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Primary Results 8th June 2015

Primary Results 8th June 2015. TECOS. Initiated in advance of FDA requirements, but consistent with that guidance Large, international trial designed to assess the impact of sitagliptin versus placebo on cardiovascular event rates When added to usual diabetes care

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Primary Results 8th June 2015

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  1. Primary Results 8th June 2015

  2. TECOS • Initiated in advance of FDA requirements, but consistent with that guidance • Large, international trial designed to assess the impact of sitagliptin versus placebo on cardiovascular event rates • When added to usual diabetes care • Minimize difference in glycemia between groups • Randomized, double-blind, placebo-controlled • Academically led in collaboration with industry sponsorship Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  3. Pragmatic Study Design • Integration with usual diabetes care • Management of diabetes, hypertension and dyslipidaemia remain responsibility of usual care provider • All laboratory results collected locally as available, except HbA1c, from the usual care setting • TECOS investigator responsible for dose adjustment of blinded study drug according to eGFR • Streamlined data collection • Streamlined safety reporting Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  4. Primary Objective To demonstrate that the risk of cardiovascular events in patients treated with sitagliptin in addition to usual care wasnon-inferior to that in patients treated without sitagliptin in addition to usual care. Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  5. Primary Composite Cardiovascular Outcome Time to first occurrence of: • Cardiovascular-related death • Nonfatal myocardial infarction • Nonfatal stroke • Hospitalization for unstable angina A Clinical Endpoints Committee, blinded to therapy allocation, reviewed all potential CVD endpoints independently. • 5 Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  6. Secondary Cardiovascular Outcomes Time to — • Secondary composite CV outcome (nonfatal MI, nonfatal stroke, or CV-related death) • First confirmed component event in the primary outcome(Cardiovascular-related death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina) • First fatal or nonfatal MI • First fatal or nonfatal stroke • All-cause mortality • Hospitalization for heart failure • Hospitalization for heart failure or CV-related death Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  7. Other Secondary Outcomes • Change in HbA1c over time • Change in renal function over time • eGFR • urinary albumin/creatinine ratio • In patients not receiving insulin at baseline, time to initiation of chronic insulin therapy • In all patients, time to next co-interventional agent (next AHA or chronic insulin) • Medical resource utilization (e.g., hospitalizations, outpatient visits) — data not shown today Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  8. Major Inclusion Criteria • Type 2 diabetes (A1c ≥6.5% and ≤8.0%) • Stable monotherapy OR dual combination therapy with metformin, pioglitazone, or sulfonylurea or *stable dose of insulin with or without metformin • ≥50 years old • Preexisting vascular disease defined as having: • History of myocardial infarction • Prior coronary revascularization • Coronary angiography with at least one ≥50% stenosis • History of ischemic stroke • Carotid arterial disease with ≥50% carotid stenosis • Peripheral arterial disease with objective evidence • Able to see usual care provider at least twice yearly *Amended 13Sept2010 Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  9. Major Exclusion Criteria • Type 1 diabetes or history of ketoacidosis • History of ≥2 episodes of severe hypoglycemia during the 12 months prior to enrollment • Estimated glomerular filtration rate (eGFR) <30mL/min/1.73 m2 • Use of another DPP-4 inhibitor, GLP-1 analogue, or thiazolidinedione other than pioglitazone in previous three months • Cirrhosis of the liver • Planned revascularization procedure • Pregnancy or planned pregnancy Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  10. Statistical Analysis Plan Primary analysis for non-inferiority performed in the per protocol (PP) population • Consistent with ICH E-9/CONSORT statement • Supporting intention-to-treat (ITT) analysis also performed • Prespecified conditional hierarchical analyses, each at =0.025 one-sided: • Non-inferiority for the secondary composite CV outcome (PP population) • Superiority for primary CV outcome (ITT population) • Superiority for the secondary composite CV outcome (ITT population) Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  11. Prohibited Medications • Use of open-label DPP-4 inhibitors or GLP-1 receptor agonists • Use of rosiglitazone as concomitant therapy subsequent to enrollment was discouraged, but not prohibited Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  12. Recruitment:December 2008 – July 2012 = country involved in TECOS ITT population Eastern Europe 3965, 27.0% Western Europe 2076, 14.2% North America 2594, 17.7% Asia Pacific 4565, 31.1% Latin America 1471,10.0% Total 14,671 Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  13. Consort Diagram 14,735 randomized • 64 excluded from all analyses • 11 did not consent • 53 at one site excluded for GCP deviations 14,671included in ITT analysis 7332 sitagliptin ITT 7180 (97.9%) VS known 6972 (95.1%) completed 61 (0.8%) LTFU 29 (48%) VS known 299 (4.1%) Withdrawn 179 (60%) VS known 7339 placebo ITT 7123 (97.0%) VS known 6905 (94.1%) completed 71 (1.0%) LTFU 33 (46%) VS known 363 (4.9%) Withdrawn 185 (51%) VS known ITT = intention-to-treat; LTFU = lost to follow-up; VS = vital status, GCP = Good Clinical Practice Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  14. Per Protocol Population Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  15. Baseline Characteristics Values are mean ±SD for continuous variables or n,% for categorical variables. *MDRD formula used to calculate eGFR. Site-reported values are presented. Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  16. Baseline Characteristics—CV Risk Management Values are mean ±SD for continuous variables or n,% for categorical variables. Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  17. Baseline Characteristics—CV Disease Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  18. Baseline Characteristics—Diabetes Values are mean ±SD or median (IQR) for continuous variables or n,% for categorical variables. Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  19. Participant Follow-up Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  20. Cumulative Proportion of Participants Lost or Withdrawn from Study At the end of Year 1 Sitagliptin: 2.7% Placebo: 3.3% At the end of Year 2 Sitagliptin: 4.0% Placebo: 5.1% At the end of Year 3 Sitagliptin: 5.0% Placebo: 6.0% Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  21. Cumulative Proportion of Participants Discontinuing Study Drug At the end ofYear 2 Sitagliptin: 17.9% Placebo: 19.9% At the end of Year 1 Sitagliptin: 11.1% Placebo: 12.2% At the end of Year 3 Sitagliptin: 24.5% Placebo: 26.6% Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  22. Glycemic Control Least Squares Mean HbA1c ± 1SD Overall LS Mean difference -0.29% (-0.32, -0.27), p<0.0001 Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  23. Initiation of Additional Antihyperglycemic Agents Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  24. Initiation of Chronic Insulin Therapy *Patients not on insulin at baseline Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  25. Estimated Glomerular Filtration Rate (eGFR)Mean ± 1SD Estimated overall mean difference*: -1.34 ml/min/1.73m2 (95%CI -1.76, -0.91), p<0.0001 *Mixed model with random intercept & slope, adjusted for baseline value and region Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  26. Severe Hypoglycemia* ITT HR (95% CI): 1.12 (0.89–1.40), p=0.33 *Hypoglycemia requiring assistance Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  27. Confirmed Acute Pancreatitis and Pancreatic Cancer ITT HR 1.93 (0.96, 3.88), p=0.065 ITT HR 0.66 (0.28, 1.51), p=0.32 Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  28. Confirmed Charter Defined Malignancy* ITT HR 0.91 (0.77, 1.08), p=0.27 *Newly diagnosed malignancy or 1st recurrence of previously diagnosed malignancy during the study period Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  29. Serious Adverse Events* *System Organ Classes with incidence ≥1% in either group Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  30. Primary Composite Cardiovascular Outcome* PP Analysis for Non-inferiority * CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  31. Primary Composite Cardiovascular Outcome* ITT Analysis for Superiority * CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  32. Primary Composite Cardiovascular OutcomeITT Population Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  33. Secondary Composite Cardiovascular Outcome* ITT Analysis for Superiority * CV death, nonfatal MI, nonfatal stroke Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  34. Secondary Composite Cardiovascular OutcomeITT Population Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  35. All-cause Mortality (ITT Population) * Counted as cardiovascular for the primary analysis Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  36. Hospitalization for Heart Failure*ITT Analysis * Adjusted for history of heart failure at baseline Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  37. Hospitalization for Heart Failure*ITT Population * Adjusted for history of heart failure at baseline† Prespecified analyses Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  38. Primary Composite Cardiovascular OutcomePrespecified Subgroup Analyses* (1) * ITT Population Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  39. Primary Composite Cardiovascular OutcomePrespecified Subgroup Analyses* (2) * ITT Population Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  40. Primary Composite Cardiovascular OutcomePrespecified Subgroup Analyses* (3) * ITT Population Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  41. Primary Composite Cardiovascular OutcomePrespecified Subgroup Analyses* (4) * ITT Population Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  42. Primary Composite Cardiovascular OutcomePrespecified Subgroup Analyses* (5) * ITT Population Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  43. Summary of Results (1) • For the primary composite cardiovascular outcome(CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina) sitagliptin, compared with placebo, wasnoninferior, and not superior • For the secondary composite cardiovascular outcome(CV death, nonfatal MI, or nonfatal stroke) sitagliptin,compared with placebo,wasnoninferior, and not superior • The rate of hospitalization for heart failuredid not differ between sitagliptin and placebo treatment groups • The incidence ofsevere hypoglycemia did not differ between sitagliptin and placebo treatment groups Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  44. Summary of Results (2) • The rates of infections, and deaths from infection,did not differ between sitagliptin and placebo treatment groups • The incidence of overall malignancies did not differ between sitagliptin and placebo treatment groups • Overall, confirmed events of acute pancreatitiswere uncommon, but numerically more frequent in the sitagliptin group • Overall, confirmed events of pancreatic cancerwere uncommon, but numerically more frequent in the placebo group Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  45. Summary of Results (3) • TECOS was a cardiovascular safety study • The study aimed for glycemic equipoise to minimize possible glycemic confounding effects on the outcomes of interest, with the result that there was only a small difference in the HbA1c levels between the sitagliptin and placebo groups • The utility of sitagliptin as a glucose-lowering agent was confirmed by the more frequent initiation of insulin therapy and the greater need for additional antihyperglycemic agents in the placebo group compared with the sitagliptin group Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

  46. Acknowledgements …in an academic collaboration with TECOS was conducted jointly by TECOS Executive Committee* Rury Holman, Joint Chair Eric Peterson, Joint Chair Paul Armstrong John Buse Robert Josse Keith Kaufman Joerg Koglin Scott Korn John Lachin Darren McGuire Eberhard Standl Peter Stein Shailaja Suryawanshi Frans Van de Werf * Robert M. Califf served as Joint Chair until taking up the post of deputy FDA commissioner on March 1, 2015

  47. Data and Safety Monitoring Board Marc Pfeffer, Chair Stuart Pocock John McMurray Hertzel Gerstein Leif Groop Independent statistician Tim Clayton

  48. Operations Committee Italy: Giuseppe Ambrosio Latvia: Valdis Pirags Lithuania: Neli Jakuboniene Malaysia: Mafauzy Mohamed Netherlands: Jan H. Cornel New Zealand: Russell Scott, Harvey White Norway: Sigrun Halvorsen Poland: Andrzej Tykarski Romania: Ioan Andrei Veresiu Russia: Alexander V. Dreval, Inna Misinkova Singapore: E. Shyong Tai Slovakia: Boris Krahulec South Africa: Larry Distiller South Korea: Yong Soo Park Spain: Adela Rovira Sweden: Michael Alvarsson Taiwan: Lee-Ming Chuang Turkey: Tuncay Delibasi United Kingdom: Amanda Adler United States: Helena Rodbard Argentina: Isaac Sinay, Australia: David Brieger, Steve Stranks, Belgium: Andre Scheen, Brazil: Antonio Chacra, Renato Lopes Bulgaria: Tsvetalina Tankova Canada: Irene Hramiak Chile: Carlos Raffo Grado China: Junbo Ge, Yang Wen Ying Colombia: Pablo Aschner Czech Republic: Jan Skrha Estonia: Anu Ambos Finland: Timo Strandberg France: Michel Marre, Florence Travert Germany: Markof Hanefeld, Axel Riefflin Hong Kong: Juliana Chan Hungary: Peter Ofner India: Priyadarshini Arambam, Johann Christopher, Mukul Manchanda, Atul Mathur, Sanjay Mittal, N. K. Reddy, Naresh Trehan Israel: Julio Wainstein

  49. Patients and Sites • We thank the patients, without whom this study and these analyses would not have been possible • We also thank the many investigators and their staff from 673 sites in 38 countries who worked diligently to help ensure TECOS was run to the highest possible standards

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