Current and Future Challenges in Diabetes Prevention, Diagnosis

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Use of the Estimated Average Glucose (eAG) in
Patient Care
2
A Typical Patient Encounter

• So, Mrs. Smith, it looks like you do have
  diabetes. Your repeat fasting blood sugar was
  178, and as you recall the first one was 187.
  Over 126 is diabetes. Also, your hemoglobin A1c
  was way too high at 8.6. Normal is less than
  6. We need to get it below 7.

3
A Typical Patient Encounter

• Whats a hemoglobin Awhatever you said? I
  remember my hemoglobin was low when I was
  pregnant. What were those other numbers? What
  do you mean, 7...of what?

4
G
G
G
G
G
G
G
G
G
G
?
__
G

G
G
G
G
5
Uh
???
6
Its Not Just Confusing forNewly Diagnosed
Patients

• High levels of testing of HbA1c for patients with
  known diabetes (gt 90).
• Of patients with test in past 6 months
• 66 did not know result
• 25 accurately reported within 1 range
• (lt 7, 7-8, 8-9)
• 9 inaccurately reported within 1 range

Heisler, Diabetes Care 28816,2005
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The Clinical Dilemma

• HbA1c useful for research, risk prediction,
  target of therapy
• Well standardized
• HOWEVER, difficult to explain to patients
• Concept of is not intuitive
• Glucose more familiar to patients from
  self-monitoring or from laboratory glucose results

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The Concept of Average Glucose

• We tell patients the HbA1c reflects their
  average glucose over 2-3 months
• But do we know this for sure?

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The A1C-Derived Average Glucose (ADAG) Study

• International study designed to
• Carefully look at relationship between HbA1c and
  average glucose
• Determine the mathematical relationship between
  the two for reliable conversion
• Establish that the relationship is valid across
• - Diabetes types
• - A wide range of HbA1c levels and age
• - Different races/ethnicities

Nathan et al, Diabetes Care 311473, 2008
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ADAG Study Centers

• Cameroon
• Denmark
• Italy
• The Netherlands

• United States
• Boston
• New York
• San Antonio
• Seattle
• India (site dropped due to specimen handling
  issues)

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Participants in ADAG

• Goal was to recruit people with
• Type 1 diabetes
• Type 2 diabetes
• No diabetes
• With a range of
• Ethnicity/race
• HbA1c levels
• Excluded those with conditions that would
  interfere with measurement/interpretation of
  HbA1c or glucose

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Measures of Glycemia in ADAG Study

• CGM (calibrated by 8-point glucose profiles with
  Hemocue meter) for at least 48 hours at baseline
  and every month for 3 months
• 7-point glucose profiles for 3 days per week with
  One Touch Ultra meter
• HbA1c at baseline and monthly X 3 months with
  DCCT-aligned assay in a central laboratory
• Four measures of HbA1c to assure stable control,
  but only final value used for correlation with
  prior 3 months glucose readings

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ADAG Study Flow
Total Enrolled 661 Eliminated from analysis 154
(23) - Dropped out or excluded 91 (14)
during study - Inadequate CGM 11 (2)
- Inadequate HbA1c samples 52 (8)
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Baseline Characteristics of ADAG Participants
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ADAG Study Distribution of Baseline HbA1c
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Number of subjects
38
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Baseline HbA1c ()
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ADAG Study Glucose Monitoring

• CGM mean of 2,400 measurements per
  participant
• LifeScan meter mean of 300 measurements per
  participant
• Mean of 25 measurements per week
• Goal was a minimum of 21 tests per week
• Total 2,700 measurements/participant during 12
  weeks

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ADAG Study Analyses

• CGM results corrected upward by 5 to be
  consistent with BG
• Each glucose measure weighted in proportion to
  the inverse of total number of measurements on
  that day (each day had equal weight)
• Arithmetic mean glucose calculated for each
  participant
• Linear regression model used to estimate
  relationship between average glucose and the
  3-month HbA1c

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ADAG Study Study Success
90 of values fell within /- 15
HbA1c ()
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ADAG Study Correlation of AG With HbA1c
AG (mg/dl) 28.7 x HbA1c 46.7 R2 0.84
P lt 0.0001
AG (mg/dl)
HbA1c ()
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ADAG Study Correlation of AG with HbA1c CGM
data vs. Meter
No difference in relationship (P0.18) whether
LifeScan or CGMS data used
HbA1c ()
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ADAG Study Other Factors Examined

• Does the HbA1c-Average Glucose relationship
  differ by
• - Type 1 or type 2 diabetes NO
• - Diabetes or no diabetes NO
• - Amount of glucose variability NO
• - Gender NO
• - Age NO
• - Ethnicity/Race NO
• (but trend toward higher HbA1c per AG in
  African and African-American participants vs.
  whites, P0.07)
• - Smoking NO

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ADAG Study Excluded Known Sources of Inaccuracy
of HbA1c

• Hemoglobinopathy
• Anemia
• Pregnancy
• Hepatic or renal disease
• Etc.

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ADAG Study Conclusion HbA1c Correlates Highly
With AG
450
400
AG (mg/dl) 28.7 x HbA1c 46.7
350
300
AG (mg/dl)
250
200
150
100
50
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4
5
6
7
8
9
10
11
12
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Measured HbA1c ()
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Implications

• Tight correlation between HbA1c and AG allows us
  to translate HbA1c into an estimated Average
  Glucose (eAG)
• eAG will apply to the majority of patients with
  diabetes
• Barring traditional conditions interfering with
  the assay or the relationship between glycemia
  and HbA1c

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ADAG Study Translation of HbA1c into eAG
eAG HbA1c () (mg/dl) (mmol/l)_ 5
97 5.4 6 126 7.0 7 154
8.6 8 183 10.2 9 212 11.8 10
240 13.4
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Note that the numbers are different
ADAG DCCT HbA1c () (mg/dl)___(mg/dl)______
6 126 135 7 154 170 8 183
205 9 212 240 10 240 275
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Consensus Statement FCC, EASD, IDF, ADA Sept 2007)

• HbA1c assay to be standardized worldwide using
  the new IFCC standard and expressed as
• as currently used (DCCT values)
• IFCC units in mmol HBA1c/mol HbA
• eAG in mmol/l or mg/dL (if ADAG study meets its
  data acceptability goals)
• This paved the way for reporting both HbA1c and
  EAG on lab reports

Diabetes Care and Diabetologia, 2007
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What Wont ChangeAnd Whats New

• To a clinician, there is no change in the HbA1c
  assay
• To clinical chemists, there is a new IFCC
  standard in the background
• We have the potential for a valuable educational
  tool for patients

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A Typical Patient Encounter

• So, Mrs. Smith, it looks like you do have
  diabetes. Your average blood sugar is around 200.
  When people dont have diabetes, this number is
  below 125. We need to work with you to try to
  get this number, the average glucose, down below
  150 over the next few months with some weight
  loss, exercise, and a medication. Lets talk some
  more about what you can do

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A Typical Patient Encounter
Wow, Im not happy to hear thatI know that
diabetes can do some bad things. Tell me what I
can do to get my average glucose down.
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What is ADA Doing to Promote Use of eAG in
Patient Care?

• Health care provider education
• ADA Scientific Sessions, June 08
• American Association of Clinical Chemists, August
  08
• AADE Annual Meeting, August 08
• eAG calculators (handheld and on
  professional.diabetes.org)
• Patient education
• Website
• Diabetes Forecast magazine, books
• Pamphlets and brochures
• ADA will include term average glucose in all
  consumer pieces

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What Can Clinicians and Educators Do?

• Choose which termA1C or Average Glucoseto use
  with each patient (some may already be used to
  A1C)
• In verbal communications, no need to say
  estimated
• We want to keep the A in A,B,Cs
• Use updated table, calculator on
  www.diabetes.org, or other tools to convert A1C
  to average glucose
• Lobby your lab to report both numbers

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What Can Clinical Chemists Do?

• Even with tools, most clinicians will not take
  the time to calculate conversions
• Reporting both HbA1c (DCCT-aligned) AND eAG on
  lab reports will do the most to promote wide use
  of the term
• Professional and patient education may drive
  demand
• Conversion is a simple regression equation

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Average Glucose Blood pressure Cholesterol
to help make the A understandable!