Introduction, Study Rationale & Design John Buse, MD, PhD 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 76 th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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Introduction, Study Rationale & Design · CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction. Presented at the American Diabetes Association 76
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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,
• 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, 1990-2010Acute 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
*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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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)
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
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
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.
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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.
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 outcomethe 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
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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Expanded MACECV 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.
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, MDFriedrich 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.
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, MDSt. 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.
• Board Member/Advisory Panel: Boehringer Ingelheim, Menarini/Berlin-Chemie, Eli Lilly and Company,
• 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
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Overview of adverse eventsadverse 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.
HypoglycemiaHypoglycemia
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.
NeoplasmsNeoplasms
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
P-values were calculated by means of Pearson’s chi-square test.
%: proportion of patients; N: number of patients.
• No change in calcitonin
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Exocrine pancreasPancreatitisPancreatitis
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, 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.
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
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
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