incretin mimetics and dpp4 inhibitors

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DETAILS OF NEW MODALITIES OF ORAL HYPOGLYCEMICS.

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Pathophysiology of Type 2 Diabetes Mellitus :Incretins and role of DPP IV Inhibitors : 

Pathophysiology of Type 2 Diabetes Mellitus :Incretins and role of DPP IV Inhibitors MD(Physician and Cardiologist)

Introduction : 

Introduction The pathophysiology of T2DM includes islet cell dysfunction and insulin resistance. Abnormal islet cell function Early and progressive islet cell dysfunction is integral to the development of type 2 diabetes and to the deterioration of glucose control over time. b cells Abnormal insulin secretion Increased post-prandial glucose Increased hepatic glucose output a cells Increased glucagon secretion Increased fasting glucose Increased post-prandial glucose Increased hepatic glucose output

Slide 3: 

TYPE 2 DM : BASICS Insulin Deficiency Insulin Resistance

Insulin and Glucagon RegulateNormal Glucose Homeostasis : 

Blood glucose  Insulin and Glucagon RegulateNormal Glucose Homeostasis Glucose output Glucose uptake Glucagon (α cell) Insulin (β cell) Pancreas Fasting state Fed state   Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

Major Defects in T2DM : 

Major Defects in T2DM Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168; Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Hepatic glucose output Insulin resistance Glucose uptake Glucagon (α cell) Insulin (β cell) Hyperglycemia Islet-cell Dysfunction Pancreas

Defects in T2DM : 

Defects in T2DM Adapted with permission in 2006 from Müller WA et al. N Engl J Med. 1970;283:109–115. Copyright © 1970 Massachusetts Medical Society. All rights reserved. Glucose, mg % Insulin, μ/mL Glucagon, μ/mL Minutes

Hepatic Glucose Output in T2DM : 

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.

The Incretin Effect in Subjects Without and With Type 2 Diabetes : 

The Incretin Effect in Subjects Without and With Type 2 Diabetes IR=Immune Reactive.Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag. Time, min IR Insulin, mU/L nmol/L 180 60 120 0 Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) Time, min IR Insulin, mU/L nmol/L 180 60 120 0 Oral glucose load Intravenous (IV) glucose infusion Incretin Effect The incretin effect is diminished in type 2 diabetes.

Role of Incretins in Glucose Homeostasis : 

Role of Incretins in Glucose Homeostasis Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. Ingestion of food β cells α cells Release of gut hormones — incretins* Pancreas Glucose-dependent  Insulin from β cells (GLP-1 and GIP) Glucose uptake by muscles Glucose dependent  Glucagon fromα cells (GLP-1) GI tract Active GLP-1 & GIP DPP-4 enzyme InactiveGIP InactiveGLP-1 *Incretins are also released throughout the day at basal levels.

Glucose-Dependent Effects of GLP-1 : 

Glucose-Dependent Effects of GLP-1 Glucose Glucagon When glucose levels approach normal values, glucagon levels rebound. When glucose levels approach normal values, insulin levels decrease. *P<0.05 Patients with type 2 diabetes (N=10) mmol/L 15.0 12.5 10.0 7.5 5.0 250 200 150 100 50 mg/dL pmol/L 250 200 150 100 50 40 30 20 10 0 mU/L Infusion Minutes pmol/L 20 15 10 5 0 60 120 180 240 pmol/L 20 15 10 5 Insulin 2.5 0 0 0 0 0 Adapted from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag. –30

Summary of Trials: GLP-1 and GIP Levels and Actions in Type 2 Diabetes : 

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.

GLP-1 Levels Are Decreased in Type 2 Diabetes : 

* 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

Effect of Des-F-Sitagliptin onBeta-Cell Mass : 

1.1% Effect of Des-F-Sitagliptin onBeta-Cell Mass 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).

Slide 16: 

Effect of GLP-1 on Differentiation of Human Pancreatic Islet-Derived Progenitor cells into insulin-Producing cells. Abraham. et al. Endocrinology, 2002; 143:3152

Slide 17: 

Old Concept – Newer Insights Incretin Defect Insulin Resistance Insulin Deficiency

Old Concept – Newer Insights : 

Old Concept – Newer Insights Incretin Defect Insulin Resistance Insulin Deficiency (Beta Cell Dysfunction) Increased HGO Non-suppressed Glucagon (Alpha Cell Dysfunction)

Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on HbA1c Quintiles : 

Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on HbA1c Quintiles Adapted from Monnier L et al. Diabetes Care. 2003;26:881–885. n=58 n=58 n=58 n=58 n=58 HbA1c Contribution, %

Incretin mimetics : 

Incretin mimetics Incretin: Gut hormone released in circulation following ingestion of meals & stimulates insulin secretion postpandrially. Imp increatins are: GLP1,GLP2, IP2, Glicentin,. GLP 1 accounts for 70– 80% of endogenous incretin effects (1) GLP 1 is 30 amino acid polypeptide secreted mainly from distal small intestin & colon subsequent studies demonstrated that intravenous administration of GLP-1 has effects on glucagon secretion, gastric function, hepatic glucose metabolism, and satiety (2) 1. Kreymann, B., Ghatei, M.A., Williams, G., and Bloom, S.R. 1987. Glucagon-like peptide-1 7-36: aphysiological incretin in man. Lancet. 2:1300–1303. Nauck, M.A., et al. 1993. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 36:741–744.

Incretin mimetics : 

Incretin mimetics GLP1 & others are encoded from proglucagon gene(2q)expressed in – Alpha cell of pancreas L cell of intestine Hypothalamus & brain stem (1) Proglucagon gene expression is controlled in tissue specific manner Forms in circulation Inactive: GLP 1(1-37),GLP (1-36) NH2 Active: GLP 1(7-37), GLP 1(7-36) NH2 Knauf, C., et al. 2005. Brain glucagon-like peptide–1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J. Clin. Invest. 115:3554–3563. doi:10.1172/ JCI25764.

Effects Incretin GLP-1 and GIP : 

Effects Incretin GLP-1 and GIP Is released from L cells in ileum and colon Stimulates insulin response from β cells in a glucose-dependent manner Inhibits gastric emptying Reduces food intake and body weight Inhibits glucagon secretion from α cells in a glucose-dependent manner Effect on β-cell turnover in preclinical models Is released from K cells in duodenum Stimulates insulin response from β cells in a glucose-dependent manner Has minimal effects on gastric emptying Has no significant effects on satiety or body weight Does not appear to inhibit glucagon secretion from α cells Effect on β-cell turnover in preclinical models GLP-1 GIP Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606; Drucker DJ. Diabetes Care. 2003;26:2929–2940. Farilla L et al. Endocrinology. 2003;144:5149–5158.

Regulation of secretion : 

Regulation of secretion Stimulants: mixed meals, glucose, AA, fatty acids, fibers. Biphasic increase – Early phase: neuroendocrine mediator – GIP, Ach (10 – 15 min) Late: direct nutrient contact

Metabolism : 

Metabolism T1/2: ≤ 2 min in circulation Degraded by Dipeptidyl peptidase 4. ( either in cell surface or in plasma) Specifically clears dipeptide from NH2 terminal GLP (7-37) to (9-37) Only GLP – 1R has been identified (in lung, stomach, intestine, ∞,beta, ∂ cell of pancreas, kidney & CNS

Biological action of GLP 1 : 

Biological action of GLP 1 Pancreas: Stimulates insulin secretion Inhibition of ATP sensitive K channel ↑intracellular Ca by voltage dependent Ca channel Direct effect on B cell exocytosis Stimulates insulin gene transcription & mRNA stability & synthesis Regulates B cell KATP channel expression & activity – up regulates the glucose sensing ( GLUT) Increases B cell neogenesis & proliferation (animal model)

Other actions … : 

Other actions … Inhibits the glucagon secretion & stimulates somatostatin secretion. – decrease the possibility of hypoglycemia GI system: Inhibits gastric empting Inhibits gastric acid secretion – both dependent on vagus nerve ↑ insulin stimulated glucose metabolism in adipocyte Stimulates glucose incorporation in glycogen in skeletal muscle & hepatocyte

Slide 27: 

doi:10.1016/j.bcp.2008.07.029 Lambeir, Scharpe, Meester 10.1002/ddr.20138, von Geldern, Trevillyan

As therapy in Diabetes : 

As therapy in Diabetes GLP 1 is required in normal glucose homeostasis Incretin effect is lost significantly in T2 DM Insulinotropic, glucagonostatic & gastric inhibitory effect is preserved when given supraphysiologically Also effective in T1 Dm insulin deprived state Peak GLP conc. after s/c inj 30 min Major side effect: nausea, vomiting No incidence of tachyphylaxis Drawback: requires continuous infusion Two most advanced products are – Exendin -4 & Liraglutide

Exendin 4 : 

Exendin 4 Purified from the lizard – Gila monstar (helsderma suspectum) Shares 53% aa sequence Function as GLP 1R agonist Has more potency & more protracted physiological action Given as 5 – 10 μg/ twice daily Most common side effect – nausea (22%) reduce to 1% at the end of 24 wks. Others – vomiting diarrhea, URTI, hypoglycemia(5%).

Exendin 4…. : 

Exendin 4…. Effect on control – HbA1c reduction – 1.3% FPG reduction – 28 mg% Wt loss – 3.4 kg Effective as – Ad on to metformin, sulfonylurea As a combination from beginning Dose dependent ↓ PPBG > FBG Dose dependent decrease in body Wt

Prospects : 

Prospects Exenatide completed fairly large trial & received FDA approval Extended release formulation are under development Oral delivery system is being investigated

Drawbacks … : 

Drawbacks … Dose titration remained problematic Subcutaneous injection remained a major problem Effect on B cell neogenesis require more trials

DPP 4 antagonist : 

DPP 4 antagonist Duration of action of GLP 1 is limited by enzymatic breakdown by DPP 4 DPP 4 knockout mice – resistant to diet induced obesity Greatest advantage : can be given orally

Sitagliptin - Overview : 

Sitagliptin - Overview 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 Provides potent and highly selective inhibition of the DPP-4 enzyme Fully reversible and competitive inhibitor

Pharmacokinetics Supports Once-Daily Dosing : 

Pharmacokinetics Supports Once-Daily Dosing With once-daily administration, trough (at 24 hrs) DPP-4 inhibition is ~ 80% > 80% inhibition provides full enhancement of active incretin l No effect of food on pharmacokinetics Well absorbed following oral dosing Tmax app 2 hours, t1/2 app 12.4 hours at 100 mg dose Low protein binding, app 38% Primarily renal excretion as parent drug 80% of a dose recovered as intact drug in urine No clinically important drug-drug interactions No meaningful P450 system inhibition or activation

Mechanism of Action of Sitagliptin : 

Mechanism of Action of Sitagliptin Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the actions of these hormones. Release of active incretins GLP-1 and GIP  Blood glucose in fasting and postprandial states Ingestion of food  Glucagon (GLP-1)  Hepatic glucose production GI tract DPP-4 enzyme Inactive GLP-1 X Sitagliptin (DPP-4 inhibitor)  Insulin (GLP-1 andGIP) Glucose- dependent Glucose dependent Pancreas Inactive GIP β cells α cells  Glucose uptake by peripheral tissues

One Dose of Sitagliptin Inhibited Plasma DPP-4 Activity : 

One Dose of Sitagliptin Inhibited Plasma DPP-4 Activity Hours post-dose ~80% ~50% Trough DPP-4inhibition 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)

Sitagliptin Improves the b-Cell Response to Glucose : 

Sitagliptin Improves the b-Cell Response to Glucose 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 Φs = static component, describes relationship between glucose concentration and insulin secretion Baseline End-Treatment Baseline End-Treatment Sitagliptin 100 mg q.d Placebo

Slide 40: 

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 NH2-Xaa~Pro-COOH --Xaa-Pro~Yaa-- NH2-Xaa-Pro~Yaa-- NH2-Xaa~Pro-Yaa---- catalytically inactive NH2-Xaa-Pro~Yaa-- Specificity DPP-4 Is a Member of a Family of Proline Specific Peptidases

Sitagliptin Is Potent & Highly Selective (>2500x) for DPP-4 : 

Sitagliptin Is Potent & Highly Selective (>2500x) for DPP-4 Herman et al. ADA. 2004.

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 A Single Dose of Sitagliptin Increased Active GLP-1 and GIP Over 24 Hours 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

Selective vs Nonselective DPP-4 - I : 

Selective vs Nonselective DPP-4 - I

Sitagliptin  Insulin,  Glucagon &  Glycemic Excursion : 

Sitagliptin  Insulin,  Glucagon &  Glycemic Excursion 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

Sitagliptin + Metformin Factorial Study Design : 

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

Initial Combination of Sitagliptin and Metformin Produced a Marked Improvement in A1C : 

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

Rapid Improvement in FPG in High Baseline PatientsTreated with Initial Combination Therapy : 

Rapid Improvement in FPG in High Baseline PatientsTreated 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

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 Mean A1C Levels Through 54 Weeks(Completers) A1C, % APT = all patients treated; sit = sitagliptin; met = metformin; Values represent mean ± SE.

Summary of Clinical Adverse Experiences (AEs) Through 54 Weeks (Phase A and B Combined, cont.) : 

Summary of Clinical Adverse Experiences (AEs) Through 54 Weeks (Phase A and B Combined, cont.)

Gastrointestinal AEs Through 54 Weeks : 

Gastrointestinal AEs Through 54 Weeks % 27.7

Change in Body Weight From Baseline at Week 54 (LS mean change ± SE) : 

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. * * * *

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 = Proportion of Patients with A1C Goal <7% at Endpoint (Week 54 Analysis) Percent of patients

Sitagliptin Added to Patients Uncontrolled on Metformin (24-Week )a : 

aIn patients inadequately controlled on metformin monotherapy. bCompared with placebo plus metformin. cLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value. dDifference from placebo. Sitagliptin Added to Patients Uncontrolled on Metformin (24-Week )a Adapted from Charbonnel B et al. Diabetes Care. 2006;29:2632–2637. Sitagliptin provided significant improvements in HbA1c, FPG, and 2-hr PPG vs placebo when added to patients inadequately controlled on metformin monotherapy.

Greater Reductions in HbA1c With Higher Baseline HbA1c : 

Greater Reductions in HbA1c With Higher Baseline HbA1c a Specifically glipizide; bSitagliptin 100 mg/day with metformin (≥1500 mg/day); Per-protocol population; post hoc analysis. Add-on sitagliptin with metformin vs sulfonylurea with metformin study. Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205. Baseline HbA1c Category Change From Baseline in HbA1c (%) n=117 <7% ≥7 to <8% ≥8 to <9% ³9% -0.14 -0.59 -1.11 -1.76 -0.26 -0.53 -1.13 -1.68 -2.0 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 Sulfonylureaa + metformin n=33 n=21 n=82 n=82 n=179 n=167 n=112 n=117 Mean Baseline HbA1c = 6.6% 6.7% 7.4% 7.4% 8.3% 8.3% 9.4% 9.2%

Change in Body Weight From Baseline at Week 54 : 

Change in Body Weight From Baseline at Week 54 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. * * * *

Gastrointestinal AEs Through 54 Weeks : 

Gastrointestinal AEs Through 54 Weeks % 27.7

HbA1c With Sitagliptin or Glipizide as Add-on With Metformin: : 

aSpecifically glipizide; bSitagliptin 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. HbA1c With Sitagliptin or Glipizide as Add-on With Metformin:

Sitagliptin & Metformin  Weight (vs Weight) &  Hypoglycemia : 

Sitagliptin & Metformin  Weight (vs Weight) &  Hypoglycemia aSpecifically glipizide; bSitagliptin (100 mg/day) with metformin (≥1500 mg/day); cAll-patients-as-treated population Least squares mean between-group difference at week 52 (95% CI): change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001);Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001) Add-on sitagliptin with metformin vs sulfonylurea with metformin study. Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.  between groups = –2.5 kg P<0.001

Add-on Study of Sitagliptin With Pioglitazone: Study Design : 

Add-on Study of Sitagliptin With Pioglitazone: Study Design Sitagliptin added to pioglitazone (30 or 45 mg/day) Rescue medication—pioglitazone given in the pioglitazone add-on study to patients who did not meet specific glycemic goals. Rosenstock JB et al. Clin Ther. 2006;28:1556–1568.

Sitagliptin Added to Patients Uncontrolled on Pioglitazone (24-Wk)a : 

Sitagliptin Added to Patients Uncontrolled on Pioglitazone (24-Wk)a 2-hr PPG was not measured in this study. aIn patients who had inadequate glycemic control while receiving pioglitazone. bCompared with placebo plus pioglitazone. cLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value. dDifference from placebo. Sitagliptin provided significant improvements in HbA1c and FPGwhen added to patients inadequately controlled on pioglitazone. Adapted from Rosenstock JB et al. Clin Ther. 2006;28:1556–1568.

Sitagliptin Improved A1C When Added to Glim : 

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* Weeks 0 6 12 18 24 A1C (%) 7.2 7.6 8.0 8.4 8.8 Sitagliptin + Glim (n=106) Placebo + Glim (n=106)

Sitagliptin Improved A1C When Added to Glimiperide + Metformin : 

Sitagliptin Improved A1C When Added to Glimiperide + Metformin 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)

Sitagliptin Increased Hypoglycemia in Combination with Glimepiride ± Metformin over 24 weeks : 

Sitagliptin Increased Hypoglycemia in Combination with Glimepiride ± Metformin over 24 weeks Hermansen et al, Diabetes Obesity Metabolism 2007 Patients With at Least One Episode of Hypoglycemia n (%)

Slide 64: 

DPP-4 InhibitorsIn Class Competition

Safety + Tolerability : 

Overall incidence of AEs, serious AEs, and discontinuation due to AEs was similar in the Sitagliptin and non-exposed groups Drug-related AEs & discontinuations due to AEs were higher in non-exposed (due to hypoglycemia in sulfonylurea-treated). 7 specific AEs (chills, Naso-pharyngitis, Meniscus lesions, nasal congestion, dermatitis contact, osteoarthritis & tremor) occurred more frequently with Sitagliptin group. Hypoglycemia was substantially less in the Sitagliptin group,but when used with a sulfonylurea  hypoglycemia Adverse reactions of Sitagliptin include hypersensitivity reactions (anaphylaxis, angioedema, rash, urticaria, Stevens-Johnson syndrome). But causal relationship not established. Safety + Tolerability Pooled safety. Stein et al. ADA 2007

How Safe? : 

How Safe? Nasopharyngitis (5.2% in sitagliptin vs. 3.3% placebo) Upper respiratory tract infection (6.3% in sitagliptin-pioglitazone vs. 3.4% in the pioglitazone-only) Headache (5.1% in the sitagliptin-pioglitazone group vs. 3.9% in the pioglitazone-only group). A slight increase in white blood cell count (200 cells/µl) primarily from an increase in neutrophils. Hypoglycemia is similar to control (1.2 vs. 0.9%). Sitagliptin is a pregnancy risk Category B agent effects on nursing babies are also unknown. Safety in < 18 years of age not been studied Sitagliptin is contraindicated in patients with T1DM Not to be used in diabetic ketoacidosis.5 In moderate renal insufficiency 50 mg/day sitagliptinslight  creatinine (0.05 mg/dl)

Minimal AEs: Pooled Phase III : 

Minimal AEs: Pooled Phase III AEs with at least 3% incidence and Numerically Higher in Sitagliptin than Placebo Group

Lowers A1C Without Hypoglycemia  Weight : 

Lowers A1C Without Hypoglycemia  Weight Neutral effect on body weight 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) In combination studies, weight changes with sitagliptin similar to placebo-treated patients Pooled Phase III Population Analysis: no statistically significant difference in incidence for either dose vs placebo Hypoglycemia Weight Changes

Placebo Subtracted Change from Baseline in HbA1c Per Country : 

Placebo Subtracted Change from Baseline in HbA1c Per Country DRCP Mohan Yang Son, 2009 Jan;83(1):106-16. Epub 2008 Dec 20

Personal Experience with Sitagliptin : 

Personal Experience with Sitagliptin 17 patients Mean duration of Diabetes :3-10 years Other Drugs : Sulfonylurea-8 Metformin -16 Insulin-4 Thiozolinediones-5 Duration of use: 1-3 months Mean reduction of FPG: 15mg/dl Mean reduction of PPG : 20 mg/dl Mean reduction of Hba1c :0.75%(in 5patients)

Is DPP-4 the Missing Link in ACEI Associated Angioedema : 

Is DPP-4 the Missing Link in ACEI Associated Angioedema Bradykinin & substance P, substrates of ACE increase vascular permeability and cause tissue edema Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P & DPP IV, may be impaired in ACEI–associated angioedema. DPP IV activity and antigen are decreased in sera of patients with ACEI– angioedema Degradation half-life of substance P correlated inversely with DPP IV antigen during angiotensin-converting enzyme inhibition. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema.

Indications and Usage : 

Indications Indicated as an adjunct to diet and exercise, to improve glycemic control in T2DM as: Monotherapy Initial combination therapy with metformin Combination therapy with metformin, sulfonylurea*, or PPARɣ, when the single agent INADEQUATE Combination therapy with metformin and a sulfonylurea*, * In combination with a sulfonylurea, REDUCE dose of sulfonylurea to reduce the risk of hypoglycemia. Dosage Recommended dose is 100 mg once daily taken with or without food For patients with renal insufficiency Milda - no dosage adjustment is required aMild = CrCl ≥50 mL/min; Moderateb - 50 mg once dailybmoderate = CrCl ≥30 to <50mL/min; Severec or end-stage renal diseased - 25 mg once daily csevere = CrCl <30 mL/min. Because there is a dose adjustment based upon renal function, assessment of renal function is recommended prior to initiation and periodically thereafter. Indications and Usage

Conclusion : 

Conclusion Sitagliptin is the first agent in DPP4 pathway Exenatide an incretin mimetic but must be given sc Sitagliptin is effective as a once daily oral dose Sitagliptin has demonstrated efficacy in reducing pre and post meal glucose and HbA1c levels Its unique ability to improve beta cell function may offer it an advantage over other oral agents along with its lack of weight gain and hypoglycemic adverse effects, which are common among many glycemic control modalities Since sitagliptin is primarily renally eliminated, dose reductions in patients with renal dysfunction BUT LONG TERM CVD SAFETY & RISK BENEFIT & TOXICITY (IMMUNE) PROFILE STUDY IS NEEDED

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