1. Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 3 of 5

2. 2 Incretins Nutrient stimulated gut hormones Favorable effects on glucose metabolism Major humans incretins 1,2 – Glucagon-like peptide-1 (GLP-1) – Glucose-dependent insulinotropic polypeptide (GIP) “Incretin effect” 1 Drucker DJ. Diabetes Educator. 2006;32(Suppl 2):65S-71S. 2 Vilsbøll T, Holst JJ. Diabetologia. 2004;47:357-366.

3. 3 Glucagon-like Peptide-1 (GLP-1) Most well-characterized incretin Secreted from L cells of the intestines Very short half-life Possibly deficient and GLP-1 resistance in type 2 diabetes Adapted from Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190.

5. Insulin secretion - overcomes decreased insulin secretion of steroids and tacrolimus Glucagon secretion Gastric emptying Appetite Cardioprotection Cardiac output Insulin biosynthesis  cell proliferation  cell apoptosis Neuroprotection Glucose production Insulin sensitivity Brain Heart GI tract Liver Muscle Stomach GLP-1 Drucker D. J. Cell Metabolism 2006 Summary of Incretin Actions on Different Target Tissues Flint A, et al. J Clin Invest.1998;101:515-520. Larsson H, et al. Acta Physiol Scand.1997;160:413-422. Nauck MA, et al. Diabetologia.1996;1546-1553. Drucker DJ. Diabetes.1998;47:159-169. Schwartz, Kohl, "Type 2 Diabetes Mellitus and the Cardiometabolic Syndrome: Impact of Incretin-based Therapies","Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy". 7/10

6. Müller WA, et al. N Engl J Med. 1970;283:109-115. Hyperglycemia in Type 2 Diabetes Results from Abnormal Meal-Related Insulin and Glucagon Dynamics Glucose (mg %) Insulin (µU/mL) Glucagon (pg/mL) Time (min) -60 060120180240 PremealPostmeal  Insulin  Insulin  Glucagon  HGP  Glucagon  HGP  FPG  PPG Meal 120 90 60 30 0 140 130 120 110 100 90 360 330 300 270 T2DM (n=12) Normal (n=11) 240 110 80

7. Mean (SE); *P < 0.05GLP-1 = glucagon-like peptide-1 Glucose-dependent Effects of GLP-1 Glucose (mg/dL)Insulin (pmol/L) Glucagon (pmol/L) Type 2 Diabetes (n = 10) Placebo GLP-1 270 180 90 0 -30060120180240 300 200 100 0 -30060120180240 20 10 0 -30060120180240 Time (min) * * * * * * * * * * * * * * * * * * * Adapted from Nauck MA, et al. Diabetologia. 1993;36:741–744.

8. CV effects of GLP-1, GLP-1 RA, DPP-4 Inh.

9. Glp1 in major Surgery in DM- Benefit in Stress/ Steroid DM Added by Dr S

10. Strategies for Enhancing GLP-1 Action GLP-1 receptor agonists (resistant to DPP-4) – Exenatide – Liraglutide DPP-4 inhibitors – Inhibit actions of DPP-4 – Sitagliptin, saxagliptin

11. Pharmacologically achieving GLP-1 effects Release of active incretins GLP-1 and GIP  Blood glucose in fasting and postprandial states Ingestion of food  Glucagon  Hepatic glucose production GI tract DPP-4 enzyme Inactive GLP-1 X Sitagliptin Saxagliptin (DPP-4 inhibitors)  Insulin Glucose- dependent Glucose dependent Pancreas Inactive GIP GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Beta cells Alpha cells  Glucose uptake by peripheral tissue GLP-1 receptor agonists Resists degradation by DPP-4 GLP-1 like effect GLP agonists 7-10 x DPP4-I 2-3 x GLP-1 Receptor Agonists= parenteral, weight loss, nausea risk DPP-4 Inhibitor = oral, weight neutral, no nausea

12. Sitagliptin, Saxagliptin Mechanism: Glucose-dependent  insulin secretion and  glucagon secretion Lowers PPG more than FPG Efficacy: modest (  HbA1c 0.6-0.8%) Advantages: weight neutral, no hypoglycemia, may use in patients with any degree renal dysfunction (dose appropriately), infrequent dosing Disadvantages: hypersensitivity reactions, ?pancreatitis (sitagliptin); interaction with CYP3A 4/5 strong inhibitors (saxagliptin); cost DPP-4 Inhibitors

13. HgA1c Drop with DPP-4 Inhibitors

14. *P<0.001 vs comparator. 1. Aschner P, et al. Diabetes Care. 2006;29:2632-2637. 2. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 3. Rosenstock J, et al. Clin Ther. 2006;28:1556-1568. 4. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745. 5. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. 6. Derosa G, et al. Metab Clin Exp. 2010;59:887-895.  Weight (kg) Weight Changes With Sitagliptin: Mono and Combination Therapy Monotherapy 24 Weeks 1 Monotherapy 24 Weeks 2 Add-on to Pioglitazone 24 Weeks 3 Add-on to Glimepiride 24 Weeks 4 Add-on to Insulin 24 Weeks 5 Add-on to Pio vs Met+Pio 12 Months 6 N741793353441641151 TreatmentPBOSitGlipSitPioSit + Pio GlimSit + Glim InsSit + Ins Met + Pio Sit + Pio * *

15. *P=0.01 vs glyburide uptitration. 1. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 2. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-622. 3. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 4. Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26:540-549. 5. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 6. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819.  Weight (kg) Weight Changes With Saxagliptin: Mono and Combination Therapy Monotherapy 24 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Add-on to Metformin 24 Weeks 3 Add-on to Metformin 18 Weeks 4 Add-on to Glyburide vs Uptitration 24 Weeks 5 Add-on to TZD 24 Weeks 6 N4011306743801768565 TreatmentPBOSaxMetSax + Met MetSax + Met Sit + Met Sax + Met GlySax + Gly TZDSax + TZD *

16. 16 DPP-4 Inhibitors: Summary Oral once-daily agents with glucose-lowering potential Can be used as monotherapy and as part of combination therapy strategies (sitagliptin approved for combination with Insulin) A1C reduction Well tolerated Weight neutral