The British Journal of Diabetes & Vascular Disease http://dvd.sagepub.com/ 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 The online version of this article can be found at: http://dvd.sagepub.com/content/10/6/261 Published by: http://www.sagepublications.com Additional services and information for The British Journal of Diabetes & Vascular Disease can be found at: Email Alerts: http://dvd.sagepub.com/cgi/alerts Subscriptions: http://dvd.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://dvd.sagepub.com/content/10/6/261.refs.html >> Version of Record - Dec 21, 2010 What is This? Downloaded from dvd.sagepub.com by guest on September 22, 2014 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: [email protected] 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. © THE The BRITISH Author(s), JOURNAL 2010. Reprints OF DIABETES and permissions: AND VASCULAR http://www.sagepub.co.uk/journalsPermissions.nav DISEASE Downloaded from dvd.sagepub.com by guest on September 22, 2014 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. VOLUME 10 ISSUE 6 . NOVEMBER/DECEMBER 2010 262 Downloaded from dvd.sagepub.com by guest on September 22, 2014 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 Downloaded from dvd.sagepub.com by guest on September 22, 2014 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). 2. Chan AYW, Swaminanthan R, Cockram CS. Effectiveness of sodium fluoride as a preservative of glucose in blood. Clin Chem 1989;35: 315-17. 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 ���������������������������������������������� characteristics of the new definition of diabetes: the insulin resistance atherosclerosis study. Diabetes Care 2010;33:335-7. 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 United States, Japan and Sweden. Clin Chem 2008; 54: 1379-8 12. ADA. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33. Suppl 1: S62-S69. VOLUME 10 ISSUE 6 . NOVEMBER/DECEMBER 2010 264 Downloaded from dvd.sagepub.com by guest on September 22, 2014
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