Clinical Overview of Combination Therapy with Sitagliptin and Metformin

Clinical Overview of Combination Therapy with Sitagliptin and Metformin 1

Contents Pathophysiology of type 2 diabetes and mechanism of action of sitagliptin Clinical data overview of sitagliptin: Monotherapy (PN021, 023, A201) Complexities of getting patients to goal: a rationale for earlier combination therapy Mechanism of action of the co-administration of sitagliptin plus metformin Clinical data overview of combination therapy with sitagliptin and metformin 8

Major Pathophysiologic Defects in Type 2 Diabetes Islet-Cell Dysfunction Glucagon (α cell) Pancreas Hepatic glucose output Liver Insulin (β cell) Hyperglycaemia Insulin resistance Glucose uptake Muscle Adipose tissue Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145 168. 4

Mechanism of Action of Sitagliptin GI tract Ingestion of food Release of active incretins GLP-1 & GIP JANUVIA (DPP-4 inhibitor) Inactive GLP-1 X DPP-4 enzyme Inactive GIP Pancreas Beta cells Alpha cells Glucosedependent Insulin (GLP-1and GIP) Glucose dependent Glucagon (GLP-1) Glucose uptake by peripheral tissue Hepatic glucose production Blood glucose in fasting and postprandial states Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels in response to a meal. Concentrations of the active intact hormones are increased by JANUVIA (sitagliptin phosphate), thereby increasing and prolonging the actions of these hormones. GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Sitagliptin - Overview F F NH 2 O F N N N N CF 3 Provides potent and highly selective inhibition of the DPP-4 enzyme Fully reversible and competitive inhibitor DPP-4 inhibitor in development for the treatment of patients with type 2 diabetes, approved by the FDA on October 17 2006, and approved in EU on March 26 2007 Approved in Korea on September 21 2007

Pharmacokinetics of Sitagliptin Supports Once-Daily Dosing With once-daily administration, trough (at 24 hrs) DPP-4 inhibition is ~ 80% > 80% inhibition provides full enhancement of active incretin levels No effect of food on pharmacokinetics Well absorbed following oral dosing T max app 2 hours, t 1/2 app 12.4 hours at 100 mg dose Low protein binding, app 38% Primarily renal excretion as parent drug Approximately 80% of a dose recovered as intact drug in urine No clinically important drug-drug interactions No meaningful P450 system inhibition or activation

Single-Dose OGTT Study One Dose of Sitagliptin Inhibited Plasma DPP-4 Activity OGTT Inhibition of plasma DPP-4 activity from baseline (%) 100 90 80 70 60 50 40 30 20 10 0 10 Hours post-dose Sitagliptin 25 mg (n=56) Sitagliptin 200 mg (n=56) Placebo (n=56) Trough DPP-4 inhibition ~80% ~50% 0 1 2 4 6 8 10 12 14 16 18 20 22 24 26 OGTT=oral glucose tolerance test; AUC=area under the curve Herman et al. J Clin Endocrinol Metab, November 2006, 91(11):4612 4619. PN005

A Single Dose of Sitagliptin Increased Active GLP-1 and GIP Over 24 Hours Crossover study in patients with T2DM Placebo Active GLP-1 Active GIP Sitagliptin 25 mg 40 OGTT 2 hrs (n=55) OGTT 24 hrs (n=19) 90 OGTT 2 hrs (n=55) OGTT 24 hrs (n=19) Sitagliptin 200 mg GLP-1 (pg/ml) 35 30 25 20 15 10 5 2-fold increase in active GLP-1 p< 0.001 vs placebo GIP (pg/ml) 80 70 60 50 40 30 20 10 2-fold increase in active GIP p< 0.001 vs placebo 0 0 2 4 6 24 26 28 0 0 2 4 6 24 26 28 Hours Postdose Hours Postdose Herman et al. J Clin Endocrinol Metab, November 2006, 91(11):4612 4619. PN005

A Single Dose of Sitagliptin Increased Insulin, Decreased Glucagon, and Reduced Glycemic Excursion After a glucose Load 40 Insulin Crossover Study in Patients with T2DM Placebo mciu/ml 30 20 Drug Glucose Dose load 22% Sitagliptin 25 mg Sitagliptin 200 mg 10 320 Glucose pg/ml 0 75 70 65 60 55 50 p<0.05 for both dose comparisons to placebo for AUC 0 1 2 3 4 Glucagon p<0.05 for both dose comparisons to placebo for AUC 0 1 2 3 4 ~12% 280 240 200 160 120 Drug Dose Glucose load 0 1 2 3 4 5 6 Time (hours) ~26% p<0.001 for both dose comparisons to placebo for AUC Time (hours) Herman et al. J Clin Endocrinol Metab, November 2006, 91(11):4612 4619. PN005

Contents Pathophysiology of type 2 diabetes and mechanism of action of sitagliptin Clinical data overview of sitagliptin: Monotherapy (PN021, PN023, A201, and PN040) Complexities of getting patients to goal: a rationale for earlier combination therapy Mechanism of action of the co-administration of sitagliptin plus metformin Clinical data overview of combination therapy with sitagliptin and metformin 8

Sitagliptin Consistently and Significantly Lowers A1C with Once-Daily Dosing in Monotherapy Δchange vs placebo* 8.4 = 18-week Study -0.6% (p<0.001) 8.4 24-week Study -0.79% (p<0.001) 8.4 Japanese Study -1.05% (p<0.001) 8.0 8.0 8.0 7.6 A1C (%) 7.6 A1C (%) 7.6 A1C (%) 7.2 7.2 Placebo (n=74) Sitagliptin 100 mg (n=168) 7.2 Placebo (n=244) Sitagliptin 100 mg (n=229) 6.8 Placebo (n=75) Sitagliptin 100 mg (n=75) 0 6 12 18 0 5 10 15 20 25 0 4 8 12 Time (weeks) Time (weeks) Time (weeks) *between group difference in LS means Raz I et al. Diabetologia 2006;49:2564-2571 ; PN023; Aschner P et al. Diabetes Care 2006;29:2638-2643 ; PN021; Nonaka K et al; A201. Abstracts presented at: ADA 2006 11

Sitagliptin Provides Significant and Progressively Greater Reductions in A1C with Progressively Higher Baseline A1C Inclusion Criteria: 7% 10% 18-week Study 24-week Study Baseline A 1c (%) <8% 8 9% >9% <8% 8 9% >9% Reduction in A 1c (%) Mean (%) 0.0-0.2-0.4-0.6-0.8-1.0-1.2-1.4-1.6-1.8 7.37 8.40 9.48 N=96 N=70-0.44-0.61 N=27-1.2 Reduction in A 1c (%) 0.0-0.2-0.4-0.6-0.8-1.0-1.2-1.4-1.6 7.39 8.36 9.58 N=130-0.57 N=62 N=62-0.8 N=37 N=37-1.8-1.52 Reductions are placebo-subtracted Raz I et al. Diabetologia 2006;49:2564-2571 ; PN023; Aschner P et al. Diabetes Care 2006;29:2638-2643 ; PN021; Nonaka K et al; A201. Abstracts presented at: ADA 2006

Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy Fasting Glucose Post-meal Glucose 189 Δ FPG* = 17.1 mg/dl (p<0.001) 288 Δ in 2-hr PPG* = 46.7 mg/dl (p<0.001) 180 Plasma Glucose mg/dl 171 162 153 144 Placebo (n=247) Sitagliptin 100 mg (n=234) Plasma Glucose mg/dl 252 216 180 144 Baseline 24 weeks Placebo (N=204) Baseline 24 weeks Sitagliptin (n=201) 0 5 10 15 20 25 0 60 120 0 60 120 Time (weeks) Time (minutes) * LS mean difference from placebo after 24 weeks Aschner P et al, PN021. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC

Sitagliptin Improved Markers of Beta-Cell Function In 24-Week Monotherapy Study 0.55 Proinsulin/insulin ratio 80 HOMA-β 75 Ratio (pmol/l / pmol/l) 0.5 0.45 0.4 0.35 p< 0.001* 70 65 60 55 50 45 40 p< 0.001* 35 0.3 Placebo Sitagliptin 100 mg 30 Placebo Sitagliptin 100 mg from baseline vs pbo = 0.078 (95% CI -0.114, -0.023) Hatched = Baseline Solid = Week 24 from baseline vs pbo = 13.2 (95% CI 3.9, 21.9) *P value for change from baseline compared to placebo Raz I et al. Diabetologia 2006;49:2564-2571 ; PN023; Aschner P et al. Diabetes Care 2006;29:2638-2643 ; PN021; Nonaka K et al; A201. Abstracts presented at: ADA 2006

Sitagliptin Monotherapy in Asian Patients (PN040) A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Sitagliptin Monotherapy in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control

Study Design Patients with T2DM 18 years of age Not on AHA A1C 7.5% and 11% On AHA A1C 7% and 10% A1C 7.5 and 11% FPG 130 mg/dl and 280 mg/dl Single-Blind Placebo R Sitagliptin 100 mg Pbo Screening Period Diet/Exercise Run-in Period Single- Blind Placebo Run-in Double-Blind Treatment Period Visit 1 Screening Wk 9 Visit 2 Run-in Start Wk 8 Visit 3 Wk 5 Visit 4 Wk 2 Start SB Visit 5 Day 1 Randomization Visit 6 Wk 6 Visit 7 Wk 12 Visit 8 Wk 18 AHA = antihyperglycemic agent; FPG = fasting plasma glucose; R = randomization; T2DM = type 2 diabetes mellitus.

Baseline Glycemic and Disease Characteristics Balanced Between Groups Characteristic Sitagliptin (n=352) Placebo (n=178) Age (yrs) BMI (mean, kg/m2 ) A1C (%) FPG (mg/dl) Fasting insulin (μiu/ml ) Duration of Diabetes Mellitus ( yrs) HOMA Beta (%) 50.9 ± 9.3 25.1 ± 3.4 8.74 ± 1.01 189.0 ± 44.0 9.7 ± 8.2 2.1 ± 1.7 33.0 50.9 ± 9.3 24.9 ± 3.4 8.75 ± 1.06 181.6 ± 42.5 10.0 ± 8.4 1.9 ±1.6 32.0

Change from Baseline in HbA1c Full-Analysis-Set Population 0.4 LS Mean Change from Baseline 0.2 0.0-0.2-0.4-0.6-0.8-1.03% 0 6 12 18 Sitagliptin 100 mg Week Placebo

Change from Baseline Per Country Country Group Placebo Subtracted % A1c change Placebo Subtracted mg/dl FPG Placebo Subtracted mg/dl PPG India Sita (n=119) Plbo (n=59) -1.36-38.8-49.8 China Sita (n=158) Plbo (n=79) -0.68-18.2-49.9 Korea Sita (n=62) Plbo (n=31) -1.37-54.5-90.6

HbA1c Reduction in Korean Diabetes Patients 0.8 Placebo 0.6 Sitagliptin 0.4 Mean change of A1C from baseline(%) 0.2 0-0.2-0.4-0.6 Sitagliptin vs. placebo = -1.37% -0.8-1 0wks 6wks 12wks 18wks Group Sita (n=62) Plbo (n=31) Placebo Subtracted mg/dl FPG Placebo Subtracted mg/dl PPG -54.5-90.6

Summary (PN040: Sitagliptin Monotherapy in Asian patients) Sitagliptin demonstrated strong glycemic efficacy compared to placebo, as measured by HbA1c, FPG and PPG Sitagliptin was overall well tolerated No hypoglycemia For adverse experiences within GI system organ class, a higher incidence was observed with Sitagliptin

ADA and IDF Guidelines: Treatment Goals for HbA 1c, FPG, and PPG Parameter Normal Level ADA Goal IDF Goal FPG, mg/dl (mmol/l) <110 (<6.1) 90 130 (5.0 7.2) <100 (<5.5) PPG, mg/dl (mmol/l) <140 (<7.8) <180 (<10.0) <140 (<7.8) HbA 1c 4% 6% <7%* <6.5% *Reference to a nondiabetic range of 4.0% to 6.0% using a DCCT-based assay. ADA=American Diabetes Association; IDF=International Diabetes Federation. American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4 S41; International Diabetes Federation. 2007:1 32. Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427 1483. 9

Societies Recommend Earlier Intervention to Help Attain Glycaemic Control 2006 Consensus statement from the ADA and EASD Our consensus is that an HbA 1c of 7 should serve as a call to action to initiate or change therapy If lifestyle intervention and maximal tolerated dose of metformin fail to achieve or sustain glycaemic goals, another medication should be added within 2 3 months of the initiation of therapy or at any time when HbA 1c goal is not achieved 2005 Global Guideline by IDF Begin with metformin unless evidence or risk of renal impairment, titrating the dose over early weeks to minimise discontinuation due to gastro-intestinal intolerance Step up doses, and add other glucose-lowering drugs, at frequent intervals until blood glucose control is at target levels EASD=European Association for the Study of Diabetes. Nathan DM et al. Diabetologia. 2006;49:1711 1721; International Diabetes Federation. 2005:1 79. 10

HbA 1c Levels Above ADA/EASD Target Goals Have Not Triggered Timely Therapy Modifications a 10 9 Metformin monotherapy (n=513 episodes) Sulfonylurea monotherapy (n=3394 episodes) 35 b 27 b months months 9.1 8.8 HbA 1c, % 8 7 8.2 7.6 7.7 7.1 ADA goal EASD goal 6 0 First HbA 1c on Treatment Best HbA 1c on Treatment Last HbA 1c before Switch or Addition c a US Physicians; 1994 2002 b Mean number of months that elapsed until a new or additional treatment was started. c Monotherapy switched to another agent or additional agent added. Brown JB et al. Diabetes Care. 2004;27:1535 1540; American Diabetes Association. Diabetes Care. ADA=American Diabetes Association. 2007;30(suppl 1):S4 S41; Nathan DM et al. Diabetologia. 2006 Aug;49(8):1711 21. EASD=European Association for the Study of Diabetes. 11

Traditional Type 2 Diabetes Management: A Treat-to-Fail Approach Published Conceptual Approach Mean HbA 1c of patients Diet and exercise OAD monotherapy OAD up-titration OAD combination OAD plus basal insulin OAD plus multiple daily insulin injections 10 HbA 1c, % 9 8 7 6 Time Duration of Diabetes OAD=oral anti-hyperglycaemic drug. Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625 631. Del Prato S et al. Int J Clin Pract. 2005;59:1345 1355. 12

Less than 50% of Adults With Type 2 Diabetes Have Achieved HbA 1c Goals 60 US Population NHANES III (1988 1994) (n=1204) NHANES 1999 2000 (n=370) 50 44.3 48.2 Adults, % 40 30 20 37.0 35.8 29.0 33.9 10 5.2 7.3 0 HbA 1c level <7% Blood pressure <130/80 mmhg Total cholesterol <200 mg/dl Achieved all 3 treatment goals CV Risk Factors NHANES=National Health and Nutrition Examination Survey of a US population. Adapted from Saydah SH et al. JAMA. 2004;291:335 342. 13

UKPDS: Improving HbA 1c Control Reduced Diabetes-Related Complications EVERY 1% reduction in HbA 1c Relative Risk N=3642 Diabetesrelated deaths REDUCED RISK (P<0.0001) 21% 1% Myocardial infarctions Microvascular complications 14% 37% Amputations or deaths from peripheral vascular disorders 43% UKPDF=United Kingdom Prospective Diabetes Study. Data adjusted for age, sex, and ethnic group, expressed for white men aged 50 54 years at diagnosis and with mean duration of diabetes of 10 years. Stratton IM et al. UKPDS 35. BMJ 2000;321:405 412. 14

Major Targeted Sites of Oral Drug Classes Liver Pancreas Impaired insulin secretion Sulfonylureas Meglitinides DPP-4 inhibitors Muscle and fat Hepatic glucose overproduction Biguanides TZDs DPP-4 inhibitors Glucose level Gut Glucose absorption Insulin resistance TZDs Biguanides α-glucosidase inhibitors Biguanides DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427 1483; DeFronzo RA. Ann Intern Med. 1999;131:281 303; Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247 254. 15

Mechanisms of Action of Major Oral Monotherapies Are Unable to Address the 3 Core Defects in Type 2 Diabetes Oral Monotherapies SUs Meglitinides TZDs Metformin α-glucosidase Inhibitors DPP-4 Inhibitors Mechanisms of Action Improves insulin secretion Improves insulin resistance Lowers hepatic glucose production SUs=sulfonylureas; TZD=thiazolidinediones; DPP-4=dipeptidyl peptidase 4. Inzucchi SE. JAMA 2002;287:360 372; Gallwitz B. Minerva Endocrinol. 2006;31:133 147; Nathan DM et al. Diabetologia. 2006;49:1711 1721. 16

Earlier Use of Combination Therapy May Improve Treating to Target Compared With Conventional Therapy Diet and exercise Published Conceptual Approach OAD monotherapy OAD up-titration OAD combination OAD plus basal insulin OAD plus multiple daily insulin injections 10 HbA 1c, % Mean HbA 1c of patients 9 8 7 6 Time Duration of Diabetes OAD=oral anti-hyperglycaemic drug. Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625 631. Del Prato S et al. Int J Clin Pract. 2005;59:1345 1355. 18

Summary Complexities of Getting Patients to Goal: A Rationale for Earlier Combination Therapy Percentage of patients with type 2 diabetes getting to glycaemic goal is far from optimal Current conventional treatment paradigm has been characterised by treatment to failure rather than treatment to success Physicians see adverse events and adherence as the main barriers to earlier use of current combination therapy regimens Revised/proactive treatment paradigm for type 2 diabetes, involving earlier use of combination therapy, is urgently needed to be more effective in reaching and maintaining HbA 1c goals Saydah SH et al. JAMA. 2004;291:335 342; Brown JB et al. Diabetes Care. 2004;27:1535 1540; Del Prato S et al. Int J Clin Pract. 2005;59:1345 1355; Campbell IW. Br J Cardiol. 2000;7:625 631; Grant RW, et al. Diabetes Care. 2003;26:1408 1412; Dailey G et al. Clin Ther. 2001;23:1311 1320. 19

The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes in a Complementary Manner Sitagliptin improves markers of β-cell function and increases insulin synthesis and release β-cell Dysfunction Insulin Resistance Metformin acts as an insulin sensitiser (liver>muscle/fat) Sitagliptin indirectly reduces HGO through suppression of glucagon from α cells Hepatic Glucose Overproduction Metformin significantly decreases HGO by directly targeting the liver to decrease gluconeogenesis and glycogenolysis HGO=hepatic glucose overproduction. Aschner P et al. Diabetes Care. 2006;29:2632 2637; Abbasi F et al. Diabetes Care. 1998;21:1301 1305; Inzucchi SE. JAMA 2002;287:360 372; Kirpichnikov D et al. Ann Intern Med. 2002;137:25 33; Zhou G et al. J Clin Invest. 2001;108:1167 1174. 22

HbA 1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy HbA 1c, % ±SE 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 LSM change from baseline (for both groups): 0.7% Sulfonylurea a + metformin (n=411) Sitagliptin b + metformin (n=382) Achieved primary hypothesis of noninferiority to sulfonylurea 6.2 0 6 12 18 24 30 38 46 52 Weeks Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194 205 with permission from Blackwell Publishing Ltd., Boston, MA. a Specifically glipizide 20 mg/day; b Sitagliptin 100 mg/day with metformin ( 1500 mg/day). Per-protocol population; LSM=least squares mean. 27 SE=standard error.

Greater Reductions in HbA 1c Associated With Higher Baseline HbA 1c 52-Week Post Hoc Analysis Baseline HbA 1c Category Mean Change From Baseline in HbA 1c, % 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 <7% 7 to <8% 8 to <9% 9% n=117 n=112 n=179 n=167 n=82 n=82 n=33 n=21 0.1 0.3 0.6 0.5 1.1 1.1 Sulfonylurea a plus metformin Sitagliptin b plus metformin 1.8 1.7 Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194 205 with permission from Blackwell Publishing Ltd., Boston, MA. a Specifically glipizide 20 mg/day. b Sitagliptin 100 mg/day with metformin ( 1500 mg/day); Per-protocol population. Add-on sitagliptin with metformin vs sulfonylurea with metformin study. 28

Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycaemia Least squares mean change over time c Hypoglycaemia c Body Weight, kg ± SE 3 2 1 0 1 2 Sulfonylurea a plus metformin (n=416) Sitagliptin b plus metformin (n=389) Δ between groups = 2.5 kg 3 0 12 24 38 52 Weeks P<0.001 Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194 205 with permission from Blackwell Publishing Ltd., Boston, MA. Patients With 1 Episode, % 50 40 30 20 10 0 Sulfonylurea a plus metformin (n=584) Sitagliptin b plus metformin (n=588) 32% Week 52 P<0.001 5% a Specifically glipizide 20 mg/day; b Sitagliptin (100 mg/day) with metformin ( 1500 mg/day); c All-patients-as-treated population. Least squares mean between-group difference at week 52 (95% CI): change in body weight = 2.5 kg [ 3.1, 2.0] (P<0.001); Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: 1.5 kg (P<0.001). Add-on sitagliptin with metformin vs sulfonylurea with metformin study. 29

Summary: Sitagliptin or Glipizide as Add-on Combination With Metformin Efficacy profile Comparable efficacy in lowering HbA 1c Both provided greater HbA 1c reductions in patients with the highest baseline HbA 1c Safety profile Both were generally well tolerated Adverse event profiles (ie, serious and GI-related adverse events, those leading to discontinuation) were similar, with the exception of hypoglycaemia Significantly lower incidence of hypoglycaemic episodes associated with sitagliptin with metformin Body weight significantly decreased for sitagliptin with metformin, but increased for glipizide with metformin Nauck MA et al. Diabetes Obes Metab. 2007;9:194 205. 30

Summary Insulin resistance, β-cell dysfunction, and elevated hepatic glucose production are the 3 core pathophysiologies of type 2 diabetes Incretins positively affect glucose homeostasis by physiologically helping to regulate Insulin secretion from β cells in a glucose-dependent manner Glucagon secretion in a glucose-dependent manner Getting patients to goal may be enhanced by targeting all 3 core defects and hyperglycaemia in the fasting and post-prandial states Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775 781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247 254; Drucker DJ. Diabetes Care. 2003;26:2929 2940; Nauck MA et al. Diabetologia. 1993;36:741 744; Monnier L et al. Diabetes Care. 2003;26:881 885; American Diabetes Association. Diabetes Care. 2007;30(Suppl 1):S4 S41; International Diabetes Federation. 2008:1 32. 41

Summary (Continued) Sitagliptin and metformin have complementary mechanisms of action that address all 3 core defects of type 2 diabetes Sitagliptin as add-on combination with metformin provided HbA1c reductions comparable to adding an SU With less hypoglycemia With weight loss Nauck MA et al. Diabetes Obes Metab. 2007;9:194 205;; Goldstein BJ et al. Diabetes Care. 2007;30:1979 1987; Hermansen K et al. Diabetes Obes Metab. 2007;9:733 745. 42

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