msd orissa apicon nov 2008 dr ka
TRANSCRIPT
- 1. Sitagliptin: A Novel Dipeptidyl Peptidase-4 Inhibitor, Improves Glycemic Control in Patients with Type 2 Diabetes Dr Karthik Anantharaman MSD Pharmaceuticals Pvt Ltd (India)
2. Agenda
- Type 2 Diabetes and Islet Cell function
- Incretins, DPP-4 inhibition, and Glucose Homeostasis
- Description of Sitagliptin ( Januvia )
- Phase III Clinical Data forSitagliptin
- Summary and Future Direction
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;44:12491258. Permission required. Diagnosis (%B) 5. Beta-Cell Function Is Abnormalin Type 2 Diabetes
- A range of functional abnormalities is present
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- Abnormal oscillatoryinsulin release
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- Increased proinsulin levels
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- Loss of 1st-phase insulin response
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- Abnormal 2nd-phase insulin response
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- Progressive loss ofbeta-cell functional mass
*p 50 mL/min Dose adjustments < 30 mL/min dose 30 50 mL/min dose > 50 mL/min full dose 44. Single-Dose OGTT StudyOne Dose of Sitagliptin Inhibited Plasma DPP-4 ActivityHours post-dose ~80% ~50% Trough DPP-4 inhibition Inhibition of plasma DPP-4 activity from baseline (%) 0 1 2 4 8 12 16 20 24 10 0 40 50 60 80 100 90 70 30 20 10 6 10 14 18 22 26 OGTT Sitagliptin 25 mg (n=56) Sitagliptin 200 mg (n=56) Placebo (n=56) 45. % Plasma Inhibition of DPP-4 ActivityWith Sitagliptin 100 mg in Healthy Adults 16 8 Percent InhibitionFrom 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;78:675688. Sitagliptin 100 mg (N=6) Placebo (N=2) 46. A Single Dose of Sitagliptin IncreasedActive GLP-1 and GIP Over 24 Hours OGTT24 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) OGTT2 hrs (n=55) Crossover study in patients with T2DM Placebo Sitagliptin25 mg Sitagliptin200 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) OGTT24 hrs (n=19) OGTT2 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 aGlucose 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 Glucoseload DrugDose 22% ~12% Insulin Glucagon Crossover Study in Patients with T2DM p