Transcript 1,5 Anhydroglucitol and the Monitoring of Postprandial

GLYCOMARK
A NEW BLOOD TEST FOR PPG
1
Importance of Postprandial
Glucose Control
2
The Glycemic Triad
HbA1c
Long term average glucose level
FPG
Basal glucose level
PPG
Peak Glucose Level
3
Duration of daily metabolic conditions
Breakfast
Lunch
Dinner
Postprandial
0:00 am
Postabsorptive
4:00 am Breakfast
Fasting
Monnier L. Eur J Clin Invest 2000;30(Suppl. 2):3–11
4
As Patients Get Closer to A1C Goal, the Need to
Successfully Manage PPG Significantly Increases
Increasing Contribution of PPG as A1C Improves
%
Contribution
100%
30%
80%
60%
70%
55%
60%
50%
40%
20%
70%
30%
45%
40%
FPG
PPG
50%
0%
< 10.2
10.2 to
9.3
9.2 to 8.5 8.4 to 7.3
< 7.3
A1C Range (%)
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.
5
Moving from A1C 8.0% to 7.0%
Difficult 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%
6
Reducing A1C Levels:
Reduces Incidence of Complications
HbA1c
Retinopathy
Nephropathy
Neuropathy
Cardiovascular
disease
DCCT
9  7.2%
63%
54%
60%
Kumamoto
9  7%
69%
70%
Improved
UKPDS
8  7%
17-21%
24-33%
-
41%
-
16%
*NCS
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
7
Coronary Artery Disease and Postprandial Hyperglycemia
Mellen PB et al. Arterioscler Thromb Vasc Biol. 2006;26:189-193.
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
9
A1C values can be “misleading”

Nearly 40% of diabetes patients in “good control”
have persistently elevated glucose levels
(Bonora et al. Diabetologia 2006)

These patients are at high risk of developing of
developing serious complications!!!!
10
So How Can We Assess Post-Prandial
Glucose Control Clinically ??





Frequent fingersticks
HbA1C
Fructosamine
Continuous Glucose
Monitoring Systems
Sensor-Augmented
Insulin Pumps
11
A New Approach to
Monitoring Postprandial
Hyperglycemia
1,5-Anhydroglucitol (1,5-AG)
GlycoMark
12
1,5-AG Physiology
13
The structure of 1,5-anhydroglucitol
(1,5AG)
HO
HO
O
O
OH
OH
HO
OH HO
OH
D-glucose
OH
1,5-anhydro-D-glucitol
(1-deoxyglucose)
14
Physiology of 1,5-AG
Oral Supply
1,5AG
(5-10mg/day)
Normoglycemia
Blood
stream
Kidney
Urinary
excretion
(5-10mg/day)
Tissues
Internal
Organs
(5001000 mg)
Oral Supply
1,5AG
(5-10mg/day)
Glucose
Blocks
Reabsorption
Hyperglycemia
Blood
Stream
(1,5-AG
Level
Lower)
Tissues
Internal
Organs
(5001000 mg)
Kidney
Urinary excretion
(INCREASED)
15
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, 5–AG
into the bloodstream at the proximal renal tubules.
GLUCOSE
>180 mg/dL
• As glucose blood levels increase, 1,5–AG blood levels decrease.
• 1,5–AG blood levels less than 10 µg/ml are abnormal.
GLYCOMARK
16
Glycemic control markers
Blood
glucose
1,5AG
Fructosamine
HbA1C
10
9
8
7
6
5
4
3
2
1
0
Weeks before measurement
17
GlycoMark Monitors Postprandial Hyperglycemia
Dungan, K., Buse, J. et al. Diabetes Care (June 2006)
Postmeal Glucose (mg/dL)
A1C (% )
(P<0.05)
250
230
180
150
100
50
0
(P<0.05)
9.00
8.00
200
GlycoMark 1,5-AG (mg/ml)
(No Significant Difference)
9.00
7.20
7.38
7.00
7.00
6.00
6.00
5.00
5.00
4.00
4.00
3.00
3.00
2.00
2.00
1.00
1.00
0.00
Patient Group 1
Patient Group 2
8.00
8.00
5.58
0.00
Patient Group 1
Patient Group 2
Patient Group 1
Patient Group 2
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.
18
GlycoMark Reveals Elevated PPG Levels in Patients
with “Good” A1Cs
A: Patient 1
400
350
52 year old female
with type 1 DM
A1C 7.43%
1,5-AG 12.4mcg/dL
PPG max 195 mg/dL
Glucose (mg/dL)
300
250
200
150
100
50
0
2/15
2/16
2/17
2/18
2/19
2/20
2/21
2/22
Time (days)
B: Patient 2
400
49 year old male with
type 2 DM
A1C 7.27%
1,5-AG 4.5mcg/dL
PPG max 235 mg/dL
350
Glucose (mg/dL)
300
250
200
150
100
50
0
2/8
2/9
2/10
2/11
2/12
2/13
2/14
2/15
Time (days)
19
Relationship of 1,5-Anhydroglucitol (1,5-AG) to Baseline
Characteristics in Insulin-naïve Type 2 Diabetes (T2DM)
Patients in the DURABLE Trial
Baseline Characteristic
Mean Premeal Glucose
Mean Postprandial Glucose
Mean Glucose
HbA1c ≤ 8.0%
HbA1c
1,5-AG
HbA1c >8.0%
HbA1c
1,5-AG
n = 503
n = 527
n = 1439
n = 1422
0.113*
-0.179**
0.403**
-0.295**
n = 502
n= 526
n = 1437
n = 1421
0.098*
-0.179**
0.364**
-0.270**
n=503
n=527
n = 1441
n = 1424
0.101*
-0.186**
0.394**
-0.293**
All values are r correlations * p <0.05; ** p <0.001
Authors’ Conclusions:
 1,5_AG had stronger correlation than HbA1c with all self-monitored plasma
glucose (SMPG) parameters, particularly PPG.
 Additionally, at HbA1c ≤ 8.0%, 1,5-AG has a stronger correlation with blood
glucose values compared with HbA1c. As such, these data support the use of 1,5-AG
in conjunction with HbA1c in moderately controlled patients with T2DM.
20
GlycoMark Values vs. PPG Levels
1,5-AG (ug/ml)
Approximate Mean Postmeal
Maximum Blood Glucose (mg/dl)
> 12
< 180
10
185
8
190
6
200
4
225
<2
> 290
21
Interpreting GlycoMark Results
GlycoMark
Diabetes
A1C
> 10
Well-Controlled
4-6
5 – 10*
Moderately Controlled
6-8
2-5
Poor Control
8 - 10
<2
Very Poor Control
> 10
22
Target Glycemic Goals



GlycoMark > 10 ug/ml
A1C <7.0% (6.5% AACE Goal)
GlycoMark may be tested monthly
23
Clinical Study
Revealing Underlying
Treatment Effects
Exenatide
24
Revealing Underlying Treatment Effects
Exenatide





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 ug) or placebo
Thirty week study
Presented at ADA 2007 Annual Meeting
25
Revealing Underlying Treatment Effects
Exenatide
Comparison of Changes in Values from Baseline to Study End
1,5-AG
A1C
Exenatide (5 ug)
Exenatide (10 ug)
+2.7 +/- 0.6 ug/ml*
45.3 +/-11.9 %
+2.9 +/-0.6 ug/ml**
69.4 +/-14.6 %
-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
26
THE USE OF 1,5 – ANHYDROGLUCITOL (GLYCOMARK) TO MONITOR NEW
CLASSES OF THERAPIES FOR MANAGING POSTMEAL GLUCOSE IN PATIENTS
WITH DIABETES
Comparison of % Changes in Values from Baseline to Study End – Treated Populations
Exenatide 5 ug
(30 weeks)
Pramlintide
(29 weeks)
Sitagliptin
(12 weeks)
BIAsp 70/30
(28 weeks)
1,5-AG
(Absolute % Change)
A1C
(Absolute % Change)
+ 45.3%
-6.1%
+30.0%
-2.4%
+83.1%
-8.6%
+273.5%
-29.9%
27
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 abnormal
28
Utilizing GlycoMark to Reach Glycemic Goals
Moderately
Controlled Patients
(A1C <8.5%)
GlycoMark
(>10 mg/ml)
Normal PPG
GlycoMark
(<10 mg/ml)
Elevated PPG
Target
Fasting Glucose
Target
After-Meal Glucose
Metformin
Sulfonylurea
Basal Insulin
Exenatide
Sitagliptin
Prandial Insulin
Maintain Fasting Therapy
29
“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
30
The Glycemic Triad
HbA1c
Long term average glucose level
FPG
Basal glucose level
PPG
GLYCOMARK
31
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.
32
GLYCOMARK
Thank you for your interest in GlycoMark
33