1 Priya Sivaraman Senior Product Manager Hemoglobin Testing Bio‐Rad Laboratories, Inc. priya_sivaraman@@bio‐rad.com June 2015 Learning Objectives Describe the importance of A1c testing by automated HPLC methods. Discuss the use of HbA1c for Screening and Diagnosis. Explain the limitations of various methods used for A1c testing. What we’ll cover Diabetes‐ Definition, Statistics A1c – Chemistry, Historical perspective, importance Methods for measuring A1c Screening and Diagnosis A1c on automated analyzer HPLC and Variant Detection Conclusion
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Priya Sivaraman
Senior Product Manager Hemoglobin Testing
Bio‐Rad Laboratories, Inc.
priya_sivaraman@@bio‐rad.com
June 2015
Learning Objectives
Describe the importance of A1c testing by automated HPLC methods.
Discuss the use of HbA1c for Screening and Diagnosis.
Explain the limitations of various methods used for A1c testing.
Diabetes is a group of diseases marked by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.
Insulin Dependent or Juvenile (IDDM)
A result of the destruction of insulin secreting pancreatic cells by the body’s own immune system
Treatment Daily Insulin Injections
Diet and Exercise
Prevalence 10% of diabetic population
Type 1 Diabetes
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Non‐Insulin Diabetes (NIDDM) or Adult onset Diabetes
Insulin Resistance
Inadequate insulin secretion
Treatment Drug Therapy
Insulin Injections if necessary
Diet and Exercise
Prevalence 90% of diabetic population
Type 2 Diabetes
If untreated Diabetes can cause
Eye Disease (retinopathy)
Kidney Disease (nephropathy)
Nerve Disease (neuropathy)
Heart Disease & stroke
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Global Diabetes Facts
U.S. Diabetes Facts (2012)
29.1M or 9.3% of the United States is diabetic
21M have been diagnosed
8.1M have not been diagnosed
http://www.cdc.gov/diabetes/index.htm
Once diagnosed, 2 methods are used to monitor diabetes disease and effectiveness of therapy
• Immediate (Many times a day)
‐ Blood Glucose Testing
• Long term (90 to 120 day)
‐ HbA1c Testing
Diabetes Monitoring
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RBC freely permeable to glucose
Glucose binds to hemoglobin in RBC
Glucose and hemoglobin
RBC & glucose in bloodstream
HbA1c is formed
Hemoglobin A1C
Red blood cells live for ~120 days
A1c represents the average blood glucose for the last 2‐3 months
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• Measures Hemoglobin A1c (HbA1c)
• Indicator of glycemic control over a 90 to 120 day period
• Performed 2 to 4 times a year
• Good Control 2 times/year
• Poor Control 4 times/year
• Ideal level is <6.5% HbA1c
Long term
HbA1c Monitoring
Multi‐center, randomized clinical trial
1,441 type 1 patients with diabetes participated
HPLC analyzer used for laboratory analysis
Subjects were randomly assigned to either intensive or conventional therapy
Overall cost: $165 million
Final report: ADA 1993 Annual Meeting
Ref: N Engl J Med 1993;329:977-86.
DCCT The Diabetes Control and Complications Trial
(1983 –1993)
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Glycemic Control
Ref: N Engl J Med 1993;329:977-86.
DCCT Study Results
Intensive therapy dramatically reduced risks for
development and/or progression of microvascular
complications of diabetes (eyes, kidneys, peripheral
nerves).
Benefit was directly related to glycemic control as
assessed by serial hemoglobin A1c determinations.
Ref: N Engl J Med 1993;329:977-86.
Risk of Retinopathy
0
4
8
12
16
20
24
0 1 2 3 4 5 6 7 8 9
Rat
e of
Ret
inop
athy
Pro
gre
ssio
n
Time During Study (Yrs)
Mean A1c = 11%
10%
9%
8%
7%
The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86.
9 Yrs
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Monitoring diabetes with HbA1c
Stratton IM, et al. BMJ 2000;321:405–12
HbA1c Advantages
No fasting
Better index of overall glycemic exposure and risk for long‐term complications
Indicator of glycemic control over a 90 to 120 day period
Well standardized
HbA1c is more reproducible and less cumbersome than OGTT
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Methods
Standardize glycohemoglobin test results (HbA1c) so that clinical laboratory
results are comparable to those reported in the DCCT where
relationships to mean blood glucose and risk for vascular complications have
been established
www.NGSP.org
NGSP Market Criteria ChangesYear Bias (95% CI of the difference
between method and NGSP)Precision
(CV)
2003 +/- 1.0% <5%
2005 +/- 1.0% <4%
2007 +/- 0.85% <4%
2010 +/- 0.75% N/A
2012 +/- 0.70% N/A
2014 +/- 6% N/A
2014 NGSP criteria corresponds to CAP Survey Grading criteria that has been +/- 6% since 2013A +/- 6% CAP Limit corresponds to +/-0.4% HbA1c at a target of 7% HbA1c
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Standardization Worked
www.NGSP.org
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
%H
bA
1c
1993 2012
Total GHB
HbA1
HbA1c
CAP Survey: Mean +/- 2sd
DCCTTarget
20041999
Method Groups
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
%H
bA
1c
1993 2012
Total GHB
HbA1
HbA1c
CAP Survey: Mean +/- 2sd
DCCTTarget
20041999
Method Groups
Paving The Way For DiagnosisHbA1c Ranges – Yesterday
HbA1c reflects a better index of overall glycemic exposure and risk for long‐term complications
HbA1c methods are now well standardized, reliable, and aligned to DCCT
Errors caused by non‐glycemic factors affecting HbA1c are infrequent and can be minimized – greater pre‐analytical stability
HbA1c is more reproducible and less cumbersome than OGTT
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ADA Recommendations
Diabetes Care, Vol 33, January 2010
• Testing for diabetes should be considered in all adults who are overweight (BMI 25 kg/m2) and have additional risk factors:
• First-degree relative with diabetes
• Members of a high-risk ethnic population (e.g., African American, Latino, Native American, Asian American, Pacific Islander)
• Women who delivered a baby weighing 9 lb or diagnosed with GDM
• Hypertension, High Cholesterol, High Triglyerides
• Women with polycystic ovary syndrome
• A1C 5.7%, IGT, or IFG on previous testing
• other clinical conditions associated with insulin resistance
Diabetes Care, Vol 33, January 2010
• In the absence of the above criteria, testing diabetes should begin at age 45 years
• If results are normal, testing should be repeated at least at 3-year intervals, with consideration of more frequent testing depending on initial results and risk status
ADA Recommendations Con’t
NGSP Certified Methods Only
Point of care HbA1c assays are only used for monitoring diabetes not screening for diabetes
HbA1c can be used for patients with Hb variants, but only those with normal RBC turnover. Assay must be free of interference from the Hb variant