GLYCOMARK A NEW BLOOD TEST FOR PPG

Importance of Postprandial Glucose Control

The Glycemic Triad HbA1c FPG PPG Long term average glucose level Basal glucose level Peak Glucose Level

Duration of daily metabolic conditions Breakfast Lunch Dinner 0:00 am 4:00 am Postprandial Postabsorptive Fasting Monnier L. Eur J Clin Invest 2000;30(Suppl. 2):3–11

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 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.

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%

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 Cardiovascular disease UKPDS 8  7% 17-21% 24-33% - 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

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

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!!!!

So How Can We Assess Post-Prandial Glucose Control Clinically ?? Frequent fingersticks HbA1C Fructosamine Continuous Glucose Monitoring Systems Sensor-Augmented Insulin Pumps

A New Approach to Monitoring Postprandial Hyperglycemia 1,5-Anhydroglucitol (1,5-AG) GlycoMark

1,5-AG Physiology

The structure of 1,5-anhydroglucitol (1,5AG) OH HO O OH HO D-glucose 1,5-anhydro-D-glucitol (1-deoxyglucose)

Physiology of 1,5-AG Normoglycemia Hyperglycemia Oral Supply 1,5AG (5-10mg/day) Normoglycemia Oral Supply 1,5AG (5-10mg/day) 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)

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

Glycemic control markers 1,5AG Fructosamine 10 8 9 7 5 6 4 3 1 2 HbA1C Blood glucose Weeks before measurement

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 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 52 year old female with type 1 DM A1C 7.43% 1,5-AG 12.4mcg/dL PPG max 195 mg/dL 49 year old male with type 2 DM A1C 7.27% 1,5-AG 4.5mcg/dL PPG max 235 mg/dL

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 HbA1c ≤ 8.0% HbA1c 1,5-AG HbA1c >8.0% 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 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; ** 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.

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

Interpreting GlycoMark Results Diabetes A1C > 10 Well-Controlled 4 - 6 5 – 10* Moderately Controlled 6 - 8 2 - 5 Poor Control 8 - 10 < 2 Very Poor Control

Target Glycemic Goals GlycoMark > 10 ug/ml A1C <7.0% (6.5% AACE Goal) GlycoMark may be tested monthly

Clinical Study Revealing Underlying Treatment Effects Exenatide

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

Revealing Underlying Treatment Effects Exenatide Comparison 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

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 1,5-AG (Absolute % Change) A1C 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%

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 Female – age 13 6.2 4.0 Female – age 15 5.7 18.1 9.5 1.5 GlycoMark values <10 µg/ml are abnormal

Utilizing GlycoMark to Reach Glycemic Goals Moderately Controlled Patients (A1C <8.5%) GlycoMark (>10 mg/ml) Normal PPG (<10 mg/ml) Elevated PPG Target After-Meal Glucose Exenatide Sitagliptin Prandial Insulin Maintain Fasting Therapy Fasting Glucose Metformin Sulfonylurea Basal Insulin

“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

The Glycemic Triad HbA1c FPG PPG Long term average glucose level Basal glucose level GLYCOMARK

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.

GLYCOMARK Thank you for your interest in GlycoMark