1,5 Anhydroglucitol and the Monitoring of Postprandial Glucose Control

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GLYCOMARK
A BLOOD TEST FOR GLYCEMIC VARABILITY
R. Scott Foster, Ph.D. TOMA-Texas ACOFP Annual
Joint Conference Arlington, Texas June 11, 2009
Sponsored by Quest Diagnostics, Inc.
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The Glycemic Triad
HbA1c
Long term average glucose level
POSTPRANDIAL HYPERGLYCEMIA
FPG
Basal glucose level
Glycemic Variability
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POSTPRANDIAL HYPERGLYCEMIA
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Duration of daily metabolic conditions
Post absorptive
Fasting
Monnier L. Eur J Clin Invest 200030(Suppl.
2)311
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As Patients Get Closer to A1C Goal, the Need to
Successfully Manage PPG Significantly Increases
Adapted from Monnier L, Lapinski H, Collette C.
Contributions of fasting and postprandial plasma
glucose increments to the overall diurnal hyper
glycemia of Type 2 diabetic patients variations
with increasing levels of HBA(1c).Diabetes Care.
200326881-885.
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Moving from A1C 8.0 to 7.0Difficult and
Important!!

• 20-25 of Patients Have A1Cs between 8.0 and
  7.0
• Moving from A1C 8.0 to 7.0 - Reduces Serious
  Complications
• UKPDS Study Results
• Reduced microvascular complications (kidney, eye,
  etc.) by 17-33
• Reduced risk of heart attack by 16
• Reduced diabetes-related deaths by 21
• Challenge More difficult to make improvements as
  A1C gets closer to 7.0

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Reducing A1C Levels Reduces Incidence of
Complications
DCCT 9 ? 7.2 63 54 60 41
Kumamoto 9 ? 7 69 70 Improved -
HbA1c Retinopathy Nephropathy Neuropathy Cardiova
scular disease
UKPDS 8 ? 7 17-21 24-33 - 16
NCS
DCCT Research Group. N Engl J Med.
1993329977-986. Ohkubo Y, et al. Diabetes Res
Clin Pract. 199528103-117. UKPDS 33 Lancet
1998 352, 837-853. Slide modified from J. Buse
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Coronary Artery Disease and Postprandial
Hyperglycemia
Mellen PB et al. Arterioscler Thromb Vasc Biol.
200626189-193.
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Summary

• Postprandial glycemia plays a clinically
  important role in the complications of diabetes
• Postprandial glycemia is a major contributor to
  overall glycemic control ESPECIALLY in
  moderately-well to well controlled patients

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So How Can We Assess Post-Prandial Glucose
Control Clinically ??

• Frequent fingersticks
• HbA1C
• Fructosamine
• Continuous Glucose Monitoring Systems
• Sensor-Augmented Insulin Pumps

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A New Approach to Monitoring Glycemic
Variability
1,5-Anhydroglucitol (1,5-AG) GlycoMark
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1,5-AG Physiology
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The structure of 1,5-anhydroglucitol (1,5AG)
D-glucose
1,5-anhydro-D-glucitol (1-deoxyglucose)
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Physiology of 1,5-AG
Oral Supply 1,5AG (5-10mg/day)
Oral Supply 1,5AG (5-10mg/day)
Normoglycemia
Hyperglycemia
Tissues Internal Organs (500- 1000 mg)
Tissues Internal Organs (500- 1000 mg)
Blood Stream (1,5-AG Level Lower)
Blood stream
Glucose Blocks Reabsorption
Kidney
Kidney
Urinary excretion (5-10mg/day)
Urinary excretion (INCREASED)
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Relationship of Blood Glucose and 1,5-AG

• As postprandial glucose rises in blood over
  the renal threshold of 180
  mg/dL glucosuria occurs.
• Excessive glucose in urine competitively
  inhibits the reabsorption of 1, 5AG into the
  bloodstream at the proximal renal tubules.

GLUCOSE gt180 mg/dL

• As glucose blood levels increase, 1,5AG blood
  levels decrease.
• 1,5AG blood levels less than 10 µg/ml are
  abnormal.

GLYCOMARK
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GLYCOMARK AND POSTPRANDIAL BLOOD GLUCOSE
CORRELATIONS
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INTERPRETING GLYCOMARK RESULTS
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GLYCEMIC BLOOD MARKERS
1,5 - AG
FBG
Fructosamine
HbA1c
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3
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8
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WEEKS PRIOR TO MEASUREMENT
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GlycoMark Monitors Postprandial Hyperglycemia
Dungan, K., Buse, J. et al. Diabetes Care (June
2006)
Patients were sorted by glycemic excursions as
measured by CGMS (AUC-180) and subdivided into
two populations bottom 50th percentile (17
patients) and top 50th percentile (17 patients).

• Authors Conclusions
• 1,5-AG (GlycoMark) assay reflects glycemic
  excursions, often in the postprandial state, more
  robustly than other established glycemic
  assays.
• 1,5-AG was reflective of varying post meal
  glucose levels, despite similarities in A1Cs.
• In clinical practice, A1C and 1,5-AG may be used
  sequentially, first employing the A1C assay to
  identify patients who are moderately controlled
  and then using the 1,5-AG assay to determine the
  extent of postprandial glycemic excursions.

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A1C values can be misleading

• Nearly 40 of diabetes patients in good control
  have persistently elevated glucose levels and
  significant glucose variability.
• (Bonora et al. Diabetologia 2006)
• These patients are at high risk of developing of
  developing serious complications.

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GlycoMark Reveals Elevated PPG Levels in
Patients with Good A1Cs
52 year old female with type 1 DM A1C
7.43 1,5-AG 12.4 µg/ml PPG max 195 mg/dL
49 year old male with type 2 DM A1C 7.27 1,5-AG
4.5 µg/ml PPG max 235 mg/dL
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GlycoMark values gt 10 µg/ml indicate normal
glycemic control.
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TYPE 2 DIABETES 1,5-AG, HbA1c and PPG CONTROL

• 10 of 22 patients (45) did not control PPG.
• 8 of 18 patients (44) at A1c goal ( 7) did not
  control PPG.
• 2 of 4 patients between 7 and 8.5 A1c did not
  control PPG.

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1,5-AG, A1c and Glycemic Variability
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GLYCEMIC VARIABILITY AND ENDOTHELIAL DYSFUNCTION
Glucose Pulse (15 mmole/l)
15 mmole/l (270 mg/dL)
10 mmole/l (180 mg/dL)
FMD Flow-Mediated Dilatation
Antonio Ceriello et al. Oscillating Glucose Is
More Deleterious to Endothelial Function and
Oxidative Stress Than Mean Glucose in Normal and
Type 2 Diabetic Patients. Diabetes, Vol. 57, May
2008.
HRS
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A1C DERIVED AVERAGE GLUCOSE STUDY (ADAG)
1,5 ANHYDROGLUCITOL AND GLYCEMIC VARIABILITY

• Correlations of 1,5-AG and glycemic variability
  measures were examined in ADAG study population
• GV Measures SD, AUCgt180, MAGE, CONGA obtained
  from CGM
• Study Population T1DM (n343) and T2DM (n268)
• Statistical Analyses Pearson Correlations and
  ROC

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A1c Derived Average Glucose Study (ADAG)
1,5 anhydroglucitol and Glycemic Variability
P-VALUE lt0.01
MBG Mean Blood Glucose SD Standard
Deviation MAGE Magnitude of the Amplitude of
Glycemic Excursions CONGA AVERAGE Continuous
Overlapping Net Glycemic Action and AUC gt180
Area Under the Curve over 180 mg glucose/dL.
Kunen, J.C., R. Borg, E. Button, B. Fabriek, D.
Nathan, H. Zheng, P. Kostense, R. Heine and M.
Diamant. 1,5 Anhydroglucitol Concentrations and
Measures of Glucose Control and Variability in
T1DM and T2DM patients. 2009 Annual Meeting of
the American Diabetes Association. June 2009.
Abstract number
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A1C DERIVED AVERAGE GLUCOSE STUDY (ADAG)
1,5 ANHYDROGLUCITOL AND GLYCEMIC VARIABILITY
CONCLUSIONS

• 1,5-AG correlates significantly with measures of
  glycemic variability with A1C levels lt 8.0
• ROC analyses confirm that 1,5-AG can detect
  hyperglycemic episodes (AUC gt 180) data not
  shown
• Validates role of 1,5-AG as marker of glycemic
  variability
• Supports use of 1,5-AG, in conjunction with A1C,
  to assess glycemic variability and hyperglycemic
  episodes in well to moderately controlled
  patients

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TYPE 1 DIABETES 1,5-AG, A1c AND GLYCEMIC
VARIABILITY

• 6 OF 7 PATIENTS HAVE HIGH GLYCEMIC VARIABILITY
• 5 OF 6 PATIENTS 7 HbA1c HAVE GLYCEMIC
  VARIABILITY.

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GlycoMark Reveals Underlying Treatment
Effects
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Revealing Underlying Treatment EffectsExenatide

• Objective To assess 1,5-AG as a marker of PPG
  control in exenatide-treated patients with type 2
  diabetes (T2DM)
• 144 Patients
• Initial A1C levels 8.2 /-1
• Randomized to exenatide (5 or 10 µg) or placebo
• Thirty week study
• Presented at ADA 2007 Annual Meeting

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Revealing Underlying Treatment
EffectsExenatide
Comparison of Changes in Values from Baseline to
Study End
P lt 0.05 P lt 0.01
Correlations Changes from baseline 1,5-AG vs.
HbA1C r - 0.74 P lt0.0001 1,5-AG vs. fasting
plasma glucose (FPG) r -0.54 P lt0.0001
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The Use of 1,5 anhydroglucitol (GlycoMark) to
monitor new classes of therapies for managing
post meal glucose in patients with diabetes
Comparison of Changes in Values from Baseline
to Study End Treated Populations
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UTILIZING GLYCOMARK TO ATTAIN TREATMENT GOALS
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(No Transcript)
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Target Glycemic Goals

• GlycoMark gt 10 µg/ml
• A1C lt7.0 (6.5 AACE Goal)
• GlycoMark may be tested monthly

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A1C is currently the gold standard measure of
the quality of glycemic control.
Alchemy is a complex subject with many
different facets literature, chemistry, fraud
searching for a gold standard in diabetes care
from among the currently available tools is
perhaps as futile as the quest for the
Philosophers' Stone to change base metals into
gold. Each tool has its limitations and the most
complete picture emerges from careful application
of at least two. John Buse
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The Glycemic Triad
HbA1c
Long term average glucose level
FPG
GLYCOMARK
Basal glucose level
Glycemic Variability
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CME CREDITS FOR 1,5-ANHYDRO-D-GLUCITOL ARE NOW
AVAILABLE FROM DiabetesWRAP
Focus on 1,5-anhydroglucitol for Monitoring and
Clinical Management of Patients with Diabetes
Implications and Relationship to Other Critical
Biomarkers of Diabetes Control
Presented by Steven D. Wittlin, M.D. , Associate
Professor of Medicine, Clinical Director of the
Endocrine-Metabolism Division, University of
Rochester School of Medicine and Dentistry,
Strong Memorial Medical Center, Rochester, NY.
Enrollment for this HealthWRAP is complimentary.
The University of Massachusetts Medical School
designates this activity for a maximum of 2 AMA
PRA Category 1 Credit(s).
Access at http//www.clinicalwebcasts.com/cvr_051.
htm.
This activity is supported by an Independent
Educational Grant from Quest Diagnostics.
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• GlycoMark, a non-fasting blood test, reflects
  glycemic excursions above the renal threshold
  over the previous two weeks. It is highly
  correlated to average glucose maximum levels and
  can replace frequent and often inaccurate
  fingerstick logs and expensive and cumbersome
  CGMS.

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• GlycoMark can differentiate type 2 patients (40
  according to Bonora et al) who, despite HbA1c
  less than 8, have poor glycemic control.

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• According to recent results from the
  international LandMark (A1c Derived Average
  Glucose) study GlycoMark correlates better than
  HbA1c with various measures of glucose
  variability.

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• GlycoMarK monitors anti-PPG drug efficacy better
  than both HbA1c and fructosamine.

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• 1. GlycoMark has a stronger correlation than
• hemoglobin A1c with
• A) average or mean glucose
• B) fasting glucose
• C) average maximum glucose and Area Under the
  Curve 180 (AUC 180)
• D) glycemic variability
• E) c d

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• 2. GlycoMark is an assay for 1,5-anhydro-D-glucit
  ol (1,5-AG). As blood glucose rises above the
  renal threshold, serum levels of 1,5-AG
• A) rise proportional to rising blood glucose
  levels
• B) remain the same
• C) fall proportional to rising blood glucose
  levels

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• 3. The target value in diabetic patients to
  control postprandial hyperglycemia is
• A) 100 µg/ml
• B) gt10 µg/ml
• C) lt10 µg/ml
• D) None of the above

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• 4. GlycoMark is useful for the following
• A) Detecting hyperglycemia in diabetic patients
  with HbA1c 8.0
• B) Differentiating 40 patients with similar
  HbA1c values in the moderately controlled HbA1c
  range who have uncontrolled hyperglycemia
• C) Detecting glycemic variability in type 1
  patients, even those at HbA1c goal
• D) Short term ( 1 to 2 weeks)monitoring
  especially in patients with hemoglobinopathies
• E) Monitoring drug efficacy
• F) All of the above

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GLYCOMARK Thank you For attending
this presentation