De-risking the development programs of CETP inhibitors after the torcetrapib failure: Endothelial function & blood

pressure

Prof. John DeanfieldUniversity College London

United Kingdom

HDL : a novel target in prevention ?

HDL

Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk

Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

1% decreasein LDL-C

reduces CHD risk by

1%

1% increasein HDL-C

reduces CHD risk by

3%

The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000

Coronary Heart Disease and HDL-C

0.8

1.0

1.5

2.0

2.53.03.5

Haz

ard

Rat

io

40 60 80HDL-C (mg/dL)

N = 302,430

30 50 70

Reduced HDL is associated with increased CV risk – despite intense

statin therapy

Barter P N Engl J Med 2007; 357: 1301-10

Quintile of HDL-C level (mg/dL)

Q1(<37)

Q2(37 to <42)

Q3(42 to <47)

Q4(47 to <55)

Q4(≥55)

0

1

2

3

4

5

6

7

8

9

10

5-yr

ris

k o

f m

ajo

rC

V e

ven

ts (

%)

ApoAI upregulation

hyperTGemia

Omega-3 FAs

Reconstituted

apoAI/HDL ;

HDL delipidation

pre-β HDL

HDLapoCIIIABCA1

induction /

LXR agonists

HDL-Raising Therapies on the Horizon

sPLA2HLEL

LCATSR-B1

ApoAI upregulation

ApoAI

mimetics

Niacin analogues

CETP Inhibitors

PPAR

agonists

apoAII

apoE

Schematic Overview of Lipoprotein Metabolism

Courtesy of Brian Brewer

Torcetrapib in High-risk Patients : ILLUMINATE Study

Barter PJ: NEJM 2008

-30-20

-10

010

20

30

4050

60

70

80

TC HDL LDL

*

*

*

% c

han

ge

0 180 360 540 720

Atorvastatin

Atorvastatin + Torcetrapib p=0.001

Days

100

98

96

94

92

90

0

wit

ho

ut

an e

ven

t (%

)

CV EventsLipid Levels

Torcetrapib causes Endothelial Dysfunction independent of CETP inhibition

Connelly J Cardiovasc Pharmacol 2010 55; 459-468

Art

eria

l d

iam

eter

(m

m)

1.00.90.80.70.60.50.40.30.20.10.0 B

LPost NE

10 17 30 56 15 min postAcetylcholine infusions (µg/min for 15 min)

VehicleTorcetrapib, 30 mg/kg x 4dTorcetrapib 2-wk washout

CETP Inhibition and Endothelial FunctionF

MD

(%

)

HDL-C <1.19 mmol/L

HDL-C >1.19 mmol/L

Dalcetrapib 600 mgPlacebo

Total population Dalcetrapib-treated patients by baseline HDL-

C

0

1

2

3

4

BL +2 +4 BL +2 +4

weeks weeks

BL +2 +4 BL +2 +4

weeks weeks

0

1

2

3

4

5

FM

D (

%)

Herman Thrombosis Research 2009 123 460-465

dal-VESSEL : Study Design

;27:141-150

Placebo

RandomisationFMD, ABPM

36 weeksFMD, ABPM

Dalcetrapib 600 mg

Pre-randomisatio

n phase 8 weeks

476 patientsrandomised

4 weeksABPM

12 weeksFMD, ABPM

Double-blind randomised, placebo-controlled, parallel-group multicentre FMD/ABPM study in patients with CHD or CHD-risk equivalent

Firm epidemiological link to CV outcome

Exciting therapeutic opportunity HDL is complex particle with

multiple functions First CETP inhibitor Torcetrapib

caused increased mortality Current trials will define clinical role

for HDL elevation

HDL as a Therapeutic Target