CETP InhibitorsWhere will they fit in practice ?
Dr. Veerendra SinghMD (Medicine)
Fellow UP Diabetes Association
Vice President UPDA
The goal of my talk today is to assess
• The clinical implications of safety and efficacyprofiles of cholesteryl ester transfer protein(CETP) inhibitors
• To suggest a potential place in therapy forCETP 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
UP-APICON-2015,Noida
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.
UP-APICON-2015,Noida
Atheroprotective functions of HDL
Anti-infectious activity
Anti-thrombotic activity
Anti-proteolyticactivity
Reverse cholesterol transport/cellular cholesterol efflux
Anti-inflammatory
activity
Immune systemAnti-oxidative
activityAnti-apoptotic
activity
HDLVasodilatory
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 hydrolysedby 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.
UP-APICON-2015,Noida
• 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
UP-APICON-2015,Noida
• 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.
UP-APICON-2015,Noida
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)”.
UP-APICON-2015,Noida
DL-
L-
n-
- (- 3)
-
Torcetrapib: ILLUMINATE Trial
Torcetrapib/ Atorvastatin Group (Post Ru In)
140 127
115 112 112 112120 TG9% 27,+1
*10082.980.979.7 H C77.5
71.880+72.1% (34.7) †
60 48.6 LD C58.2 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
Lip
ids
(mg/d
L)
ButInhibiting CETP with Torcitrapib inhumans did not reduce atherosclerosis inthree human imaging trials and a largescale cilincal end point trial (ILLUMINATE)torcitrapib increased both cardiovascularand non cardiovascular events andmortality
UP-APICON-2015,Noida
Torcetrapib treatment resulted in significantlyincreased aldosterone levels, altered serumelectrolytes and elevated blood pressure,indicating an off-target mechanism oftorcetrapib 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
DalcetrapibOUTCOMES
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
%ch
an
ge f
rom
baselin
e
*p<0.0001
*p<0.01
*p=0.002
D Dalcetrapib 900 mg/day
21
b al-
n y
b
DL-
The reason for the failure of
dalcetrapib in del-may
is a
OUTCOMES is nothave 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
All CETP Inhibitors
Just because an intervention
raises HDL-C,
we cannot ASSUME that MI
risk will be lowered
HDL intervention; failuresTorcetrapib, Dalcetrapib, Niacin
HDL intervention; failuresTorcetrapib, Dalcetrapib, Niacin
HDL intervention; failuresTorcetrapib, Dalcetrapib, Niacin
HDL intervention; failuresTorcetrapib, Dalcetrapib, Niacin
T
b
The results with torcetrapib and
dalcitratib have not adequately
tested the hypothesis that effectiveinhibition of CETP reduces CV risk
The hypothesis is currently beingtested in two large, clinical outcome
trials
id
ne L-
w-n
REVEAL trialRandomized Evaluation of the Effects ofAnacetrapib through Lip -
modification
Anacetrapib 100 mg30,000 patients aged > 50 with with occlusive
arterial disease
Atorvastati toachiev target
LD C
Sites in North America, Europe and Asia
4 year follo up
Primary End Point
Coronary death, myocardial infarction coronary revascularization
Planned completionin 2017
or
Placebo
Eof yl
b gh-
b 0
V h, , y scor
3 w-
n nd sia
16-
ACCELERAT trialAssessmentof Clinical Effects Cholester EsterTransferProtein Inhibition with
EvacetrapibI Patients at a High Risk for VascularOutcomes
Evacetrapi 13 mgTreatment with a12,000 patients
at high CV riskstatin for at30 days
least
Sites in North America, Europe and Asia-Pacific countries
year follo up
Primary End PointPlanned
in 20completion
2017CV 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 TA-8995 10mg + placebo
N=42 TA-8995 5mg + placebo
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 andmajor 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 aftercessation 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.
UP-APICON-2015,Noida
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...
Thank you!!!