CETP inhibitors Future in lipid management

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.

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• 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

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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!!!