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1 GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics Shannon I. Brow, RN, CDE, FNP-C Medical Science Liaison Amylin Pharmaceuticals,

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Presentation on theme: "1 GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics Shannon I. Brow, RN, CDE, FNP-C Medical Science Liaison Amylin Pharmaceuticals,"— Presentation transcript:

1 1 GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics Shannon I. Brow, RN, CDE, FNP-C Medical Science Liaison Amylin Pharmaceuticals, Inc

2 2 Faculty Disclosures: Shannon I. Brow, RN, CDE, FNP-C –Employee of Amylin Pharmaceuticals, Inc –Stockholder: Amylin Pharmaceuticals, Inc

3 3 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010 Review incretin physiology in healthy individuals and in patients with type 2 diabetes Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists Identify where incretin therapies can be used in the treatment of type 2 diabetes

4 4 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010 Review incretin physiology in healthy individuals and in patients with type 2 diabetes Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists Identify where incretin therapies can be used in the treatment of type 2 diabetes

5 5 Microvascular changes Macrovascular changes Clinical features Kendall DM, et al. Am J Med 2009;122:S37-S50. Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343. IFG, impaired fasting glucose; IGT, impaired glucose tolerance. Years Relative Amount Insulin resistance Insulin level Incretin effect  -cell function β-cell failure Onset diabetes Glucose (mg/dL) Diabetes diagnosis Fasting glucose Prediabetes (Obesity, IFG, IGT) Postmeal Glucose Years Progressive Nature of Type 2 Diabetes

6 6 Postprandial Glucose Contribution to A1C % Contribution A1C Range (%) FPG (Fasting Plasma Glucose) PPG (Postprandial Plasma Glucose) > % 30% % 40% % 45% % <7.3 30% 70% Data from Monnier L, et al. Diabetes Care 2003; 26:

7 7 Plasma Glucose (mg/dL) Time of Day (h) Plasma Glucose Is Normally Maintained in a Narrow Range BreakfastLunchDinner N = 30; Mean (SE) Data from Polonsky KS, et al. N Engl J Med. 1988;318: Healthy Subjects Type 2 Diabetes

8 8 A1C Goals Unmet in Majority of Patients With Diabetes Upper limit of normal range (6%) ACE recommended target (<6.5%) 4 ADA recommended target (<7%) 3 1. Data from Saydah SH, et al. JAMA 2004; 291: Calculated from Koro CE, et al. Diabetes Care 2004; 27: Data from ADA. Diabetes Care 2003; 26(suppl 1):S33-S Data from ACE. Endocrine Practice A1C (%) % have A1C >8% 20.2% have A1C >9% 12.4% have A1C >10% % of patients with type 2 diabetes have A1C  7% 2

9 9 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010 Review incretin physiology in healthy individuals and in patients with type 2 diabetes Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists Identify where incretin therapies can be used in the treatment of type 2 diabetes

10 10 Criteria for the Diagnosis of Diabetes 1. A1c ≥ 6.5%. This test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* OR 2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* OR 3. 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. This test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.* OR 4.In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dl (11.1 mmol/l). * In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing American Diabetes Association. Diabetes Care 2010;33(suppl 1):S62-S69.

11 11 Hyperglycemia Insulin Resistance Insulin Resistance Insulin Deficiency Insulin Deficiency Diminished Beta-Cell Response (Insulin Deficiency) Diminished Beta-Cell Response (Insulin Deficiency) Increased Beta-Cell Workload (Insulin Resistance) The Pathogenesis of Type 2 Diabetes A New Perspective of the Core Defects Paradigm Adapted from ©2005 International Diabetes Center, Minneapolis, MN All rights reserved

12 12 Decreased Beta-Cell Response   Insulin resistance  Obesity   Food intake   Gastric Emptying –  Rate of nutrient absorption   Glucagon secretion   Hepatic glucose output   Insulin secretion in response to elevated glucose   First-phase insulin response Increased Beta-Cell Workload Hyperglycemia The Pathogenesis of Type 2 Diabetes An Imbalance of Beta-Cell Workload and Beta-Cell Response

13 13 The Pathophysiology of Type 2 Diabetes Insulin Resistance Incretin “Defect” Relative Insulin Deficiency Hyperglycemia Type 2 Diabetes

14 14 Clinical Challenges With Type 2 Diabetes Weight A1C Diet and Exercise MET SFU Insulin 6.2% A1C Upper limit of normal 0246 Time From Randomization (y) Median A1C (%)  Weight (kg) 0246 Time From Randomization (y) n = 1704; A1C indicates glycosylated hemoglobin A1c; MET, metformin; SFU, sulfonylurea Data from UKPDS Group (34). Lancet 1998;352: Diet and Exercise MET SFU Insulin

15 15 Blood Glucose Concentrations Are Largely Determined by Beta-Cell Function Beta-Cell Function –Insulin synthesis –Insulin secretion Beta-Cell Functional Capacity –Beta-cell mass (cell turnover and neogenesis) –First-phase/second-phase insulin release –Insulin processing (proinsulin to insulin) –Glucose sensitivity Beta-Cell Functional Demand –Glucose absorption (diet, gastric emptying) –Hepatic glucose production (glycolysis, gluconeogenesis) –Peripheral glucose uptake (insulin sensitivity, exercise)

16 16 Multihormonal Regulation of Glucose Appearance and Disappearance Time (min) Mixed Meal (With ~85 g Dextrose) Grams of Glucose (flux/min) -30 Insulin-mediated glucose uptake Balance of insulin suppression and glucagon stimulation Regulated by hormones: GLP-1, amylin, CCK, etc. Meal-Derived Glucose Hepatic Glucose Production Total Glucose Uptake N = 5; Mean (SE) Data from Pehling G, et al. J Clin Invest 1984;74:

17 17 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010 Review incretin physiology in healthy individuals and in patients with type 2 diabetes Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists Identify where incretin therapies can be used in the treatment of type 2 diabetes

18 18 The Incretin Effect in Healthy Subjects C-Peptide (nmol/L) Time (min) Incretin Effect * * * * * * * Oral Glucose Intravenous (IV) Glucose Plasma Glucose (mg/dL) Time (min) N = 6; Mean (SE); *P  0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:

19 19 Incretins Gut-derived factors that potentiate insulin secretion following meal ingestion 2 principal incretins identified to date: GIP 42-amino acid peptide GLP-1 30-amino acid peptide Adapted from Holst JJ, et al. Am J Physiol Endocrinol Metab 2004; 287:E199-E206. Drucker DJ. Diabetes Care 2003; 26:

20 20 Yes Promotes insulin biosynthesis NoYesReduces food intake NoYesDecreases secretion in T2DM Yes Knockout mice (result in IGT) Yes Stimulates beta-cell mass/growth NoYesSlows gastric emptying NoYes Inhibits glucagon secretion postprandially Site of Production Adapted from Mayo KE, et al. Pharmacol Rev 2003;55: Adapted from Drucker DJ. Diabetes Care 2003;26: Adapted from Nauck M, et al. Diabetologia 1986;29: Comparison of the Incretins GIP K-cells (Duodenum and Jejunum) GLP-1 L-cells (Ileum and Colon)

21 21 Insulin (mU/L) The Incretin Effect Is Reduced in Type 2 Diabetes Time (min) Healthy Subjects Insulin (mU/L) Time (min) Type 2 Diabetes N = 22; Mean (SE); *P  0.05 Data from Nauck M, et al. Diabetologia 1986;29: Intravenous (IV) Glucose Oral Glucose Incretin Effect * * * * * * * * * *

22 22 Glucagon-Like Peptide-1 (GLP-1) is an Important Incretin Hormone The “incretin effect” started the search Incretins –Gut hormones that enhance insulin secretion in response to food –Glucose-dependent insulin secretion GLP-1 –Secreted from L cells of the intestines –Most well-characterized incretin –Diminished in type 2 diabetes Glucagon –Secreted from pancreatic alpha cells –Counterregulatory hormone to insulin –Elevated in type 2 diabetes Adapted from Aronoff SL, et al. Diabetes Spectrum 2004;17:

23 Postprandial GLP-1 Concentrations Are Lower in Subjects With IGT and Type 2 Diabetes N = 102; Mean (SE); *P<0.05 between type 2 diabetes and healthy subjects Data from Toft-Nielsen MB, et al. J Clin Endocrinol Metab 2001;86: Time (min) GLP-1 (pmol/L) * * * * * * * * Meal Healthy Subjects Impaired Glucose Tolerance Type 2 Diabetes

24 Time (min) Insulin and Glucagon Responses Are Altered in Type 2 Diabetes Healthy Subjects Type 2 Diabetes 600 N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med 1970;283: Insulin (µU/mL) Glucagon (pg/mL) Glucose (mg/dL) Carbohydrate Meal Meal

25 25 GLP-1 Modulates Numerous Functions in Humans Stomach: Helps regulate gastric emptying Promotes satiety and reduces appetite Liver:  Glucagon reduces hepatic glucose output Beta cells: Enhances glucose-dependent insulin secretion Alpha cells:  Glucose-dependent postprandial glucagon secretion GLP-1: Secreted upon the ingestion of food Data from Flint A, et al. J Clin Invest 1998;101: Data from Larsson H, et al. Acta Physiol Scand 1997;160: Data from Nauck MA, et al. Diabetologia 1996;39: Data from Drucker DJ. Diabetes 1998;47:

26 26 GLP-1 Effects Are Glucose Dependent in Type 2 Diabetes Placebo Glucagon (pmol/L) GLP Insulin (pmol/L) Time (min) PBO GLP-1 * * * * * * * * Glucose (mg/dL) * * * * * * * PBO GLP-1 Time (min) * * * * PBO GLP-1 Time (min) N = 10; Mean (SE); *P<0.05 Data from Nauck MA, et al. Diabetologia 1993;36:

27 27 GLP-1 Has a Short Duration of Effect Due to Degradation by Dipeptidyl Peptidase IV (DPP-IV) HisAlaGluGlyThrPheThrSerAsp LysAla GlnGlyGluLeuTyrSer IleAlaTrpLeuVal Lys GlyArgGly Val Ser Glu Phe Lys DPP-IV Adapted from Mentlein R. Eur. J. Biochem 1993;214:

28 28 Leveraging the Therapeutic Potential of GLP-1 GLP-1 –Short half-life (  2 minutes)  Rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) DPP-IV inhibition –Extends endogenous GLP-1 half-life  Approved in US: –Sitagliptin (Merck) –Saxaglitpin (BMS and AZ)  In development, e.g., –Alogliptin (Takeda) –Denagliptin (Glaxo) –Melogliptin (Glenmark) –Vildagliptin – LAF 237 (Novartis)

29 29 Leveraging the Therapeutic Potential of GLP-1 GLP-1 receptor agonists –Mimic many of the glucoregulatory effects of GLP-1 –Resistant to DPP-IV  Approved in US: –Exenatide (Amylin and Lilly) –Liraglutide (Novo Nordisk)  In development, e.g., –Albiglutide (Glaxo Smith Kline) –CJC (ConjuChem) –Exenatide once weekly (Amylin, Lilly, Alkermes) –Lixisenatide (Sanofi- Aventis) –Taspoglutide (Roche)

30 30 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010 Review incretin physiology in healthy individuals and in patients with type 2 diabetes Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists Identify where incretin therapies can be used in the treatment of type 2 diabetes

31 31 DPP-4 Inhibitor and GLP-1 Receptor Agonist Discussion The slides that follow include data from the first FDA approved agent in each class Concepts are broad, yet representative of drugs that are FDA approved in each class There is no intent to claim superiority of the drug discussed compared to the other same class agent

32 32 Continuously Infused GLP-1 Improved the Defects of T2D T2D Defects 1 Continuously Infused GLP-1 1,2 Insulin production First-phase insulin response Glucagon; glucose output Gastric emptying Food intake 1. Aronoff SL, et al. Diabetes Spectrum 2004;17: Nielsen LL, et al. Regul Pep. 2004;117:77-88.

33 33 Effects of GLP-1 on the  cell in Healthy Subjects

34 34 GLP-1 in T2D

35 35 GLP-1 Is Cleaved and Inactivated by DPP-4

36 36 Mechanism of Action: DPP-4 Inhibitors Sitagliptin example

37 37 Sitagliptin Decreased A1C From Baseline Over 24 wks Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009

38 38 Sitagliptin Decreased A1C Over 52 wks Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009

39 39 DPP-4 Inhibitors Prevent the Inactivation of GLP-1

40 40 The Beginning Exenatide –Synthetic version of salivary protein found in the Gila monster –More than 50% amino acid sequence identity with human GLP-1  Binds to known human GLP-1 receptors on beta cells (in vitro)  Resistant to DPP-IV inactivation Adapted from Nielsen LL, et al. Regul Pept 2004;117: Adapted from Kolterman OG, et al. Am J Health-Syst Pharm 2005;62: Following injection, exenatide is measurable in plasma for up to 10 hours Site of DPP-IV Inactivation

41 41 Exenatide Restored First-Phase Insulin Response Time (min) Evaluable; N = 25; Mean (SE) Fehse F, et al. J Clin Endocrinol Metab 2005;90(11): Healthy Controls IV Glucose Type 2 Diabetes Exenatide Placebo Insulin (pM/kg/min) Time (min)

42 42 Exenatide Suppressed Postprandial Glucose and Glucagon in Type 2 Diabetes N = 20; Mean (SE) Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88: Plasma Glucagon (pg/mL) Plasma Glucose (mg/dL) Exenatide or Placebo Standardized Breakfast Exenatide or Placebo Standardized Breakfast Time (min) Placebo 0.10 µg/kg Exenatide Time (min)

43 43 Exenatide Acutely Reduced Glucose Through Enhanced Glucose-Dependent Insulin Secretion Type 2 Diabetes; N = 34; Mean (SE) Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88: Time (h) Plasma Glucose (mg/dL) SC Injection Placebo 0.05 µg/kg Exenatide 0.10 µg/kg Exenatide Time (h) Serum Insulin (pmol/L)

44 44 Exenatide Is Not Inactivated by DPP-4

45 45 Exenatide vs Sitagliptin MOA Study: Study Design Primary endpoint: comparison of the effects of exenatide and sitagliptin on 2-hour PPG concentrations in patients with T2D MET background; MOA indicates mechanism of action; QAM, once per day in the morning DeFronzo RA, et al. Curr Med Res Opin 2008;24; Study Termination Crossover Treatment Period 1Treatment Period 2 Randomization Placebo Lead-in Exenatide 5 µg BIDExenatide 10 µg BIDExenatide 5 µg BIDExenatide 10 µg BID Standard Meal Test Standard Meal Test Standard Meal Test 1 week2 weeks Sitagliptin 100 mg Q AM Sequence A Sequence B

46 46 Plasma GLP-1 Plasma Exenatide Postprandial Plasma Levels of Exenatide Exceeded Physiologic Levels of GLP-1 Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE 2-wk posttreatment concentration data; DeFronzo RA, et al. Curr Med Res Opin 2008;24: Baseline Exenatide Sitagliptin 2-h Postprandial Plasma GLP-1 (pM) 2-h Plasma Exenatide (pM)

47 47 PPG (mg/dL) Time (min) Standard Meal Exenatide Reduced PPG Concentrations To a Greater Extent Than Sitagliptin Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE; * LS mean ± SE, P< DeFronzo RA, et al. Curr Med Res Opin 2008;24: Baseline Exenatide Sitagliptin Primary Endpoint

48 48 2-hr PPG (mg/dL) BaselineEnd of Period 1 End of Period 2 Patients with T2D; Evaluable population: exenatide-sitagliptin, n = 29; sitagliptin-exenatide, n = 32 Mean ± SE; DeFronzo RA, et al. Curr Med Res Opin 2008;24: Reductions in 2-Hour PPG Were Greater With Exenatide Than With Sitagliptin Exenatide Sitagliptin After Period 1, patients were switched to the other therapy

49 49 Improvement in Insulinogenic Index Was Greater With Exenatide Than With Sitagliptin Insulinogenic Index P = ExenatideSitagliptin Patients with T2D; Evaluable population, n = 61 for both treatment groups; Geometric LS mean ± SE Standard meals administered at t = 0 min; 1. DeFronzo RA, et al. Curr Med Res Opin 2008;24: Data on file, Amylin Pharmaceuticals, Inc. Geometric Mean Baseline Insulinogenic Index 2 :

50 50 Exenatide Reduced Postprandial Glucagon Levels to a Greater Extent Than Sitagliptin Plasma Glucagon (pg/mL) Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE DeFronzo RA, et al. Curr Med Res Opin 2008;24: Time (min) Standard Meal Baseline Exenatide Sitagliptin

51 51 Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SD; Acetaminophen was administered immediately before the standard meal; DeFronzo RA, et al. Curr Med Res Opin 2008;24: Plasma Acetaminophen (µg/mL) Exenatide Slowed Gastric Emptying Compared to Sitagliptin Time (min) Standard Meal Baseline Exenatide Sitagliptin

52 52 Action GLP-1 Receptor Agonists 1,2 DPP-4 Inhibitors 1,2 Insulin production First-phase insulin response Glucagon; glucose output ++++ Gastric emptyingDelayedNo effect Food intakeDecreasedNo effect Actions of Incretin-Based Therapies for T2D: GLP-1 Receptor Agonists and DPP-4 Inhibitors 1. DeFronzo RA, et al. Curr Med Res Opin 2008;24: Drucker DJ and Nauck MA. Lancet 2006;368:

53 53 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010 Review incretin physiology in healthy individuals and in patients with type 2 diabetes Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists Identify where incretin therapies can be used in the treatment of type 2 diabetes

54 54 Diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Sulfonylurea Lifestyle + Metformin + Intensive insulin Step 1Step 2Step 3 Lifestyle + Metformin + Pioglitazone (no hypoglycemia /edema (CHF)/ bone loss) Tier 1 : well-validated core therapies Tier 2 : less well-validated core therapies Lifestyle + Metformin + GLP-1 agonist (no hypoglycemia/weight loss /nausea/vomiting ) Lifestyle + Metformin + Pioglitazone + Sulfonylurea Lifestyle + Metformin + Basal insulin Algorithm for Type 2 Diabetes Validation based on clinical trials & clinical judgment Nathan DM, et al. Diabetes Care 2008;31(12):1-11.

55 55 AACE/ACE Glycemic Control Algorithm: T2 Diabetes 6.5% 7.5% 7.6% 9.0% >9.0 Lifestyle Modification (to be considered throughout treatment) Monotherapy Can include: MET DPP4 GLP-1 TZD AGI Dual Therapy MET+GLP- 1, DPP4,or TZD TZD+GLP-1 or DPP4 MET+Colse velam or AGI Dual Therapy MET+GLP- 1, DPP4, or TZD MET+SFU or Glinide Triple Therapy MET+GLP-1 or DPP4 with TZD or SFU Triple Therapy MET+GLP-1 or DPP4 + TZD or SFU MET + TZD + SFU After Orals Insulin ± other agents Symptoms Insulin ± other agents No Symptoms MET+GLP-1 or DPP4 + TZD or SFU MET + TZD + SFU Insulin ± other agents A1C Adapted from AACE Glycemic Control Algorithm, Rodbard HW, et al. Endocr Pract Reproductions can be found at Increase therapy every 2-3 months if glycemic goal is not achieved

56 56 AACE/ACE Algorithm Summary The algorithm is intended for use in conjunction with more detailed and comprehensive information (e.g., prescribing information, ACE/AACE Road Maps, etc) The algorithm is intended to provide guidance A1C goal of ≤ 6.5% or less –Needs to be individualized to minimize risks of hypoglycemia Therapeutic pathways stratified based on current A1C values 8 major classes of medications –Prioritized by safety, efficacy, risk of hypo, simplicity, patient adherence and cost of medication –Combination medications that have complimentary mechanisms of action Rodbard HW, et al. Endocr Pract 2009;15(6):


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