HbA1c as a compass-pointing you to the right diagnosis?

Eric S. KilpatrickDepartment of Clinical Biochemistry

Hull Royal Infirmary/Hull York Medical School

HbA1c: Historical Aspects1962: 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: RahbarComponent the same structure as the previously described HbA1c

Formation of Glycated Haemoglobin

HC=O HC=N-A HC=N+H2-A HCOH HCOH HCOH HOCH HOCH HOCH

-NH2 + HCOH HCOH HCOH HCOH HCOH HCOH

CH2OH CH2OH CH2OH

Glucose Schiff Base Amadori Product (Aldimine) (Ketoamine)

HbA1c: Historical Aspects

HbA1c correlated with:• Plasma ‘glucose brackets’

Koenig RJ et al. N Engl J Med 1976; 295: 417-420

• Daily mean plasma glucoseGonen B et al. Lancet 1977; ii; 734-737

• 24 hour urinary glucose excretionsGabbay KH et al. J Clin Endocrinol Metab 1977; 44: 859-864

• Glucose control over past 6-8 weeksGoldstein D et al. Clin Chem 1986; 32(Suppl): B64-70

DCCT: Risk of Microvascular Complications

DCCT Group. N Engl J Med. 1993; 329: 977-86

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;321:405-412

HbA1c: Historical Aspects

HbA1c correlated with:• Plasma ‘glucose brackets’

Koenig RJ et al. N Engl J Med 1976; 295: 417-420

• Daily mean plasma glucoseGonen B et al. Lancet 1977; ii; 734-737

• 24 hour urinary glucose excretionsGabbay KH et al. J Clin Endocrinol Metab 1977; 44: 859-864

• Glucose control over past 6-8 weeksGoldstein D et al. Clin Chem 1986; 32(Suppl): B64-70

Model of Glycated Haemoglobin Formation

0123456789

0-1 month 1-2 months 2-3 months 3-4 months

Red Cell Age

HbA

1c (

%)

Model of Glycated Haemoglobin Formation

0

20

40

60

80

100

120

0 1 2 3 4 5

Months Prior to Sampling

% o

f H

bA

1c V

alu

e

y= 2x -x2

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

(%)

6

7

8

9

10

IFCC (SI) HbA1c(%)

4.2

5.3

6.4

7.5

8.6

DCCT vs. IFCC HbA1c

DCCT HbA1c

(%)

6

7

8

9

10

IFCC (SI) HbA1c(mmol/mol)

4.2

5.3

6.4

7.5

8.6

DCCT vs. IFCC HbA1c

DCCT HbA1c

(%)

6

7

8

9

10

IFCC (SI) HbA1c(mmol/mol)

42

53

64

75

86

Clin Chem Lab Med 2007;45:1081-1082

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 heartdiseaseX

• Someone at increased risk of diabeticretinopathy

• Someone at increased risk of diabeticnephropathy

X

DETECT-2 study n=44,623

ROC 0.90(0.88-0.92)

ROC 0.87(95% CI 0.85-0.89)

ROC 0.89(0.87-0.91)

Diabetes Care doi: 10.2337/dc10-1206

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;362:800-11.

HbA1c vs. glucose for detecting vascular complications

But Doctor, WHO

WHO, January 2011

www.who.int/cardiovascular_diseases/report-hba1c_2011_edited.pdf

Executive Summary

www.who.int/cardiovascular_diseases/report-hba1c_2011_edited.pdf

UK Guidance

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

UK GuidanceDiagnosing Diabetes - NON-URGENT situations in adults over 18years old

Laboratory venous HbA1c (ensure CPA accredited lab)

Symptoms Symptoms Present Absent Rpt HbA1c test Within 2 weeks Diabetes Manage as High Diabetes Risk Diabetes extremely unlikely Diagnosis High DM Risk CVD risk factor management May still be high risk Confirmed Rpt HbA1c at 6mths Lifestyle measures Lifestyle and CVD Rpt HbA1c at a year, earlier if management as clinically Any diabetes Sx develop. Indicated.

Asymptomatic targeted screening Mild symptoms possible diabetes of MORE than 2 months duration

HbA1c 42-47mmol/mol HbA1c <42mmol/mol HbA1c ≥ 48mmol/mol

<48mmol/mol ≥48mmol/mol

Diabet. Med. 29, 1350–1357 (2012)

Some case studies

56 yr old male

• BMI 34kg/m2

• 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 repeatHbA1c in a yearX

• Check a fasting blood glucoseimmediately

• Check HbA1c in a year

X

56 yr old male

• BMI 34kg/m2

• Father developed type 2 diabetes aged 60 years

• Asymptomatic

• Fasting glucose 6.5mmol/L

What would you do next?

• Check the fasting glucoseX

• Do a GTT

• Check HbA1c

X

16 year old boy

• BMI 38kg/m2

• Lethargic for last year

• Glucose + in urine

• Glucose or HbA1c?

68 year old female

• BMI 32kg/m2

• Thirst and polyuria for the last 2 weeks

What would you do next?

• A fasting glucoseX• 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

Glucose HbA1c

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