Role of HbA1c in

Diabetes Mellitus
Prof. S. Thakur
 Diabetes management
 Comprehensive and holistic
 Defining, achieving, maintaining, and
monitoring various targets
 Glycemia
 HTN

 Dyslipidemia
 Why glycemia
 UKPDS/DCCT/Kemanoto study
Assessment of Glycemic
Goals
 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

 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
 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
 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
 Hemoglobin variant and chemically
modified Hb (carbamylated and
acetylated).
 Reduced RBC life span
 Impact on reactivity N terminal
amino group B chain
 Physiological
confounders
 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
 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% mg/dl mmol/l
5 97 (76-120) 5.4 (4.2 – 6.7)
6 126 (100-152) 7.0 (5.5 – 8.5)
7 154 (123 – 185) 8.6 (6.8 –
10.3)
8 183 (147 – 217) 10.2 (8.1-
12.1)
9 212 (170 – 249) 11.8 (9.4 –
13.9)
10 240 (193 – 282) 13.4
(10.7 – 15.7)
11 269 (217 – 314) 14.9
 Reference range of
HbA1c
 4-6% - NGSP, DCCT.
 2% - 4% - IFCC.
 AIC Targets
 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
 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
 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
 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.