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Sitagliptin:   A Novel Dipeptidyl Peptidase-4 Inhibitor, Improves Glycemic Control in Patients with Type 2 Diabetes   Dr K...
Agenda <ul><li>Type 2 Diabetes and Islet Cell function </li></ul><ul><li>Incretins, DPP-4 inhibition, and Glucose Homeosta...
Old Concept of T2DM Insulin Resistance Insulin Deficiency (Beta Cell Dysfunction) Hyperglycemia
Patients with T2DM Have Already Lost Substantial   -Cell Function at Diagnosis *Diet and exercise. N= 376.  Adapted from ...
Beta-Cell Function Is Abnormal  in Type 2 Diabetes <ul><li>A range of functional abnormalities is present </li></ul><ul><u...
Decrease in Glucose-Stimulated Insulin Secretion in T2DM (Beta Cell glucose sensitivity) Reprinted from Ferrannini E et al...
 
 
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 %) Insul...
Hepatic Glucose Output in T2DM Mixed meal  Fasting Fed Glucose uptake Meal-derived glucose Hepatic glucose production Hepa...
 
Summary –    cell in T2DM <ul><li>Lack of suppression of glucagon secretion  </li></ul><ul><ul><li>Reduced insulin </li><...
Old Concept – Newer Insights Incretin Defect Insulin Resistance Insulin Deficiency (Beta Cell Dysfunction) Increased HGO  ...
No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Major Pathophysiologies 1.   Glyse...
Challenges of not being able to treat patient to goal Medicines
Incretins, DPP-4 inhibition, and glucose homeostasis
 
GLP-1 and GIP Are  the Two Major Incretins GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptide...
Incretins (GLP-1 and GIP) Regulate Glucose Homeostasis Through Effects on Islet Cell Function Active  GLP-1 and GIP Releas...
GLP-1 Actions Are Glucose Dependent  in Patients With Type 2 Diabetes Placebo GLP-1 Time (min) *p<.05 Insulin Glucagon  Fa...
Summary of Trials: GLP-1 and GIP Levels  and Actions in Type 2 Diabetes *When corrected for gender and BMI Adapted from To...
Decreased Postprandial Levels of the Incretin  Hormone GLP-1 in Patients With Type 2 Diabetes * P <0.05, Type 2 diabetes v...
Effects of GLP-1 and GIP on the First- and Second-Phase Insulin Response in Type 2 Diabetes Type 2 diabetes Early-phase in...
DPP9 DPP8 FAP DPP-4 DPP6 PEP QPP/DPPII APP prolidase DPP-4 Gene Family Other Proline Specific Peptidases Function unknown ...
Anatomical Relationship Between  GLP-1+ L Cells and DPP-4+ Endothelium Cleft Hole Active site Probable entrance to active ...
DPP- 4 Active GLP-1 Inactive GLP-1 Inhibition of DPP-4 Increases Active Incretin Levels, Enhancing Downstream Incretin Act...
Sitagliptin - Overview <ul><li>DPP-4 inhibitor in development for the treatment of patients with type 2 diabetes, approved...
Sitagliptin Is Potent and Highly Selective (>2500x)  for the DPP-4 Enzyme Herman et al.  ADA . 2004. >100,000 APP >100,000...
Selective DPP-4 Inhibitors Are Not Associated With Preclinical Toxicities Observed With Non-Selective Inhibitors 1.  Leiti...
Pharmacokinetics of Sitagliptin  Supports Once-Daily Dosing <ul><li>With once-daily administration,  trough  (at 24 hrs) D...
Sitagliptin AUC  0-inf  vs. creatinine clearance: AUC increases with decreasing creatinine clearance  AUC GMR increase < 2...
Single-Dose OGTT Study  One Dose of Sitagliptin Inhibited Plasma DPP-4 Activity  Hours post-dose ~80% ~50% Trough DPP-4 in...
% Plasma Inhibition of DPP-4 Activity  With Sitagliptin 100 mg in Healthy Adults 16 8 Percent Inhibition  From Baseline Ho...
A Single Dose of Sitagliptin Increased  Active GLP-1 and GIP Over 24 Hours OGTT  24 hrs (n=19) Herman et al.  Diabetes . P...
A Single Dose of Sitagliptin Increased Insulin, Decreased Glucagon, and Reduced Glycemic Excursion After a  Glucose Load 0...
Phase III Clinical Studies of Sitagliptin ●  M onotherapy use  (P021, P023, A201, P040) ●  Combination use with Metformin,...
Monotherapy Studies – Patients Studied <ul><li>Multinational studies </li></ul><ul><ul><li>Mean duration of T2DM of 4.4 ye...
Sitagliptin Consistently and Significantly Lowers A1C with Once-Daily Dosing in Monotherapy  7.2 7.6 8.0 8.4 *between grou...
Sitagliptin Provides Significant and Progressively Greater Reductions in A1C with Progressively Higher Baseline A1C  Basel...
Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy Fasting Glucose Plasma Glu...
Sitagliptin Improves the   -Cell Response to Glucose     Monotherapy Studies   200 400 600 800 1000 1200 1400 160 180 200...
Sitagliptin Improved Markers of  Beta-Cell Function  24-Week Monotherapy Study Proinsulin/insulin ratio Aschner P et al. P...
Indian Clinical Trial
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 Me...
Placebo Subtracted Change from Baseline in HbA1c  Per Country  (-1.92, -0.83)  -1.38 Korea (-0.92, -0.46) -0.69 China (-1....
Sitagliptin Reduces FPG Levels Significantly From Baseline (APT Population)  Values represent mean ± SE. 0 6 12 18 – 30 – ...
Four-Point Meal Tolerance Test at Baseline and Week 18 (APT Population) 120 170 220 270 Sitagliptin 100 mg Placebo Minutes...
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) Disc...
Incidence of Laboratory Adverse Events LAE = laboratory adverse event. 0 0 Discontinued due to  drug-related LAE 1 (0.6) 1...
Summary <ul><li>Compared with placebo, treatment with Sitagliptin for 18 weeks resulted in </li></ul><ul><ul><li>Significa...
Phase III Clinical Studies of Sitagliptin ●  M onotherapy use  (P021, P023, A201, P040) ●  Combination use with Metformin,...
Sitagliptin Once Daily Significantly Lowers A1C  When Added On to Metformin or Pioglitazone    in A1C vs Pbo* = –0.65%  (...
Sitagliptin Added to Ongoing Metformin or Pioglitazone  Therapy in Patients With T2DM:  Change in Body Weight Over Time LS...
Sitagliptin Once Daily Significantly Increases Proportion of Patients Achieving Goal in Mono- or Combination Therapy Sitag...
Placebo Controlled Add-on to Glimperide or Glimepiride/Metformin Study – Design and Patients 035 Placebo Phase B Sitaglipt...
Sitagliptin Improved A1C When Added to  Glim  *Difference in LS Mean change from baseline  Hermansen et al, Diabetes Obesi...
Sitagliptin Improved A1C When Added to Glim + MF 035 Δ  -0.9%; p<0.001* *Difference in LS Mean change from baseline  Herma...
Sitagliptin Increased Rates of Hypoglycemia in Combination with Sitagliptin ± Metformin 035 Treatment Group N 222 219 4 (1...
Sitagliptin + Metformin Factorial Study Design   N = 1091 Randomized Mean baseline A1C = 8.8% Screening Period   Single-bl...
Initial Combination of Sitagliptin and Metformin  Produced a Marked Improvement in A1C -0.8 -1.0  -1.3 -1.6 -2.1 Mean base...
Rapid Improvement in FPG in High Baseline Patients Treated with Initial Combination Therapy * Mean Change from Baseline p<...
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...
Summary of Clinical Adverse Experiences (AEs)  Through 54 Weeks (Phase A and B Combined, cont.) Sita 50 mg + MF 1000 mg b....
Gastrointestinal AEs Through 54 Weeks % 27.7
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...
Proportion of Patients with A1C Goal <7% at Endpoint (Week 54 Analysis) Sita 50 mg BID + Met 1000 mg BID Sita 50 mg BID + ...
Active-Comparator (Glipizide) Controlled Add-on to Metformin Study (024) – Design and Patients <ul><li>Design </li></ul><u...
Sitagliptin Once Daily Shows Similar Glycemic Efficacy to Glipizide When Added to Metformin (52 Weeks) Mean Change in HbA ...
Progressively Greater Reductions in A1C  as Baseline A1C Rises Baseline A1C Category Study inclusion criteria 6.5-10% Chan...
Sitagliptin Once Daily Shows Better Safety and Tolerability Profile Compared to Glipizide (52 Weeks) Glipizide  (n=584) Si...
Safety and Tolerability Overview  <ul><li>Well tolerated in Phase I through III trials – in completed and ongoing studies ...
Summary Measures of Clinical Adverse Events for  Sitagliptin is Similar to Placebo Recommended dose in proposed label: 100...
Only Small Differences in Incidence of AEs:  Pooled Phase III Population  AEs with at least 3% incidence  and  Numerically...
Sitagliptin Lowers A1C Without Increasing the Incidence of Hypoglycemia or Leading to Weight Gain  <ul><li>Neutral effect ...
 
Summary on Sitagliptin <ul><li>Sitagliptin is a potent and selective DPP-4 inhibitor administered once-daily for the treat...
Advantages of DPP-IV Inhibition <ul><li>Oral, Once daily </li></ul><ul><li>Meal independent administration </li></ul><ul><...
Effect of  Des-F-Sitagliptin on Beta-Cell Mass 1.1% Nondiabetic Control H&E  insulin (I)  glucagon (G)  I/G Diabetic  Cont...
GLP-1 Preserved Morphology of Human Islet Cells In Vitro Day 1 GLP-1–treated cells Control Day 3 Day 5 Islets treated with...
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  1. 1. Sitagliptin: A Novel Dipeptidyl Peptidase-4 Inhibitor, Improves Glycemic Control in Patients with Type 2 Diabetes Dr Karthik Anantharaman MSD Pharmaceuticals Pvt Ltd (India)
  2. 2. Agenda <ul><li>Type 2 Diabetes and Islet Cell function </li></ul><ul><li>Incretins, DPP-4 inhibition, and Glucose Homeostasis </li></ul><ul><li>Description of Sitagliptin ( Januvia ™) </li></ul><ul><li>Phase III Clinical Data for Sitagliptin </li></ul><ul><li>Summary and Future Direction </li></ul>
  3. 3. Old Concept of T2DM Insulin Resistance Insulin Deficiency (Beta Cell Dysfunction) Hyperglycemia
  4. 4. Patients with T2DM Have Already Lost Substantial  -Cell Function at Diagnosis *Diet and exercise. N= 376. Adapted from UKPDS 16. Diabetes . 1995;44:1249–1258. Permission required. Diagnosis (%B)
  5. 5. Beta-Cell Function Is Abnormal in Type 2 Diabetes <ul><li>A range of functional abnormalities is present </li></ul><ul><ul><li>Abnormal oscillatory insulin release </li></ul></ul><ul><ul><li>Increased proinsulin levels </li></ul></ul><ul><ul><li>Loss of 1st-phase insulin response </li></ul></ul><ul><ul><li>Abnormal 2nd-phase insulin response </li></ul></ul><ul><ul><li>Progressive loss of beta-cell functional mass </li></ul></ul>*p<0.05 between groups. Buchanan TA. Clin Ther. 2003;25(suppl B):B32–B46; Polonsky KS et al. N Engl J Med. 1988;318:1231–1239; Quddusi S et al. Diabetes Care. 2003;26:791–798; Porte D Jr, Kahn SE. Diabetes. 2001;50(suppl 1):S160–S163; Figure adapted from Vilsbøll T et al. Diabetes. 2001;50:609–613. Insulin (pmol/L) Mixed meal Normal subjects Type 2 diabetics Time (min) * * 500 400 300 200 100 0 0 60 120 180
  6. 6. Decrease in Glucose-Stimulated Insulin Secretion in T2DM (Beta Cell glucose sensitivity) Reprinted from Ferrannini E et al. J Clin Endocrinol Metab . 2005;90:493–500. 1000 800 600 400 200 0 5 10 15 20 25 Insulin secretion rate (pmoL·min -1 ·m -2 ) Plasma glucose (mmol/L) Obese NGT tertiles Lean NGT IGT T2DM quartiles
  7. 9. 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
  8. 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.
  9. 12. Summary –  cell in T2DM <ul><li>Lack of suppression of glucagon secretion </li></ul><ul><ul><li>Reduced insulin </li></ul></ul><ul><ul><li>? Insulin resistance in  cell </li></ul></ul><ul><li>Increased secretory capacity </li></ul><ul><li>Increased  cell number </li></ul><ul><li>Altered Islet morphology – loss of normal relationship between  and  cells </li></ul>
  10. 13. Old Concept – Newer Insights Incretin Defect Insulin Resistance Insulin Deficiency (Beta Cell Dysfunction) Increased HGO Non-suppressed Glucagon (Alpha Cell Dysfunction) Hyperglycemia
  11. 14. 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
  12. 15. Challenges of not being able to treat patient to goal Medicines
  13. 16. Incretins, DPP-4 inhibition, and glucose homeostasis
  14. 18. GLP-1 and GIP Are the Two Major Incretins GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptide Adapted from Drucker DJ Diabetes Care 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122: 531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246. <ul><li>Suppresses hepatic glucose output by inhibiting glucagon secretion in a glucose-dependent manner </li></ul><ul><li>Enhances beta-cell proliferation and survival in islet cell lines </li></ul><ul><li>Enhances beta-cell proliferation and survival in animal models and isolated human islets </li></ul><ul><li>Secreted by L-cells in the distal gut (ileum and colon) </li></ul><ul><li>Stimulates glucose-dependent insulin release </li></ul>GLP-1 <ul><li>Secreted by K-cells in the proximal gut (duodenum) </li></ul><ul><li>Stimulates glucose-dependent insulin release </li></ul>GIP
  15. 19. Incretins (GLP-1 and GIP) Regulate Glucose Homeostasis Through Effects on Islet Cell Function Active GLP-1 and GIP Release of incretin gut hormones More stable glucose control GI tract Ingestion of food  Glucose uptake and storage in muscles and adipose tissue <ul><li>Glucose dependent </li></ul><ul><li>Insulin </li></ul><ul><li>from beta cells (GLP-1 and GIP) </li></ul>Brubaker PL, Drucker DJ. Endocrinology . 2004;145:2653–2659; Zander M et al. Lancet . 2002;359:824–830; Ahrén B. Curr Diab Rep . 2003;3:365–372; Holst JJ. Diabetes Metab Res Rev . 2002;18:430–441; Holz GG, Chepurny OG. Curr Med Chem . 2003;10:2471–2483; Creutzfeldt WOC et al. Diabetes Care . 1996;19:580–586; Drucker DJ. Diabetes Care . 2003;26:2929–2940. GLP-1 and GIP metabolites DPP-4 enzyme <ul><li>In animal models of diabetes both GLP-1 and GIP have been shown to increase β -cell mass </li></ul><ul><li>The incretin axis is abnormal in patients with T2DM: Reduced release of GLP-1; reduced response to GIP </li></ul>Pancreas Beta cells Alpha cells <ul><li>Glucagon </li></ul><ul><li>from alpha cells (GLP-1) Glucose dependent </li></ul> Glucose release into the bloodstream by liver
  16. 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. * * * * * * * * * * * * * * * * * * *
  17. 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
  18. 22. Decreased Postprandial Levels of the Incretin Hormone GLP-1 in Patients With Type 2 Diabetes * P <0.05, Type 2 diabetes vs NGT. Reprinted with permission from Toft-Nielsen MB et al. J Clin Endocrinol Metab . 2001;86:3717–3723. Copyright © 2001, The Endocrine Society. 17 * * * * * * * Meal Started Meal Finished (10–15)
  19. 23. Effects of GLP-1 and GIP on the First- and Second-Phase Insulin Response in Type 2 Diabetes Type 2 diabetes Early-phase insulin AUC 0-20 min (20 min x nmol/L) * * Type 2 diabetes Late-phase insulin AUC 20-120 min (100 min x nmol/L) ** GLP-1 and GIP increased first-phase insulin response. GLP-1 but not GIP increased second-phase insulin response. n=6 * P <0.05 vs saline.; ** P <0.05 vs saline and GIP. Data are (mean ± SEM) from the cohort of lean patients with type 2 diabetes, who underwent 3 hyperglycemic clamps with continuous infusion of saline, GLP-1 or GIP. Adapted with permission from Vilsbøll T et al. J Clin Endocrinol Metab . 2003:88;4897–4903. Copyright © 2003, The Endocrine Society.
  20. 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
  21. 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
  22. 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
  23. 27. Sitagliptin - Overview <ul><li>DPP-4 inhibitor in development for the treatment of patients with type 2 diabetes, approved by the FDA on October 17 2006. EU approval March 2007 </li></ul><ul><li>Provides potent and highly selective inhibition of the DPP-4 enzyme </li></ul><ul><li>Fully reversible and competitive inhibitor </li></ul>
  24. 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
  25. 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)
  26. 30. Pharmacokinetics of Sitagliptin Supports Once-Daily Dosing <ul><li>With once-daily administration, trough (at 24 hrs) DPP-4 inhibition is ~ 80% </li></ul><ul><ul><li>> 80% inhibition provides full enhancement of active incretin levels </li></ul></ul><ul><li>No effect of food on pharmacokinetics </li></ul><ul><li>Well absorbed following oral dosing </li></ul><ul><li>T max app 2 hours, t 1/2 app 12.4 hours at 100 mg dose </li></ul><ul><li>Low protein binding, app 38% </li></ul><ul><li>Primarily renal excretion as parent drug </li></ul><ul><ul><li>Approximately 80% of a dose recovered as intact drug in urine </li></ul></ul><ul><li>No clinically important drug-drug interactions </li></ul><ul><ul><li>No meaningful P450 system inhibition or activation </li></ul></ul>
  27. 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
  28. 32. Single-Dose OGTT Study One Dose of Sitagliptin Inhibited Plasma DPP-4 Activity Hours post-dose ~80% ~50% Trough DPP-4 inhibition Inhibition of plasma DPP-4 activity from baseline (%) 0 1 2 4 8 12 16 20 24 – 10 0 40 50 60 80 100 90 70 30 20 10 6 10 14 18 22 26 OGTT Sitagliptin 25 mg (n=56) Sitagliptin 200 mg (n=56) Placebo (n=56)
  29. 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)
  30. 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
  31. 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
  32. 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)
  33. 37. Monotherapy Studies – Patients Studied <ul><li>Multinational studies </li></ul><ul><ul><li>Mean duration of T2DM of 4.4 years </li></ul></ul><ul><ul><li>Baseline mean A1C - 8.0% </li></ul></ul><ul><ul><ul><li>54% of patients had A1C < 8% </li></ul></ul></ul><ul><ul><li>53% prior OHA, mean BMI 31 kg/m 2 , mean age 54 years, 55% male </li></ul></ul><ul><li>Japanese study </li></ul><ul><ul><li>Mean duration of T2DM of ~ 4 years </li></ul></ul><ul><ul><li>Baseline mean A1C 7.6% </li></ul></ul><ul><ul><ul><li>~ 65% had A1C < 8% </li></ul></ul></ul><ul><ul><li>~ 45% on prior OHA, mean BMI 25 kg/m 2 , mean age 55 years, 60% male </li></ul></ul>
  34. 38. Sitagliptin Consistently and Significantly Lowers A1C with Once-Daily Dosing in Monotherapy 7.2 7.6 8.0 8.4 *between group difference in LS means Adapted from Raz et al. Diabetologia. 2006;49:2564–2571; Aschner et al. Diabetes Care. 2006;29:2632–2637. ; Nonaka K et al; A201. Abstract presented at: ADA 2006 Placebo (n=244) Sitagliptin 100 mg (n=229) 24-week Study Time (weeks) 0 5 10 15 20 25 -0.79% (p<0.001) Japanese Study -1.05% (p<0.001) Placebo (n=75) Sitagliptin 100 mg (n=75) Time (weeks) 0 4 8 12 A1C (%) 7.6 8.0 8.4 7.2 6.8 <ul><li>change vs placebo* </li></ul>18-week Study Placebo (n=74) Sitagliptin 100 mg (n=168) Time (weeks) 0 6 12 18 A1C (%) 7.2 7.6 8.0 8.4 -0.6% (p<0.001) A1C (%) =
  35. 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
  36. 40. Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy Fasting Glucose Plasma Glucose mg/dL Time (weeks) 0 5 10 15 20 25 144 153 162 171 180 189 Placebo (n=247) Sitagliptin 100 mg (n=234)  FPG* = –17.1 mg/dL ( p <0.001) Post-meal Glucose * LS mean difference from placebo after 24 weeks Adapted from Aschner et al. Diabetes Care. 2006;29:2632–2637. Time (minutes) Plasma Glucose mg/dL <ul><li>in 2-hr PPG* = –46.7 mg/dL (p<0.001) </li></ul>0 60 120 0 60 120 144 180 216 252 288 Placebo (N=204) Sitagliptin (n=201) Baseline 24 weeks Baseline 24 weeks
  37. 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
  38. 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
  39. 43. Indian Clinical Trial
  40. 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
  41. 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
  42. 46. Sitagliptin Reduces FPG Levels Significantly From Baseline (APT Population) Values represent mean ± SE. 0 6 12 18 – 30 – 20 – 10 0 10 Week LSM Change From Baseline, mg/dL  31.0 p<0.001 Sitagliptin 100 mg Placebo
  43. 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
  44. 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 (%)
  45. 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 (%)
  46. 50. Summary <ul><li>Compared with placebo, treatment with Sitagliptin for 18 weeks resulted in </li></ul><ul><ul><li>Significantly lower HbA1C, </li></ul></ul><ul><ul><li>Significant improvements in FPG and 2-hour PPG levels </li></ul></ul><ul><ul><li>Slight weight gain (0.6 kg) </li></ul></ul><ul><li>Sitagliptin was well tolerated and showed no clinically meaningful difference with placebo in incidence of AEs. </li></ul><ul><li>No events of hypoglycemia </li></ul>PPG = postprandial plasma glucose.
  47. 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)
  48. 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)
  49. 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)
  50. 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.
  51. 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
  52. 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*
  53. 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
  54. 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)
  55. 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
  56. 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
  57. 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
  58. 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)
  59. 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
  60. 64. Gastrointestinal AEs Through 54 Weeks % 27.7
  61. 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. * * * *
  62. 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
  63. 67. Active-Comparator (Glipizide) Controlled Add-on to Metformin Study (024) – Design and Patients <ul><li>Design </li></ul><ul><li>Patients with T2DM (on monotherapy or combination OHA) ➜ started/continued on metformin monotherapy (at least 1500 mg/d) during run-in period, randomized if A1C 6.5–10% after run-in period </li></ul><ul><li>Patient population </li></ul><ul><li>1172 randomized patients, mean age 57 years, ~ 60% male </li></ul><ul><li>Mean duration of T2DM 6 years, baseline mean A1C = 7.5% </li></ul>Screening Period Single-blind placebo Double-blind Treatment Period: Glipizide or Sitagliptin 100 mg q.d. Metformin monotherapy Run-In Period Week -2: eligible if A1C 6.5 to 10% Continue/start regimen of met monotherapy Day 1 Randomization monotherapy with metformin (stable dose > 1500 mg/d) Week 52 Glipizide : 5 mg qd increased to 10 mg bid (held if FS < 110 mg/dL or hypoglycemia)
  64. 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)
  65. 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
  66. 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)
  67. 71. Safety and Tolerability Overview <ul><li>Well tolerated in Phase I through III trials – in completed and ongoing studies more than 7000 patients on sitagliptin (to doses of 200 mg q.d. in Phase III studies) </li></ul><ul><li>Pre-specified Pooled Phase III analysis, including monotherapy and combination studies: over 1500 patients on sitagliptin and over 750 patients on placebo </li></ul><ul><ul><li>Summary measures of adverse experiences (AEs) were similar to placebo </li></ul></ul><ul><ul><ul><li>Including overall clinical AEs, serious AEs, discontinuations due to AEs, drug-related AEs, laboratory AE summary measures </li></ul></ul></ul><ul><ul><li>Small differences in incidence of specific AEs </li></ul></ul><ul><ul><ul><li>Between group difference (sitagliptin 100 mg – placebo group) in incidence > 1% for only 1 specific AE (nasopharyngitis 1.2% difference) </li></ul></ul></ul>
  68. 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
  69. 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)
  70. 74. Sitagliptin Lowers A1C Without Increasing the Incidence of Hypoglycemia or Leading to Weight Gain <ul><li>Neutral effect on body weight </li></ul><ul><ul><li>In monotherapy studies, small decreases from baseline (~ 0.1 to 0.7 kg) with sitagliptin; slightly greater reductions with placebo (~ 0.7 to 1.1 kg) </li></ul></ul><ul><ul><li>In combination studies, weight changes with sitagliptin similar to placebo-treated patients </li></ul></ul>Pooled Phase III Population Analysis: no statistically significant difference in incidence for either dose vs placebo Hypoglycemia Weight Changes 0.9% 1.2% 0.9% Patients with hypoglycemia (%) Sitaglitpin 200 mg q.d. Sitagliptin 100 mg q.d. Placebo
  71. 76. Summary on Sitagliptin <ul><li>Sitagliptin is a potent and selective DPP-4 inhibitor administered once-daily for the treatment of T2DM </li></ul><ul><li>Once-daily regimen of sitagliptin provides </li></ul><ul><li>A once-daily regimen of sitaglitpin provides substantial glycemic efficacy </li></ul><ul><ul><li>Significant reductions in A1C across a range of starting A1C levels in monotherapy and combination use </li></ul></ul><ul><ul><li>Sustained A1C reduction to 1 year </li></ul></ul><ul><ul><li>Improvements in multiple measures of beta-cell function </li></ul></ul><ul><li>Compared to a sulfonylurea agent, sitagliptin provides </li></ul><ul><ul><li>Similar efficacy </li></ul></ul><ul><ul><li>Superior improvements in beta-cell function, less hypoglycemia, and weight loss (vs weight gain) </li></ul></ul><ul><li>Sitagliptin was well tolerated with summary measures of AEs similar to placebo </li></ul>
  72. 77. Advantages of DPP-IV Inhibition <ul><li>Oral, Once daily </li></ul><ul><li>Meal independent administration </li></ul><ul><li>Low risk of hypoglycemia </li></ul><ul><li>No clinically meaningful drug-drug interactions </li></ul><ul><li>Significant improvements in Glucose sensitivity of beta cells, pro-insulin/insulin ratio & HOMA-beta </li></ul><ul><li>Oral therapy, providing dosing convenience to the patient </li></ul><ul><li>Endogenous GLP-1 & GIP levels are increased in response to meal and are transient </li></ul><ul><li>Avoid tolerability/immunogenicity issues with exogenous GLP-1 </li></ul><ul><li>Multiple mechanisms of GLP-1 in T2DM </li></ul><ul><ul><li>Insulin release is glucose dependent </li></ul></ul><ul><ul><li>Reduced hepatic glucose production </li></ul></ul><ul><ul><li>Improved peripheral glucose utilization </li></ul></ul><ul><ul><li> -cell preservation / neogenesis and restoration in animal models </li></ul></ul>Source: Drucker DJ. Diabetes Care 2003;26:2929-2940.
  73. 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).
  74. 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.
  75. 80. Thank You

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