Background
• HDL-C levels are inversely related to CV event rates.
• Torcetrapib, a cholesteryl ester transfer protein (CETP)
inhibitor, raises HDL-C levels, but the functional effects
of these increases remain uncertain.
• The ILLUSTRATE Trial was designed to assess
whether torcetrapib plus atorvastatin would slow
CAD progression, compared with atorvastatin alone.
• December 2, 2006: A 15,000 patient outcome trial
was stopped because of a significant increase in allcause mortality in the torcetrapib treatment group.
1188 patients at 137 centers in North America and Europe
Symptomatic CAD, coronary angiography with >20% stenosis
Intravascular ultrasound with 40 MHz transducer
Motorized pullback at 0.5 mm/sec through >40 mm segment
4-10 week run-in atorvastatin 10-80 mg
to achieve LDL-C of 100±15 mg/dL
Atorvastatin
monotherapy
24 months
treatment
Torcetrapib 60mgatorvastatin
140 patients withdrew
135 patients withdrew
446 atorvastatin patients
464 torcetrapib patients
24 Month follow-up IVUS of originally imaged “target” vessel (n=910)
Ultrasound Determination of Atheroma Area
Precise Planimetry of EEM and Lumen Borders
EEM area
Lumen
area
Atheroma area
Intravascular Ultrasound Efficacy Parameters
EEM area
Change
Lumen
area
in Percent =
Atheroma
Volume
 n AtheromaCSA
 n EEMCSA
(Month 24)
–
 n AtheromaCSA
 n EEM
CSA
(baseline)
Atheroma area
Median number
AtheromaCSA –
Normalized
n

n LumenCSA
x of slices in
Atheroma =
Number of slices in patient’s pullback
all pullbacks
Volume

Atheroma Volume
Atheroma Volume
Change in
=
–
Atheroma Volume
(baseline)
(Month 24)
Baseline Demographics and Medications
Atorvastatin
monotherapy
(n=597)
Torcetrapibatorvastatin
(n=591)
p value
Age
57.0
56.9
0.96
Male
70.5%
70.4%
0.96
BMI
30.3
30.6
0.41
Current Smokers
18.8%
17.3%
0.50
History of Hypertension
77.6%
74.5%
0.21
Prior Statin Use
91.0%
90.7%
0.88
History of Diabetes Mellitus
22.3%
20.1%
0.37
Aspirin usage
94.3%
93.7%
0.68
Characteristic
Titrated atorvastatin dosage 23mg in both treatment groups
Baseline Lipid Levels and Blood Pressure
Characteristic
Atorvastatin
Monotherapy
(n=597)
Torcetrapibatorvastatin
(n=591)
p value
Total Cholesterol (mg/dL)
157.5
157.7
0.91
LDL-cholesterol (mg/dL)
84.3
83.1
0.35
HDL-cholesterol (mg/dL)
45.2
46.0
0.34
LDL-C/HDL-C ratio
1.90
1.88
0.39
Triglycerides (mg/dL)
123.9
122.0
0.66
C-reactive Protein (mg/L)
1.8
2.1
0.04
Systolic BP (mmHg)
120.0
119.8
0.81
Diastolic BP (mmHg)
73.4
73.3
0.70
Final Lipid Values and Percentage Change
Lipid Value
(mg/dL)
Atorvastatin
monotherapy
(n=446)
TorcetrapibAtorvastatin
(n=464)
p
value*
Final
Value
Change
(%)
Final
Value
Change
(%)
Total Cholesterol
157.2
1.9%
167.5
7.2%
<0.001
LDL-cholesterol
87.2
6.6%
70.1
-13.3%
<0.001
HDL-cholesterol
43.9
-2.2%
72.1
58.6%
<0.001
LDL-C/HDL-C ratio
2.03
NA
0.93
NA
<0.001
Triglycerides
110
-8.2%
104
-14.3%
<0.001
C-Reactive Protein
1.5
-0.2
1.85
-0.1
0.19
Time Course: Change in LDL-C Levels
LDL cholesterol Level (mg/dL)
100
Atorvastatin Monotherapy
90
Difference 19.9%
80
70
Torcetrapib-Atorvastatin
60
50
40
0
1
3
6
9
12
Time (months)
15
18
21
24
Time Course: Change in HDL-C Levels
HDL-cholesterol Level (mg/dL)
90
80
Torcetrapib-Atorvastatin
70
60
Difference 60.8%
50
40
Atorvastatin Monotherapy
30
20
0
1
3
6
9
12
Time (months)
15
18
21
24
Cumulative Histogram: Change in Systolic BP
Percentage of Subjects (%)
100%
80%
LS Mean difference
4.6 mm Hg
60%
Atorvastatin
Monotherapy
Torcetrapib
Atorvastatin
40%
20%
0%
>-20
-15
-10
-5
0
5
10
15
20
Change in Systolic Blood Pressure (mmHg)
25
Blood Pressure Related Adverse Events
30%
Atorvastatin
Torcetrapib
23.7%
25%
21.3%
20%
15%
10.6%
9.0%
8.2%
10%
3.2%
5%
0%
Investigator
reported HTN
Pressure
>140/90 mmHg
Systolic BP
Increase >15 mmHg
Primary Efficacy Parameter
Change in Percent Atheroma Volume
0.35
p = 0.72†
0.3
0.25
Change
in percent
atheroma
volume
0.2
0.19
0.15
0.12
0.1
0.05
0
Atorvastatin
monotherapy
*LS Mean change
Torcetrapibatorvastatin
†p
value from ANCOVA
Secondary IVUS Efficacy Parameters
Change in Normalized
Atheroma Volume (mm3)
0
Change in 10 mm Most
Diseased Segment (mm3)
0
-1
-4
-2
-3
-6.3
-8
-4
-3.3
-9.5
-5
-12
p = 0.023†
-16
*LS Mean change
-4.2
-6
p = 0.12†
-7
†p
value from ANCOVA
Atorvastatin
Torcetrapib
Prespecified Subgroups: No Heterogeneity
• Men vs. women
• Age greater or less than 65
• Smokers vs. Non-smokers
• LDL-C greater or less than the median
• HDL-C greater or less than 40 mg/dL
• hsCRP greater or less than 3.0 mg/L
• Presence or absence of diabetes
• Presence or absence of metabolic syndrome
Subgroup With Significant Heterogeneity
Baseline Percent Atheroma Volume (PAV) above/below the median
0.8
Interaction
p value = 0.005
0.61
0.6
Change
In Percent
Atheroma
Volume
(%)
0.4
0.21
0.2
0.19
0
-0.2
-0.4
-0.37
-0.6
PAV <median
Atorvastatin monotherapy
PAV іmedian
Torcetrapib-atorvastatin
Adverse Events: Safety Population (n=1188)
Atorvastatin
Monotherapy
(n=597)
TorcetrapibAtorvastatin
(n=591)
Death
6 (1.0%)
8 (1.4%)
CHD death
1 (0.2%)
1 (0.2%)
16 (2.7 %)
13 (2.2%)
Fatal or nonfatal stroke
8 (1.3%)
2 (0.3%)
Hospitalization for unstable angina
34 (5.7%)
47 (8.0%)
Coronary revascularization
95 (15.9%)
114 (19.3%)
Peripheral vascular disease
13 (2.2%)
10 (1.7%)
Hospitalization for CHF
4 (0.7%)
9 (1.5%)
Composite: CHD death, MI, stroke, and
unstable angina
57 (9.5%)
62 (10.5%)
117 (19.6%)
124 (21.0%)
Nonfatal myocardial infarction
Composite: CHD death, MI, stroke,
unstable angina, and revasculariztion
Relationship between LDL-C and Percent
Atheroma Volume in Six Recent IVUS Trials
1.8
CAMELOT
placebo
1.2
REVERSAL
pravastatin
ACTIVATE
placebo
Change 0.6
in Percent
Atheroma
Volume
0
(%)
ILLUSTRATE
torcetrapib
REVERSAL
atorvastatin
A-Plus
placebo
ILLUSTRATE
Atorvastatin
-0.6
ASTEROID
rosuvastatin
-1.2
50
60
70
80
90
100
110
Mean Low-Density Lipoprotein Cholesterol (mg/dL)
120
Conclusions
• Torcetrapib 60mg in combination with atorvastatin
increased HDL-C by 61% and lowered LDL-C by 20%,
compared with atorvastatin monotherapy.
• However, torcetrapib also increased systolic blood
pressure by an average of 4.6 mmHg.
• Torcetrapib-atorvastatin did not reduce the progression
of coronary atherosclerosis for the primary efficacy
parameter, compared with atorvastatin alone.
• Adverse events showed a numerical excess in the
torcetrapib group, but these differences did not reach
statistical significance (trial not powered for outcomes).
Failure of Torcetrapib: Interpretation
The absence of a beneficial effect for torcetrapib
was particularly striking for the achieved LDL level
of 70 mg/dL, 20% lower than atorvastatin monotherapy.
1) CETP inhibition may not generate HDL particles that
function normally in facilitating reverse cholesterol
transport.
2) The torcetrapib-mediated increase in BP may have
counterbalanced any favorable effects on lipid levels.
3) The increased BP may reflect a more generalized
toxicity, simultaneously preventing beneficial effects on
progression and increasing adverse clinical outcomes.
Some Final Thoughts
In 20 years since introduction of statins, no new classes
of anti-atherosclerotic drugs have been introduced.
We continue to believe that raising drugs to raise HDL-C
levels represents promising therapeutic targets.
It remains uncertain whether the unfavorable torcetrapib
results were due to the “molecule” or the “mechanism”
Although discouraging, we do not think these results
preclude the possibility that another CETP inhibitor will
produce favorable effects, but they do “raise the bar.”