Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 5 of 5

Liraglutide:Once-daily GLP-1 Agonist Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. Contraindicated in Patients with personal or family history of MTC or MEN-2 Use with caution in patients with a history of pancreatitis or renal/ liver dis.Increased albumin binding and slowed absorption and degradation (T½ 13 hours) 97% homology to human GLP-1  A1c, FPG, PPG, and weight Side effects: GI mainly, no hypoglycemia No antibody induction No effect with renal or hepatic impairment 2 Victoza ® [package insert]. Princeton, NJ: Novo Nordisk Inc.; 2010.

3 Effect of Liraglutide on FPG Reduction Mean FPG change (mg/dL) SU 3 ll Metformin 2 Met + TZD 4 Met + SU 5 Monotherapy 1 Liraglutide 1.2 mgLiraglutide 1.8 mgGlimepirideRosiglitazoneGlarginePlacebo -30 ‡ ‡ -40 ‡ -28 ‡ -30 ‡ -15* ‡ -29 ‡ -26 † *P<0.05 vs glimepiride; † P < vs glimepiride; ‡ P< vs placebo. Data are LOCF. FPG=fasting plasma glucose. ll Rosiglitazone dose was ½ of approved maximal US dose. Optimal titration of glargine dose was not achieved in most patients. 1. Garber A et al. Lancet Nauck M et al. Diabetes Care Marre M et al. Diabetic Med Zinman B et al. Diabetes Care Russell-Jones D et al. Diabetologia Add-On to

Liraglutide: A1C Baseline A1C % Change in A1C (%) SU combinatio nLEAD 1 Metformin combination LEAD 2 Met + TZD combination LEAD 4 Met + SU combination LEAD * -1.5* Monotherapy LEAD * * -1.2* -1.5* Significant *vs. comparator; # Change in HbA 1c from baseline for overall population (LEAD 4,5) add-on to diet and exercise failure (LEAD 3); or add-on to previous OAD monotherapy (LEAD 2,1) Liraglutide 1.8 mgLiraglutide 1.2 mg Glimepiride Rosiglitazone Glargine Placebo Buse JB, et al. Lancet. 2009;374: Garber A, et al. Lancet. 2009;373: Marre M. Diabet Med. 2009;26: Nauck M. Diabetes Care. 2009;32: Russell-Jones D, et al. Diabetologia. 2009;52: Zinman B, et al. Diabetes Care. 2009;32:

5 Effect of Liraglutide Versus Standard Therapy on Weight Mean weight change (lb) SU 4 ll Metformin 3 Met + TZD 5 Met + SU 6 Monotherapy 1,2 Liraglutide 1.2 mgLiraglutide 1.8 mg GlimepirideRosiglitazoneGlarginePlacebo * P< vs glimepiride; † P<0.05 vs placebo; ‡ P< vs placebo. Data are LOCF. ll Rosiglitazone dose was ½ of approved maximal US dose. Optimal titration of glargine dose was not achieved in most patients. ‡ † ‡ *†*† Add-On to *†*† 1. Garber A et al. Lancet Nauck M et al. Diabetes Care Marre M et al. Diabetic Med Zinman B et al. Diabetes Care Russell-Jones D et al. Diabetologia. 2009

6 Minor Hypoglycemic Events* in Clinical Trials of Liraglutide Episodes per patient year SU ll MetforminMet + TZDMet + SUMonotherapy LiraglutideGlimepirideRosiglitazoneGlarginePlacebo *Plasma glucose <55.8 mg/dL and could be self treated. Data are LOCF. ll Rosiglitazone dose was ½ of approved maximal US dose. Optimal titration of glargine dose was not achieved in most patients Add-On to 1.66 Major hypoglycemia (could not be self treated) occurred in 7 patients treated with liraglutide; 6 of the 7 were also taking an SU

7 Nausea Declined Over Time With Liraglutide Monotherapy Patients (%) Liraglutide Monotherapy vs SU Victoza ® [package insert]. Princeton, NJ: Novo Nordisk Inc.; 2010.

8 Liraglutide QD Versus Exenatide BID Blonde L, et al. Poster 107. Presented at: CDA; October 15-18, 2008; Montreal, Quebec, Canada. Liraglutide 1.8 mg QD Exenatide 10 mcg BID A1C (%) FPG (mg/dL) Weight (kg) Nausea (%) Baseline p < p = NS p = NR

Differences between liraglutide and exenatide Liraglutide 1 Exenatide 2 Dosing guidelinesOnce daily, independent of meals Twice daily, within 60 min before morning and evening meals Half-life13 h2.4 h Maximum dose1.8 mg10 mcg (BID) Renal eliminationNoYes Homology to native GLP-1 97%53% Antibodies8.6%44% 1 Victoza PI, 2010; 2 Byetta PI, BID, twice daily

Upper Normal Range Males Calcitonin (pg/mL) Weeks Upper Normal Range Females Compared to variations during study (see placebo curve), differences between comparators are extremely small and far within normal ranges /2839/405264/6576/7891/92104 Geometric means; Studies 1572 and 1573 Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Active comparator Placebo Calcitonin Levels Observed in LEAD Studies of Liraglutide in Human Diabetic Subjects

11 Conclusions: Liraglutide Clinical Overview Once daily GLP-1 analog; 97% homology to endogenous human GLP-1 Increases insulin secretion from beta cells in a glucose-dependent manner In clinical trials, liraglutide produced clinically and statistically significant improvements in A1C and FPG compared to placebo –Patients in most trials also demonstrated statistically significant weight loss vs placebo –Most common adverse events were headache, nausea, diarrhea, and anti-liraglutide antibody formation Use of Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2 based on preclinical findings in rodents- no requirement to check calcitonin levels or do thyroid ultrasounds Victoza ® [package insert]. Princeton, NJ: Novo Nordisk Inc.; 2010.

12 GLP-1 Agonists: Summary SC agents with substantial glucose-lowering potential Can be used as monotherapy and as part of combination therapy strategies Nausea is major side effect that is self-limiting minimized by advising patients to stop eating as soon as feels ‘full’ Associated with weight loss

1. DeFronzo RA, et al. Curr Med Res Opin 2008; 24: Drucker DJ and Nauck MA. Lancet. 2006;368: Properties/Effect GLP-1 Receptor Agonists 1,2 DPP-4 Inhibitors 1,2 Insulin production+++++ First-phase insulin response Glucagon; glucose output ++++ Gastric emptyingDelayedNo effect Food intakeNo effect Body WeightNo effect HypoglycemiaNo Side effectsNausea, vomitingMinimal Incretin Therapies: Major Differences

Exenatide, DPP-4 Inhibitors and Long-Acting GLP-1 Agonists: Similarities and Differences Properties/EffectExenatide 1 DPP-4 Inhibitor 1 Liraglutide, Exenatide-OW 2,3 Glucose-dependent insulin secretion Yes Glucose-dependent glucagonYes Slows gastric emptyingYesNoLittle or no Effect on body weightWeight lossWeight neutralWeight loss Effect on A1c~1%<1%>1% Effect on fasting glucoseModest Good Effect on postprandial glucoseGoodModest Effect on CVD risk factors Improve (with weight loss) No consistent change Improve Side effects Nausea (?pancre- atitis, CRF) ~ None observed (pancreatitis) Less nausea, skin, (?pancreatitis, ?CRF, ?MTC) Administration Subcutaneous Twice daily Oral Once daily Subcutaneous Daily or weekly 1. Amori RE, et al. JAMA. 2007;298: Exenatide LAR (once weekly): Drucker DJ, et al. Lancet. 2008;372: Liraglutide: Buse JB, et al. Lancet. 2009;374:39-47.

15 A1C 6.5 – 7.5% ** Monotherapy MET + GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD + GLP-1 or DPP4 1 MET + Colesevelam AGI 3 MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4, Mos. *** Dual Therapy MET + GLP-1 or DPP4 1 ± SU 7 TZD 2 GLP-1 or DPP4 1 ± TZD 2 MET + GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 MET + GLP-1 or DPP4 1 + TZD 2 GLP-1 or DPP4 1 + SU 7 TZD 2 MET † DPP4 1 GLP-1TZD 2 AGI 3 A1C > 9.0% No Symptoms Drug Naive Under Treatment INSULIN ± Other Agent(s) 6 Symptoms INSULIN ± Other Agent(s) 6 INSULIN ± Other Agent(s) 6 Triple Therapy AACE/ACE Algorithm for Glycemic Control Committee Cochairpersons: Helena W. Rodbard, MD, FACP, MACE Paul S. Jellinger, MD, MACE Zachary T. Bloomgarden, MD, FACE Jaime A. Davidson, MD, FACP, MACE Daniel Einhorn, MD, FACP, FACE Alan J. Garber, MD, PhD, FACE James R. Gavin III, MD, PhD George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Edward S. Horton, MD, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, MACE Etie S. Moghissi, MD, FACP, FACE Stanley S. Schwartz, MD, FACE * May not be appropriate for all patients ** For patients with diabetes and A1C < 6.5%, pharmacologic Rx may be considered *** If A1C goal not achieved safely †Preferred initial agent 1DPP4 if  PPG and  FPG or GLP-1 if  PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3AGI if  PPG 4Glinide if  PPG or SU if  FPG 5Low-dose secretagogue recommended 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered A1C 7.6 – 9.0% Dual Therapy Mos. *** Triple Therapy 9 INSULIN ± Other Agent(s) 6 Available at © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

Other Therapies: Likely Effects on Islet-Cell Function Pramlintide

DM2: progressive  of insulin and amylin Pramlintide is a synthetic analog of amylin Regulates postprandial glucose concentrations Reduces postprandial glucagon secretion Slows rate of gastric emptying Centrally-mediated appetite suppression Side effects: nausea, hypoglycemia* Young. Amylin: Physiology and pharmacology 2005; Edelman, et al. Int J Clin Pract 2006; 60: *Label includes a Boxed Warning describing increased risk of insulin-induced severe hypoglycemia, particularly in type 1 patients

Hormonal Regulation of Insulin Secretion and Glucose Homeostasis Insulin Amylin Glucagon  -cells α -cells Amylin is normally co-secreted with insulin by pancreatic β cells Kruger D, et al. Diabetes Educ 1999; 25: Plasma Insulin (pM) amMidnight5 pm12 noon Time (24 h) Meal Plasma Amylin (pM) 30 Insulin Amylin

Pramlintide in DM2 Indication: those on multiple daily injections or insulin pump therapy with persistent postprandial hyperglycemia Efficacy: %  in A 1c Decreases FPG and PPG Weight reductions of 1-2 kg Dosing (Pen injectors) – Start with 60 mcg before meals (10 units) – Increase to 120 mcg (20 units) before each meal as tolerated

Pramlintide (Symlin) 113 subjects being treated with basal insulin and prior oral antihyperglycemic drugs randomly assigned 1:1: Mealtime pramlintide (120 mcg) Titrated rapid-acting insulin analog Basal insulin dosage titrated from day 1, seeking fasting plasma glucose mg/dl. Pramlintide and an RAIA initiated on day 1 and week 4, respectively. Riddle M, et al. Diabetes Care Sep;32(9): Black bars = pramlintide; white bars = RAIA. = basal insulin in the pramlintide group. Δ = basal insulin in the RAIA group. = total insulin (basal plus mealtime) in the RAIA group Mean changes in insulin dosage over course of the trial.PPG from before to after meals at 24 weeks.

Conclusion Multiple defects result in fasting and post- prandial hyperglycemia in DM2 These multiple defects as well as FPG and PPG are appropriate targets for therapy directed at attaining A1c goals Incretins are evolving as new treatment options for DM2 Other new agents shed light on other defects to be targeted for therapy