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. 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
10. Hepatic Glucose Output in T2DM Mixed meal Fasting Fed Glucose uptake Meal-derived glucose Hepatic glucose production Hepatic glucose production Glucose uptake Meal-derived glucose Subjects with diabetes (n=7) Control subjects (n=5) Glucose flux (mg·kg -1 ·min -1 ) Glucose flux (mg·kg -1 ·min -1 ) Fasting Fed Adapted from Lebovitz HE et al. Changing the Course of Disease: Gastrointestinal Hormones and Tomorrow's Treatment of Type 2 Diabetes . Available at: http://www.medscape.com from Medscape Diabetes & Endocrinology , Nov 2004 . Accessed August 2005. Data for controls and diabetes calculated from Pehling G et al. J Clin Invest . 1984;74:985–991.
20. 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. * * * * * * * * * * * * * * * * * * *
21. 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
24. 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
25. 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
26. DPP- 4 Active GLP-1 Inactive GLP-1 Inhibition of DPP-4 Increases Active Incretin Levels, Enhancing Downstream Incretin Actions Active GIP Inactive GIP Increased insulin secretion Decreased glucagon release Glucose control improved DPP-4 inhibitor Χ
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28. 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
29. 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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31. 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
33. % 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)
34. 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
35. 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
36. 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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39. 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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41. 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
42. 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
44. 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
45. 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
47. Four-Point Meal Tolerance Test at Baseline and Week 18 (APT Population) 120 170 220 270 Sitagliptin 100 mg Placebo Minutes After Initiation of Meal Challenge Mean Plasma Glucose, mg/dL Baseline Week 18 0 30 60 120 0 30 60 120
48. Incidence of Adverse Events AE = adverse event. 1 (0.6) 2 (0.6) Discontinued due to drug-related AE 2 (1.1) 5 (1.4) Discontinued due to AE 1 (0.6) 1 (0.3) Serious drug-related AE 2 (1.1) 6 (1.7) Serious AE 3 (1.7) 10 (2.8) Drug-related AE 27 (15.2) 82 (23.3) One or more AE Placebo n = 178 Sitagliptin 100 mg n = 352 Event, n (%)
49. Incidence of Laboratory Adverse Events LAE = laboratory adverse event. 0 0 Discontinued due to drug-related LAE 1 (0.6) 1 (0.3) Discontinued due to LAE 0 0 Serious drug-related LAE 0 0 Serious LAE 3 (1.8) 9 (2.6) Drug-related LAE 12 (7.0) 22 (6.5) One or more LAE Placebo n = 178 Sitagliptin 100 mg n = 352 Tolerability, n (%)
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51. 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)
52. 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)
53. 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)
54. 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.
55. 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
56. 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*
57. 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
58. 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)
59. 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
60. Initial Combination of Sitagliptin and Metformin Produced a Marked Improvement in A1C -0.8 -1.0 -1.3 -1.6 -2.1 Mean baseline A1C = 8.8% Placebo change from Baseline = 0.17 % *Placebo-subtracted LS mean change from baseline at Week 24 Open Label Sita 50 mg + MF 1000 mg b.i.d. Sita 50 mg + MF 1000 mg b.i.d. Sita 50 mg + MF 500 mg b.i.d. MF 1000 mg b.i.d. MF 500 mg b.i.d. Sita 100 mg q.d. Goldstein et al, Diabetes Care: 30; 1979 – 1987, 2007
61. Rapid Improvement in FPG in High Baseline Patients Treated with Initial Combination Therapy * Mean Change from Baseline p<0.001 Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. ∆ FPG = -7.32 mmol/l* ∆ A1C = -2.94%* A1C (%) FPG (mmol/l) Weeks Weeks Goldstein et al, Diabetes Care: 30; 1979 – 1987, 2007
62. Mean A1C Levels Through 54 Weeks (Completers) 24-Week (Phase A) Continuation Phase (Phase B) 6.00 6.50 7.00 7.50 8.00 8.50 9.00 0 6 12 18 24 30 38 46 54 Week A1C, % APT = all patients treated; sit = sitagliptin; met = metformin; Values represent mean ± SE. Sit 50 mg BID + met 1000 mg BID (n = 153) Met 1000 mg BID (n = 134) Sit 100 mg QD (n = 106) Sit 50 mg BID + met 500 mg BID (n = 147) Met 500 mg BID (n = 117)
63. 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
65. 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. * * * *
66. 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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68. 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)
69. 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
70. 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)
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72. 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
73. 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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78. 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).
79. 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.
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.
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.
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.
Effects of GLP-1 and GIP on the First- and Second-Phase Insulin Response in Type 2 Diabetes In patients with type 2 diabetes, GLP-1 infusion as well as GIP infusion have been shown to enhance the first phase of insulin secretion, although total insulin secretion is still lower than that of healthy subjects. 1 In this study, study participants underwent 3 hyperglycemic clamps with continuous infusion of GLP-1, GIP, or saline. Results are shown for the cohort of lean patients with type 2 diabetes (n=6). 2 As shown in the graph on the left, both GLP-1 and GIP increased the first-phase insulin response. 2 As shown in the graph on the right, GLP-1, unlike GIP, also affected the second-phase insulin response. 2 Thus in this study, GLP-1 had a positive effect on both the first and second phases of insulin secretion, and the ability of the patients with type 2 diabetes to respond to the insulinotropic actions of GLP-1 appeared to be preserved. 2,3 GIP had little effect on the second-phase insulin response. 2 References: 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. 2. 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. 3. Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. 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.
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.
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.
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