CETP inhibitors Future in lipid management

CETP Inhibitors
Where will they fit in practice ?
Dr. Veerendra Singh
MD (Medicine)
Fellow UP Diabetes Association
Vice President UPDA

The goal of my talk today is to assess
• The clinical implications of safety and efficacy
profiles of cholesteryl ester transfer protein
(CETP) inhibitors
• To suggest a potential place in therapy for
CETP inhibitors
UP-APICON-2015,Noida

What we know
- CVD major burden
- LDL-C causally related with CVD
- LDL-C goals: the lower the better
- Statins : corner stone in therapy

Potential for further
risk reduction
=
Reduction
in MACE statin vs placebo (%)
0
further LDL-C
lowering?
and or
Additional Rx?
-100
-30
-50
How well do we do?

93-
D
n
Lipoproteins and Coronary Heart isease
302,430 participants in 68 studies
The Emerging Risk Factors Collaboration. JAMA. 2009;302:19 2000.

• Although statins reduce LDL cholesterol and
concomitantly decrease cardiovascular
morbidity and mortality by up to 40%,
substantial residual cardiovascular risk remains.
• Subnormal levels of HDL cholesterol constitute
a major, independent cardiovascular risk
factor. Attention has, therefore, shifted towards
novel strategies for raising HDL cholesterol as a
preventive therapy for cardiovascular disease.

Atheroprotective functions of HDL
Anti-infectious
activity
Anti-thrombotic
activity
Anti-proteolytic
activity
Reverse cholesterol
transport/cellular
cholesterol efflux
Anti-
inflammatory
activity
Immune system
Anti-oxidative
activity
Anti-apoptotic
activity
HDL
Vasodilatory
activity/
endothelial
repair

Infusion of Recombinant Apo AI Milano/Phospholipid complexes over
5 weeks produced significant regression of coronary
atherosclerosis as estimated on the basis of atheroma volume
by IVUS in patients with acute coronary syndromes.
Nissen et al., JAMA, 2003, 290 : 2292-2300
These findings suggest that elevation of HDL/Apo AI
may enhance cholesterol efflux from plaque tissue
and may therefore be a critical component of
atherosclerotic plaque regression
Impact of HDL on Plaque Evolution :
Experimental Evidence for Plaque Regression

HDL therapy
Rader DJ and Hovingh GK, Lancet 2014;384:618-25

CETP inhibition
HDL
LDL /
VLDL
Liver
Bile
CE
LDL-R
FC
F
C
LCAT
CETP
C
ESR-B1
X inhibition
Free Cholesterol (FC)
in Extrahepatic tissues
The more CETP is working, the more it reduces HDL-C

• High CETP activity, typical of metabolic diseases
enriches the triglyceride content of HDL
particles. Triglyceride-rich HDL are hydrolysed
by hepatic lipase, with shedding of apoAI and
elimination from the circulation by the kidney. .
• CETP inhibitors could theoretically correct not
only the core lipid composition of HDL
(cholesteryl ester:triglyceride ratio) but also HDL
functional defects.

• CETP inhibitors provide remarkable elevations in
HDL cholesterol up to around 140% and drop the
serum concentrations of the entire spectrum of
atherogenic lipoprotein including VLDL
remnants, LDL, and even lipoprotein(a).[11]
• The HDL is functional, activates cholesterol
transport, capable of extracting cholesterol
from loaded cells, and is engaging the
transporters in all membranes

• In Asia -- in populations in the Kochi Prefecture of
Japan, in South Korea, and in parts of China --
loss-of-function polymorphisms in CETP are
actually associated with reduced risk for
cardiovascular events.[2]
• However, in western studies such as PREVEND,
REGRESS and Framingham low CETP activity in all
of those studies correlates with increased risk for
cardiovascular events.

Torcetrapib was the first CETP inhibitor
to enter a large-scale, prospective,
placebo-controlled interventional trial—
”Investigation of Lipid Level Management to
Understand its Impact in Atherosclerotic
Events (ILLUMINATE)”.

DL-
L-
n-
- (- 3)
-
Torcetrapib: ILLUMINATE Trial
Torcetrapib/ Atorvastatin Group (Post Ru In)
140 127
115 112 112 112120 TG
9% 27,+1
*100
82.980.979.7 H C77.5
71.880
+72.1% (34.7) †
60 48.6 LD C
58.2 58.359.7 59.3 24.9% (28.5) †
40
20
0
Baseline 1 3
Study Month
6 12
Barter et al, NEJM 2007;357:2109
Lipids(mg/dL)

But
Inhibiting CETP with Torcitrapib in
humans did not reduce atherosclerosis in
three human imaging trials and a large
scale cilincal end point trial (ILLUMINATE)
torcitrapib increased both cardiovascular
and non cardiovascular events and
mortality

Torcetrapib treatment resulted in significantly
increased aldosterone levels, altered serum
electrolytes and elevated blood pressure,
indicating an off-target mechanism of
torcetrapib related toxic effects

s ff-
e s ( d
at Y e
e e
n
However
Torcetrapib had seriou o target
adverse effects (unrelated to
CETP) that
responsible
outcome in
MAY have been
for the adverse
the ILLUMINATE trial

b al
S
. N gl d. 89- 9
Dalcetrapib
OUTCOMES
was investigated in the d -
and found to have no safety
issues but also no effect on CV events
Schwartz et al En J Me 2012; 367:20 209 .

Lipid effects with dalcetrapib
-5
0
5
10
15
20
25
30
35
HDL-C LDL-C ApoA-I
D 24 weeks
D 48 weeks
Placebo
* D 48 weeks vs. placebo Stein EA et al. Eur Heart J
2010;31(4):480-8
%changefrombaseline
*p<0.0001
*p<0.01
*p=0.002
D Dalcetrapib 900 mg/da

b al-
n y
b
DL-
The reason for the failure of
dalcetrapib in del-
may
is a
OUTCOMES is not
have been because
weak inhibitor and had
C
known but
dalcetrapib
no effect on LDL-

25
Up to 33% reduction in LDL
Up to 130%% reduction in HDL

Percent change from baseline in HDL and LDL cholesterol with statin plus evacetrapib
Controversies in dyslipidaemia management: Atherosclerosis Volume 221, Issue 2
2012 321 - 324
Evacetrapibe

Just because an intervention
raises HDL-C,
we cannot ASSUME that MI
risk will be lowered

HDL intervention; failures
Torcetrapib, Dalcetrapib, Niacin

T
b
The results with torcetrapib and
dalcitratib have not adequately
tested the hypothesis that effective
inhibition of CETP reduces CV risk

The hypothesis is currently being
tested in two large, clinical outcome
trials

id
n
e L-
w-
n
REVEALtrial
Randomized Evaluation of the Effects ofAnacetrapib through Lip -
modification
Anacetrapib 100 mg30,000 patients
aged > 50 with
with occlusive
arterial disease
Atorvastati to
achiev
target
LD C
Sites in NorthAmerica, Europe and Asia
4 year follo up
Primary End Point
Coronary death, myocardial infarction
coronary revascularization
Planned completion
in 2017
or
Placebo

E
of yl
b gh-
b 0
V h, , y sc
or
3 w-
n nd sia
16-
ACCELERAT trial
Assessmentof Clinical Effects Cholester EsterTransferProtein Inhibition with
EvacetrapibI Patientsat a High Risk for VascularOutcomes
Evacetrapi 13 mg
Treatment with a12,000 patients
at high CV risk statin for at
30 days
least
Sites in NorthAmerica, Europe and Asia-
Pacific countries
year follo up
Primary End Point
Planned
in 20
completion
2017
CV death MI stroke, coronary revascularisation
hospitalization for UA
Placebo

TA8995:
A new potent CETP inhibitor

N=42 placebo + placebo
N=42 TA-8995 1mg + placebo
N=42 TA-8995 2.5mg + placebo
N=42 TA-8995 10mg+ Atorvastatin 20mg
N=42 placebo +Atorvastatin 20mg
N=42 placebo + Rosuvastatin 10mg
N=42 TA-8995 10mg + Rosuvastatin 10mg
Washout/run in treatment 12 weeks FU
TULIP Design
- mild dyslipidemia
- no CVD
- LDL-C 2.5- 4.5
mmol/L
- HDL-C 0.8-1.8
mmol/L
- TG <4.5 mmol/L

0%
100% 76%
122%
180%
50%
200%
HDL-C %change at 12 weeks
Placebo
TA-8995 (mg/day)
1 2.5 5 10
150%
2%
166%

0%
-20%
-27%
-34%
-47% -47%
-40%
LDL-C %change at 12 weeks
-60% Placebo
TA-8995 (mg/day)
1 2.5 5 10

M
s f
TA8995 is a potent inhibitor of CETP•
• Major reduction in atherogenic lipoproteins and
major increase in HDLs at low dose o TA8995
• Treatment with TA8995 enhances the ability to
of serum to promote the efflux of cholesterol
from macrophages
• TA8995 has an excellent safety profile
• TA8995 is rapidly removed from the body after
cessation of therapy

• KEY POINTS
• Inhibitors of cholesteryl ester transfer protein (CETP) are presently the most
potent agents for raising HDL cholesterol
• Torcetrapib, the first CETP inhibitor to enter a large-scale, prospective, placebo-
controlled interventional trial (ILLUMINATE), was associated with excess
cardiovascular and noncardiovascular mortality in the active-treatment group
• Torcetrapib treatment resulted in significantly increased aldosterone levels, altered
serum electrolytes indicative of mineralocorticoid excess, and elevated blood
pressure, indicating an off-target mechanism of torcetrapib related toxic effects
involving activation of mineralocorticoid receptors by aldosterone with subsequent
induction of hypertension
• Other CETP inhibitors such as JTT-705 and MK-825 do not increase blood pressure
in humans, an observation that tends to discount a class effect
• Potential adverse effects of CETP inhibition cannot, however, be excluded; CETP
inhibition could result in the generation of HDL particles that have deficient
antiatherogenic activities and a deleterious impact on reverse cholesterol
transport and steroid metabolism

CETP inhibitors are a very exciting new drug
class. They remain in development. They are not
yet approved for use. Everyone is awaiting the
results of heart outcomes trials with REVEAL and
ACCELERATE, but in the meantime they are
definitely drugs very worthy of discussion and
further understanding.

Trials, trials, trials, and nothing but
trials
will tell us whether
- HDL based therapy
and
- further LDL-C lowering,
reduces risk for CVD....

Don’t give up on HDL,
researchers plead
At a session on the subject, Dr Alan Tall
(Columbia University, New York)
summarized the situation:
Hughs S, Jun, 2012
"The HDL hypothesis is certainly under attack.
And there have been a lot of setbacks.
But we mustn't throw the baby out with the bathwater.
I think we need a new, modified HDL hypothesis."

An interesting road ahead of us...

CETP inhibitors Future in lipid management

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