1) The LEADER trial investigated the cardiovascular outcomes of treatment with liraglutide vs placebo in patients with type 2 diabetes at high risk of cardiovascular events. 2) The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Liraglutide was found to be non-inferior and superior to placebo for reducing the primary outcome. 3) When outcomes were analyzed according to history of prior myocardial infarction or stroke, liraglutide was found to reduce the primary outcome and cardiovascular death compared to placebo regardless of prior history.

1. Risk of major cardiovascular events in
patients with type 2 diabetes with and
without prior cardiovascular events –
results from the LEADER trial
Neil Poulter, Stephen C. Bain, John Buse, Tea Monk-Hansen,
Michael Nauck, Søren Rasmussen, Richard Pratley,
Bernard Zinman, David Ørsted, Steven P. Marso; on behalf of
the LEADER Trial Steering Committee and Investigators

2. Disclosures relevant to
this presentation
• Fees for serving on Steering Committees from
AstraZeneca and Novo Nordisk
• Lecture fees from Novo Nordisk, AstraZeneca
and Takeda Pharmaceuticals

3. Liraglutide: A once-daily GLP-1 analogue1
*Long-acting analogues have only a minor/transient effect on gastric emptying, compared with short-acting analogues. GLP-1: glucagon-like peptide-1.
1. Knudsen LB et al. J Med Chem 2000;43:1664–1669; 2. Drucker DJ et al. Proc Natl Acad Sci USA 1987;84:3434–3438; 3. Drucker DJ, Nauck MA. Lancet
2006;368:1696–1705; 4. Nauck M et al. Diabetologia 1993;36:741–744; 5. Campbell JE and Drucker DJ. Cell Metab 2013;17:819–837; 6. Pratley RE and
Gilbert M. Rev Diabet Stud 2008;5:73–94; 7. van Can J et al. Int J Obes 2014;38:784–793; 8. Drucker DJ. Cell Metab 2016;24:15–30; 9. Marso SP et al.
N Engl J Med 2016;375:311–322; 10. Marso SP et al. N Engl J Med 2016;375:1834–1844.
Glucose:
• Insulin ↑
• β-cell function ↑
• Glucagon ↓
• Gastric emptying* ↓
Cardiovascular:
• Inflammation ↓
• (Post-prandial) lipids ↓
• Systolic blood pressure ↓
• Heart rate ↑
Kidney:
• Inflammation ↓
• Systolic blood pressure ↓
Body weight:
• Appetite ↓
• Energy intake ↓
• GLP-1 is a peptide hormone from the incretin family, which mediates multiple effects in
the body, including glucose-dependent insulin secretion in response to meal ingestion1–4
Main effects of
liraglutide5–10

4. Rationale for LEADER
CV: cardiovascular; EMA: European Medicines Agency; FDA: Food and Drug Administration; T2DM: type 2 diabetes mellitus.
To assess the long-term CV safety (non-inferiority) of
liraglutide vs placebo in patients with T2DM and high CV risk,
as per the 2008 FDA and EMA requirements
Hierarchical testing to assess potential superiority of
liraglutide vs placebo for reducing risk of CV events

5. Study design
BMI: body mass index; CKD: chronic kidney disease; CV: cardiovascular; HbA1c: glycosylated haemoglobin; OAD: oral antidiabetic drug; OD: once daily;
SD: standard deviation; T2DM: type 2 diabetes mellitus.
Baseline characteristics (mean ± SD)
• Age (years): 64.3 ± 7.2
• HbA1c (%): 8.7 ± 1.5
• BMI (kg/m2): 32.5 ± 6.3
• Diabetes duration (years): 12.8 ± 8.0
Key inclusion criteria
• T2DM, HbA1c ≥7.0%
• Antidiabetic drug naïve; OADs and/or basal/premix
insulin
• Age ≥50 years and established CV disease or CKD
or
• Age ≥60 years and risk factors for CV disease
Liraglutide 0.6–1.8 mg OD + standard of care
Placebo + standard of care
Duration 3.5–5 years
Randomisation (1:1) End of treatment
Placebo
run-in
Safety follow-up
Safety follow-up
30 days2 weeks
Screening
Marso SP et al. N Engl J Med 2016;375:311–322.

6. Primary and key secondary outcomes
*Including silent MI.
CV: cardiovascular; HF: heart failure; MACE: major adverse cardiac event; MI: myocardial infarction.
Primary
outcome
Time to first MACE composed of
• CV death
• Non-fatal MI*
• Non-fatal stroke
Key secondary
outcomes
Time to first occurrence of
• Expanded composite CV outcome
(CV death, non-fatal MI*, non-fatal stroke, coronary revascularisation, unstable
angina pectoris requiring hospitalisation, or hospitalisation for HF)
• All-cause death
• Each individual component of expanded composite CV outcome
Marso SP et al. N Engl J Med 2016;375:311–322.

7. Primary outcome: CV death, non-fatal MI or
non-fatal stroke
*One-sided p-value for non-inferiority.
The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazards
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; MI: myocardial infarction.
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4
0
5
1 0
1 5
2 0
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4
0
5
1 0
1 5
2 0
Patientswithanevent(%)
Time from randomisation (months)
HR: 0.87
95% CI (0.78 ; 0.97)
p<0.001 for non-inferiority*
p=0.01 for superiority
Placebo
Liraglutide
20
15
10
5
0
0 6 12 18 24 30 36 42 48 54
Marso SP et al. N Engl J Med 2016;375:311–322.

8. Hazard ratio
(95% CI) p-value
Liraglutide Placebo
N % R N % R
Total number of patients 4668 100.0 – 4672 100.0 –
Primary outcome 0.87 (0.78 ; 0.97) 0.01 608 13.0 3.4 694 14.9 3.9
CV death 0.78 (0.66 ; 0.93) 0.007 219 4.7 1.2 278 6.0 1.6
Non-fatal MI 0.88 (0.75 ; 1.03) 0.11 281 6.0 1.6 317 6.8 1.8
Non-fatal stroke 0.89 (0.72 ; 1.11) 0.30 159 3.4 0.9 177 3.8 1.0
Components of the primary outcome
Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards regression model with treatment as a covariate.
%: percentage of group; CI: confidence interval; CV: cardiovascular; MI: myocardial infarction; N: number of patients;
R: incidence rate per 100 patient-years of observation.
Favours placeboFavours liraglutide
0.5
Hazard ratio (95% CI)
Marso SP et al. N Engl J Med 2016;375:311–322.
1.0 2.0

9. What about patients
with versus those without
prior MI or stroke?
MI: myocardial infarction.

10. Baseline characteristics and demographics stratified by
prior MI or stroke
Data are mean (standard deviation) unless otherwise stated
BMI: body mass index; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; HbA1c: glycosylated haemoglobin; MDRD: modification of diet
in renal disease; MI: myocardial infarction; SBP: systolic blood pressure; T2DM: type 2 diabetes mellitus.
Prior MI/stroke No prior MI/stroke
N=3692 N=5648
Age, years 63.4 (5.5) 64.9 (7.0)
Sex, % F/M 27.1/72.9 41.4/58.6
BMI, kg/m2
32.0 (5.9) 32.8 (6.5)
SBP, mmHg 134.7 (17.7) 136.7 (17.7)
DBP, mmHg 77.0 (10.2) 77.1 (10.3)
Total cholesterol, mmol/L 4.3 (1.1) 4.5 (1.2)
T2DM duration, years 12.6 (8.1) 13.0 (7.9)
HbA1c, % 8.7 (1.5) 8.7 (1.5)
eGFR, mL/min/1.73 m2
, MDRD 81.5 (27.6) 79.6 (27.2)

11. 0
4
8
12
16
20
24
0 10 20 30 40 50 60
Primary outcome stratified by prior MI or stroke
CI: confidence interval; HR: hazard ratio; MI: myocardial infarction.
Patientswithevent(%)
Time from randomisation (months)
LiraglutidePlacebo
1865
1827
1791
1733
1709
1645
1603
1545
1519
1459
363
359
Number at risk
Liraglutide
Placebo
Patientswithevent(%)
Time from randomisation (months)
LiraglutidePlacebo
HR: 0.84
95% CI (0.72 ; 0.97)
Patients with prior MI/stroke Patients without prior MI/stroke
0
4
8
12
16
20
24
0 10 20 30 40 50 60
HR: 0.89
95% CI (0.76 ; 1.05)
2803
2845
2740
2781
2662
2674
2569
2578
2487
2486
588
551
Number at risk
Liraglutide
Placebo

12. 0 1 0 2 0 3 0 4 0 5 0
0 . 0 0
0 . 0 2
0 . 0 4
0 . 0 6
0 . 0 8
0 . 1 0
CV death stratified by prior MI or stroke
CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MI: myocardial infarction.
0 1 0 2 0 3 0 4 0 5 0
0 . 0 0
0 . 0 2
0 . 0 4
0 . 0 6
0 . 0 8
0 . 1 0
Time from randomisation (months)
Patientswithevent(%)
0
2
4
6
8
10
0 10 20 30 40 50
HR: 0.76
95% CI (0.58 ; 0.99)
2803
2845
2775
2823
2739
2765
2695
2705
2641
2645
635
599
Number at risk
Liraglutide
Placebo
1865
1827
1835
1795
1811
1758
1750
1702
1697
1644
420
416
Number at risk
Liraglutide
Placebo
Time from randomisation (months)
Patientswithevent(%)
0
2
4
6
8
10
0 10 20 30 40 50
HR: 0.80
95% CI (0.63 ; 1.01)
LiraglutidePlacebo LiraglutidePlacebo
Patients with prior MI/stroke Patients without prior MI/stroke

13. Outcome Prior event
No. events* Rate/100 PYO Hazard ratio
(95% CI)
Interaction
p-valueLira Pbo Lira Pbo
Primary composite
With 322 372 4.6 5.4 0.84 (0.72 ; 0.97)
0.56
Without 286 322 2.7 3.0 0.89 (0.76 ; 1.05)
CV death
With 120 147 1.7 2.1 0.80 (0.63 ; 1.01)
0.79
Without 99 131 0.9 1.2 0.76 (0.58 ; 0.99)
MI (fatal and
non-fatal)
With 157 185 2.2 2.7 0.82 (0.66 ; 1.01)
0.64
Without 135 154 1.3 1.4 0.88 (0.70 ; 1.11)
Stroke (fatal and
non-fatal)
With 95 101 1.3 1.5 0.92 (0.69 ; 1.21)
0.52
Without 78 98 0.7 0.9 0.80 (0.60 ; 1.08)
0.5
CV outcomes stratified by prior MI or stroke
*First events.
CI: confidence interval; CV: cardiovascular; MI: myocardial infarction; PYO: patient-years of observation.
Favours placeboFavours liraglutide
With prior MI/stroke
Liraglutide N=1865
Placebo N=1827
Without prior MI/stroke
Liraglutide N=2803
Placebo N=2845
Hazard ratio (95% CI)
1.0 2.0

14. Outcome Prior event
No. events Rate/100 PYO
Hazard ratio (95% CI)
Interaction
p-valueLira Pbo Lira Pbo
Primary composite
With 322 372 4.6 5.4 0.84 (0.72 ; 0.97)
0.56
Without 286 322 2.7 3.0 0.89 (0.76 ; 1.05)
Expanded primary
composite
With 500 552 7.1 8.0 0.87 (0.77 ; 0.98)
0.90
Without 448 510 4.2 4.7 0.88 (0.78 ; 1.00)
CV death
With 120 147 1.7 2.1 0.80 (0.63 ; 1.01)
0.79
Without 99 131 0.9 1.2 0.76 (0.58 ; 0.99)
MI (fatal or non-fatal)
With 157 185 2.2 2.7 0.82 (0.66 ; 1.01)
0.64
Without 135 154 1.3 1.4 0.88 (0.70 ; 1.11)
Stroke (fatal or non-fatal)
With 95 101 1.3 1.5 0.92 (0.69 ; 1.21)
0.52
Without 78 98 0.7 0.9 0.80 (0.60 ; 1.08)
Coronary
revascularisation
With 219 239 3.1 3.5 0.89 (0.74 ; 1.07)
0.75
Without 186 202 1.7 1.9 0.93 (0.76 ; 1.13)
Hospitalisation for
unstable angina pectoris
With 78 66 1.1 1.0 1.15 (0.83 ; 1.60)
0.12
Without 44 58 0.4 0.5 0.76 (0.52 ; 1.13)
Hospitalisation for
heart failure
With 110 134 1.6 1.9 0.80 (0.62 ; 1.02)
0.33
Without 108 114 1.0 1.1 0.95 (0.73 ; 1.24)
Primary and expanded composite outcome stratified by
prior MI or stroke
Prior CV event is based on CV history from the case report form with positive response for MI, ischaemic stroke or haemorrhagic stroke. CI: confidence interval; CV: cardiovascular;
MI: myocardial infarction; PYO: patient-years of observation.
Favours placeboFavours liraglutide
Hazard ratio (95% CI)
With prior MI/stroke
Liraglutide N=1865
Placebo N=1827
Without prior
MI/stroke
Liraglutide N=2803
Placebo N=2845
Favours placeboFavours liraglutide
0.5 1.0 2.0

15. • Similar results for the primary and expanded composite outcomes were
observed when patients were stratified by prior MI/stroke/CABG/PCI
• Liraglutide reduced all-cause death in the total LEADER population, and in
patients with and without prior MI or stroke
Additional analyses of secondary outcomes
CABG: coronary artery bypass grafting; MI: myocardial infarction; PCI: percutaneous coronary intervention.

16. • Liraglutide reduced the risk of the composite primary outcome (CV death,
non-fatal MI and non-fatal stroke) in patients with T2DM and high CV risk
• Significant reduction in the primary outcome in patients with prior MI or stroke
• Reduction of similar (albeit non-significant) magnitude of the primary outcome in
patients without prior MI or stroke
• Similar benefits across all CV events were observed for those with or without
prior MI or stroke
Summary
CV: cardiovascular; MI: myocardial infarction; T2DM: type 2 diabetes mellitus.

17. Questions
?