Introduction, Study Rationale & Design · CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction. Presented at the American Diabetes Association 76

Introduction, Study Rationale & Design

John Buse, MD, PhDJohn Buse, MD, PhDVerne 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

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

• 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

Disclosures

• 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



Diabetes-related complications in the USA, 1990-2010Acute myocardial infarction

Adapted from Gregg EW, et al. N Engl J Med 2014;370:1514–1523. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

CVD is the leading cause of death in people with T2D

1. Seshasai et al. N Engl J Med 2011;364:829-41; 2. Centers for Disease Control and Prevention National Diabetes Fact Sheet 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf; 3. International Diabetes

Federation. IDF Diabetes Atlas, 7th edition. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org

*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 23

CVD, cardiovascular disease; CI, confidence interval; T2D, type 2 diabetes.


All Cause MortalityIntensive vs Standard Glucose Lowering

Ray KK et al Lancet 2009;373:1765–1772.Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

CI: confidence interval; HR: hazard ratio.

Ussher JR, Drucker DJ. Circ Res 2014;114:1788–803.Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Academic Members

John Buse USA (Chair)

Steven P Marso USA (Co-Chair)

Richard Bergenstal USA

Gilbert Daniels USA

Johannes Mann Germany

Sponsor (Novo Nordisk)

Kirstine Brown-Frandsen

Peter Kristensen

Mette Stockner

Lasse S Ravn (2011-2016)

Steering Committee

Johannes Mann Germany

Michael Nauck Germany

Steven Nissen USA

Stuart Pocock UK

Neil Poulter UK

William Steinberg USA

Bernard Zinman Canada

Lasse S Ravn (2011-2016)

Alan Moses (2009-2014)

Marcin Zychma (2009-2011)


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

S Jacob, Germany

G Kaddaha, UAE

A Khalil, UAE

B Kilhovd, Norway

M Laakso, Finland

L Leiter, Canada

N Lalic, Serbia

J Linong, China

T Pieber, Austria

R Pratley, USA

I Raz, Israel

R Rea, Brazil

G Rutten, The Netherlands

I Satman, Turkey

M Shestakova, Russia

R Simpson, AustraliaL 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

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

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


LEADER: Study design

CV: cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; HbA1c: 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.


Primary and key secondary outcomes

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


Event adjudication

*Requiring hospitalization.

ACS: acute coronary syndrome.


LEADER standard of care guidelines

CV: cardiovascular; CVA: cerebrovascular accident; HbA1c: glycated hemoglobin; LDL: low-density lipoprotein; MI: myocardial infarction.


• Data monitoring committee

• Calcitonin monitoring committee

• Patient retention panel

Additional committee efforts

• Patient retention panel


Study population

Neil Poulter, F.Med.SciNeil Poulter, F.Med.SciProfessor of Preventive Cardiovascular Medicine

Co-Director of International Centre for Circulatory Health and Imperial Clinical Trials Unit

Imperial College LondonLondon, UK


• Fees for serving on Steering Committees from AstraZeneca and Novo Nordisk,

and lecture fees from Novo Nordisk and Takeda Pharmaceuticals

Disclosures


LEADER: A Global Trial


Study patient disposition

FAS: full analysis set.


Baseline characteristics (mean ± SD unless stated)

*Heart failure includes New York Heart Association class I, II and III. BMI: body mass index; HbA1c: glycated hemoglobin.


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.


Baseline cardiovascular risk profile

Data are number of patients (%).

CVD: cardiovascular disease.


Cardiovascular medication at baseline


Antihyperglycemic medication at baseline

TZD: thiazolidinediones.


Trial follow-up and drug exposure

*Excluding pre-scheduled 30 day off-treatment follow-up period.†Including off-treatment periods.

IQR: interquartile range.


Clinical & Metabolic Outcomes

Bernard Zinman, CM, MD, FRCPC, FACP

UNIVERSITY OF TORONTO

Bernard Zinman, CM, MD, FRCPC, FACPDirector, 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


• Consultations and Honoraria

• Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi

• Grant Support

• Boehringer Ingelheim, Novo Nordisk, Astra Zeneca

Disclosures

• Boehringer Ingelheim, Novo Nordisk, Astra Zeneca


HbA1c

Data are estimated mean values from randomization to month 48.

CI: confidence interval; ETD: estimated treatment difference; HbA1c: glycated hemoglobin.


Antihyperglycemic medication at baseline

TZD: thiazolidinediones.


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.


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.


Cardiovascular medication introduced during trial


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.


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.


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.


Health-related quality of life Patient-reported outcomes EQ-5D index score and VAS score

EQ5D Index score

• Mobility

• Self-care

• Usual activities

EQ5D VAS score

• Assessment of health state by the visual analogue scale

• Usual activities

• Pain/discomfort

• Anxiety/depression

Imaginable health state

Worst Best10 20 30 40 50 60 70 80 90


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.


Cardiovascular Outcomes

Steven Marso, MDSteven Marso, MDMedical Director of Interventional Cardiology

Professor Internal Medicine

University of Texas Southwestern Medical Center

Dallas, TX, USA


• Consulting fees from Novo Nordisk and Astra Zeneca, honoraria for physician

education from Abbott, and grant support to his institution from Novo Nordisk

Disclosures


Primary outcome



Confirmatory statistical analysis

CI: confidence interval; CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.


Analyses of MACE and time to first event



Primary outcomeCV 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.


Primary outcome: Sensitivity analysis

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


Time to first event analysisanalysis


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.


Time to non-fatal myocardial infarction





Time to non-fatal stroke





Subgroup analyses of the primary outcomethe primary outcome


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.Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

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.Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Expanded MACEAll-cause deathAll-cause death

Hospitalization for HF


Expanded MACECV death, non-fatal MI, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure



CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MACE: major adverse cardiovascular event; MI: myocardial infarction.


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 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.


Hospitalization for heart failure





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.


Microvascular Outcomes

Johannes Mann, MDFriedrich Alexander University of Erlangen

Germany


• 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

Disclosures

Boehringer, Celgene, Novo Nordisk, Roche, Sandoz

• Consultant: AbbVie, Astra Zeneca, Celgene, Fresenius, Eli Lilly, Lanthio,

Novo Nordisk, Relypsa, Sanifit, Vifor


Microvascular event definitions

Event type Event definition – one or more of the below

Renal

• New onset of persistent macroalbuminuria

• Persistent doubling of serum creatinine

• Need for continuous renal replacement therapy

Microvascular

events• Death due to renal disease

Eye

• Need for retinal photocoagulation or treatment with

intravitreal agents

• Vitreous hemorrhage

• Diabetes-related blindness


Adjudication of microvascular endpoints


Microvascular event analyses


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.


Time to first microvascular event





Time to first renal eventMacroalbuminuria, doubling of serum creatinine, ESRD, renal death



months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio.


Time to first eye eventPhotocoagulation or treatment with intravitreal agents, vitreous hemorrhage or blindness





Microvascular events

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


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 m2 per MDRD. %: proportion of patients; CI: confidence interval; EAC: event adjudication committee; N: number of patients.


Safety

Michael Nauck, MDSt. Josef-Hospital (Ruhr University)

Bochum, Germany


• 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

•

Disclosures

• 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


Overview of adverse eventsadverse events


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.


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.


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.


HypoglycemiaHypoglycemia


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.


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.


NeoplasmsNeoplasms


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.


Malignant neoplasms by tissue type Confirmed by adjudication

Exploratory analysis.

CI: confidence interval.


Pancreatic cancer


Thyroid neoplasms

P-values were calculated by means of Pearson’s chi-square test.

%: proportion of patients; N: number of patients.

• No change in calcitonin


Exocrine pancreasPancreatitisPancreatitis


Pancreatic enzymes

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


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.


Conclusions

John Buse, MD, PhDJohn Buse, MD, PhDVerne 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


Number needed to treat to prevent one…

CV: cardiovascular; MACE: major adverse cardiovascular event. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

PerspectivePerspective


Glucagon-like peptide-1 receptor agonists

ELIXATime to first occurrence of CV death, non-fatal MI,

non-fatal stroke or hospitalization for unstable angina

LEADERTime 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;373:2247–2257.


Empagliflozin and Liraglutide

EMPA-REG OUTCOME LEADERCV death, non-fatal MI, or non-fatal stroke 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;373:2117-2128.


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.


• 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 m2 subgroups

LEADER: Summary

• 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.


• 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

LEADER: Summary (2)

• Driven by reduced new and persistent macroalbuminuria

• Liraglutide resulted in reductions in HbA1c, 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

HbA1c: glycated hemoglobin; MACE: major adverse cardiovascular event.


• 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%

LEADER: Summary (3)

• Liraglutide reduced the risk of all-cause death by 15%

• Liraglutide reduced the risk of CV death by 22%

CV: cardiovascular.


Documents

Introduction, Study Rationale & Design · CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction. Presented at the American Diabetes Association 76