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Incretins: The New Frontier in Diabetes Therapy Augusto D. Litonjua, M.D., FPCP, FPSEM, FACE Professor Emeritus UP College Of Medicine.

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Presentation on theme: "Incretins: The New Frontier in Diabetes Therapy Augusto D. Litonjua, M.D., FPCP, FPSEM, FACE Professor Emeritus UP College Of Medicine."— Presentation transcript:

1 Incretins: The New Frontier in Diabetes Therapy Augusto D. Litonjua, M.D., FPCP, FPSEM, FACE Professor Emeritus UP College Of Medicine

2 Present Anti-Diabetic Medications 1.Insulin Secretagogues a.Sulfonylureas b.Glinides 2.Insulin Sensitizers a.Glitazones b.(?) Metformin 3.Insulin

3 But, is insulin the only hormone involved in Diabetes Mellitus?

4 Islet  -Cell and  -Cell Hormones Regulate Glucose Homeostasis Islet of Langerhans Healthy Subjects   cells secrete glucagon   cells secrete insulin Type 2 Diabetic Subjects   cells dysfunction secrete inappropriately high levels of glucagon  Fewer  cells: secrete insufficient levels of insulin  Cells (orange)  Cells (yellow) Amyloid Plaques Rhodes CJ Science: 2005: 307:380-381

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6 GLUCAGON, the forgotten islet hormone Does it have a place in Diabetes Mellitus? Is Type 2 DM a state of insulin deficiency and glucagon over-secretion?

7 Incretins IN testinal Se ion of sulin cret In cretin

8 Mean ± SE; *P  0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498 Plasma Glucose (mg/dL) Time (min) The Incretin Effect in Healthy Subjects C-Peptide (nmol/L) 060120 180 Oral Glucose Intravenous (IV) Glucose Incretin Effect 200 100 0 0.0 0.5 1.0 1.5 2.0 Crossover of Healthy Subjects (n = 6) * * * * * * * 060120 180

9 Incretins The major incretins are: GLP-1 (glucagonlike peptide 1) GIP (glucose-dependent insulinotropic polypeptide)

10 Comparison of the Incretins Site of Production GLP-1 L-Cells (Ileum and Colon) GIP K-Cells (Duodenum and Jejunum) Decreases secretion in T2DMYesNo Inhibits glucagon secretion postprandiallyYesNo Reduces food intakeYesNo Slows gastric emptyingYesNo Stimulates  -cell mass/growth Yes Promotes insulin biosynthesisYes Knockout mice (result in IGT)Yes Adapted from Mayo KE, et al Pharmacol Rev 2003; 55:167-194 Adapted from Drucker DJ Diabetes Care 2003; 26:2929-2940 Adapted from Nauck M. et al. Diabetologia 1986:29:46-52

11 GLP-1 Is Derived From Proglucagon GRPPGlucagonIP-1GLP-1IP-2GLP-2 130646978107/8126158 336172111123158 Amino acid residue: GlicentinMPGF Oxyntomodulin Glucagon MPGF Glucagon Osyntomodulin GLP-1 GLP-2 IP-2 Intestin Brain Pancreas Adapted from Drucker DJ Mol Endocrinol. 2003:17:161-171.

12 Glucagonlike Peptide 1 (GLP-1) 30 amino acid peptide Secreted by L cells, primarily in the ileum and colon Stimulated by oral ingestion of nutrients Receptors in the islet cells, CNS, elsewhere Metabolized by DPP-4 Secretion impaired in type 2 diabetes

13 Glucagonlike Peptide 1 (GLP-1) Actions Slows gastric emptying Suppresses glucagon secretion Enhances glucose-dependent insulin secretion Enhances b-cell proliferation Possible improves insulin sensitivity

14 Release and Action of GLP-1 Mixed Meal GLP-1 (7- 36) Active Intestinal GLP-1 Release DPP-4 Rapid inactivation (>80% of pool) GLP-1 (9- 36) Inactive GLP-1 actions that combine to control glycemia: Inhibits glucagon secretion and hepatic glucose production Augments glucose- induced insulin secretion Slows gastric emptying Promotes satiety Additional characteristics of GLP-1 – based therapies: Restores  -cell function Increases insulin biosynthesis Promotes  -cell differentiation

15 Insulin and GLP-1 Responses to Meals 400 200 40 20 0 0 Meal 9 AM1 PM7 PM10 PM9 AM Hours Insulin (pmol/L) GLP-1 (pmol/L) Orskov C. et al. Scand J Gastroenterol: 1996:31; 665-670

16 Incretin Effect in Subjects Without and With Type 2 Diabetes Intravenous Glucose Oral Glucose *P ≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52.

17 GLP-1 Release Is Reduced in Type 2 Diabetes Mean ± SE; N = 102; *P <.05 between T2DM and NGT groups. Toft-Nielsen M, et al. J Clin Endocrinol Metab. 2001;86:3717-3723. 20 15 10 5 0 060120180240 Time (min) Meal GLP-1 (pmol/L) Normal Glucose Tolerance Impaired Glucose Tolerance Type 2 Diabetes * * * * * * *

18 Liver: ↓ Glucagon reduces hepatic glucose output GLP-1 Modulates Numerous Functions in Humans Promotes satiety and reduces appetite Beta-cells: Enhance glucose- dependent insulin secretion Alpha cells: ↓ Postprandial glucagon secretion Stomach: Helps regulate gastric emptying Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.

19 Can GLP-1 be used in the therapy of Type 2 DM?

20 6-Week Continuous GLP-1 Infusion Improved Glycaemic Control Mean (SE) Glucose Concentration in Plasma (mg/dL) Time (hour) 450 360 270 180 90 0 012345678 8-hour Plasma Glucose Profile Mean ± SE; N = 20; Only data of patients treated with GLP-1 shown; *P =.003. Zander M, et al. Lancet. 2002;359:824-830. HbA 1c Mean (SE) HbA 1c (%) 0 2 4 6 8 10 12 9.2% 7.9% * Week 0Week 6 Week 0 Week 6

21 GLP-1 Enhanced First Phase Insulin Response in Patients With Type 2 Diabetes Mean ± SE; N = 18; P <.05 prolonged infusion; P =.33 acute infusion; *Note the different scale for insulin data used. Quddusi S, et al. Diabetes Care. 2003;26:791-798.

22 6-Week Continuous GLP-1 Infusion Improved β-Cell Function GLP-1 GroupSaline Group C-peptide (pmol/L) 0 100 200 300 400 500 600 700 Mean ± SE; N = 19; difference in change values between groups P =.02. Zander M, et al. Lancet. 2002;359:824-830. In the GLP-1 group, insulin sensitivity increased by 77% (P =.002) P =.006 Patients With Type 2 Diabetes Week 0 Week 6

23 GLP-1 Subcutaneous Injection Slowed Gastric Emptying in Type 2 Diabetes Mean ± SEM; N = 7; *P <.0001. Nauck MA, et al. Diabetologia. 1996;39:1546-1553.

24 6-Week Continuous GLP-1 Infusion Increases Satiety and Reduces Food Intake Mean ± SE; N = 10; Only data of patients treated with GLP-1 shown. *P <.05 for Week 0 vs Week 6; † P <.05 for Week 0 vs Week 1. Adapted from Zander M, et al. Lancet. 2002;359:824-830.

25 6-Week Continuous GLP-1 Infusion Reduced Mean Body Weight Mean ± SE; N = 20; Change between GLP-1 and saline groups not significant (P =.13). Zander M, et al. Lancet. 2002;359:824-830.

26 GLP-1 Exerts Multiple Actions in Patients With Type 2 Diabetes Administration of GLP-1 to patients with type 2 diabetes has been associated with: –Reduced fasting hyperglycaemia –Normalised postprandial glucose excursions –Suppression of inappropriately high glucagon secretion –Improved β-cell responsiveness and maximal insulin secretory capacity –Reduced food intake and weight loss –Significant reductions in HbA 1c (6-week continuous infusion) Drucker DJ. Diabetes Care. 2003;26:2929-2940.; Zander M, et al. Lancet. 2002;359:824-830.

27 Rapid Degradation of GLP-1 by DPP-IV Limits its Duration of Action Mean ± SEM;N = 4-7 (rats); P <.05. Adapted from Parkes D, et al. Drug Dev Res. 2001;53:260-267.; Eng J, et al. J Biol Chem. 1992;267:7402-7405.

28 Rapid inactivation (DPP-IV), Short elimination half-life (~1-2 min) GLP-1 must be administered continuously (infusion) Inconvenient for treating a chronic disease like type 2 diabetes Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940. The Therapeutic Potential of GLP-1 Is Limited by Its Rapid Inactivation

29 So, what is the next step?

30 Exenatide (Exendin-4) –Synthetic version of salivary protein found in the Gila monster –Approximately 50% identity with human GLP-1 Binds to known human GLP-1 receptors on  cells in vitro Resistant to DPP-IV inactivation Development of Exenatide: An Incretin Mimetic Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117:77-88.; Fineman MS, et al. Diabetes Care. 2003;26:2370-2377. Reprinted from Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes, 77-88, Copyright 2004, with permission from Elsevier. Site of DPP-IV Inactivation H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S – NH 2 H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R – NH 2 Exenatide GLP-1 Human

31 Current GLP-1-based Approaches for Improving Glycaemic Control Agents that mimic the actions of GLP-1 (incretin mimetics) –DPP-IV–resistant GLP-1 derivatives GLP-1 analogues, albumin-bound GLP-1 –Novel peptides that mimic the glucoregulatory actions of GLP-1 Exenatide Agents that prolong the activity of endogenous GLP-1 –DPP-IV inhibitors Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940; Baggio LL, et al. Diabetes. 2004;53:2492-2500.

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33 Does Exenatide work?

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35 BYETTA Restored First-Phase Insulin Response

36 BYETTA Sustained A1C Reductions at 2 Years Open-Label Extension 0102030405060708090100 110 6.5 7.0 7.5 8.0 8.5 Time (wk) Mean Baseline A1C 8.3% 10 mcg BYETTA BID -1.1 ± 0.1% Mean  A1C (%) Mean  A1C at 2 y N = 283; Mean (± SE); P<0.05. Buse JB, et. al, Clin Ther. 2007;29:139-153

37 0102030405060708090100110 -12 -10 -8 -6 -4 -2 0 Baseline Weight 220 lbs 10 mcg BYETTA BID -10.4 ± 0.8 lbs Mean  Weight (lbs) Mean  Weight at 2 y Time (wk) BYETTA Continued to Reduce Weight at Two Years No diet and exercise regimen was provided; N = 283; Mean (± SE); P<0.05. Henry R, et al. Diabetes 2006; 55:A116.

38 BYETTA Reduced A1c SFU Mean ± SE; *P<0.005 Data from DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100 Data from Buse JB, et al. Diabetes Care. 2004;27:2628-2635 Data from Kendall DM, et al. Diabetes Care. 2005;28:1083-1091 Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg BID MET + SFU 0.2 -0.6 * * -0.8 247 245 241 8.5 8.5 8.5 0.1 -0.5 * * -0.9 123 125 129 8.7 8.5 8.6 MET -0.4 * - 0.8 * -0.5 0 0.5 Baseline n 113 110 113 8.2 8.3 8.2  A1C (%) 0.1

39 MET (N = 240) 0 20 40 60 * * % 30-wk data; Mean; *P<0.01 Data from DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100 Data from Buse JB, et al. Diabetes Care. 2004;27:2628-2635 Data from Kendall DM, et al. Diabetes Care. 2005;28:1083-1091 % Achieving A1C ≤7% 13 32 46 MET + SFU (N = 550) SFU (N = 234) 9 33 * 41 * * 27 * 34 9 Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg BID BYETTA: Proportion of Patients Achieving A1C < 7%

40 Exenatide Reduced Weight: Phase 3 Clinical Studies Placebo 5  g Exenatide BID10  g Exenatide BID METSFUMET + SFU ITT 30-wk data; N=1446; Mean (SE); *P <.05; Weight was a secondary endpoint DeFronzo R.A. et al. Diabetes Care. 2005:28:1092-1100. Buse JB, et al. Diabetes Care 2004:27;2628-2635. Kendall DM, et al. Diabetes Care. 2005; 28:1083-1091

41 Nausea: Phase 3 Clinical Studies - Combined Most episodes mild to moderate in intensity Episodes were generally Intermittent More frequent at initiation of treatment Decreased over time Low incidence of severe nausea (placebo 1%, exenatide 4% Low dropout rate due to nausea (placebo < 1%, exenatide 3%) ITT 30-wk data; N = 1446 Exenatide Prescribing Information, 2005

42 Inadequate Glycemic Control Weight Gain Loss of  cells function

43 Current GLP-1-based Approaches for Improving Glycaemic Control Agents that mimic the actions of GLP-1 (incretin mimetics) –DPP-IV–resistant GLP-1 derivatives GLP-1 analogues, albumin-bound GLP-1 –Novel peptides that mimic the glucoregulatory actions of GLP-1 Exenatide Agents that prolong the activity of endogenous GLP-1 –DPP-IV inhibitors Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940; Baggio LL, et al. Diabetes. 2004;53:2492-2500.

44 Thank you


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