The document discusses the role of DPP-4 inhibition and sitagliptin in the management of type 2 diabetes. It provides evidence that sitagliptin increases active GLP-1 and GIP levels, resulting in improved glycemic control through increased insulin secretion, decreased glucagon levels, and reduced glucose levels. Studies show sitagliptin to be an effective monotherapy and when added to other oral medications, with benefits seen within days and a generally well-tolerated safety profile compared to sulfonylureas.
8. Role of Dipeptidyl Peptidase-4 1. Kieffer TJ, Habener JF. Endocr Rev . 1999;20:876–913. 2. Ahrén B. Curr Diab Rep . 2003;2:365–372. 3. Drucker DJ. Diabetes Care . 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev . 2002;18:430–441. Insulin synthesis and secretion from beta cells (GLP-1 and GIP) Glucagon from alpha cells (GLP-1) Release of gut hormones— Incretins 1,2 Pancreas 2,3 Glucose Dependent Active GLP-1 & GIP DPP-4 enzyme Inactive GIP Inactive GLP-1 Glucose Dependent ↓ Blood glucose GI tract ↓ Glucose production by liver Food ingestion ↑ Glucose uptake by peripheral tissue 2,4 Beta cells Alpha cells
9. GLP-1 Levels Are Decreased in Type 2 Diabetes * Control (n=33) Type 2 diabetes (n=54) 0 5 10 15 20 0 60 120 180 240 GLP-1 (pmol/L) *p<0.05, type 2 diabetes vs control Adapted from Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723. Meal Started Meal Finished (10–15) Time after start of meal, minutes BUT, the levels are never ZERO * * * * * *
10. DPP4 activity increases in Hyperglycemia Mannucci et al, Diabetologia April 2005
11. doi:10.1016/j.bcp.2008.07.029 Lambeir, Scharpe, Meester 10.1002/ddr.20138, von Geldern, Trevillyan Incretin Based Therapies GLP1 receptor agonists (DPP4 resistant) Incretin Enhancers (DPP4 Inhibitors) Substrate-like inhibitors (Vildagliptin, Saxagliptin) 1 st Generation Gliptins (Shorter Half Life, Less DPP4 Specificity) Non Substrate-like inhibitors ( Sitagliptin , Alogliptin) 2 nd Generation Gliptins (Longer Half Life, Very High DPP4 Specificity) Exendin Based Therapies (Exenatide) Human GLP1 Analogue (Liraglutide)
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15. What is the effect of a Single Tablet of Sitagliptin?
16. 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
17. 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
25. SITAGLIPTIN: Significant A1C Reductions From Baseline When Added to Metformin or Pioglitazone Add-on to patients failing on pioglitazone 2 Mean Baseline A1C: 8.0%, 8.1% Mean Change in A1C From Baseline, % n=224 Metformin + Sita – 1.0 – 0.8 – 0.6 0 – 1.0 0 Mean Change in A1C From Baseline, % – 0.7% Mean Baseline A1C: 8.0% P <0.001* P <0.001* Add-on to patients uncontrolled on metformin 1 – 0.0% Metformin + Placebo Pioglitazone + Sita Pioglitazone + Placebo *Compared with placebo. 1. Charbonnel B et al. Diabetes Care . 2006;29:2638–2643. 2. Rosenstock J et al. Clin Ther . 2006;28:1556–1568. n=453 n=174 n=163 0.7% placebo- subtracted result 0.7% placebo- subtracted result – 0.9% – 0.4 – 0.2 – 0.8 – 0.6 – 0.4 – 0.2 – 0.2%
27. HbA 1c Over Time With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy a Specifically glipizide; b Sitagliptin 100 mg/day with metformin (≥1500 mg/day); Per-protocol population; LS=least squares. Adapted from Nauck et al. Diabetes Obes Metab . 2007;9:194–205. Continuous Up-titration in Glipizide arm LS mean change from baseline (for both groups): –0.67% Achieved primary hypothesis of noninferiority to sulfonylurea Sulfonylurea a + metformin (n=411) Sitagliptin b + metformin (n=382) HbA 1c (% ± SE) Weeks 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6 7.8 0 6 12 18 24 30 38 46 52 8.0 8.2
28. Effects of Sitagliptin and Glipizide on Body Weight and Hypoglycemia *(95% CI) LS Means Change in Body Weight (kg) in Between Treatment Groups CSR Incidences similar to Placebo+Metformin 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)*
30. Pooled Results from all Phase III studies of Sitagliptin 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) *Significant reduction of A1c across all duration
31. Sitagliptin Improved A1C When Added to Glim + MF *T2DM of long duration Δ -0.9%; p<0.001* *Difference in LS Mean change from baseline Hermansen et al, Diabetes Obesity Metabolism 2007 Weeks 0 6 12 18 24 A1C (%) 7.2 7.6 8.0 8.4 8.8 Sitagliptin +Glim + MF (n=116) Placebo + Glim + MF (n=113)
33. 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 Sitagliptin 100mg monotherapy *Significant efficacy shown even when baseline Beta cell function is poor
35. Placebo Subtracted Change from Baseline in HbA1c Per Country DRCP Mohan Yang Son, 2009 Jan;83(1):106-16. Epub 2008 Dec 20 (-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 *Baseline 8.74% Country
36. Sitagliptin Reduces Hyperglycemia Sitagliptin helps to improve beta-cell function and increases insulin synthesis and release. Sitagliptin helps to reduce HGO through suppression of glucagon from alpha cells. Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis. Metformin has insulin- sensitizing properties. Beta-Cell Dysfunction Hepatic Glucose Overproduction (HGO) Metformin Reduces Hyperglycemia The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of T2DM in a Complementary Manner Insulin Resistance *Please see corresponding speaker note for references.
37. 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
38. 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 >77% of patients achieved target A1c in Sita Met1000 arm
48. 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
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50. Clinically Insignificant Differences in Incidence of AEs: Pooled Phase III Population AEs with at least 3% incidence and Numerically Higher in Sitagliptin than Placebo Group Difference vs Placebo (95% CI) 0.1 0 1.2 0.7 0.3 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)
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, Unger RH. 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 hyperglycaemia. Diabetologia . 2003;46(suppl 1):M2–M8. Purpose : To show the abnormalities in insulin and glucagon secretory patterns in patients with type 2 diabetes. Take-away: In type 2 diabetes, both relative insulin deficiency and a failure to suppress glucagon contribute to elevated glucose after a meal challenge.