HDL

1
Figure 1
Role of CETP in plasma cholesterol transport in
rabbits and humans
Liver
LDL-R
CE
CE
SR-B1
SR-B1
VLDL/LDL
FC
CETP
Extrahepatic tissues FC
CE
LCAT
FC
HDL
Bile
2
Figure 2
Effect of CETP inhibition on plasma cholesterol
transport
Liver
LDL-R
CE
CE
SR-B1
SR-B1
VLDL/LDL
FC
CETP
Extrahepatic tissues FC
CE
LCAT
FC
HDL
Bile
3
Figure 3
CETP and atherosclerosis in rodents and rabbits
Rodents Rodents are naturally deficient in
CETP Rodents are naturally resistant to
development of atherosclerosis Expression of
CETP in transgenic mice and rats increases
atherosclerosis in most (but not all) models
Rabbits Rabbits have a high level of activity of
CETP Rabbits are naturally highly susceptible to
the development of atherosclerosis Inhibition of
CETP in rabbits decreases atherosclerosis in all
models
4
ILLUMINATE TrialOff-target pharmacological
effects of torcetrapib unrelated to CETP
inhibition
Figure 4

• In patients receiving torcetrapib/atorvastatin
  (but not in those receiving atorvastatin alone)
  there was a significant
• Increase in blood pressure
• Reduction in serum potassium
• Increase in serum bicarbonate
• Increase in serum sodium
• Increase in serum aldosterone

Barter et al, NEJM 20073572109-2122
5
Deaths by changes in K and HCO3- from baseline
to month 1
Figure 5
ILLUMINATE TrialPost-hoc Exploratory Analyses
in the Torcetrapib/Atorvastatin Group
Decrease in serum potassium
Decrease lt Median (lt 0.1 mmol/L)
Decrease gt Median (gt 0.1 mmol/L)
-
N/C
-
3629
195
3709
Sample size
4 (2.05)
35 (0.96)
54 (1.46)
Deaths ()
Increase in serum bicarbonate
Increase gt Median (gt 0.7 mmol/L)
-
N/C
3695
169
Sample size
3669
4 (2.37)
35 (0.95)
Deaths ()
54 (1.47)
N/C not classified due to missing value
Barter et al, NEJM 20073572109-2122
6
Figure 6
ILLUMINATE TrialPost-hoc Exploratory Analyses
in the Torcetrapib/Atorvastatin Group
Hazard ratios for CHD Death or Non-Fatal MI by
quintile of on-trial HDL-C (referent group is
HDL-C lt 60 mg/dL stratum)
1.00
1.0
0.8
0.67
Plt0.05

0.57
0.6

CHD Death or Non-Fatal MI (Hazard Ratio)

0.47
0.43
0.4
0.2
0
lt60
60-70
71-80
81-93
gt93
Quintiles of HDL-C (mg/dL) at Month 3
Cox proportional hazard model adjusted for age,
gender and baseline HDL-C.
Barter, AHA 2007