The British Journal of Diabetes & Vascular Disease

The British Journal of Diabetes & Vascular
Disease
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How to diagnose diabetes? practicalities and comments on the WHO Provisional recommendation in
favour of HbA1c
Peter H Davies, Palanichamy Chellamuthu and Vinod Patel
British Journal of Diabetes & Vascular Disease 2010 10: 261
DOI: 10.1177/1474651410394258
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EDITORIAL
How to diagnose diabetes?
practicalities and comments on the
WHO Provisional recommendation
in favour of HbA1c
PETER H DAVIES1, PALANICHAMY CHELLAMUTHU2, VINOD PATEL2
Introduction
Abbreviations and acronyms
“We like glucose, we like HbA1c;
but which is better, and what should we do?”
Recently on British television, comedian Harry Hill settled similar
arguments with a fight. Gladly there were no fisticuffs in
Stockholm at the EASD-ADA joint symposium, entitled
“Provisional new WHO diagnostic criteria 2010”.
Professor Sir George Alberti began by outlining the history
and background to this issue. Previous committees had examined, but rejected HbA1c as recently as 2006 (table 1). A major
barrier had been lack of standardisation for the old DCCT-aligned
assay methodology. Since the widespread adoption of the IFCC
standard for HbA1c (2008), most diabetes associations have made
recommendations in favour of HbA1c and Alberti went on to
explain why, despite many detractors, the WHO Technical
Guideline Development Group has now done the same.
Whilst accepting that HbA1c-based diagnosis will not ‘capture’ exactly the same group of patients as an OGTT, he was
keen to remind his audience of the “chaos” that reigned prior
to acceptance of a worldwide standard in 1979. He proposed
that a move to HbA1c would represent a change on an altogether smaller scale.
Diagnostic criteria - the past
The lessons from history included such nuggets as how OGTT
cross-sectional data underpinning the 1978 diagnostic criteria
1
Sandwell Diabetes Centre, Sandwell NHS Trust, Birmingham, UK.
Diabetes and Endocrinology Centre, George Eliot Hospital NHS Trust,
Nuneaton, UK.
2
Correspondence to: Dr Vinod Patel
Diabetes and Endocrinology Centre,
George Eliot Hospital NHS Trust,
Nuneaton. CV10 7DJ, UK
Tel: +44 (0) 2476 865212; Fax: +44 (0) 2476 865210
E-mail: Vinod.patel@warwick.ac.uk
ADA
American Diabetes Association
DCCT
Diabetes Control and Complications Trial
DETECT-2IDF-WHO collaboration on detecting diabetes
2003-current
EASD
European Association for the Study of Diabetes
FPG
fasting plasma glucose
HbA1c
glycated haemoglobin A1c
IDF
International Diabetes Federation
IFCC International Federation of Clinical Chemists
NHANES
National Health and Nutrition Examination Survey
OGTT
oral glucose tolerance test
WHO
World Health Organisation
came only from three sources (NHANES, Pima Indians and
Egyptians), contrasting with thirteen studies from 9 countries in
the DETECT-2 Collaboration, which lends support to HbA1c use1.
Indeed the DETECT-2 Collaboration has suggested that the fasting glucose value, if used, should be lowered to 6.5mmol/L to be
consistent with the marked increase in diabetic retinopathy at
this level.
Hitherto, convenience has been at the heart of decisionmaking by the committee and Alberti described how the
11.1mmol/L cut-off was chosen: not for precision, but since it
represented a round figure of 200 mg/dL to US diabetes teams.
In 1999, the 7.0 mmol/L threshold was likewise chosen for
European convenience. Clinically, the fasting level was chosen
from the inflection point on the increasing prevalence of diabetic retinopathy versus fasting plasma glucose levels curve.
The variability of the OGTT, with results depending on dietary
preparation, was said to “tarnish” it, whilst stability and nonvariability of HbA1c make it in theory, a better test. Strengths and
weaknesses of each method are shown in table 2.
Attention was drawn to pre-analytical problems which
affect glucose measurement and how awareness of these issues
remains poor. Even in a fluoride tube, a blood sample stored at
room temperature for two hours may see a fall in glucose concentration of 5-7%, e.g. from 5.55 mmol/L to 4.88 mmol/L2.
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10.1177/1474651410394258
261
EDITORIAL
Table 1. Key events and recommendations concerning the diagnosis of diabetes mellitus
Year
Recommending body
Significance
1978-80
WHO-NDDG Criteria for the Diagnosis of Diabetes
First worldwide acceptance of unifying diagnostic criteria
Mellitus
1999
2006
2008-9
2009-10
WHO Revised Criteria for the Classification and
Introduction of impaired fasting glucose as an intermediate
Diagnosis of Diabetes (in parallel to similar ADA
hyperglycaemia entity.
Recommendations)
HbA1c considered, but rejected
WHO Definition and Classification of Diabetes
HbA1c reconsidered, but rejected.
Mellitus and Intermediate Hyperglycaemia
No change to diagnostic tests or thresholds.
EASD, ADA and IDF (incorporating WHO Expert
HbA1c as the diagnostic test
Group members)
Questioned term ‘prediabetes’
WHO Technical Guideline Development Group
Awaited, but likely to endorse:
HbA1c as the diagnostic test
Diagnosis must be confirmed by the same test
Key: ADA = American Diabetes Association; EASD = European Association for the study of Diabetes; IDF = International Diabetes Federation;
NDDG = National Diabetes Data Group; WHO = World Health Organisation
Table 2. Pros and cons of using either HbA1c or glucose-based tests for the diagnosis of diabetes mellitus
HbA1c measurement
Glucose measurements
Pros
Stable
Cons
Influenced by many factors:
Pros
Diabetes is a
Cons
Pre-analytical
Time averaged
Reproducible
Requires no
Haematinic: ‘Odd’ Hb
Systemic:
problems
Need to fast
fasting
Pregnancy
‘glucose disease’
Time honoured
Many data
Allows international
Dyslipidaemia
Malignancy
Cirrhosis
Renal disease
Table 3. Performance of diagnostic tests in predicting complications of
diabetes mellitus
Predicting microvascular events:
HbA1c > 2 hr = FPG
Predicting macrovascular events:
HbA1c > 2 hr >> FPG
Key: FPG = fasting plasma glucose; HbA1c = glycated haemoglobin A1c
Variable identification
Commenting on Alberti’s presentation, Knut Borch-Johnsen
(Steno Diabetes Centre, Copenhagen, Denmark) described
how there is no ‘gold standard’ and emphasised the fact that
different tests will not identify the same subjects. Furthermore,
it is vital not to switch between tests to confirm the diagnosis
in an individual.
comparison
Analysis accurate
Much cheaper
He presented data for FPG, the 2 hour OGTT post-challenge
glucose and HbA1c, illustrating clear differences in how well
each performed in predicting future microvascular and mac­
rovascular adverse outcomes in diabetes3. In both instances
HbA1c outperforms FPG and 2 hr OGTT (table 3). BorchJohnson pointed out how the argument over different tests
identifying different subjects is redundant: more importantly
HbA1c-based diagnosis is a better predictor of future diabetes
complications and so identifies the group at greatest risk.
In concluding the symposium Borch-Johnsen pointed out
that the world diabetes-community is losing patience (Germany,
USA and countries using ADA recommendations have already
adopted HbA1c as the preferred diagnostic test). He suggested
that if WHO continue to procrastinate, the EASD, ADA and IDF
should reconvene and endorse the WHO Technical Guideline
Development Group’s document.
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EDITORIAL
Table 4. Diagnostic criteria for diabetes mellitus and other dysglycaemia
HbA1c criteria: IFCC assay11
DCCT aligned – HbA1c (%)
IFCC- HbA1c (mmol/mol)
≥ 6.5
≥ 48
5.7 – 6.4
39-47
≤ 5.6
≤ 38
Diabetes mellitus
Pre-diabetes
Normal
Please note the above values may not apply in the following clinical circumstances
•Abnormal red cell turnover conditions: such as anaemias from haemolysis, spherocytosis or iron deficiency (such as in
pregnancy)
•Haemoglobinopathies: certain ones will affect diagnostic criteria (eg HbS, HbC, HbF, HbE). With Sickle cell trait, specific
HbA1c assays will overcome this problem.
•Rapid onset diabetes: such as most Type 1 diabetes mellitus and some Type 2: the HbA1c can be within the normal range
despite marked hyperglycaemia
•Near patient testing: using current HbA1c tests are not deemed to be sufficiently accurate for diagnosis
•In these and other cases where there is doubt as to the use of HbA1c, the glucose criteria below must be used. Renal failure
concerns can be overcome if specific assays are used.
Glucose criteria (mmol/L)
Diabetes mellitus
Impaired fasting glucose
Fasting*
Random
OGTT
(2 hr value)
≥ 7.0
≥ 11.1**
≥ 11.1
5.6 – 6.9
Impaired glucose tolerance
7.9 – 11.0
≤ 5.5
Normal
≤ 7.8
* includes fasting value on OGTT (oral glucose tolerance test) or no calorie intake for ≥8 hours.
** with classic symptoms or hyperglycaemic crisis.
Diagnosis of Diabetes Mellitus: Summary of ADA criteria12
Any one criterion is sufficient even if others normal
1: HbA1c: ≥ 6.5% (≥ 48 mmol/mol) using an IFCC standardised assay
2: Fasting glucose: ≥ 7.0 mmol/L
3: OGTT 2 hour value: ≥ 11.1 mmol/L
4: Random glucose ≥ 11.1 mmol/L with classic symptoms or hyperglycaemic crisis.
In the absence of classic symptoms or hyperglycaemic crisis,
criteria 1 - 3 need repeating.
Key: ADA= American Diabetes Association; DCCT= Diabetes Control and Complications Trial; HbA1c=glycated haemoglobin A1c; IFCC= International
Federation of Clinical Chemists; OGTT= oral glucose tolerance test
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
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263
EDITORIAL
Conclusions and final points
References
There are several points to consider before we wholeheartedly
accept the changes. Important clinical outcome-based studies
will be needed to assuage the legimate sceptics, included
amongst the authors of this editorial. Firstly, in the developing
world it is unlikely that HbA1c measurement will be affordable.
It is estimated to be over 13 times more expensive4. Whilst there
was a distinct inflection point for prevalence of diabetic retinopathy and a fasting glucose level there appears to be only a
continuous phenomenon with the HbA1c value5. The HbA1c criteria would change the prevalence of diabetes in USA to 19.7
million as opposed to 26.5 million with the OGTT, this is a
25.7% reduction4. Other studies confirm that the HbA1c diagnostic criteria will identify fewer patients6,7. A study in India
showed that an HbA1c of 6.1% had the best diagnostic performance for type 2 diabetes mellitus8. These concerns were further expressed in an EASD 2010 session9. What is not clear is
the harm (or benefit) conferred by not being diagnosed using
the HbA1c criteria in comparison to being diagnosed by the
glucose criteria. It is likely that important opportunities to formally diagnose impaired fasting glucose and effectively treat it
will be missed. It may well be that the “pre-diabetes” category
can be treated in the same way but evidence is lacking.
Nevertheless, global acceptance of HbA1c would not alter
worldwide prevalence of diabetes, whilst it may change within
each individual country, or region. An additional benefit is that
its adoption would help identify undiagnosed diabetes and prediabetes. We will also need to contend with the changing units
of expressing HbA1c from % to mmol/mol, however, this journal has already published a very useful article in this regard10.
In this time of change, in the meantime, the three less august
authors of this brief editorial offer the readers a practical table
for use in clinical practice (table 4).
1. Detect-2 Collaboration Writing Group: Colagiuri S, Lee CMY, Wong
TY et al. Glycemic thresholds for diabetes-specific retinopathy: implications for diagnostic criteria for diabetes. Diabetes Care 2010 (in
press).
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fluoride as a preservative of glucose in blood. Clin Chem 1989;35:
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3. DECODE Study Group. Is the current definition for diabetes relevant to
mortality risk from all causes and cardiovascular and noncardiovascular
diseases? Diabetes Care 2003, 26, 688-96
4. Gomez-Perez FJ, Aguilar-Salinas CA, Almeda-Valdes P, Cuevas-Ramos D,
Lerman Garber I, Rull JA. HbA1c for the diagnosis of diabetes mellitus
in a developing country. A position article. Arch Med Res. 2010 May;
41:302-8.
5. Sabanayagam C, Liew G, Tai ES, et al. Relationship between glycated
haemoglobin and microvascular complications: is there a natural cutoff point for diagnosis of diabetes? Diabetologia 2009;52:1279-89.
6.���������������������������������������������������������������������
Lorenzo C, Haffner SM. Performance
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7. Bao Y, Ma X, Li H et al . Glycated haemoglobin A1c for diagnosing
diabetes in Chinese population: cross sectional epidemiological survey.
BMJ 2010;340:c2249. doi: 10.1136/bmj.c2249.
8.����������������������������������������������������������������������
Ravi Kumar P, Bhansali A, ravikiran M et al. �������������������������
Utility of glycated hemoglobin in diagnosing type 2 diabetes mellitus: a community-based
study. J Clin Endocrinol Metab 2010;95:2832-35.
9. HbA1c for diabetes mellitus diagnosis: need for reassessment? EASD
2010 OP33. Abstracts 193-198. http://easd.conference2web.com/
content/all#/?events=3&page=1) Accessed November 2010.
10. Day C, Bailey CJ. HbA1c - Changing Units. Br J Diabetes Vasc Disease
2009;9:134-6.
11. Geistanger A, Arends S, Berding C et al on behalf of the IFCC Working
Group on Standardization of HbA1c: Statistical Methods for Monitoring
the Relationship between the IFCC Reference Measurement Procedure
for Hemoglobin A1c and the Designated Comparison Methods in the
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