The ACCELERATE trial investigated the effects of the CETP inhibitor evacetrapib on cardiovascular outcomes. It found that while evacetrapib significantly increased HDL-C and decreased LDL-C, it did not reduce the risk of major cardiovascular events compared to placebo. Multivariable analyses showed that the changes in lipids induced by evacetrapib were not significantly associated with cardiovascular outcomes. The trial demonstrates that favorable changes in lipids alone through CETP inhibition are not sufficient to improve clinical outcomes in high-risk patients receiving standard treatment.

1. AMLAML
Lipid Levels andLipid Levels and CardiovascularCardiovascular Outcome withOutcome with
Cholesteryl Ester Transfer ProteinCholesteryl Ester Transfer Protein (CETP)(CETP) Inhibition byInhibition by
Evacetrapib in the ACCELERATE TrialEvacetrapib in the ACCELERATE Trial
A.A. Michael Lincoff, M.D.Michael Lincoff, M.D.
for thefor the ACCELERATE TrialACCELERATE Trial InvestigatorsInvestigators
Director, C5ResearchDirector, C5Research
(Cleveland Clinic Coordinating Center for Clinical Research)(Cleveland Clinic Coordinating Center for Clinical Research)
Vice Chairman of Cardiovascular MedicineVice Chairman of Cardiovascular Medicine
Professor of MedicineProfessor of Medicine
Late Breaking Clinical Trials –Late Breaking Clinical Trials – ESC Congress 2016,ESC Congress 2016, RomeRome
ACCELERATE was sponsored by Eli Lilly andACCELERATE was sponsored by Eli Lilly and CompanyCompany

2. AMLAML

3. AMLAML
Speaker Disclosure – A. Michael Lincoff, MDSpeaker Disclosure – A. Michael Lincoff, MD
Relationships withRelationships with IndustryIndustry
Research Funding:Research Funding:
AstraZeneca, CSL Behring, Eli Lilly, Esperion, Pfizer, RocheAstraZeneca, CSL Behring, Eli Lilly, Esperion, Pfizer, Roche
Consultant:Consultant:
Abbott, Amgen, Sarepta, SermonixAbbott, Amgen, Sarepta, Sermonix
Supervisory – C5Research Director:Supervisory – C5Research Director:
Amgen, Atricure, Cardiovascular Systems, Centocor, Covidien, EdwardsAmgen, Atricure, Cardiovascular Systems, Centocor, Covidien, Edwards
Lifesciences, Early Sense, Ethicon, Janssen, Juventas, MedicinesLifesciences, Early Sense, Ethicon, Janssen, Juventas, Medicines
Company, Medtronic, Novartis, Orexigen, Stemedica, TakedaCompany, Medtronic, Novartis, Orexigen, Stemedica, Takeda

4. AMLAML
ACCELERATE TrialACCELERATE Trial
Background and RationaleBackground and Rationale
·· Despite widespread use of statins, many patients continue toDespite widespread use of statins, many patients continue to
experience cardiovascular events.experience cardiovascular events.
·· Considerable efforts have focused on protective effects of HDL as aConsiderable efforts have focused on protective effects of HDL as a
potential therapeutic approach.potential therapeutic approach.
·· Animal and genetic studies suggest that CETP deficiency isAnimal and genetic studies suggest that CETP deficiency is
cardioprotectivecardioprotective
·· Prior trials of CETP inhibitors demonstrated adverse outcomes withPrior trials of CETP inhibitors demonstrated adverse outcomes with
torcetrapib and futility withtorcetrapib and futility with dalcetrapibdalcetrapib
·· Evacetrapib is a potent CETP inhibitor with favorable effects on HDL-C,Evacetrapib is a potent CETP inhibitor with favorable effects on HDL-C,
LDL-C,LDL-C, Lp(aLp(a) and cholesterol efflux in phase 2.) and cholesterol efflux in phase 2.

5. AMLAML
ACCELERATE – Trial DesignACCELERATE – Trial Design
Evacetrapib 130 mgEvacetrapib 130 mg PlaceboPlacebo
1:11:1
RandomizationRandomization
• Event driven - Primary endpoint in 1670 patients (CV death, MI, stroke,
coronary revascularization or hospitalization for unstable angina)
• 84% power to detect a 13.5% reduction in the primary endpoint
• Terminated October 2015 for futility - median 26 months on study drug
(IQR 23-29 months)
High Risk Vascular Disease – 12,092 PatientsHigh Risk Vascular Disease – 12,092 Patients
•• ACS 30-365 daysACS 30-365 days
•• Diabetes with CADDiabetes with CAD
•• Peripheral arterial diseasePeripheral arterial disease
•• CerebrovascularCerebrovascular diseasedisease
LDL-C at target or on maximum tolerated statinLDL-C at target or on maximum tolerated statin

6. AMLAML
Placebo
(n=6054)
Evacetrapib
(n=6038)
Index diagnosis
Acute coronary syndrome 31% 30%
Mean months from event 5.7 5.5
Cerebrovascular atherosclerotic disease 12% 12%
Peripheral arterial disease 14% 14%
Diabetes with coronary artery disease 64% 65%
Statin use 98% 97%
High intensity statin use 46% 46%
ACCELERATE TrialACCELERATE Trial
Enrollment Diagnosis and Statin UseEnrollment Diagnosis and Statin Use

7. AMLAML
Placebo
(n=6054)
Evacetrapib
(n=6038)
Lipids – mg/dL
LDL-C 81.6 81.1
HDL-C 45.3 45.3
ApoA-1 139.0 138.8
ApoB 78.6 78.0
hs-CRP, median (IQR), mg/L 1.5 1.5
Systolic blood pressure, mmHg 131 131
Baseline Lipids,Baseline Lipids, hs-CRPhs-CRP and Blood Pressureand Blood Pressure
ACCELERATE TrialACCELERATE Trial

8. AMLAML
ChangesChanges inin HDL-CHDL-C andand LDL-CLDL-C
ACCELERATE TrialACCELERATE Trial

9. AMLAML
ACCELERATE TrialACCELERATE Trial
Distribution of HDL-C at 3 MonthsDistribution of HDL-C at 3 Months
N=5834N=5834
Mean = 46Mean = 46
Median = 44Median = 44
N=5798N=5798
Mean = 104Mean = 104
Median = 104Median = 104
Placebo
Evacetrapib
%%
%%
HDL Cholesterol (mg/dL)HDL Cholesterol (mg/dL)

10. AMLAML
ACCELERATE TrialACCELERATE Trial
Distribution of LDL-C at 3 MonthsDistribution of LDL-C at 3 Months
N=5833N=5833
Mean = 84Mean = 84
Median = 79Median = 79
N=5798N=5798
Mean = 55Mean = 55
Median = 49Median = 49
Placebo
Evacetrapib
LDL Cholesterol (mg/dL)LDL Cholesterol (mg/dL)
%%
%%

11. AMLAML
Cumulative Incidence of Primary Efficacy EndpointCumulative Incidence of Primary Efficacy Endpoint
ACCELERATE TrialACCELERATE Trial
No. at RiskNo. at Risk
EvacetrapibEvacetrapib 6038603858165816 56035603 54385438 49594959 16261626
PlaceboPlacebo 6054605458255825 56295629 54555455 49774977 16291629
Hazard Ratio 1.01
(95% Cl, 0.91-1.11)
p=0.91

12. AMLAML
Individual Efficacy EndpointsIndividual Efficacy Endpoints
ACCELERATE TrialACCELERATE Trial
Placebo
(n=6054)
Evacetrapib
(n=6038)
HR
(95% CI)
P
Value
Primary composite endpoint 776 (12.8) 779 (12.9)
1.01
(0.91-1.11)
0.91
Cardiovascular death 166 (2.7) 143 (2.4)
0.86
(0.69-1.08)
0.19
Myocardial infarction 259 (4.3) 258 (4.3)
1.00
(0.84-1.18)
0.97
Stroke 98 (1.6) 94 (1.6)
0.96
(0.72-1.27)
0.77
Hosp for unstable angina 146 (2.4) 155 (2.6)
1.06
(0.85-1.33)
0.60
Coronary revascularization 485 (8.0) 487 (8.1)
1.01
(0.89-1.14)
0.94
CV death, MI, or stroke 453 (7.5) 437 (7.2)
0.97
(0.85-1.10)
0.59

13. AMLAML
Primary Efficacy Endpoint – Lipid Related SubgroupsPrimary Efficacy Endpoint – Lipid Related Subgroups
ACCELERATE TrialACCELERATE Trial
Hazard Ratio & 95% CIHazard Ratio & 95% CI
Baseline LDLBaseline LDL
<70 mg/dL<70 mg/dL
70 to <10070 to <100 mg/mg/dLdL
>>100100 mg/mg/dLdL
EvacetrapibEvacetrapib
BetterBetter
0.00.0 0.050.05 1.01.0 1.51.5
PlaceboPlacebo
BetterBetter
EvacetrapibEvacetrapib ControlControlTotalTotal
Baseline HDLBaseline HDL
<40 mg/dL<40 mg/dL
40 to <6040 to <60 mg/mg/dLdL
>>6060 mg/mg/dLdL
Baseline TriglyceridesBaseline Triglycerides
<100 mg/dL<100 mg/dL
100 to <150100 to <150 mg/mg/dLdL
150 to <200150 to <200 mg/mg/dLdL
>>200200 mg/mg/dLdL
Statins at BaselineStatins at Baseline
NoneNone
Low IntensityLow Intensity
Medium IntensityMedium Intensity
High IntensityHigh Intensity
NN EventsEvents
1209212092
41004100
64416441
14541454
34453445
39483948
22262226
22082208
302302
537537
55515551
55575557
43454345
52325232
24172417
60386038
20522052
32183218
723723
17061706
19751975
11231123
11161116
161161
258258
27922792
27542754
21442144
26412641
12081208
NN EventsEvents
779779
281281
398398
9191
191191
244244
152152
172172
3434
2828
350350
354354
253253
345345
172172
60546054
20482048
32233223
731731
17391739
19731973
11031103
10921092
141141
279279
27592759
28032803
22012201
25912591
12091209
776776
277277
407407
8585
206206
243243
165165
139139
3131
3535
329329
372372
260260
333333
176176
1.011.01
1.011.01
0.980.98
1.081.08
0.930.93
1.001.00
0.910.91
1.241.24
0.960.96
0.860.86
1.051.05
0.960.96
0.990.99
1.011.01
0.980.98
0.910.91
0.800.80
0.190.19
0.580.58
0.960.96
HRHR
(95% /CI)(95% /CI)
PP
valuevalueNN
All PatientsAll Patients

14. AMLAML
Why did favorable changes in HDL-C and LDL-CWhy did favorable changes in HDL-C and LDL-C
induced by CETP inhibition with evacetrapib fail toinduced by CETP inhibition with evacetrapib fail to
improve clinical outcome?improve clinical outcome?
ACCELERATE TrialACCELERATE Trial
§§ Were favorable effects on LDL-C offset byWere favorable effects on LDL-C offset by
unfavorable effects on HDL-C, or vice versa, inunfavorable effects on HDL-C, or vice versa, in
individual patients?individual patients?
§§ Were LDL-C reductions reflective of changes inWere LDL-C reductions reflective of changes in
atherogenic lipoproteins?atherogenic lipoproteins?
§§ Were there other potential adverse effects?Were there other potential adverse effects?

15. AMLAML
Change in HDL-C vs Change in LDL-CChange in HDL-C vs Change in LDL-C
ACCELERATE TrialACCELERATE Trial
r = 0.18
p < 0.001
Placebo r = -0.20
p < 0.001
Evacetrapib

16. AMLAML
Placebo
(n=6054)
Evacetrapib
(n=6038)
P-Value
LDL-C mg/dL 83.7 54.7
% Change +6.0 -31.1 <0.001
Apo-B mg/dL 79.6 64.3
% Change +3.8 -15.5 <0.001
HDL-C mg/dL 45.6 104.1
% Change +1.6 +133.2 <0.001
ApoA-1 mg/dL 138.7 206.9
% Change +1.1 +50.5 <0.001
Changes in Lipids andChanges in Lipids and AApoproteins by Month 3poproteins by Month 3
ACCELERATE TrialACCELERATE Trial

17. AMLAML
Change in Apo-B vs Change in LDL-CChange in Apo-B vs Change in LDL-C
ACCELERATE TrialACCELERATE Trial
r = 0.86
p < 0.001
Placebo
r = 0.85
p < 0.001
Evacetrapib

18. AMLAML
Changes in hs-CRP and Blood Pressure by Month 3Changes in hs-CRP and Blood Pressure by Month 3
ACCELERATE TrialACCELERATE Trial
Placebo
(n=6054)
Evacetrapib
(n=6038)
P-
Value
hs-CRP
mg/L 1.54 1.64
Change from baseline 0 +0.08 <0.001
SBP
mm Hg 131 132
Change from baseline 0 1.2 <0.001

19. AMLAML
hs-CRP – Cumulative Frequency Distributionhs-CRP – Cumulative Frequency Distribution
ACCELERATE TrialACCELERATE Trial
3 Months3 Months 12 Months12 Months

20. AMLAML
Blood Pressure – Cumulative Frequency DistributionBlood Pressure – Cumulative Frequency Distribution
Time-Weighted Change in Systolic BPTime-Weighted Change in Systolic BP
ACCELERATE TrialACCELERATE Trial

21. AMLAML
Multivariable Model of Primary EndpointMultivariable Model of Primary Endpoint
ACCELERATE TrialACCELERATE Trial
Parameter Baseline
Relative (%) Change from
Baseline
HR (95% CI) P-value HR (95% CI) P-value
LDL-C
(per 10 mg/dl)
1.04 (1.02, 1.06) <0.001 1.01 (0.99, 1.03) 0.17
HDL-C
(per 10 mg/dl)
0.96 (0.91, 1.01) 0.11 1.0 (0.98, 1.02) 0.68
SBP
(per 5 mmHg)
1.03 (1.01, 1.05) <0.001 1.01 (0.99, 1.04) 0.17
* Models adjusted for age, diabetes, hypertension, ACS, CHF, renal impairment and
cerebrovascular atherosclerosis
N = 11,543, # events = 1323N = 11,543, # events = 1323

22. AMLAML
Multivariable Model of Primary EndpointMultivariable Model of Primary Endpoint
(Apo B substituted for LDL-C)(Apo B substituted for LDL-C)
ACCELERATE TrialACCELERATE Trial
Parameter Baseline
Relative (%) Change from
Baseline
HR (95% CI) P-value HR (95% CI) P-value
Apo-B
(per 10 mg/dl)
1.05 (1.03, 1.08) <0.001 1.02 (0.99, 1.04) 0.16
HDL-C
(per 10 mg/dl)
0.97 (0.93, 1.02) 0.32 1.00 (0.99, 1.01) 0.83
SBP
(per 5 mmHg)
1.03 (1.01, 1.05) <0.001 1.02 (0.99, 1.04) 0.09
* Models adjusted for age, diabetes, hypertension, ACS, CHF, renal impairment and
cerebrovascular atherosclerosis
N = 11,398, # events = 1304N = 11,398, # events = 1304

23. AMLAML
Parameter Baseline
Relative (%) Change from
Baseline
HR (95% CI) P-value HR (95% CI) P-value
LDL-C
(per 10 mg/dl)
1.03 (1.01, 1.06) 0.004 1.01 (0.99, 1.03) 0.37
HDL-C
(per 10 mg/dl)
0.97 (0.91, 1.02) 0.25 1.00 (0.99, 1.01) 0.61
SBP
(per 5 mmHg)
1.03 (1.01, 1.05) 0.006 1.02 (0.99, 1.05) † 0.08
Log hs-CRP 1.16 (1.09, 1.23) <0.001 1.08 (0.99, 1.16) † 0.06
Multivariable Model of Primary EndpointMultivariable Model of Primary Endpoint
(including hs-CRP)(including hs-CRP)
ACCELERATE TrialACCELERATE Trial
* Model adjusted for covariates
† Absolute changes are used for SBP and hs-CRP
N = 8115, # events = 941N = 8115, # events = 941

24. AMLAML
Parameter Baseline
Relative (%) Change from
Baseline
HR (95% CI) P-value HR (95% CI) P-value
LDL-C
(per 10 mg/dl)
1.04 (1.01, 1.07) 0.008 1.02 (0.99, 1.05) 0.26
HDL-C
(per 10 mg/dl)
0.94 (0.88, 1.01) 0.12 1.00 (0.99, 1.01) 0.84
SBP
(per 5 mmHg)
1.03 (1.00, 1.06) 0.02 1.03 (1.00, 1.06) † 0.05
Log hs-CRP 1.18 (1.10, 1.28) <0.001 1.11 (1.01, 1.21) † 0.03
Multivariable Model of Primary EndpointMultivariable Model of Primary Endpoint
Sensitivity Analysis – no change in statin dose and compliantSensitivity Analysis – no change in statin dose and compliant
ACCELERATE TrialACCELERATE Trial
* Model adjusted for covariates
† Absolute changes are used for SBP and hs-CRP
N = 6214, # events = 645N = 6214, # events = 645

25. AMLAML
ACCELERATE TrialACCELERATE Trial
Lipids and Outcome with EvacetrapibLipids and Outcome with Evacetrapib
§§ Evacetrapib treatment for ~2 years did not reduce CV events,Evacetrapib treatment for ~2 years did not reduce CV events,
despite decreasing LDL-C and increasing HDL-Cdespite decreasing LDL-C and increasing HDL-C
§§ Ischemic events were associated withIschemic events were associated with baselinebaseline LDL-C and apo-B,LDL-C and apo-B,
consistent with epidemiologic dataconsistent with epidemiologic data
•• bbutut changeschanges in these lipoproteins by CETP inhibition werein these lipoproteins by CETP inhibition were notnot
correlated with outcomecorrelated with outcome
•• rreasons for lack of association between outcome and changeseasons for lack of association between outcome and changes
in LDL-C and HDL-C remain unclearin LDL-C and HDL-C remain unclear
•• highlights difficulties with even respected surrogates such ashighlights difficulties with even respected surrogates such as
LDL-C to assess therapies with different mechanismsLDL-C to assess therapies with different mechanisms
§§ Inflammatory (CRP) and blood pressure effects of CETP inhibitionInflammatory (CRP) and blood pressure effects of CETP inhibition
with evacetrapib appear to attenuate any potential benefitwith evacetrapib appear to attenuate any potential benefit

26. AMLAML
Heart and Vascular InstituteHeart and Vascular Institute