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)
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3. Old Concept of T2DM Insulin Resistance Insulin Deficiency (Beta Cell Dysfunction) Hyperglycemia
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)
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 +
10. Beta Cell Volume in Autopsy Studies A. Butler et al. Diabetes, 2003. Vol 52, 102-110.
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
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
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
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
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
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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
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. * * * * * * * * * * * * * * * * * * *
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
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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
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)
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
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
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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
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)
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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
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)
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
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
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)
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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
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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
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
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
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
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
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)
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)
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.
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)
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.
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
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
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, %
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
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*
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
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)
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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
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
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
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
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
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
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
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
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
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)
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
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 * * * * †
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
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
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. * * * *
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
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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)
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
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)
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
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
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)*
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)
103. Substantial Proportion of Patients Achieved Goal on Sitagliptin Once-Daily As Add-on to Metformin % A1C < 7% after 52 Weeks Per Protocol Population
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106. JANUVIA TM works consistently well in various patient subtypes
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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
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
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
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
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
114.
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
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)
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118.
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120.
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).
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.
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
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 )
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.
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
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)
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.
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.
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145.
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
147.
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.
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
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
151.
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)
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
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156.
157.
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
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
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.
161.
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
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)
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)
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
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
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
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
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170.
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.
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.
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176.
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.
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
180.
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.
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.
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.
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.
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
195.
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?
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
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
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
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)
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)
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203.
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
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
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
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
213. Effect of JANUVIA TM on fasting blood glucose
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).
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.
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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
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
219. Sitagliptin Improved A1C When Added to Glim ± MF 035 *Difference in LS Mean change from baseline Δ -0.7 %;p<0.001*
220. Sitagliptin Improved A1C When Added to Glim 035 *Difference in LS Mean change from baseline Δ -0.6 %;p<0.001*
221. Sitagliptin Improved A1C When Added to Glim + MF 035 *Difference in LS Mean change from baseline Δ -0.9%; p<0.001*
222.
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
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
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
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)
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)
228. Mean FPG Through 54 Weeks (Entire Cohort, Completers) Values represent mean ± SE. 24-Week Phase Continuation Phase Sitagliptin 100 mg (n = 92)
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)
Type 2 Diabetes: Phase III Data for the DPP-4 Inhibitor Sitagliptin
Beta-Cell Function Is Abnormal in Type 2 Diabetes Beta-cell dysfunction in patients with type 2 diabetes is manifested by a range of functional abnormalities. The normal pulsed oscillatory release of insulin is impaired, and proinsulin levels are increased. 1,2 The first-phase insulin response is essentially absent, whereas the second-phase insulin response is slow and blunted. 3,4 In an experimental study, abnormalities, in beta-cell function in patients with type 2 diabetes are reflected in differing insulin response to a meal vs that for normal subjects. Fasting levels of insulin are similar in healthy subjects and those with type 2 diabetes, but postprandial insulin responses were reduced and delayed in patients with type 2 diabetes. 5 References: 1. Buchanan TA. Pancreatic beta-cell loss and preservation in type 2 diabetes. Clin Ther. 2003;25(suppl B):B32–B46. 2. Polonsky KS, Given BD, Hirsch LJ, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988;318:1231–1239. 3. Quddusi S, Vahl TP, Hanson K, et al. Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care. 2003;26:791–798. 4. Porte D Jr, Kahn SE. Beta-cell dysfunction and failure in type 2 diabetes: Potential mechanisms. Diabetes. 2001; 50(suppl 1):S160–S163. 5. Vilsbøll T, Krarup T, Deacon CF, et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50:609–613.
The natural history of T2DM can thus be explained in terms of pancreatic islet activity. In healthy individuals, glucagon and insulin are secreted in a reciprocal manner from pancreatic - and -cells, respectively. 1,2 After meals, insulin secretion is increased in order to promote postprandial glucose uptake at the liver and peripheral tissues. Glucagon exhibits the opposite pattern: a steep and rapid decline occurs after a high-carbohydrate meal, followed by a slow recovery toward preprandial levels. Between meals, the rise in glucagon secretion prompts Hepatic Glucose Production to ensure an adequate steady-state plasma level of glucose. 2,3 Maintaining a physiologic reciprocal balance between insulin and glucagon secretion is key to ensuring normal glucose homeostasis. References Aronoff SL, Berkowitz K, Shreiner B, Want L. Glucose metabolism and regulation: Beyond insulin and glucagon. Diabetes Spectrum. 2004;17(3):183–190. Muller WA, Faloona GR, Aguilar-Parada E, Unger RH. Abnormal alpha-cell function in diabetes: response to carbohydrate and protein ingestion. N Engl J Med . 1970;283:109–115. Unger RH. Alpha- and beta-cell interrelationships in health and disease. Metabolism. 1974;23:581.
Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes A clinical study described postprandial glucose, insulin, and glucagon dynamics in patients with type 2 diabetes mellitus (n=12) vs nondiabetic control subjects (n=11). 1 After a large carbohydrate meal, mean plasma glucose concentrations rose from 228 mg/100 mL to a peak of 353 mg/100 mL in patients with type 2 diabetes mellitus, compared with an increase from 84 mg/100 mL to a peak of 137 mg/100 mL in nondiabetic subjects. 1 Insulin rose in normal subjects from a mean fasting level of 13 µU/mL to a peak of 136 µU/mL at 45 minutes after the meal. The insulin response in patients with type 2 diabetes mellitus was delayed and suppressed in comparison, increasing from a fasting level of 21 µU/mL to a peak of only 50 µU/mL at 60 minutes. 1 Mean plasma glucagon levels declined significantly from the fasting value of 126 pg/mL to 90 pg/mL at 90 minutes (p<0.01) in the control group. By contrast, no significant fall in glucagon was observed in patients with type 2 diabetes mellitus; in fact, the mean plasma glucagon level rose slightly from the fasting level of 124 pg/mL to 142 pg/mL at 60 minutes and returned to 124 pg/mL at 180 minutes. 1 Therefore, this study showed that patients with type 2 diabetes mellitus have a delayed and suppressed insulin response and fail to exhibit the normal postprandial decline in glucagon concentrations. These abnormalities contribute markedly to hyperglycemia both at the level of body tissues where insulin is not sufficient to drive glucose uptake and at the level of the liver where increased glucagon and decreased insulin cause the liver to inappropriately release glucose into the blood, thereby causing fasting hyperglycemia or increasing postprandial hyperglycemia. 1,2 References: 1. Müller WA, Faloona GR, Aguilar-Parada E, et al. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med. 1970;283:109–115. 2. Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycemia. Diabetologia . 2003;46(suppl 1):M2–M8.
No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Speaker Notes No single-agent monotherapy has an MOA that addresses all key pathophysiologies of type 2 diabetes. Alpha-glucosidase inhibitors decrease intestinal absorption of glucose. 1,2 Meglitinides and sulfonylureas stimulate insulin secretion. 3–5 TZDs are insulin sensitizers that also lower hepatic glucose output. 6,7 Metformin, a biguanide, lowers hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity. 8 DPP-4 inhibitors improve insulin synthesis and release and lower hepatic glucose production, both through suppressing glucagon production and release, and by improving insulin synthesis and release. Each class of oral antihyperglycemic agent does not address at least 1 key pathophysiology of type 2 diabetes. Purpose: To examine the key pathophysiologies targeted by each class of oral antihyperglycemic agent. Takeaway: No one class targets all key pathophysiologies of type 2 diabetes. References: 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004. 3. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007. 4. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 5. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 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.
Incretins are gut hormones released in response to ingestion of a meal, the most important of which are glucagon-like peptide 1 (GLP-1), which is synthesized by L cells in the distal gut (ileum and colon), and glucose-dependent insulinotropic polypeptide (GIP), which is secreted by K cells in the proximal gut (duodenum). 1,2 GLP-1 and GIP are the major incretins that play a role in the insulin response as nutrients are absorbed by the body. 1 In addition to stimulating insulin release when glucose is elevated, GLP-1 inhibits glucagon secretion. 3 These actions are highly glucose dependent. 3 In healthy volunteers, administration of GLP-1, at levels surpassing physiologic production, has been shown to exert profound, dose-dependent inhibition of gastric emptying. 4 In in vitro and in vivo rodent studies and isolated human islets, GLP-1 has been shown to promote the expansion of beta-cell mass through proliferative and anti-apoptotic pathways. 1,5,6 Whereas GIP also stimulates a glucose-dependent insulin response, 2 this hormone does not appear to affect gastric emptying. 7 When given at supraphysiologic doses to patients with type 2 diabetes, the insulinotropic activity of GIP was less than that observed in normal subjects. 8 GIP does not appear to affect satiety or body weight. 1 In islet cell lines, GIP has been shown to enhance beta-cell proliferation and survival. 9,10 References Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929–2940. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531–544. Nauck MA, Niedereichholz U, Ettler R et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997;273(5 pt 1):E981–E988. Farilla L, Bulotta A, Hirshberg B et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003;144:5149–5158. Farilla L, Hui H, Bertolotto C et al. Glucagon-like peptide-1 promotes islet growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 2002;143:4397–4408. Meier JJ, Goetze O, Anstipp J et al. Gastric inhibitory polypeptide does not inhibit gastric emptying in humans. Am J Physiol Endocrinol Metab 2004;286:E621–E625. Nauck MA, Heimesaat MM, Ørskov C et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993;91:301–307. Tr ü mper A, Tr ü mper K, Trusheim H et al. Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. Mol Endocrinol 2001;15:1559–1570. Tr ü mper A, Tr ü mper K, H ö rsch D. Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in β (INS-1)-cells. J Endocrinol 2002;174:233–246. 2/Ahren 2003, p 370, C1, ¶2, L8-9 9/Trümper 2001, p 1567, C1, ¶2, L14-16 10/Trümper 2002, p 244, C2, ¶2, L1-3
References: 1. Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145:2653–2659. 2. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 3. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β -cell function in type 2 diabetes: A parallel-group study. Lancet. 2002;359:824–830. 4. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122:531–544. 5. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, et al, eds. Williams Textbook of Endocrinology . 10th ed. Philadelphia, Pa: Saunders; 2003:1427–1483. 6. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940. Incretins (GLP-1 and GIP) Regulate Glucose Homeostasis Through Effects on Islet Cell Function The presence of nutrients in the gastrointestinal tract rapidly stimulates the release of incretins: GLP-1 from L cells located primarily in the distal gut (ileum and colon) and GIP from K cells in the proximal gut (duodenum). 1,2 Collectively, GLP-1 and GIP exert several beneficial actions, including stimulating the insulin response in pancreatic beta cells (GLP-1 and GIP) and inhibiting glucagon secretion from pancreatic alpha cells when glucose levels are elevated. 2-4 Increased insulin levels improve glucose uptake by peripheral tissues, while the combination of increased insulin and decreased glucagon reduce hepatic glucose output. 5,6
GLP-1 Actions Are Glucose Dependent in Patients With Type 2 Diabetes 1 This slide shows results from a study that characterized changes in glucose, insulin, and glucagon levels in response to a pharmacologic dose of GLP-1. The patients were studied on 2 occasions (once with GLP-1 and once with placebo). Ten patients with type 2 diabetes mellitus received an intravenous infusion of GLP-1 over 240 minutes. During infusion, blood was drawn at 30-minute intervals to permit assay of glucose, insulin, and glucagon concentrations. A day later, the procedure was repeated with a placebo infusion. Infusion of GLP-1 over 240 minutes lowered plasma glucose to normal basal levels in all patients, with significant mean reductions observed at all time points from 60 minutes onward (p<0.05 vs placebo). During GLP-1 infusion, plasma insulin increased and glucagon decreased. However, as plasma glucose values approached normal basal levels, insulin and glucagon returned to baseline or near-baseline values, thus indicating the glucose-dependent nature of the effects of GLP-1. Reference: 1. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.
This slide summarizes the actions and postprandial levels of GLP-1 and GIP from the trials presented. In patients with type 2 diabetes, postprandial GLP-1 levels were significantly decreased compared with levels in subjects with NGT (p<0.05), while the insulinotropic action of this synthetic human incretin hormone was not significantly different. 1,2 Conversely, postprandial GIP levels were not significantly different in patients with type 2 diabetes mellitus versus individuals with NGT when corrected for BMI and gender; however, the insulinotropic action of supraphysiologic doses of synthetic human GIP was significantly diminished (p=0.047) in patients with type 2 diabetes mellitus versus individuals with NGT. The low rate of infusion resulted in similar insulin levels in both groups (p=0.14). 1,2 References Toft-Nielsen M-B, Damholt MB, Madsbad S et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001;86:3717–3723. Nauck MA, Heimesaat MM, Ørskov C et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993;91:301–307.
The presence of nutrients in the gastrointestinal tract rapidly stimulates the release of incretins: GLP-1 from L cells located primarily in the distal gut (ileum and colon), and GIP from K cells in the proximal gut (duodenum). 1,2 Collectively, these incretins exert several beneficial actions, including stimulating the insulin response in pancreatic beta cells and reducing glucagon production from pancreatic alpha cells when glucose levels are elevated in a glucoxse dependent manner. 3,4 Increased insulin levels improve glucose uptake by peripheral tissues; the combination of increased insulin and decreased glucagon reduces hepatic glucose output. 5 The incretins are rapidly inactivated by the dipeptidyl peptidase 4 (DPP-4) enzyme. Patients with type 2 diabetes have a diminished incretin effect as a consequence of reduced GLP-1 levels 3 and reduced GIP effect. 3 Preventing the degradation of the incretins by inhibiting DPP-4 enhances the level of active incretins. 3 This in turn enhances the body’s own ability to control glucose. References Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004;145: 2653–2659. Zander M, Madsbad S, Madsen JL et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β -cell function in type 2 diabetes: A parallel-group study. Lancet 2002;359:824–830. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531–544. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.
Plasma Levels of GLP-1, GIP, and Insulin in Normal Subjects 1 A study in normal subjects demonstrated that the secretion of GLP-1 and GIP (incretins) correlates with insulin release throughout the day. After an overnight fast, normal healthy volunteers (n=6) received 3 mixed meals (at 09.00 h, 13.00 h, and 19.00 h, as indicated by arrows) and their GLP-1, GIP, and insulin plasma levels were measured during the day. The secretion of GIP and GLP-1 increased in response to meals and significantly correlated with insulin release throughout the study period (mean correlation coefficients 0.49 ± 0.07 and 0.56 ± 0.06, respectively, p<0.01 for both incretins). Reference: 1. Ørskov C, Wettergren A, Holst JJ. Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day. Scand J Gastroenterol . 1996;31:665–670.
GLP-1 Levels in Patients With Type 2 Diabetes and Normal Subjects 1 A clinical study investigated the meal-stimulated GLP-1 and GIP responses in patients with type 2 diabetes (n=54) vs matched subjects with NGT (n=33, controls) and unmatched subjects with IGT (n=15). After an overnight fast following 3 days without antidiabetic medication, subjects consumed a mixed meal and underwent blood sampling periodically for 4 hours. The slide shows GLP-1 levels in patients with type 2 diabetes vs subjects with NGT. Postprandial GLP-1 concentrations were significantly decreased in patients with type 2 diabetes compared with control subjects with NGT ( AUC: 2482 vs 3101 pmol/L • 240 min, p<0.024 ). The incremental postprandial GLP-1 response (incremental area under the curve [iAUC], AUC calculated as above basal levels) was even more significantly reduced ( AUC: 907 vs 1927 pmol/L • 240 min in controls, p<0.001).
Plasma Concentrations of Glucagon, Pancreatic Polypeptide, and GIP in Patients With Type 2 Diabetes and Normal Subjects 1 A clinical study investigated the meal-stimulated GLP-1, GIP, and glucagon responses in patients with type 2 diabetes (n=54) vs matched control subjects with normal glucose tolerance (NGT) (n=33) and unmatched subjects with impaired glucose tolerance (IGT) (n=15). After an overnight fast following 3 days without antidiabetic medication, subjects consumed a mixed meal and underwent blood sampling periodically for 4 hours. The graph shows plasma glucagon, pancreatic polypeptide, and GIP levels in patients with type 2 diabetes vs subjects with NGT. In patients with type 2 diabetes, fasting (13 vs 8.4 pmol/L in subjects with NGT, p<0.001) and postprandial glucagon plasma levels were significantly increased compared with NGT subjects (area under the curve [AUC]: 3585 vs 2386 pmol/L • 240 min, p<0.001). Fasting GIP levels were similar in both groups (12.7 vs 8.6 pmol/L in subjects with NGT, p<0.13) and postprandial plasma concentrations were slightly, but significantly, decreased in patients with type 2 diabetes compared with NGT subjects (AUC: 13.4 vs 16 pmol/L • 240 min, p<0.047). Reference: 1. Toft-Nielsen M-B, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab . 2001;86:3717–3723.
Decreased Postprandial Levels of the Incretin Hormone GLP-1 in Patients With Type 2 Diabetes This clinical study investigated the meal-stimulated GLP-1 response (shown in the slide) and GIP response (not shown) in patients with type 2 diabetes (n=54) vs subjects with IGT (n=15), and control subjects with NGT (n=33). 1 After 3 days without antidiabetic medication and after an overnight fast, subjects consumed a mixed meal and underwent blood sampling periodically for 4 hours. The meal was started at time zero and finished within 10 to 15 minutes. 1 The plasma GLP-1 concentrations for patients with type 2 diabetes vs subjects with IGT and control subjects with NGT are shown on the slide. Postprandial GLP-1 concentrations were significantly decreased in patients with type 2 diabetes compared with those in control subjects with NGT ( P <0.05). Concentrations were also decreased in subjects with IGT compared with those in control subjects with NGT. The GLP-1 concentrations of the IGT group ranged between those of patients with type 2 diabetes and control subjects with NGT. 1 Reference 1. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide 1 in type 2 diabetic patients. J Clin Endocrinol Metab . 2001;86:3717–3723. Purpose : To demonstrate the abnormality of the incretin axis in patients with type 2 diabetes. Take-away: GLP-1 levels are decreased in subjects with IGT and even more so in patients with type 2 diabetes.
DPP-IV is a widely expressed enzyme produced in many different cell types. DPP-IV exists as 2 principal forms, a soluble form that circulates in the plasma not directly associated with specific cell types, and a membrane anchored form directly tethered to cell membranes. DPP-IV+ endothelial cells are anatomically located in close approximation to the enteroendocrine L cells that synthesize GLP-1.
Single doses of sitagliptin 25 mg and 200 mg resulted in rapid and marked inhibition of plasma DPP-4 activity. 1 Throughout the 12-hour post-dose period, the 200 mg dose was associated with approximately 95% plasma DPP-4 inhibition, falling to approximately 80% inhibition at 24 hours post dose. The 25 mg dose was associated with peak inhibition of approximately 85%, falling to approximately 50% inhibition at 24 hours post dose. 1 Reference Data on file, MSD ______________________.
Data from Study PN005
040 Early Results Memo: Table 1, page 4.
040 Early Results Memo: Figure 3, page 14.
040 Early Results Memo: Figure 5, page 18.
040 Early Results Memo: Table 13, page 20.
040 Early Results Memo: Table 14, page 21.
Eff_HbA1C_Completers document – table 4
Psychiatric rating scales commonly used in clinical trials include the following: Positive and Negative Syndrome Scale (PANSS™) Young Mania Rating Scale (YMRS) Clinical Global Impression (CGI) Scale Brief Psychiatric Rating Scale (BPRS) Montgomery-Åsberg Depression Rating Scale (MADRS) These measures are intended to assist healthcare professionals in identifying individuals who need treatment and in assessing clinical features beyond diagnosis (eg, severity) to inform initial treatment choices and/or level of care. The PANSS™, YMRS and MADRS are frequently used to determine the severity of existing psychopathology or changes in symptom severity over time, while the CGI and BPRS are frequently used in clinical trials to measure response to treatment or efficacy of the trial medications. Some of these scales are also useful for monitoring beneficial and/or adverse effects of treatment, as well as for other purposes (eg, determining prognosis) that may not directly influence treatment decisions. The scales may also be used for administrative purposes such as to assess the performance of healthcare delivery systems. Rush JA, Pincus HA, et al. Handbook of Psychiatric Measures. American Psychiatric Association. 1st ed. 2000.
1/Raz p.538 C1 P3 L1-4 p.547 C1 P2 L1-3, C2 Pcont L1-2 p.539 Figure 1 p.538 C2 P2 L1-10 p.538 C2 P2 L10-20; C1 P3 L3 p.538 C2 P2 L22-24 p.539 C1 Pcont L1-3 p.539 Figure 1 p.539 C1 Pcont L7-9 p.539 C1 Pcont L3-6 1/Raz p.539 Figure 1 p.538 C1 P3 L1-4 p.538 C2 P1 L1-6 p.538 C2 P2 L1-20 L22-24 p.539 C1 Pcont L1-3 This was a multinational, double-blind, randomized, placebo-controlled, parallel-group study comparing the addition of sitagliptin 100 mg/day with placebo in patients with T2DM who had moderately severe hyperglycemia with metformin monotherapy. 1 After a 1-week run in period, metformin was titrated to an effective dose in one of the following ways: Patients treated with metformin monotherapy at a dose of ≥ 1500 mg/day directly entered the metformin monotherapy dose-stable run-in period 1 Patients taking any oral antihyperglycemic agent (AHA) monotherapy other than metformin >1500 mg/day discontinued the AHA and entered a metformin monotherapy titration period. 1 After titration of a metformin dose to ≥ 1500 mg/day, patients entered a metformin monotherapy dose-stable run-in period 1 After the stable-dose run-in period, patients with HbA 1c between 8% and11% entered a 2-week, single-blind, placebo run-in period. 1 A total of 190 patients who had shown adequate treatment compliance ( ≥85%) and for whom a fasting finger stick glucose measurement was between 7.2 mmol/L and 15.6 mmol/L were assigned randomly in a 1:1 ratio to receive the addition of placebo or sitagliptin 100 mg/day to ongoing metformin therapy for 30 weeks. 1 In patients not meeting specific glycemic goals during the study, rescue therapy was initiated with glipizide when: Fasting plasma glucose (FPG) level was consistently >15.6 mmol/L after randomization through week 9 1 FPG level was consistently >13.9 mmol/L after week 9 up to and including week 18 1 FPG level was consistently >12.2 mmol/L after week 18 1 Patients were discontinued from the study if they were taking rescue medication >2 weeks and FPG levels were consistently >11.1 mmol/L. 1 Efficacy data obtained after glycemic rescue were not included in the efficacy analysis. 1 Reference 1. Raz I, Chen Y, Wu M, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin . 2008;24:537–550.
1/Raz p.539 C1 P2 L1-2 p.542 Table 2 p.543 Figure 3a 1/Raz p.539 C1 P2 L1-2 p.539 C2 P2 L1-4 p.541 Table 1 p.542 Table 2 p.543 Figure 3 p.540 C2 P3 L1-7 The primary end point of this study was change from baseline in mean HbA 1c at 18 weeks. 1 This figure illustrates the results at 18 and 30 weeks. The mean baseline HbA 1c for the sitagliptin with metformin and placebo with metformin treatment groups were 9.3% and 9.1%, respectively. 1 At week 18, the addition of sitagliptin 100 mg/day to metformin monotherapy resulted in a –1.0% least squares mean (LSM) change in HbA 1c from baseline, compared to placebo with metformin ( P <0.001). 1 At week 30, the sitagliptin-with-metformin group sustained a 1.0% decrease in LSM HbA 1c from baseline, compared to the placebo-with-metformin group ( P <0.001). 1 Reference 1. Raz I, Chen Y, Wu M, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin . 2008;24:537–550.
1/Raz p.543 Figure 4a p.541 Table 1 2/0431_P053V1_PUBLISHED_CSR p.139 Table 11-36 1/Raz p.540 C1 P3 L1-3 p.540 C2 Pcont 1-5 p.543 Figure 4a p.541 C1 Pcont L3-10 A prespecified subgroup analysis in this study was HbA 1c change from baseline by HbA 1c at baseline. 1 This figure illustrates the change from baseline at 18 weeks in patients with baseline HbA 1c values of <9%, between 9% and10%, and ≥ 10%. 1 In the subgroup of sitagliptin with metformin patients with a baseline HbA 1c ≥ 10%, the placebo-subtracted reduction was – 1.8%, which was substantially larger than the reduction for the subgroups with lower baseline HbA 1c values. 1 References 1. Raz I, Chen Y, Wu M, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin . 2008;24:537–550. 2. Data on file, MSD______.
Initiation of Pharmacotherapy With JANUMET ™ (sitagliptin/metformin HCl) Study: A1C Results at 24 Weeks This slide demonstrates that after initiating pharmacotherapy with sitagliptin plus metformin in patients with uncontrolled blood glucose after a trial of diet and exercise, the A1C change from baseline was greater than that achieved when either agent was used alone. 1 Mean reductions from baseline A1C were generally greater for patients with higher baseline A1C values. 1 Initiation of pharmacotherapy with combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options should be left to the discretion of the health care provider. Purpose To demonstrate the A1C-lowering efficacy of sitagliptin plus metformin when used as initiation of pharmacotherapy. Takeaway Initiation of pharmacotherapy with sitagliptin plus metformin provides significantly greater decrease in A1C from baseline than achieved when either agent is used alone. Reference 1. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care . 2007;30(8):1979–1987. Goldstein p1982,A JANUMET PI p19,B JANUMET PI p19,C Goldstein p1981,A Goldstein p1981,B Slide adapted from Approved Core Deck: 20752744(1)-10/07-JAN
Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results From a Subset Patients not on Antihyperglycemic Therapy at Study Entry In the study of initial combination therapy with sitigliptin and metformin, an analysis was done on a subset of patients not receiving antihyperglycemic therapy at study entry. Mean A1C reductions were 1.6% and 1.9% in the sitagliptin 50 mg plus metformin 500 mg twice daily and sitagliptin 50 mg plus metformin 1,000 mg twice daily, respectively. Additionally, in this subset of patients, monotherapy with sitagliptin 100 mg daily or metformin 500 mg twice daily resulted in a mean reductions in A1C of 1.1%. The group receiving monotherapy with metformin 1,000 mg twice daily had a mean reduction of 1.2%. Considerations regarding initial treatment and subsequent management of type 2 diabetes should be left to the discretion of the health care provider. Purpose To demonstrate the A1C reductions in patients not on antihyperglycemic therapy at study entry. Takeaway Initial therapy with sitagliptin and or metformin provided improvements in A1C in patients not receiving antihyperglycemic therapy at study entry.
Greater Reductions in HbA 1c Associated With Higher Baseline HbA 1c Without Regard to Therapy at Week 54 This slide shows that after initial therapy with sitagliptin plus metformin, the HbA 1c change from baseline was greater than that achieved when either agent was used alone. 1,2 Mean reductions from baseline HbA 1c were generally greater for patients with higher baseline HbA 1c values. 1,2 This 54-week study (a 24-week, double-blind, placebo-controlled period [phase A] followed by an additional active-controlled 30-week continuation phase [phase B]) evaluated the efficacy of the co-administration of sitagliptin and metformin, sitagliptin monotherapy or metformin monotherapy. 1 In a subgroup analysis, the study evaluated patients grouped by baseline HbA 1c : those with HbA 1c levels <8% (n=172), HbA 1c levels ≥8% to <9% (n=244), HbA 1c levels ≥9% to <10% (n=163) and the HbA 1c levels ≥10% (n=78). 1 Purpose: To review the importance of the degree of HbA 1c elevation at baseline. Take-away: Greater reductions in HbA 1c , up to 3.1%, with initial combination therapy with sitagliptin plus metformin are associated with higher baseline HbA 1c . References 1. Data on file, MSD. 2. Williams-Herman D, Johnson J, Lunceford J. Initial combination therapy with sitagliptin and metformin provides effective and durable glycemic control over 1 year in patients with type 2 diabetes: a pivotal phase III clinical trial. Poster presentation at ADA 67th Annual Scientific Sessions in Chicago, Illinois, USA, 22–26 June 2007. Late Breaker (04-LB). 34 1/CSR 0431_P036_09_Efficacy Section 11.4, p.59 Table 11-26 1/CSR 0431_P036_02_Synopsis Objectives, p.2 P1 L1-5 Study Design p.3 P1 L1-3 1/CSR 0431_P036_09_Efficacy Section 11.4, p.59 Table 11-26 p.57 P1 L1-4 2/ADA Poster Williams-Herman D et al. 2007 ADA 04-LB Figure 4. APT population 2/ADA Poster Williams-Herman D et al. 2007 ADA 04-LB Figure 4. APT population
Initiation of Pharmacotherapy With JANUMET ™ (sitagliptin/metformin HCl) Study: FPG and PPG Results at 24 Weeks This slide shows the results of glycemic parameters at 24 weeks after combination therapy with sitagliptin plus metformin. Sitagliptin plus metformin provided significant improvements in fasting plasma glucose (FPG) and 2-hour postprandial glucose (PPG) concentrations compared with metformin monotherapy 1 : FPG: –20 mg/dL to –37 mg/dL ( P <0.001 relative to placebo) PPG: –39 mg/dL to –63 mg/dL ( P <0.001 vs placebo) Purpose To demonstrate the mean FPG and 2-hour PPG reductions at 24 weeks in the sitagliptin plus metformin initiation of pharmacotherapy study. Takeaway Sitagliptin combined with metformin provided significant improvements in mean FPG and 2-hour PPG vs metformin monotherapy in patients whose diabetes was inadequately controlled on diet and exercise. Reference 1. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care . 2007;30(8):1979–1987. Goldstein p1984,A Goldstein p1982,B Goldstein p1982,B p1984,A Goldstein p1982,B Goldstein p1984,A Slide adapted from Approved Core Deck: 20752744(1)-10/07-JAN
Co-administration of Sitagliptin and Metformin in Healthy Adults Increased Active GLP-1 Greater Than Either Agent Alone Among 18 healthy adults who were randomised in a double-blind, placebo-controlled, 4-period crossover, study that consisted of 2-day–long treatment periods with a 7-day washout period between them, 16 healthy adults completed the study. The objective of the study was to examine the effect of sitagliptin, metformin and the combination of sitagliptin with metformin on the post-meal incretin hormone concentrations, specifically GLP-1 and GIP. 1 Subjects were randomly assigned to receive sitagliptin, metformin, co-administration of sitagliptin and metformin, or placebo. On the second day of each treatment period, blood samples were obtained for active and total GLP-1 and active and total GIP concentrations before and at specific time points after the post-dose meal was consumed. 1 Results for the incremental 4-hour post-meal weighted averages showed that after administration of metformin alone or co-administration of sitagliptin and metformin, total GLP-1 concentrations were increased compared with placebo alone, whereas total GLP-1 concentrations were significantly decreased when sitagliptin was administered alone. 1 On the other hand, administration of sitagliptin or metformin alone increased active GLP-1 to nearly double that seen with placebo. Moreover, active GLP-1 concentrations were increased by more than 2 times after concomitant administration of sitagliptin with metformin compared with either agent alone. Thus, there was a more than additive effect on active GLP-1 concentrations when sitagliptin and metformin were co-administered. 1 Both sitagliptin and the combination of sitagliptin and metformin increased active GIP; however, metformin alone had no effect on active GIP, indicating that metformin is not a DPP-4 inhibitor. 1 The increase in active GIP observed after the co-administration of metformin with sitagliptin likely resulted from the effect of sitagliptin. 1 Purpose: To show data in support of the additive effects of sitagliptin and metformin co-administration on active concentrations GLP-1. Take-away: Although sitagliptin increased active GLP-1 concentrations, as expected based on its MOA, the co-administration of metformin and sitagliptin have complementary MOAs to enhance active GLP-1 concentrations. Reference 1. Data on file, MSD. 24
This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50 mg b.i.d.) with metformin (1000 mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50 mg sitagliptin twice daily and placebo to metformin twice daily; 1000 mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50 mg of sitagliptin twice daily and 1000 mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasmaconcentrations–time curve over the dosing interval (AUC0–12 h), maximum observed plasma concentrations ( C max), and time of occurrence of maximum observed plasma concentrations ( T max). Renal clearance was also determined for sitagliptin. Results: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration–time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC0–12 h geometric mean ratio (GMR; [metformin + sitagliptin]/ metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC0–12 h GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics. Conclusions: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steadystate pharmacokinetics of either agent.
This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50 mg b.i.d.) with metformin (1000 mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50 mg sitagliptin twice daily and placebo to metformin twice daily; 1000 mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50 mg of sitagliptin twice daily and 1000 mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasmaconcentrations–time curve over the dosing interval (AUC0–12 h), maximum observed plasma concentrations ( C max), and time of occurrence of maximum observed plasma concentrations ( T max). Renal clearance was also determined for sitagliptin. Results: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration–time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC0–12 h geometric mean ratio (GMR; [metformin + sitagliptin]/ metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC0–12 h GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics. Conclusions: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steadystate pharmacokinetics of either agent.
Slide . Generated from data provided by Rujun Teng (BARDS) 042508. Data from BARDS
Slide . Generated from data provided by Rujun Teng (BARDS) 042508. Data from BARDS
Slide . PN036 ERM, Tables 4 and 5, p8 and 9
MK-0431 PN024 mgjrck v12.ppt 02/24/10 This slide presents the change from baseline in body weight over time and summarizes hypoglycemic events during the 2-year treatment period (Week 0 through Week 104). Despite similar glycemic control in the two treatment groups,[PN024 CSR p215A] a modest decrease from baseline in body weight was observed in the sitagliptin treatment group, while the glipizide treatment group had a modest increase of body weight compared to baseline.[PN024 CSR p203A] During the 2nd year treatment group, a modest decrease in body weight was observed in both treatment groups, with the between-group difference generally stable from the end of the 1st year to the end of the 2nd year treatment period.[PN024 CSR p203A] The LS Means for the change of body weight from baseline at Week 104 were -1.6 kg for the sitagliptin and +0.7 kg for the glipizide treatment groups, which resulted in a difference of -2.3 kg between the two groups. The LS Means for the change of body weight from baseline at Week 104 were -1.6 kg for the sitagliptin and +0.7 kg for the glipizide treatment groups, which resulted in a difference of -2.3 kg between the two groups. With regard to hypoglycemic events, a substantial and clinically important differences in the proportion of patients experiencing at least one hypoglycemic event and in the total number of hypoglycemic events between the treatment groups were observed.[PN024 CSR p215C] Despite similar glycemic control in the two study groups, more than 14 times more events of hypoglycemia occurred in the glipizide group compared to the sitagliptin group during the entire 2-year treatment period. During the 2-year double-blind treatment period, 31 (5.3%) patients in the sitagliptin treatment group reported 57 episodes of hypoglycemia compared to 199 patients (34.1%) who reported 805 episodes of hypoglycemia in the glipizide group. In the sitagliptin treatment group, 1 (0.2%) patient required non-medical assistance but did not exhibit marked severity of the hypoglycemic episode, and 1 (0.2%) patient required medical assistance. In the glipizide treatment group, 9 (1.5%) patients required non-medical assistance but did not exhibit marked severity and 9 (1.5%) patients experienced 14 episodes requiring medical assistance or exhibiting marked severity. Moreover, 31 events in the glipizide group met criteria for severity (i.e., requiring medical or non-medical assistance or with neurological symptoms) compared to 2 such events in the sitagliptin group.[PN024 CSR p215C] PN024 CSR Fig 12-11 p204 PN024 CSR Table 12-29 p178
MK-0431 PN024 mgjrck v12.ppt 02/24/10 02/24/10 Slide . This slide shows the results of change of HbA1c from baseline at Week 104 in the Per Protocol Population (44.4% of the patients in the All Patients as Treated Population). The LS means for change from baseline in HbA1c at Week 104 were -0.54% and -0.51% for the sitagliptin and glipizide groups, respectively.[PN024 CSR p80B] The difference in change from baseline at Week 104 between the sitagliptin and glipizide groups was -0.03% (95% CI -0.13%, 0.07%). Note that the duration of the active treatment period in this study was 104 weeks.[PN024 CSR p212B] However, the primary efficacy hypothesis was based on results at Week 52. The efficacy results at the 52-week time-point as well as the safety information over the 52-week treatment period are presented in CSR P024V1. The results at 52 weeks showed that the primary efficacy hypothesis, that sitagliptin was non-inferior to glipizide in efficacy (as defined by change from baseline in HbA1c), was met for the protocol-specified primary per protocol population.[PN024 CSR p212B] This was confirmed by the secondary analysis of the All Patients as Treated Population; there was only a minimal between-group difference such that noninferiority would also have been established had this All Patients Treated Population been the primary focus of the analysis. Although the study did not include an efficacy hypothesis tested at Week 104, the efficacy results at this time point presented in this slide demonstrate a clinically important reduction of HbA1c from baseline with sitagliptin treatment, which was numerically similar to that observed with glipizide for the Per Protocol Population and the All Patients as Treated Population.[PN024 CSR p212C] Minimal between-group differences in reduction from baseline in HbA1c in the Per Protocol Population over 104 weeks suggests a robust glycemic improvement with sitagliptin relative to glipizide.[PN024 CSR p212D] PN024 CSR, from Table 11-1 p81
Reference: 1. Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: A randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205.
Reference: 1. Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: A randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205.
Beta-Cell Function Is Abnormal in Type 2 Diabetes Beta-cell dysfunction in patients with type 2 diabetes is manifested by a range of functional abnormalities. The normal pulsed oscillatory release of insulin is impaired, and proinsulin levels are increased. 1,2 The first-phase insulin response is essentially absent, whereas the second-phase insulin response is slow and blunted. 3,4 In an experimental study, abnormalities, in beta-cell function in patients with type 2 diabetes are reflected in differing insulin response to a meal vs that for normal subjects. Fasting levels of insulin are similar in healthy subjects and those with type 2 diabetes, but postprandial insulin responses were reduced and delayed in patients with type 2 diabetes. 5 References: 1. Buchanan TA. Pancreatic beta-cell loss and preservation in type 2 diabetes. Clin Ther. 2003;25(suppl B):B32–B46. 2. Polonsky KS, Given BD, Hirsch LJ, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988;318:1231–1239. 3. Quddusi S, Vahl TP, Hanson K, et al. Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care. 2003;26:791–798. 4. Porte D Jr, Kahn SE. Beta-cell dysfunction and failure in type 2 diabetes: Potential mechanisms. Diabetes. 2001; 50(suppl 1):S160–S163. 5. Vilsbøll T, Krarup T, Deacon CF, et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50:609–613.
First-Phase Insulin Response to IV Glucose Is Lost in Type 2 Diabetes The normal beta-cell insulin response to IV glucose is biphasic. That is, there are 2 distinct phases noted: The first (early) phase consists of a rapid increase in insulin secretion that occurs immediately after exposure of the beta cells to glucose. This phase is brief and is followed by a return to near basal levels within 10 minutes. The first phase is important in response to a rapidly shifting metabolic state, from the production of glucose to the disposal of glucose. 1 A second (late) phase consists of a sustained increase in insulin secretion that begins 10 to 20 minutes after exposure to glucose. This phase can last for several hours. 1 In the study shown on this slide, the release of insulin from beta cells was measured in normal subjects and patients with type 2 diabetes after they were given an intravenous glucose tolerance test with a 20-g bolus injection. 2,3 Normal subjects showed a sharp first-phase insulin response. However, patients with type 2 diabetes showed an absent first-phase response, 2 with preservation of the second-phase insulin response. 3 References: 1. Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia . 2001;44:929–945. 2. Ward WK, Beard JC, Halter JB, Pfeifer MA, Porte D Jr. Pathophysiology of insulin secretion in non-insulin- dependent diabetes mellitus. Diabetes Care . 1984;7:491–502. 3. Pfeifer MA, Halter JB, Porte D Jr. Insulin secretion in diabetes mellitus. Am J Med . 1981;70:579–588.
Fewer Pancreatic Islets in Type 2 Diabetes 1 This slide shows the adult pancreatic morphology and illustrates the structural islet cell changes in type 2 diabetes. In nondiabetic obesity, the pancreas appears enlarged because of the increased number and size of beta cells. Beta cells become larger in size to compensate for the higher metabolic demand, thereby maintaining normal cell function. In the pancreas of subjects with type 2 diabetes the number of islets can decrease, the number of beta cells per islet is reduced, and amyloid plaques dominate. Reference: 1. Rhodes CJ. Type 2 diabetes—A matter of beta-cell life and death? Science . 2005;307:380–384.
Fasting and Postprandial Glucagon Levels Are Elevated in Patients With Impaired Glucose Tolerance and Type 2 Diabetes 1 Elevated glucagon secretion, which may result in excessive hepatic glucose production in patients with type 2 diabetes, is illustrated in this study. A meal test was performed over 240 minutes in patients with type 2 diabetes, normal glucose tolerance, or impaired glucose tolerance. Patients with type 2 diabetes had higher glucagon concentrations not only postprandially but also in the fasting state. This study also showed that patients with impaired glucose tolerance had higher glucagon values than those with normal glucose tolerance. Reference: 1. Toft-Nielsen M-B, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab . 2001;86:3717–3723.
Lack of Suppression of Glucagon Causes Postprandial Hyperglycemia in Type 2 Diabetes 1 This study measured glucose levels after 50 g of oral glucose was administered on 2 separate occasions in 9 subjects with type 2 diabetes, shown by the red and white curves, respectively. A low dose of somatostatin was initially given to all study subjects so that endogenous glucagon and insulin secretion were inhibited. Insulin was also infused to ensure equal insulin concentrations on both occasions. On one occasion, demonstrated in the red nonsuppressed curve, glucagon was infused at a constant rate. The resultant glucose levels are illustrated. On the other occasion, demonstrated in the white suppressed curve, glucagon infusion was delayed for 2 hours to cause a temporary decrease in endogenous glucagon, mimicking the pattern seen in normal subjects. The resultant glucose levels are suppressed. These data demonstrated that lack of glucagon suppression worsens glucose tolerance in patients with type 2 diabetes. Reference: 1. Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab . 2000;85:4053–4059.
Lowest insulin sensitivity - BMI 30.4, Middle – BMI 26.4, Highest – BMI 23.9 Correlation bewteen incretin secretion and insulin sensitivity maintained even after adjusting for age and BMI
GLP-1 Levels in Patients With Type 2 Diabetes and Normal Subjects 1 A clinical study investigated the meal-stimulated GLP-1 and GIP responses in patients with type 2 diabetes (n=54) vs matched subjects with NGT (n=33, controls) and unmatched subjects with IGT (n=15). After an overnight fast following 3 days without antidiabetic medication, subjects consumed a mixed meal and underwent blood sampling periodically for 4 hours. The slide shows GLP-1 levels in patients with type 2 diabetes vs subjects with NGT. Postprandial GLP-1 concentrations were significantly decreased in patients with type 2 diabetes compared with control subjects with NGT ( AUC: 2482 vs 3101 pmol/L • 240 min, p<0.024 ). The incremental postprandial GLP-1 response (incremental area under the curve [iAUC], AUC calculated as above basal levels) was even more significantly reduced ( AUC: 907 vs 1927 pmol/L • 240 min in controls, p<0.001).
Summary of the Study by Toft-Nielsen et al 2001 1 This study demonstrated that the meal-induced secretion of GLP-1: Is significantly decreased in type 2 diabetes Is unchanged in patients with diabetic neuropathy Is not influenced by GIP or free fatty acids (nonesterified fatty acids [NEFA]), that have been considered potential regulators of L-cell activity (stimulating or inhibiting, respectively) Is influenced by the following factors (identified by multiple regression analysis): Type 2 diabetes: Reduced secretion Gender: Reduced secretion in males compared with females BMI: Reduced secretion with increasing BMI Reference: 1. Toft-Nielsen M-B, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab . 2001;86:3717–3723.
The Impaired Secretion of GLP-1 in Type 2 Diabetes Does Not Precede Diabetes The results from 3 clinical studies support the hypothesis that impaired GLP-1 secretion does not precede type 2 diabetes. In a study of 12 identical twin pairs discordant for type 2 diabetes, the incremental GLP-1 response to glucose load was significantly reduced only in the twins with type 2 diabetes (AUC: 0.55 vs 1.17 mmol/L • min in controls without a family history of diabetes, p<0.05). 1 The 24-hour plasma profile of GLP-1 in healthy offspring of parents with type 2 diabetes was similar to that of normal control subjects (AUC: 23,321 vs 18,384 pmol • 1 –1 • min, p=0.38). 2 GLP-1 and GIP responses to oral glucose ingestion were not different between first-degree relatives of patients with type 2 diabetes and healthy controls ( p =0.89 for GIP and p =0.88 for GLP-1). References: 1. Vaag AA, Holst JJ, Volund A, Beck-Nielsen H. Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)—evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol . 1996;135:425–432. 2. Nyholm B, Walker M, Gravholt CH, et al. Twenty-four-hour insulin secretion rates, circulating concentrations of fuel substrates and gut incretin hormones in healthy offspring of type II (non-insulin-dependent) diabetic parents: Evidence of several aberrations. Diabetologia . 1999;42:1314–1323.
Second-Phase Insulin Responses to Hyperglycemic Clamp During IV GIP and GLP-1 1 The study investigated the effect of GLP-1 and GIP on the insulin response to glucose in obese patients with type 2 diabetes (n=8) and in matched healthy subjects (n=6). To this aim, a hyperglycemic clamp experiment was performed in the absence or presence of incretin hormones (GIP at 4 and 16 pmol/kg/min, GLP-1 (7–36) at 1 pmol/kg/min). Plasma insulin levels were measured before and after the increase of plasma glucose up to 240 minutes in subjects with type 2 diabetes and up to 120 minutes in healthy controls. As shown in this slide, the late-phase (20–120 minutes) insulin response to glucose was lower in patients with type 2 diabetes than in normal subjects. IV administration of GLP-1 at 1 pmol/kg/min to patients with type 2 diabetes led to a significant increase in the late glucose-dependent insulin response compared with GIP administration at 4 pmol/kg/min (AUC: 20–120; 97.2 vs 22.2 [100 min • nmol/L], p<0.01). This GLP-1 effect was similar to the one observed in healthy subjects after glucose infusion. In patients with type 2 diabetes, GIP infused at 4 pmol/kg/min or even at 16 pmol/kg/min was not able to increase the glucose-dependent insulin response. Thus, in obese patients with type 2 diabetes, the amplification of the late- phase insulin response by GIP is defective. In contrast, the late-phase insulin response to GLP-1 is preserved. Reference: 1. Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia . 2002;45:1111–1119.
Inhibition of Glucagon Secretion by Glucose and GIP or GLP-1 in Patients With Type 2 Diabetes and Matched Controls 1 In a clinical study, glucagon responses to glucose (hyperglycemic clamp at 15 mmol/L glucose) were assessed in obese patients with type 2 diabetes (n=8) and in matched healthy subjects (n=6). The experiments were conducted in the absence or presence of incretin hormones (GIP at 4 and 16 pmol/kg/min, GLP-1 (7–36) at 1 pmol/kg/min). Plasma glucagon levels were measured before and after the increase of plasma glucose up to 240 minutes in subjects with type 2 diabetes and up to 120 minutes in healthy controls. In healthy subjects, glucose infusion without incretins (white) induced a considerable decrease of glucagon levels (at 120 minutes) in comparison with glucagon fasting levels (2.7 vs 10 pmol/L). In patients with type 2 diabetes, glucose infusion (yellow) induced only a small decrease in glucagon levels (5.8 vs 8.4 pmol/L). GLP-1 stimulation, however, led to a marked decrease in glucagon release (black) in patients with type 2 diabetes when compared with fasting levels (2.9 vs 9.5 pmol/L). GIP administration (4 pmol/kg/min) did not have any effect on the glucagon response in healthy subjects (blue), or in patients with type 2 diabetes (pink). Reference: 1. Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia . 2002;45:1111–1119.
Beta-Cell Responsiveness to Glucose 1 The effect of GLP-1 on glucose-stimulated insulin secretion rate (ISR) was studied in patients with type 2 diabetes (n=7) and in matched normal subjects (n=7) with no family history of diabetes. Participants received a stepwise increasing IV infusion of glucose (2, 4, 6, 8, and 12 mg/kg/min) and plasma insulin secretion was measured in the absence (saline infusion) or presence of GLP-1 (at 0.5, 1.0, or 2.0 pmol/kg/min). The ISRs in response to glucose concentrations resulted in approximately linear curves. The slopes of these linear curves were regarded as measures of beta-cell responsiveness to glucose and were then analyzed in relation to increasing GLP-1 concentrations, as depicted in this slide. In patients with type 2 diabetes, GLP-1 infusion significantly and linearly increased beta-cell responsiveness (from 0.2–1.3 pmol/kg/min, at the highest GLP-1 rate, p<0.01). However, the increase was 3 to 5 times lower than in control subjects (from 0.6–6.7 pmol/kg/min at the highest GLP-1 rate, p<0.01 for all relationships). In this study, infusion of a low dose of GLP-1 (0.5 pmol/kg/min) in patents with type 2 diabetes induced a beta-cell responsiveness to glucose (slope) practically identical to the one measured in control subjects after saline infusion (0.60 vs 0.60 pmol/kg/min/mmol/L). Reference: 1. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: Effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes . 2003;52:380–386.
Insulinotropic Effects of GIP and GLP-1 in Diabetes of Different Etiology 1 A clinical study was conducted to assess the insulin response to glucose in lean patients with type 2 diabetes (n=6) and in patients with diabetes of different etiology (secondary to chronic pancreatitis; in latent autoimmune diabetes in adults [LADA]; in type 1 diabetes, n=6 in each group). A hyperglycemic clamp was performed at a plasma glucose level of 15 mmol in the absence or presence of incretin hormones (GIP at 4 pmol/kg/min or GLP-1 (7 – 36) at 1 pmol/kg/min). Here we describe the insulin response in lean patients with type 2 diabetes in the absence or presence of incretin hormones. Plasma glucose and insulin levels were measured before and after the increase of plasma glucose (up to 120 minutes). Lean patients with type 2 diabetes (and patients with other types of diabetes) had a higher early-phase plasma insulin response to both GLP-1 and GIP. In contrast, late-phase insulin response to glucose after GLP-1 infusion was significantly higher in these patients compared with GIP and saline (p<0.05 for both comparisons, GLP-1 vs GIP, and GLP-1 vs saline). The first-phase insulin response to glucose was amplified by both incretins. There is very little effect of GIP on the second-phase insulin response.
Incretin Function in Type 2 Diabetes In type 2 diabetes: The secretion of GLP-1 is impaired 1 The beta-cell sensitivity to GLP-1 is decreased 2 The secretion of GIP is normal or slightly impaired 1 The effect of GIP is abolished or grossly impaired 3,4 References: 1. Toft-Nielsen M-B, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab . 2001;86:3717–3723. 2. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: Effects on ß-cell sensitivity in type 2 and nondiabetic subjects. Diabetes . 2003;52:380–386. 3. Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia . 2002;45:1111–1119. 4. Vilsbøll T, Knop FK, Krarup T, et al. The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide—regardless of etiology and phenotype. J Clin Endocrinol Metab . 2003;88:4897–4903.
IV Infusion of GLP-1 restored normal glucose excursion in type 2 diabetic patients, as shown by the yellow line which si very similar to blue non-diabetic patients.
The graph on the right shows that with SC GLP-1, with delayed gastric emptying, gastric volume is increased within the first 30 minutes. The gastric volume is then decreases over time. The rate of emptying a[pears to be 30 minutes longer than placebo. On the left, one sees improved post-prandial glucose excursion and improved insulin secretion (particularly early insulin secretion).
This study shows a dose-response curve to GLP-1’s effect on food intake in healthy men.
This schematic shows the accepted mechanism of DPP-4 inhibition which leads to higher levels of active GLP-1 and GIP. The inactive GLP-1 is thought to be physiologically unimportant but some recent studies suggest that the cleaved GLP-1 products may have some function on cardiovascular tissue. The significance of this s unknown. GLP-1 and GIP are excreted renally and thus it is difficult to ascertain the increased half-life of GLP-1 and GIP. The levels go up to physiological levels but are not unusually prolonged.
Active GLP1 only make sup 10-20% of total GLP-1
IN a pig model, DPP-4 inhibition demonstrates the vastly increased levels of intact GLP-1 in yellow. The levels are high for about 60 minutes and then are cleared normally.
DPP-4 exists primarily in circulating and cell-membrane associated pools. Sitagliptin appears to inhibit primarily circulating DPP-4 and thus has minimal effects on cell-membrane associated DPP-4. DPP-4 is widely expressed in a variety of tissues, including kidney, brain and other organs. Sitagliptin inhibits the DPP-4 dimer from interacting with its substrate protein. This inhibition occurs primarily in the circulating pool of DPP-4.
In this mouse model of DPP-KO, one sees improved glucose tolerance, increased levels of insulin and GLP-1. There was no evidence of any growth or cardiac abnormalities in this KO model.
This series of experiments show the effects of DPP-4 inhibition combined with infusing GLP1, GIP, PACAP38 and GRP. The larger graphs show insulin levels and the inset graphs show glucose levels. In mice, GLP-1 and PACAP appear to have significant effects on insulin secretion. This suggests a potential CNS mechanism for enhancing insulin secretion. One may want to take these data in stride. Firstly animal models. Secondly, these type of acute experiments may under-rate the potential chronic benefits of GIP on beta cell function.
DPP-4 inhibition leads to improved glucose handling as shown in the Wild-type graph in upper left hand corner. In the GIP Receptor knockout mice, DPP-4 inhibition led to some improvement in glucose handling (upper right hand corner) And more dramatically in the GLP-1 receptor knock out mice. These data would suggest that GIP receptors may be more relevant than GLP-1 receptors. In the lower Right hand corner, in Knock out of both GLP-1 and GIP receptors, administering a DPP-4 inhibitor did not significantly affect glucose tolerance.
In mice, peripheral venous glucose infusion but not portal infusion of glucose led to peripheral hyperglycemia. Could this mean a role for incretins?
GLP-1 and GIP Modulate Insulin and GLP-1 Modulates Glucagon to Decrease Blood Glucose Levels During Hyperglycemia Speaker notes This schematic summarizes the pathways related to the observed effects of glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) on insulin and GLP-1 on glucagon. During hyperglycemia, the high glucose level rapidly stimulates the release of incretins: GLP-1 from L cells located primarily in the distal gut (ileum and colon) and GIP from K cells in the proximal gut (duodenum). 1–3 Together, these incretins enhance the insulin response of the pancreatic beta cells to a glycemic challenge. 1,3,4 GLP-1 helps suppress glucagon secretion from pancreatic alpha cells when glucose levels are elevated. 1,3 The subsequent increase in glucose uptake by muscles and other tissues 5,6 and the reduced glucose output from the liver 7 result in lowered plasma glucose levels. 3 References 1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep . 2003;3:365–372. 2. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology . 2002;122:531–544. 3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care . 2003;26:2929–2940. 4. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β -cell function in type 2 diabetes: a parallel-group study. Lancet . 2002;359:824–830. 5. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev . 2002;18:430–441. 6. Holz GG, Chepurny OG. Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. Curr Med Chem . 2003;10:2471–2483. 7. Creutzfeldt WO, Kleine N, Willms B, Ørskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7–36) amide in type I diabetic patients. Diabetes Care . 1996;19:580–586. Purpose: To introduce the concept of incretins and to demonstrate how they fit into normal glucose physiology. Takeaway: Both incretins help regulate insulin secretion from beta cells, and GLP-1 suppresses glucagon secretion from alpha cells.
Effect of IV GLP-1 Infusion in Type 2 Diabetes 1 A clinical study demonstrated that GLP-1 infusion is able to normalize blood glucose levels in patients with type 2 diabetes. On different occasions, patients with type 2 diabetes (n=7) were infused with either 1.2 pmol/kg/min GLP-1 (7 – 36) or saline starting at 22.00 hours and continuing until 17.00 hours on the following day. Their blood glucose levels were monitored throughout the infusion period. Normal control subjects (n=6) underwent the same protocol but did not receive GLP-1. Fasting and postprandial blood glucose levels were markedly higher in patients with type 2 diabetes on saline infusion than in control subjects (p<0.001). However, GLP-1 infusion induced a significant reduction of both overnight (7.8–5.1 mmol/L, p<0.02) and daytime (11.0–7.6 mmol/L, p<0.02) plasma glucose concentrations in patients with type 2 diabetes to near-normal glucose levels (5.6 mmol/L overnight, and 6.7 mmol/L daytime, no significant difference).
Disease progression in type 2 diabetes As UKPDS demonstrated, even with intensive therapy, target glycaemic levels are not maintained long-term. One of the main reasons for this is that type 2 diabetes is a progressive disease characterised by continued, worsening -cell failure. Indeed, at the time of diagnosis, -cell function is already markedly compromised (by approximately 50%), and, as the above slide shows, function continues to worsen, even in patients receiving pharmacological treatment. Furthermore, as the extrapolation on this slide demonstrates, -cell function may have been suboptimal for 10 years prior to diagnosis. As insulin secretagogues, the efficacy of sulphonylureas may be particularly affected by continued -cell failure because of their reliance on residual -cell function. The ideal long-term treatment for diabetes should therefore address continued -cell deterioration. References UKPDS 16. Diabetes 1995;44:1249–58
ADVANCE, ACCORD, & VA-DT Results: Intensive vs Standard Glucose Control ADVANCE Trial 11,140 patients with type 2 diabetes underwent standard glucose control or intensive glucose control with a median of 5 years of follow-up. Intensive control reduced the incidence of Major macrovascular and microvascular events (18.1%, vs 20.0%; 95% CI, 0.82 to 0.98; p = 0.01) Major microvascular events (9.4% vs 10.9%; 95% CI, 0.77 to 0.97; p = 0.01), The effect on microvascualr events was primarily due to a reduction in the incidence of nephropathy There were no significant effects of the type of glucose control on major macrovascular events, death from cardiovascular causes, or death from any cause. Severe hypoglycemia,was more common in the intensive-control group (2.7%, vs 1.5% in the standard-control group; 95% CI, 1.42 to 2.40; p <0.001). ACCORD Trial 10,251 patients with type 2 diabetes underwent intensive therapy or standard therapy. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. There was no difference between groups in primary outcome; however more patients in the intensive-therapy group died (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; p = 0.04). The intensive therapy arm was discontinued after 3.5 years because of this finding. Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group ( p <0.001). VA-DT 1,791 US veterans with type 2 diabetes underwent intensive therapy or standard therapy for an average follow-up time of 6.25 years. 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. No significant benefit of glucose control on any of the individual components except a small, insignificant increase in cardiovascular death in the intensive-control group. Severe hypoglycemia (defined as altered mental status) requiring medical assistance (definition = altered mental status) occurred in 21% in the intensive group and in 10% of those in the standard group ( p <0.05 Purpose To provide an overview of 3 studies examining the effects of intensive vs standard glycemic control on cardiovascular outcomes. Takeaway Large outcomes studies show that intensive glycemic does not reduce the incidence macrovascular complications. The ADVANCE trial results show that microvascular complications are reduced. References 1. The ADVANCE Collaborative Group. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. 2008 N Engl J Med . 2008;358:2560-2572. 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med . 2008;358:2545-2559. 3. Intense blood glucose control yields no significant effect on CVD reduction in VA diabetes trial―7.5 year trial surpasses goals in blood glucose, lipids, blood pressure. American Diabetes Association Web site. http://www.diabetes.org/diabetesnewsarticle.jsp?storyId=17769625&filename=20080608/comtex20080608iw00000390KEYWORDMissingEDIT.xm. Accessed June 13, 2008.
Slide Data from BARDS email of May 20, 2008 via Harvey Katzeff Baseline HbA1c : Mean (SE) Sitagliptin 7.82 (0.08) Placebo 7.71 (0.07) Data from BARDS
Slide Data from BARDS email of May 20, 2008 via Harvey Katzeff Baseline HbA1c : Mean (SE) Sitagliptin 7.82 (0.08) Placebo 7.71 (0.07)
Slide Data from BARDS email of May 20, 2008 via Harvey Katzeff Baseline HbA1c : Mean (SE) Sitagliptin 7.82 (0.08) Placebo 7.71 (0.07)
Demog_baseline.doc data table
Demog_baseline.doc data table
035 Early Results Memo – tables 4, 5, and 6
035 Early Results Memo – tables 7, 8, and 9
035 Early Results Memo – table 13 and Figure 7
035 Early Results Memo – Figures 8 and 9 and final paragraph of page 3
035 Early Results Memo – Tables 25 and 27
035 Early Results Memo – Tables 25 and 27
035 Early Results Memo – Tables 18 and 20
035 Early Results Memo – Table 16
035 Early Results Memo – Tables 18 and 20
035 Early Results Memo – Tables 25 and 27
035 Early Results Memo – Tables 25 and 27
035 Early Results Memo – Tables 17
035 Early Results Memo – Table 16
035 Early Results Memo – Table 23
This was a multinational, randomized, double-blind, parallel-group 54-week study of patients with type 2 diabetes with inadequate glycemic control on a rosiglitazone (PPARγ agonist) in combination with metformin. Although the study was a 54-week study, the primary endpoint was the change in baseline in A1C after 18 weeks treatment with sitagliptin or placebo. (Protocol 052-01 p. 9) Patients already on a stable regimen of PPARγ agonist + metformin, rosiglitazone at a dose of ≥4 mg per day or pioglitazone at a dose of ≥30 mg per day (treated for ≥12 weeks) in combination with metformin at a dose of ≥1500 mg per day (treated for ≥8 weeks), and with A1C ≥7.5% and ≤11.0% at the Screening Visit entered a 6-week dose-stable period followed by a 2-week single-blind run-in period. (Protocol 052-01 p. 9 and table p. 10) Patients on dual combination therapy who are not already on a stable regimen including: -- PPARγ agonist + metformin: on rosiglitazone at a dose of ≥4 mg per day or pioglitazone at a dose of ≥30 mg per day (treated for ≥12 weeks); metformin at a dose of <1500 mg per day, or on rosiglitazone at a dose of <4 mg per day or pioglitazone at a dose of <30 mg per day; metformin any dose and with A1C ≥8% at the Screening Visit were titrated to the protocol specific doses or rosiglitazone and/or metformin for an 8 and 12-week dose-stable period, respectively, followed by a 2-week single-blind run-in period. (Protocol 052-01 p. 9& 10, and table p. 10) -- metformin + a sulfonylurea (SFU): on metformin ≥1500 mg per day (treated for ≥8 weeks), or on metformin <1500 mg per day) and with A1C ≥7.5% and ≤11.0% at the Screening Visit were titrated to the protocol specific doses or rosiglitazone and/or metformin for a 12-week dose-stable period followed by a 2-week single-blind run-in period. (Protocol 052-01 p. 9 & 10, and table p. 11) -- PPARγ agonist + SFU: on rosiglitazone at a dose of ≥4 mg per day or pioglitazone at a dose of ≥30 mg per day (treated for ≥12 weeks), or on rosiglitazone at a dose of <4 mg per day or pioglitazone at a dose of <30 mg per day and with A1C ≥7.5% and ≤11.0% at the Screening Visit were titrated to the protocol specific doses or rosiglitazone and/or metformin for an 8 and 12-week dose-stable period, respectively, followed by a 2-week single-blind run-in period. (Protocol 052-01 p. 9 & 10, and table p. 11) At Visit 5/Day 1, patients who meet the study enrollment criteria entered the double-blind placebo-controlled treatment period with randomization to once daily sitagliptin 100 mg or placebo in a 2:1 ratio. Patients not meeting specific glycemic goals during the 54-week treatment period were administered rescue therapy. Outside of Canada, rescue therapy was the sulfonylurea agent glipizide (US) or any sulfonylurea (Canada). (Protocol 052-01 p. 11) The study duration was up to 77 weeks (14 visits) for each patient, and this included: 1-week screening period (Visits 1 to 2), PPARγ agonist + metformin dose-titration and dose-stable run-in period of up to 20 weeks (Visits 2 to 4), 2-week single-blind placebo run-in period (Visits 4 to 5), and 54-week double-blind placebo-controlled treatment period (Visits 5 to 14). (SAP 052, p. 7D) A post-study telephone follow-up was performed 14 days after early discontinuation or completion of the study treatment to query for serious adverse experiences. (Protocol 052-01 p. 41) Protocol 052-01, p. 12
Out of the 278 patients randomized at Visit 5/Day 1, a total of 259 patients (173 out of 181 patients in the sitagliptin 100 mg treatment group and 86 out of 97 patients in the placebo treatment group) finished 18 weeks of study treatment. (ERM 10/15/07, p. 2A) ERM 10/15/07, p. 2A
This figure shows the LS mean change from baseline in A1C (%) over time (LS Mean ± SE). In the sitagliptin group, a sustained decrease in change from baseline A1C was observed over 18 weeks, while there was no change from baseline A1C in the placebo group. (ERM 10/15/07, p. 2B) Baseline A1C values were 8.80% for the sitagliptin 100 mg treatment group, and 8.74% for the placebo group. (ERM 10/15/07, p. 4A) The significant LS mean change from baseline A1C for the sitagliptin group was -0.87% at Week 18 (p<0.001) (ERM 10/17/07, p. 4, Table 1) compared with the non-significant mean LS change from baseline for the placebo group of -0.20% (p=0.173) (ERM 10/17/07, p. 4, Table 1). The between-group difference in LS mean A1C values was -0.68% at Week 18 (p<0.001). (ERM 10/17/07, p. 2B) This figure shows the LS mean change from baseline in A1C (%) over time (LS Mean ± SE). In the sitagliptin group, a sustained decrease in change from baseline A1C was observed over 18 weeks, while there was no change from baseline A1C in the placebo group. (ERM 10/15/07, p. 2B) Baseline A1C values were 8.80% for the sitagliptin 100 mg treatment group, and 8.74% for the placebo group. (ERM 10/15/07, p. 4A) The significant LS mean change from baseline A1C for the sitagliptin group was -0.87% at Week 18 (p<0.001) (ERM 10/17/07, p. 4, Table 1) compared with the non-significant mean LS change from baseline for the placebo group of -0.20% (p=0.173) (ERM 10/17/07, p. 4, Table 1). The between-group difference in LS mean A1C values was -0.68% at Week 18 (p<0.001). (ERM 10/17/07, p. 2B) ERM 10/17/07 Figure 1 p.4
This figure summarizes the Week 18 efficacy results for A1C, 2-hour PPG, and FPG values for the sitagliptin and placebo treatment groups. (ERM 10/15/07, p. 4A, 5A, and 6A) The results show a consistently greater decrease in values at Week 18 for those receiving sitagliptin compared to placebo. The magnitude of the differences ranged from approximately three- to four-fold. ERM 10/17/07 Table 1, p. 4; Table 2, p. 4; Table 3 p. 6
This figure summarizes the Week 18 efficacy results for A1C, 2-hour PPG, and FPG values for the sitagliptin and placebo treatment groups. (ERM 10/15/07, p. 4A, 5A, and 6A) The results show a consistently greater decrease in values at Week 18 for those receiving sitagliptin compared to placebo. The magnitude of the differences ranged from approximately three- to four-fold. ERM 10/17/07 Table 1, p. 4; Table 2, p. 4; Table 3 p. 6
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