1. "Not all of us can do great things. But we can do small things with great love." — Mother TeresaMother Teresa

2. GLP-1 Receptor Agonists

3. Diabetes Prevalence: Projected Increase 2000-2030

4. Metabolic Syndrome 24% of U.S. adults Diagnosis 3 or more of the following –Hypertension > 130/85 –Waist > 40” men, >35” women –HDL < 40 for men, < 50 in women –Triglycerides > 150 –Fasting glucose > 110 JAMA May 16, 2001 JAMA Jan 16, 2002

5. Prevalence of The Met Syn : US Adults Prevalence (%) 0 5 10 15 20 25 30 35 40 45 20–2930–3940–4950–5960–69  70 Men Women Age (years) Ford ES, et al. JAMA. 2002;287:356-359.

6. Prevalence Rates (%) of Insulin Resistance in Selected Metabolic Disorders Bonora E, et al. Diabetes 1998;47:1643- 49

7. Coronary Heart Disease Mortality 0 2 4 6 81012 0 5 10 15 20 RR (95% CI), 3.77 (1.74-8.17) Follow-up, Y Cumulative Hazard (%) Yes No 866 288 852 279 834 234 292 100 Met Syn: Survival Curves No. at Risk Metabolic Syndrome Yes Metabolic Syndrome: 0 2 4 6 81012 0 5 10 15 20 RR (95% CI), 3.55 (1.96-6.43) Follow-up, Y 866 288 852 279 834 234 292 100 0 2 4 6 81012 0 5 10 15 20 RR (95% CI), 2.43 (1.64-3.61) Follow-up, Y 866 288 852 279 834 234 292 100 Cardiovascular Disease Mortality All Cause Mortality Lakka H-M, et al. JAMA. 2002;288:2709-2716. No

8.  -Cell Function (%) * Postprandial Hyperglycemia IGT † Type 2 Diabetes Phase I Type 2 Diabetes Phase II Type 2 Diabetes Phase III 25 100 75 0 50 -12-10-6-20261014 Years From Diagnosis Patients treated with insulin, metformin, sulfonylureas ‡ * Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on Homeostasis Model Assessment (HOMA) data from UKPDS. † IGT=impaired glucose tolerance ‡ The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the UPKDS population and were determined by the HOMA model. Lebovitz HE. Diabetes Rev. 1999;7:139-153. UKPDS:  -Cell Loss Over Time

10. History: GLP1-RAs  1902 Bayliss & Starling: role of a gut-derived hormone (“secretin”) stimulated pancreatic juices. Introduced the word “hormone” (Gr: impetus).  1932 LaBarre term “incretin” to refer to a substance derived from the gut that caused hypoglycemia but did not cause exocrine secretion after eating.  1964–1967 Clinical proof that a gut-derived factor positively modulated insulin secretion; that more insulin was secreted from oral glucose than IV glucose.  1971 John Brown: Isolated, sequenced gastric inhibitory peptide (GIP), and renamed it glucose dependent insulinotropic peptide after finding that plasma glucose has to be elevated in order for GIP to induce insulin secretion.  1985 The second incretin, GLP-1, described.  2002 Exendin-4, a GLP-1 receptor agonist extracted from Gila monster lizard saliva, shown to stimulate insulin secretion in a glucose-dependent manner in subjects with and without T2DM.

16. Mean ± SE; N=6; *P  0.05; 0 1 -0 2 =glucose infusion time Nauck. J Clin Endocrinol Metab. 1986;63:492. Copyright 1986, The Endocrine Society. Venous Plasma Glucose (mmol/L) Time (min) C-Peptide (nmol/L) 11 5.5 0 0101 60120180 0101 60120180 0.0 0.5 1.0 1.5 2.0 Time (min) 0202 0202 Incretin Effect Oral Glucose IV Glucose * * * * * * * Incretin Effect: Amplification of the Beta-cell Response to Oral vs IV Glucose Challenge

17. Two Incretins: GIP and GLP-1  Both secreted by enteroendocrine cells by sensing an increase in the concentration of carbs/fats in the lumen of the GI tract.  Both degraded by DPP-4 (dipeptidyl peptidase-4). T/2 < 2min.  Both stimulate beta cells to secrete ~80% more insulin in response to the same amount of blood glucose.  GIP  GIP produced by K cells in the proximal small intestine.  GIP enhances insulin induced lipoprotein lipase activity, triglyceridegenesis, beta cell proliferation and survival.  GLP-1  L-cells in the small bowel and ascending colon synthesize GLP-1 and GLP-2  Posttranslational product of the proglucagon gene encode glucagon, GLP-1 and GLP-2  Tissue-specific post-translational processing of proglucagon, product secretion and degradation.  In T2DM: hyperglycemia down-regulates GIPR expression/activity but not GLP-1 receptor expression/activity.  Defective GLP-1 secretion in pts with impaired glucose tolerance, resulting in reduced concentrations of post-prandial GLP-1, contributing to a blunted insulin secretory response to meals.

18. Incretin effect in T2DM Nauck. Diabetologia. 1986;29:46. ©2006, ICHE Infuse glucose to maintain glycemia at same levels as following a 50-g oral challenge Record  -cell secretory responses to oral and IV administration of glucose Compare healthy with T2DM

19. Nauck. Diabetologia. 1986;29:46. Incretin Effect Reduced in T2DM Compared With NGT Incretin Effect Insulin (mmol/L/min) Glucose: IV (isoglycemic infusion) Oral (50 g) 30.0 72.8 23.5 34.7 11.3 38.9  -Cell Secretory Response NGT=normal glucose tolerance Contributions of Incretin Factors (%) ©2006, ICHE

20. 0 5 10 15 20 060120180240 NGT IGT T2DM Breakfast * * * * * ** * Time (min) Toft-Nielsen. J Clin Endocrinol Metab. 2001;86:3717; with permission. GLP-1 Secretion Impaired in T2DM GLP-1 (pmol/L) *P<0.05 vs T2DM NGT=normal glucose tolerance IGT=impaired glucose tolerance ©2006, ICHE

21. GLP Degraded by DPP-4

22. DPP-4 requires an Ala, Pro or HOPro at the penultimate N-terminal position.

23. 82-Week Extension Study Exenatide (10 mcg BID) Added to Metformin Change in A1C Change in Weight Change From Baseline (%) Change From Baseline (kg) Ratner. Diabetes Obes Metab. 2006;8:419.

24. GLP-1 in the Pancreas  Beta Cell  Stimulates insulin synthesis, secretion, and glucokinase expression.  Stimulates expression of GLUT-2 transporter, thereby increasing efficacy and potency of glucose as a stimulus for insulin secretion  Restores first phase insulin response  Increases proinsulin mRNA stability & gene transcription  GLP-1 increases number of beta cells by:  Up-regulates beta-cell transcription factor pancreatic duodenal homeobox-1 protein  Transactivates the epidermal growth factor receptor  Up regulates glucokinase and glucose transporter-2  Inhibiting beta cell apoptosis  Delta Cell: Stimulates somatostatin secretion.  Alpha Cell: Inhibits glucagon secretion in T1 and T2 DM depending on glucose levels.  Probably mediated by paracrine effects via insulin or beta cell product, since no GLP-1 receptors on the alpha cell.

27. Extrapancreatic Effects of GLP-1  Stomach:  Decreases gastric acid secretion, delays gastric emptying and motility, which helps to spread glucose absorption out over time, and thus limit hyperglycemia.  Neurally mediated central vagal stimulation.  CNS:  GLP-1 from L-cells and CNS increases satiety.  GLP-1 crosses BBB  Muscle:  Increases glucose uptake, glycogen synthase a activity.  Liver:  Decreases glucose production  Stimulates glycogen synthase a activity  Adipocyte  Stimulates glucose uptake, lipogenesis  Cardiovascular  Improves LVEF post MI (Nickolaides et al, 2004)  Improves endothelial dysfunction in pts with T2DM with CAD (Nystrom 2004)  Cardioprotective effects against ischemia

28. Metformin: decreases hepatic glucose production, decreases GI glucose absorption and increases glucose uptake by fat and muscle.

29. W.B.: 54 yo sero (-) T2DM 12/08/09  12/08/09: 295 #  Met 500 mg bid  Lantus 90 U/d  Glu 177, A1C 10.2  C-pep 3 ng/ml, 24 h UFC (-), IgF1 (-)  GAD, IAA (-)  Microalbuminuria  12/22/09:  Met 1000 bid  Lantus 85 U/d  Novolog 1/10 g CCF, 1/25 mg/dl >100  Byetta 5 mcg sq bid

30. Labs

31. Stopping Lantus

32. Stopping Novolog

33. Investigational Agonists Subcutaneous injection AdministrationAgent Base Peptide/Protract. Mechanism Half-Life/Dosing Frequency a Development Status Exenatide QW Exendin-4 Microsphere with biodegrad. polymer > 1 week 1X weekly FDA review Albiglutide GLP-1 Dimer Bound to albumin DPP-4 site AA subst. 6-8 days ≤ 1X weekly Phase 3 trials Taspoglutide GLP-1 Sustained-release DPP-4 site AA subst. NEP site AA subst. ≈ 6-7 days ≤ 1X weekly Phase 3 trials LY2189265 GLP-1 DPP-4-protected IgG4-Fc-linked ≈ 4 days 1X weekly Phase 3 trials Lixisenatide Exendin-4 6 C-terminal lysines 2.7 - 4.3 hours 1X daily Phase 3 trials

34. GLP-1 RAs AEs (% of Pts) Nausea – LEAD-6 Study: Lira vs Exn bid: 25.5 vs 28% – DURATION-5: Exn bid vs Exn qW: 14 vs 35% – T-EMERGE-2: Taspo 20 vs Exn bid: 47 vs 30% Vomiting – LEAD-6 Study: Lira vs Exn bid: 6 vs 9.9% – T-EMERGE: Taspo 20 vs Exn bid: 23 vs 11% Antibody Formation – LEAD-6 Study: Lira vs Exn bid: 2.6 vs 61.1%

35. GLP-1 AEs cont. Pancreatitis – Wide baseline incidence: 4.21-45.33/100,000 annual incidence rates for first attack – Diabetics have a 3 fold increased incidence – Post marketing incidence in 2007 with Exenatide 27/100,000 pt-yrs – Liraglutide 7 cases pancreatitis/4257 pts a.c.t. 1/2381 in comparator group Elevation in Calcitonin – Thyroid C-cell responsiveness to GLP-1 RAs are species specific and appear to activate rodent but not human C-cells – 2 yrs of liraglutide exposure no change in CT levels vs comparator Hypoglycemia – Does not inhibit counter-regulatory response of glucagon

36. T1DM and T2DM