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DIABETICMedicine

DOI: 10.1111/j.1464-5491.2010.03159.x

Short Report: Epidemiology


HbA1c measurement for the diagnosis of diabetes: is it
enough?

G. Cavagnolli*, J. Comerlato, C. Comerlato, P. B. Renz, J. L. Gross* and J. L. Camargo*


*Postgraduate Program in Endocrinology, Federal University of Rio Grande do Sul (UFRGS), Clinical Pathology Division and Endocrinology Division, Hospital de
Clnicas de Porto Alegre, Porto Alegre, Brazil

Accepted 4 October 2010

Abstract
Aim To analyse the performance of HbA1c in diagnosing Type 2 diabetes based on fasting plasma glucose and or 2-h plasma
glucose measurements after a 75-g oral glucose tolerance test.
Methods This is a study of diagnostic test accuracy in individuals referred to the Clinical Pathology Department for oral
glucose tolerance testing. After fasting overnight, HbA1c, fasting plasma glucose and 2-h plasma glucose were measured. The
receiver operating characteristic curve was used to evaluate the diagnostic performance of HbA1c.
Results Four hundred and ninety-eight subjects (195 male, mean age 56 years) were enrolled and 115 (23.1%) were diagnosed
with diabetes according to glucose-based methods and only 56 (11.2%) individuals were identified by HbA1c 6.5%
(48 mmol mol) (sensitivity 20.9%, specificity 95.3%). There is poor agreement between the newly recommended criterion and
the current glucose-based diagnostic criteria (j = 0.217; P < 0.001), probably because the diagnostic methods identify different
populations of patients. Adding a glucose-based method into an algorithm, as proposed by the UK Department of Health,
improved HbA1c performance.
Conclusions HbA1c 6.5% (48 mmol mol) showed limited sensitivity to diabetes diagnosis, although with high specificity.
The results suggest that this cut-off point would not be enough to diagnose diabetes. Its use as the sole diabetes diagnostic test
should be interpreted with caution to assure the correct classification of diabetic individuals.
Diabet. Med. 28, 3135 (2011)
Keywords diabetes, diagnosis, diagnostic tests, glycated hemoglobin

or, alternatively, HbA1c measurements combined or not with


Introduction
glucose measurements. In non-symptomatic patients, a
Recently, an International Expert Committee, composed of confirmed HbA1c 6.5% (48 mmol mol) is enough to
members from the European Association for the Study of diagnose Type 2 diabetes [6]. However, this guideline also
Diabetes, the International Diabetes Federation and the recommends that patients with HbA1c levels 6.0%
American Diabetes Association reported values of HbA1c (42 mmol mol) and < 6.5% (48 mmol mol) should undergo
6.5% (48 mmol mol) as the cut-off point for diagnosing an oral glucose tolerance test to establish a diabetes diagnosis. No
diabetes [1]. The selection of this cut-off point was to emphasize further test is required for those patients presenting with HbA1c
specificity rather than sensitivity; however, the diagnostic levels < 6.0% (42 mmol mol), but health lifestyle advice is
performance of this specific cut-off point is not mentioned. given.
Other studies had suggested lower HbA1c values, such as 5.8% Until recently, the lack of HbA1c standardization prevented the
(40 mmol mol) and 6.0% (42 mmol mol), for this purpose use of HbA1c as part of a potential screening and diagnostic
[25]. The United Kingdom Department of Health recommends programme. The introduction of a new reference method
the use of algorithms for diabetes screening in high-risk improved HbA1c assay standardization worldwide and its role
individuals that include traditional glucose diagnostic criteria in the screening and diagnosis of Type 2 diabetes has been
considered [79].
Taking into account that increased prevalence of
Correspondence to: Joiza Lins Camargo, Servico de Patologia Clnica, Hospital
de Clnicas de Porto Alegre, Rua Ramiro Barcellos, 2350; 2 andar, Porto retinopathy in different populations is already observed
Alegre, RS, 90035-903, Brazil. E-mail: jcamargo@hcpa.ufrgs.br around HbA1c values of 6.0% (42 mmol mol) [1], the risk

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Diabetic Medicine 2010 Diabetes UK 31
DIABETICMedicine HbA1c test and diabetes diagnosis G. Cavagnolli et al.

for cardiovascular disease is greater at the HbA1c level of


Statistical analysis
5.66.1% (3843 mmol mol) [10] and, bearing in mind that
these individuals would benefit from early intervention, the Data are expressed as mean and sd when normally distributed
aim of this report was to analyse the performance of and as median (range) for non-Gaussian variables. Students
the recommended HbA1c 6.5% (48 mmol mol) value for t-test, the MannWhitney U-test, McNemar test and kappa
the diagnosis of Type 2 diabetes [1,6] according to current coefficient were used as appropriate. The receiver operating
diagnostic criteria based on fasting plasma glucose and or characteristic curve was used to analyse the performance of
2-h plasma glucose after a 75-g oral glucose tolerance test the HbA1c test to diagnose diabetes, using fasting plamsa
[11,12]. glucose and or 2-h plasma glucose as reference diagnostic
criteria. In addition, the UK Department of Health algorithm
based on HbA1c results was also used to verify if an additional
Research design and methods
blood glucose measurement would improve the performance
This is a study of diagnostic accuracy to evaluate the HbA1c test of HbA1c in diagnosing diabetes. A significance level of 5%
for diagnosis of diabetes (see also Supporting Information, was adopted.
Fig. S1). Conventional diagnostic tests of fasting plamsa glucose
7.0 mmol l and or 2-h plasma glucose 11.1 mmol l were
Results
considered to be the reference standard [1113].
Four hundred and ninety-eight individuals were selected to
participate in this study; 418 (83.8%) of those were of White
Patients
ethnicity. The clinical and laboratory characteristics of all
The study included individuals at high risk of developing or individuals are summarized in Table 1. There was poor
having diabetes being referred to the Clinical Pathology agreement between the diagnosis of diabetes using HbA1c
Department of the Hospital de Clinicas de Porto Alegre, 6.5% (48 mmol mol) and any of the glycaemic tests
between September 2008 and May 2009, to perform an oral (j = 0.217; P < 0.001). According to the traditional criteria,
glucose tolerance test. Porto Alegre is situated in Southern Brazil, 115 (23.1%) individuals were diagnosed with diabetes: 26 by
where the majority of the population has European ancestry and fasting plasma glucose, 54 by 2-h plasma glucose and 35 using
approximately 86% of the population is of White ethnicity. All both tests. In contrast, although the HbA1c cut-off value of 6.5%
conditions known to interfere or lead to misinterpretation of (48 mmol mol) has a specificity of 95.3%, this criterion
HbA1c results were excluded [7,8]: patients with anaemia [14], identified only 56 (11.2%) individuals with diabetes; of those,
estimated glomerular filtration rate < 60 ml min)1 1.73 m)2 29 (25.2%) had the diagnosis established by current criteria: 22
[15] and or the presence of variant haemoglobin [16]. Patients by fasting plasma glucose and 2-h plasma glucose and seven by
signed an informed consent form and answered a standardized either fasting plasma glucose or 2-h plasma glucose. Therefore,
questionnaire. The protocol was approved by the Ethics the proportion of individuals with and without diabetes
Committee. significantly differs between the glucose- and HbA1c-based
methods (P < 0.001).
There were 86 individuals with a diagnosis established by
Laboratory analysis
current criteria and HbA1c < 6.5% (48 mmol mol),
After overnight fast, blood samples were drawn to determine corresponding to 74.8% of all diabetes cases. The sensitivity
HbA1c, lipid profile, creatinine and glucose levels,and an oral and specificity of the HbA1c cut-off value of 6.5%
glucose tolerance test was also performed according to World (48 mmol mol), compared with the diagnosis of diabetes
Health Organization recommendations [12]. Plasma glucose established by fasting plasma glucose and or 2-h plasma
was determined by an enzymatic method and creatinine by Jaffe glucose were 20.9 and 95.3%, respectively, resulting in a
reaction (Modular P; Roche Diagnostics, Basel, Switzerland). negative predictive value of 80.5%.
HbA1c was determined by HPLC method (Tosoh 2.2 Based on receiver operating characteristic curve analysis, and
Plus HbA1c; Tosoh Corporation, Tokyo, Japan). This is a considering fasting plasma glucose alone as the reference
National Glycohemoglobin Standardization Program (NGSP)- criterion, the cut-off point obtained by the point with the best
certified method (http://www.ngsp.org/prog/index.html) and equilibrium between sensitivity and specificity (100%-to-100%
also International Federation of Clinical Chemistry and diagonal), a value of HbA1c of 6.0% (42 mmol mol)
Laboratory Medicine (IFCC) aligned [8]. The Clinical was obtained. The sensitivity and specificity were 74.2 and
Pathology Department is a participant in and meets the 72.0%, respectively. The cut-off points of HbA1c of 7.0%
standards of the HbA1c External Quality Assurance Program. (53 mmol mol)and 8.0% (64 mmol mol) presented specificities
Diagnosis of diabetes and impaired glucose tolerance were made of 99.5 and 99.8%.
according to current diagnosis criteria [11,12]. Impaired fasting Alternatively, when fasting plasma glucose and or 2-h plasma
glucose was classified as stated by American Diabetes glucose and 2-h plasma glucose alone were considered as the
Association criteria [11]. reference criteria, an HbA1c level of 5.9% (41 mmol mol) was

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32 Diabetic Medicine 2010 Diabetes UK
Original article DIABETICMedicine

Table 1 Characteristics of individuals participating in the study according to HbA1c values

HbA1c
< 6.0% 66.4% 6.5%
(< 42 mmol mol) (4246 mmol mol) ( 48 mmol mol)

n 331 111 56
Sex (man woman) 139 192 35 76 21 35
Age (years) 53  13 61  11 61  12
BMI 27  5.6 28  6.0 30  6.3
Waist circumference (cm) 94  17 97  18 103  13
Without diabetes 113 (34.1%) 8 (7.2%) 1 (1.78%)
Pre-diabetes 168 (50.7%) 67 (60.3%) 26 (46.4%)
Diabetes mellitus 50 (15.1%) 36 (32.4%) 29 (51.7%)
Hypertension 162 (48.9%) 79 (71.1%) 44 (78.5%)
Family history of diabetes 162 (48.9%) 61 (54.9%) 30 (53.5%)
Family history of hypertension 238 (71.9%) 75 (67.5%) 40 (71.4%)
Family history of cardiovascular disease 207 (62.5%) 72 (64.8%) 40 (71.4%)
Fasting plasma glucose (mmol l) 5.7  0.7 6.2  0.8 7.6  2.5
2-h plasma glucose (mmol l) 7.4  2.9 8.8  4.0 12.7  5.8
HbA1c (%) 5.3  0.4 6.1  0.14 7.2 1.5
Creatinine ((mol l) 74.2  17.7 81.3  17.7 83.0  16.8

n = 498.
Data are mean  sd or median (interval).

1 and current diagnostic criteria was also poor (j = 0.274;


P < 0.001).
Applying the UK Department of Health algorithm to verify if
0.8
an additional blood glucose measurement would improve the
performance of HbA1c in diagnosing diabetes, 82 individuals
Sensitivity

0.6 would be diagnosed with diabetes: in 56 individuals, HbA1c was


6.5% (48 mmol mol) and, in 26, the HbA1c level was
between 6.0 and 6.5% (4248 mmol mol) and they had a
0.4
positive oral glucose tolerance test. Fifty individuals with HbA1c
< 6.0% (42 mmol mol) and diabetes by the current criteria
0.2 remained undiagnosed. There were 168 individuals presenting
with HbA1c < 6.0% (42 mmol mol) and an intermediate
0 hyperglycaemia (50.7%). The sensitivity and specificity for
0 0.2 0.4 0.6 0.8 1 this strategy were 47.8 and 92.9%, respectively. The agreement
1 Specificity between this approach and current diagnostic criteria improved
FIGURE 1 HbA1c receiver operating characteristic curves for diabetes
(j = 0.416; P < 0.001).
diagnosis: HbA1c vs. fasting plasma glucose ( ); HbA1c vs. 2-h plasma
glucose ( ); HbA1c vs. fasting plasma glucose and or 2-h plasma glucose
( ).
Discussion
This study shows that there is poor agreement between the
newly recommended criterion and the current glucose-based
the equilibrium point for sensitivity and specificity (63.5 66.1 diagnostic criteria and, consequently, the proportion of patients
and 62.9 64.1%, respectively) (Fig. 1). diagnosed with diabetes by one or other method is significantly
In our study, 167 patients had HbA1c 6.0% (42 mmol mol). different.
Sixty-five individuals were diagnosed with diabetes by the HbA1c Our results are in agreement with recent reports carried out
6.0% (42 mmol mol) criterion and 50 were misclassified. in larger populations, which pointed out the poor diagnostic
There were 102 false positive results. Only nine individuals of performance of HbA1c [1719] and that it is not superior to
those had normoglycaemia; however, 93 presented with fasting plasma glucose and or 2-h plasma glucose [20]. The
hyperglycaemia (41 with impaired fasting glucose and 52 with cut-off point of HbA1c 6.5% (48 mmol mol) had a
impaired glucose tolerance). The sensitivity and specificity of the sensitivity of only 25% to diagnose diabetes. However, by
HbA1c cut-off value of 6.0% (42 mmol mol) were 51.3 and adopting the cut-off of HbA1c 6.0% (42 mmol mol), the
78.3%, respectively. The agreement between this cut-off point sensitivity increased to 51.3%. Even so, approximately 50%

2010 The Authors.


Diabetic Medicine 2010 Diabetes UK 33
DIABETICMedicine HbA1c test and diabetes diagnosis G. Cavagnolli et al.

of patients with diabetes will not be identified. In addition, we diagnostic test should be interpreted with caution to assure the
observed an increase in false positive results using the cut-off correct classification of diabetic individuals.
point of HbA1c 6.0% (42 mmol mol); 93% of the
individuals misclassified presented some degree of glucose
Competing interests
abnormality.
These findings suggest that the HbA1c method and the glucose- Nothing to declare.
based methods identify different patient populations.
Several studies had suggested lower values than the present
Acknowledgements
recommended values of HbA1c 6.5% (48 mmol mol) to
diagnose diabetes [35]. Besides, the cut-off value of HbA1c We thank the staff of the Pre-Analytical Unit and the Clinical
> 6.1% (43 mmol mol) presented high sensitivity and Biochemistry Unit at the Clinical Pathology Department for
specificity to screen for diabetes in high-risk individuals, OGTT performance and HbA1c analysis, respectively. This study
and the combination of HbA1c and fasting plasma glucose was supported by Fundo de Incentivo a Pesquisa (FIPE) to
improved the sensitivity for both tests alone [4]. Moreover, Hospital de Clnicas de Porto Alegre (HCPA). GC and JC
there is a continuous relationship between fasting plasma were recipients of scholarships from Coordenacao de
glucose and HbA1c and cardiovascular risk. It has been Aperfeicoamento de Pessoal de Ensino Superior (CAPES) and
suggested that individuals with an HbA1c level of 5.66.1% Fundacao de Amparo a Pesquisa do Rio Grande do Sul
(3843 mmol mol) and a fasting plamsa glucose level of (FAPERGS), respectively.
5.66.3 mmol l are at greatest risk for cardiovascular disease
and should be targeted for further evaluation [10]. In a
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Diabetic Medicine 2010 Diabetes UK 35

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