HbA1c as a compass- pointing you to the right diagnosis? Eric S. Kilpatrick Department of Clinical Biochemistry Hull Royal Infirmary/Hull York Medical School

HbA 1c : Historical Aspects 1962: Huisman and Dozy Increases in minor fractions of haemoglobin in four diabetic patients treated with tolbutamide. 1968: Rahbar ‘Diabetic haemoglobin component’ found in 49 Iranian diabetic patients. 1968: Rahbar Component the same structure as the previously described HbA 1c

Formation of Glycated Haemoglobin

HbA 1c : Historical Aspects HbA 1c correlated with: Plasma ‘glucose brackets’ Koenig RJ et al. N Engl J Med 1976; 295: Daily mean plasma glucose Gonen B et al. Lancet 1977; ii; hour urinary glucose excretions Gabbay KH et al. J Clin Endocrinol Metab 1977; 44: Glucose control over past 6-8 weeks Goldstein D et al. Clin Chem 1986; 32(Suppl): B64-70

DCCT: Risk of Microvascular Complications DCCT Group. N Engl J Med. 1993; 329:

Retinopathy Risk Reduction Absolute risk reduction in falling from: HbA1c= 86 mmol/mol (10%) to HbA1c= 83mmol/mol (9.7%) is the same as HbA1c= 53mmol/mol (7%) to HbA1c= 36mmol/mol (5.4%)

UKPDS: Risk of Macro and Microvascular Complications UKPDS Group. BMJ 2000;321:

HbA 1c : Historical Aspects HbA 1c correlated with: Plasma ‘glucose brackets’ Koenig RJ et al. N Engl J Med 1976; 295: Daily mean plasma glucose Gonen B et al. Lancet 1977; ii; hour urinary glucose excretions Gabbay KH et al. J Clin Endocrinol Metab 1977; 44: Glucose control over past 6-8 weeks Goldstein D et al. Clin Chem 1986; 32(Suppl): B64-70

Model of Glycated Haemoglobin Formation

y= 2x -x 2

What about using HbA1c to diagnose diabetes? Why did it take so long?

Advantages in using HbA1c Does not require a fasting sample Assesses glycaemia over previous weeks/months Lower biological variability than FPG or 2hr Fewer pre-analytical concerns Already used to guide management

HbA1c to diagnose diabetes Lack of standardisation in measurement Unsure whether it was as good as glucose in diagnosing diabetes

DCCT vs. IFCC HbA1c DCCT HbA1c (%) IFCC (SI) HbA1c (%)

DCCT vs. IFCC HbA1c DCCT HbA1c (%) IFCC (SI) HbA1c (mmol/mol)

DCCT vs. IFCC HbA1c DCCT HbA1c (%) IFCC (SI) HbA1c (mmol/mol) Clin Chem Lab Med 2007;45:

HbA1c to diagnose diabetes Lack of standardisation in measurement Unsure whether it was as good as glucose in diagnosing diabetes

What is diabetes defined as being? Someone at increased risk of heart disease X Someone at increased risk of diabetic retinopathy Someone at increased risk of diabetic nephropathy  X

DETECT-2 study n=44,623 ROC 0.90 ( ) ROC 0.87 (95% CI ) ROC 0.89 ( ) Diabetes Care doi: /dc

HbA1c and CV risk ARIC (n=11,092) HbA1c was as predictive of future diabetes as FPG HbA1c was at least as predictive as FPG for CV disease No mention of 2hr glucose N Engl J Med 2010;362:

HbA1c vs. glucose for detecting vascular complications

But Doctor, WHO

WHO, January

Executive Summary

UK Guidance John et al Practical Diabetes 2012; 29: 12-13

UK Guidance Diabet. Med. 29, 1350–1357 (2012)

Some case studies

56 yr old male BMI 34kg/m 2 Father developed type 2 diabetes aged 60 years Asymptomatic Glucose or HbA1c? HbA1c 45mmol/mol

What would you do next? Check a fasting glucose now and repeat HbA1c in a year X Check a fasting blood glucose immediately Check HbA1c in a year X 

56 yr old male BMI 34kg/m 2 Father developed type 2 diabetes aged 60 years Asymptomatic Fasting glucose 6.5mmol/L

What would you do next? Check the fasting glucose X Do a GTT Check HbA1c  X

16 year old boy BMI 38kg/m 2 Lethargic for last year Glucose + in urine Glucose or HbA1c?

68 year old female BMI 32kg/m 2 Thirst and polyuria for the last 2 weeks

What would you do next? A fasting glucose X An HbA1c A fasting or a non-fasting glucose X 

DO NOT use HbA1c in these circumstances All children and young people. Pregnancy—current or recent (< 2 months). Suspected type 1 diabetes, no matter what age Short duration of diabetes symptoms. Patients at high risk of diabetes who are acutely ill

DO NOT use HbA1c in these circumstances Patients taking medication that may cause rapid glucose rise; for example, corticosteroids, antipsychotic drugs (2 months or less). Acute pancreatic damage or pancreatic surgery. Renal failure. Human immunodeficiency virus (HIV) infection.

BE CAREFUL using HbA1c in these circumstances Abnormal haemoglobins Anaemia Altered red cell lifespan Ethnicity

HbA1c vs. glucose for detecting vascular complications

Predicting risk using glucose and HbA1c GlucoseHbA1c

Summary HbA1c can now be used for type 2 diabetes diagnosis POCT HbA1c measurement is not currently recommended Be mindful of the exclusions to using the test Do not ‘mix and match’ HbA1c and glucose