, and there are
no conditions present which preclude its accurate measurement.
An HbA1c of 6.5% is recommended as the cut point for diagnosing diabetes. A value of less than 6.5%
does not exclude diabetes diagnosed using glucose tests.
Quality of evidence assessed by GRADE: moderate.

Strength of recommendation based on GRADE criteria: conditional.

GRADE = Grading of Recommendations Assessment, Development and Evaluation.

Table 3
Australian recommendations for HbA1c as a diagnostic test for diabetes (Ref. 3).
Measurement of HbA1c level can be used as a diagnostic test for diabetes if analysis is performed in a
facility producing acceptable performance in external quality assurance, assays are standardised to
criteria aligned to international reference values, and if no conditions which preclude its accuracy are
present. It is important to note that HbA1c testing is not currently funded by Medicare for the purpose of
diagnosis of diabetes.
An HbA1c level of 48 mmol/mol (6.5%) is recommended as the cut-off point for diagnosing diabetes.
An HbA1c level of <48 mmol/mol (<6.5%) does not negate a diagnosis of diabetes based on elevated
glucose parameters. The existing criteria based on fasting and random glucose levels, and on the oral
glucose tolerance test, remain valid, and are the diagnostic tests of choice for gestational diabetes, type
1 diabetes and in the presence of conditions that interfere with HbA1c measurement.

Table 5
Arguments for and against the use of HbA1c as a diagnostic test.
Advantages

Disadvantages

Indicative of chronic glycaemia and reflective

of tissue glycation status.

Results can be affected by haemolysis and other conditions with increased red cell
turnover (reduced HbA1c) or conditions with reduced red cell turnover e.g. iron
deficiency (increased HbA1c) or in any other chronic disease state.

More convenient, as patient not required to

fast and only one blood sample taken.

May vary with age and between different ethnic groups.

Validated against clinical outcomes,

particularly retinopathy as a long-term
microvascular complication of diabetes.

More expensive, being unaffordable in many low income country situations.

Less intra-individual variability compared

with fasting and 2-hour glucose in an OGTT.
Greater pre-analytical stability compared with
plasma glucose.

ear : 2013 | Volume : 67 | Issue : 7 | Page : 149-154

Correlation between glycated haemoglobin and glucose testing for diabetes mellitus
screening
Nandini Agarwal1, Sandeep Joshi2, VK Deshpande1, DA Biswas1
1

Department of Physiology, Jawaharlal Nehru Medical College, Sawangi (Meghe) Wardh, India

Department of Anesthesiology, Jawaharlal Nehru Medical College, Sawangi (Meghe) Wardha, India

Date of Web Publication

27-Jan-2014

Correspondence Address:
Nandini Agarwal
Yashoda Postgraduate Hostel, Jawaharlal Nehru Medical College, Sawangi (Meghe) Wardha
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5359.125875

Abstract
Hemoglobin A1C is used to screen and diagnose diabetes but measurement of glucose in the blood is subject to
several limitations, many of which are not widely appreciated. Blood glucose testing should be taken into consideration
before taking the patient to be diabetic on the basis of abnormal HbA1c values.

Keywords: Diabetes, glucose testing, HbA1c, screening

How to cite this article:

Agarwal N, Joshi S, Deshpande V K, Biswas D A. Correlation between glycated haemoglobin and glucose testing for diabetes mellitus
screening. Indian J Med Sci 2013;67:149-54

How to cite this URL:

Agarwal N, Joshi S, Deshpande V K, Biswas D A. Correlation between glycated haemoglobin and glucose testing for diabetes mellitus
screening. Indian J Med Sci [serial online] 2013 [cited 2016 May 21];67:149-54. Available from: http://www.indianjmedsci.org/text.asp?
2013/67/7/149/125875

 Introduction

Diabetes mellitus is metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances
of carbohydrate, fat and protein metabolism resulting from defects of insulin secretion, insulin action or both. The
metabolic dysregulation associated with diabetes mellitus causes secondary pathophysiological changes in multiple
organ systems that impose a tremendous burden on the individuals with diabetes and on the health care system.
Often the hyperglycemia sufficient to cause pathological and functional changes is present for a long time before the
diagnosis is made. Tests to measure glucose in the blood were developed over 100 years ago, and hyperglycemia
subsequently became the sole criterion recommended for the diagnosis of diabetes. Initial diagnostic criteria relied on
the response to an oral glucose challenge, while later measurement of blood glucose in an individual who was fasting
also became acceptable. The most widely accepted glucose-based criteria for diagnosis are fasting plasma glucose
(FPG) 126 mg/dL or a 2-h plasma glucose 200 mg/dL during an oral glucose tolerance test (OGTT) on more than one
,

occasion. [1] [2]In a patient with classic symptoms of diabetes, single random plasma glucose 200 mg/dL is considered
diagnostic. [1] Before 2010 virtually all diabetes societies recommended blood glucose analysis as the exclusive method
to diagnose diabetes. Notwithstanding these guidelines, over the last few years many physicians have been using
hemoglobin A1C to screen for and diagnose diabetes. [3] Although considered the "gold standard" for diagnosis,
measurement of glucose in the blood is subject to several limitations, many of which are not widely appreciated.
Measurement of A1C for diagnosis is appealing but has some inherent limitations. This review will provide an overview
of the glucose and A1C testing.

Glycated Hemoglobin

Glycated hemoglobin is a form of hemoglobin which is measured primarily to identify the average plasma glucose
concentration over prolonged periods of time. It is formed in a non-enzymatic glycation pathway by hemoglobin's
exposure to plasma glucose and binding to the N-terminal of valine of chain of hemogobin. Normal levels of glucose
produce a normal amount of glycated hemoglobin. As the average amount of plasma glucose increases, the fraction of
glycated hemoglobin increases in a predictable way. This serves as a marker for average blood glucose levels over the
previous months prior to the measurement.
The 2010 American Diabetes Association Standards of Medical Care in Diabetes added the A1c 48 mmol/mol
(6.5%) as another criterion for the diagnosis of diabetes. [4]
In diabetes mellitus, higher amounts of glycated hemoglobin, indicating poorer control of blood glucose levels, have
been associated with cardiovascular disease, nephropathy, and retinopathy. The HbA
blood glucose concentration over the previous four weeks to three months. [5]

1c

level is proportional to average

All the major institutions like International Expert Committee Report, drawn from the International Diabetes
Federation (IDF), the European Association for the Study of Diabetes (EASD), and the American Diabetes Association
(ADA), suggests the A1C level of 48 mmol/mol (6.5%) as a diagnostic level. [6]
FPG test
The FPG test is the preferred test for diagnosing diabetes because of its convenience and low cost. However, it will
miss some diabetes or pre-diabetes that can be found with the OGTT. The FPG test is most reliable when done in the
morning. Results and their meaning are shown in [Table 1]. People with a fasting glucose level of 100 to 125 milligrams
per deciliter (mg/dL) have a form of pre-diabetes called impaired fasting glucose (IFG). Having IFG means a person

has an increased risk of developing type 2 diabetes but does not have it yet. A level of 126 mg/dL or above, confirmed
by repeating the test on another day, means a person has diabetes. [7]
Table 1: Diagnostic values of HbA1c for diabetes

Click here to view

OGTT
OGTT is more sensitive than the FPG test for diagnosing pre-diabetes, but it is less convenient to administer. The
OGTT requires fasting for at least eight hours before the test. The plasma glucose level is measured immediately
before and two hours after a person drinks a liquid containing 75 grams of glucose dissolved in water. Results and
their meaning are shown in [Table 2]. If the blood glucose level is between 140 and 199 mg/dL two hours after drinking
the liquid, the person has a form of pre-diabetes called impaired glucose tolerance (IGT). Having IGT, like having IFG,
means a person has an increased risk of developing type 2 diabetes but does not have it yet. A 2-hour glucose level of
200 mg/dL or above, confirmed by repeating the test on another day, means a person has diabetes. [8]
Table 2: Diagnostic values of fasting blood sugar for diabetes

Click here to view

Random Plasma Glucose Test

A random, or casual, blood glucose level of 200 mg/dL or higher, plus the presence of the following symptoms, can
mean a person has diabetes:

increased urination

increased thirst

unexplained weight loss.

Other symptoms can include fatigue, blurred vision, increased hunger, and sores that do not heal. The doctor will
check the person's blood glucose level on another day using the FPG test or the OGTT to confirm the diagnosis.
How are diabetes and pre-diabetes diagnosed?
The following tests are used for diagnosis:

A fasting plasma glucose (FPG) test measures blood glucose in a person who has not eaten anything for at
least eight hours. This test is used to detect diabetes and pre-diabetes.

An oral glucose tolerance test (OGTT) measures blood glucose after a person fasts at least eight and two
hours after the person drinks a glucose-containing beverage. This test can be used to diagnose diabetes and
pre-diabetes.

A random plasma glucose test, also called a casual plasma glucose test, measures blood glucose without
regard to when the person being tested last ate. This test, along with an assessment of symptoms, is used to
diagnose diabetes but not pre-diabetes.

Gill et al. [9] suggested that clinic measured random blood glucose plasma levels below 10 mmol/L predict acceptable
overall glycemic control in NIDDM patients, particularly on di et al one. A clinic measured random blood plasma
glucose above 10 mmol/L was of limited value in predicting glycated hemoglobin values above 10% and a blood
glucose cut off of 14 mmol/L is more useful. They concluded that if resources are limited, clinic random blood glucose
estimation may allow clinicians to use glycated hemoglobin measurements more discriminately. Otieno et al.
[10]
reported that morning random blood glucose in the ambulatory diabetic patients related well to simultaneously
assayed HbA1c. Blood glucose within usual therapeutic targets of 4-8 mmol/L predicted good glycemic control with
high sensitivity at a range of 86.3%-98.4%. In resource poor settings morning random blood glucose assay, which is
done in patients who attend the diabetic clinic in morning hours, may be used to predict the quality of their diabetic
control.
In line with the above mentioned studies, Curt L. Rohlfing et al.[11] defined the relationship between HbA1c and plasma
glucose by measuring quarterly HbA1c and corresponding seven point capillary blood glucose profiles. They concluded
that among individual time points, afternoon and evening plasma glucose (post-lunch, pre-dinner, post-dinner and
bedtime) showed higher correlations with HbA1c than the morning time points (pre-breakfast, post-breakfast and prelunch). Knowing this relationship can help patients with diabetes and their healthcare providers set day-to-day targets
for plasma glucose to chieve HbA1c goals. Christopher.et al. [12] supported using HbA1c as a screening and diagnostic
test because it does not require patient fasting and it reflects longer term glycemia than does the plasma glucose.
They also supported the fact that errors caused by nonglycemic factors affecting HbA1c such as hemoglobinopathies
are infrequent and can be minimized by confirming the diagnosis of diabetes with a plasma glucose specific test.
Glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes.
Glycated hemoglobin and death from any cause were found to have J-shaped association curve as described by
Elizabeth Selvin et al. [13] All these associations were significant after adjustment for baseline fasting glucose level. For
coronary heart disease, measures of risk discrimination showed significant improvement when glycated hemoglobin
was added to models including fasting glucose. Therefore, in non diabetic adults glycated hemoglobin is associated
with risks of cardiovascular disease and death from any cause as compared with fasting glucose.Glycated hemoglobin
estimation can be done to assesses the microvascular and macrovascular complications of diabetes mellitus, as it has
been supported by Yun Huang et al.[14] in their study of finding the Glycosylated HbA1c, fasting plasma glucose and two
hour post challenge plasma glucose levels in relation to carotid intima media thickness in Chinese population with
normal glucose tolerance [Table 3]. They found the increasing trend of carotid intima media thickness was found in
HbA1c quartiles rather than fasting plasma glucose and postchallenge glucose quartiles. So, HbA1c could be more
informative of cardiovascular risk factor as compared with fasting plasma glucose and post challenge glucose in
subject with normal glucose tolerance.
Table 3: Diagnostic values of post prandial blood sugar for diabetes

Click here to view

A study conducted by Waqar Azim et al.[15] pointed out that there is a direct correlation between glycated hemoglobin
and random plasma glucose levels with no correlation between age of the patients and the glycated hemoglobin or the
age and the random plasma glucose levels. They stated that for every 1% rise in HbA1c, plasma glucose level rose by
2.3 mmol/L.
In contrast to the above mentioned studies Ghazan farri et al.[16] stated that fasting blood glucose is more reliable to

separate diabetic from non-diabetic subjects than HbA1c. They found that the association of HbA1c with fasting blood
glucose was relatively stronger particularly in diabetic subjects by determining the sensitivity, specificity and predictive
values in detection of abnormal values. Similarly, Rajni Dawar Mahajan et al.[17] suggested that though HbA1c has
advantages over fasting plasma blood glucose levels for diagnosing diabetes but its use as a single diagnostic agent is
limited because of number of biochemical, clinical and economical factors. In developing countries and
underdeveloped countries the laboratories are not standardized for HbA1c. Also the clinician should consider the
overall patient profile and a number of local variations and disorders as hemoglobinopathies or anemias. It is also not
cost effective, so HbA1c cannot be used as a sole and independent test to diagnose diabetes mellitus.

Perspective

Notwithstanding the use of glucose (FPG and/or the OGTT) as the "gold standard" for the diagnosis of diabetes for
many years, glucose testing suffers from several deficiencies, but the clinician must consider the overall profile of the
patient before taking into consideration the abnormal HbA1c value. In the present scenario in third world countries
due to lack of proper laboratories and fragmented and unorganized health sector, HbA1c cannot be accepted as a sole
and independent test to diagnose diabetes mellitus.

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World Health Organization. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycermia:
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Curt L. Rohlfing BE. Hsiao-Mei Weidmeyer. Defining the relationship between plasma glucose and HbA1c.
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Saudek CD, Herman WH, Sacks DB, Bergenstal RM, Edelman D, Davidson MB. A new look at screening and
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Azmi W, Omair MM. Khan QA, Shaheen N, Azim S. Correlation between glycated hemoglobin and random plasma
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