high density lipoproteins (hdl) protect against cardiovascular disease a novel mechanism for...
TRANSCRIPT
High density lipoproteins (HDL) protect against cardiovascular diseaseHigh density lipoproteins (HDL) protect against cardiovascular disease
A novel mechanism for raising HDL levels is to inhibit a protein known A novel mechanism for raising HDL levels is to inhibit a protein known as CETP. This protein transfers cholesterol from the protective HDL as CETP. This protein transfers cholesterol from the protective HDL fraction to the harmful LDL fraction. Thus, inhibiting CETP retains fraction to the harmful LDL fraction. Thus, inhibiting CETP retains cholesterol in the protective HDL.cholesterol in the protective HDL.
Torcetrapib is a drug that inhibits CETP and had been shown in Torcetrapib is a drug that inhibits CETP and had been shown in humans to raise the level of HDL cholesterol and lower that of LDL humans to raise the level of HDL cholesterol and lower that of LDL cholesterol.cholesterol.
Studies in rabbits have shown that inhibiting CETP with torcetrapib Studies in rabbits have shown that inhibiting CETP with torcetrapib protects against atherosclerosis.protects against atherosclerosis.
The ILLUMINATE trial was designed to test the hypothesis that The ILLUMINATE trial was designed to test the hypothesis that inhibiting CETP with torcetrapib would also protect against inhibiting CETP with torcetrapib would also protect against cardiovascular disease in humans.cardiovascular disease in humans.
RationaleRationale
Torcetrapib Torcetrapib – – Final Results of the ILLUMINATE TrialFinal Results of the ILLUMINATE TrialPhilip Barter, The Heart Research Institute, Sydney, Australia for the Philip Barter, The Heart Research Institute, Sydney, Australia for the
ILLUMINATE Steering Committee and InvestigatorsILLUMINATE Steering Committee and Investigators
Torcetrapib + titrated atorvastatin doseTorcetrapib + titrated atorvastatin dose
Titrated atorvastatin doseTitrated atorvastatin dose
Planned 4.5 years of treatment Planned 4.5 years of treatment
Investigation of Lipid Level Management to Understand Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Eventsits Impact in Atherosclerotic Events
Patient PopulationPatient Population SubjectsSubjects Primary End PointPrimary End Point• Men or postmenopausal Men or postmenopausal
women women • Statin eligibleStatin eligible• Any HDL-C levelAny HDL-C level• CHD or risk equivalent CHD or risk equivalent
(type 2 DM)(type 2 DM)
• 15,000 15,000 • 7 countries7 countries
• Major cardiovascular Major cardiovascular events events
Atorvastatin run-in to Atorvastatin run-in to LDL <100 mg/dL LDL <100 mg/dL
(2.6 mmol/L)(2.6 mmol/L)
4-10 weeks4-10 weeks
ILLUMINATE: Long-term Outcomes in ILLUMINATE: Long-term Outcomes in Patients With CHD or CHD Risk EquivalencePatients With CHD or CHD Risk Equivalence
Atorvastatin Group=A Atorvastatin Group=A (n=7534)(n=7534)Torcetrapib/Atorvastatin Group=T/A Torcetrapib/Atorvastatin Group=T/A (n=7533)(n=7533)
Compared to A, T/A increased HDL-C by 72% and reduced LDL-C by 25%Compared to A, T/A increased HDL-C by 72% and reduced LDL-C by 25%
AA T/AT/A
Major cardiovascular events Major cardiovascular events 373373 464 464 (p=0.001)(p=0.001)
DeathsDeaths 5959 93 (p=0.006) 93 (p=0.006)
Cardiovascular events and mortality in the Cardiovascular events and mortality in the ILLUMINATE trial at termination of the trial on ILLUMINATE trial at termination of the trial on
Dec 02, 2006Dec 02, 2006
Causes Of DeathCauses Of Death
Fatal strokeFatal stroke
4444Reason unknownReason unknown3344Trauma/suicide/homicideTrauma/suicide/homicide
4422Other non-cardiovascularOther non-cardiovascular
9900InfectionInfection
24241414CancerCancer
40402020Any non-cardiovascularAny non-cardiovascular3322Other vascular death/procedure related MIOther vascular death/procedure related MI
2211Fatal heart failureFatal heart failure
4411Other cardiac deathOther cardiac death6600
8866Fatal MI - not procedure relatedFatal MI - not procedure related
26262525Sudden cardiac deathSudden cardiac death
49493535Any cardiovascular deathAny cardiovascular death
Torcetrapib/ Torcetrapib/ Atorvastatin (n=93)Atorvastatin (n=93)
Atorvastatin Atorvastatin (n=59 )(n=59 )
Investigator-reported SAEs of neoplasmsInvestigator-reported SAEs of neoplasms
Atorvastatin GroupAtorvastatin Group 136136
Torcetrapib/atorvastatin GroupTorcetrapib/atorvastatin Group 128128
Investigator-reported SAEs of infections/infestationsInvestigator-reported SAEs of infections/infestations
Atorvastatin GroupAtorvastatin Group 177177
Torcetrapib/atorvastatin GroupTorcetrapib/atorvastatin Group 182182
In patients receiving torcetrapib/atorvastatin (but not in those receiving In patients receiving torcetrapib/atorvastatin (but not in those receiving atorvastatin alone) there was a significant:atorvastatin alone) there was a significant:
• Increase in blood pressureIncrease in blood pressure• Reduction in serum potassiumReduction in serum potassium• Increase in serum bicarbonateIncrease in serum bicarbonate• Increase in serum sodiumIncrease in serum sodium• Increase in serum aldosteroneIncrease in serum aldosterone
These changes are consistent with activation of the renin-angiotensin-These changes are consistent with activation of the renin-angiotensin-aldosterone systemaldosterone system
The adverse clinical outcome associated with use of torcetrapib may The adverse clinical outcome associated with use of torcetrapib may have been the consequence of an off-target pharmacology but the have been the consequence of an off-target pharmacology but the possibility of an adverse effect of CETP inhibition cannot be excluded by possibility of an adverse effect of CETP inhibition cannot be excluded by the results of this randomized trial.the results of this randomized trial.
Off-target pharmacological effects of Off-target pharmacological effects of torcetrapib unrelated to CETP inhibitiontorcetrapib unrelated to CETP inhibition
Cox proportional hazard model adjusted for age, gender and baseline HDL-C. Excludes 265 patients with Cox proportional hazard model adjusted for age, gender and baseline HDL-C. Excludes 265 patients with missing month 3 HDL-C. Preliminary analysis initiated and authorised by P Barter and conducted by Pfizermissing month 3 HDL-C. Preliminary analysis initiated and authorised by P Barter and conducted by Pfizer
Hazard ratios for CHD Death or Non-Fatal MI Hazard ratios for CHD Death or Non-Fatal MI by quintile of on-trialby quintile of on-trial HDL-C HDL-C
(referent group is HDL-C < 60 mg/dL stratum)(referent group is HDL-C < 60 mg/dL stratum)
1.001.00
0.670.67
0.470.470.570.57
0.430.43
00
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
CH
D D
eath
or
No
n-F
ata
l MI
CH
D D
eath
or
No
n-F
ata
l MI
(Ha
zard
Ra
tio)
(Ha
zard
Ra
tio)
<60<60 60-7060-70 71-8071-80 81-9381-93 >93>93Quintiles of HDL-C (mg/dL) at Month 3Quintiles of HDL-C (mg/dL) at Month 3
*P<0.05*P<0.05
****
**
Post-hoc Exploratory Analyses in the Post-hoc Exploratory Analyses in the Torcetrapib/Atorvastatin GroupTorcetrapib/Atorvastatin Group