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INCRETINS

INCRETINS. Glucagon-like Peptide 1 (GLP-1) and Glucose-Dependent Insulinotrophic Polypeptide (GIP) account for ~90% of the incretin effect. In response to equivalent hyperglycemic stimuli, ORAL glucose elicits a greater insulin response than IV glucose. Insulin.

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INCRETINS

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  1. INCRETINS Glucagon-like Peptide 1 (GLP-1)and Glucose-Dependent Insulinotrophic Polypeptide (GIP) account for ~90% of the incretin effect In response to equivalent hyperglycemic stimuli, ORAL glucose elicits a greater insulin response than IV glucose

  2. Insulin Glucose-Stimulated Secretion of Insulin Glucose GLUT2 Pancreatic βCell SUR Glucose Potassium channel GK K+ Pyruvate GLP-1 ATP + ATP GIP TCA Cycle* AC + Calcium channel cAMP [Ca2+] Amplifying Triggering AC = adenylyl cyclase; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; GK = glucokinase; GLUT2 = glucose transporters; SUR = sulfonylurea receptor; *TCA = Tricarboxylic acid (Krebs cycle). Hinke SA, et al. J Physiol. 2004;558:369-380. Henquin JC. Diabetes. 2000;49:1751-1760. Henquin JC. Diabetes. 2004;53(suppl 3):S48-S58.

  3. Holst JJ, Physiol Rev 87:1409-39, 2007 Drucker FJ, Cell Metab 135-165, 2006 INSULIN SECRETION PKA IC Ca++ MOLECULAR ACTIONS OF GLP-1 ON BETA CELL Insulin Secretion cAMP Epac2 PI-3K INSULIN GENE TRANSCRIPTION – Pdx-1 • replenishes beta cell insulin stores • prevents beta cell exhaustion BETA CELL GLUCOSE SENSITIVITY • increased GLUT2 and Glucokinase • restores glucose responsitivity to resistant • beta cells

  4. INSULIN RESPONSES TO PHYSIOLOGICALAND PHARMACOLOGICAL LEVELS OF GLP-1 Pharmacological GLP-1 levels2(15 mM hyperglycemic clamp) Physiological GLP-1 levels1(15 mM hyperglycemic clamp) 6000 6000 GLP-1 infusion-0.5 pmol/kg/min GLP-1 infusion-1.0 pmol/kg/min Plasma GLP-1: 46 pM Healthy controls 4000 4000 Insulin (pmol/L) Insulin (pmol/L) Plasma GLP-1:126 pmol/L Type 2 diabetes 2000 2000 Plasma GLP-1:41 pM Type 2 diabetes 0 0 0 60 120 0 60 120 Time (min) Time (min) 1. Adapted from Højberg P et al. Diabetologia 2009;52:199–207 2. Adapted from Vilsbøll T et al. Diabetologia 2002;45:1111–1119

  5. EXENATIDE AND LIRAGLUTIDE Effectively reduce HbA1c Preserve beta cell function Promote weight loss Correct known pathophysiologic defects in T2DM Do not cause hypoglycemia Have an excellent safety profile Rad 03/20/00 Triplitt & DeFronzo, Expert Rev Endo Metab 1:329-41, 2006

  6. TIME COURSE OF EFFECT OF EXENATIDE ON HbA1c Time (weeks) 0 20 40 60 80 156 0.5 Placebo Baseline HbA1C=8.3% 0 Exenatide- 10 g bid DeFronzo et al, Diabetes Care 28:1092-1100, 2005 D HbA1c (%) Klonoff et al, Curr Med Res Opin 24:275-285, 2008 -1.0 Exenatide- 10 g bid -2.0 Open-Label Extension Placebo-Controlled Trials

  7. EFFECT OF EXENATIDE VERSUS GLARGINE INSULIN ON INSULIN SECRETION IN T2DM Subjects: 59 T2DM; Age = 58y; BMI = 30.5 kg/m2 HBA1c = 7.5%; FPG = 9.1 mM Rx = Metformin only Exptl Design: Exenatide*(n=29) vs Glargine (n=30) Treatment goal = HbA1c ≤ 7.0% Actual HbA1c = 6.8±0.1%Hyperglycemic (15 mM) clamps Study Duration: One year * Up to 15-20 ug tid

  8. C-PEPTIDE SECRETION DURING HYPERGLYCEMIC CLAMP AFTER 1 YEAR OF EXENATIDE VS GLARGINE INSULIN 10 8 6 4 2 0 -15 0 10 30 60 4 P< 0.0001 3 2 Ratio to Baseline 1 C-peptide (nmol/L) 3.19 1.31 0 GLAR EXEN Glargine Exenatide Glucose 15 mM 80 Time (min) Exenatide

  9. LEAD 3 Mono RX 51% 42% 42% 54% 53% Percent Reaching A1c < 7.0% -1.1 DECREMENT IN A1c IN PIVOTAL LIRAGLUTIDE (1.8 mg/d) TRIALS LEAD 1 SU LEAD 4 MET + TZD LEAD 2 MET LEAD 5 MET + SU 0 -0.4  A1c (%) -0.8 -1.0 -1.1 -1.2 -1.3 Buse JB, Lancet 374:39-47, 2009 Garber A, Lancet 373(9662):473-81, 2009 Marre M, Diabet Med 26:268-78, 2009 Nauck MA, Diabetes Care 32:84-90, 2009 Russell-Jones, Diabetologia 52:2046-55, 2009 Zinman B, Diabetes Care 32:1224-30, 2009 -1.5 -1.6

  10. NGT Controls 12 8 Insulin Secretion Rate (pmol/min kg) T2DM (Lira) 4 T2DM (Placebo) 0 240 120 160 200 80 Glucose (mg/dl) A SINGLE DOSE OF LIRAGLUTIDE (7.5 ug/kg) RESTORES BETA CELL INSULIN RESPONSE TO HYPERGLYCEMIA IN T2DM PATIENTS Chang et al, Diabetes 52:1786-91, 2003

  11. EXENATIDE AND LIRAGLUTIDE Effectively reduce HbA1c Preserve beta cell function Promote weight loss Correct known pathophysiologic defects in T2DM Do not cause hypoglycemia Have an excellent safety profile Rad 03/20/00

  12. IMPACT OF EXENATIDE THERAPY OVER 3 YEARS:EFFECT ON A1C AND BODY WEIGHT Change in A1c (%) Change in Body Weight (kg) 0 8.5 15-20% reduction in food intake 8.0 -2 -1.1 ±0.1% -1.1 ±0.1% 7.5 -4 -5.3 ± 0.4 kg 7.0 -6 54% % achieving A1C £ 7% 46% 0 26 52 78 104 130 156 0 26 52 78 104 130 156 Treatment (wk) Treatment (wk) N = 217; Mean ± SE Klonoff DC, et al. Curr Med Res Opin 2008; 24:275-286 Baseline Weight = 99 kg

  13. EXENATIDE AND LIRAGLUTIDE Effectively reduce HbA1c Preserve beta cell function Promote weight loss Correct known pathophysiologic defects in T2DM Do not cause hypoglycemia Have an excellent safety profile Rad 03/20/00

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