GlycoMark 1,5-Anhydroglucitol Detecting Underlying Treatment Effects Not Revealed by A1C

1. 1 GlycoMark 1,5-AnhydroglucitolDetecting Underlying Treatment Effects Not Revealed by A1C

2. 2 Presentation Outline Is A1C the Best Measure of Glycemic Control? 1,5-AG Physiology 1,5-AG Postprandial Studies 1,5-AG as Short-Term Glycemic Marker Clinical Utility Clinical Studies � Revealing Underlying Treatment Effects Exenatide (Byetta) Pramlintide (Symlin) Sitagliptin (Januvia) Others - Novolog Mix 70/30, Miglitol Glycemic Instability Study Summary and Conclusions

3. 3 Is A1C the Best Measure of Glycemic Control?

4. 4 �A1C is currently the gold standard measure of the quality of glycemic control.� A1C is an excellent marker of glycemia BUT A1C is one marker reflecting a complex disease state GAPS ARE INEVITABLE

5. 5 HbA1c Measurement Not a Gold Standard A reasonable measure of glycemic control in populations A good measure of liability to chronic (microvascular) complications An inconsistent marker of good control -- in the individual Slow response to glycemic changes Inappropriate reliance on HbA1c results can lead to imperfect assessment of the quality of disease management Lack of a standardization due in part to the large number of commercially available assays

6. 6 If HbA1c is not the gold standard measure of the quality of glycemic control, then what? SMBG (self-monitored blood glucose) CGMS (continuous glucose monitoring system) Fructosamine 1,5-Anhydroglucitol (GlycoMark)

7. 7 1,5-AG Physiology

8. 8 The structure of 1,5-anhydroglucitol (1,5AG)

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10. 10 Renal Tubular Absorption of Glucose and 1,5 AG

11. 11 Renal Tubular Absorption of Glucose and 1,5 AG

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13. 13 1,5-AG Postprandial Studies

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23. 23 1,5-AG and Postmeal Glucose Levels

24. 24 ADA 2007 Abstract 1,5-Anhydroglucitol and Postprandial Hyperglycemia as Assessed by Self-Monitoring of Blood Glucose in Japanese Patients with Moderately Controlled Diabetes Yutaka Mori, et al. Scientific Sessions of the American Diabetes Association � 2007 �1,5-AG has been shown to reflect glycemic excursions, often in the postprandial state, more robustly than A1C or glycated albumin.� Confirms study by Dungan et al. (Diabetes Care 2006)

25. 25 Publication � In Press Serum 1,5-Anhydroglucitol (GlycoMrk) in Children with and without Type-1 Diabetes Nguyen, et al. (Baylor University) Pediatric Diabetes �Our findings suggest the despite good glycemic control, postprandial glucose concentrations are elevated and that 1,5-AG showed a difference between controls and T1DM.� �They support the use of 1,5-AG concentrations, together with A1C to evaluate therapy especially to target postprandial hyperlycemia.� Confirms study by Dungan et al. (Diabetes Care 2006)

26. 26 1,5-AG as a Short-Term Glycemic Marker

27. 27 Glycemic control markers

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32. 32 Clinical Utility

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35. 35 Clinical StudiesRevealing Underlying Treatment Effects

36. 36 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 ug) or placebo Thirty week study Presented at ADA 2007 Annual Meeting

37. 37 Revealing Underlying Treatment EffectsExenatide

38. 38 Revealing Underlying Treatment EffectsExenatide Exenatide 5ug dosage showed no significant difference in A1C, while there was a significant change in 1,5-AG Exenatide 10 ug dosage showed significant differences in A1C and 1,5-AG 1,5-AG confirmed previously reported improvements in PPG in exenatide-treated patients

39. 39 Revealing Underlying Treatment EffectsExenatideADA 2007 Abstract Exenatide Improves Postprandial Glucose (PPG) Control in Patients With Type 2 Diabetes as Measured by 1,5-Anhydroglucitol (GlycoMark) David Kendall, Amylin Pharmaceuticals, Inc., John Holcombe, Eli Lilly and Company, et al. Scientific Sessions of the American Diabetes Association � 2007 �As such, 1,5-AG may be a useful complement to A1C to reflect PPG in patients with T2DM treated with agents that target PPG. In this post-hoc analysis, the increase in 1,5-AG confirms previously reported improvements in PPG in exenatide-treated patients.�

40. 40 Revealing Underlying Treatment EffectsPramlintide Objective: To assess 1,5-AG as a marker of PPG control in Pramlintide-treated patients with type 1 diabetes (T1DM) Initial A1C levels: 7.2 to 8.0% Randomized to Pramlintide (n=18) or placebo (n=19) Twenty-nine week study Presented at AACE 2007 Annual Meeting

41. 41 Revealing Underlying Treatment EffectsPramlintide

42. 42 Revealing Underlying Treatment EffectsPramlintide Pramlintide, as an adjunct treatment for T1DM patients on intensive insulin therapy, led to improved PPG and significant reduction in body weight. Despite similar reductions in A1C, the change in 1,5 AG levels was consistent with improvement in PPG control in pramlintide-treated subjects, as measured by SMBG. 1,5-AG, as a complement to A1C, may be a useful marker of PPG control.

43. 43 Revealing Underlying Treatment EffectsPramlintideAACE 2007 Abstract 1,5-Anhydroglucitol (GlycoMark), a PPG Excursion Marker In Pramlintide-Treated Subjects Cameron Lush, Amylin Pharmaceuticals, Inc., et al. American Association of Clinical Endocrinologists 2007 Annual Meeting �Despite similar reductions in A1C, the change in 1,5-AG levels was consistent with improvement in PPG control in pramlintide-treated subjects, as measured by SMBG.�

44. 44 Revealing Underlying Treatment EffectsSitagliptin Evaluated efficacy and tolerability of sitagliptin in Japanese patients with T2DM over 12 weeks Initial A1C levels: 6.5 to 10.0% Randomized to sitagliptin (n=75) or placebo (n=76) Presented at ADA 2006 Annual Meeting

45. 45 Revealing Underlying Treatment EffectsSitagliptin

46. 46 Revealing Underlying Treatment EffectsSitagliptin

47. 47 Revealing Underlying Treatment EffectsSitagliptin Although 2-hour postprandial glucose decreased by 69.2 mg/dL in the sitagliptin group, A1C changed only 8.6% in absolute % change. This is compared to a % change of 83% for 1,5-AG. 1,5-AG is more reflective of PPG changes than A1C in sitagliptin-treated patients.

48. 48 Revealing Underlying Treatment EffectsSitagliptinADA 2006 Abstract Twelve Week Efficacy and Tolerability of Sitagliptin, a DPP-4 Inhibitor, in Japanese Patients with T2DM Peter Stein, Merck, et al. Scientific Sessions of the American Diabetes Association � 2006 �In a subset that underwent a meal tolerance test, 2-hour postprandial glucose decreased by -69.2 mg/dL in the sitagliptin group compared with an increase of 11.7 mg/dL on placebo at week 12.� At week 12, 1,5-AG decreased by 4.45 ug/ml in the sitagliptin-treated group compared with a decrease of 0.33 ug/ml � a percentage change of 83% compared to a 8.6% absolute percentage change of A1C.

49. 49 Revealing Underlying Treatment EffectsMiglitolClinical Drug Trial � T. Yamanouchi (University of Teikyo)

50. 50 Revealing Underlying Treatment EffectsNovolog Mix 70/30 Serum 1,5-anhydroglucitol (GlycoMark) as a Marker of Glycemic Control in Subjects Receiving Twice-Daily Biphasic Insulin Aspart 70/30 (BIAsp 70/30) vs. Once-Daily Insulin Glargine in Patients with Type 2 DM on Oral Antidiabetic Agents � The INITIATE Trial Alan Moses, Novo Nordisk, et al. Scientific Sessions of the American Diabetes Association � 2005 �The dynamic range of 1,5-AG in the circulation makes it a useful marker of overall glycemic control as reflected by A1C and a potentially useful marker for subject with target or near target A1C levels who continue to have excessive postprandial glucose excursions.�

51. 51 ADA 2007 Abstract Glycemic Instability Estimated By 1,5-Anhydroglucitol Persists Even After Normalization of A1C By Treatment in Patients With Type 2 Diabetes Toshikazu Yamanouchi, et al. Scientific Sessions of the American Diabetes Association � 2007 �Glycemic instability (glycemic excursions or postprandial hyperglycemia as measured by 1,5-anhydroglucitol) in diabetic patients is not easily restored for long periods even with treatment that maintains normoglycemia.�

52. 52 Summary and Conclusions

53. 53 1,5-Anydroglucitol (GlycoMark) Summary A1C is not the only measure of glycemic control 1,5-AG is most robust indicator of postprandial hyperglycemia Controlling postprandial hyperglycemia is important as growing body of evidence suggests that it is linked to cardiovascular complications of diabetes Several clinical studies show 1,5-AG can detect underlying treatment effects on PPG (exenatide, pramlintide, sitagliptin, etc.) not revealed by A1C This has important implications for diabetes patient care and pharmaceutical research studies

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55. 55 GlycoMark Ordering Information

56. 56 GlycoMark 1,5-AnhydroglucitolDetecting Underlying Treatment Effects Not Revealed by A1C