Download Primary outcome

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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Diabetes-related complications in the USA, 1990-2010
Acute 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
*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.
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
All Cause Mortality
Intensive vs Standard Glucose Lowering
CI: confidence interval; HR: hazard ratio.
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.
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.
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 (2011-2016)
Alan Moses (2009-2014)
Marcin Zychma (2009-2011)
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Primary and key secondary outcomes
CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Event adjudication
*Requiring hospitalization.
ACS: acute coronary syndrome.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
LEADER standard of care guidelines
CV: cardiovascular; CVA: cerebrovascular accident; HbA1c: glycated hemoglobin; LDL: low-density lipoprotein; MI: myocardial infarction.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Additional committee efforts
• Data monitoring committee
• Calcitonin monitoring committee
• Patient retention panel
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Disclosures
• Fees for serving on Steering Committees from AstraZeneca and Novo Nordisk,
and lecture fees from Novo Nordisk and Takeda Pharmaceuticals
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
LEADER: A Global Trial
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Study patient disposition
FAS: full analysis set.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Baseline cardiovascular risk profile
Data are number of patients (%).
CVD: cardiovascular disease.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Cardiovascular medication at baseline
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Antihyperglycemic medication at baseline
TZD: thiazolidinediones.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Trial follow-up and drug exposure
*Excluding pre-scheduled 30 day off-treatment follow-up period.
†Including off-treatment periods.
IQR: interquartile range.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Disclosures
• Consultations and Honoraria
• Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi
• Grant Support
• Boehringer Ingelheim, Novo Nordisk, Astra Zeneca
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
HbA1c
Data are estimated mean values from randomization to month 48.
CI: confidence interval; ETD: estimated treatment difference; HbA 1c: glycated hemoglobin.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Antihyperglycemic medication at baseline
TZD: thiazolidinediones.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Cardiovascular medication introduced during trial
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Health-related quality of life
Patient-reported outcomes EQ-5D index score and VAS score
EQ5D Index score
EQ5D VAS score
•
•
•
•
•
• Assessment of health state by the visual
analogue scale
Mobility
Self-care
Usual activities
Pain/discomfort
Anxiety/depression
Imaginable health state
Worst
10
20
30
40
50
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
60
70
80
90
Best
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Cardiovascular
Outcomes
Steven Marso, MD
Medical Director of Interventional Cardiology
Professor Internal Medicine
University of Texas Southwestern Medical Center
Dallas, TX, USA
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Disclosures
• Consulting fees from Novo Nordisk and Astra Zeneca, honoraria for physician
education from Abbott, and grant support to his institution from Novo Nordisk
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Primary outcome
CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Confirmatory statistical analysis
CI: confidence interval; CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Analyses of MACE and time to first event
CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Primary outcome: Sensitivity analysis
Analyzed using Cox proportional hazard regression with treatment as a fixed factor. FAS: full analysis set; PP: per protocol.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Time to first event
analysis
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Subgroup analyses of
the primary outcome
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Primary outcome: Subgroup analyses
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Primary outcome: Subgroup analyses
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Expanded MACE
All-cause death
Hospitalization for HF
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Microvascular
Outcomes
Johannes Mann, MD
Friedrich Alexander University of Erlangen
Germany
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Microvascular event definitions
Event type
Event definition – one or more of the below
• New onset of persistent macroalbuminuria
• Persistent doubling of serum creatinine
Renal
• Need for continuous renal replacement therapy
Microvascular
events
• Death due to renal disease
• Need for retinal photocoagulation or treatment with
intravitreal agents
Eye
• Vitreous hemorrhage
• Diabetes-related blindness
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Adjudication of microvascular endpoints
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Microvascular event analyses
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Microvascular events
%: percentage of group; CI: confidence interval; HR: hazard ratio; N: number of patients; Rate: incidence rate per 100 patient-years of observation.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Safety
Michael Nauck, MD
St. Josef-Hospital (Ruhr University)
Bochum, Germany
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Overview of
adverse events
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Hypoglycemia
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Neoplasms
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Malignant neoplasms by tissue type
Confirmed by adjudication
Exploratory analysis.
CI: confidence interval.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Pancreatic cancer
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Exocrine pancreas
Pancreatitis
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Pancreatic enzymes
Data are observed geometric mean values from randomization to the last scheduled visit for lipase and amylase measurements (month 48).
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, 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.
Perspective
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Glucagon-like peptide-1 receptor agonists
ELIXA
LEADER
Time to first occurrence of CV death, non-fatal MI,
non-fatal stroke or hospitalization for unstable angina
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;373:2247–2257.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Empagliflozin and Liraglutide
EMPA-REG OUTCOME
LEADER
CV 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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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 m2 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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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 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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.