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Abstract

Background

To assess the usefulness of erythrocyte glycated haemoglobin (HbA_1C) as a screening tool to identify those subjects with impaired fasting glycaemia (IFG) who do not have impaired glucose tolerance (IGT) or diabetes mellitus (DM) on a 75 g oral glucose tolerance test (OGTT).

Design and methods

All subjects undergoing an OGTT had HbA_1C measured at baseline. Receiver operator characteristics analysis was used to identify optimal HbA_1C cut-off values for diagnosing and excluding IGT and DM.

Results

We studied 140 subjects (69 women) with IFG (fasting capillary plasma glucose between 6.1–6.9 mmol/L). Using World Health Organisation criteria, 27 had isolated IFG, 56 had IGT and 57 had DM. HbA_1C was higher (P < 0.001) in patients with DM (6.8 ± 0.93%) when compared with those with IGT (6.3 ± 0.68%) and isolated IFG (6.2 ± 0.30%), but HbA_1C was similar in those with IGT and isolated IFG. There was no HbA_1C cut-off value differentiating isolated IFG from IGT or DM. None of the subjects with isolated IFG had HbA_1C concentration of >6.8%, but 76% and 54% subjects with IGT and DM, respectively, had HbA_1C of ≤6.8%.

Conclusions

HbA_1C measurement is of limited value in differentiating isolated IFG, IGT and DM in subjects with IFG. It cannot be used to identify which subjects with IFG do not require an OGTT.

Introduction

The World Health Organisation (WHO) and Diabetes UK recommend that subjects with impaired fasting glycaemia (IFG) should undergo a 75-g oral glucose tolerance test (OGTT) to exclude diabetes mellitus (DM).¹ This has resulted in an increase in the number of OGTT requests in our laboratory. An OGTT should be performed in a controlled environment and is time consuming for the patient and health-care professionals. It may also be unpleasant for some patients as it may induce nausea and vomiting. An alternative single blood test to replace the OGTT has, therefore, long been sought to simplify the diagnosis of DM.

Erythrocyte glycated haemoglobin (HbA_1C) reflects average plasma glucose concentrations over the preceding 2–3 months. HbA_1C correlates with fasting glucose concentrations, 2 h glucose concentrations on OGTT and postprandial glucose concentrations.^1–4 HbA_1C can be performed at any time of the day and does not require any special preparation such as fasting. The use of HbA_1C to diagnose DM is therefore appealing,¹ and it has been suggested that HbA_1C, either on its own or in combination with fasting plasma glucose, can be used to diagnose diabetes,^3–13 but this remains controversial.^14–19

There are no data on HbA_1C predicting glucose-intolerance states in subjects with impaired fasting glycaemia (IFG). We therefore studied whether measurement of HbA_1C in subjects with IFG could be used to reduce the number of OGTT by predicting those without impaired glucose tolerance (IGT) and DM.

Patients, materials and methods

Patients

As part of a service evaluation, we analysed one-year prospective data on OGTT referrals from primary care to the Department of Clinical Chemistry, New Cross Hospital, Wolverhampton. Exclusion criteria included those <18 years of age, pregnant women and known diabetics. We limited this study to those with IFG as these form the vast majority of requests for an OGTT, and therefore we also excluded those with fasting capillary plasma glucose <6.1 mmol/L and >6.9 mmol/L.

The OGTT

Following an overnight fast of 12 h, a free-flowing capillary blood sample was collected from medial aspect of the finger tip for measurement of plasma glucose and HbA_1C. Subjects then consumed 75 g of glucose dissolved in 200 mL of water within 5 min and a further capillary blood sample collected 2 h later for measurement of plasma glucose. Interpretation of capillary plasma glucose concentrations, which are different from those of plasma venous glucose, was based on the WHO criteria.¹

Analytical methods

Plasma glucose was measured using an automated hexokinase method (Roche modular P, Roche Diagnostics GmbH, Mannheim, Germany). Diabetes Control and Complication Trial (DCCT)-aligned HbA_1C was measured using an automated cationic non-porous ion exchange high-performance liquid chromatography method (Tosoh Corporation, Kanagawa, Japan). The inter-assay coefficients of variation (CVs) for glucose at 7.0 and 14.0 mmol/L were 1.7% and 1.9%, respectively, and intra-assay CVs at 7.0 and 15.2 mmol/L were 1.0% and 0.8%, respectively. Inter-assay CVs for HbA_1C at 4.1% and 9.1% were 1.2% and 0.8%, respectively, and intra-assay CVs at 4.1% and 13.4% were 0.5% and 0.9%, respectively.

Statistical analysis

Data were normally distributed and therefore analysed using parametric tests. One-way analysis of variance was used to compare the differences in means between groups. Pearson's linear correlation was used to measure the significance of association between the variables. Data were shown as mean ± standard deviation unless otherwise specified and were analysed using Statistical Programme for Social Sciences version 13 (SPSS Inc., IL, USA). Receiver operator characteristics (ROC) analysis was used to derive an optimum cut-off value for HbA_1C diagnostic of either diabetes or glucose intolerance in individuals with IFG.

Results

Using WHO criteria, there were 140 subjects with IFG (fasting capillary plasma glucose between 6.1–6.9 mmol/L). This comprised 71 men and 69 women aged 65.5 ± 11.2 and 63.9 ± 14.6 years, respectively, and weighing 81 ± 16.4 and 86.7 ± 16.4 kg, respectively.

Of the 140 subjects with IFG, 27 had isolated isolated IFG, 56 had IGT and 57 had DM. HbA_1C was higher (P < 0.001) in patients with DM (6.8 ± 0.93%) when compared with those with IGT (6.3 ± 0.68%) and isolated IFG (6.2 ± 0.30%), but there was no significant difference in HbA_1C between those with IGT and isolated IFG.

HbA_1C correlated (r = 0.448; P < 0.01) with 2 h glucose concentrations, but there was no correlation between fasting glucose concentrations and 2 h glucose concentrations or HbA_1C.

ROC curves for HbA_1C as a diagnostic indicator for DM and for IGT are shown in Figure 1. In summary, ROC analysis gave an optimum HbA_1C value of 6.48% with a sensitivity of 68% and specificity of 67% to predict a 2 h capillary plasma glucose of ≥12.2 mmol/L, and an HbA_1C value of 6.15% with a sensitivity of 62% and specificity of 58% to predict a 2 h capillary plasma glucose of ≥8.9 mmol/L and <12.2 mmol/L.

Figure 1

Receiver operator characteristics (ROC curve for erythrocyte glycated haemoglobin (HbA1c) as a diagnostic indicator for impaired glucose tolerance (IGT) and diabetes mellitus (DM) in subjects with impaired fasting glycaemia (IFG).

There was no lower HbA_1C cut-off value differentiating isolated IFG from IGT or DM. None of the subjects with isolated IFG had HbA_1C concentration >6.8% but 76% subjects with IGT and 54% with DM had HbA_1C ≤6.8%.

Discussion

HbA_1C in conjunction with fasting plasma glucose concentrations has been used to diagnose DM,^3–13 but this is not widely accepted.^14–19 We did not use HbA_1C for diagnostic purposes but to investigate whether there was an HbA_1C concentration that would exclusively predict isolated IFG as this had the potential to reduce the number of OGTTs. There was, however, no HbA_1C cut-off concentration that differentiated isolated IFG from IGT or DM. Although an HbA_1C value of >6.8% excluded isolated IFG, this was of little practical value as these patients would still require an OGTT to confirm DM and distinguish it from IGT. Our results are consistent with a meta-analysis that concluded that although an HbA_1C value above the upper reference limit could indicate developing or overt glucose intolerance, a normal value did not exclude it,⁵ however, they differ from those studies reporting HbA_1C to be of value in predicting glucose intolerance.^3–13 Differences in these studies may be related to different study groups, reproducibility of OGTT, glucose sample type as well as analytical and biological variability of HbA_1C.

In our study, fasting glucose concentrations were between 6.1 and 6.9 mmol/L, whereas other studies have included those with glucose concentrations <6.0 mmol/L and >7.0 mmol/L.^5,6,12 The high prevalence of IGT (40%) and diabetes (41%) in our subjects with IFG is different from other studies reporting a much lower prevalence of IGT and diabetes.^20,21 The high prevalence of IGT and diabetes in our subjects suggest the necessity to revisit the current definition of IFG and consider lower cut-off values for fasting glucose as an indication for OGTT. The importance of identifying isolated IFG is that although it is associated with cardiovascular risk factors,^22–25 unlike IGT and diabetes it is not associated with adverse cardiovascular outcomes.²⁶

The OGTT is poorly reproducible.^27,28 Capillary blood, unlike venous blood, is not subject to tissue extraction of glucose and therefore improves reliability of postprandial glucose measurements.²⁹ Our results using capillary samples, however, are similar to those studies using venous samples⁵ probably because WHO diagnostic criteria¹ take account of sample type.

Although analytical variability of HbA_1C between methods has largely been addressed by DCCT alignment,³⁰ the biological variability of HbA_1C remains an inherent limitation of testing HbA_1C. ^14,15

In summary, measurement of HbA_1C is of little value in differentiating between subjects with IFG who have isolated IFG and those with IGT or DM. In subjects with IFG, HbA_1C measurement will not reduce OGTT requests, since it does not identify which subjects with IFG do not require an OGTT.

References

WHO Consultation. Definition, Diagnosis and Classification of Diabetes mellitus and its Complications. Part1: Diagnosis and Classification of Diabetes Mellitus. Geneva: World health Organization, 1999

Anand

Razak

Vuksan

Diagnostic strategies to detect glucose intolerance in a multiethnic population. Diabetes Care 2000;26:290–6

McCance

Hanson

Charles

Comparison of tests for glycated haemoglobin and fasting and 2-hour plasma glucose concentrations as diagnostic methods for diabetes. BMJ 1994;308:1323–8

Norberg

Eriksson

Lindahl

A combination of HbA_1C, fasting glucose and BMI is effective in screening for individuals at risk of future type diabetes: OGTT is not needed. J Intern Med 2006;260:263–71

Peters

Davidson

Schriger

A clinical approach for the diagnosis of diabetes mellitus: an analysis using glycosylated hemoglobin levels. Meta-analysis Research Group on the diagnosis of diabetes using glycated hemoglobin levels. JAMA 1996;276:1246–52

Geberhiwot

Haddon

Labib

. HbA_1C predicts the likelihood of having impaired glucose tolerance in high risk patients with normal fasting plasma glucose. Ann Clin Biochem 2005;42:193–5

Jorde

Hagen

. Screening for diabetes using HbA_1C in elderly patients. Acta Diabetol 2006;43:52–6

Vines

Roubicek

Gonzalez Sanguineti

. Comparative study of glycosylated hemoglobin with oral glucose tolerance test in a selected population. Medicina 1998;58:728–32

Simon

Coignet

Thibult

Comparison of glycosylated hemoglobin and fasting plasma glucose with two-hour post-load plasma glucose in the detection of diabetes mellitus. Am J Epidemiol 1985;122:589–93

10.

Tanaka

Atsumi

Matsuoka

Usefulness of stable HbA_1C for supportive marker to diagnose diabetes mellitus in Japanese subjects. Diabetes Res Clin Pract 2001;53:41–5

11.

Chan

Cockram

. Use of a paired value of fasting plasma glucose and glycated hemoglobin in predicting the likelihood of having diabetes in a community. Diabetes Care 1999;22:1908–9

12.

GTC

Chan

JCN

Yeung

VTF

The combined use of fasting plasma glucose concentration and glycated haemoglobin or fructosamine predicts the likelihood of having diabetes mellitus in high risk subjects. Diabetes Care 1998;21:1221–5

13.

Bennett

Guo

Dharmage

. HbA(1C) as a screening tool for detection of type 2 diabetes: a systematic review. Diabet Med 2007;24:333–43

14.

Kilpatrick

. HbA1C or glucose for diabetes diagnosis? Ann Clin Biochem 2005;42:165–6

15.

Jeffcoate

. Diabetes control and complications: the role of glycated haemoglobin, 25 years on. Diabet Med 2004;21:657–5

16.

Yudkin

Forrest

Jackson

Unexplained variability of glycated haemoglobin in non-diabetic subjects not related to glycemia. Diabetologia 1990;33:208–15

17.

Virtue

Furne

Nutall

Relationship between GHb concentration and erythrocyte survival determined from breath carbon monoxide concentration. Diabetes Care 2004;27:931–5

18.

Snieder

Sawtell

Ross

HbA1c levels are genetically determined even in type 1 diabetes: evidence from healthy and diabetic twins. Diabetes 2001;50:2858–63

19.

Hudson

Child

Jones

Differences in rates of glycation may significantly affect individual HbA1c results in type 1 diabetes. Ann Clin Biochem 1999;36:451–59

20.

DECODE Study Group. Age- and sex-specific prevalence of diabetes and impaired glucose regulation in 13 European Cohorts. Diabetes Care 2003;26:61–9

21.

Qiao

Tuomilehto

Age- and sex-specific prevalence of diabetes and impaired glucose regulation in 11 Asian Cohorts. Diabetes Care 2003;26:1770–80

22.

Davies

Raymond

Day

Impaired glucose intolerance and fasting hyperglycaemia have different characteristic. Diabet Med 2000;17:433–40

23.

Larsson

Berglund

Lindgarde

Comparison of ADA and WHO criteria for diagnosis of diabetes and glucose intolerance. Diabetologia 1998;41:1124–5

24.

Rathmann

Giani

Mielck

. Cardiovascular risk factors in newly diagnosed abnormal glucose tolerance: comparison of 1997 ADA and 1995 WHO criteria. Diabetologia 1999;42:1268–9

25.

Hanefeld

Temelkova

Schaper

Impaired fasting glucose is not a risk factor for atherosclerosis. Diabet Med 1999;16:212–8

26.

Unwin

Shaw

Zimmet

Alberti

. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med 2002;19:708–23

27.

Olefsky

Reaven

. Insulin and glucose responses to identical oral glucose tolerance tests performed forty-eight hours apart. Diabetes 1974;23:449–53

28.

The DECODE-Study Group. Is fasting glucose sufficient to define diabetes? Epidemiological data from 20 European studies. Diabetologia 1999;42:647–54

29.

Tustison

Bowen

Crampton

. Clinical interpretation of plasma glucose values. Diabetes 1996;15:775–7

30.

Stott

Casson

Higgins

. Glycated haemoglobin assays. Approaches to standardization of results. Diabet Med 2001;18:274–9

Does HbA 1C predict isolated impaired fasting glycaemia in the oral glucose tolerance test in subjects with impaired fasting glycaemia?

Abstract

Abstract

Background

Design and methods

Results

Conclusions

Introduction

Patients, materials and methods

Patients

The OGTT

Analytical methods

Statistical analysis

Results

Discussion

References