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CETP as a target in HDL-raising therapy: lessons from APOE*3-Leiden.CETP transgenic mice

Slides (presentatie) - Mar. 25, 2010

CETP as a Target in HDL-Raising Therapy: Lessons from APOE*3-Leiden.CETP Transgenic Mice

CETP as a target in HDL-raising therapy lessons from APOE*3-Leiden.CETP mice

Outline of Presentation

Outline of Presentation

Lipoprotein metabolism

Lipoprotein metabolism

Role of CETP in lipoprotein metabolism

Therapy of CVD-associated dyslipidemia money spent on drugs to treat dyslipidemia

CVD-associated dyslipidemia mainly treated with statins

Novel therapeutic strategies currently in development

Outline of Presentation

HDL-C is a strong inverse predictor of CHD risk at all levels of LDL-C

Antiatherogenic properties of HDL

First HDL-raising strategy: CETP inhibition

CETP inhibitor: Torcetrapib

Torcetrapib strongly increases HDL-C levels Phase I studies in normolipidemic healthy volunteers

Torcetrapib strongly increases HDL but does not reduce atherosclerosis!

Elucidation of (adverse) effects of torcetrapib in mice through translational research

Wild-type mice: low (V)LDL and high HDL

Mouse model for human-like lipoprotein metabolism

Structure apoE

APOE*3-Leiden.CETP transgenic mice: human-like lipoprotein metabolism

APOE*3-Leiden.CETP transgenic mice: human-like lipoprotein metabolism

APOE*3-Leiden.CETP mice: human-like lipoprotein metabolism

Effect CETP expression on atherosclerosis study design

CETP expression in APOE*3-Leiden mice aggravates diet-induced atherosclerosis

Atherosclerosis development in E3L.CETP mice is not simply predicted from cholesterol exposure

APOE*3-Leiden.CETP mouse: model for human-like lipoprotein metabolism

Torcetrapib in E3L.CETP mice

Torcetrapib decreases CETP activity Oral gavage in solutol:ethanol:saline (10:10:80)

Torcetrapib decreases CETP activity Oral gavage in solutol:ethanol:saline (10:10:80) (10 mg/kg)

Torcetrapib tends to decreases cholesterol Diet + 0.1% cholesterol + torcetrapib

Torcetrapib increases HDL in E3L.CETP mice Diet + 0.1% cholesterol + 0.01% torcetrapib

Effect of torcetrapib on atherosclerosis development in APOE*3-Leiden.CETP mice

Torcetrapib reduces CETP activity and increases CETP mass

Torcetrapib reduces CETP activity

Torcetrapib reduces plasma total cholesterol and increases HDL-cholesterol

Torcetrapib reduces atherosclerotic lesion area, but does not add to the effect of atorvastatin

Torcetrapib reduces atherosclerotic plaque severity, but not beyond atorvastatin

Torcetrapib increases MCP-1 content, monocyte adherence, and macrophage content of the plaque

Torcetrapib decreases collagen content of the plaque, independent of smooth muscle cell content

Torcetrapib induces an unstable lesion phenotype as compared to atorvastatin

Torcetrapib tends to increase general inflammatory status

Torcetrapib increases general inflammatory status and plasma aldosterone

Torcetrapib increases plasma aldosterone via class-specific effect independent of CETP inhibition

Outline of Presentation

Current drugs that increase HDL-C levels

Fenofibrate and atorvastatin in E3L.CETP mice

Fenofibrate

Fenofibrate decreases TG in E3L.CETP mice Diet + 0.25% cholesterol + 0-0.04% fenofibrate (males)

Fenofibrate increases HDL in E3L.CETP mice Diet + 0.25% cholesterol + fenofibrate (males)

Fenofibrate increases HDL in E3L.CETP mice Diet + 0.25% cholesterol + 0.04% fenofibrate (males)

Fenofibrate increases HDL in E3L.CETP mice Diet + 0.25% cholesterol + 0.04% fenofibrate (males)

FF does not differentially affect HDL genes Diet + 0.25% cholesterol + 0.04% fenofibrate (males)

Fenofibrate increases HDL in E3L.CETP mice Diet + 0.25% cholesterol + 0.04% fenofibrate (males)

Atorvastatin in E3L.CETP mice

Atorvastatin

Atorvastatin decreases TC in E3L.CETP mice Diet + 0.1% cholesterol + atorvastatin (females)

Atorvastatin increases HDL in E3L.CETP mice Diet + 0.25% cholesterol + 0.01% atorvastatin (males)

Atorvastatin increases HDL in E3L.CETP mice Diet + 0.25% cholesterol + 0.01% atorvastatin (males)

Atorva does not differentially affect HDL genes Diet + 0.25% cholesterol + 0.01% atorvastatin (males)

Atorvastatin reduces CETP expression Diet + 0.25% cholesterol + 0.01% atorvastatin (males)

Atorvastatin reduces CETP mass and activity Diet + 0.25% cholesterol + atorvastatin (females)

Mechanism underlying HDL-raising effect of statins and fibrates

Niacin

Niacin strongly reduces cardiac events

Atheroprotective effect of niacin is accompanied by a large increase in HDL level

Niacin potently increases plasma HDL levels

Niacin does not affect HDL in E3L mice Diet + 0.1% cholesterol + 0.3% niacin (female mice)

Niacin decreases TG and TC in E3L.CETP Diet + 0.1% cholesterol + niacin (female mice)

Niacin decreases TG and TC in E3L.CETP Diet + 0.1% cholesterol + niacin (female mice)

Niacin increases HDL in E3L.CETP mice Diet + 0.1% cholesterol + niacin (female mice)

Niacin increases HDL in E3L.CETP mice Diet + 0.1% cholesterol + niacin (female mice)

Niacin decreases clearance of 125I-apoAI-HDL Diet + 0.1% cholesterol + niacin (female mice)

Niacin decreases liver lipids Diet + 0.1% cholesterol + niacin (female mice)

Niacin decreases plasma CETP activity Diet + 0.1% cholesterol + niacin (female mice)

Niacin increases HDL particle size Diet + 0.1% cholesterol + niacin (female mice)

Mechanism underlying HDL-raising effect of niacin

Niacin causes regression of atherosclerosis

Translational research: relation between liver lipid, CETP and HDL-C in humans

Determination of liver TG by proton MR spectroscopy of the liver

Pioglitazone and metformin equally reduce plasma apoB100 and TG

Pioglitazone raises HDL-C, reduces CETP and reduces liver lipid

Outline of Presentation

Conclusions

APOE*3-Leiden.CETP mouse

APOE*3-Leiden.CETP mice

Acknowledgments

Thank you!

The atherogenicity of CETP depends on TG Prospective data from the Epic-Norfolk study

CETP mutation Ile405Val increases HDL…

… but increases CVD risk!

Effect of CETP on VLDL levels seem to largely explain increased atherosclerosis

Slide 94

Effect of CETP expression on atherosclerosis in APOE*3-Leiden mice

APOE*3-Leiden.CETP mice altered lipoprotein profile (female, chow diet)

Effect CETP expression on atherosclerosis study design

CETP expression increases plasma cholesterol and shifts cholesterol distribution

Quantification of atherosclerosis development in heart valve area in aortic root

CETP aggravates lesion severity in aortic root Western-type diet (19 weeks); HPS staining

CETP increases atherosclerotic lesion area Western-type diet (19 weeks); HPS staining

LXR agonist in E3L.CETP mice

LXR agonist decreases HDL in E3L.CETP Diet + 0.25% cholesterol + 0.01% T0901317 (male mice)

LXR agonist decreases HDL in E3L.CETP Diet + 0.25% cholesterol + 0.01% T0901317 (male mice)

LXR agonist decreases HDL in E3L.CETP Diet + 0.25% cholesterol + 0.01% T0901317 (male mice)

Torcetrapib

Torcetrapib increases HDL in E3L.CETP mice Oral gavage in solutol:ethanol:saline (10:10:80) (females)

Torcetrapib tends to decreases cholesterol Diet + 0.1% cholesterol + torcetrapib (females)

Torcetrapib increases HDL in E3L.CETP mice Diet + 0.1% cholesterol + 0.01% torcetrapib (females)

CETP inhibitor Merck in CETP mice

CETP-I increases HDL-C in CETP mice Chow diet + 0.05% CETP inhibitor (~50 mg/kg)

CETP-I increases HDL-C in CETP mice Chow diet + 0.05% CETP inhibitor (male mice)

CETP-I increases HDL-C in CETP mice Diet + 0….% cholesterol + …% CETP-I (male mice)

Bile acids in E3L.CETP mice

Bile acids decrease HDL-C in E3L.CETP mice Chow diet + 0.5% TCA (male mice)

Bile acids increase CETP in E3L.CETP mice Chow diet + 0.5% TCA (male mice)

Conclusions

Human Lipoprotein Metabolism

Lipoprotein metabolism – back to basics!

Reduction of LDL cholesterol by statins (II)

Lipoproteins - Composition

Lipoproteins - Size

Lipoproteins differ in size and density

Lipoproteins differ in size and density

Lipoprotein Metabolism

Dyslipidemia

Statins reduce LDL-cholesterol by inhibiting HMG-CoA reductase

Factors known to reduce HDL-C levels (I)

Factors known to reduce HDL-C levels (II)

Anti-atherogenic activities of HDL particles (II)

Anti-atherogenic activities of HDL particles (I)

HDL is an anti-inflammatory agent

Torcetrapib strongly increases HDL-C levels Phase I studies in normolipidemic healthy volunteers (II)

Torcetrapib: large phase III trial in patients

Torcetrapib lacks anti-atherosclerotic efficacy!

Potential explanations for failure of torcetrapib

Lipoprotein Metabolism - mouse

Lipoprotein Metabolism

APOE*3-Leiden mouse

Atherosclerosis development in APOE*3-Leiden mice depends on cholesterol exposure

Rosuvastatin reduces plasma cholesterol in APOE*3-Leiden mice

Rosuvastatin reduces atherosclerosis compared to high and low cholesterol groups

Rosuvastatin reduces expression of monocyte chemotactic protein-1 (MCP-1)

Rosuvastatin reduces expression of MCP-1 compared to high and low cholesterol groups

Rosuvastatin reduces serum amyloid A (SAA) compared to high and low cholesterol groups

Regression of atherosclerosis in APOE*3-Leiden mice

Introduction of CETP in APOE*3-Leiden mice

Introduction of CETP in APOE*3-Leiden mice

Overview of Presentation

raising HDL: novel therapeutic targets

raising HDL: novel therapeutic targets

Experimental HDL-directed drugs

ApoAIMilano (I)

ApoAIMilano (II)

D4F

Niacin decreases plasma lipase activity Diet + 0.1% cholesterol + niacin (female mice)

Therapy of CVD-associated dyslipidemia market for drugs to treat dyslipidemia

Anti-atherogenic activities of HDL particles

HDL plays role in reverse cholesterol transport

Anti-atherogenic activities of HDL particles

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