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GLYCOMARKGLYCOMARK

A NEW BLOOD TEST FOR PPGA NEW BLOOD TEST FOR PPG

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Importance of Importance of Postprandial Glucose Postprandial Glucose

ControlControl

The Glycemic TriadThe Glycemic Triad

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HbA1cHbA1cLong term average Long term average glucose levelglucose level

FPGFPGBasal Basal glucose glucose levellevel

PPGPPGPeak Glucose Peak Glucose LevelLevel

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Duration of daily metabolic Duration of daily metabolic conditionsconditions

Breakfast Lunch Dinner 0:00 am 4:00 amBreakfast

Postprandial Postabsorptive Fasting

Monnier L. Eur J Clin Invest 2000;30(Suppl. 2):3–11

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As Patients Get Closer to A1C Goal, As Patients Get Closer to A1C Goal, the Need to Successfully Manage PPG the Need to Successfully Manage PPG

Significantly IncreasesSignificantly IncreasesIncreasing Contribution of PPG as A1C Improves

30%40% 45% 50%

70%

60% 55% 50%30%

70%

0%

20%

40%

60%

80%

100%

< 10.2 10.2 to9.3

9.2 to 8.5 8.4 to 7.3 < 7.3

A1C Range (%)

%

Contribution

FPGPPG

Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasnma glucose increments to the overall diurnal hyper glycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c).Diabetes Care. 2003;26:881-885.

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Moving from A1C 8.0% to 7.0%Moving from A1C 8.0% to 7.0%Difficult and Important!!Difficult and Important!!

20-25% of Patients Have A1Cs between 8.0% and 20-25% of Patients Have A1Cs between 8.0% and 7.0%7.0%

Moving from A1C 8.0% to 7.0% - Reduces Serious Moving from A1C 8.0% to 7.0% - Reduces Serious Complications Complications

UKPDS Study ResultsUKPDS Study Results Reduced microvascular complications (kidney, eye, etc.) Reduced microvascular complications (kidney, eye, etc.) by 17-33%by 17-33%

Reduced risk of heart attack by 16%Reduced risk of heart attack by 16% Reduced diabetes-related deaths by 21%Reduced diabetes-related deaths by 21%

Challenge:Challenge: More difficult to make improvements as More difficult to make improvements as A1C gets closer to 7.0%A1C gets closer to 7.0%

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DCCT Research Group. N Engl J Med. 1993;329:977-986.Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117.UKPDS 33: Lancet 1998; 352, 837-853.Slide modified from J. Buse

HbA1c

Retinopathy

Nephropathy

Neuropathy

Cardiovascular disease

DCCT

9 7.2%

63%

54%

60%

41%

Kumamoto

9 7%

69%

70%

Improved

-

UKPDS

8 7%

17-21%

24-33%

-

16%

Reducing A1C Levels: Reducing A1C Levels: Reduces Incidence of Reduces Incidence of

ComplicationsComplications

*NCS

Coronary Artery Disease and Coronary Artery Disease and Postprandial Hyperglycemia Postprandial Hyperglycemia

Mellen PB et al. Mellen PB et al. Arterioscler Thromb Vasc Biol. Arterioscler Thromb Vasc Biol. 2006;26:189-193. 2006;26:189-193.

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SummarySummary Postprandial glycemia plays a Postprandial glycemia plays a clinically important role in clinically important role in the complications of diabetesthe complications of diabetes

Postprandial glycemia is a Postprandial glycemia is a major contributor to overall major contributor to overall glycemic control ESPECIALLY glycemic control ESPECIALLY in moderately-well to well in moderately-well to well controlled patientscontrolled patients

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A1C values can be A1C values can be “misleading”“misleading”

Nearly 40% of diabetes patients in Nearly 40% of diabetes patients in “good control” have persistently “good control” have persistently elevated glucose levels elevated glucose levels (Bonora et al. (Bonora et al. DiabetologiaDiabetologia 2006) 2006)

These patients are at high risk of These patients are at high risk of developing of developing serious developing of developing serious complications!!!!complications!!!!

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

Clinically ??Clinically ??

Frequent Frequent fingersticksfingersticks

HbA1C HbA1C FructosamineFructosamine Continuous Continuous Glucose Glucose Monitoring Monitoring SystemsSystems

Sensor-Sensor-Augmented Augmented Insulin PumpsInsulin Pumps

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A New Approach to A New Approach to Monitoring Monitoring

Postprandial Postprandial HyperglycemiaHyperglycemia

1,5-Anhydroglucitol 1,5-Anhydroglucitol (1,5-AG)(1,5-AG)

GlycoMarkGlycoMark

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1,5-AG Physiology1,5-AG Physiology

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The structure of 1,5-anhydroglucitol The structure of 1,5-anhydroglucitol (1,5AG)(1,5AG)

O

OH

OH

HO

HO OH

O

OH

OH

HO

HO

D-glucose 1,5-anhydro-D-glucitol(1-deoxyglucose)

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Oral Supply1,5AG

(5-10mg/day)

Blood stream

TissuesInternal Organs

(500-1000 mg)

Kidney

Urinary excretion

(5-10mg/day)

Oral Supply1,5AG

(5-10mg/day)

Blood Stream(1,5-AG

LevelLower)

TissuesInternal Organs

(500-1000 mg)

Kidney

Urinary excretion (INCREASED)

Normoglycemia Hyperglycemia

GlucoseBlocks

Reabsorption

Physiology of 1,5-AG

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Relationship of Blood Relationship of Blood Glucose and 1,5-AGGlucose and 1,5-AG

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

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

GLUCOSEGLUCOSE>180 mg/dL>180 mg/dL

GLYCOMARKGLYCOMARK

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Glycemic control markersGlycemic control markers

1,5AGFructosamine

10 89 7 56 4 3 12 0

HbA1C

Bloodglucose

Weeks before measurement

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GlycoMark Monitors Postprandial GlycoMark Monitors Postprandial HyperglycemiaHyperglycemia

Postmeal Glucose (mg/dL)

180

230

0

50

100

150

200

250

Patient Group 1 Patient Group 2

(P<0.05)

GlycoMark 1,5-AG (μg/ml)

8.00

5.58

0.00

1.002.00

3.00

4.005.00

6.00

7.008.00

9.00

Patient Group 1 Patient Group 2

(P<0.05)

Dungan, K., Buse, J. et al. Diabetes Care (June 2006)

A1C (%)

7.20 7.38

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00

Patient Group 1 Patient Group 2

(No Significant Difference)

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 postmeal 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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0

50

100

150

200

250

300

350

400

2/15 2/16 2/17 2/18 2/19 2/20 2/21 2/22

Time (days)

0

50

100

150

200

250

300

350

400

2/8 2/9 2/10 2/11 2/12 2/13 2/14 2/15

Time (days)

52 year old female with type 1 DMA1C 7.43%1,5-AG 12.4mcg/dLPPG max 195 mg/dL

49 year old male with type 2 DMA1C 7.27%1,5-AG 4.5mcg/dLPPG max 235 mg/dL

GlycoMark Reveals Elevated PPG Levels in Patients with “Good” A1Cs

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Relationship of 1,5-Anhydroglucitol (1,5-AG) Relationship of 1,5-Anhydroglucitol (1,5-AG) to Baseline Characteristics in Insulin-naïve to Baseline Characteristics in Insulin-naïve Type 2 Diabetes (T2DM) Patients in the Type 2 Diabetes (T2DM) Patients in the DURABLE TrialDURABLE TrialBaseline Characteristic

HbA1c ≤ 8.0% HbA1c 1,5-AG

HbA1c >8.0% HbA1c 1,5-AG

Mean Premeal Glucose

n = 503

0.113*

n = 527

-0.179**

n = 1439

0.403**

n = 1422

-0.295**

Mean Postprandial Glucose

n = 502

0.098*

n= 526

-0.179**

n = 1437

0.364**

n = 1421

-0.270**

Mean Glucose n=503

0.101*

n=527

-0.186**

n = 1441

0.394**

n = 1424

-0.293**

All values are r correlations * p <0.05; ** All values are r correlations * p <0.05; ** p <0.001p <0.001Authors’ Conclusions:Authors’ Conclusions: 1,5_AG had stronger correlation than HbA1c with all 1,5_AG had stronger correlation than HbA1c with all self-monitored plasma glucose (SMPG) parameters, self-monitored plasma glucose (SMPG) parameters, particularly PPG.particularly PPG. Additionally, at HbA1c ≤ 8.0%, 1,5-AG has a stronger Additionally, at HbA1c ≤ 8.0%, 1,5-AG has a stronger correlation with blood glucose values compared with correlation with blood glucose values compared with HbA1c. As such, these data support the use of 1,5-AG HbA1c. As such, these data support the use of 1,5-AG in conjunction with HbA1c in moderately controlled in conjunction with HbA1c in moderately controlled patients with T2DM.patients with T2DM.

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1,5-AG (ug/ml)1,5-AG (ug/ml)Approximate Mean PostmealApproximate Mean Postmeal

Maximum Blood Glucose (mg/dl)Maximum Blood Glucose (mg/dl)

> 12> 12 < 180< 180

1010 185185

88 190190

66 200200

44 225225

< 2< 2 > 290> 290

GlycoMark Values vs. PPG LevelsGlycoMark Values vs. PPG Levels

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Interpreting GlycoMark Interpreting GlycoMark ResultsResults

GlycoMarkGlycoMark DiabetesDiabetes A1CA1C

> 10> 10 Well-ControlledWell-Controlled 4 - 64 - 6

5 – 10*5 – 10* Moderately ControlledModerately Controlled 6 - 86 - 8

2 - 52 - 5 Poor ControlPoor Control 8 - 108 - 10

< 2< 2 Very Poor ControlVery Poor Control > 10> 10

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Target Glycemic GoalsTarget Glycemic Goals

GlycoMark > 10 ug/mlGlycoMark > 10 ug/ml A1C <7.0% (6.5% AACE Goal)A1C <7.0% (6.5% AACE Goal) GlycoMark may be tested monthlyGlycoMark may be tested monthly

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Clinical StudyClinical Study

Revealing Underlying Revealing Underlying Treatment EffectsTreatment Effects

Exenatide Exenatide

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Revealing Underlying Revealing Underlying Treatment EffectsTreatment Effects

ExenatideExenatide Objective: To assess 1,5-AG as a marker Objective: To assess 1,5-AG as a marker of PPG control in Exenatide-treated of PPG control in Exenatide-treated patients with type 2 diabetes (T2DM)patients with type 2 diabetes (T2DM)

144 Patients144 Patients Initial A1C levels: 8.2 +/-1%Initial A1C levels: 8.2 +/-1% Randomized to Exenatide (5 or 10 ug) or Randomized to Exenatide (5 or 10 ug) or placeboplacebo

Thirty week studyThirty week study

Presented at ADA 2007 Annual MeetingPresented at ADA 2007 Annual Meeting

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Revealing Underlying Revealing Underlying Treatment EffectsTreatment Effects

ExenatideExenatideComparison of Changes in Values from Baseline to Study End

Exenatide (5 ug) Exenatide (10 ug)

1,5-AG +2.7 +/- 0.6 ug/ml*45.3 +/-11.9 %

+2.9 +/-0.6 ug/ml**69.4 +/-14.6 %

A1C -0.5 +/-0.1 % -0.9 +/-0.1 %**

* P < 0.05; ** P < 0.01

Correlations: Changes from baseline

1,5-AG vs. HbA1C: r = - 0.74; P <0.0001

1,5-AG vs. fasting plasma glucose (FPG): r = -0.54; P <0.0001

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THE USE OF 1,5 – ANHYDROGLUCITOL (GLYCOMARK) TO MONITOR NEW THE USE OF 1,5 – ANHYDROGLUCITOL (GLYCOMARK) TO MONITOR NEW CLASSES OF THERAPIES FOR MANAGING POSTMEAL GLUCOSE IN CLASSES OF THERAPIES FOR MANAGING POSTMEAL GLUCOSE IN PATIENTS WITH DIABETESPATIENTS WITH DIABETES

1,5-AG(Absolute % Change)

A1C(Absolute % Change)

Exenatide 5 ug(30 weeks)

+ 45.3% -6.1%

Pramlintide(29 weeks)

+30.0% -2.4%

Sitagliptin(12 weeks)

+83.1% -8.6%

BIAsp 70/30(28 weeks)

+273.5% -29.9%

Comparison of % Changes in Values from Baseline to Study End – Treated Populations

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Patient Cases Patient Cases Patient

HbA1c (%)

GlycoMark (µg/ml)

Intrepretation

Male – age 15

13.8 0.7 Tests Consistent – Poor Control

Female – age 11

5.6 22.7 Tests Consistent – Good Control

Female – age 19

7.4 2.7 Tests Inconsistent – Poor PPG control indicated by GlycoMark

Male – age 14

5.5 53.3 Tests Consistent – Good Control

Female – age 13

6.2 4.0 Tests Inconsistent – Poor PPG control indicated by GlycoMark

Female – age 15

5.7 18.1 Tests Consistent – Good Control

Female – age 19

9.5 1.5 Tests Consistent – Poor Control

GlycoMark values <10 µg/ml are abnormalGlycoMark values <10 µg/ml are abnormal

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Moderately Controlled

Patients (A1C <8.5%)

GlycoMark(>10 μg/ml)Normal PPG

GlycoMark(<10 μg/ml)Elevated PPG

Target After-Meal GlucoseExenatide Sitagliptin

Prandial Insulin

Maintain Fasting Therapy

Target Fasting GlucoseMetformin

SulfonylureaBasal Insulin

Utilizing GlycoMark to Reach Utilizing GlycoMark to Reach Glycemic GoalsGlycemic Goals

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““A1C is currently the gold A1C is currently the gold standardstandard measure of the quality measure of the quality

of glycemic control.”of glycemic control.”

“ “Alchemy is a complex subject Alchemy is a complex subject with many different facets – with many different facets – literature, chemistry, fraud; literature, chemistry, fraud; searching for a gold standard in searching for a gold standard in diabetes care from among the diabetes care from among the currently available tools is currently available tools is perhaps as futile as the quest for perhaps as futile as the quest for the Philosophers' Stone to change the Philosophers' Stone to change base metals into gold. Each tool base metals into gold. Each tool has its limitations and the most has its limitations and the most complete picture emerges from complete picture emerges from careful application of at least careful application of at least two.” two.” John BuseJohn Buse

The Glycemic TriadThe Glycemic Triad

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HbA1cHbA1cLong term average Long term average glucose levelglucose level

FPGFPGBasal Basal glucose glucose levellevel

PPGPPGGLYCOMARKGLYCOMARK

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CME CREDITS FOR 1,5-ANHYDRO-D-GLUCITOL CME CREDITS FOR 1,5-ANHYDRO-D-GLUCITOL ARE NOW AVAILABLE FROM DiabetesARE NOW AVAILABLE FROM DiabetesWRAPWRAP

Presented by Steven D. Wittlin, M.D. , Presented by Steven D. Wittlin, M.D. , Associate Associate Professor of Medicine, Clinical Director of the Endocrine-Professor of Medicine, Clinical Director of the Endocrine-Metabolism Division, University of Rochester School of Metabolism Division, University of Rochester School of Medicine and Dentistry, Strong Memorial Medical Center, Medicine and Dentistry, Strong Memorial Medical Center, Rochester, NY.Rochester, NY.Enrollment for this HealthWRAP is complimentary. Enrollment for this HealthWRAP is complimentary. The University of Massachusetts Medical School The University of Massachusetts Medical School designates this activity for a maximum of 2 AMA designates this activity for a maximum of 2 AMA PRA Category 1 Credit(s). PRA Category 1 Credit(s).

Focus on 1,5-anhydroglucitol for Monitoring Focus on 1,5-anhydroglucitol for Monitoring and Clinical Management of Patients with and Clinical Management of Patients with Diabetes: Implications and Relationship to Diabetes: Implications and Relationship to Other Critical Biomarkers of Diabetes Other Critical Biomarkers of Diabetes ControlControl

This activity is supported by an Independent Educational This activity is supported by an Independent Educational Grant from Quest Diagnostics.Grant from Quest Diagnostics.

Access at Access at http://www.clinicalwebcasts.com/cvr_05http://www.clinicalwebcasts.com/cvr_051.htm. 1.htm.

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GLYCOMARKGLYCOMARK

Thank you for your interest in Thank you for your interest in

GlycoMarkGlycoMark