Role of HbA1c in Diabetes Mellitus

Prof. S. Thakur

Diabetes management
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Comprehensive and holistic Defining, achieving, maintaining, and monitoring various targets
Glycemia  HTN  Dyslipidemia

Why glycemia

UKPDS/DCCT/Kemanoto study

Assessment of Glycemic Goals
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SMBG HbA1c Glycated Protein (Fructosamine) Continuous blood glucose monitoring 1,5 anhydroglucitol (1,5 AG)

History of HbA1c

S. Rahbar 1960 – description of abnormal Hb in DM 1970 – HbA1c increases in direct proportion to hyperglycemia Koenig RJ 1976 – periodic HbA1c monitoring indicates degree of control 1980 – HbA1c available as method of glucose monitoring

HbA1c – not fully integrated in management of DM in India
5.9% - tested at diagnosis Bjork et  7.6% - tested at diagnosis al;2003

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Mean HbA1cin India (8.9 +/- 2.1%) Diab care Asia Other Asian Countries (8.6 +/-1998 2%) Significant higher HbA1c>2% above normal in India. Chuang et al. Diabet Med. 2002.

Terminology
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HbA – unglycated hemoglobin. GHb – Glycated Hb
HbA1 – Carbohydrates bound to N terminal valine of B chain. HbA1a1 – Fructose 1-6 bisphospate ” HbA1a2 – Glucose – 6 – phosphate ” HbA1b – Unknown carbohydrate residue ” HbA1c – Glucose bound to N terminal of valine of B chain

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Steps in glycation

Non – enzymatic binding of glucose to various proteins Maillard reaction
Freee amino group (Hb) = aldehyde group (glucose) shiff base (alamine labie form)  Alamine (shiff base) ketoamine (amadori rearrangement)

Methods used for determination of HbA1c

A1c Assay – percent of hemoglobin that is glycated
Boronate affinity chromography  Cation or ion exchange chromatography (HPLC, LPLC)  Immuno assay (turbidometry)  Agar gelelectrophoresis  Mass spectroscopy  Capillary electrophoresis.

Confounders for determination of HbA1c

When to suspect
HbA1c reading low or high  Significant change in various methods

Types of confounders
Methodological  Physiological

Methodological confounders

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Hemoglobin variant and chemically modified Hb (carbamylated and acetylated). Reduced RBC life span Impact on reactivity N terminal amino group B chain

Physiological confounders
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RBC kinetic – decreased RBC life span -Decreased HbA1c Kidney, liver disease, hemolytic anemia, hemoglobinopathies and recovery from blood loss. Decreased erythropoiesis – increased HbA1c – Aplastic anemia, Iron deff. Anemia. Inhibition of glycation decreased HbA1c – Vit C, Vit E. Pregnancy – HbA1c lower (decreased RBC

Contribution of fasting and PP sugar to HbA1c

Relationship of HbA1c to mean plasma glucose (DCCT trial)
A1c Mean plasma glucose (mg/dl) Mmol/l 6 135 7.5 7 170 9.5 8 205 11.5 9 240 13.5 10 275 15.5 11 310 17.5 12 345 19.5

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A1c derived average glucose (ADAG) – CAG (diabetes care Aug 2008)
eAG (mg/dl)= 28.7 x A1c – 46.7 eAG (mmol/dl) = 1.5 A1c – 2.59
A1c% 5 6 7 10.3) 8 12.1) 9 13.9) 10 (10.7 – 15.7) 11 mg/dl 97 (76-120) 126 (100-152) 154 (123 – 185) 183 (147 – 217) 212 (170 – 249) 240 (193 – 282) 269 (217 – 314) mmol/l 5.4 (4.2 – 6.7) 7.0 (5.5 – 8.5) 8.6 (6.8 – 10.2 (8.111.8 (9.4 – 13.4 14.9

Reference range of HbA1c
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4-6% - NGSP, DCCT. 2% - 4% - IFCC.

AIC Targets
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AIC Targets Level of Disease ADA - <7% A DAF - <6.5% >6% ? B No single HbA1c that confer maximum benefit Targets individualized, balancing optimal control, safety, feasibility. Less stringent goals in – h/o hyperglycemic episodes, limited life expectancy in children, comorbidities, long standing DM with stable or minimal microvascular complications (E)

Frequency of monitoring HbA1c

3 month
unstable DM  change of treatment

6 month

stable DM

Pregnancy – more frequent

Clinical application of HbA1c
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Only indicated for monitoring, not diagnosis & screening Curvilinear relationship between HbA1c and microvascular complications( DCCT/EDIC/UKPDS/kumomoto study) Evidence for CVD reduction – only epidemiological evidence Lowering AIc from 7% - 6% absolute risk reduction however smaller given increased risk of hypoglycemia

Limitation

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Only for monitoring not diagnosis and screening Hypoglycemic episodes not detected Variability not detected Methodological and physiological confounders Lack of standardization/availability/cost Weighted to most recent change
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50% HbA1c – 30 days 25% HbA1c – 30-60 days 25% HbA1c – 60 – 120 days

Fructosamine vs. HbA1c

Alternative or suppplement to HbA1c in glycemic control Particularly in pregnancy or altered RBC kinetics Unlike HbA1c Fructosamine has not proven to be reliable and useful in routine management of Diabetes

SMBG vs HbA1c

Both are complimentary in management SMBG – predominantly point of care testing and type 1 and type 2 on insulin treatment.

Utility

A1c serves as check on accuracy of meter. Adequacy of SMBG testing schedules.

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