10th Postgraduate Course December 7-8, 2007 at City De Luxe Restaurant, Dagupan City, Pangasinan

1. WHAT’S NEW IN DIABETES CARE? EDITH S. BERMUDEZ,MD,DPAMS,MHSA

2. Global Projections for the Diabetes Epidemic: 2003-2025 23.0 M 36.2 M ↑ 57.0 % 14.2 M 26.2 M ↑ 85 % 48.4 M 58.6 M ↑ 21 % 43.0 M 75.8 M ↑ 79 % 7.1M 15.0 M ↑ 111 % 39.3 M 81.6 M ↑ 108 % M=million, AFR=Africa, NA=North America, EUR=Europe, SACA=South and Central America, EMME=Eastern Mediterranean and Middle East, SEA=South-East Asia, WP=Western Pacific Diabetes Atlas Committee. Diabetes Atlas . 2003. World 2003=194 M 2025=333 M ↑ 72% AFR NA SACA EUR SEA WP 19.2 M 39.4 M ↑ 105% EMME 2003 2025

4. Natural History of Type 2 Diabetes (Can we change the course of DM?) Glucose Relative to normal -10 -5 0 5 10 15 20 25 30 0 100 200 50 150 Post-prandial glucose Fasting glucose Insulin resistance Insulin level Years At risk for diabetes Beta-cell dysfunction 250 R.M. Bergenstal, International Diabetes Center mg/dL (%) 100 200 150 300 250 350

5. Natural History of Type 2 Diabetes € 0 50 100 150 200 250 -10 -5 0 5 10 15 20 25 30 Years of Diabetes Glucose (mg/dL) Relative Function (%) Insulin Resistance Insulin Level  -Cell Failure * IFG=impaired fasting glucose. 50 100 150 200 250 300 350 Fasting Glucose Post-meal Glucose Obesity IFG * Diabetes Uncontrolled Hyperglycemia At Risk

6. Major Pathophysiologic Defects in Type 2 Diabetes Hepatic glucose output Insulin resistance Glucose uptake in muscle and fat Glucagon (alpha cell) Insulin (beta cell) Hyperglycemia Islet-cell dysfunction Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus . 14th ed. Lippincott Williams & Wilkins; 2005:145–168. Del Prato S, Marchetti P. Horm Metab Res . 2004;36:775–781. Porte D Jr, Kahn SE. Clin Invest Med . 1995;18:247–254. Pancreas Liver Adipose tissue Liver Muscle

9. VALUES STARTED OUT WITH A DIAGNOSTIC FBS OF 140 MG/DL THEN IT WAS BROUGHT DOWN TO 126 mg/dL TODAY, FURTHER BROUGHT DOWN TO <100 mg/dL Recommended Values are now more aggressive in order to PREVENT the progression of DM & its clinical consequences!

11. Prior to 2006 Oral Therapies Did Not Address the Metabolic Needs of Type 2 Diabetes Sulfonylureas Glinides Insulin resistance Inadequate glucagon suppression (  -cell dysfunction) Glucose influx from GI tract α-Glucosidase inhibitors TZDs Metformin Chronic β -cell dysfunction Acute β -cell dysfunction Unmet need Unmet need

12. Traditional Therapies Do Not Maintain A 1c Control Over Time United Kingdom Prospective Diabetes Study (UKPDS) *Conventional=diet therapy. UK Prospective Diabetes Study (UKPDS 34) Group. Lancet . 1998;352:854-865. Median A 1c (%) Conventional* Insulin Glibenclamide (glyburide) Metformin 0 3 0 6 7 8 9 6 9 10 Time from Randomization (Years) ADA goal

13. A More Rational View of Opportunities for Intervention Given T2DM Physiology (treating to change the course of the disease) 25 100 75 0 50 -12 -10 -6 0 2 6 -2 Years From Diagnosis *Metabolic syndrome β -Cell Function (%) 50% of β cells may still be functioning Add TZD to MET or SU; new role for incretin mimetics/enhancers Initiate MET or SU or other agent; ? Incretins *Opportunities for intervention Intensify lifestyle, risk factor modification* Atherosclerosis Hyperglycemia Hypertension Insulin resistance Hyperinsulinemia Dyslipidemia

30. G lucagon- L ike P eptide- 1 (GLP-1) An Important Incretin Hormone

31. GLP-1 Effects in Humans Understanding the Natural Role of Incretins

32. Incretins Play an Important Role in Glucose Homeostasis 1. Kieffer TJ, Habener JF. Endocr Rev . 1999;20:876–913. 2. Ahrén B. Curr Diab Rep . 2003;2:365–372. 3. Drucker DJ. Diabetes Care . 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev . 2002;18:430–441.  Insulin from beta cells (GLP-1 and GIP)  Glucagon from alpha cells (GLP-1) Release of gut hormones— Incretins 1,2 Pancreas 2,3 Glucose Dependent Active GLP-1 & GIP DPP-4 enzyme Inactive GIP Inactive GLP-1 Glucose Dependent ↓ Blood glucose GI tract ↓ Glucose production by liver Food ingestion ↑ Glucose uptake by peripheral tissue 2,4 Beta cells Alpha cells

34. Properties and Biological Actions of GIP and GLP-1 Reduced GLP-1 secretion in diabetic subjects Normal GIP secretion in diabetic subjects Promotes expansion of ß-cell mass Promotes expansion of ß-cell mass Inhibits food intake and weight gain No regulation of satiety and BW Inhibits glucagon secretion No effect on glucagon secretion Inhibits gastric emptying Minimal effect on gastric emptying Stimulates insulin secretion Stimulates insulin secretion NH 2 -terminal inactivated by DPP-IV NH 2 -terminal inactivated by DPP-IV from distal small bowel and colon Released from duodenum 30/31–Amino acid peptide 42–Amino acid peptide GLP-1 GIP

35. Augmenting GLP-1 Levels by Inhibiting DPP-IV Activity GLP-1 Inactive GLP-1 Actions Mixed meal Plasma Intestinal GLP-1 release DPP-IV Rapid inactivation (>80% of pool) Excreted by kidneys GLP-1 Active Deacon et al. Diabetes .1995;44:1126. ©2005. American College of Physicians. All Rights Reserved.

36. GLP-1 Effect : Blocked By DPP-4 GLP-1 Actions Mixed Meal GLP-1(7-36) Active Plasma Intestinal GLP-1 Secretion GLP-1(9-36) Inactive DPP-IV Rapid Inactivation Renal Clearance Deacon et al. Diabetes 1995; 44:1126

37. GLP-1 Effects in Humans Understanding the Natural Role of Incretins

40. Incretins Play an Important Role in Glucose Homeostasis 1. Kieffer TJ, Habener JF. Endocr Rev . 1999;20:876–913. 2. Ahrén B. Curr Diab Rep . 2003;2:365–372. 3. Drucker DJ. Diabetes Care . 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev . 2002;18:430–441.  Insulin from beta cells (GLP-1 and GIP)  Glucagon from alpha cells (GLP-1) Release of gut hormones— Incretins 1,2 Pancreas 2,3 Glucose Dependent Active GLP-1 & GIP DPP-4 enzyme Inactive GIP Inactive GLP-1 Glucose Dependent ↓ Blood glucose GI tract ↓ Glucose production by liver Food ingestion ↑ Glucose uptake by peripheral tissue 2,4 Beta cells Alpha cells

41. The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag. Time, min Control Subjects (n=8) IR Insulin, mU/L 180 60 120 0 Normal Incretin Effect 180 60 120 0 Subjects With Type 2 Diabetes (n=14) Diminished Incretin Effect Time, min IR Insulin, mU/L Oral glucose load Intravenous (IV) glucose infusion 80 60 40 20 0 80 60 40 20 0

42. The Incretin Effect Beta-Cell Response to Oral vs. Intravenous Glucose Mean (SE); * P  0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab . 1986;63:492-498 Plasma Glucose (mg/dL) 0 60 120 180 Time (min) C-peptide (nmol/L) 0 60 120 180 Oral Glucose Intravenous (IV) Glucose Incretin Effect 200 100 0 0.0 0.5 1.0 1.5 2.0 Crossover of Healthy Subjects (n = 6) * * * * * * *

43. Acutely Improving Beta-Cell Response BYETTA Restored First-Phase Insulin Response BYETTA BYETTA Placebo Placebo

44. Glucose-Dependent Effects of GLP-1 * * * * * * * * * * * * * * * * * * * GLP-1 GLP-1 GLP-1

45. GLP-1 Effects in Humans Understanding the Natural Role of Incretins

46. GLP-1 Infusion Has Glucose-Dependent Effects on Insulin and Glucagon in Patients With Diabetes Type 2 GLP-1 Infusion 0 GLP-1 Infusion Glucose Glucagon When glucose levels approach normal values, glucagon levels rebound. When glucose levels approach normal values, insulin levels decrease. * P <0.05 Patients with type 2 diabetes (N=10) 250 200 150 100 50 mg/dL 40 30 20 10 0 mU/L Time, min pmol/L 20 15 10 5 0 60 120 180 240 Insulin 0 Adapted from Nauck MA et al. Diabetologia . 1993;36:741–744. Copyright © 1993 Springer-Verlag. – 30 GLP-1 Infusion * * * * * * * * * * * * * * * * * * * Placebo GLP-1

48. Modest but Significant Decrease in Meal-stimulated Intact GLP-1 in T2DM * P <0.05 Vilsbøll T, et al. Diabetes . 2001;50:609–613. Copyright © 2001 American Diabetes Association. Total GLP-1 controls Total GLP-1 patients Intact GLP-1 controls Intact GLP-1 patients GLP-1 (pmol/L) Time (min) 30 25 20 15 10 5 0 0 50 100 150 * * *

49. The Effect of GLP-1 and GIP on Insulin Secretion in Patients With Type 2 Diabetes 0 2000 4000 6000 8000 Time (min) C-peptide (pmol/L) GLP-1 GIP Saline Hyperglycemic Clamp Saline or GIP or GLP-1 -15 -10 0 5 10 15 20 30 45 60 75 90 105 120 150 Adapted from Vilsbøll T, et al. Diabetologia. 2002;45:1111 - 1119.

50. Loss of 1st-Phase Insulin Secretion in Type 2 Diabetes 1st phase, sharp increase in insulin response during 1st 10 min; 2nd phase, persistent increase in insulin concentration from 10 to 120 min *Based on IV GTT Adapted with permission from Pfeifer MA et al. Am J Med. 1981;70:579 Normal* – 30 0 30 60 90 120 Time (min) Plasma Immunoreactive Insulin (µU/mL) Type 2 Diabetes* – 30 0 30 60 90 120 Time (min) 20 g glucose pulse 120 100 80 60 40 20 0 1st phase (acute release) 2nd phase 120 100 80 60 40 20 0 Plasma Immunoreactive Insulin (µU/mL) 120 100 80 60 40 20 0 20 g glucose pulse

51. Diabetes GLP-1 Infusion Has Glucose-Dependent Effects on Insulin and Glucagon in Patients With Type 2 GLP-1 Infusion 0 GLP-1 Infusion Glucose Glucagon When glucose levels approach normal values, glucagon levels rebound. When glucose levels approach normal values, insulin levels decrease. * P <0.05 Patients with type 2 diabetes (N=10) 250 200 150 100 50 mg/dL 40 30 20 10 0 mU/L Time, min pmol/L 20 15 10 5 0 60 120 180 240 Insulin 0 Adapted from Nauck MA et al. Diabetologia . 1993;36:741–744. Copyright © 1993 Springer-Verlag. – 30 GLP-1 Infusion * * * * * * * * * * * * * * * * * * * Placebo GLP-1

52. Multiple Sites of Action of GLP-1: Controls Glucose Appearance Flint A, et al. J Clin Invest . 1998;101:515-520. Larsson H, et al. Acta Physiol Scand . 1997;160:413-422. Nauck MA, et al. Diabetologia. 1996;1546-1553. Drucker DJ. Diabetes . 1998;47:159-169. CNS: Promotes satiety and reduction of appetite Stomach: Slows gastric emptying Beta cell: Stimulates glucose-dependent insulin secretion Alpha cell: Inhibits glucagon secretion Liver: Reduces hepatic glucose output by inhibiting glucagon release

53. Augmenting GLP-1 Levels by Inhibiting DPP-IV Activity GLP-1 Inactive GLP-1 Actions Mixed meal Plasma Intestinal GLP-1 release DPP-IV Rapid inactivation (>80% of pool) Excreted by kidneys GLP-1 Active Deacon et al. Diabetes .1995;44:1126. ©2005. American College of Physicians. All Rights Reserved.

54. Augmenting GLP-1 Levels by Inhibiting DPP-IV Activity GLP-1 Inactive GLP-1 Actions Mixed meal Plasma Intestinal GLP-1 release DPP-IV Rapid inactivation (>80% of pool) Excreted by kidneys GLP-1 Active Deacon et al. Diabetes .1995;44:1126. ©2005. American College of Physicians. All Rights Reserved.

55. The Beginning The Beginning….

57. Exenatide Restored First-phase Insulin Response Time (min) Healthy Controls IV Glucose IV Glucose -180 -90 0 30 60 90 120 0 10 20 30 -180 -90 0 30 60 90 120 Type 2 Diabetes 0 10 20 30 Insulin (pM/kg/min) Insulin (pM/kg/min) Time (min) Evaluable; N=25; Mean (SE) Data from Fehse F, et al. Diabetologia . 2004;47(Suppl 1):A279. Exenatide Exenatide Placebo Placebo

58. Natural History of Type 2 Diabetes € € 0 50 100 150 200 250 -10 -5 0 5 10 15 20 25 30 Years of Diabetes Glucose (mg/dL) Relative Function (%) Insulin Resistance Insulin Level  -Cell Failure * IFG=impaired fasting glucose. 50 100 150 200 250 300 350 Fasting Glucose Post-meal Glucose Obesity IFG * Diabetes Uncontrolled Hyperglycemia

59. No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Major Pathophysiologies 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004. 3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007. 5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004. 7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005. 8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.           Excess hepatic glucose output Meglitinides 3 Insulin resistance Insulin deficiency DPP-4 Inhibitors Metformin 8 TZDs 6,7 SUs 4,5 Alpha-Glucosidase Inhibitors 1,2 Intestinal glucose absorption

61. Major Targeted Sites of Oral Drug Classes Glucose absorption Hepatic glucose overproduction Beta-cell dysfunction Insulin resistance DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. DeFronzo RA. Ann Intern Med . 1999;131:281–303. Buse JB et al. In: Williams Textbook of Endocrinology . 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. Pancreas ↓ Glucose level Muscle and fat Liver Biguanides- 1960s TZDs- 1990s Biguanides – 1960s Sulfonylureas -1950s Meglitinides- 1990s TZDs – 1990s Alpha-glucosidase inhibitors – 1980s Gut The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production. DPP-4 inhibitors-2005s GLP-1 DPP-4 inhibitors- 2007s Biguanides – 1960s

62. Incretins as Pharmacologic Agents Incretin Mimetic DPP-4 Inhibitors Exenatide Liraglutide Vildagliptin Sitagliptin Administration Injection Tablet Insulin Secretion Increased Increased Glucagon Secretion Decreased Decreased HbA Reduction -0.8 to 2.0% -0.8 to 2.0% -0.5 to -1.5 % -0.5 to -1.5% Weight Reduction Yes (-3 to 5 Kg) Yes (-3 to 5 Kg) No No Hypoclycemia No No No No Nausea Yes Less None None

63. The Incretins Provide a Powerful Addition to Our Current Treatment Arsenal in Diabetes Care Their unique mechanism of action, with a strong focus on improving the function of islet cells, makes these agents potentially attractive for use in the full spectrum of the natural history of diabetes, from prediabetes to later stages of the disease.

78. MiniMed Paradigm Real Time System

82. Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity Metformin Blood glucose ↑ Glucose uptake in muscle and fat by increasing insulin sensitivity 5 1. Kirpichnikov D et al. Ann Intern Med . 2002;137:25–33. 2. Setter SM et al. Clin Ther . 2003;25:2991–3026. 3. Hundal RS et al. Diabetes. 2000;49:2063–2069. 4. Chu CA et al. Metabolism. 2000;49:1619–1626. 5. Bailey CJ et al. N Engl J Med. 1996;334:574–579. Muscle Adipose tissue Liver ↓ Gluconeogenesis ↓ Glycogenolysis ↑ Glycogen synthesis ↓ Glucose production reduced by 1–4 : Liver

83. Sitagliptin Reduces Hyperglycemia Sitagliptin improves beta-cell function and increases insulin synthesis and release. Sitagliptin reduces HGO through suppression of glucagon from alpha cells. Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis. Metformin has insulin- sensitizing properties. Beta-Cell Dysfunction Hepatic Glucose Overproduction (HGO) Metformin Reduces Hyperglycemia The Combination of S itagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes in a Complementary Manner Insulin Resistance *Please see corresponding speaker note for references.

84. Sites of Action by Therapeutic Options Presently Available to Treat Type 2 Diabetes GLUCOSE ABSORPTION GLUCOSE PRODUCTION Biguanides Thiazolidinediones MUSCLE PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones (Biguanides) PANCREAS INSULIN Secretion Sulfonylureas Meglitinides Insulin Amylin ADIPOSE TISSUE LIVER alpha-glucosidase inhibitors INTESTINE Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5