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Msd Orissa Apicon Nov 2008 Dr Ka

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Msd Orissa Apicon Nov 2008 Dr Ka

  1. 1. Sitagliptin: A Novel Dipeptidyl Peptidase-4 Inhibitor, Improves Glycemic Control in Patients with Type 2 Diabetes Dr Karthik Anantharaman MSD Pharmaceuticals Pvt Ltd (India)
  2. 2. Agenda <ul><li>Type 2 Diabetes and Islet Cell function </li></ul><ul><li>Incretins, DPP-4 inhibition, and Glucose Homeostasis </li></ul><ul><li>Description of Sitagliptin ( Januvia ™) </li></ul><ul><li>Phase III Clinical Data for Sitagliptin </li></ul><ul><li>Summary and Future Direction </li></ul>
  3. 3. Old Concept of T2DM Insulin Resistance Insulin Deficiency (Beta Cell Dysfunction) Hyperglycemia
  4. 4. Patients with T2DM Have Already Lost Substantial  -Cell Function at Diagnosis *Diet and exercise. N= 376. Adapted from UKPDS 16. Diabetes . 1995;44:1249–1258. Permission required. Diagnosis (%B)
  5. 5. Beta-Cell Function Is Abnormal in Type 2 Diabetes <ul><li>A range of functional abnormalities is present </li></ul><ul><ul><li>Abnormal oscillatory insulin release </li></ul></ul><ul><ul><li>Increased proinsulin levels </li></ul></ul><ul><ul><li>Loss of 1st-phase insulin response </li></ul></ul><ul><ul><li>Abnormal 2nd-phase insulin response </li></ul></ul><ul><ul><li>Progressive loss of beta-cell functional mass </li></ul></ul>*p<0.05 between groups. Buchanan TA. Clin Ther. 2003;25(suppl B):B32–B46; Polonsky KS et al. N Engl J Med. 1988;318:1231–1239; Quddusi S et al. Diabetes Care. 2003;26:791–798; Porte D Jr, Kahn SE. Diabetes. 2001;50(suppl 1):S160–S163; Figure adapted from Vilsbøll T et al. Diabetes. 2001;50:609–613. Insulin (pmol/L) Mixed meal Normal subjects Type 2 diabetics Time (min) * * 500 400 300 200 100 0 0 60 120 180
  6. 6. Decrease in Glucose-Stimulated Insulin Secretion in T2DM (Beta Cell glucose sensitivity) Reprinted from Ferrannini E et al. J Clin Endocrinol Metab . 2005;90:493–500. 1000 800 600 400 200 0 5 10 15 20 25 Insulin secretion rate (pmoL·min -1 ·m -2 ) Plasma glucose (mmol/L) Obese NGT tertiles Lean NGT IGT T2DM quartiles
  7. 9. Pancreatic Islet Dysfunction leads to Hyperglycemia in T2DM ↑ Glucose Ohneda A, et al . J Clin Endocrinol Metab. 1978;46:504–510 Gomis R, et al. Diabetes Res Clin Pract . 1989;6:191–198. Fewer  -Cells  -Cells Hypertrophy Insufficient Insulin Excessive Glucagon – + ↓ Glucose uptake ↑ HGO +
  8. 10. Beta Cell Volume in Autopsy Studies A. Butler et al. Diabetes, 2003. Vol 52, 102-110.
  9. 11. Higher α-Cell : β-Cell Ratio in the Islet of Patients with T2DM *P <.05 vs. control groups 1 and 2 Control group 1= free of pancreatic disease; Control group 2= benign or malignant pancreatic tumor or changes in nutritional status Adapted from Yoon KH, et al . J Clin Endocrinol Metab 2003;88: 2300–2308 . * 0.81 0.2 0.3 α -Cell: β -Cell Ratio 0 0.2 0.4 0.6 0.8 1.0 1.2 Control 1 Control 2 DM
  10. 12. In T2DM, β-Cell Mass in Pancreatic Islets is Significantly Reduced 35%  -cells 65% β -cells 52%  -cells 48% β -cells P <0.01 Adapted from Deng S, et al . Diabetes 2004; 53:624–632. T2DM Control
  11. 13. Insulin and Glucagon Dynamics in T2DM -60 0 60 120 180 240 360 330 300 270 240 110 80 120 90 60 30 0 Glucose (mg %) Insulin ( µ U/mL) Glucagon (pg/mL) Meal Time (min) Delayed/depressed insulin response Nonsuppressed glucagon Normal subjects, n=11; Type 2 diabetes, n=12. Adapted from M ü ller WA et al. N Engl J Med . 1970;283:109–115. 140 130 120 110 100 90 Type 2 diabetes Normal subjects
  12. 14. Old Concept – Newer Insights Incretin Defect Insulin Resistance Insulin Deficiency (Beta Cell Dysfunction) Increased HGO Non-suppressed Glucagon (Alpha Cell Dysfunction) Hyperglycemia
  13. 15. Questions to ask ourselves….. <ul><li>As a physician treating patients, what is the use of all the science we just discussed? </li></ul><ul><li>What does all this science mean to my patient? </li></ul>
  14. 16. <ul><li>In our clinical practice, what proportion of patients with Type 2 Diabetes are at/below the ADA recommended glycemic targets, at any given point of time? </li></ul><ul><ul><li>20%-40% patients </li></ul></ul>
  15. 17. Glycemic Profile of Treated Type 2 patients in India The Diabcare-Asia 1998 Study – Outcomes on Control and Complications in Type 1 and Type 2 Diabetic Patients. Nityanant et al. Current Medical Research and Opinion 2002; 18 (5): 317-327
  16. 18. Glycemic Profile of Treated Type 2 patients in India The Diabcare-Asia 1998 Study – Outcomes on Control and Complications in Type 1 and Type 2 Diabetic Patients. Nityanant et al. Current Medical Research and Opinion 2002; 18 (5): 317-327
  17. 19. <ul><li>Therapeutic gaps that currently exist in management of patients with Type 2 Diabetes? </li></ul><ul><ul><li>I International Guidelines vs. Actual personal targets set by ourselves </li></ul></ul><ul><ul><li>II Actual personal Set targets vs. Glycemic control actually achieved </li></ul></ul>
  18. 20. <ul><li>If drugs are to be considered as one of the important factors responsible for the therapeutic gap, which is their most important shortcoming? </li></ul><ul><ul><li>Limited therapeutic options </li></ul></ul><ul><ul><li>Safety issues </li></ul></ul><ul><ul><li>Inconvenient dosing regimen </li></ul></ul>
  19. 21. 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
  20. 22. Challenges of not being able to treat patient to goal Medicines
  21. 23. Old Concept – Newer Insights Incretin Defect Insulin Resistance Insulin Deficiency (Beta Cell Dysfunction) Increased HGO Non-suppressed Glucagon (Alpha Cell Dysfunction) Hyperglycemia
  22. 24. Incretins, DPP-4 inhibition, and glucose homeostasis
  23. 26. What are Incretin Hormones? <ul><li>Glucagon-like peptide-1 ( GLP-1 ) and glucose-dependent insulinotropic polypeptide ( GIP ) are the 2 major incretins in humans </li></ul><ul><li>Both are peptide hormones ( 30 and 42 amino acids ) </li></ul><ul><li>Secreted from open-type endocrine cells ( L- and K-cells, respectively ) mainly in the distal ( GLP-1, ileum, colon ) or proximal ( GIP, duodenum ) small intestinal mucosa </li></ul><ul><li>Released in response to meal ingestion </li></ul><ul><li>Responsible for the incretin effect </li></ul>GLP-1 positive endocrine L-cells (green) in human small intestine
  24. 27. GLP-1 and GIP Are the Two Major Incretins GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptide Adapted from Drucker DJ Diabetes Care 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122: 531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246. <ul><li>Suppresses hepatic glucose output by inhibiting glucagon secretion in a glucose-dependent manner </li></ul><ul><li>Enhances beta-cell proliferation and survival in islet cell lines </li></ul><ul><li>Enhances beta-cell proliferation and survival in animal models and isolated human islets </li></ul><ul><li>Secreted by L-cells in the distal gut (ileum and colon) </li></ul><ul><li>Stimulates glucose-dependent insulin release </li></ul>GLP-1 <ul><li>Secreted by K-cells in the proximal gut (duodenum) </li></ul><ul><li>Stimulates glucose-dependent insulin release </li></ul>GIP
  25. 28. Incretin Hormones Regulate Insulin and Glucagon Levels  -cells  -cells Pancreas Gut <ul><li>Nutrient signals </li></ul><ul><li>Glucose </li></ul><ul><li>Hormonal signals </li></ul><ul><ul><li>GLP-1 </li></ul></ul><ul><ul><li>GIP </li></ul></ul>Insulin (GLP-1,GIP) Glucagon (GLP-1) Neural signals Adapted with permission from Creutzfeldt W. Diabetologia . 1979;16:75–85. Copyright © 1979 Springer-Verlag. Drucker DJ. Diabetes Care . 2003;26:2929–2940. Nauck MA et al. Diabetologia . 1993;36:741–744. Copyright © 1993 Springer-Verlag. Food
  26. 29. Incretins (GLP-1 and GIP) Regulate Glucose Homeostasis Through Effects on Islet Cell Function Active GLP-1 and GIP Release of incretin gut hormones More stable glucose control GI tract Ingestion of food  Glucose uptake and storage in muscles and adipose tissue <ul><li>Glucose dependent </li></ul><ul><li>Insulin </li></ul><ul><li>from beta cells (GLP-1 and GIP) </li></ul>Brubaker PL, Drucker DJ. Endocrinology . 2004;145:2653–2659; Zander M et al. Lancet . 2002;359:824–830; Ahrén B. Curr Diab Rep . 2003;3:365–372; Holst JJ. Diabetes Metab Res Rev . 2002;18:430–441; Holz GG, Chepurny OG. Curr Med Chem . 2003;10:2471–2483; Creutzfeldt WOC et al. Diabetes Care . 1996;19:580–586; Drucker DJ. Diabetes Care . 2003;26:2929–2940. GLP-1 and GIP metabolites DPP-4 enzyme <ul><li>In animal models of diabetes both GLP-1 and GIP have been shown to increase β -cell mass </li></ul><ul><li>The incretin axis is abnormal in patients with T2DM: Reduced release of GLP-1; reduced response to GIP </li></ul>Pancreas Beta cells Alpha cells <ul><li>Glucagon </li></ul><ul><li>from alpha cells (GLP-1) Glucose dependent </li></ul> Glucose release into the bloodstream by liver
  27. 30. GLP-1 Actions Are Glucose Dependent in Patients With Type 2 Diabetes Placebo GLP-1 Time (min) *p<.05 Insulin Glucagon Fasting glucose 250 150 5 250 200 100 50 40 30 20 10 0 mU/L 20 15 10 0 60 120 180 240 15.0 12.5 10.0 7.5 5.0 200 150 100 50 Infusion mmol/L mg/dL pmol/L pmol/L Effect declines as glucose reaches normal n=10. Adapted from Nauck NA et al. Diabetologia . 1993;36:741–744. * * * * * * * * * * * * * * * * * * *
  28. 31. Summary of Trials: GLP-1 and GIP Levels and Actions in Type 2 Diabetes *When corrected for gender and BMI Adapted from Toft-Nielsen M-B et al J Clin Endocrinol Metab 2001;86:3717–3723; Nauck MA et al J Clin Invest 1993;91:301–307.  (p=0.047 vs. NGT) Intact* GIP Intact  (p<0.05 vs. NGT) GLP-1 Incretin actions Incretin levels Patients with type 2 diabetes mellitus
  29. 32. DPP-4 Inhibitors Improve Glucose Control by Increasing Incretin Levels in Type 2 Diabetes <ul><li>Glucose dependent </li></ul><ul><li>Insulin </li></ul><ul><li>from beta cells (GLP-1 and GIP) </li></ul>Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology . 10th ed. Philadelphia, Saunders, 2003:1427–1483. Hyperglycemia <ul><li>Glucagon </li></ul><ul><li>from alpha cells (GLP-1) Glucose dependent </li></ul>Release of incretins from the gut Pancreas α -cells β -cells Insulin increases peripheral glucose uptake Ingestion of food Inactive incretins Improved Physiologic Glucose Control DPP-4 Enzyme DPP-4 = dipeptidyl peptidase 4 GI tract ↑ insulin and ↓ glucagon reduce hepatic glucose output JANUVIA (sitagliptin, MSD) DPP-4 Inhibitor X
  30. 33. Plasma Levels of GLP-1, GIP and Insulin in Normal Subjects <ul><li>GLP-1 and GIP are secreted in response to meals (arrows) in normal subjects and correlate to insulin secretion. </li></ul><ul><li>The insulinotropic effects of GLP-1 and GIP can fully explain the incretin effect. </li></ul>Reprinted from Ørskov C et al. Scand J Gastroenterol . 1996;31:665  670. pmol/L 400 200 0 40 20 0 300 0 09 13 19 22 09 Hours GIP GLP-1 Insulin
  31. 34. Meal-Induced GLP-1 Secretion is Impaired in Patients with Type 2 Diabetes *p<0.05 between the T2DM and NGT group. T2DM=type 2 diabetes mellitus, NGT=normal glucose tolerant, IGT=impaired glucose tolerant. Reprinted from Toft-Nielsen M-B et al. Clin Endocrinol Metab . 2001:86;3717–3723. 5 15 15 20 0 60 120 180 240 (min) 0 GLP-1 (pmol/l) * * * * * * * NGT IGT T2DM meal
  32. 35. Plasma Concentrations of Glucagon and GIP in Patients With Type 2 Diabetes and Normal Subjects T2DM=type 2 diabetes, n=54; NGT=normal glucose tolerance, n=33 Reprinted from Toft-Nielsen M-B et al. J Clin Endocrinol Metab . 2001;86:3717–3723. * NGT T2DM NGT * * p<0.001 T2DM meal P-GIP (pmol/L) P-Glucagon (pmol/L)
  33. 36. Decreased Postprandial Levels of the Incretin Hormone GLP-1 in Patients With Type 2 Diabetes * P <0.05, Type 2 diabetes vs NGT. Reprinted with permission from Toft-Nielsen MB et al. J Clin Endocrinol Metab . 2001;86:3717–3723. Copyright © 2001, The Endocrine Society. 17 * * * * * * * Meal Started Meal Finished (10–15)
  34. 37. DPP9 DPP8 FAP DPP-4 DPP6 PEP QPP/DPPII APP prolidase DPP-4 Gene Family Other Proline Specific Peptidases Function unknown unknown unknown unknown unknown unknown unknown GLP-1 / GIP cleavage unknown NH 2 -Xaa ~ Pro-COOH --Xaa-Pro ~ Yaa-- NH 2 -Xaa-Pro ~ Yaa-- NH 2 -Xaa ~ Pro-Yaa---- catalytically inactive NH 2 -Xaa - Pro ~ Yaa-- Specificity DPP-4 Is a Member of a Family of Proline Specific Peptidases
  35. 38. Anatomical Relationship Between GLP-1+ L Cells and DPP-4+ Endothelium Cleft Hole Active site Probable entrance to active site Possible exit of cleaved dipeptide Hole
  36. 39. Sitagliptin - Overview <ul><li>DPP-4 inhibitor in development for the treatment of patients with type 2 diabetes, approved by the FDA on October 17 2006. EU approval March 2007 </li></ul><ul><li>Provides potent and highly selective inhibition of the DPP-4 enzyme </li></ul><ul><li>Fully reversible and competitive inhibitor </li></ul>
  37. 40. Sitagliptin Is Potent and Highly Selective (>2500x) for the DPP-4 Enzyme Herman et al. ADA . 2004. >100,000 APP >100,000 PEP >100,000 FAP >100,000 DPP-2, DPP-7 >100,000 DPP-9 48,000 DPP-8 18 DPP-4 IC 50 (nM) Enzyme
  38. 41. Selective DPP-4 Inhibitors Are Not Associated With Preclinical Toxicities Observed With Non-Selective Inhibitors 1. Leiting B et al. Abstract 6-OR. 64 th ADA;2004. 2. Lankas GK et al. Diabetes. 2005;54:2988–2994. – + + Decreased Proliferation Study of T-Cell Proliferation 1 2-Week Rat Toxicity Study 2 – + + Bloody diarrhea Acute Dog Toxicity Study 2 – + + Mortality – + + Enlarged spleen – + + Anemia – + + Thrombocytopenia – + + Alopecia Sitagliptin – highly selective DPP-4 inhibitor Selective DPP-8/9 inhibitor Nonselective inhibitor (DPP-8/9 and DPP-4)
  39. 42. Pharmacokinetics of Sitagliptin Supports Once-Daily Dosing <ul><li>With once-daily administration, trough (at 24 hrs) DPP-4 inhibition is ~ 80% </li></ul><ul><ul><li>> 80% inhibition provides full enhancement of active incretin levels </li></ul></ul><ul><li>No effect of food on pharmacokinetics </li></ul><ul><li>Well absorbed following oral dosing </li></ul><ul><li>T max app 2 hours, t 1/2 app 12.4 hours at 100 mg dose </li></ul><ul><li>Low protein binding, app 38% </li></ul><ul><li>Primarily renal excretion as parent drug </li></ul><ul><ul><li>Approximately 80% of a dose recovered as intact drug in urine </li></ul></ul><ul><li>No clinically important drug-drug interactions </li></ul><ul><ul><li>No meaningful P450 system inhibition or activation </li></ul></ul>
  40. 43. Sitagliptin AUC 0-inf vs. creatinine clearance: AUC increases with decreasing creatinine clearance AUC GMR increase < 2-fold when CrCl > 50 mL/min Dose adjustments < 30 mL/min – ¼ dose 30 – 50 mL/min – ½ dose > 50 mL/min – full dose
  41. 44. Single-Dose OGTT Study One Dose of Sitagliptin Inhibited Plasma DPP-4 Activity Hours post-dose ~80% ~50% Trough DPP-4 inhibition Inhibition of plasma DPP-4 activity from baseline (%) 0 1 2 4 8 12 16 20 24 – 10 0 40 50 60 80 100 90 70 30 20 10 6 10 14 18 22 26 OGTT Sitagliptin 25 mg (n=56) Sitagliptin 200 mg (n=56) Placebo (n=56)
  42. 45. % Plasma Inhibition of DPP-4 Activity With Sitagliptin 100 mg in Healthy Adults 16 8 Percent Inhibition From Baseline Hours postdose 100 90 80 70 60 50 40 30 20 10 0 – 10 – 20 0 1 2 4 6 12 24 36 48 Protocol 001. Herman GA et al. Clin Pharmacol Ther . 2005;78:675–688. Sitagliptin 100 mg (N=6) Placebo (N=2)
  43. 46. A Single Dose of Sitagliptin Increased Active GLP-1 and GIP Over 24 Hours OGTT 24 hrs (n=19) Herman et al. Diabetes . PN005, 2005. Active GLP-1 0 5 10 15 20 25 30 35 40 0 2 4 6 24 26 28 Hours Postdose GLP-1 (pg/mL) OGTT 2 hrs (n=55) Crossover study in patients with T2DM Placebo Sitagliptin 25 mg Sitagliptin 200 mg 2-fold increase in active GLP-1 p< 0.001 vs placebo Active GIP 0 10 20 30 40 50 60 70 80 90 0 2 4 6 24 26 28 Hours Postdose GIP (pg/mL) OGTT 24 hrs (n=19) OGTT 2 hrs (n=55) 2-fold increase in active GIP p< 0.001 vs placebo
  44. 47. A Single Dose of Sitagliptin Increased Insulin, Decreased Glucagon, and Reduced Glycemic Excursion After a Glucose Load 0 10 20 30 40 0 1 2 3 4 mcIU/mL 50 55 60 65 70 75 0 1 2 3 4 Time (hours) pg/mL Glucose load Drug Dose 22% ~12% Insulin Glucagon Crossover Study in Patients with T2DM p<0.05 for both dose comparisons to placebo for AUC p<0.05 for both dose comparisons to placebo for AUC Placebo Sitagliptin 25 mg Sitagliptin 200 mg Glucose load Drug Dose 120 160 200 240 280 320 0 1 2 3 4 5 6 Time (hours) Glucose ~26% p<0.001 for both dose comparisons to placebo for AUC
  45. 48. Phase III Clinical Studies of Sitagliptin ● M onotherapy use (P021, P023, A201, P040) ● Combination use with Metformin, a PPAR  agent or SU (P019, P020, P035 and P036) ● Active Sulph comparator trial, added to metformin (P024)
  46. 49. Monotherapy Studies – Patients Studied <ul><li>Multinational studies </li></ul><ul><ul><li>Mean duration of T2DM of 4.4 years </li></ul></ul><ul><ul><li>Baseline mean A1C - 8.0% </li></ul></ul><ul><ul><ul><li>54% of patients had A1C < 8% </li></ul></ul></ul><ul><ul><li>53% prior OHA, mean BMI 31 kg/m 2 , mean age 54 years, 55% male </li></ul></ul><ul><li>Japanese study </li></ul><ul><ul><li>Mean duration of T2DM of ~ 4 years </li></ul></ul><ul><ul><li>Baseline mean A1C 7.6% </li></ul></ul><ul><ul><ul><li>~ 65% had A1C < 8% </li></ul></ul></ul><ul><ul><li>~ 45% on prior OHA, mean BMI 25 kg/m 2 , mean age 55 years, 60% male </li></ul></ul>
  47. 50. Sitagliptin Consistently and Significantly Lowers A1C with Once-Daily Dosing in Monotherapy 7.2 7.6 8.0 8.4 *between group difference in LS means Adapted from Raz et al. Diabetologia. 2006;49:2564–2571; Aschner et al. Diabetes Care. 2006;29:2632–2637. ; Nonaka K et al; A201. Abstract presented at: ADA 2006 Placebo (n=244) Sitagliptin 100 mg (n=229) 24-week Study Time (weeks) 0 5 10 15 20 25 -0.79% (p<0.001) Japanese Study -1.05% (p<0.001) Placebo (n=75) Sitagliptin 100 mg (n=75) Time (weeks) 0 4 8 12 A1C (%) 7.6 8.0 8.4 7.2 6.8 <ul><li>change vs placebo* </li></ul>18-week Study Placebo (n=74) Sitagliptin 100 mg (n=168) Time (weeks) 0 6 12 18 A1C (%) 7.2 7.6 8.0 8.4 -0.6% (p<0.001) A1C (%) =
  48. 51. Sitagliptin Provides Significant and Progressively Greater Reductions in A1C with Progressively Higher Baseline A1C Baseline A 1c (%) Mean (%) Reduction in A 1c (%) Inclusion Criteria: 7%–10% Reduction in A 1c (%) <8% 8–9% > 9% 7.37 8.40 9.48 <8% 8–9% > 9% 7.39 8.36 9.58 Reductions are placebo-subtracted Adapted from Raz et al. Diabetologia. 2006;49:2564–2571 ; Aschner et al. Diabetes Care. 2006;29:2632–2637. N=96 N=130 N=70 N=62 N=27 N=37
  49. 52. Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy Fasting Glucose Plasma Glucose mg/dL Time (weeks) 0 5 10 15 20 25 144 153 162 171 180 189 Placebo (n=247) Sitagliptin 100 mg (n=234)  FPG* = –17.1 mg/dL ( p <0.001) Post-meal Glucose * LS mean difference from placebo after 24 weeks Adapted from Aschner et al. Diabetes Care. 2006;29:2632–2637. Time (minutes) Plasma Glucose mg/dL <ul><li>in 2-hr PPG* = –46.7 mg/dL (p<0.001) </li></ul>0 60 120 0 60 120 144 180 216 252 288 Placebo (N=204) Sitagliptin (n=201) Baseline 24 weeks Baseline 24 weeks
  50. 53. Sitagliptin Improves the  -Cell Response to Glucose Monotherapy Studies 200 400 600 800 1000 1200 1400 160 180 200 220 240 260 Glucose concentration (mg/dL) Insulin secretion (pmol/min) Pooled monotherapy studies – subset of patients with frequently sampled MTT Model-based assessment of β -cell function Φ s = static component, describes relationship between glucose concentration and insulin secretion Baseline End-Treatment Baseline End-Treatment Sitagliptin 100 mg q.d Placebo
  51. 54. Sitagliptin Improved Markers of Beta-Cell Function 24-Week Monotherapy Study Proinsulin/insulin ratio Aschner P et al. PN021; Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC. p< 0.001* *P value for change from baseilne compared to placebo Hatched = Baseline Solid = Week 24 ∆ from baseline vs pbo = 0.078 (95% CI -0.114, -0.023) Placebo Sitagliptin 100 mg Ratio (pmol/L / pmol/L) HOMA- β p< 0.001* ∆ from baseline vs pbo = 13.2 (95% CI 3.9, 21.9) Placebo Sitagliptin 100 mg
  52. 55. Indian Clinical Trial PN040 PN040 has been accepted for publication in Diabetes Research and Clinical Practice Exact publication time has not been given as yet Estimate: Feb or March edition
  53. 56. PN040, Comparable Baseline Characteristics BMI = body mass index. 66.6 66.8 Mean weight, kg 24.9 8.75 1.9 25.1 8.74 2.1 Mean BMI, kg/m 2 Mean A1c, % Duration of Diabetes 63 (35.4) 127 (36.1) Indian 33 (18.5) 62 (17.6) Korean 82 (46.1) 163 (46.3) Chinese Race/Ethnicity, n (%) 72 (40.4) 152 (43.2) Female, n (%) 50.9 50.9 Mean age, y Placebo n = 178 Sitagliptin 100 mg n = 352
  54. 57. Placebo Subtracted Change from Baseline in HbA1c Per Country (-1.92, -0.83) -1.38 Korea (-0.92, -0.46) -0.69 China (-1.73, -0.99) -1.36 India 95% Confidence limits Placebo Subtracted % A1c change Country
  55. 58. Sitagliptin Reduces FPG Levels Significantly From Baseline (APT Population) Values represent mean ± SE. 0 6 12 18 – 30 – 20 – 10 0 10 Week LSM Change From Baseline, mg/dL  31.0 p<0.001 Sitagliptin 100 mg Placebo
  56. 59. Four-Point Meal Tolerance Test at Baseline and Week 18 (APT Population) 120 170 220 270 Sitagliptin 100 mg Placebo Minutes After Initiation of Meal Challenge Mean Plasma Glucose, mg/dL Baseline Week 18 0 30 60 120 0 30 60 120
  57. 60. Incidence of Adverse Events AE = adverse event. 1 (0.6) 2 (0.6) Discontinued due to drug-related AE 2 (1.1) 5 (1.4) Discontinued due to AE 1 (0.6) 1 (0.3) Serious drug-related AE 2 (1.1) 6 (1.7) Serious AE 3 (1.7) 10 (2.8) Drug-related AE 27 (15.2) 82 (23.3) One or more AE Placebo n = 178 Sitagliptin 100 mg n = 352 Event, n (%)
  58. 61. Incidence of Laboratory Adverse Events LAE = laboratory adverse event. 0 0 Discontinued due to drug-related LAE 1 (0.6) 1 (0.3) Discontinued due to LAE 0 0 Serious drug-related LAE 0 0 Serious LAE 3 (1.8) 9 (2.6) Drug-related LAE 12 (7.0) 22 (6.5) One or more LAE Placebo n = 178 Sitagliptin 100 mg n = 352 Tolerability, n (%)
  59. 62. Summary <ul><li>Compared with placebo, treatment with Sitagliptin for 18 weeks resulted in </li></ul><ul><ul><li>Significantly lower HbA1C, </li></ul></ul><ul><ul><li>Significant improvements in FPG and 2-hour PPG levels </li></ul></ul><ul><ul><li>Slight weight gain (0.6 kg) </li></ul></ul><ul><li>Sitagliptin was well tolerated and showed no clinically meaningful difference with placebo in incidence of AEs. </li></ul><ul><li>No events of hypoglycemia </li></ul>PPG = postprandial plasma glucose.
  60. 63. Protocol 021 –Completers Phase B results A1c -  from Baseline Phase A Phase B
  61. 64. Phase III Clinical Studies of Sitagliptin ● M onotherapy use (P021, P023, A201, P040) ● Combination use with Metformin, a PPAR  agent or SU (P019, P020, P035 and P036) ● Active Sulph comparator trial, added to metformin (P024)
  62. 65. Sitagliptin Once Daily Significantly Lowers A1C When Added On to Metformin or Pioglitazone  in A1C vs Pbo* = –0.65% (p<0.001)  in A1C vs Pbo* = –0.70% (p<0.001) *Placebo Subtracted Difference in LS Means. Charbonnel et al. Diabetes Care. 2006;29:2638–2643 ; Rosenstock et al. Clin Ther. 2006;28:1556–1568. Placebo (n=224) Sitagliptin 100 mg (n=453) Placebo (n=174) Sitagliptin 100 mg (n=163)
  63. 66. PN020: Extended Treatment With Sitagliptin and Metformin Maintained Lower A1C Levels to 104 Weeks (Completers) Continuation Phase 24-Week Phase 0 6 12 18 24 30 38 46 54 62 70 78 91 104 Week Values represent mean ± SE.
  64. 67. Sitagliptin Added to Ongoing Metformin or Pioglitazone Therapy in Patients With T2DM: Change in Body Weight Over Time LS Mean Change from Baseline in Body Weight (kg) 0.0 -0.4 -0.6 -0.8 -0.2 0 12 24 Study Week -1.0 Charbonnel et al. Diabetes Care. 2006;29:2638–2643 ; Rosenstock et al. Clin Ther. 2006;28:1556–1568. Placebo + Met (n=169) Sita 100 mg qd + Met (n=399) 0.0 0.5 1.0 1.5 2.0 -0.5 -1.0 0 6 12 18 24 Weeks Placebo + pioglitazone (n=174) Sita 100 mg qd + pioglitazone (n=163)
  65. 68. Sitagliptin Once Daily Significantly Increases Proportion of Patients Achieving Goal in Mono- or Combination Therapy Sitagliptin Placebo Monotherapy Study Add-On to Metformin Study Add-On to TZD Study Percentage Percentage Percentage P <0.001 P <0.001 P <0.001 17% 41% 18% 47% 23% 45% Goal A1C < 7% Aschner et al. Diabetes Care. 2006;29:2632–2637 . Charbonnel et al. Diabetes Care. 2006;29:2638–2643 ; Rosenstock et al. Clin Ther. 2006;28:1556–1568.
  66. 69. Study Design R Discontinue other AHA Visit 2 Run-in start Visit 10 Week 30 Visit 8 Week 18 Visit 6 Week 6 Visit 7 Week 12 Visit 9 Week 24 30 weeks Visit 1 Screening 1 week Visit 4 Week –2 Visit 3 Up to 12 weeks Visit 5 Day 1 2 weeks Screen patient according to inclusion and exclusion criteria Metformin titration/stable-dose period Placebo Primary end point Glipizide rescue HbA 1c 8%–11% AHA=antihyperglycemic agent; R=randomization. Raz I et al. Curr Med Res Opin. 2008;24:537–550. Single-blind placebo run-in Sitagliptin 100 mg/day Placebo Titrate metformin Continue stable dose of metformin at ≥1500 mg/day
  67. 70. Adding Sitagliptin 100 mg Once Daily to Metformin Reduced HbA 1c LSM=least squares mean; SE=standard error. a Sitagliptin=100 mg/day; b Metformin≥1500 mg/day; c Change from baseline at week 18 was the primary end point. Raz I et al. Curr Med Res Opin. 2008;24:537–550. Week 9.0 8.0 8.5 Mean ± SE Change in HbA 1c , % Between-group difference in LSM was –1.0% at 18 and 30 weeks; P <0.001 Sitagliptin a + metformin b (n=95) Placebo + metformin b (n=92) 6 0 12 18 c 24 30
  68. 71. Greater HbA 1c Reductions in Patients With Higher Baseline HbA 1c at 18 Weeks SE=standard error. a Sitagliptin=100 mg/day; b Metformin≥1500 mg/day. Raz I et al. Curr Med Res Opin. 2008;24:537–550. Sitagliptin a + metformin b Placebo + metformin b Mean ± SE Change in HbA 1c From Baseline, % – 2.0 – 1.5 – 1.0 – 0.5 0 0.5 34 9.4 41 9.4 9%–10% 45 8.4 35 8.4 <9% Baseline HbA 1c Subgroup 13 10.5  10% 19 10.5 n = Baseline mean, %
  69. 72. Placebo Controlled Add-on to Glimperide or Glimepiride/Metformin Study – Design and Patients 035 Placebo Phase B Sitagliptin 100 mg qd Screening Period Single-blind Placebo Stratum 1 Glim (≥ 4 mg/day) alone (~50%, n=212) Stratum 2 Glim + MF ≥1500 mg/d ) (~50%, n=229) Week 24 R A N D O M I Z A T I O N Week 80 Week 0 T2DM, Baseline A1c = 8.34 Age 18-78 yrs Continue/start regimen of glimepiride ± metformin Week -2 eligible if A1c 7.5-10.5% Double-blind Sitagliptin 100 mg qd Pio 30 mg qd
  70. 73. Sitagliptin Improved A1C When Added to Glim *Difference in LS Mean change from baseline Hermansen et al, Diabetes Obesity Metabolism 2007 Δ -0.6 %;p<0.001*
  71. 74. Sitagliptin Improved A1C When Added to Glim + MF 035 Δ -0.9%; p<0.001* *Difference in LS Mean change from baseline Hermansen et al, Diabetes Obesity Metabolism 2007
  72. 75. Sitagliptin Increased Rates of Hypoglycemia in Combination with Sitagliptin ± Metformin 035 Treatment Group N 222 219 4 (1.8) 0 Requiring Non-Medical Assistance and Not Exhibiting Marked Severity ‡ 0 0 Requiring Medical Assistance or Exhibiting Marked Severity ‡ Patients With at Least One Episode † n (%) Total Number of Episodes† Sitagliptin + Glim ± MF Overall n 55 20 9 0 0 0 Placebo + Glim ± MF Placebo + Glim ± MF Sitagliptin + Glim ± MF Overall n (%) 27 (12.2) 4 (1.8)
  73. 76. Efficacy Results – Phase III Clinical Studies <ul><li>Multinational, randomized, double-blind, placebo-controlled, parallel-group studies to assess the efficacy of JANUVIA in patients with type 2 diabetes inadequately controlled on specified therapy. The primary efficacy endpoint was change from baseline at end of follow up period in HbA1C. </li></ul><ul><li>Itamar Raz et al. Current Medical Research and Opinion 2008; 24 (2): 537-550 </li></ul><ul><li>Bernard Charbonnel et al. Diabetes Care. 2006;29:2638–2643 </li></ul><ul><li>Rosenstock et al, Clinical Therapeutics 2006;28(10):1556-1568 </li></ul><ul><li>Hermansen et al, Diabetes Obesity Metabolism 2007 </li></ul>* In the entire cohort in K. Hermansen et al , placebo adjusted reduction in HbA1c was -0.74%. NA -17.7 -0.7 8.0 24 163/174 Placebo controlled study in patients with inadequate glycemic control on Pioglitazone mono-therapy (≥15mg/d) Rosenstock et al. 3 -37.1 -20.7 -0.9 8.27 24 115/105-109 K Hermansen et al. 4,* Placebo controlled study in patients with inadequate glycemic control on Glimepiride (≥4mg/d) & Metformin (≥1500mg/d) combination -35.1 -19.3 -0.6 8.42 24 102-104/103-104 K Hermansen et al. 4,* Placebo controlled study in patients with inadequate glycemic control on Glimepiride mono-therapy (≥4mg/d) -50.4 -25.2 -0.65 7.96 24 453/224 Charbonnel et al. 2 -54 -25.2 -1 9.3 18 95/92 Itamar Raz et al. 1 Placebo controlled study in patients with inadequate glycemic control on Metformin mono-therapy (≥1500mg/d) Placebo Subtracted reduction in 2-hr PPG (mg/dL) Placebo adjusted reduction in FPG (mg/dL) Placebo adjusted reduction in HbA1c (%) Baseline HbA1c (%) in active arm Duration of Follow-up (weeks) Number of patients in active & placebo groups (N/n)  
  74. 77. Sitagliptin + Metformin Factorial Study Design N = 1091 Randomized Mean baseline A1C = 8.8% Screening Period Single-blind Placebo Double-blind Treatment Period Diet/exercise Run-in Period Eligible if A1C 7.5 to 11% If on an OHA, D/C’ed Week- 2 Day 1 Sitagliptin 50/Met 1000 BID Placebo Sitagliptin 100 mg qd Metformin 500 BID Metformin 1000 BID Sitagliptin 50/Met 500 BID Week 24 Duration up to 12 weeks based on prior therapy Open Label Cohort Sitagliptin 50/Met 1000 BID R A N D O M I Z A T I O N Goldstein et al, Diabetes Care: 30; 1979 – 1987, 2007
  75. 78. A1C Results at 24 Weeks Mean A1C = 8.8% Sitagliptin 50 mg + metformin 1,000 mg bid Metformin 1,000 mg bid Sitagliptin 100 mg qd Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bid LSM A1C Change From Baseline, % – 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 0.0 0.5 n=178 n=177 n=183 n=178 n=175 – 0.8 a – 1.0 a – 1.3 a – 1.6 a – 2.1 a Open label n=117 – 2.9 b All patients Treated Population a LSM placebo adjusted change b LSM change from baseline without adjustment for placebo. bid=twice a day; qd=once a day. 24-Week Placebo-Adjusted Results Mean A1C = 11.2% Sitagliptin With Metformin Coadministration Initial Therapy Study Goldstein et al. Diabetes Care 2007; 30: 1979-1987
  76. 79. Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results From a Subset of Patients not on Antihyperglycemic Therapy at Study Entry LSM Change From Baseline, % Study 036 – 1.2 n=87 – 2.0 – 1.8 – 1.6 – 1.4 – 1.2 – 1.0 – 0.8 – 0.6 – 0.4 – 0.2 0 Sitagliptin 50 mg + metformin 1,000 mg bid Metformin 1,000 mg bid Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bid Sitagliptin 100 mg qd Placebo LSM=least squares mean change. – 1.1 n=88 – 1.1 n=90 – 1.6 n=100 – 1.9 n=86 – 0.2 n=83
  77. 80. Greater Reductions in HbA 1c Associated With Higher Baseline HbA 1c Without Regard to Therapy at Week 54 (APT) Williams-Herman D et al. Poster presentation at ADA 67th Annual Scientific Sessions in Chicago, Illinois, USA, 22–26 June 2007. Late Breaker (04-LB). Sitagliptin With Metformin Coadministration Initial Therapy Study All patients Treated Population
  78. 81. FPG and PPG Results at 24 Weeks 24-Week Placebo-Adjusted Results All Patients Treated Population FPG=fasting plasma glucose; PPG=postprandial glucose. a LSM adjusted for baseline value. b Difference from placebo. Sitagliptin 50 mg + metformin 1,000 mg bid Metformin 1,000 mg bid Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bid LSM PPG Change, mg/dL b 2-hour PPG Mean baseline level: 283–293 mg/dL – 54 a – 117 a – 125 – 100 – 75 – 50 – 25 0 LSM FPG Change, mg/dL b FPG Mean baseline level: 197–205 mg/dL – 33 a – 70 a – 75 – 50 – 25 0 – 53 a n=183 – 35 a n=179 n=141 – 93 a n=147 – 78 a n=138 n=152 – 23 a n=180 n=178 n=179 – 52 a Sitagliptin 100 mg qd n=136 Sitagliptin With Metformin Coadministration Initial Therapy Study Goldstein et al. Diabetes Care 2007; 30: 1979-1987
  79. 82. Co-administration of Sitagliptin and Metformin in Healthy Adults Increased Active GLP-1 Greater Than Either Agent Alone * Values represent geometric mean±SE. Placebo Metformin 1000 mg Sitagliptin 100 mg Co-administration of sitagliptin 100 mg + metformin 1000 mg Mean AUC ratio* Sita + Met: 4.12 Mean AUC ratios* Sita: 1.95 Met: 1.76 – 2 0 10 20 30 40 50 – 1 0 1 2 3 4 Active GLP-1 Concentrations, pM Meal Morning Dose Day 2 Time (hours pre/post meal) N=16 healthy subjects AUC=area under the curve Migoya EM et al. 67th ADA 2007. Oral Presentation OR-0286. Data available on request from Merck & Co., Inc. Please specify 20752937(1)-JMT. Metformin + Sitagliptin: Effect on Incretin Axis
  80. 83. Metformin + Sitagliptin : Pharmacokinetics of Co-Administration Herman G A Et al. Current Medical Research & Opinion 2006; 22 (10): 1939-1947 Mean (± standard error) metformin plasma concentrations following administration of metformin (1000 mg twice daily) with or without sitagliptin (50 mg twice daily) for 7 days in 13 patients with type 2 diabetes The mean Metformin plasma concentration–time profiles were nearly identical with or without Sitagliptin co-administration
  81. 84. Herman G A Et al. Current Medical Research & Opinion 2006; 22 (10): 1939-1947 Mean (± standard error) sitagliptin plasma concentrations following administration of sitagliptin (50 mg twice daily) with or without metformin (1000 mg twice daily) for 7 days in 13 patients with type 2 diabetes The mean Sitagliptin plasma concentration–time profiles were nearly identical with or without Metformin co-administration Metformin + Sitagliptin : Pharmacokinetics of Co-Administration
  82. 85. Recent efficacy findings from the blinded extension phase for total of 104 weeks Williams-Herman D et al. Poster presentation at ADA 68th Annual Scientific Sessions in USA, 22–26 June 2008. Sitagliptin With Metformin Coadministration Initial Therapy Study Results are presented for patients initially randomized to active therapy The initial combination treatment with Sitagliptin & Metformin was generally well tolerated over 2 years
  83. 86. Sitagliptin and Metformin–Initial Combination Therapy Extension Phase 0 6 12 18 24 30 38 46 54 62 70 78 91 104 6 6.5 7 7.5 8 8.5 9 Sita = sitagliptin; Met = metformin Time (weeks) 24-Week Phase Continuation Phase Extension Phase HbA 1c (LS mean change %) Sita 100 mg q.d. (n=22) Met 500 mg b.i.d. (n=26) Met 1000 mg b.i.d. (n=53) Sita 50 mg b.i.d. + Met 500 mg b.i.d. (n=64) Sita 50 mg b.i.d. + Met 1000 mg b.i.d. (n=77)
  84. 87. Effect of Initial Combination Therapy with Sitagliptin and Metformin on FPG Through Week 104 0 3 6 12 18 24 30 38 46 54 62 70 78 91 104 24-Week (Phase A) Continuation Phase (Phase B) Week FPG (LS Mean mg/dL) Completers Population in the Extension Phase Extension Phase Sita = sitagliptin; Met = metformin
  85. 88. Sitagliptin + Metformin: ß Cell function modelling Williams-Herman, Poster # 543, ADA 2008
  86. 89. Sitagliptin Alone and in Combination with Metformin improved both the Proinsulin to Insulin Ratio and HOMA-  HOMA-  Mean Baseline (pmol/L/pmol/L): .455 ± 0.035 *= p<0.01; †= p<0.001 Proinsulin/Insulin Ratio Sita 50 mg b.i.d + Met 1000 mg b.i.d . Sita 50 mg b.i.d + Met 500 mg b.i.d. Met 1000 mg b.i.d. Met 500 mg b.i.d. Sita 100 mg q.d. Placebo * * Mean Baseline 41.8 ± 3.7 *= p<0.001 Proinsulin/Insulin Ratio -0.25 -0.20 -0.15 -0.10 -0.05 0.00 0.05 * * * * †
  87. 90. Summary of Clinical Assessment of Hypoglycemia Extension Phase Results (Weeks 54 – 104) 39 14 (14) 98 1 1 (2.4) 42 Placebo/Met 1000 mg b.i.d. Including Data After Initiation of Glycemic Rescue Therapy ‡ Excluding Data After Initiation of Glycemic Rescue Therapy ‡ Treatment Group Total Number of Episodes † Patients with at Least One Episode † N Total Number of Episodes † Patients with at Least One Episode † N 122 134 121 107 103 107 100 88 65 52 7 5 (4.1) 5 5 (4.7) Sita 50 mg b.i.d. + Met 1000 mg b.i.d. 13 7 (6.5) 1 1 (1.5) Met 500 mg b.i.d. 1 1 (1.0) 0 0 (0.0) Sita 100 mg q.d. n (%) n (%) Met 1000 mg b.i.d. 2 (2.3) 3 6 (5.0) 11 Sita 50 mg b.i.d. + Met 500 mg b.i.d. 2 (2.0) 2 8 (6.0) 14 † Any given episode may belong to multiple categories; ‡ Patients meeting glycemic rescue criteria were treated with open-lable glyburide b.i.d. = twice daily; Met = Metformin; q.d. = once daily; Sita = Sitagliptin
  88. 91. Summary of Clinical Adverse Experiences (AEs) Through 54 Weeks (Phase A and B Combined, cont.) Sita 50 mg + MF 1000 mg b.i.d. N = 182  Sita 50 mg + MF 500 mg b.i.d. N = 190  Sita 100 mg q.d. N = 179   Metformin 1000 mg b.i.d. N = 182 Metformin 500 mg b.i.d N = 182   Number (%) of patients: 48 (26) 36 (19) 56 (31) 26 (14) 18 (10) All Gastrointestinal AEs 5 (3) 4 (2) 2 (1) 2 (1) 2 (1) Hypoglycemia Special AEs of Clinical Interest
  89. 92. Gastrointestinal AEs Through 54 Weeks % 27.7
  90. 93. Change in Body Weight From Baseline at Week 54 (LS mean change ± SE) Body Change From Baseline At Week 54 (kg) – 2.0 – 1.5 – 1.0 – 0.5 0.0 0.5 1.0 Sit 50 mg BID + met 1000 mg BID Sit 50 mg BID + met 500 mg BID Met 1000 mg BID Met 500 mg BID Sit 100 mg QD n=100 n=116 n=132 n=143 n=153 *Change from baseline P < 0.05. * * * *
  91. 94. Proportion of Patients with A1C Goal <7% at Endpoint (Week 54 Analysis) Sita 50 mg BID + Met 1000 mg BID Sita 50 mg BID + Met 500 mg BID Met 1000 mg BID Met 500 mg BID Sita 100 mg QD 58 77 101 106 124 106 117 134 147 153 n = Percent of patients
  92. 95. Active-Comparator (Glipizide) Controlled Add-on to Metformin Study (024) – Design and Patients <ul><li>Design </li></ul><ul><li>Patients with T2DM (on monotherapy or combination OHA) ➜ started/continued on metformin monotherapy (at least 1500 mg/d) during run-in period, randomized if A1C 6.5–10% after run-in period </li></ul><ul><li>Patient population </li></ul><ul><li>1172 randomized patients, mean age 57 years, ~ 60% male </li></ul><ul><li>Mean duration of T2DM 6 years, baseline mean A1C = 7.5% </li></ul>Screening Period Single-blind placebo Double-blind Treatment Period: Glipizide or Sitagliptin 100 mg q.d. Metformin monotherapy Run-In Period Week -2: eligible if A1C 6.5 to 10% Continue/start regimen of met monotherapy Day 1 Randomization monotherapy with metformin (stable dose > 1500 mg/d) Week 52 Glipizide : 5 mg qd increased to 10 mg bid (held if FS < 110 mg/dL or hypoglycemia)
  93. 96. Sitagliptin Once Daily Shows Similar Glycemic Efficacy to Glipizide When Added to Metformin (52 Weeks) Mean Change in HbA 1c Mean change from baseline (for both groups)*: - 0.67% 6.0 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.4 0 12 24 38 52 Time (weeks) *per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis Nauck et al, Diabetes Obesity Metabolism 9: 194 – 205, 2007 Sitagliptin 100 mg qd + Metformin (n= 382 ) Glipizide + Metformin (n=411)
  94. 97. Progressively Greater Reductions in A1C as Baseline A1C Rises Baseline A1C Category Study inclusion criteria 6.5-10% Change from baseline in A1C (%) Sitagliptin 100 mg q.d. Glipizide N=112 N=167 N=82 N=21 N=117 N=179 N=82 N=33 Per Protocol Population
  95. 98. Sitagliptin Once Daily Shows Better Safety and Tolerability Profile Compared to Glipizide (52 Weeks) Glipizide (n=584) Sitagliptin 100 mg (n=588) p<0.001 Nauck et al, Diabetes Obesity Metabolism 9: 194 – 205, 2007  between groups = –2.5 kg (p<0.001) Hypoglycemia 32% 4.9% 0 10 20 30 40 50 Week 52 Incidence (%) Sitagliptin 100 mg qd (n= 382 ) Glipizide (n=411)
  96. 99. Mean Change from Baseline in Waist Circumference (cm) Over Time All-Patients-as-Treated Population -2 -1 0 1 0 12 24 38 52 Week Mean Change from Baseline (cm) ±SE Sitagliptin 100 mg Glipizide
  97. 100. Mean Change from Baseline in ALT (IU/L) Over Time Week Mean Change from Baseline (IU/L) ±SE -2 -1 0 1 0 12 24 38 52 -3 6 18 30 46 3 Sitagliptin 100 mg Glipizide
  98. 101. Effects of Sitagliptin and Glipizide on Body Weight and Hypoglycemia *(95% CI) LS Means Change in Body Weight (kg) in Between Treatment Groups CSR LS Mean Change in Body Weight (kg) Over Time (APaT population) Overall Number of Episodes of Hypoglycemia: Week 0 Through Week 104 Sitagliptin 100 mg/d (n = 253) Glipizide (n = 261) LS Mean Change From Baseline (kg) 0 12 24 38 52 78 104 – 2 – 1 0 1 2 Week ∆ =−2.3 (−3.0, −1.6)*
  99. 102. HbA1c (%) Change from Baseline CSR Per Protocol Population Week 104 Difference in LS Means HbA1c -0.03; 95% CI -0.13, 0.07 HbA1c (%) Change from Baseline (LS Mean ±SE) (248) (256)
  100. 103. Substantial Proportion of Patients Achieved Goal on Sitagliptin Once-Daily As Add-on to Metformin % A1C < 7% after 52 Weeks Per Protocol Population
  101. 104. ADA 2008 Update <ul><li>Comparable efficacy of Sitagliptin, Metformin, Glimepiride, Rosiglitazone, Pioglitazone </li></ul>
  102. 105. Meta-analysis & a virtual head-to-head clinical trial simulation to estimate the contribution of differences in baseline A1c to the apparent differences in efficacy between OAHAs <ul><li>For each 1% increase in baseline A1c, an average decrease of 0.44% A1c was found in response to oral AHA therapies. </li></ul><ul><li>At a common baseline A1c of 8.0%, the differences in efficacy between therapies were ± 0.3% A1c. </li></ul>Differences in Reported Efficacy Between Oral Anti-Hyperglycemic Agents Largely Reflect Differences in Baseline A1C. Brian G. Topp et al. poster presented at ADA 2008.
  103. 106. JANUVIA TM works consistently well in various patient subtypes
  104. 107. <ul><li>Pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients 1, 2 </li></ul><ul><li>Study 021 (Aschner et al., Diabetes Care 2006): Patients with type 2 diabetes (HbA1c ≥7 and ≤10%; mean baseline = 8.0%) were randomized to once-daily sitagliptin 100 mg, 200 mg or placebo in a 1:1:1 ratio for 24 weeks. </li></ul><ul><li>Study 023 (Raz et al., Diabetologia 2006): Patients with type 2 diabetes (HbA1c ≥7 and ≤10%; mean baseline = 8.1%) were randomized to once-daily sitagliptin 100 mg, 200 mg or placebo in a 2:2:1 ratio for 18 weeks. </li></ul><ul><li>Study 036 (Goldstein et al., Diabetes Care 2007): Patients with type 2 diabetes (HbA1c ≥7 and ≤10%; mean baseline = 8.8%) were randomized to 1 of 6 treatments (1:1:1:1:1:1 ratio) for 24 weeks: sitagliptin 100 mg once-daily; placebo; sitagliptin 100 mg/metformin 2000 mg; sitagliptin 100 mg/metformin 1000 mg; metformin 2000 mg; or metformin 1000 mg (all as divided doses administered BD). </li></ul><ul><li>Study 040 (Yang et al., ASEAN Federation of Endocrine Societies 2007): Patients from China, India, and Korea with type 2 diabetes (HbA1c ≥7.5 and ≤11%; mean baseline = 8.7%) were randomized to once-daily sitagliptin 100 mg or placebo in a 2:1 ratio for 18 weeks. </li></ul><ul><li>Poster by Williams-Herman et al. at ADA 2008. </li></ul><ul><li>Poster by Harvey L. Katzeff et al. at ADA 2008. </li></ul>
  105. 108. <ul><li>Baseline characteristics of the population studied (mean ± SD; N = 1,691) 1,2 </li></ul><ul><li>Age, 53.0 ± 9.9 y (range, 20 to 78) </li></ul><ul><li>Gender, 45% female </li></ul><ul><li>Race: </li></ul><ul><ul><li>White, 37% </li></ul></ul><ul><ul><li>Asian, 37% </li></ul></ul><ul><ul><li>Hispanic, 17% </li></ul></ul><ul><ul><li>Black, 5% </li></ul></ul><ul><ul><li>Other, 4% </li></ul></ul><ul><li>BMI, 29.5 ± 5.9 kg/m2 (range, 16.3 to 54.7) </li></ul><ul><li>HbA1c, 8.4 ± 1.0 (range, 6.2 to 12.2) </li></ul><ul><li>FPG, 185 ± 46 mg/dL (range, 73 to 427) </li></ul><ul><li>HOMA-β, 45.5 ± 47.2 (range, 0.4 to 877) </li></ul><ul><li>P/I ratio, 0.5 ± 0.4 (range, 0.0 to 11.7) </li></ul><ul><li>Duration of type 2 diabetes, 3.7 ± 4.2 y (range, 0 to 38) </li></ul><ul><li>Poster by Williams-Herman et al. at ADA 2008. </li></ul><ul><li>Poster by Harvey L. Katzeff et al. at ADA 2008. </li></ul>
  106. 109. Demographic/Anthropometric Subgroups (and MS) Placebo-subtracted A1C LS mean change from baseline (%) Sex Age Median BMI Metabolic yrs kg/m 2 Syndrome F M <65 ≥65 ≤ 30.8 >30.8 - + p-values for treatment by ALL subgroup interactions are >0.05
  107. 110. Glycemic endpoints analyzed by baseline body mass index (BMI) In Patients with Type 2 Diabetes, Sitagliptin Effectively Lowers A1C Regardless of Patient Age, Gender, or Body Mass Index – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Williams-Herman et al. at ADA 2008. Pooled Results from all Phase III studies of JANUVIA ® 100mg monotherapy Placebo adjusted LS mean change from baseline HbA 1c, %, (95% CI) Placebo adjusted LS mean change from baseline FPG mg/dl, (95% CI) Placebo adjusted LS mean change from baseline 2-h PPG mg/d) (95% CI) Baseline values (mean ± SD) of HbA1c, FPG, and 2-h PPG in subgroups defined by baseline BMI subgroups
  108. 111. Pooled Results from all Phase III studies of JANUVIA ® 100mg monotherapy Glycemic endpoints analyzed by duration of type 2 diabetes Influence of Measures of Beta Cell Function on Efficacy of Sitagliptin in Patients with Type 2 Diabetes – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Harvey L. Katzeff et al. at ADA 2008. Placebo adjusted LS mean change from baseline HbA 1c, %, (95% CI) Placebo adjusted LS mean change from baseline FPG mg/dl, (95% CI) Placebo adjusted LS mean change from baseline 2-h PPG mg/d) (95% CI) Baseline values (mean ± SD) of HbA1c, FPG, and 2-h PPG in subgroups defined by baseline duration of type 2 diabetes
  109. 112. Influence of Measures of Beta Cell Function on Efficacy of Sitagliptin in Patients with Type 2 Diabetes – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Harvey L. Katzeff et al. at ADA 2008. Glycemic endpoints analyzed by baseline HOMA β Pooled Results from all Phase III studies of JANUVIA ® 100mg monotherapy Baseline values (mean ± SD) of HbA1c, FPG, and 2-h PPG in subgroups defined by baseline BMI subgroups
  110. 113. Influence of Measures of Beta Cell Function on Efficacy of Sitagliptin in Patients with Type 2 Diabetes – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Harvey L. Katzeff et al. at ADA 2008. Glycemic endpoints analyzed by baseline Pro-insulin/Insulin ratio Pooled Results from all Phase III studies of JANUVIA ® 100mg monotherapy Baseline values (mean ± SD) of HbA1c, FPG, and 2-h PPG in subgroups defined by baseline BMI subgroups
  111. 114. Safety and Tolerability Overview <ul><li>Well tolerated in Phase I through III trials – in completed and ongoing studies more than 8000 patients on sitagliptin (to doses of 200 mg q.d. in Phase III studies) </li></ul><ul><li>Pre-specified Pooled Phase III analysis, including monotherapy and combination studies: over 1500 patients on sitagliptin and over 750 patients on placebo </li></ul><ul><ul><li>Summary measures of adverse experiences (AEs) were similar to placebo </li></ul></ul><ul><ul><ul><li>Including overall clinical AEs, serious AEs, discontinuations due to AEs, drug-related AEs, laboratory AE summary measures </li></ul></ul></ul><ul><ul><li>Small differences in incidence of specific AEs </li></ul></ul><ul><ul><ul><li>Between group difference (sitagliptin 100 mg – placebo group) in incidence > 1% for only 1 specific AE (nasopharyngitis 1.2% difference) </li></ul></ul></ul>
  112. 115. Summary Measures of Clinical Adverse Events for Sitagliptin is Similar to Placebo Recommended dose in proposed label: 100 mg q.d. 0.1 0.6 0.8 1.9 0.0 0.1 3.2 10.0 55.5 % Placebo (N=778) 0.0 0.1 Discontinued due to drug-related SAE 0.7 1.3 Discontinued due to SAE 0.0 0.6 Discontinued due to drug-related AE 0.9 2.6 Discontinued due to AE 0.0 0.0 Deaths 0.0 0.3 Drug-related SAEs 3.3 3.2 Serious AEs 9.4 9.5 Drug-related AEs 54.2 55.0 One or more AEs % % % of Patients with Sitagliptin 200 mg (N=456) Sitagliptin 100 mg (N=1082) Pooled Phase III Population
  113. 116. Only Small Differences in Incidence of AEs: Pooled Phase III Population AEs with at least 3% incidence and Numerically Higher in Sitagliptin than Placebo Group Recommended dose in proposed label: 100 mg q.d. Difference vs Pbo (95% CI) 0.1 (-2.3, 2.4) 0 1.2 (-0.7, 3.0) 0.7 (-0.9, 2.2) 0.3 (-1.1, 1.6) 0 3.0 2.3 Diarrhea 3.6 3.6 Headache 6.8 6.7 Upper Respiratory Tract Infection 1.7 1.8 3.3 % Placebo (N = 778) 1.7 Urinary Tract Infection 2.1 Arthralgia 4.5 Nasopharyngitis % Sitagliptin 100 mg (N = 1082)
  114. 117. Sitagliptin Lowers A1C Without Increasing the Incidence of Hypoglycemia or Leading to Weight Gain <ul><li>Neutral effect on body weight </li></ul><ul><ul><li>In monotherapy studies, small decreases from baseline (~ 0.1 to 0.7 kg) with sitagliptin; slightly greater reductions with placebo (~ 0.7 to 1.1 kg) </li></ul></ul><ul><ul><li>In combination studies, weight changes with sitagliptin similar to placebo-treated patients </li></ul></ul>Pooled Phase III Population Analysis: no statistically significant difference in incidence for either dose vs placebo Hypoglycemia Weight Changes 0.9% 1.2% 0.9% Patients with hypoglycemia (%) Sitaglitpin 200 mg q.d. Sitagliptin 100 mg q.d. Placebo
  115. 119. Summary on Sitagliptin <ul><li>Sitagliptin is a potent and selective DPP-4 inhibitor administered once-daily for the treatment of T2DM </li></ul><ul><li>Once-daily regimen of sitagliptin provides </li></ul><ul><li>A once-daily regimen of sitaglitpin provides substantial glycemic efficacy </li></ul><ul><ul><li>Significant reductions in A1C across a range of starting A1C levels in monotherapy and combination use </li></ul></ul><ul><ul><li>Sustained A1C reduction to 1 year </li></ul></ul><ul><ul><li>Improvements in multiple measures of beta-cell function </li></ul></ul><ul><li>Compared to a sulfonylurea agent, sitagliptin provides </li></ul><ul><ul><li>Similar efficacy </li></ul></ul><ul><ul><li>Superior improvements in beta-cell function, less hypoglycemia, and weight loss (vs weight gain) </li></ul></ul><ul><li>Sitagliptin was well tolerated with summary measures of AEs similar to placebo </li></ul>
  116. 120. Advantages of DPP-IV Inhibition <ul><li>Oral, Once daily </li></ul><ul><li>Meal independent administration </li></ul><ul><li>Low risk of hypoglycemia </li></ul><ul><li>No clinically meaningful drug-drug interactions </li></ul><ul><li>Significant improvements in Glucose sensitivity of beta cells, pro-insulin/insulin ratio & HOMA-beta </li></ul><ul><li>Oral therapy, providing dosing convenience to the patient </li></ul><ul><li>Endogenous GLP-1 & GIP levels are increased in response to meal and are transient </li></ul><ul><li>Avoid tolerability/immunogenicity issues with exogenous GLP-1 </li></ul><ul><li>Multiple mechanisms of GLP-1 in T2DM </li></ul><ul><ul><li>Insulin release is glucose dependent </li></ul></ul><ul><ul><li>Reduced hepatic glucose production </li></ul></ul><ul><ul><li>Improved peripheral glucose utilization </li></ul></ul><ul><ul><li> -cell preservation / neogenesis and restoration in animal models </li></ul></ul>Source: Drucker DJ. Diabetes Care 2003;26:2929-2940.
  117. 121. Effect of Des-F-Sitagliptin on Beta-Cell Mass 1.1% Nondiabetic Control H&E insulin (I) glucagon (G) I/G Diabetic Control Diabetic Mice Treated with Des-F-sitagliptin 0.1% 0.4% Figure 3. HFD/STZ diabetic mice were treated with vehicle or des-fluoro-sitagliptin at indicated dosages for 11 weeks. Whole pancreas from each group was cryopreserved and consecutive sections were stained with H&E, anti-insulin antibody (green), or anti-glucagon antibody (red). Shown are representative islets from each group with single staining and the overlay of the insulin and glucagon staining (I/G).
  118. 122. GLP-1 Preserved Morphology of Human Islet Cells In Vitro Day 1 GLP-1–treated cells Control Day 3 Day 5 Islets treated with GLP-1 in culture were able to maintain their integrity for a longer period of time. Adapted from Farilla L et al. Endocrinology . 2003;144:5149–5158.
  119. 123. Thank You
  120. 124. Back up slides
  121. 125. Islet Cell Dysfunction: Beta-Cell Dysfunction in Type 2 Diabetes
  122. 126. The Beta Cell Micrograph: Lelio Orci, Geneva 10 µm ~ 10,000 granules
  123. 127. The Secretory Granule Micrograph: Lelio Orci, Geneva 100 nm 200,000 molecules of insulin
  124. 128. Beta-Cell Function Is Abnormal in Type 2 Diabetes <ul><li>A range of functional abnormalities is present </li></ul><ul><ul><li>Abnormal oscillatory insulin release </li></ul></ul><ul><ul><li>Increased proinsulin levels </li></ul></ul><ul><ul><li>Loss of 1st-phase insulin response </li></ul></ul><ul><ul><li>Abnormal 2nd-phase insulin response </li></ul></ul><ul><ul><li>Progressive loss of beta-cell functional mass </li></ul></ul>*p<0.05 between groups. Buchanan TA. Clin Ther. 2003;25(suppl B):B32–B46; Polonsky KS et al. N Engl J Med. 1988;318:1231–1239; Quddusi S et al. Diabetes Care. 2003;26:791–798; Porte D Jr, Kahn SE. Diabetes. 2001;50(suppl 1):S160–S163; Figure adapted from Vilsbøll T et al. Diabetes. 2001;50:609–613. Insulin (pmol/L) Mixed meal Normal subjects Type 2 diabetics Time (min) * * 500 400 300 200 100 0 0 60 120 180
  125. 129. First-Phase Insulin Response is lost in T2DM Normal Type 2 Diabetes n=9 normal; n=9 type 2 diabetes. Adapted from Pfeifer MA et al. Am J Med . 1981;70:579–588. 0 20 40 60 80 100 120 – 30 0 30 60 90 120 Time (min) 0 20 40 60 80 100 120 – 30 0 30 60 90 120 Time (min) Plasma insulin (µU/mL) Plasma insulin (µU/mL)
  126. 130. Decrease in Glucose-Stimulated Insulin Secretion in T2DM (Beta Cell glucose sensitivity) Reprinted from Ferrannini E et al. J Clin Endocrinol Metab . 2005;90:493–500. 1000 800 600 400 200 0 5 10 15 20 25 Insulin secretion rate (pmoL·min -1 ·m -2 ) Lean NGT Plasma glucose (mmol/L)
  127. 131. Decrease in Glucose-Stimulated Insulin Secretion in T2DM (Beta Cell glucose sensitivity) Reprinted from Ferrannini E et al. J Clin Endocrinol Metab . 2005;90:493–500. 1000 800 600 400 200 0 5 10 15 20 25 Insulin secretion rate (pmoL·min -1 ·m -2 ) Obese NGT tertiles Lean NGT Plasma glucose (mmol/L)
  128. 132. Decrease in Glucose-Stimulated Insulin Secretion in T2DM (Beta Cell glucose sensitivity) Reprinted from Ferrannini E et al. J Clin Endocrinol Metab . 2005;90:493–500. 1000 800 600 400 200 0 5 10 15 20 25 Insulin secretion rate (pmoL·min -1 ·m -2 ) Obese NGT tertiles Lean NGT IGT Plasma glucose (mmol/L)
  129. 133. Decrease in Glucose-Stimulated Insulin Secretion in T2DM (Beta Cell glucose sensitivity) Reprinted from Ferrannini E et al. J Clin Endocrinol Metab . 2005;90:493–500. 1000 800 600 400 200 0 5 10 15 20 25 Insulin secretion rate (pmoL·min -1 ·m -2 ) Obese NGT tertiles Lean NGT IGT T2DM quartiles Plasma glucose (mmol/L)
  130. 134. Decreased Insulin Content in Type 2 Diabetes T2DM=Type 2 diabetes. Data obtained from pancreatic islets isolated from 6 T2DM organ donors and 10 nondiabetic cadaveric organ donors. Marchetti P et al. J Clin Endocrinol Metab . 2004;89:5535–5541. p<0.05
  131. 135.  Cells Contain less Insulin Secretory Granules in T2DM *p<0.05 vs control; T2DM=type 2 diabetes. Data obtained from pancreatic islets isolated from 6 T2DM organ donors and 10 nondiabetic cadaveric organ donors. Marchetti P et al. J Clin Endocrinol Metab . 2004;89:5535–5541. * Secretory granules (No/ 70 µm 2 )
  132. 136. Increased Beta-Cell Apoptosis Occurs in T2DM * *p<0.05. Islet cell death was assessed by an ELISA method, which evaluates the cytoplasmic histone-associated DNA fragments. After incubation absorbance of samples was read spectrophotometrically. Data obtained from pancreatic islets isolated from 6 T2DM organ donors and 10 nondiabetic cadaveric organ donors. Adapted from Marchetti P et al. J Clin Endocrinol Metab . 2004;89:5535–5541.
  133. 137. Adapted from Rhodes CJ. Science . 2005;307:380–384. Fewer Pancreatic Islets in Type 2 Diabetes Normal Compensation More islets Larger islets More beta cells/islet Larger beta cells Nondiabetic Obesity Decompensation Fewer islets Fewer beta cells/islet Amyloidosis Type 2 diabetes
  134. 138. Summary –  cell in T2DM <ul><li>Reduced secretory granules </li></ul><ul><li>Reduced secretory capacity </li></ul><ul><li>Reduced  cell number </li></ul>
  135. 139. Islet Cell Dysfunction: Excess Glucagon Secretion From Alpha Cells in Type 2 Diabetes
  136. 140. Glucagon Levels Are Elevated in IGT and T2DM p<0.001 Fasting p<0.001 Postprandial NGT=normal glucose tolerance, n=33; IGT=impaired glucose tolerance, n=15; T2DM=type 2 diabetes mellitus, n=54. Toft-Nielsen M-B et al. J Clin Endocrinol Metab . 2001;86:3717–3723. Fasting plasma glucagon (pmol/L) Postprandial glucagon at 240 min (pmol/L)
  137. 141. Postprandial Glucagon is not suppressed in T2DM * 72 108 144 180 216 – 60 0 60 120 180 240 300 360 Time (min) Glucose (mg/dL) Nonsuppressed glucagon Suppressed glucagon *p<0.001; N=9 (7 men, 2 women). Reprinted from Shah P et al. J Clin Endocrinol Metab . 2000;85:4053–4059.
  138. 142. Increase in Alpha-Cell Area in Type 2 Diabetes * *p<0.05; n: immunoperoxidase-stained postmortem pancreatic tissue from T2D=15, control=10. Adapted from Clark A et al. Diabetes Research . 1988;9:151–159.
  139. 143. Summary –  cell in T2DM <ul><li>Lack of suppression of glucagon secretion </li></ul><ul><ul><li>Reduced insulin </li></ul></ul><ul><ul><li>? Insulin resistance in  cell </li></ul></ul><ul><li>Increased glucagon secretory capacity </li></ul><ul><li>Increased  cell number </li></ul><ul><li>Altered Islet morphology – loss of normal relationship between  and  cells </li></ul>
  140. 144. Summary <ul><li>The pathophysiology of T2DM includes islet cell dysfunction and insulin resistance. </li></ul><ul><li>Abnormal islet cell function </li></ul><ul><li>Early and progressive islet cell dysfunction is integral to the development of type 2 diabetes and to the deterioration of glucose control over time. </li></ul> cells Reduced insulin secretion Increased post-prandial glucose Increased hepatic glucose output  cells Increased glucagon secretion Increased fasting glucose Increased post-prandial glucose Increased hepatic glucose output
  141. 145. GLP-1: A New Mechanism <ul><li>This in turn… </li></ul><ul><li>Stimulates glucose-dependent insulin secretion </li></ul><ul><li>Inhibits glucagon secretion </li></ul><ul><li>Slows gastric emptying </li></ul><ul><li>Reduces food intake </li></ul>GLP-1 is secreted from the L cells in the ileum Upon ingestion of food… L cells GLP-1 Drucker DJ. Diabetes Care. 2003;26:2929–2940.
  142. 146. Dipeptidyl Peptidase-4 (DPP-4) Is Involved in the Inactivation of GLP-1 and GIP XA- t 1/2 ~1 min DPP-4 agonist, active inactive GLP-1 active GIP active
  143. 147. DPP-4 <ul><li>Cell surface serine dipeptidase; member of the prolyl oligopeptidase family </li></ul><ul><li>Cleaves the N-terminal dipeptide from peptides with proline or alanine in the penultimate position </li></ul><ul><li>Widely expressed </li></ul><ul><li>Shed into the circulation in a soluble form lacking the transmembrane region </li></ul><ul><li>Identical to CD26, a marker for activated T cells </li></ul>-SS- -SS- -SS- -SS- -SS- -SS- Šedo A et al. Biochim Biophys Acta. 2001;550:107 – 116.
  144. 148. The DPP Protease Family DPP-9 DPP-8 FAP DPP-4 DPP-6 PEP QPP/DPP-II APP prolidase DPP Gene Family Other Proline- Specific Peptidases Function unknown unknown unknown unknown unknown unknown unknown GLP-1/GIP regulation unknown NH 2 -Xaa ~ Pro-COOH --Xaa - Pro ~ Yaa-- NH 2 -Xaa - Pro ~ Yaa-- NH 2 -Xaa ~ Pro-Yaa---- catalytically inactive NH 2 -Xaa - Pro ~ Yaa-- Specificity Šedo A et al. Biochim Biophys Acta. 2001;550:107 – 116.
  145. 149. Inhibition of DPP-4 Leads to Increased Levels of GLP-1 (in Anesthetized Pigs) *Val-pyrrolidide; 300 µmol/kg, a DPP-4 inhibitor. Plasma concentration curves for GLP-1, measured with NH 2 -terminal and COOH-terminal radioimmunoassays. Holst JJ et al. Diabetes . 1998;47:1663–1670. Adapted from Deacon CF et al. Diabetes. 1998;47:764–769. Permission required. Minutes GLP-1, pmol/L GLP-1 infusion DPP-4 inhibitor* GLP-1 infusion Glucose Glucose Intact GLP-1 (NH 2 -terminal) Total GLP-1 (COOH-terminal, intact + NH 2 -terminally degraded peptide) 500 400 300 200 100 0 0 20 40 60 80 100 120 140 160 180 200 220
  146. 150. Increased Active GLP-1 and Improved Glucose Tolerance in DPP-4 Knockout Mice * P <0.05 Conarello SL et al. Proc Natl Acad Sci USA. 2003;100:6825–6830. Marguet D et al. Proc Natl Acad Sci USA. 2000;97:6874–6879. Increased Active GLP-1 Improved Glucose Tolerance Wild type – /– 0 2 4 6 8 * GLP-1 (7-36), pmol/L 20 40 60 80 90 135 180 225 270 315 360 400 * * Minutes Blood Glucose, mg/dL 0 100 120 DPP-4 –/– Wild type
  147. 151. Why is the Incretin Effect Reduced in Type 2 Diabetes? <ul><li>Is something wrong with the secretion of the incretin hormones? </li></ul><ul><li>Is something wrong with the action of the incretin hormones? </li></ul>
  148. 152. GLP-1 Secretion is Reduced in Obesity Reprinted from Verdich C et al. Int J Obes . 2001;25:1206 – 1214. meal 0 10 20 30 0 20 40 60 80 100 120 140 160 180 Time (min) Plasma GLP-1 (pmol/L) Lean (BMI 23 kg/m 2 ; n=12) Obese (BMI 38.7 kg/m 2 ; n=19) Reduced obese (BMI 33.0 kg/m 2 n=19)
  149. 153. Meal-Stimulated Incretin Hormone Concentrations Correlate Positively with Insulin Sensitivity in Non-Diabetic Men Rask et al. Diabetes Care (2001) GLP-1 GIP meal meal Lowest insulin sensitivity tertile (n=11) Middle insulin sensitivity tertile (n=11) Highest insulin sensitivity tertile (n=11) 0 30 60 90 120 180 Time (min) 80 60 40 20 0 Plasma GIP (pmol/l) # * 0 30 60 90 120 180 Time (min) 20 15 10 5 0 Plasma GLP-1 (pmol/l) *
  150. 154. Meal-Stimulated Incretin Secretion is Impaired in Patients with Type 2 Diabetes T2DM=type 2 diabetes; NGT=normal glucose tolerance Reprinted from Toft-Nielsen M-B et al. J Clin Endocrinol Metab . 2001;86:3717–3723. meal GIP (pmol/L) * * * * * * * 20 15 10 5 0 GLP-1 (pmol/l) NGT (n=33) T2DM (n=54) AUC, p<0.05 AUC, p<0.05
  151. 155. Summary of the Study Toft-Nielsen et al 2001 <ul><li>The meal-induced secretion of GLP-1: </li></ul><ul><ul><li>Is significantly decreased in type 2 diabetes </li></ul></ul><ul><ul><li>Is unaltered by diabetic neuropathy </li></ul></ul><ul><ul><li>Is not influenced by candidate L-cell regulators such as FFA or GIP </li></ul></ul><ul><ul><li>By multiple regression, the diabetic state (DM < NGT) gender (M < F), insulin sensitivity (+), and BMI (–) emerge as significant factors </li></ul></ul>FFA=free fatty acids. Toft-Nielsen M-B et al. J Clin Endocrinol Metab . 2001; 86:3717–3723 .
  152. 156. The Impaired Secretion of GLP-1 in Type 2 Diabetes does not Precede Diabetes <ul><li>Vaag et al, 1996: In identical twins discordant for type 2 diabetes, GLP-1 was decreased in the diabetic twin only </li></ul><ul><li>Nyholm et al, 1999: 24-hour plasma profiles of GLP-1 were normal in healthy offspring of parents with type 2 diabetes </li></ul><ul><li>Nauck et al, 2004: Incretin hormone concentrations after oral glucose were not significantly different between first-degree relatives of patients with type 2 diabetes and healthy controls </li></ul><ul><li>Impaired incretin hormone secretion is unlikely to be genetically determined </li></ul>
  153. 157. Summary GLP-1 and GIP Secretion in Patients with Type 2 Diabetes <ul><li>Meal-induced secretion of GLP-1 is significantly decreased. </li></ul><ul><li>Meal-induced secretion of GIP is normal or only slightly impaired. </li></ul><ul><li>The impaired secretion of GLP-1 is likely to be a consequence, rather than a primary cause, of insulin resistance and the development of hyperglycaemia. </li></ul>
  154. 158. Native GLP-1 is Rapidly Degraded by DPP IV Plasma T ½ =1-2 minutes (i.v.) MCR = 5-10 l/min DPP IV (red) and GLP-1 (green) in human small intestine DPP IV=dipeptidyl peptidase IV Hansen L et al, Endocrinology 1999; 140:5356-5363 MCR= metabolic clearance rate. Vilsb ø ll T et al. J Clin Endocrinol Metab . 2003;88:220 – 224 . DPP-IV 7 36 9 -NH 2 His Ala Ala Ala Ala Glu Glu Gly Gly Gly Glu Thr Phe Thr Phe Ser Ser Ser Asp Val Tyr Leu Leu Val Gln Lys Lys Ile Trp Ala
  155. 159. Intact GLP-1 + metabolite 1.5 nmol/kg sc Only ~10% GLP-1 survives intact after sc injection ** ** ** ** ** ** * Intact GLP-1 Survival of sc GLP-1 in Type 2 Diabetes 0 30 60 90 120 150 180 210 240 Time (min) 0 100 200 300 400 GLP-1 (pmol/l) Deacon CF et al, Diabetes 1995; 44:1126-1131
  156. 160. Plasma Concentrations of Active GLP-1 are Decreased in Type 2 Diabetes Total GLP-1, type 2 diabetic patients Total GLP-1, control group Intact GLP-1, type 2 diabetic patients Intact GLP-1, control group Time (min) GLP-1 (pmol/L) 50 0 100 150 10 20 30 0 * * * *p<0.05 Adapted from Vilsb ø ll T et al. Diabetes . 2001;50:609 – 613.
  157. 161. Why is the Incretin Effect Reduced in Type 2 Diabetes? <ul><li>Is something wrong with the secretion of the incretin hormones? </li></ul><ul><li>Is something wrong with the action of the incretin hormones? </li></ul>
  158. 162. Impaired Second-Phase Insulin Responses to Hyperglycaemic Clamp During IV GIP in T2DM All subjects were obese (BMI 29 kg/m 2 ); patients with type 2 diabetes (n=8); control subjects (n=6). IV=intravenous. Blood glucose was clamped at 15 mmol/l Adapted from Vilsbøll Tl et al. Diabetologia . 2002;45:1111 – 1119. 240 120 Glucose Obese Diabetic Patients Obese Control Subjects 0 1000 2000 3000 4000 5000 0 60 180 Time (min) Insulin (pmol/L) Glucose Low GIP High GIP Low GIP GLP-1
  159. 163. Insulin Responses (cont) High GIP, Patients Low GIP, Patients Glucose, Patients All patients were obese with type 2 diabetes (n=8). Insulin responses to the glucose clamp alone and with a low (4 pmol/kg/min) and high (16 pmol/kg/min) dose of GIP. Vilsbøll T et al. Diabetologia . 2002;45:1111 – 1119 . 0 200 400 600 -20 0 20 40 60 80 100 120 140 160 180 200 220 240 Time (min) Insulin (pmol/L)
  160. 164. Glucagon Responses to Hyperglycaemic Clamp During IV GLP-1 and GIP Reprinted from Vilsbøll T et al. Diabetologia . 2002;45:1111–1119. All subjects were obese (BMI 29 kg/m2); patients with type 2 diabetes (n=8); control subjects (n=6). 240 Glucose Obese Diabetic Patients Obese Control Subjects 0 5 10 15 0 60 120 180 Time (min) Glucagon (pmol/L) Glucose Low GIP (4 pmol/kg/min) High GIP (16 pmol/kg/min) Low GIP (4 pmol/kg/min) GLP-1 (1 pmol/kg/min)
  161. 165. Effect of GLP-1 on β -Cell Glucose Responsiveness in Type 2 Diabetes ISR=insulin secretion rate. Reprinted from Kjems LL et al. Diabetes . 2003;52:380–386 . Relationship between average glucose concentrations and ISR in Control subjects Patients with Type 2 diabetes Saline infusion GLP-1 (0.5 pmol/kg/min) GLP-1 (1.0 pmol/kg/min) GLP-1 (2.0 pmol/kg/min) ISR (pmol/kg/min) 4 9 15 20 4 9 15 20 4 9 15 20 Glucose (mmol/l) 4 9 15 20 0 20 30 10 0 20 30 10 0 20 30 10 0 20 30 10 Glucose (mmol/l) ISR (pmol/kg/min) 0 20 30 10 0 20 30 10 4 9 15 20 4 9 15 20 0 20 30 10 4 9 15 20 0 20 30 10 4 9 15 20
  162. 166. Effect of GLP-1 on β -Cell Responsiveness to Glucose Adapted from Kjems LL et al. Diabetes . 2003;52:380–386. Glucose (mmol/l) 4 9 15 20 12 0 4 8 Type 2 diabetic: GLP-1 (0.5 pmol/kg/min) + Controls: Saline infusion ISR (pmol/kg/min) 4 9 15 20 0 4 8 12 Type 2 diabetic: Saline infusion Type 2 diabetic: GLP-1 (0.5 pmol/kg/min) 4 9 15 20 0 4 8 12
  163. 167. β -Cell Responsiveness to Glucose ISR=insulin secretion rate. β -cell responsiveness to glucose expressed as the slope of the linear relation between ISR and glucose concentration. Reprinted from Kjems LL et al. Diabetes . 2003;52:380 – 386 . GLP-1 (pmol • kg -1 • min -1 ) ISR vs glucose (pmol • kg -1 • min -1 /mmol/L) 0 2 4 6 8 0 0.5 1 1.5 2 Patients with type 2 diabetes Control subjects
  164. 168. Insulinotropic Effects of GIP and GLP-1 in Diabetes of Different Etiology n=6 in each group. Modified from from Vilsbøll T et al. J Clin Endocrinol Metab . 2003;88:4897–4903. Chronic pancreatitis 0 5 10 15 20 Time (min) Plasma glucose (mmol/l) -20 -5 10 25 40 55 70 85 100 115 LADA -20 -5 10 25 40 55 70 85 100 115 Type 1 DM -20 -5 10 25 40 55 70 85 100 115 Lean, Type 2 DM 0 100 200 300 400 500 600 700 -20 -5 10 25 40 55 70 85 100 115 Plasma insulin (pmol/l) Chronic pancreatitis Lean, Type 2 DM LADA Type 1 DM GLP-1 (1 pmol/kg/min) GIP (4 pmol/kg/min) Glucose
  165. 169. Effects of GLP-1 and GIP on Insulin Secretion in Patients with Type 2 Diabetes <ul><li>GLP-1 restores the late-phase insulin response to glucose in obese patients with type 2 diabetes </li></ul><ul><li>Glucose-induced insulin secretion may thereby be restored to normal values by GLP-1 </li></ul><ul><li>The potency of GLP-1 with respect to enhancing the β -cell responsiveness to glucose is decreased </li></ul><ul><li>Amplification of the late-phase response by GIP is defective </li></ul>
  166. 170. Incretin Function in Type 2 Diabetes <ul><li>Secretion of GLP-1 impaired </li></ul><ul><li>β -cell sensitivity to GLP-1 decreased </li></ul><ul><li>Secretion of GIP normal (or slightly impaired) </li></ul><ul><li>Effect of GIP abolished or grossly impaired </li></ul><ul><li>Inhibition of glucagon is impaired </li></ul><ul><li>The defect is secondary to diabetes </li></ul><ul><li>The loss occurs at even slight hyperglycaemia </li></ul>Toft-Nielsen M-B et al. J Clin Endocrinol Metab . 2001;86:3717–3723; Kjems LL et al. Diabetes . 2003;52:380–386; Vilsbøll T et al. Diabetologia . 2002;45:1111–1119; Vilsbøll T et al. J Clin Endocrinol Metab . 2003;88:4897–4903.
  167. 171. How Important Is the Gut as an Endocrine Organ? Apelin, Amylin Bombesin Calcitonin Gene-Related Peptide Cholecystokinin Galanin Gastric Inhibitory Polypeptide Gastrin Gastrin-releasing Peptide Ghrelin Glucagon, Glicentin, GLP-1, GLP-2, Oxyntomodulin Motilin Neuropeptide Y Neurotensin, Neuromedins, Neurokinins Peptide YY Pancreatic Polypeptide Pituitary Adenylate Cyclase Activating Peptide Secretin Somatostatin Tachykinins Thyrotropin-releasing Hormone Vasoactive Intestinal Peptide Ahrén B. Curr Diab Rep. 2003;3:356–372.
  168. 172. Measurement of the Incretin Effect: OGTT and Matched IV Infusion 400 210 Minutes 0 100 200 300 – 30 0 30 60 90 120 150 180 Glucose (mg/dL) Insulin (pmol/L) Nauck MA et al. J Clin Endocrinol Metab. 1986;63:492–498. Copyright © 1986. The Endocrine Society. Glucose Insulin 200 Minutes 0 50 100 150 – 30 0 30 60 90 120 150 180 210 Oral IV
  169. 173. Reduced Incretin Effect in Patients With Type 2 Diabetes 0 20 40 60 80 Insulin (mU/L ) 0 30 60 90 120 150 180 Minutes Control Subjects * * * * * * * 0 20 40 60 80 0 30 60 90 120 150 180 Patients With Type 2 Diabetes * * * Minutes <ul><ul><li>Insulin (mU/L ) </li></ul></ul>Oral Glucose P ≤0.05, indicating significant difference to the respective value after the oral load. Nauck M et al. Diabetologia . 1986;29:46–52. Intravenous Glucose
  170. 174. The Incretins Y A E G T F I S D Y S I A M D K I H Q Q D F V N W L L A Q K G K K N D W K H N Q T I GIP: Glucose-dependent Insulinotropic Peptide H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R G GLP-1: Glucagon-like Peptide–1 Amino acids shown in blue are homologous with the structure of glucagon. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
  171. 175. GIP <ul><li>42-amino acid peptide produced in duodenal K cells </li></ul><ul><li>Secretion stimulated by nutrient ingestion, acts through a distinct GIP receptor expressed on islet β - cells and adipocytes </li></ul><ul><li>Functions as an incretin to enhance postprandial insulin secretion </li></ul><ul><li>Inactivated by the enzyme DPP-4 </li></ul>Drucker DJ. Diabetes Care. 2003;26:2929–2940.
  172. 176. GLP-1 <ul><li>A 30- to 31-amino acid peptide produced in the distal gut in enteroendocrine L cells </li></ul><ul><li>Exists in two biologically active forms: </li></ul><ul><ul><li>GLP-1 (7–36 amide) (dominant) </li></ul></ul><ul><ul><li>GLP-1 (7–37) </li></ul></ul><ul><li>Rapidly secreted, and plasma levels increase following nutrient ingestion </li></ul>Drucker DJ. Diabetes Care. 2003;26:2929–2940.
  173. 177. Synthesis and Secretion of GLP-1 and GIP L cell (ileum) Proglucagon GLP-1 [7–37] GLP-1 [7–36NH 2 ] K cell (jejunum) ProGIP GIP [1–42] Drucker DJ. Diabetes Care. 2003;26:2929–2940.
  174. 178. Incretin Secretion Is Proportional to the Amount of Food Ingested in Healthy Individuals GLP-1 GIP 0 40 80 120 160 – 30 0 30 60 90 120 150 180 210 Minutes Total GIP (pmol/L) 0 10 20 30 40 50 – 30 0 30 60 90 120 150 180 210 Minutes Total GLP-1 (pmol/L) kcal 260 kcal 520 kcal 260 kcal 520 Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88:2706–2713. Copyright © 2003. The Endocrine Society.
  175. 179. Meal-Stimulated Levels of GLP-1 Are Decreased in Type 2 Diabetes 0 10 20 30 0 50 100 150 Minutes GLP-1 (pmol/L) * * * * P <0.05 for differences between patients with type 2 diabetes and healthy subjects. Vilsbøll T et al. Diabetes. 2001;50:609–613. Total GLP-1, Controls Total GLP-1, Patients Intact GLP-1, Controls Intact GLP-1, Patients
  176. 180. Overlapping and Contrasting Actions of GLP-1 and GIP Drucker DJ. Diabetes Care. 2003;26:2929–2940. <ul><li>Reduction of food intake and body weight </li></ul><ul><li>Potent inhibition of glucagon secretion </li></ul><ul><li>Potent inhibition of gastric emptying </li></ul><ul><li>Stimulates insulin release from β -cell </li></ul><ul><li>Released from L cells in ileum and colon </li></ul>GLP-1 <ul><li>No significant effects on satiety or body weight </li></ul><ul><li>No significant inhibition of glucagon secretion </li></ul><ul><li>Modest effects on gastric emptying </li></ul><ul><li>Stimulates insulin release from β -cell </li></ul><ul><li>Released from K cells in duodenum </li></ul>GIP
  177. 181. GLP-1 Stimulates Insulin Secretion in Patients With Type 2 Diabetes 0 2000 4000 6000 8000 Minutes 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.
  178. 182. GLP-1 Infusion Normalized Blood Glucose in Patients With Diabetes 0 36 72 108 144 180 216 252 288 00:00 04:00 08:00 12:00 16:00 Diabetic-saline Diabetic-GLP-1 Nondiabetic Glucose (mg/dL) Time of day Breakfast Lunch Snack Rachman J et al. Diabetologia. 1997;40:205–211.
  179. 183. Effect of Exogenous GLP-1 on Gastric Emptying 500 400 300 200 100 0 360 270 180 90 0 Plasma glucose (mg/dL) * – 30 0 30 60 90 120 150 180 210 240 GLP-1 [7–36 amide] sc Liquid meal P <0.0001 * * * * * * Gastric volume (mL) * GLP-1 [7–36 amide] sc Liquid meal P <0.0001 * Placebo GLP-1 * * * – 30 0 30 60 90 120 150 180 210 240 Minutes 350 300 250 200 150 100 50 0 Insulin (pmol/L) * GLP-1 [7–36 amide] sc Liquid meal P =0.0002 – 30 0 30 60 90 120 150 180 210 240 * * Minutes P values indicate significance for the interaction of experiment (GLP-1 [7–36 amide] vs placebo) and time. Asterisks indicate differences at specific time points (t test, P<0.05). Nauck MA et al. Diabetologia. 1996;39:1546–1553. Copyright © 1996 Springer. Reprinted with permission.
  180. 184. Effect of Exogenous GLP-1 on Food Intake in Healthy Men * * † 0 200 400 600 800 0 0.375 0.75 1.5 GLP-1 (pmol/kg/min) Food intake (g) * P <0.05; † P <0.001 vs control. Gutzwiller JP et al. Gut. 1999;44:81–86. Copyright © 1999. Reprinted with permission.
  181. 185. <ul><li>Native GLP-1 and GIP are rapidly inactivated by the protease dipeptidyl peptidase-4 (DPP-4) </li></ul>Metabolism of GLP-1 and GIP Capillary Active Hormones GLP-1 [7–36NH 2 ] GIP [1–42] Inactive Metabolites GLP-1 [9–36NH 2 ] GIP [3–42] DPP-4 Drucker DJ. Diabetes Care. 2003;26:2929–2940.
  182. 186. Incretin Secretion and DPP-4–Mediated Inactivation Intestinal GLP-1 Release GLP-1 (9–36) Inactive (~80% of pool) GLP-1 (7–36) Active DPP-4 t 1/2 = 1 to 2 min Increased insulin secretion Intestinal GIP Release GIP (1–42) Active Effect on gastric emptying, food intake, and glucagon secretion Mixed Meal Drucker DJ. Diabetes Care. 2003;26:2929–2940. DPP-4i
  183. 187. The Concept of Incretin Degradation: Role of DPP-4 Plasma profile of total vs intact GLP-1 following exogenous GLP-1 administration in diabetic subjects 0 30 60 90 120 150 180 210 240 Minutes 0 100 200 300 400 GLP-1 (pmol/L) ** ** ** ** ** ** * Total GLP-1(7–36) + (9–36)amide Intact GLP-1(7–36)amide N = 8 **P<0.05; *P<0.01; paired t test. Deacon CF et al. Diabetes. 1995;44:1126–1131.
  184. 188. DPP-4 Inhibition Prevents N-Terminal Degradation of GLP-1 in Anesthetized Pigs 0 20 40 60 80 100 120 140 160 180 200 220 Minutes 0 100 200 300 400 500 GLP-1 (pmol/L) GLP-1 infusion Glucose GLP-1 infusion Glucose Val-pyr DPP-4 Inhibition Deacon CF et al. Diabetes. 1998;47:764–769.
  185. 189. Dipeptidyl Peptidase-4 (DPP-4) <ul><li>Cell surface serine dipeptidase; belongs to the prolyl oligopeptidase family </li></ul><ul><li>Specificity for P1 Pro >>> Ala </li></ul><ul><li>Widely expressed </li></ul><ul><li>Identical to CD26, a marker for activated T cells </li></ul>active site  -propeller domain  /  hydrolase domain Rasmussen HB et al. Nat Struct Biol. 2003;10:19 –25.
  186. 190. Pharmacological or Genetic Inactivation of DPP-4 Potentiates Incretin Action and Glucose Clearance In Vivo in Knockout Mice – 30 0 30 60 120 180 0 90 180 270 Blood glucose (mg/dL) ‡ † +/+ – /– Lower glucose in DPP-4 –/– mice +/+ -/- 0 180 360 * Plasma glucose (mg/dL) +/+ -/- 0 50 100 150 * Plasma insulin (pM) +/+ -/- 0 1 2 3 * Plasma GLP-1 (pM) * P <0.05 † P <0.01 ‡ P <0.001 Increased levels of insulin and intact GLP-1 and GIP in DPP-4 –/– mice Minutes Marguet D et al. Proc Natl Acad Sci. 2000;97:6874–6879.
  187. 191. Potentiation of Insulinotropic Activity of Exogenous DPP-4 Substrates Following Administration of Val-Pyr in Mice Minutes 0 10 20 30 40 50 Insulin (pmol/L) 0 3000 6000 9000 12000 Time (minutes) 0 10 20 30 40 50 Glucose (mmol/L) 90 270 375 525 GLP-1 Minutes 0 10 20 30 40 50 Insulin (pmol/L) 0 3000 6000 9000 12000 Glucose (mmol/L) PACAP38 Minutes 0 10 20 30 40 50 Insulin (pmol/L) 0 3000 6000 Glucose (mmol/L) GIP Minutes 0 10 20 30 40 50 Insulin (pmol/L) 0 3000 6000 Glucose (mmol/L) GRP Ahrén B, Hughes TE. Endocrinology. 2005;146:2055–2059. Val-pyr + Peptide Peptide alone Time (minutes) 0 10 20 30 40 50 90 270 375 525 Time (minutes) 0 10 20 30 40 50 90 270 375 525 Time (minutes) 0 10 20 30 40 50 90 270 375 525
  188. 192. DPP-4 Inhibitors Acutely Lower Blood Glucose and Stimulate Insulin Secretion in Single Incretin Receptor –/– but Not in DIRKO Mice – 30 0.3 0.9 Insulin * – 30 0 30 60 90 120 0 90 180 270 360 ** * * Minutes 0.6 – 30 0 30 60 90 120 0 90 180 270 360 *** *** Minutes Blood Glucose (mg/dL) 0.3 Insulin 0.6 – 30 0 30 60 90 120 0 *** Minutes 0.3 0.9 Insulin 0.6 0 30 60 90 120 0 Minutes 0.3 Insulin 0.6 Wild-type GIPR –/– GLP-1R –/– DIRKO Blood Glucose (mg/dL) GLP-1 and GIP receptors are essential for DPP-4 inhibitor action ** *** *** * P <0.05; ** P <0.01; *** P <0.001 vehicle vs Val-pyr–treated mice Blood Glucose (mg/dL) Blood Glucose (mg/dL) Vehicle DPP-4 Inhibitors 90 180 270 360 90 180 270 360 Hansotia T et al. Diabetes. 2004;53:1326–1335.
  189. 193. Peripheral but Not Portal Glucose Infusion Increases Blood Glucose in Mice 36 73 108 144 0 Blood glucose (mg/dL) Saline Portal glucose infusion Femoral glucose infusion 0 20 60 100 140 180 Minutes – 400 – 200 0 200 400 600 800 AUC (mmol/L · min) S P F † * * † S= Saline P= Portal glucose F= Femoral glucose 180 *Statistically different from portal-vein mice; † Statistically different from saline-infused mice; P <0.05. Burcelin R et al. Diabetes. 2001;50:1720–1728.
  190. 194. GLP-1 and GIP Modulate Insulin and GLP-1 Modulates Glucagon to Decrease Blood Glucose Levels During Hyperglycemia Glucose output Glucose uptake Glucagon (alpha cells) Insulin (beta cells) Pancreas GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Drucker DJ. Diabetes Care. 2003;26:2929–2940. Liver Decreased blood glucose GLP-1 GIP Muscle Adipose tissue
  191. 195. DPP-4 Inhibitors and the Treatment of Type 2 Diabetes <ul><li>Glucoregulatory actions mediated by activation of the GIP and GLP-1 receptors </li></ul><ul><li>GLP-1 and GIP are rapidly inactivated by DPP-4 </li></ul><ul><li>Incretins control glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion </li></ul><ul><li>Are important mechanisms for control of blood glucose </li></ul>
  192. 196. Question Will 4 weeks of near-normalisation of blood glucose normalise incretin hormone secretion and improve β -cell sensitivity in type 2 diabetes patients?
  193. 197. Meal-Induced GLP-1 and GIP Secretion in Type 2 Diabetic Patients Before and After 4 Weeks of Normoglycaemia Blood glucose was normalised using insulin HbA1c = 7.9 ±0.4% before treatment and 6.7±0.3% at week 4; n=9 Højberg PV et al. Diabetes 2006; 55:(suppl 1): A85 -50 0 50 100 150 200 250 300 Time (min) 50 40 30 20 10 0 -50 0 50 100 150 200 250 300 Time (min) 0 40 20 60 100 80 GLP-1 (pmol/l) GIP (pmol/l) Matched control Patients, baseline Patients, after 4 wk normoglycaemia Patients, after 24 hr normoglycaemia
  194. 198.  -Cell Responsiveness to GLP-1 Improves After 4 Weeks of Normoglycaemia in Patients with Type 2 Diabetes Units are mol.min - 1 .kg -1 /(mmol/l), evaluated from the slope of the linear regression between insulin secretion rate and concomittant plasma glucose during graded glucose infusions and infusions of saline or GLP-1 (1 pmol/kg/min) Højberg PV et al. Diabetes 2005; 54:(suppl 1): A362 Unpublished data: β -cell responsiveness to GIP improves after near-normalisation of glycaemia in T2DM ( submitted ADA ) P<0.0001 P< 0.001 P< 0.0001 P-value Saline vs GLP-1 P =0.40 P <0.02 0.39  0.04 1.73  0.24 0.33  0.04 1.27  0.24 1.01  0.14 4.79  0.53 Saline GLP-1 P-value Diabetics, Before vs After Type 2 patients ” After” Type 2 patients ” Before” Control subjects
  195. 199. If the impaired incretin response contributes significantly to the defective insulin secretion in type 2 diabetes, will restoration of incretin action improve metabolism? Question
  196. 200. 0 2 4 6 8 10 12 14 16 00:00 04:00 08:00 12:00 16:00 Snack Lunch Breakfast Diabetic - saline Non-diabetic Glucose (mmol/L) Time of day Rachman J et al., Diabetologia 1997;40:205-211 Proof of Hypothesis: Glucose Tolerance can be Restored by iv GLP-1 in T2DM Diabetic - GLP-1 (1.2 pmol/kg/min)
  197. 201. Continuous s.c. Infusion of GLP-1 Reduces Blood Glucose and Improves β -cell Function in Patients with Type 2 Diabetes Zander M et al, Lancet 2002;359:824-830 Week 0 Week 1 GLP-1 Week 6 GLP-1 Plasma glucose (mmol/l) 0 5 10 15 20 25 0 1 2 3 4 5 6 7 8 Hours post-injection 8-hour BG profiles Minutes 0 1000 2000 3000 4000 5000 6000 7000 10 30 50 70 90 arginine Hyperglycaemic clamp C-peptide (pmol/l)
  198. 202. Disease Progression in Type 2 Diabetes <ul><li>At start of UKPDS, ß-cell function was already compromised </li></ul><ul><li>β -cell function deteriorates over time ( ~ 4%/year) </li></ul><ul><li>Beneficial effect of sulphonylureas on β -cell function is not sustained </li></ul>Adapted from: UKPDS 16. Diabetes 1995;44:1249–58 HOMA: homeostasis model assessment Diet Extrapolation of  -cell function prior to UKPDS ß -cell function (%, HOMA) Years from diagnosis 0 20 40 100 -4 6 -10 -8 -6 -2 0 2 4 80 60 UKPDS Sulphonylurea Metformin
  199. 203. Summary <ul><li>Incretin hormone secretion and actions are impaired in type 2 diabetes. </li></ul><ul><li>Although β -cell responsiveness to GLP-1 is reduced, exogenous GLP-1 can still restore β -cell sensitivity to glucose and improve glucose-induced insulin secretion. </li></ul><ul><li>A GLP-1 based therapy of type 2 diabetes may therefore be expected to </li></ul><ul><ul><li>Reduce hyperglycaemia and HbA 1c levels </li></ul></ul><ul><ul><li>Improve α -cell and β -cell function </li></ul></ul><ul><ul><li>Improve insulin sensitivity </li></ul></ul><ul><ul><li>Improve metabolism </li></ul></ul>
  200. 204. Type 2 diabetic phenotype Actions of GLP-1 • ↑ insulin secretion and biosynthesis • Improves β -cell function • Impaired β -cell function ( glucose sensitivity, proinsulin/insulin ratio ) • Upregulates other genes essential for β -cell function ( eg. GLUT 2, glucokinase ) • Reduced β -cell mass • ↑ β -cell proliferation/differentiation animal studies • ↓ β -cell apoptosis + in vitro • Glucagon hypersecretion • ↓ glucagon secretion • Accelerated gastric emptying • ↓ gastric emptying • Overeating, obesity • ↑ satiety, ↓ appetite  weight loss • Macrovascular complications • Beneficial cardiovascular effects Actions which may be secondary to improved metabolic control • Insulin resistance • Improvements in insulin sensitivity GLP-1: Therapeutic Potential in Type 2 Diabetes
  201. 205. Sitagliptin Was Not Associated With Cutaneous Toxicity in Monkeys <ul><li>FDA indicated that other DPP-4 inhibitors in development were associated with skin toxicity in monkeys </li></ul><ul><li>FDA requested that Merck conduct a 3-month toxicity study with sitagliptin in monkeys </li></ul><ul><li>Results of Merck’s 3-month toxicity study in monkeys </li></ul><ul><ul><li>No treatment-related skin lesions were observed with sitagliptin </li></ul></ul><ul><ul><ul><li>>90% inhibition of DPP-4 activity was sustained throughout dosing interval </li></ul></ul></ul><ul><ul><ul><li>Concentration achieved was >40-fold higher than Cmax of highest human dose </li></ul></ul></ul><ul><ul><li>A nonselective DPP-4 inhibitor (DPP-4, DPP-8/9) showed treatment-related skin lesions </li></ul></ul><ul><li>Conclusion: skin toxicities reported with other DPP-4 inhibitors are highly unlikely to be a class effect of inhibition of DPP-4 but rather due to off-target inhibition </li></ul>Kim, Merck Research Overview. [Slide presentation] 2006
  202. 206. <ul><li>Conclusion </li></ul><ul><ul><li>“ Off-target” peptidase inhibition (i.e. inhibition of other DPP family peptidases such as DPP-8/9) can produce severe toxicity in preclinical species </li></ul></ul><ul><li>Variables that may determine degree of toxicity </li></ul><ul><ul><li>Cell penetration </li></ul></ul><ul><ul><ul><li>Unlike DPP-4, DPP-8/9 are intracellular proteins </li></ul></ul></ul><ul><ul><li>Extent of inhibition of DPP-8 and/or DPP-9 </li></ul></ul><ul><ul><ul><li>Not known if inhibition of both enzymes (or how much) is required to produce toxicities </li></ul></ul></ul><ul><ul><li>Intra-species differences in inhibition of DPP-8/9 </li></ul></ul><ul><ul><li>Have not definitively ruled out modulation of a closely </li></ul></ul><ul><ul><li>related protein </li></ul></ul>Potential Importance of Selective Inhibition for the Treatment of Type 2 Diabetes from Demuth et al. Biochim. Biophys. Acta 2005 , 1751 , 33 DPP-4
  203. 207. Veterans Affairs Diabetes Trial (VADT) <ul><li>Designed to test whether intensive blood glucose control can reduce major cardiovascular events in patients with type 2 diabetes </li></ul><ul><li>The study involved 1791 patients aged 41 years and older with type 2 diabetes who were at high risk for cardiovascular disease, and who were no longer responding to a maximum dose of an oral antidiabetic drug or daily insulin, 5 – 7 year follow-up </li></ul><ul><li>Both arms receive step therapy: glimepiride or metformin plus rosiglitazone and addition of insulin or other oral agents </li></ul><ul><li>HbA1c targets: </li></ul><ul><ul><li>Intensive arm ≤ 6% </li></ul></ul><ul><ul><li>Standard arm 8–9% (standard arm) , </li></ul></ul><ul><li>Results: </li></ul><ul><ul><li>intensive arm did not have significant reduction in major cardiovascular events </li></ul></ul><ul><ul><li>was a &quot;favourable trend&quot; in reducing all cardiovascular events except death </li></ul></ul><ul><ul><li>preliminary findings suggested that the most important predictor of a cardiovascular event or death was a severe hypoglycaemic event in the previous three months. </li></ul></ul><ul><ul><ul><li>multiple hypoglycaemic events -> 2 fold risk of cardiovascular death, 3 fold risk of death from any cause. </li></ul></ul></ul><ul><li>&quot;hypoglycaemia should be avoided, no matter what treatment is used.&quot; </li></ul>
  204. 208. ADVANCE, ACCORD, & VA-DT Results: Intensive vs Standard Glucose Control <ul><li>Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial </li></ul><ul><ul><li>Intensive control reduced the incidence of combined major macrovascular and microvascular events and the incidence of major microvascular events (primarily nephropathy </li></ul></ul><ul><ul><li>No significant effects of the type of glucose control on major macrovascular events, death from cardiovascular causes, or death from any cause </li></ul></ul><ul><li>Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial </li></ul><ul><ul><li>No difference in composite endpoint of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes </li></ul></ul><ul><ul><li>Overall mortality was higher in the intensive-therapy group </li></ul></ul><ul><li>Veterans’ Affairs Diabetes Trial (VA-DT) </li></ul><ul><ul><li>No difference in composite endpoint of myocardial infarction, stroke, or death from cardiovascular disease; severe congestive heart failure; surgical intervention for revascularization surgery for the brain, heart, and legs; amputations; and inoperable vascular disease </li></ul></ul><ul><ul><li>No significant benefit of glucose control on any of the individual components except a small, insignificant increase in cardiovascular death in the intensive-therapy group </li></ul></ul>1. The ADVANCE Collaborative Group. N Engl J Med . 2008;358:2560-2572. 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med . 2008;358:2545-2559. 3. ADA press release on blood glucose control and CVD reduction.   http://www.diabetes.org/diabetesnewsarticle.jsp?storyId=17769625&filename=20080608/comtex20080608iw00000390KEYWORDMissingEDIT.xml.
  205. 209. Data from elderly patients
  206. 210. Elderly: Effect of Sitagliptin and Placebo on HbA 1c Through Week 24 HbA 1c (%) LS Mean Full Analysis Set Time (weeks) BARDS data Table 4 7.30 8.00
  207. 211. Elderly Monotherapy : HbA 1c Change from Baseline by Age at Baseline Age <75 years ≥75 years Full Analysis Set at Week 24 HbA 1c (%) Placebo-subtracted Change from Baseline (LS MeanI) Data on file. Safety & Tolerability consistent with overall profile. No Hypoglycemia. (71) (30) ( Sitagliptin
  208. 212. Elderly: HbA 1c Change from Baseline by HbA1c at Baseline HbA 1c <8% ≥8% and <9% ≥9% Full Analysis Set at Week 24 BARDS data Table 30 HbA 1c (%) Placebo-subtracted Change from Baseline (LS MeanI) (68) (20) (13) ( Sitagliptin
  209. 213. Effect of JANUVIA TM on fasting blood glucose
  210. 214. By effectively inhibiting DPP-4 enzyme for a full 24 hours, JANUVIA TM provides substantial HbA1c lowering through effect both on FPG & PPG. Levels of incretins increase substantially following a meal though incretins are also released in the body throughout the day. Incretins affect both insulin & glucagon, which help regulate hepatic glucose production (primary mechanism for maintaining glucose homeostasis in fasting state).
  211. 215. Steady-state 24-hour glucose measures over 24 hours after 4 weeks of treatment with JANUVIA TM (50 mg twice daily) plus metformin (≥1500 mg daily) vs. placebo plus metformin JANUVIA TM 50 mg BD provides no additional glycemic efficacy compared to 100 mg OD. Period 1 (4 weeks) in a double-blind, randomized, placebo-controlled, 8-week crossover study to assess the effect on glycemic control of adding JANUVIA TM to ongoing metformin therapy in patients inadequately controlled on ≥1500 mg/day of metformin. Dose 1 of JANUVIA TM administered at 7:30, dose 2 at 18:30. Brazg R et al. Diabetes Obesity & Metabolism 2007; 9: 186–193.
  212. 216. Efficacy Results – Phase III Clinical Studies <ul><li>Multinational, randomized, double-blind, placebo-controlled, parallel-group studies to assess the efficacy of JANUVIA in patients with type 2 diabetes inadequately controlled on specified therapy. The primary efficacy endpoint was change from baseline at end of follow up period in HbA1C. </li></ul><ul><li>Itamar Raz et al. Current Medical Research and Opinion 2008; 24 (2): 537-550 </li></ul><ul><li>Bernard Charbonnel et al. Diabetes Care. 2006;29:2638–2643 </li></ul><ul><li>Rosenstock et al, Clinical Therapeutics 2006;28(10):1556-1568 </li></ul><ul><li>Hermansen et al, Diabetes Obesity Metabolism 2007 </li></ul>* In the entire cohort in K. Hermansen et al , placebo adjusted reduction in HbA1c was -0.74%. NA -17.7 -0.7 8.0 24 163/174 Placebo controlled study in patients with inadequate glycemic control on Pioglitazone mono-therapy (≥15mg/d) Rosenstock et al. 3 -37.1 -20.7 -0.9 8.27 24 115/105-109 K Hermansen et al. 4,* Placebo controlled study in patients with inadequate glycemic control on Glimepiride (≥4mg/d) & Metformin (≥1500mg/d) combination -35.1 -19.3 -0.6 8.42 24 102-104/103-104 K Hermansen et al. 4,* Placebo controlled study in patients with inadequate glycemic control on Glimepiride mono-therapy (≥4mg/d) -50.4 -25.2 -0.65 7.96 24 453/224 Charbonnel et al. 2 -54 -25.2 -1 9.3 18 95/92 Itamar Raz et al. 1 Placebo controlled study in patients with inadequate glycemic control on Metformin mono-therapy (≥1500mg/d) Placebo Subtracted reduction in 2-hr PPG (mg/dL) Placebo adjusted reduction in FPG (mg/dL) Placebo adjusted reduction in HbA1c (%) Baseline HbA1c (%) in active arm Duration of Follow-up (weeks) Number of patients in active & placebo groups (N/n)  
  213. 217. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of the Addition of Sitagliptin for Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Glimepiride, Alone or in Combination With Metformin Study 035 – Continuation Phase
  214. 218. Study Design Placebo Sitagliptin 100 mg QD Single-blind Placebo Week 24 Continue/start regimen of glimepiride ± metformin Single-blind eligible if A1C 7.5% to 10.5% 24-Week Phase R Stratum 1: Glimepiride (≥4 mg/d) Stratum 2: Glimepiride + Metformin (≥1500 mg/d) Continuation Phase Week 54 Patients not requiring rescue medication in 24-week phase could continue through 54 weeks. Active Treatment* *=Pioglitazone 30 mg QD Week 0 Screening Period Patients with treated or untreated T2DM, ages 18 to 78 years
  215. 219. Sitagliptin Improved A1C When Added to Glim ± MF 035 *Difference in LS Mean change from baseline Δ -0.7 %;p<0.001*
  216. 220. Sitagliptin Improved A1C When Added to Glim 035 *Difference in LS Mean change from baseline Δ -0.6 %;p<0.001*
  217. 221. Sitagliptin Improved A1C When Added to Glim + MF 035 *Difference in LS Mean change from baseline Δ -0.9%; p<0.001*
  218. 222. Goal of Continuation Phase <ul><li>To assess the longer term safety and efficacy of sitagliptin in patients who have type 2 diabetes inadequately controlled on glimepiride, alone or in combination with metformin </li></ul>
  219. 223. Disposition of Patients Screened: N = 1098 Randomized: N = 441 Glimepiride n = 106 Completed Week 24 n = 83 Glimepiride + Metformin n = 116 Completed Week 24 n = 87 Glimepiride n = 106 Completed Week 24 n = 102 Glimepiride+ Metformin n = 113 Completed Week 24 n = 92 Placebo n = 219 Sitagliptin n = 222 Entered Continuation Phase Sitagliptin + Glimepiride + Metformin n = 93 Entered Continuation Phase Pioglitazone + Glimepiride n = 58 Excluded: n = 657 Entered Continuation Phase Sitagliptin + Glimepiride n = 67 Entered Continuation Phase Pioglitazone + Glimepiride + Metformin n = 64
  220. 224. BMI = body mass index. Comparable Baseline Characteristics of Patients Entering Continuation Phase 10 (8.2) 13 (8.1) Other 82.2 85.6 Mean weight, kg 29.8 30.6 Mean BMI, kg/m 2 19 (15.6) 21 (13.1) Asian 20 (16.4) 28 (17.5) Hispanic 8 (6.6) 7 (4.4) Black 65 (53.3) 91 (56.9) Caucasian Race/Ethnicity, n (%) 58 (47.5) 70 (43.8) Female, n (%) 56.6 55.5 Mean age, y Placebo/pioglitazone n = 122 Sitagliptin 100 mg n = 160
  221. 225. FPG = fasting plasma glucose. Comparable Baseline Disease Characteristics of Patients Entering Continuation Phase 75 (61.5) 109 (68.1) Combination therapy 44 (36.1) 45 (28.1) Monotherapy 3 (2.5) 6 (3.8) None 9.4 8.0 Mean duration of diabetes, y Antihyperglycemic therapy, n (%) 11.3 14.0 Mean fasting insulin, µIU/mL 167.5 173.3 Mean FPG, mg/dL 18 (15.0) 28 (17.5) ≥ 9% 52 (43.3) 66 (41.3) ≥ 8% and <9% 50 (41.7) 66 (41.3) <8% Distribution of A1C, n (%) 8.2 8.2 Mean A1C, % Placebo/pioglitazone n = 122 Sitagliptin 100 mg n = 160
  222. 226. Extended Treatment With Sitagliptin + Glimepiride, With or Without Metformin, Maintained Lower A1C Levels to 54 Weeks ( Entire Cohort , APT ) Values represent mean ± SE. APT = all patients treated. 24-Week Phase Continuation Phase 0 6 12 18 24 30 38 46 54 Week Sitagliptin 100 mg (n = 158)
  223. 227. Extended Treatment With Sitagliptin + Glimepiride, With or Without Metformin, Maintained Lower A1C Levels to 54 Weeks ( Entire Cohort , Completers ) Values represent mean ± SE. 24-Week Phase Continuation Phase 0 6 12 18 24 30 38 46 54 Week Sitagliptin 100 mg (n = 93)
  224. 228. Mean FPG Through 54 Weeks (Entire Cohort, Completers) Values represent mean ± SE. 24-Week Phase Continuation Phase Sitagliptin 100 mg (n = 92)
  225. 229. FPG Approached Baseline With Extended Treatment With Sitagliptin + Glimepiride, With or Without Metformin, at 54 Weeks (Entire Cohort, APT) Values represent mean ± SE. 24-Week Phase Continuation Phase 0 6 12 18 24 30 38 46 54 Week 2 Sitagliptin 100 mg (n = 159)
  226. 230. Values represent mean ± SE. 24-Week Phase Continuation Phase 0 6 12 18 24 30 38 46 54 Week Extended Treatment With Sitagliptin + Glimepiride Maintained Lower A1C Levels to 54 Weeks (Stratum 1, APT) Sitagliptin 100 mg (n = 66)
  227. 231. Values represent mean ± SE. 24-Week Phase Continuation Phase 0 6 12 18 24 30 38 46 54 Week Extended Treatment With Sitagliptin + Glimepiride Maintained Lower A1C Levels to 54 Weeks (Stratum 1, Completers ) Sitagliptin 100 mg (n = 38)
  228. 232. Mean FPG Through 54 Weeks (Stratum 1, Completers) Values represent mean ± SE. 24-Week Phase Continuation Phase Sitagliptin 100 mg (n = 37)
  229. 233. FPG Approached Baseline With Extended Treatment With Sitagliptin + Glimepiride at 54 Weeks (Stratum 1, APT) Values represent mean ± SE. 24-Week Phase Continuation Phase 0 6 12 18 24 30 38 46 54 Week 2 Sitagliptin 100 mg (n = 67)
  230. 234. Extended Treatment With Sitagliptin + Glimepiride With Metformin Maintained Lower A1C Levels to 54 Weeks (Stratum 2, APT ) Values represent mean ± SE. 24-Week Phase Continuation Phase 0 6 12 18 24 30 38 46 54 Week Sitagliptin 100 mg (n = 92)
  231. 235. Extended Treatment With Sitagliptin

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