1 Core Defects of Type 2 Diabetes Targeting Mechanisms for a Comprehensive Approach Part 2 1

2 Alpha- Glucosidase Inhibitors 1,2 Meglitinides 3 SUs 4,5 TZDs 6,7 Metformin 8 DPP-4 Inhibitors Insulin deficiency Insulin resistance Excess hepatic glucose output Major Pathophysiologies 1. Glyset [package insert]. New York, NY: Pfizer Inc; Precose [package insert]. West Haven, Conn: Bayer; Prandin [package insert]. Princeton, NJ: Novo Nordisk; Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; Glucotrol [package insert]. New York, NY: Pfizer Inc; Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; Intestinal glucose absorption No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies

3 The Role of Incretins in Type 2 Diabetes

4 The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes Oral glucose loadIntravenous (IV) glucose infusion Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag. Time, min Control Subjects (n=8) IR Insulin, mU/L Normal Incretin Effect Subjects With Type 2 Diabetes (n=14) Diminished Incretin Effect Time, min IR Insulin, mU/L

5 GLP-1 Infusion 0 GLP-1 Infusion Has Glucose-Dependent Effects on Insulin and Glucagon in Patients With Type 2 Diabetes Glucose Glucagon When glucose levels approach normal values, glucagon levels rebound. When glucose levels approach normal values, insulin levels decrease. *P <0.05 Patients with type 2 diabetes (N=10) mg/dL * * * * * * * mU/L * * * * * * * * Time, min pmol/L * * * * Placebo GLP-1 Insulin 0 Adapted from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag. –30 GLP-1 Infusion

6 Incretins Play an Important Role in Glucose Homeostasis 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876– Ahrén B. Curr Diab Rep. 2003;2:365– Drucker DJ. Diabetes Care. 2003;26:2929– Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.  Insulin from beta cells (GLP-1 and GIP)  Glucagon from alpha cells (GLP-1) Release of gut hormones— Incretins 1,2 Pancreas 2,3 Glucose Dependent Active GLP-1 & GIP DPP-4 enzyme Inactive GIP Inactive GLP-1 Glucose Dependent ↓ Blood glucose GI tract ↓ Glucose production by liver Food ingestion ↑ Glucose uptake by peripheral tissue 2,4 Beta cells Alpha cells

7 Tips for Diabetes treatment  Reduced HBA1C as low as possible at least below 6.5% without hypoglycemia  Use DM meds that shows benefit beyound glycemic control(Heart, vascular inflamation, microalbuminuria)  Medications that showed sustained effect and preservation of B-cell function  Use meds that have the least side effect.

8 Pills available for DM 2 No hypoglycemiaNo hypoglycemia: TZD(Actos, Avandia) Metformin/glucophage) Alpha glucosidase inhibitor(Precose, Glyset) Combo(avandamet, actoplusmet, janumet DPP IV inhibitor: –Januvia –Onglyza –Tradjenta –Nesina Can Cause HypoglycemiaCan Cause Hypoglycemia: SU(glyburide,Amaryl) Prandin/Starlix Combo(glucovance, avandaryl, duetact )

9 Non insulin injection for DM2 GLP-1 analog Amylin(Symlin)

10 Metformin + insulin sensitizer  Less cardiac event by UKPDS  Weight reduction  Dm prevention data  __ ____ ______  contraindicated in renal failure  GI side effect  had to be stopped 48 hors before and after contrast

11 TZD( actos, Avandia) Plus: Insulin Sensitizer Heart and vascular benefit (Proactive,Chicago) Preservation of B- cell( dream, Adopt) DM prevention data (-): contraindicated in heart failure Stage 3- 4, or liver failure  Edema, weight gain  ? Bone density

12 ADOPT: A Diabetes Outcome Progression Trial Avandia Sustained A1C Over Time* Treatment Difference at 4 Years RSG vs MET –0.13 (–0.22 to –0.05), P=.002 RSG vs SU –0.42 (–0.50 to –0.33), P<.001 *Mean A1C values per visit are based on a repeated measures mixed model. Kahn SE et al. N Engl J Med. 2006;355: Number of patients: Time (years) HbA1C% RSG SU MET

13 Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Primary Outcome: Rosiglitazone  No. at Risk Rosiglitazone Placebo The DREAM Trial Investigators. Lancet. 2006;368:  60% risk reduction of development of diabetes or death was seen with rosiglitazone  This reduction was additive to standard counseling on healthy eating and exercise HR = 0.40 ( ); P < Cumulative Hazard Placebo Rosiglitazone Years

14 Blood glucose Blood glucose Inactive GIP Inactive GLP-1 DPP-4 Inhibitor Targets 2 Physiologic Glucose-Lowering Actions With a Single Oral Agent  Insulin (GLP-1 and GIP)  Glucagon (GLP-1) Release of active incretins GLP-1 and GIP Pancreas Glucose dependent DPP-4 enzyme Glucose dependent GI tract Food ingestion X (DPP-4 inhibitor) Incretin hormones GLP-1 and GIP are released by the intestine throughout the day; their levels increase in response to a meal. Dpp-4 inhibitor blocks DPP-4 to enhance the level of active incretins for 24 hours. Beta cells Alpha cells Glucose production by liver Glucose production by liver Glucose uptake by peripheral tissue Glucose uptake by peripheral tissue X

15 DPP-4 Inhibitors Indications and Usage Monotherapy –Indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Combination therapy –Indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a PPAR  agonist (eg, thiazolidinediones) when the single agent alone, with diet and exercise, does not provide adequate glycemic control. Important limitations of use –Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. PPARγ=peroxisome proliferator-activated receptor gamma.

16 Mean Change in A1C, % ‡ A1C CI=confidence interval. *Compared with placebo. † Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ Difference from placebo. § Combined number of patients on JANUVIA or placebo. || P<0.001 overall and for treatment-by-subgroup interactions. 1. Raz I et al. Diabetologia. 2006;49:2564– Aschner P et al. Diabetes Care. 2006;29:2632–2637. Mean Baseline: 8.0% P<0.001* –0.6 † –1.0 –0.8 –0.6 –0.4 – –0.8 † Placebo-adjusted results 24-week monotherapy study 2 (95% CI: – 1.0, – 0.6) 18-week monotherapy study 1 (95% CI: – 0.8, – 0.4) n=193 n=229 Inclusion Criteria: 7%–10% Overall<8 ≥8–<9 ≥ 9 Baseline A1C, % –1.4 –0.6 –0.7 –1.8 –1.6 –1.4 –1.2 –1.0 –0.8 –0.6 –0.4 – n=411 § n=239 § n=119 § Mean Change in A1C, % Prespecified Pooled Analysis at 18 Weeks || –0.7 n=769 § DPP-4 Inhibitors Significant A1C Reductions as Monotherapy

17 *Compared with placebo. † Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ Difference from placebo. CI=confidence interval; FPG=fasting plasma glucose; PPG=postprandial plasma glucose (meal challenge test). Aschner P et al. Diabetes Care. 2006;29:2632–2637. FPG2-Hour PPG 24-week placebo-adjusted results Mean Baseline: 170 mg/dL P<0.001* Mean Change in FPG, mg/dL ‡ (95% CI: – 24, – 10) –17 † n = 234 Mean Change in 2-Hour PPG, mg/dL ‡ Mean Baseline: 257 mg/dL P<0.001* (95% CI: –59, –34) –47 † n = 201 –60 –40 –30 –20 –10 0 –50 –60 –40 –30 –20 –10 0 –50 Sitagliptin Monotherapy Significantly Lowers FPG and PPG Levels

18 Add-on to pioglitazone study 2 Mean Baseline A1C: 8.0%, 8.1% Mean Change in A1C From Baseline, % Sitagliptin Significant A1C Reductions From Baseline When Added to Metformin or Pioglitazone 24-week change from baseline n=224 Metformin + JANUVIA –1.0 –0.8 –0.6 0 –1.0 0 Mean Change in A1C From Baseline, % –0.7% Mean Baseline A1C: 8.0% P<0.001* Add-on to metformin study 1 –0.0% Metformin + Placebo Pioglitazone + JANUVIA Pioglitazone + Placebo *Compared with placebo. 1. Charbonnel B et al. Diabetes Care. 2006;29:2638– Rosenstock J et al. Clin Ther. 2006;28:1556–1568. n=453n=174n= % placebo- subtracted result –0.9% –0.4 –0.2 –0.8 –0.6 –0.4 –0.2 –0.2%

19 Monotherapy studies –No increase in body weight from baseline with JANUVIA compared with a small reduction in the placebo group Add-on to metformin –A similar decrease in body weight for both treatment groups Add-on to pioglitazone –No significant difference in body weight change between treatment groups JANUVIA™ (sitagliptin): Effect on Body Weight