1. Overview and rational of main international guiderlines for the treatment of type 2 diabetes Dr. med. Bernd Voss Specialist in Internal Medicine / Munich, Germany Regional Director Medical Affairs Diabetes Eastern Europe, Middle East, Africa MSD

2. Development and Progression of Type 2 Diabetes and Related Complications 1,a 2 a Conceptual representation. 1. Reprinted from Primary Care, 26(4), Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier. Insulin level Insulin resistance Hepatic glucose production Postprandial glucose glucose Fasting plasma glucose Beta-cell function Progression of Type 2 Diabetes Mellitus Impaired Glucose Tolerance Diabetes Diagnosis Frank Diabetes 4–7 years Development of Macrovascular Complications Development of Microvascular Complications

3. UKPDS: Correlation Between HbA 1c and Macro- and Microvascular End Points 1 3 Fatal and Nonfatal Myocardial Infarction 0.5 1 5 0567891011 14% decrease per 1% decrement in HbA 1c P < 0.0001 Hazard Ratio Updated Mean HbA 1c UKDPS= UK Prospective Diabetes Study. 1. Reproduced from the British Medical Journal, Stratton IM, Adler AI, Neil AW, et al., Vol. 321, 405-412, copyright notice (2000) with permission from BMJ Publishing Group Ltd. 0.5 1 10 15 0567891011 Microvascular End Points 37% decrease per 1% decrement in HbA 1c P < 0.0001

4. ADA/EASD Consensus statement 2012

5. Type 2 diabetes The management of type 2 diabetes NICE clinical guideline, May 2009 www.nice.org.uk Developed by the National Collaborating Centre for Chronic Conditions and the Centre for Clinical Practice at NICE

6. Algorithm HbA 1C ≥ 6.5%* HbA 1C ≥ 6.5%* after trial of lifestyle measures SU Where blood glucose control remains or becomes inadequate on metformin Usual approach Alternatives Sitagliptin Where insulin is unacceptable or inappropriate Insulin (NPH insulin, long-acting insulin analogues, pre-mix insulin) Monitor use and response and adjust doses if necessary Exenatide If BMI ≥35 kg/m 2‡ and there are problems associated with high body weight; or BMI <35 kg/m 2‡ and insulin is unacceptable because of occupational implications or weight loss would benefit other co-morbidities HbA 1C ≥ 7.5%* 1 2 + 3 + TZD (glitazones)† Consider adding instead of an SU where Patients are at significant risk of hypoglycaemia or its consequences Patients are intolerant of or contra-indicated to SU May be preferable to DPP-4 inhibitors where The patient has marked insulin insensitivity DPP-4 inhibitors are contra-indicated Previous poor response or intolerance to a DPP-4 inhibitor Where either a DPP-4 inhibitor or a TZD may be suitable, the choice of treatment should be based on patient preference * Or individually agreed target. Monitor patient following initiation of a new therapy and continue only if beneficial metabolic response occurs (refer to guideline for suggested metabolic responses). Discuss potential risks and benefits of treatments with patients so informed decision can be made. † When selecting a TZD take into account up-to-date advice from the relevant regulatory bodies, cost, safety and prescribing issues. Do not commence or continue a TZD in people who have heart failure, or who are at higher risk of fracture. ‡ In people of European descent (adjusted for other ethnic groups) DPP-4 inhibitor Consider adding instead of an SU where Patients are at significant risk of hypoglycaemia or its consequences Patients are intolerant of or contra-indicated to SU May be preferable to TZD where Further weight gain would cause or exacerbate sign- ificant problems associated with a high body weight TZDs are contra-indicated Previous poor response or intolerance to a TZD Where either a DPP-4 inhibitor or a TZD may be suitable, the choice of treatment should be based on patient preference TZD (glitazones) † Where insulin is unacceptable or inappropriate Metformin Consider SU in people who Are not overweight Require a rapid response due to hyperglycaemic symptoms Are unable to tolerate metformin or where metformin is contra-indicated

7. IDF Guidelines 2012 © International Diabetes Federation, 2012, ISBN 2-930229-43-8. This document is also available at www.idf.org

8. Guidelines of the German Diabetes Society DDG Matthaei S et al. Medical Antihyperglycaemic Treatment of Diabetes … Exp Clin Endocrinol Diabetes 2009; 117: 522 – 557

9. Guidelines of the German Diabetes Society DDG (continued) Matthaei S et al. Medical Antihyperglycaemic Treatment of Diabetes … Exp Clin Endocrinol Diabetes 2009; 117: 522 – 557

10. SIGN Scottish Intercollegiate Guidelines Network Part of NHS Quality Improvement Scotland Management of Diabetes March 2010 ISBM 978 1 905813599 www.sign.ac.uk

12. 12 AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology; AGI=α-glucosidase inhibitor; DPP-4=dipeptidyl peptidase-4; FPG=fasting plasma glucose; GLP-1=glucagon-like peptide-1; MET=metformin; NAFLD=nonalcoholic fatty liver disease; PPG=postprandial glucose; SU=sulfonylurea; TZD=thiazolidinedione. 1. Rodbard HW et al. Endocr Pract. 2009;15(6):540–559. Permission obtained from American Association of Clinical Endocrinologists. HbA 1c 6.5%–7.5% b Monotherapy MET+ GLP-1 or DPP-4 d TZD e Glinide or SU h TZD+GLP-1 or DPP-4 d MET+ Colesevelam AGI f 2–3 Months g Dual Therapy MET+ GLP-1 or DPP-4 d ± SU j TZD e GLP-1 or DPP-4 d ± TZD e HbA 1c >9.0% No Symptoms Drug Naive Under Treatment INSULIN ± Other Agent(s) k Symptoms INSULIN ± Other Agent(s) k INSULIN ± Other Agent(s) k MET + GLP-1 or DPP-4 d + TZD e Glinide or SU i,j MET+ GLP-1 or DPP-4 d or TZD e SU or Glinide h,i Triple Therapy HbA 1c 7.6%–9.0% Dual Therapy l 2–3 Months g Triple Therapy m INSULIN ± Other Agent(s) k MET c DPP-4 d GLP-1TZD e AGI f MET+ GLP-1 or DPP-4 d + TZD e GLP-1 or DPP-4 d + SU j TZD e HbA 1c Goal ≤6.5% a aMay not be appropriate for all patients bFor patients with diabetes and HbA 1c <6.5%, pharmacologic Rx may be considered cPreferred initial agent dDPP-4 if  PPG and  FPG or GLP-1 if  PPG eTZD if metabolic syndrome and/or NAFLD fAGI if  PPG gIf HbA 1c goal not achieved safely hLow-dose secretagogue recommended iGlinide if  PPG or SU if  FPG jDecrease secretagogue by 50% when added to GLP-1 or DPP-4 ka) Discontinue insulin secretagogue with multidose insulin b) Can use pramlintide with prandial insulin lIf HbA 1c <8.5%, combination Rx with agents that cause hypoglycemia should be used with caution mIf HbA 1c >8.5%, in patients on dual therapy, insulin should be considered

13. DPP-4 Inhibitors in the AACE/ACE Diabetes Algorithm For Glycemic Control 1  A guiding principle of the current algorithm is “the recognition of the importance of avoiding hypoglycemia.”  The AACE/ACE diabetes algorithm favors the use of DPP-4 inhibitors and GLP-1 agonists as dual therapy with metformin over sulfonylureas, in patients with HbA 1c levels 6.5%-9.0%, based on efficacy and overall safety profiles. – Sulfonylureas have been associated with greater risks of hypoglycemia and weight gain.  In combination with metformin, DPP-4 inhibitors are a preferred oral option in dual therapy for patients with HbA 1c levels between 6.5% and 9.0%. 13 AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagonlike peptide-1. 1. Rodbard HW et al. Endocr Pract. 2009;15(6):540–559.

14. NHANES: Patients With Diabetes Are Not at Goal (A1C <7%) 1 n=790 n=904 43 48 38 37 62 44 41 57 NHANES=National Health and Nutrition Examination Survey. 1. Cheung BM, et al. Am J Med. 2009;122:443–453. 37 54

15. Persistence of Metformin Monotherapy in Patients Not at HbA 1c Goal 1 15 FPG=fasting plasma glucose. a Patients with type 2 diabetes and HbA 1C ≥7% or ≥2 FPG levels ≥126 mg/dL while on metformin monotherapy for ≥6 months; index period of January 1, 1997 to December 31, 2008; mean follow-up time = 2.9 years 1. Fu AZ et al. Diabetes Obes Metab. 2011;13:765–769. Proportions of Patients on Metformin Monotherapy 0.00 1.00 0.75 0.50 0.25 012345 Years Index HbA 1C 7% to <8% Index HbA 1C 8% to <9% Index HbA 1C ≥9% All patients (Mean HbA 1C = 8.0%) 14.0 months Retrospective analysis using a large US electronic medical record database (N=12,566) a

16. 16 Cardiovascular Complications Are Very Costly Among Patients With Diabetes 1 1. ADA. Diabetes Care. 2008;31:596–615. US health care expenditures for chronic complications of diabetes in 2007: hospital inpatient expenses based on annual medical claims for 16.3 million people $ US, millions NeurologicPeripheral Vascular Cardio- vascular RenalMetabolicOphthalmicOther

17. Hypoglycemia Is Associated With Increased Health Care Costs 1 17 Hospital Outcomes, mean Patients With Hypoglycemia Patients Without Hypoglycemia Between-Group Difference or Odds Ratio (unadjusted) a P n Mean Valuen Length of hospital stay, d 823411.795,5795.16.6<0.001 Hospital mortality, % 79944.893,0122.32.12 a <0.001 Discharged to skilled nursing facility, % b 778726.593,13414.51.83 a <0.001 Total hospital charges, 2006 $ 602085,90572,68154,03859%<0.001  A retrospective cohort study of inpatients with diabetes compared those who developed laboratory evidence of hypoglycemia after 24 hours of hospitalization to those who did not develop hypoglycemia during their entire hospital stay a Difference is shown as the percentage difference for charges, mean difference in days for length of stay, odds ratio for hospital mortality, and odds ratio for discharge to SNF. b Patients who were admitted to the hospital from a SNF were excluded from this analysis. 1. Copyright © 2009 AACE. Curkendall SM et al. Endocr Pract. 2009;15(4):302–312. Reprinted with permission from the AACE. Base-case analysis (blood glucose <70 mg/dL)

18. Potential Complications and Effects of Severe Hypoglycemia 18 Plasma glucose level 10 20 30 40 50 60 70 80 90 100 110 1 2 3 4 5 6 mg/dL mmol/L 1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307. 2. Cryer PE. J Clin Invest. 2007;117:868–870. Arrythmia 1 Neuroglycopenia 2  Abnormal prolonged cardiac repolarization — ↑ QTc and QT dispersion  Sudden death  Cognitive impairment  Unusual behavior  Seizure  Coma  Brain death

19. ADVANCE: Severe Hypoglycemia Was Associated With Adverse Clinical End Points and Death 1 19 ADVANCE=Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation; CI=confidence interval; CV=cardiovascular; HR=hazard ratio. a Adjusted for multiple baseline covariates. b Primary end points. Major macrovascular event=CV death, nonfatal myocardial infarction, or nonfatal stroke; major microvascular event=new or worsening nephropathy or retinopathy. 1. Zoungas S et al. N Engl J Med. 2010;363:1410–1418. HR (95% CI): 3.53 (2.41–5.17) a HR (95% CI): 2.19 (1.40–3.45) a HR (95% CI): 3.27 (2.29–4.65) a HR (95% CI): 3.79 (2.36–6.08) a HR (95% CI): 2.80 (1.64–4.79) a bb

20. Non-Severe Hypoglycemic Events Were Associated With Substantial Loss of Productivity 1 20 Estimated Productivity Loss Due to Absenteeism From an NSHE, $ a The majority of patients were treated with insulin (72.9% with insulin vs 27.1% with oral antihyperglycemic agents). Significant cross-country differences were found for age, gender, and diabetes duration ( P <0.001 for each). NSHE=non-severe hypoglycemic event. a These estimates were calculated based on the proportion of respondents reporting missed work, multiplied by hourly income and hours missed; the 2009 gross domestic product per capita was used to estimate annual income. 1. Brod M et al. Value Health. 2011;14:665–671. 1,404 adult patients with self-reported type 1 or type 2 diabetes participated in a 20-minute internet survey conducted in 4 countries to assess the effect of NSHEs occurring during work, outside of work hours, and overnight, on productivity. Analysis sample consisted of all respondents who reported an NSHE in the past month. n = 307n = 278n = 205n = 287n = 232n = 153n = 279n = 283n = 166n = 173n = 170n = 88

21. Significantly More Emergency Department Visits and Hospital Admissions Associated With Hypoglycemia 1 21 a Includes insulin-treated patients with type 1 and type 2 diabetes; US medical insurance claims. Hypoglycemia occurrence= claims coded by (ICD-9-CM) 250.8, 251.1, or 251.2 at any time in the identified period. 1. Copyright © 2005. Rhoads GG et al. J Occup Environ Med. 2005;47(5):447–452. Reprinted with permission. Emergency department visitsHospital admissions 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 HypoglycemiaOther reasons Any hypoglycemia claim a No hypoglycemia claim a Any hypoglycemia claim a No hypoglycemia claim a 0.0 0.2 0.4 0.6 0.8 1.0 1.2 Annual Average

22. Hypoglycemia Was Associated With Decreased Health-Related Quality of Life 1 22 Without SymptomsWith Symptoms With Mild Symptoms With Moderate Symptoms With Severe Symptoms P <0.0001 a P <0.0001 b EQ-5D=EuroQoL-5D, a standardized measure of health-related QoL; QoL=quality of life; RECAP-DM=Real-Life Effectiveness and Care Patterns of Diabetes Management ;T2DM=type 2 diabetes; TZD=thiazolidinedione; VAS=visual analog scale. a Based on the t test of the null of no differences in the mean quality of life scores between patients with and without hypoglycemic symptoms. b Based on the F test of the joint hypothesis of no differences in the mean quality of life scores across hypoglycemic symptom severity groups, including patients reporting no symptoms of hypoglycemia. 1. Álvarez Guisasola F et al. Health Qual Life Outcomes. 2010;8:86–93. RECAP-DM: observational, cross-sectional, multicenter study conducted in 7 European countries; 1,709 patients with T2DM who added a sulfonylurea or a TZD to ongoing metformin therapy

23. Hypoglycemia Was Associated With More Short-Term Disability and Higher Health Care Costs 1 Patients With Hypoglycemia a n=442 Patients Without Hypoglycemia a n=2222 P ≥1 episode of short-term disability 47%32% P < 0.01 Days of short-term disability per person-years 19.511.0 P < 0.01 Annualized health care expenditures b $3169$1812 P < 0.01 23  Incidence of disability increased from 0.8% to 4.7% the week after a hypoglycemic episode. a Includes insulin-treated patients with type 1 and type 2 diabetes; US medical insurance claims. b Attributable to short-term disability work loss. Hypoglycemia occurrence=claims coded by (ICD-9-CM) 250.8, 251.1, or 251.2 at any time in the identified period. 1. Rhoads GG et al. J Occup Environ Med. 2005;47(5):447–452.

24. Sweden: Health Care–Related Costs and Hypoglycemia 1 24 Mild, moderate, and severe episodes of hypoglycemia were considered in this analysis. 1. Reproduced with permission of John Wiley and Sons. Jonsson L et al. Value Health. 2006;9:193–198. Permission conveyed through Copyright Clearance Center, Inc.  Based on 300,000 patients with type 2 diabetes in Sweden, health care costs per year attributed to hypoglycemic events in patients with type 2 diabetes are €4.25 million or €14.1/person using cost-of-illness methodology. Cost Insulin Users ≤65 Years Insulin Users >65 Years Oral Treatment Users ≤65 Years Oral Treatment Users >65 Years All Type 2 Diabetes Patients Mild events, M€ 0.350.260.090.030.73 Moderate events, M€ 0.851.280.210.312.65 Severe events, M€ 0.310.390.080.100.87 Total, M€ 1.521.910.380.454.25 Per type 2 patient, € 45.733.78.05.614.1 Expected Yearly Cost of Hypoglycemic Events

25. Abdominal Obesity is Linked to a Higher Risk for MI 1 MI=myocardial infarction; OR=odds ratio. a Waist-to-hip ratio: upper tertile vs lowest tertile. 1. Yusuf S. et al. Lancet 2004; 364:937-52 INTERHEART Study: Case control study in 52 countries: 15152 cases vs 14820 controls Abdominal obesity a leads to a significantly higher risk for MI: OR (99%CI): 4.5 and 4.7 in W European and N American populations 25

26. A Brief History of Incretins DPP-4=dipeptidyl peptidase-4; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. 1. Creutzfeldt W. Regul Pept. 2005;128:87–91. 2. Bayliss WM et al. J Physiol. 1902;28:325–353. 3. La Barre J. Bull Acad R Med Belg. 1932;120:620–634. 4. McIntyre N et al. Lancet. 1964;284:20-21.. 5. Elrick H et al. J Clin Endocr. 1964;24:1076–1082. 6. Hopsu-Havu VK et al. Histochemie. 1966;7(3):197–201. 7. Nauck M et al. Diabetologia. 1986;29:46–52. 8. Kreymann B et al. Lancet. 1987;330:1300-1304.. 9. Kieffer TJ et al. Endocrinology. 1995;136;3585–3596. 10. Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952–957. 1902 – First observation of intestinal effect on pancreatic secretion 1,2 1932 – First definition of incretins 3 1964 – Demonstration of the incretin effect 1,4,5 1966 – First description of DPP-4 6 1973 – GIP identified as a human incretin 1 1986 – Incretin effect shown to be reduced in patients with type 2 diabetes 7 1987 – GLP-1 identified as a human incretin 8 1995 – DPP-4 identified as an enzyme that inactivates GIP and GLP-1 9,10

27. GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. a Effects occur only with pharmacologic levels of GLP-1. 1. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 2. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606. Incretin Hormones Have Key Roles in Glucose Homeostasis GLP-1  Inhibits gastric emptying a,1,2  Reduces food intake and body weight a,2  Inhibits glucagon secretion from alpha cells in a glucose-dependent manner 1  Stimulates insulin response from beta cells in a glucose-dependent manner 1  Is released from L cells in ileum and colon 1,2 GIP  Has no significant effects on satiety or body weight 2  Does not affect gastric emptying 2  Stimulates insulin response from beta cells in a glucose-dependent manner 1  Is released from K cells in duodenum 1,2

28. DPP-4 Inhibitors: An Incretin-Based Glucose-Dependent Mechanism for Improving Glycemic Control 1–4 28 DPP-4=dipeptidyl peptidase-4; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. a Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. 1. Kieffer TJ et al. Endocr Rev. 1999;20(6):876–913. 2. Ahrén B. Curr Diab Rep. 2003;3(5):365–372. 3. Drucker DJ. Diabetes Care. 2003;26(10):2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18(6):430–441. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Release of active incretins GLP-1 and GIP a  Blood glucose in fasting and postprandial states Ingestion of food  Glucagon from alpha cells (GLP-1)  Hepatic glucose production GI tract DPP-4 enzyme Inactive GLP-1 X Sitagliptin (DPP-4 inhibitor )  Insulin from beta cells (GLP-1 and GIP) Glucose-dependent Pancreas Inactive GIP Beta cells Alpha cells  Peripheral glucose uptake

29. Sitagliptin Was Noninferior to Glipizide in Reducing HbA 1c at Week 52 (Primary End Point) 1 29 Per-Protocol Population LS mean change from baseline at 52 weeks (for both groups): –0.7% Sulfonylurea a + metformin (n=411 at 52 weeks) Sitagliptin b + metformin (n=382 at 52 weeks) Change in HbA 1c From Baseline ( ± SE), % Weeks 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6 7.8 0612182430384652 8.0 8.2 LS=least-squares; SE=standard error. a Specifically glipizide ≤20 mg/day; b Sitagliptin 100 mg/day with metformin (≥1,500 mg/day). Adapted from Nauck MA et al. Diabetes Obes Metab. 2007;9(2):194–205 with permission from Blackwell Publishing Ltd., Boston, MA. Achieved primary hypothesis of noninferiority to sulfonylurea

30. HbA 1c Reductions at Week 104 1 30 2-Year Per-Protocol Population (Patients Inadequately Controlled on Metformin) Difference in LS Mean HbA 1c = –0.03 (95% CI: –0.13, 0.07) LS Mean (95% CI) Change in HbA 1c From Baseline, % –0.7 –0.5 –0.3 0 Glipizide + metformin (n=256) Sitagliptin + metformin (n=248) Mean baseline HbA 1c,% 7.30 7.31 LS=least-squares; SD=standard deviation. 1. Seck T et al. Int J Clin Pract. 2010;64(5):562–576.

31. Sitagliptin vs Glipizide: Weight Change and Incidence of Hypoglycemia 1 31 Patients With at Least 1 Episode, % APaT Population (Patients Inadequately Controlled on Metformin) Sitagliptin + metformin Glipizide + metformin Between-groups difference = –28.8% (95% CI: –33.0, –24.5) n=588n=584 APaT=all-patients-as-treated; CI=confidence interval; LS=least-squares. 1. Seck T et al. Int J Clin Pract. 2010;64(5):562–576. LS Mean (±95% CI) Body Weight Change From Baseline, kg Between-groups difference = –2.3 kg (95% CI: –3.0, –1.6) Hypoglycemia over 104 weeksBody weight at week 104 n=253n=261

32. Sitagliptin Was Assoicated With a Lower Risk of Hypoglycemia Compared With Glipizide 1 a A hypoglycemic event accompanied by a fingerstick blood glucose measurement of ≤70 mg/dL. b Total number of events/total number of patients in each subgroup. 1. Krobot K et al. Curr Med Res Opin. 2012;28:1–7. Most recently measured HbA 1c value (%) 9876 0.001.002.003.004.005 Risk Glipizide (age group ≥65 years) Glipizide (age group <65) Sitagliptin (age group ≥65 years) Sitagliptin (age group <65 years) Confirmed Hypoglycemia a n/N b 316/461 132/123 27/468 4/120

33. Rationale for Once-Daily Dosing of Sitagliptin Based on DPP-4 Inhibition 1 DPP-4=dipeptidyl peptidase-4; qd=once daily. a DPP-4 inhibition corrected for sample assay dilution. 1. Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. Single-dose study in healthy subjects (n=6) Hours Postdose 012468121624 DPP-4 Inhibition, % a 0 20 40 60 80 100 Sitagliptin 100 mg qd

34. Select Pharmacodynamic Properties of DPP-4 Inhibitors Sitagliptin (Merck) 1,2 Vildagliptin (Novartis) 3–5 Saxagliptin (BMS/AZ) 3,6 Alogliptin (Takeda) 7 Linagliptin (BI) 8,9 DPP-4 Peak Inhibition ~97%~95%~80%N/A92%–94% IC 50 for DPP-418 nM5.28 nM3.37 nM6.9 nM ~1 nM IC 50 for DPP-8 (DPP-8/DPP-4) 48,000 nM (2600) 1112 ± 50 nM (210) 244 ± 8 nM (72) >100,000 nM (>10,000) 40,000 nM (~40,000) IC 50 for DPP-9 (DPP-9/DPP-4) >100,000 nM (>5000) 66.2 ± 7.3 nM (13) 104 ± 7 nM (31) >100,000 nM (>10,000) >10,000 nM (>10,000) IC 50 for FAP (FAP/DPP-4) >100,000 nM 7 (>5000) 73,000 ± 8000 nM 7 N/A >100,000 nM (>10,000) 89 nM (~89) DPP-4=dipeptidyl peptidase-4. 1. Alba M et al. Curr Med Res Opin. 2009;25:2507–2514. 2. Kim D et al. J Med Chem. 2005;48:141–151. 3. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98– 107. 4. European Public Assessment Report for Galvus. Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/galvus/H-771-en6.pdf. Accessed May 4, 2011. 5. Ahrén B et al. J Clin Endocrinol Metab. 2004;89:2078–2084. 6. European Public Assessment Report for Onglyza. Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/onglyza/H-1039-en6.pdf. Accessed May 4, 2011. 7. Lee B et al. Eur J Pharmacol. 2008;589:306–314. 8. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. 9. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175–182.

35. Sitagliptin Pooled Safety Analysis: Design 1 19 double-blind, randomized, controlled clinical studies up to 2 years in durationa  Sitagliptin as monotherapy  Sitagliptin in initial combination with metformin (MET) or pioglitazone (PIO)  Sitagliptin in combination with MET, PIO, sulfonylurea (SU) (±MET), MET + rosiglitazone (ROSI), or insulin (±MET)  Patients included in the non-exposed group received the following: placebo, MET, PIO, SU (±MET), ROSI (±MET), or insulin (±MET) Population (N=10,246)  Sitagliptin 100 mg/day group (n=5429) – 1805 patients were treated for at least 1 year – 584 patients were treated for 2 years – Mean duration of exposure was 282 days  Non-exposed group (n=4817) – 1320 patients were treated for at least 1 year – 470 patients were treated for 2 years – Mean duration of exposure was 259 days 35 a Studies with results available as of July 2009. 1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.

36. Sitagliptin Pooled Safety Analysis: Summary of Adverse Experiences 1 Incidence Rate per 100 Patient-Years Sitagliptin n=5429 Non-exposed n=4817 Between-Groups Difference (95% CI) a 1 or more AEs153.5162.6–7.6 (–15.6, 0.3) Drug-related AEs b 20.026.8–6.4 (–8.7, –4.1) Serious AEs7.87.9–0.1 (–1.3, 1.1) Serious drug-related AEs b 0.40.30.1 (–0.1, 0.4) Died0.30.5–0.2 (–0.5, 0.1) Discontinued due to AEs4.85.2–0.5 (–1.5, 0.4) Discontinued due to drug-related AEs b 1.72.3 –0.5 (–1.1, 0.1) Discontinued due to serious AEs1.7 –0.0 (–0.6, 0.5) Discontinued due to serious drug-related AEs b 0.20.1 0.1 (–0.1, 0.3) 36 AE=adverse experience; CI=confidence interval. a Between-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group was higher than the incidence rate for the non- exposed group. "0.0" and "–0.0" represent rounding for values that were slightly greater and slightly less than zero, respectively. b Considered by the investigator to be drug related. 1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.

37. Sitagliptin and Metformin Target the Core Metabolic Defects of Type 2 Diabetes 37 Sitagliptin improves measures of (or markers) beta-cell function and increases insulin synthesis and release. 1 Sitagliptin reduces HGO through suppression of glucagon from alpha cells. Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis. 3 Metformin has insulin- sensitizing properties. 2–4 (Liver > Muscle, Fat) Beta-Cell Dysfunction Hepatic Glucose Overproduction (HGO) Insulin Resistance 1. Aschner P et al. Diabetes Care. 2006;29:2632–2637. 2. Abbasi F et al. Diabetes Care. 1998;21:1301–1305. 3. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 4. Zhou G et al. J Clin Invest. 2001;108:1167–1174. 5. Data on file, MSD

38. Initial Combination Therapy With Sitagliptin Plus Metformin Provided Sustained HbA 1c Reductions Through 104 Weeks 1 38 APT=all-patients-treated; bid=twice daily; LS=least-squares; qd=once daily. 1. Williams-Herman D et al. Diabetes Obes Metab. 2010;12(5):442–451. Sitagliptin 100 mg qd (n=50) Metformin 500 mg bid (n=64)Sitagliptin 50 mg bid + metformin 1000 mg bid (n=105) Metformin 1000 mg bid (n=87) Sitagliptin 50 mg bid + metformin 500 mg bid (n=96) Extension Study 24-Week Phase Continuation Phase LS Mean HbA 1c Change From Baseline, % –1.2 –1.1 –1.3 –1.4 –1.7 Mean baseline HbA 1c = 8.5%–8.7% 061218243038465462707891104 6.0 6.5 7.0 7.5 8.0 8.5 9.0 Weeks APT Population (Extension Study)

39. Sitagliptin Is the Most Widely Prescribed DPP-4 Inhibitor With the Broadest Range of Indications 39 Sitagliptin: Powerful efficacy and proven experience as an adjunct to diet and exercise in appropriate adult patients with type 2 diabetes The clinical efficacy of Januvia has been demonstrated in the following uses: Initial Monotherapy As initial therapy for appropriate patients Initial Combination Therapy With 1 Agent As initial therapy in combination with metformin As initial therapy in combination with glitazone Add-on Therapy to 1 Agent In combination with metformin In combination with sulfonylurea In combination with glitazone In combination with insulin Add-on Therapy to 2 Agents In combination with sulfonylurea + metformin In combination with glitazone + metformin In combination with insulin + metformin DPP-4=dipeptidyl peptidase-4.

40. Ongoing Cardiovascular Outcome Trials With DPP-4 Inhibitors 40 TECOS 1 Start: Dec 2008 Estimated Proj. Completion: Dec 2014 N = 14,000 Trial Evaluating Cardiovascular Outcomes With Sitagliptin Primary Outcome:  Time to first confirmed occurrence of CV event, a composite defined as CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization EXAMINE 2,5 Start: Sept 2009 Estimated Proj. Completion: Dec 2014 N = 5,400 Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome Primary Outcome:  Time from randomization to the occurrence of the Primary Major Adverse Cardiac Events, a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke SAVOR 3,6 Start: May 2010 Estimated Proj. Completion: April 2014 N = 16,500 Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial Primary Outcome:  The primary efficacy outcome variable of the study is defined as the composite endpoint of cardiovascular death, non-fatal myocardial infarction or non-fatal ischemic stroke CAROLINA 4 Start: Oct 2010 Estimated Proj. Completion: Sept 2018 N = 6,000 Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Patients With Type 2 Diabetes Primary Outcome:  Time to first occurrence of composite CV outcome, components of the primary composite endpoint: CV death, non-fatal MI, non-fatal stroke and hospitalisation for unstable angina pectoris ClinicalTrials.gov NCT identifiers: 1. 00790205; 2. 00968708 ; 3. 01107886; 4. 01243424. 5. White W et al. Am Heart J. 2011;162:620-626; 6. Scirica B et al. Am Heart J. 2011;162:818-825.

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43. Incretin Hormones Regulate Insulin and Glucagon Levels GLP-1 = glucagon-like peptide-1; GIP = glucose insulinotropic polypeptide Adapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes Care. 2003;26:2929–2940. Nauck MA et al. Diabetologia. 1993;36:741–744. Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. Copyright © 1979 Springer-Verlag. 13 Pancreas Gut Nutrient signals ● Glucose Hormonal signals GLP-1 GIP Glucagon (GLP-1) Insulin (GLP-1,GIP) Neural signals  cells  cells

44. Complementary Effects of Sitagliptin and Metformin on Incretin Hormone Concentrations in Healthy Adult Subjects 1 Total GLP- 1Active GLP-1Active GIP Observations in Healthy Subjects Compared With Placebo a Sitagliptin  Increases active GLP-1 and GIP Metformin No effect  Increases total GLP-1 and increases active GLP-1  Does not increase active GIP Sitagliptin + Metformin  Additive effect on active GLP-1; increases active GIP 44 GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. a Data observations reported for post-prandial (4hr) weighted mean GLP-1 levels 1. Migoya EM. Clin Pharmacol Ther. 2010;88:801–808. 2. Data on file, MSD In a study of drug-naïve patients with type 2 diabetes, active GLP-1 levels were increased more when patients received both sitagliptin and metformin compared with either agent alone. 2

45. Patients Were Worried About the Risk of Hypoglycemia 1 45 24% of patients in this study were on insulin therapy. T2DM=type 2 diabetes. 1. Mohamed M. Curr Med Res Opin. 2008;24(2):507–514. Diabcare-Asia 2003 cross-sectional survey of 15,549 Asian patients with diabetes (96% type 2, 4% type 1); answer to the question “I am worried about the risk of hypoglycemic events” Respondents, %

46. Patients With Type 2 Diabetes and Hypoglycemia Were More Likely to Have Lower Health-Related Quality of Life 1 46 Cross-sectional, internet-based survey a of 2,074 patients with type 2 diabetes who were taking ≥1 oral antidiabetic agent (excluding insulin) CI=confidence interval; EQ-5D=EuroQoL-5D, a standardized measure of HRQL; HRQL=health-related quality of life; OR=odds ratio. a Survey used a 30-item Diabetes Symptom Measure (DSM) to assess the frequency of cognitive and physiological symptoms in the 2 weeks prior to the survey. Data were not verified against clinician diagnoses or chart reviews, nor were reports of low blood sugar confirmed by blood glucose monitoring. 1. Williams SA et al. Diab Res Clin Pract. 2011;91:363–370. P < 0.0001 P = 0.1627 EQ-5D Domains P < 0.0001 Adjusted effects of experiencing hypoglycemia symptoms on HRQL

47. In a Longitudinal Study, a History of Severe Hypoglycemia Was Associated With a Greater Risk of Dementia 1 47 The clinical significance of minor glycemic episodes with dementia risk is unknown. a Attributable risk calculated as difference between rate in group and rate in reference group (0 hypoglycemic events). 1. Whitmer RA et al. JAMA. 2009;301:1565–1572. Attributable risk of dementia with any hypoglycemia: 2.39% (1.72–3.01) a n=1,002n=258n=205 1.64 4.34 4.28

48. Earlier and Appropriate Intervention May Improve Patients’ Chances of Reaching Goal 1 Published Conceptual Approach A1C,% Mean A1C of patients Duration of Diabetes OAD monotherapy Diet and exercise OAD combination OAD up-titration OAD + multiple daily insulin injections OAD + basal insulin 6 7 8 9 10 Conventional stepwise treatment approach Earlier and proactive intervention approach A1C goal of 7% OAD=oral antidiabetic agent. 1. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355. Copyright © 2005. Adapted with permission of Blackwell Publishing Ltd.

49. Severe Hypoglycemia May Cause a Prolongation of QT Interval in Patients With Type 2 Diabetes 1 49 P =NS P =0.0003 NS=not significant. Thirteen patients with type 2 diabetes taking combined insulin and glibenclamide treatment were studied during hypoglycemia; 8 participated in the euglycemic experiment clamped between 5.0 and 6.0 mmol/L. The aim was to achieve stable hypoglycemia between 2.5 and 3.0 mmol/L (45 and 54 mg/dL) during the last 60 minutes of the experiment. 1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307. Euglycemic clamp (n=8) Hypoglycemic clamp 2 weeks after glibenclamide withdrawal (n=13)  Significant prolongation of QT interval after hypoglycemic clamps – Increased risk of arrhythmias 0 360 370 380 390 400 410 420 430 440 450 Mean QT interval, ms Baseline (t=0) End of clamp (t=150 min) All patients participated in one hypoglycemic clamp while on treatment with insulin only, and another during combined glibenclamide and insulin therapy. Hypoglycemic clamp 6–8 months after resuming glibenclamide (n=13) 460 P <0.0001

50. Severe Hypoglycemia May Cause a Prolongation of QT Interval in Patients With Type 2 Diabetes 1 50 P =NS P =0.0003 NS=not significant. Thirteen patients with type 2 diabetes taking combined insulin and glibenclamide treatment were studied during hypoglycemia; 8 participated in the euglycemic experiment clamped between 5.0 and 6.0 mmol/L. The aim was to achieve stable hypoglycemia between 2.5 and 3.0 mmol/L (45 and 54 mg/dL) during the last 60 minutes of the experiment. 1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307. Euglycemic clamp (n=8) Hypoglycemic clamp 2 weeks after glibenclamide withdrawal (n=13)  Significant prolongation of QT interval after hypoglycemic clamps – Increased risk of arrhythmias 0 360 370 380 390 400 410 420 430 440 450 Mean QT interval, ms Baseline (t=0) End of clamp (t=150 min) All patients participated in one hypoglycemic clamp while on treatment with insulin only, and another during combined glibenclamide and insulin therapy. Hypoglycemic clamp 6–8 months after resuming glibenclamide (n=13) 460 P <0.0001

51. Antecedent Hypoglycemia Impaired Markers of Autonomic Function 1 51 CVD=cardiovascular disease. 1. Adler GK et al. Diabetes. 2009;58:360–366. Measures of autonomic function in 20 young healthy subjects after antecedent euglycemic ( ■ ) or hypoglycemic ( o ) clamp studies. Sympathetic response to hypotensive stress Baroreflex sensitivity 0.0 12.5 15.0 17.5 20.0 5.02.8 0 20 30 40 50 60 70 BaselinePost- Nitroprusside Antecedent Clamp Glucose (mmol/L) Cardiac Vagal Baroreflex Sensitivity, ms/mmHg Sympathetic Burst Frequency, bursts/minute P < 0.04 P < 0.01

52. Glucose-Dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in Patients With Type 2 Diabetes 1 52 1. Adapted with permission of Springer Verlag. Adapted from Nauck MA et al. Diabetologia. 1993;36(8):741–744. Copyright © 1993 Springer Verlag. Permission conveyed through Copyright Clearance Center, Inc. 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) mmol/L 15.0 12.5 10.0 7.5 5.0 250 200 150 100 50 mg/dL * * * * * * * pmol/L 250 200 150 100 50 40 30 20 10 0 mU/L * * * * * * * * Infusion Minutes pmol/L 20 15 10 5 060120180240 * * * * pmol/L 20 15 10 5 Placebo GLP-1 Insulin 2.5 0 0 0 0 0 –30

53. Sitagliptin vs Sulfonylurea in Muslim Patients With Type 2 Diabetes Treated During Ramadan 53

54. 54 Middle East: Switching to Sitagliptin Treatment Was Associated With a Significantly Lower Incidence of Symptomatic Hypoglycemia Compared With Remaining on Sulfonylurea Treatment 1 Primary End Point (APaT Population): Incidence of Symptomatic Hypoglycemia (Proportion of Patients With ≥1 Events)  195 symptomatic hypoglycemic events were reported by 68 patients in the SU group compared with 128 events in 34 patients for the sitagliptin group  Most common symptoms were headache, sweating, dizziness, hunger, and tremor APaT=all patients as treated; CI=confidence interval; qd=once daily; RRR=relative risk ratio; SU=sulfonylurea. 1. Al Sifri S et al. Int J Clin Pract. 2011; 65:1132–1140. RRR (95% CI) = 0.51 (0.34, 0.75); P < 0.001 50% Risk Reduction

55. India/Malaysia: Switching to Sitagliptin Treatment Was Associated With a Significantly Lower Risk of Symptomatic Hypoglycemia Compared With Remaining on Sulfonylurea Treatment 1 55 N=427N=421 RRR (95% CI) = 0.52 (0.29, 0.94); P =0.027 APaT=all patients as treated; CI=confidence interval; RRR=relative risk ratio; SU=sulfonylurea. 1. Data on file, MSD. APaT Population 63 symptomatic hypoglycemic events were reported by 31 patients in the SU group compared with 22 events in 16 patients for the sitagliptin group In the overall study population, switching to sitagliptin was associated with a 50% reduction of risk 50% Risk Reduction

56. Sitagliptin as Add-on Therapy to Insulin vs Insulin Dose- increase Therapy in Uncontrolled Korean T2DM: Study Design 1 56 RandomizationWeek 24 24-Week Insulin ± Sitagliptin Dose Period Patients with type 2 diabetes Age 30–70 Receiving insulin (including glargine, glargine + rapid-acting insulin, and combination of NPH insulin and regular insulin) for ≥ 3 months at a dose of 10 U/day, and for at least 4 weeks prior to enrollment FPG < 15 mmol/L (270 mg/dL) BMI 18–35 kg/m 2 HbA 1c ≥7.5% and ≤11% Insulin Increasing a Regimen (n=70) Sitagliptin Adding Regimen 100 mg qd (n=70) R Screening visit Week –4 Week 12 a Subjects were guided to increase their daily insulin dose by 10% at random and then by a further 10% at 12 weeks if their HbA 1c ≥7%. In addition to this 20% increase, subjects were allowed to adjust their insulin dose by 2 U every week, based on the self-monitoring of their blood glucose. BMI=body-mass index; FPG=fasting plasma glucose; T2DM=type 2 diabetes mellitus; qd=once daily. 1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.

57. Add-on Sitagliptin vs Insulin Increasing: Study Endpoints 1  The primary endpoint of the study was to compare changes in HbA 1c levels after 24-weeks of add-on sitagliptin or insulin increasing treatment  Secondary efficacy endpoints included: – The proportion of participants who had an HbA 1c ≤ 7% without hypoglycemia – The change in body weight – The change in insulin dose  Safety endpoints were: – Adverse events – Serious adverse events – Hypoglycemia – Severe hypoglycemic events 57 1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.

58. Addition of Sitagliptin Significantly Decreased HbA 1c Compared to Patients With Insulin Increasing at Week 24 1 58 HbA 1c, % Time (weeks) CI=confidence interval a P < 0.05 vs. baseline; b P < 0.05 between arms. 1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x. -0.63% a (95% CI, -0.93, -0.38) -0.22% a (95% CI, -0.55, 0.31) -0.42% b (95% CI, -0.91, 0.11)

59. Significantly More Subjects Adding Sitagliptin Achieved HbA 1c ≤ 7% 1 59 1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x. All Subjects P=0.021 Proportion of Subjects Achieving HbA 1c ≤ 7%, %

60. Addition of Sitagliptin Was Associated With a Lower Incidence of Hypoglycemia and Reduced Body Weight vs the Insulin Increasing Regimen 1 60 Body Weight Change at Week 24 1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x. Change in Body Weight From Baseline, kg Sitagliptin Add-on Insulin Increasing  = –1.8 kg (P <0.05) Hypoglycemia Over 24 Weeks Patients With ≥1 Hypoglycemic Episode, % P <0.05 Sitagliptin Add-on Insulin Increasing

61. Mean Daily Insulin Use Increased Significantly in the Insulin Increasing Patients 1 61 a P <0.05 for the between-treatment difference. 1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x. Week 0Week 24Week 0Week 24 Mean Insulin Use (U/day) 25% increase from baseline -2.5 (95% CI, -4.5, -1.3) 10.1 (95% CI, 4.5, 14.9)

62. Sitagliptin Adding vs Insulin Increasing in T2DM: Adverse Event Summary 1 Sitagliptin Add-onInsulin Increasing N%N% One or more AEs2134.42336.5 Drug-related AEs914.8812.7 Serious AEs34.946.3 Drug-related serious AEs11.646.3 Discontinued due to AEs69.869.5 Discontinued due to drug-related AEs 23.346.3 62 AE=adverse event; T2DM=type 2 diabetes mellitus. 1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.

63. Conclusions 1  In this 24-week study, the addition of sitagliptin in patients with uncontrolled T2DM on insulin therapy led to: – Significantly decreased HbA 1c levels compared with patients with increasing doses of insulin – Significantly more subjects able to achieve HbA 1c ≤ 7% – A lower incidence of hypoglycemia vs. increasing doses of insulin – Reduced body weight compared with subjects in the insulin increasing group – A modest decrease in the insulin dose compared with a significant increase of 25% in the insulin dose of the insulin increasing arm – A similar AE frequency 63 AE=adverse event; T2DM=type 2 diabetes mellitus. 1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.

64. Sitagliptin Pooled Analysis: No Difference in Incidence of Pancreatitis Between Sitagliptin and Non-exposed Groups 1 Incidence Rate per 100 Patient-Years Adverse Experience Sitagliptin n=5,429 Non-exposed n=4,817 Between-Groups Difference, (95% CI) a Pancreatitis0.080.10–0.02 (–0.20, 0.14) Chronic pancreatitis0.040.030.02 (–0.11, 0.13) 64  Preclinical and clinical trial data a with sitagliptin to date do not indicate an increased risk of pancreatitis in patients with type 2 diabetes treated with sitagliptin. CI=confidence interval. a Data available through July 2009. 1. Engel SS et al. Int J Clin Pract. 2010;6497):984–990.

65. Sitagliptin Pooled Safety Analysis: Malignant and Non-malignant Neoplasms 1 Adverse Experience n / Patient-Years of Exposure (incidence rate per 100 patient-years) Sitagliptin n=5429 Non-exposed n=4817 Between-Groups Difference (95% CI) a Any malignancy46/4690 (1.0)40/3930 (1.0)–0.0 (–0.5, 0.4) 65  Incidences of malignancies were similarly low for both treatment groups. – The most common malignancies were basal cell carcinoma, breast cancer (women), and prostate cancer (men).  The incidence of non-malignant neoplasms was higher in the sitagliptin group than in the non- exposed group (1.3 per 100 PY vs 0.7 per 100 PY). – The most common non-malignant events were uterine leiomyoma and lipoma (women). CI=confidence interval; PY=patient years. a Between-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group was higher than the incidence rate for the non-exposed group. "0.0" and "–0.0" represent rounding for values that were slightly greater and slightly less than zero, respectively. 1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.

66. Sitagliptin Pooled Safety Analysis: No Difference in MACE a Between Sitagliptin and Non-exposed Groups 1 Adverse Experience Incidence Rate per 100 Patient-Years Sitagliptin n=5429 Non-exposed n=4817 Between-Groups Difference (95% CI) b Relative Risk Ratio (95% CI) MACE0.60.9–0.3 (–0.7, 0.1)0.68 (0.41, 1.12) 66  Custom MACE analysis with terms similar to those requested by the US Food and Drug Administration for recent MACE analyses with other antihyperglycemic agents  Total of 64 patients with at least 1 MACE-related event CI=confidence interval; MACE=major adverse cardiovascular events. a There was no adjudication of any cardiac event. b Between-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group was higher than the incidence rate for the non-exposed group. 1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.

67. Chemical Class β-Phenethylamines 1 CyanopyrrolidinesAminopiperidine 8 Xanthine Generic Name Sitagliptin 2,3 Vildagliptin 2, 4,5 Saxagliptin 2,6,7 Alogliptin 9,10 Linagliptin 11,12 Molecular Structure DPP-4 Inhibitory Activity (IC 50 ) 9.96 ± 1.03 nM5.28 ± 1.04 nM3.37 ± 0.90 nM6.9 ± 1.5 nM~1 nM Half-life12.4 h~2–3 h 2.5 h (parent) 3.1 h (metabolite) 12.4–21.4 h113–131 h DPP-4 Inhibitors Differ in Molecular Structures and Pharmacologic Properties DPP-4=dipeptidyl peptidase-4. IC50 =half maximal inhibitory concentration 1. Kim D et al. J Med Chem. 2005;48:141–151. 2. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98–107. 3. JANUVIA EU-SPC 2010. 4. Villhauer EB et al. J Med Chem. 2003;46:2774–2789. 5. Galvus EU-SPC 2010. 6. Augeri DJ et al. J Med Chem. 2005;48:5025–5037. 7. Onglyza EU-SPC 2010. 8. Feng J et al. J Med Chem. 2007;50:2297–2300. 9. Lee B et al. Eur J Pharmacol. 2008;589:306–14. 10. Christopher R et al. Clin Ther. 2008;30:513–527. 11. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175–182. 12. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. F F F O N NH 2 N N N CF 3 N N O H 3 C O N CN N H 2 N O H H NC H O NH 2 HO N H O N NC N N O N N N N N O NH 2

68. Pharmacokinetic Properties of DPP-4 Inhibitors Sitagliptin (Merck) 1 Vildagliptin (Novartis) 2 Saxagliptin (BMS/AZ) 3 Alogliptin (Takeda) 5 Linagliptin (BI) 6–8 Absorption t max (median) 1–4 h1.7 h 2 h (4 h for active metabolite) 1–2 h1.34–1.53 h Bioavailability ~87%85%>75 % 4 N/A29.5% Half-life (t 1/2 ) at clinically relevant dose 12.4 h~2–3 h 2.5 h (parent) 3.1 h (metabolite) 12.4–21.4 h (25–800 mg) 113–131 h (1–10 mg) Distribution 38% protein bound9.3% protein boundLow protein bindingN/A Prominent concentration- dependent protein binding: 100 nM: 70%–80% Metabolism ~16% metabolized 69% metabolized mainly renal (inactive metabolite) Hepatic (active metabolite) CYP3A4/5 <8% metabolized~26% metabolized Elimination Renal 87% (79% unchanged) Renal 85% (23% unchanged) Renal 75% (24% as parent; 36% as active metabolite) Renal (60%–71% unchanged) Feces 81.5% (74.1% unchanged); Renal 5.4% (3.9% unchanged) DPP-4=dipeptidyl peptidase-4. 1. JANUVIA EU-SPC 2010. 2. Galvus EU-SPC 2010. 3. Onglyza EU-SPC 2010. 4. EPAR for Onglyza. Available at: http://www.ema.europa.eu/. Accessed September 17, 2010. 5. Christopher R et al. Clin Ther. 2008;30:513–527. 6. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. 7. Reitlich S et al. Clin Pharmacokinet. 2010;49:829–840. 8. Fuchs H et al. J Pharm Pharmacol. 2009;61:55–62.

69. 69 Conclusion:Inhibition of DPP-8 and/or DPP-9 resulted in multiorgan toxicities in rats and dogs. 2-Week Rat Study at 10, 30 100 mg/kg/day; Acute dog toxicity at 10 mg/kg DPP=dipeptidyl peptidase; QPP=quiescent cell proline dipeptidase. 1. Lankas GK et al. Diabetes. 2005;54:2988–2994. Selectivity: Comparative Toxicity Studies 1 2-Week Rat ToxicityNonselective QPP Selective DPP-8/9 Selective DPP-4 Selective Alopecia Thrombocytopenia Anemia Enlarged spleen Mortality Acute Dog Toxicity Bloody diarrhea

70. Administration Schedule of Sitagliptin (100 mg Once or 50 mg Twice Daily) Results in Similar Glucose Reductions and Glycemic Variability 70 Time, h Mean Plasma Glucose, mmol/L 5.0 7.0 9.0 11.0 13.0 15.0 Placebo (n = 27) Sitagliptin 50 mg 2x/day (n = 24) Sitagliptin 100 mg 1x/day (n = 25) 8:0013:00 BreakfastLunchDinner Dose 1 7:30 Dose 2 18:30 19:000:007:30 Day 1Day 2 1. Nonaka K et al. Horm Metab Res. 2009;41:232–2371.

71. Saxagliptin Was Noninferior to Sitagliptin in Reducing HbA 1c at 18 Weeks 1 71 Primary End Point (Per-Protocol Population; on background of metformin therapy) Mean baseline HbA 1c, % Change From Baseline in Adjusted Mean HbA 1c (SE), % 0.09 (95% CI: –0.01, 0.20) a (Prespecified noninferiority margin=0.30%) Sitagliptin 100 mg + metformin Saxagliptin 5 mg + metformin In the FAS population, the adjusted mean HbA 1c reductions from baseline to week 18 were observed for sitagliptin 100 mg (-0.59%) and saxagliptin 5 mg (-0.42%). Difference between groups: 0.17% (95% CI: 0.06, 0.28) 7.697.68 –0.62 (95% CI: –0.69, –0.54) –0.52 (95% CI: –0.60, –0.45) –0.60 –0.45 –0.30 –0.15 0.00 –0.75 CI=confidence interval; FAS=full-analysis-set; SE=standard error. a Difference in adjusted change from baseline vs sitagliptin + metformin. 1. Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549. n=343n=334

72. FPG Reductions With Sitagliptin vs. Saxagliptin at 18 Weeks 1 72 Secondary End Point (FAS Population; on background of metformin therapy) FPG LS Mean (±SE) Change From Baseline, mmol/L –0.90 –0.60 –1.2 –0.9 –0.6 –0.3 0 Mean baseline FPG, mmol/L 8.89 8.86 CI=confidence interval; FAS=full-analysis-set; FPG=fasting plasma glucose; LS=least squares; SE=standard error. a Between-groups difference vs sitagliptin + metformin. 1. Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549. Sitagliptin 100 mg + metformin Saxagliptin 5 mg + metformin n=392n=397 0.30 (95% CI: 0.08, 0.53) a

73. OPTIMA : Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Study Design 1 CGM=continuous glucose monitoring. 1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299. R Inclusion Criteria: Age > 18 yrs HbA 1c between 6.5 and 8.0% BMI between 22 and 45 kg/m 2 Currently on stable, maximum tolerated metformin dose 8 Weeks Vildagliptin + Metformin (N=19) Sitagliptin + Metformin (N=19) CGM for 3 days 2-4 Weeks

74. OPTIMA : Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Study Objectives 1  Primary Objective: – Change in mean amplitude of glycemic excursions (MAGE) after 8 weeks of treatment  Secondary Objectives: – Time spent in the optimal glycemic range, ≥ 70 and ≤ 140 mg/dL – Time spent in hyperglycemic range, ≥140 and ≥180 mg/dL – Time spent in hypoglycemic range, < 70 mg/dL 74 1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.

75. OPTIMA : Glycemic Variability Results Were Similar Between Sitagliptin and Vildagliptin Treated Groups 1 75 At baseline At 8 weeks BID=twice daily; MAGE=mean amplitude of glycemic excursions; MODD=mean of daily differences; QD=once daily; SD=standard deviation. 1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299. SD of 24-h Mean Glycemia MAGE Variable, mg/dL MODD P =0.61 P =0.83 P =0.89