Introduction, Study Rationale & Design

Transcription

1 Introduction, Study Rationale & Design John Buse, MD, PhD Verne S. Caviness Distinguished Professor Chief, Division of Endocrinology Director, NC Translational and Clinical Sciences Institute Executive Associate Dean, Clinical Research University of North Carolina School of Medicine Chapel Hill, NC, USA

2 Disclosures Consultant: PhaseBio Research support: AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, GI Dynamics, Intarcia, J&J, Lexicon, Medtronic, Novo Nordisk, Orexigen, Sanofi, Scion NeuroStim, Takeda, Theracos Stocks/shareholder: PhaseBio Other (advisor under contract between employer and the company): Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, Elycylex, F. Hoffman LaRoche, GI Dynamics, Lexicon, Merck, Metavention, Novo Nordisk, Orexigen, Quest, Takeda, vtv Therapeutics

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4 Diabetes-related complications in the USA, Acute myocardial infarction Adapted from Gregg EW, et al. N Engl J Med 2014;370:

5 CVD is the leading cause of death in people with T2D *Information on diabetes type (i.e., type 1 or 2) was generally not available, though the age of the participants suggests that the large majority with diabetes would have type 2. In high income countries, up to 91% of adults with diabetes have type 2 3 CVD, cardiovascular disease; CI, confidence interval; T2D, type 2 diabetes. 1. Seshasai et al. N Engl J Med 2011;364:829-41; 2. Centers for Disease Control and Prevention National Diabetes Fact Sheet International Diabetes Federation. IDF Diabetes Atlas, 7th edition. Brussels, Belgium: International Diabetes Federation,

6 All Cause Mortality Intensive vs Standard Glucose Lowering CI: confidence interval; HR: hazard ratio. Ray KK et al Lancet 2009;373:

7 Ussher JR, Drucker DJ. Circ Res 2014;114:

8 Steering Committee Academic Members John Buse USA (Chair) Steven P Marso USA (Co-Chair) Richard Bergenstal USA Gilbert Daniels USA Johannes Mann Germany Michael Nauck Germany Steven Nissen USA Stuart Pocock UK Neil Poulter UK William Steinberg USA Bernard Zinman Canada Sponsor (Novo Nordisk) Kirstine Brown-Frandsen Peter Kristensen Mette Stockner Lasse S Ravn ( ) Alan Moses ( ) Marcin Zychma ( )

9 Global Expert Panel S Akalın, Turkey R Arechavaleta, Mexico S Bain, UK M Babkowski, Spain M Benroubi, Greece L Berard, Canada A Comlekci, Turkey L Czupryniak, Poland M Eriksson, Sweden V Fonseca, USA E Franek, Poland J Gross, Brazil K Hafidh, UAE M Haluzik, Czech Republic F Hayes, Ireland Y-Y Huang, Taiwan S Jacob, Germany G Kaddaha, UAE A Khalil, UAE B Kilhovd, Norway M Laakso, Finland L Leiter, Canada N Lalic, Serbia J Linong, China J Luedemann, Germany E Mannucci, Italy M Marre, France L Masmiquel, Spain M Mota, Romania M Omar, South Africa D O Shea, Ireland CY Pan, China J Petrie, UK T Pieber, Austria R Pratley, USA I Raz, Israel R Rea, Brazil G Rutten, The Netherlands I Satman, Turkey M Shestakova, Russia R Simpson, Australia D Smith, Ireland C Tack, The Netherlands L Tarnow, Denmark N Thomas, India L Van Gaal, Belgium F Travert, France J Vidal, Spain M Warren, USA K-H Yoon, Republic of Korea

10 LEADER: Study design CV: cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; HbA 1c : glycated hemoglobin; MEN-2: multiple endocrine neoplasia type 2; MTC: medullary thyroid cancer; OAD: oral antidiabetic drug; OD: once daily; T2DM: type 2 diabetes mellitus.

11 Primary and key secondary outcomes CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.

12 Event adjudication *Requiring hospitalization. ACS: acute coronary syndrome.

13 LEADER standard of care guidelines CV: cardiovascular; CVA: cerebrovascular accident; HbA 1c : glycated hemoglobin; LDL: low-density lipoprotein; MI: myocardial infarction.

14 Additional committee efforts Data monitoring committee Calcitonin monitoring committee Patient retention panel

15 Study population Neil Poulter, F.Med.Sci Professor of Preventive Cardiovascular Medicine Co-Director of International Centre for Circulatory Health and Imperial Clinical Trials Unit Imperial College London London, UK

16 Disclosures Fees for serving on Steering Committees from AstraZeneca and Novo Nordisk, and lecture fees from Novo Nordisk and Takeda Pharmaceuticals

17 LEADER: A Global Trial

18 Study patient disposition FAS: full analysis set.

19 Baseline characteristics (mean ± SD unless stated) *Heart failure includes New York Heart Association class I, II and III. BMI: body mass index; HbA 1c : glycated hemoglobin.

20 Baseline cardiovascular risk profile Data are number of patients (%). CHD: coronary heart disease; CKD: chronic kidney disease; CVD: cardiovascular disease; egfr: estimated glomerular filtration rate; NYHA: New York Heart Association; TIA: transient ischemic attack.

21 Baseline cardiovascular risk profile Data are number of patients (%). CVD: cardiovascular disease.

22 Cardiovascular medication at baseline

23 Antihyperglycemic medication at baseline TZD: thiazolidinediones.

24 Trial follow-up and drug exposure *Excluding pre-scheduled 30 day off-treatment follow-up period. Including off-treatment periods. IQR: interquartile range.

25 UNIVERSITY OF TORONTO Clinical & Metabolic Outcomes Bernard Zinman, CM, MD, FRCPC, FACP Director, Leadership Sinai Centre for Diabetes Sam and Judy Pencer Family Chair in Diabetes Research Senior Scientist, Lunenfeld-Tanenbaum Research Institute Professor of Medicine, University of Toronto Mount Sinai Hospital Toronto, Canada

26 Disclosures Consultations and Honoraria Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi Grant Support Boehringer Ingelheim, Novo Nordisk, Astra Zeneca

27 HbA 1c Data are estimated mean values from randomization to month 48. CI: confidence interval; ETD: estimated treatment difference; HbA 1c : glycated hemoglobin.

28 Antihyperglycemic medication at baseline TZD: thiazolidinediones.

29 Antihyperglycemic medications introduced during trial DPP-4: dipeptidyl peptidase-4; GLP-1RA: glucagon-like peptide-1 receptor agonist; SGLT-2: sodium-glucose co-transporter-2; TZD: thiazolidinedione.

30 Body weight Data are estimated mean values from randomization to last scheduled visit for body weight measurement (month 48). CI: confidence interval; ETD: estimated treatment difference.

31 Cardiovascular medication introduced during trial

32 Blood pressure Data are estimated mean values from randomization to last scheduled visit for blood pressure measurement (month 48). CI: confidence interval; DBP: diastolic blood pressure; ETD: estimated treatment difference; SBP: systolic blood pressure.

33 Heart rate Data are estimated mean values from randomization to last scheduled visit for heart rate measurement (month 48). Bpm: beats per minute; CI: confidence interval; ETD: estimated treatment difference.

34 Cholesterol Data are observed geometric mean values from randomization to last scheduled visit for LDL and HDL cholesterol measurement (month 48). CI: confidence interval; ETD: estimated treatment difference; LDL: low-density lipoprotein; HDL: high-density lipoprotein.

35 Health-related quality of life Patient-reported outcomes EQ-5D index score and VAS score EQ5D Index score Mobility Self-care Usual activities Pain/discomfort Anxiety/depression Worst EQ5D VAS score Assessment of health state by the visual analogue scale Imaginable health state Best

36 Quality of life: EQ5D Full analysis set. Estimated means. Change from baseline to 3-year assessment analysed using a linear mixed model accounting for repeated measures within patients using an unstructured residual covariance matrix. Interaction between visit and respectively treatment, sex, region and antidiabetic therapy at baseline are included as fixed effects and interaction between visit and respectively baseline EQ5D Index/VAS score and age at baseline are included as covariates. CI: confidence interval; EQ5D: EuroQol 5 Dimensions; ETD: estimated treatment difference; VAS: visual analog scale.

37 Cardiovascular Outcomes Steven Marso, MD Medical Director of Interventional Cardiology Professor Internal Medicine University of Texas Southwestern Medical Center Dallas, TX, USA

38 Disclosures Consulting fees from Novo Nordisk and Astra Zeneca, honoraria for physician education from Abbott, and grant support to his institution from Novo Nordisk

39 Primary outcome CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.

40 Confirmatory statistical analysis CI: confidence interval; CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.

41 Analyses of MACE and time to first event CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.

42 Primary outcome CV death, non-fatal myocardial infarction, or non-fatal stroke The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio.

43 Primary outcome: Sensitivity analysis Analyzed using Cox proportional hazard regression with treatment as a fixed factor. FAS: full analysis set; PP: per protocol.

44 Time to first event analysis

45 CV death The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio.

46 Time to non-fatal myocardial infarction The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio.

47 Time to non-fatal stroke The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio.

48 Subgroup analyses of the primary outcome

49 Primary outcome: Subgroup analyses Prespecified Cox proportional-hazard regression analyses were performed for subgroups of patients with respect to the primary outcome (first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). P values signify tests of homogeneity for between-group differences with no adjustment for multiple testing. The percentages of patients with a first primary outcome between the randomization date and the date of last follow-up are shown. Race or ethnic group was self-reported. CI: confidence interval.

50 Primary outcome: Subgroup analyses Prespecified Cox proportional-hazard regression analyses were performed for subgroups of patients with respect to the primary outcome (first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke). P values signify tests of homogeneity for between-group differences with no adjustment for multiple testing. The percentages of patients with a first primary outcome between the randomization date and the date of last follow-up are shown. There were missing data for BMI in 5 patients in the liraglutide group and 4 in the placebo group and for the duration of diabetes in 11 patients in the liraglutide group and 8 in the placebo group.

51 Expanded MACE All-cause death Hospitalization for HF

52 Expanded MACE CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MACE: major adverse cardiovascular event; MI: myocardial infarction.

53 All-cause death The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio.

54 Hospitalization for heart failure The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio.

55 Primary and secondary cardiovascular outcomes* *Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate. The primary composite outcome in the time-to-event analysis consisted of the first occurrence of death from cardiovascular causes (181 patients in the liraglutide group vs. 227 in the placebo group), non-fatal (including silent) myocardial infarction (275 vs. 304), or non-fatal stroke (152 vs. 163). The p-value is for superiority. The expanded composite outcome included death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure. This analysis was not prespecified. CI: confidence interval; CV: cardiovascular; UAP: unstable angina pectoris.

56 Microvascular Outcomes Johannes Mann, MD Friedrich Alexander University of Erlangen Germany

57 Disclosures Speaker honoraria: Amgen, Astra Zeneca, Braun, Fresenius, Gambro, Medice, Novo Nordisk, Relypsa, Roche Research support: European Union, Canadian Institutes of Health Research, Boehringer, Celgene, Novo Nordisk, Roche, Sandoz Consultant: AbbVie, Astra Zeneca, Celgene, Fresenius, Eli Lilly, Lanthio, Novo Nordisk, Relypsa, Sanifit, Vifor

58 Microvascular event definitions Event type Event definition one or more of the below New onset of persistent macroalbuminuria Microvascular events Renal Eye Persistent doubling of serum creatinine Need for continuous renal replacement therapy Death due to renal disease Need for retinal photocoagulation or treatment with intravitreal agents Vitreous hemorrhage Diabetes-related blindness

59 Adjudication of microvascular endpoints

60 Microvascular event analyses

61 Baseline renal function Full analysis set. Data are means ± standard deviations or number of patients (percentage of either liraglutide-treated or placebo-treated group). Percentage data refer to proportion of patients. egfr: estimated glomerular filtration rate.

62 Time to first microvascular event The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio.

63 Time to first renal event Macroalbuminuria, doubling of serum creatinine, ESRD, renal death The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio.

64 Time to first eye event Photocoagulation or treatment with intravitreal agents, vitreous hemorrhage or blindness The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio.

65 Microvascular events %: percentage of group; CI: confidence interval; HR: hazard ratio; N: number of patients; Rate: incidence rate per 100 patient-years of observation.

66 Time to first microvascular endpoints Full analysis set. EAC-confirmed microvascular events including events with onset between date of randomization and date of follow-up. Cox proportional hazard model adjusted for treatment. Development of diabetes-related blindness was not analyzed as an individual component as only one event was observed. *New onset of persistent macroalbuminuria: urine albumin 300 mg/g creatinine. Persistent doubling of serum creatinine level and egfr 45 ml/min/1.73 m 2 per MDRD. %: proportion of patients; CI: confidence interval; EAC: event adjudication committee; N: number of patients.

67 Safety Michael Nauck, MD St. Josef-Hospital (Ruhr University) Bochum, Germany

68 Disclosures Board Member/Advisory Panel: Boehringer Ingelheim, Menarini/Berlin-Chemie, Eli Lilly and Company, GlaxoSmithKline, Hoffmann-La Roche, Merck Sharp & Dohme, Novartis, Novo Nordisk, Takeda Consultant: AstraZeneca, Bristol-Myers Squibb, Hoffmann-La Roche, MetaCure, Versatis, Xoma Employee: St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany Research Support: Bayer Vital, Eli Lilly and Company, GlaxoSmithKline, Hoffmann-La Roche, Menarini/Berlin-Chemie, Merck Sharp & Dohme, Novartis, Novo Nordisk (to my institution) Speaker Bureau: AstraZeneca, Menarini/Berlin-Chemie, Eli Lilly and Company, GlaxoSmithKline, Hoffmann-La Roche, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis, Takeda Stock/Shareholder: None Travel support in conjunction with above-mentioned activities

69 Overview of adverse events

70 Adverse events Full analysis set. A serious adverse event was defined as an experience that at any dose resulted in any of the following: death, a life-threatening experience, in-patient hospitalization or prolongation of hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, important medical events that may jeopardize the patient based upon appropriate medical judgement. A severe adverse event was defined as an adverse event that resulted in considerable interference with the patient s daily activities. N: number of patients.

71 Selected adverse events of special interest Serious adverse events and nonserious medical events of special interest were identified by search in the Medical Dictionary for Regulatory Activities, version 18.0, or by action to trial product: trial product permanently discontinued due to adverse event. P-values were calculated by means of Pearson s chi-square test.

72 AEs leading to permanent treatment discontinuation *Exploratory analysis with no adjustment of p-values for multiplicity. Permanent discontinuation of the treatment regimen was indicated by the investigator in the adverse event form. P-values were calculated by means of Pearson s chi-square test.

73 Hypoglycemia

74 Hypoglycemia Full analysis set. Confirmed hypoglycemia was defined as plasma glucose level of less than 56 mg per deciliter (3.1 mmol per liter) or a severe event. Hypoglycemic episodes on and after randomization date and up to visit 15 (end of treatment) are included (episodes with a missing date are included). %: proportion of subjects; ADA: American Diabetes Association; N: number of subjects; PG: plasma glucose; R: event rate per 100 observation years.

75 Hypoglycemia Confirmed hypoglycemia was defined as plasma glucose level of less than 56 mg per deciliter (3.1 mmol per liter) or a severe event. Severe hypoglycemia was defined as hypoglycemia for which the patient required assistance from a third party. Analyzed using a negative binomial regression model. CI: confidence interval; PG: plasma glucose.

76 Neoplasms

77 Neoplasms Confirmed by adjudication *EAC-confirmed neoplasms with EAC onset date from randomization date to follow-up; includes malignant, pre-malignant, benign and unspecified neoplasms. Neoplasms were adjudicated by the event adjudication committee. This committee interpreted neoplastic growth as clonal disorders that grow in an autonomous manner. The abnormality of clonal disorder may not always have been identified nor could autonomous growth always be determined, but both were considered to be fundamental aspects of neoplastic growth. Cox proportional hazard regression model adjusted for treatment. %: proportion of patients; CI: confidence interval; EAC: Event Adjudication Committee; N: number of patients.

78 Malignant neoplasms by tissue type Confirmed by adjudication Exploratory analysis. CI: confidence interval.

79 Pancreatic cancer

80 Thyroid neoplasms No change in calcitonin P-values were calculated by means of Pearson s chi-square test. %: proportion of patients; N: number of patients.

81 Exocrine pancreas Pancreatitis

82 Pancreatic enzymes Data are observed geometric mean values from randomization to the last scheduled visit for lipase and amylase measurements (month 48).

83 Pancreatitis (confirmed by adjudication) Full analysis set. The occurrence of pancreatitis was adjudicated by the event adjudication committee. P-values were calculated by means of Pearson s chi-square test. %: proportion of patients; N: number of patients.

84 Conclusions John Buse, MD, PhD Verne S. Caviness Distinguished Professor Chief, Division of Endocrinology Director, NC Translational and Clinical Sciences Institute Executive Associate Dean, Clinical Research University of North Carolina School of Medicine Chapel Hill, NC USA

85 Number needed to treat to prevent one CV: cardiovascular; MACE: major adverse cardiovascular event.

86 Perspective

87 Glucagon-like peptide-1 receptor agonists ELIXA Time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalization for unstable angina LEADER Time to first occurrence of CV death, non-fatal MI or non-fatal stroke CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MI: myocardial infarction. Pfeffer MA et al. N Engl J Med 2015;373:

88 Empagliflozin and Liraglutide EMPA-REG OUTCOME CV death, non-fatal MI, or non-fatal stroke LEADER CV death, non-fatal MI, or non-fatal stroke CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MI: myocardial infarction. Zinman B et al. N Engl J Med 2015;373:

89 Individual components of the primary endpoint EMPA-REG OUTCOME LEADER *95.02% CI. CV: cardiovascular; Empa: empaglifloin; Lira: liraglutide; MACE: major adverse cardiovascular event; MI: myocardial infarction; Pbo: placebo. Zinman B et al. Presented at European Association for the Study of Diabetes 2015, Stockholm, Sweden.

90 LEADER: Summary Population studied High risk of cardiovascular events receiving standard of care 81% with prior CVD or CKD Potentially greater benefit in established CVD and egfr <60 ml/min/1.73 m 2 subgroups Follow-up and retention 96.8% of patients completed the study Vital status known for 99.7% of patients Robust event adjudication by external committee CKD: chronic kidney disease; CVD: cardiovascular disease; egfr: estimated glomerular filtration rate.

91 LEADER: Summary (2) Liraglutide reduced the risk for 3-point MACE by 13% All 3 components of MACE contributed to the risk reduction Liraglutide reduced composite microvascular endpoints Driven by reduced new and persistent macroalbuminuria Liraglutide resulted in reductions in HbA 1c, body weight, and hypoglycemia Liraglutide was generally well tolerated. In line with previous trials, liraglutide was associated with gastrointestinal side effects, increases in pancreatic enzymes and heart rate HbA 1c : glycated hemoglobin; MACE: major adverse cardiovascular event.

92 LEADER: Summary (3) No increase in pancreatitis but an increase in acute gallstone disease No increase in hospitalization for heart failure Liraglutide reduced the risk of all-cause death by 15% Liraglutide reduced the risk of CV death by 22% CV: cardiovascular.