1. 1 Part 4 1,5-Anhydroglucitol Outcomes Research and Link to Complications An Educational Service from G LYCO M ARK G LYCO M ARK is a registered trademark of GlycoMark, Inc. © GlycoMark, Inc. All rights reserved NOTE: Please see slide notes below each page for study and slide details

2. 2 Low 1,5-AG Levels Link to Higher Risk of Complications Low 1,5-AG levels linked with risk of diabetes and its complications Retinopathy in Type 2 Diabetes 1 Nephropathy in Type 2 Diabetes 2 Stroke and Coronary Heart Disease (CHD) 3 Macrosomia (high birth weight babies) 4 Higher risk of developing diabetes 5 Increased coronary stiffness (presented in Part 1) High 1,5-AG levels may play protective role 1,2,4,5,6 1 WJ Kim, et al, Serum 1,5-anhydroglucitol is associated with diabetic retinopathy in Type 2 diabetes, Diabetic Medicine, Feb 2012 2 Yamanouchi et al, Diabetes Care Apr 1998, Vol 21(4) pp. 619-624 3 M Watanabe, et al, Serum 1,5-anhydro-d-glucitol levels predict first-ever cardiovascular disease: An 11-year population-based Cohort study in Japan, the Suita study, Atherosclerosis June 2011 Vol 216, Issue 2, 477-483 4 I Hirsch, et al, University of Washington, Endocrine Society Meeting 2012 - Publication pending 5 S Juraschek, et al, Johns Hopkins, Diabetes Care Aug 2012 6 X Meng et al, International Journal of Immunopathology and Pharmacology, Vol 22, No 3, 2009

3. 3 WJ Kim, et al, Serum 1,5-anhydroglucitol is associated with diabetic retinopathy in Type 2 diabetes, Diabetic Medicine, DOI: 10.1111/j.1464-5491. Feb 2012 N=567 P<0.01 Low 1,5-AG with A1C < 8% Tied to Higher Incidence of Retinopathy in Type 2 Diabetes Results after control for age, sex, binary HbA1C levels, duration of diabetes, triglyceride, systolic blood pressure, smoking status, history of hypertension and dyslipidaemia, and the use of ACE inhibitor/angiotensin receptor 2.56 2.77 1.0 HbA1C < 8% 1,5-AG >10 µg/mL n = 201 HbA1C < 8% 1,5-AG <10 µg/mL n = 105 HbA1C > 8% n = 138

4. 4 Correlation of 1,5-AG vs. Urinary Albumin in Newly Diagnosed Type 2 Urinary albuminN-acetylglucosaminidase I,5-AGr = - 0.632 P < 0.0001r = - 0.790 P < 0.0001 A1Cr = 0.337 P < 0.0001r = 0.351 P < 0.001 FPGr = 0.383 P < 0.0001r = 0.512 P < 0.0001 Yamanouchi et al. Relationship between 1,5-Anhydroglucitol and urinary excretion of N-acetylglucosaminidase and albumin at onset of NIDDM with 3 year follow up, Diabetes Care Volume: 21 Issue: 4 Pages: 619-624. APR 1998.

5. 5 1,5-AG Predicts New Cardiovascular Disease in Healthy Men in 11 Year Prospective Study No CVD (BP, Hypercholesterolemia, events) 991 men (<6% diabetes; mean age 63) 1104 women (3% diabetes; mean age 58) Outcomes New stroke (Ischemic and other) New CHD (MI, Coronary angioplasty, CABG, sudden cardiac death) Compared hazard ratios in cohort with 1,5-AG 24.5 µg/mL 147 CVD events (64 CHD; 83 strokes) occurred The risk increased linearly in men as 1,5-AG levels decreased No significant correlation was found at 11 years in women, but… Female 1,5-AG scores in the high risk group averaged 10.5 vs. 8.8 in men The females were on average 5 years younger All risk factors in <14 1,5-AG female group were lower than men for all risk factors measured except hypercholesterolemia and alcohol intake M Watanabe, et al., Serum 1,5-anhydro-d-glucitol levels predict first-ever cardiovascular disease: An 11-year population- based Cohort study in Japan, the Suita study, Atherosclerosis June 2011 Vol. 216, Issue 2, Pages 477-483

6. 6 Men risk adjusted for FPG & PPG < 110 mg/dL in addition to other cardiovascular factors and diabetes diagnosis M Watanabe, et al., Serum 1,5-anhydro-d-glucitol levels predict first-ever cardiovascular disease: An 11-year population- based Cohort study in Japan, the Suita study, Atherosclerosis June 2011 Vol. 216, Issue 2,Pages 477-483 Low 1,5-AG levels linked to significant risk of stroke in non- diabetic men

7. 7 Female CVD Hazard Ratios M Watanabe, et al., Serum 1,5-anhydro-d-glucitol levels predict first-ever cardiovascular disease: An 11-year population-based Cohort study in Japan, the Suita study, Atherosclerosis June 2011 Vol. 216, Issue 2, Pages 477-483 Low 1,5-AG levels linked to increased risk of CHD in women, but P=NS

8. 8 1,5-AG is Strongly Associated with Neonatal Birth Weight (NBW) Across All Trimesters in Pregnancy Complicated by Diabetes Women with T1D (N=42), T2D (N=31) and Gestational Diabetes (N=28) were studied Association between 1,5-AG and NBW z-scores during pregnancy may be explained by hyperglycemia above the renal threshold for glucose, particularly postprandial hyperglycemia By providing more information on the risk of large for gestational age infants, 1,5-AG is a promising adjunct in the management of pregnancy complicated by diabetes Lorena A. Wright and Irl B. Hirsch, et al, 1,5-Anhydroglucitol (1,5-AG) is Strongly Associated with Neonatal Birth Weight Across All Trimesters in Pregnancy Complicated by Diabetes, Poster Presented at The Endocrine Society Meeting – June 2012, Publication pending

9. 9 1,5-AG as Independent Risk Factor for Predicting Diabetes 1,299 participants - Atherosclerosis Risk in Communities (ARIC) Study – Tested with 3 markers – 1,5-AG, fructosamine, glycated albumin – Tracked for 20 years for diagnosis of diabetes – All 3 markers found to be independently predictive of diabetes (adjusted for A1C, FPG) – High 1,5-AG levels (>22 µg/mL) predicted reduced risk of developing diabetes Fructosamine µmol/L Glycated Albumin % 1,5-AG µg/mL Juraschek S et al, Johns Hopkins University, Alternative Markers of Hyperglycemia and Risk of Diabetes, Diabetes Care, August 2012 Higher risk below 14 Risk High Low Higher risk above 240 Higher risk above 15

10. 10 Compendium of Evidence Review of Published 1,5-Anhydroglucitol Clinical Trials 1,5-Anhydroglucitol Studies/ Abstracts NTypes of Subjects/Outcomes Vs. Continuous Glucose Monitor6844Type 1 (T1), Type 2 (T2) Vs. Oral Glucose Tolerance Test63608Normal (Nml), IGT, Obese Youth Vs. Postprandial Glucose11802T1, T2, GDM, Pregnancy, Pediatrics Pediatric Populations3762T1, T2 (MODY) Pregnant Populations3788Nml, T1, T2, GDM Renal Disease Populations2352Nml, Stage 1-3; Stage 4-5 Renal Vs. A1C338968All Types Accuracy for Therapy Monitoring121025Different drugs, diet, comparative Risk of Developing Diabetes11299CVD without Diabetes Link to Microvascular Complications3679T2 (retinopathy, nephropathy) Link to Macrovascular Complications53130Nml, Stroke, CHD, HDL/ACS, FMD, CAVI, AMI Ventricular Dysfunction Total Human Studies4012,349 N does not total due to multiple markers

11. 11 For more information For a listing of postprandial hyperglycemia outcome studies, please visit www.glycomark.com/postprandialhyperglycemiawww.glycomark.com/postprandialhyperglycemia For a listing of studies about the 1,5-anhydroglucitol biomarker for postprandial hyperglycemia, please visit www.glycomark.com/product/studies www.glycomark.com/product/studies For a 3-minute overview about the 1,5-anhydroglucitol biomarker, please visit www.glycomark.com/moviewww.glycomark.com/movie