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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.

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Background l.jpg
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 slowCAD progression, compared with atorvastatin alone.

  • December 2, 2006: A 15,000 patient outcome trialwas stopped because of a significant increase in all-cause mortality in the torcetrapib treatment group.


Slide2 l.jpg

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 mgto achieve LDL-C of 100±15 mg/dL

Atorvastatin

monotherapy

Torcetrapib 60mg-atorvastatin

24 monthstreatment

140 patients withdrew

135 patients withdrew

446 atorvastatin patients

464 torcetrapib patients

24 Month follow-up IVUS of originally imaged “target” vessel (n=910)

1188 patients at 137 centers in North America and EuropeSymptomatic CAD, coronary angiography with >20% stenosis


Ultrasound determination of atheroma area l.jpg
Ultrasound Determination of Atheroma Area

Precise Planimetry of EEM and Lumen Borders

EEM area

Lumen

area

Atheroma area


Intravascular ultrasound efficacy parameters l.jpg

EEM area

Changein PercentAtheromaVolume

AtheromaCSA

AtheromaCSA

=

Lumen

area

EEMCSA

EEMCSA

(baseline)

(Month 24)

Atheroma area

n

n

n

n

n

n

Change in

Atheroma Volume

Atheroma Volume

Atheroma Volume

=

(Month 24)

(baseline)

Intravascular Ultrasound Efficacy Parameters

Median numberof slices inall pullbacks

AtheromaCSA

NormalizedAtheroma

Volume

LumenCSA

=

x

Number of slices in patient’s pullback


Baseline demographics and medications l.jpg
Baseline Demographics and Medications

Titrated atorvastatin dosage 23mg in both treatment groups




Slide8 l.jpg

Time Course: Change in LDL-C Levels

Atorvastatin Monotherapy

Difference 19.9%

Torcetrapib-Atorvastatin


Slide9 l.jpg

Time Course: Change in HDL-C Levels

Torcetrapib-Atorvastatin

Difference 60.8%

Atorvastatin Monotherapy


Slide10 l.jpg

Cumulative Histogram: Change in Systolic BP

LS Mean difference

4.6 mm Hg

Atorvastatin

Monotherapy

Torcetrapib

Atorvastatin


Blood pressure related adverse events l.jpg

Atorvastatin

Torcetrapib

Blood Pressure Related Adverse Events

30%

23.7%

25%

21.3%

20%

15%

10.6%

9.0%

8.2%

10%

3.2%

5%

0%

Systolic BPIncrease >15 mmHg

Investigatorreported HTN

Pressure>140/90 mmHg


Primary efficacy parameter change in percent atheroma volume l.jpg
Primary Efficacy ParameterChange in Percent Atheroma Volume

p = 0.72†

Changein percent

atheroma

volume

Atorvastatinmonotherapy

Torcetrapib-atorvastatin

†p value from ANCOVA

*LS Mean change


Secondary ivus efficacy parameters l.jpg

Atorvastatin Torcetrapib

Secondary IVUS Efficacy Parameters

Change in NormalizedAtheroma Volume (mm3)

Change in 10 mm MostDiseased Segment (mm3)

p = 0.023†

p = 0.12†

*LS Mean change

†p value from ANCOVA


Prespecified subgroups no heterogeneity l.jpg
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 l.jpg

Atorvastatin monotherapy Torcetrapib-atorvastatin

Subgroup With Significant Heterogeneity

Baseline Percent Atheroma Volume (PAV) above/below the median

Interactionp value = 0.005

Change

In Percent

Atheroma

Volume

(%)



Relationship between ldl c and percent atheroma volume in six recent ivus trials l.jpg
Relationship between LDL-C and Percent Atheroma Volume in Six Recent IVUS Trials

CAMELOT

placebo

REVERSAL

pravastatin

ACTIVATE

placebo

Changein Percent

Atheroma

Volume

(%)

REVERSAL

atorvastatin

A-Plus

placebo

ILLUSTRATE

torcetrapib

ILLUSTRATE

Atorvastatin

ASTEROID

rosuvastatin

Mean Low-Density Lipoprotein Cholesterol (mg/dL)


Conclusions l.jpg
Conclusions Six Recent IVUS Trials

  • 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 l.jpg
Failure of Torcetrapib: Interpretation Six Recent IVUS Trials

The absence of a beneficial effect for torcetrapibwas particularly striking for the achieved LDL levelof 70 mg/dL, 20% lower than atorvastatin monotherapy.

  • CETP inhibition may not generate HDL particles that function normally in facilitating reverse cholesterol transport.

  • The torcetrapib-mediated increase in BP may have counterbalanced any favorable effects on lipid levels.

  • The increased BP may reflect a more generalized toxicity, simultaneously preventing beneficial effects on progression and increasing adverse clinical outcomes.


Some final thoughts l.jpg
Some Final Thoughts Six Recent IVUS Trials

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.”


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