Interpretation and Management of Interpretation and Management of Abnormal Concentrations of High Abnormal Concentrations of High Density Lipoprotein-Cholesterol Density Lipoprotein-Cholesterol

(HDL-C)(HDL-C)

Jorge Mera, MDJorge Mera, MD

Presbyterian Hospital of DallasPresbyterian Hospital of Dallas

October 11, 2005October 11, 2005

Interpretation and Management of Interpretation and Management of Abnormal Concentrations of HDL-CAbnormal Concentrations of HDL-C

HDL-C as a risk factor for CHDHDL-C as a risk factor for CHD AtherogenesisAtherogenesis HDL Metabolism HDL Metabolism Causes of abnormal HDL-C levelsCauses of abnormal HDL-C levels Treatment Treatment

• Mechanisms of used agentsMechanisms of used agents• Novel targets for treatmentNovel targets for treatment• Treatment with available toolsTreatment with available tools

Risk Factors for CHDRisk Factors for CHD

ModifiableModifiable• DyslipidemiaDyslipidemia

Raised LDL-CRaised LDL-C Raised TGsRaised TGs Low HDL-CLow HDL-C

• Smoking Smoking

• HypertensionHypertension

• Diabetes mellitusDiabetes mellitus

• ObesityObesity

• Dietary factorsDietary factors

• Thrombogenic factorsThrombogenic factors

• Sedentary lifestyleSedentary lifestyle

Wood DJ et al. Atherosclerosis. 1998;140:199-270.

• Nonmodifiable– Age

– Sex

– Family history of premature CHD

Dyslipidemia: DefinitionDyslipidemia: Definition Elevation above the 90Elevation above the 90thth percentile of the general percentile of the general

population ofpopulation of• Total cholesterolTotal cholesterol• LDL-cholesterolLDL-cholesterol• TriglicyrideTriglicyride• Apo-BApo-B• Lp(a)Lp(a)

Concentrations below the the 10Concentrations below the the 10thth Percentile of Percentile of the general population ofthe general population of• HDL –cholesterol HDL –cholesterol • Apo A-1Apo A-1

The above mentioned disorders can be Primary or The above mentioned disorders can be Primary or Secondary to some underlying diseaseSecondary to some underlying disease

What is the Relation Between HDL-C What is the Relation Between HDL-C and Coronary Heart Disease (CHD)and Coronary Heart Disease (CHD)

Primary reductions in HDL-C are common Primary reductions in HDL-C are common in patients with premature CHDin patients with premature CHD

• Low HDL levels are more common in patients with a first Low HDL levels are more common in patients with a first myocardial infarction (MI) than in age matched controls myocardial infarction (MI) than in age matched controls without CHD (19% vs 4 %)without CHD (19% vs 4 %)11

• In the Beza fibrate Infarction Prevention Study 52 % of In the Beza fibrate Infarction Prevention Study 52 % of patients with CHD and with normal LDL-C cholesterol patients with CHD and with normal LDL-C cholesterol had low HDL-C (below 35mg/dL)had low HDL-C (below 35mg/dL)

Genest,JJ et al, J Am Coll Cariol 1992;19:792

What is the Relation Between HDL-C What is the Relation Between HDL-C and Coronary Heart Disease (CHD)and Coronary Heart Disease (CHD)

The Incidence of CHD events in a normal The Incidence of CHD events in a normal population appears to be inversely related to the population appears to be inversely related to the serum HDL-C concentrationserum HDL-C concentration

• Data from the Framingham Heart Study showed that the Data from the Framingham Heart Study showed that the risk for MI increases by 25 % for every 5 mg/dL risk for MI increases by 25 % for every 5 mg/dL decrement in serum HDL-C below median values for decrement in serum HDL-C below median values for men and womenmen and women

• HDL-C Levels are also predictive of Coronary events in HDL-C Levels are also predictive of Coronary events in patient with known CHD, specially in the subgroup with patient with known CHD, specially in the subgroup with LDL-C < 125mg dL. (LIPID and CARE trials)LDL-C < 125mg dL. (LIPID and CARE trials)

• Concentrations of HDL-C > 75 mg/dL are associated with Concentrations of HDL-C > 75 mg/dL are associated with longevity and relative freedom from CHDlongevity and relative freedom from CHD

Framingham Heart Study: Risk of CAD in Men Aged 50–70 by LDL-C and HDL-C

Levels

Castelli W. Can J Cardiol. 1988;4(suppl A):5A-10A.

CHD Risk According to HDL-C Levels: Framingham Study

4.0

3.0

2.0

1.0

25 45 65HDL-C (mg/dL)

CH

D R

isk

Rati

o

Kannel WB. Am J Cardiol. 1983;52:9B–12B.

2.0

1.0

0

4.0

Major Risk Factors (Excluding LDL-C) Major Risk Factors (Excluding LDL-C) That Modify LDL-C GoalsThat Modify LDL-C Goals

Cigarette smokingCigarette smoking Hypertension (BP Hypertension (BP 140/90 mmHg or on 140/90 mmHg or on

antihypertensive medication)antihypertensive medication) Low HDL-C (<40 mg/dL)Low HDL-C (<40 mg/dL)** Family history of premature CHDFamily history of premature CHD

• CHD in male first degree relative <55 yearsCHD in male first degree relative <55 years

• CHD in female first degree relative <65 yearsCHD in female first degree relative <65 years Age (men Age (men 45 years; women 45 years; women 55 years)55 years)

*HDL-C 60 mg/dL counts as a “negative” risk factor; its presence removes 1 risk factor from the total count.

HDL-C, high-density lipoprotein cholesterol.

HDL AS CAD RISK FACTOR

NCEP ATP III recognizes that NCEP ATP III recognizes that any serum any serum HDL level < 40HDL level < 40 mg/dL mg/dL

constitutes an independent risk constitutes an independent risk factor for CAD, and therapeutic factor for CAD, and therapeutic effort should be made to raise effort should be made to raise

HDL above this threshold.HDL above this threshold.CAD, coronary artery disease.

Framingham CHD Risk Framingham CHD Risk Assessment inAssessment in MenMen

TC(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79<160 0 0 0 0 0

160-199 4 3 2 1 0200-239 7 5 3 1 0240-279 9 6 4 2 1

>280 11 8 5 3 1

PointsStep 2: Total Cholesterol

Years Points20-34 -935-39 -440-44 045-49 350-54 655-59 860-64 1065-69 1170-74 1275-79 13

Step 1: Age

HDL-C(mg/dL) Points

>60 -150-59 040-49 1<40 2

Step 3: HDL-C

SBPmm Hg Utreated Treated<120 0 0

120-129 0 1130-139 1 2140-159 1 2

>160 2 3

PointsStep 4: Systolic Blood Pressure

20-39 40-49 50-59 60-69 70-79Nonsmoker 0 0 0 0 0Smoker 8 5 3 1 1

Step 5: Smoking StatusPoints at Age

Category: PointsAgeTotal-CHDL-CSBPSmoking status

Point Total:

Step 6: Adding Up The Points

Point Total 10-Year Risk<0 <1%0 1%1 1%2 1%3 1%4 1%5 2%6 2%7 3%8 4%9 5%

10 6%11 8%12 10%13 12%14 16%15 20%16 25%

>17 >30%

Step 7: CHD Risk

Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.SBP, systolic blood pressure.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Years Points20-34 -735-39 -340-44 045-49 350-54 655-59 860-64 1065-69 1270-74 1475-79 16

Step 1: Age

TC(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79<160 0 0 0 0 0

160-199 4 3 2 1 1200-239 8 6 4 2 1240-279 11 8 5 3 2

>280 13 10 7 4 2

Step 2: Total CholesterolPoints

HDL-C(mg/dL) Points

>60 -150-59 040-49 1<40 2

Step 3: HDL-C

SBPmm Hg Utreated Treated<120 0 0

120-129 1 3130-139 2 4140-159 3 5

>160 4 6

Step 4: Systolic Blood PressurePoints

20-39 40-49 50-59 60-69 70-79Nonsmoker 0 0 0 0 0Smoker 9 7 4 2 1

Step 5: Smoking StatusPoints at Age

Category: PointsAgeTotal-CHDL-CSBPSmoking status

Point Total:

Step 6: Adding Up The Points

Point Total 10-Year Risk<9 <1%9 1%

10 1%11 1%12 1%13 2%14 2%15 3%16 4%17 5%18 6%19 8%20 11%21 14%22 17%23 22%24 27%

>25 >30%

Step 7: CHD Risk

Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Framingham CHD Risk Framingham CHD Risk Assessment inAssessment in WomenWomen

Endothelium

LDLLDLO2

-

Lipoxygenase

**

**

Oxidized Oxidized

LDLLDL*

*

ScavengerReceptor

Smooth Muscle Cells

Macrophage

Bloodstream

Oxidized Low-Density Lipoprotein:Oxidized Low-Density Lipoprotein:A Potent AtherogenA Potent Atherogen

LDL, low-density lipoprotein. Courtesy of P Libby.

Evolution of Atherosclerotic Plaque

Libby P. The vascular biology of atherosclerosis. In: Braunwald E et al. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, PA: Elsevier; 2001:995-1009.

Sphingosine

Ceramide

Sphingomyelinase

Sphingomyelin

Sphingosine 1-P

Activate NF-

Increase ICAM-1/VCAM-1

TNF -

MCP-1 Gradient

Subendothelial Space

Transmigration

Bound MonocyteCirculating

Monocyte

ICAM – 1 VCAM – 1 ICAM – 1 VCAM – 1

Endothelium

Vascular Lumen

HDL3 inhibits

Sphingosine Kinase

+

HDL, high-density lipoprotein; MCP, monocyte chemotactic protein; VCAM, vascular adhesion molecule. Xia P et al. Biol Chem. 1999;274:33143-33147.

Endothelial Cell Endothelial Cell Adhesion MoleculesAdhesion Molecules

Liver LDLr

SR-BI

LPL

E

B

C-II

VLDL

HLB

LDL 1

C-II

E

C-III B

C-III

IDL

ABCA1

Macrophage

HL

A-I

NascentHDL

A-I

HDL 2

LCAT

Degradation

Metabolism of ApoA-Containing Lipoproteins

LPL

E

B C-II

VLDL

B

LDL 3

Oxidation

CD36

SR-A

Cholesterol

Pool

Arterial Wall

LCAT

B

LDL 2LPL

LDL 4

LDL 5

B

BB

B

HDL 3

CETP

CholChol

TG

A-IA-I

A-II Chol

A-I

Chol

Chol

TG

CETP

Adapted from B Brewer.

Liver LDLr

SR-BI

LPL

E

B

C-II

VLDL

HLB

LDL 1

C-II

E

C-III B

C-III

IDL

ABCA1

Macrophage

HL

A-I

NascentHDL

A-I

HDL 2

LCAT

Degradation

Non-HDL-C

LPL

E

B C-II

VLDL

B

LDL 3

Oxidation

CD36

SR-A

Cholesterol

Pool

Arterial Wall

LCAT

LPL

LDL 4

LDL 5

B

BB

B

HDL 3

CETP

CholChol

TG

A-IA-I

A-II Chol

A-I

Chol

Chol

TG

CETP

Adapted from B Brewer.

Reverse Cholesterol Transport

Tóth PP. Am J Cardiol. 2005. In press.

Structure of HDL Particle

A-IA-I

A-II

A-I, A-II, apolipoprotein A-I, A-II; CE, cholesteryl ester; TG, triglycerides.

CETG

Production of HDL-C by Liver and Intestine

A-I A-I

A-II

LiverIntestine

HDL HDL

HDL Metabolism and Reverse Cholesterol Transport

A-I

Liver

CE

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABC1, ATP-binding cassette protein 1; FC, free cholesterol; LCAT, lecithin-cholesterol acyltransferase; SR-BI, scavenger receptor class BI.

ABC1Macrophage

Mature HDL

Nascent HDL

Role of CETP in HDL Metabolism

A-I

Liver

CECE

FCFCLCATFC

Bile

SR-BI

A-I

ABC1

Macrophage

CE B

CETP, cholesteryl ester transfer protein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; VLDL, very-low-density lipoprotein.

LDLR

VLDL/LDL

CETP

Mature HDLNascent HDL

CE

SRA

Oxidation

Role of HL and LPL in HDL Metabolism

CM, chylomicron; CMR, chylomicron remnant; HDL, high-density lipoprotein; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LPL, lipoprotein lipase; PL, phospholipase.

B

Kidney

EndotheliumB

TG

CMR/IDL

C-II

CM/VLDL

HL

LPL

A-I

CE TG

HDL2

PLA-I

CE

HDL3

PL

Phospholipids and

apolipoproteins

HDL-C: Anti-Atherogenic Properties

HDL is Anti-Atherogenic by two main mechanisms

– Reverse Cholesterol transport Transporting Cholesterol from peripheral tissues

(macrophages) back to the liver

– Transferring cholesterol to VLDL, IDL or LDL via the Cholesterol Esther Transport Protein (CETP) That cholesterol ideally will go back to the liver

Primary (Genetic) Causes of Low HDL-C

ApoA-I– Complete ApoA-I deficiency– ApoA-I mutations (eg, ApoA-IMilano)

LCAT– Complete LCAT deficiency– Partial LCAT deficiency (fish eye disease)

ABC1– Tangier disease

Homozygous Heterozygous

– Familial hypoalphalipoproteinemia (some families) Unknown genetic etiology

– Familial hypoalphalipoproteinemia (most families) – Familial combined hyperlipidemia with low HDL-C– Metabolic syndrome

HDL Metabolism in LCAT Deficiency

A-I

FCFCLCAT

A-I

ABC1

MacrophageRapid

catabolism

Nascent HDL

CE

HDL Metabolism in Tangier Disease

A-I

FCFC

A-I

ABC1Macrophage

Rapid catabolism

LCAT

Nascent HDL

CE

Tangiers DiseaseTangiers Disease

Orange TonsilsOrange Tonsils HepatomegalyHepatomegaly NeuropathyNeuropathy Low or absent HDL-Low or absent HDL-

CC

Familial Hypoalphalipoproteinemia

Dominant disorder; due to mutations in one allele of ABC1 gene in some families and of unknown genetic etiology in other families

Moderate reduction in HDL-C and ApoA-I

Increased risk of premature atherosclerotic vascular disease

Secondary Causes of Low HDL-C

Smoking Obesity (visceral fat) Very-low-fat diet Hypertriglyceridemia Drugs

– Beta blockers – Androgenic steroids– Androgenic progestins

Primary (Genetic) Causes of High HDL-C

CETP– CETP deficiency

HL– HL deficiency

Unknown genetic etiology– Familial hyperalphalipoproteinemia

CETP Deficiency

Autosomal co-dominant; due to mutations in both alleles of CETP gene

Markedly elevated levels of HDL-C and ApoA-I Delayed catabolism of HDL CE and ApoA-I HDL particles enlarged and enriched in CE Evidence of protection against atherosclerosis

is controversial

HDL Metabolism in CETP Deficiency

A-I

CE FCFCLCAT

A-I

Macrophage

B

Delayed catabolism

CETP

ABC1

HDL

VLDL/LDL

Nascent HDL

CE

Familial Hyperalphalipoproteinemia

Autosomal dominant; molecular etiology unknown Modest to marked elevations in HDL-C and ApoA-I Selective increased synthesis of ApoA-I in some

families Associated with longevity and protection against

atherosclerotic vascular disease in epidemiologic studies

Secondary Causes of Increased HDL-C

Extensive regular aerobic exercise Very-high-fat diet Regular substantial alcohol intake Estrogen replacement therapy Drugs

– Phenytoin

Genes Involved in HDL MetabolismPotential Targets for Novel Therapies for Atherosclerosis

HDL-associated apolipoproteins

— ApoA-I — ApoE

HDL-modifying plasma enzymes and transfer proteins

— LCAT — LPL

— CETP — HL

— Endothelial lipase

Cellular and cell-surface proteins that influence HDL metabolism

— ABC1 — SR-BI

TREATMENT OPTIONS

Drug Effects on HDL: Niacin

Liver

B

B

TG

CMR/IDL

C-II

CM/VLDL

LPL

A-I

CE

CE FCFCLCAT

A-I

ABC1

MacrophageMature HDL

Nascent HDL

LDLR

HL

Intestine

NIACINNIACIN

NIACINNIACIN

*

*Inhibits uptake of ApoA-I but not CE.

.Arterioscler Thromb Vasc Biol. 1999;19:1051–1059

Side Effects of RR Niacin

Flushing, itching Hepatitis Glucose intolerance Gout Peptic ulcer activation

RR, rapid-release.

Tricks for Using Niacin

Use only the bedtime dose

Give all doses with food

Start low and increase slowly

Use only the sustained release

Give with ASA

Do not exceed 2 g QD of sustained-released Niacin

– It is 2 times more effective than regular niacin BUT 10 times more

hepatotoxic

ASA, acetylsalicylic acid.

Drug Effects on HDL: Fibrates

Liver

B

B

TG

CMR/IDL

C-II

CM/VLDL

LPL

A-I

CE FCLCAT

A-I

ABC1

Mature HDL

Nascent HDL

LDLR

HL

FIBRATESFIBRATES+

+

FIBRATESFIBRATES

Intestine

CEFC

Macrophage

Fenofibrate Clofibrate, Gemfibrozil

Drug Effects on HDL: Statins

Liver

B

B

TG

CMR/IDL

C-II

CM/VLDL

LPL

A-I

CE FCLCAT

A-I

ABC1

Mature HDL

Nascent HDL

LDLR

HL

+

STATINSSTATINS

STATINSSTATINS

STATINSSTATINS

+

?

CEFC

Macrophage

Intestine

They Cure Almost Every Lipid Problem That Ails You

LDL-C TG HDL-C LDL particle size hs-CRP

hs-CRP, high-sensitivity C-reactive protein; TG, triglycerides.

Novel HDL Raising Therapies

• ABCAI activators

• PPAR-alpha agonists

• Apo AI gene therapy

• CETP inhibitors

• Apo AI mimetics

Peroxisome Proliferator Activated Receptors (PPAR)

PPAR agonists elicit their action by combining with an retinoid receptor (RXR) to form what are called response elements. These response elements regulate gene expression that are involved in lipid metabolism. Alpha agonists increase lipid metabolism to burn fat for energy. Gamma agonists effect not only glucose homeostasis, but also lipid metabolism in which fat is redistributed into subcutaneous fat cells.

PPAR: Fenofibric acid

Peroxisome Proliferator Activated Receptors

PPARPPAR RXRRXR PPARPPAR RXRRXR

Primary

TissueLiver, muscle Adipose, muscle

LigandsFatty acids

Fibrates

Fatty acids

TZDs

Function

Lipid metabolism

(“fat burning”)

Lipid metabolism

Glucose homeostasis

(“fat storage”)

Regulation of genes involved in lipid metabolism

RXR, retinoid X receptor; TZDs, thiazolidinediones.

Effects of PPAR-α Agonism

PPARa activation regulates expression of the

five key genes involved in HDL metabolism.

This results in:

– increased levels of apo A-I and A-II;

– increased LPL activity;

– increased reverse cholesterol transport

via

Increased expression of (i) the

ABCA-1 receptor (cholesterol efflux

via CERP) and

The Cla-1/SR-BI receptor (HDL

capture and catabolism

CETP: A Potential Therapeutic Target for the

Prevention of Cardiovascular DiseaseRole of CETP in Lipoprotein Metabolism

CETP Lowers HDL-C

Increases LDL-C– Small dense LDL

Pharmacologic inhibition of CETP increases HDL-C and lowers LDL-C

CETP

HDLHDL

Apo B

VLDLVLDL

Cholesteryl Ester

CETCETPP

TG

or Chylomicron Remnantor Chylomicron Remnant

Apo AI

Apo E

Age-Adjusted 6-Year CHD/CVD Rates for Elderly Japanese

American Men With/Without CETP Mutations

HDL-C <60 mg/dL HDL-C 60 mg/dL

CH

D I

nci

de

nce

(ra

te/1

00

0 p

ers

on

-ye

ars

)171/1713*

31/509†5/76

2/42

*Number of CHD events/men at risk.†Significantly lower risk compared to men with HDL-C <60 mg/dL and without a CETP mutation (P < 0.05).

CETP Mutation:

absentpresent

18

15

12

9

6

3

0

Curb JD et al. J Lipid Res. 2004;45:948-953.

Torcetrapib Mechanism of Action Summary

Enhances CETP’s affinity for lipoproteins

– Does not block lipid binding to CETP

Binds to CETP with 1:1 stoichiometry

Creates a CETP/lipoprotein complex that inhibits lipid transfer

– Blocks CETP’s neutral-lipid and phospholipid

transfer activity

CETP takes on the plasma kinetic characteristics of the bound

lipoprotein (HDL); CETP mass increases as a nonproductive

complex

- 40

- 20

0

20

40

60

80

0 10 30 60 120

Torcetrapib (mg)

% C

han

ge

HDL- CLDL- CTG

Torcetrapib: Dose-Dependent CETP Inhibition, HDL

Raising and LDL Lowering in Healthy Individuals

Adapted from Clark RW et al. Arterioscler Thromb Vasc Biol. 2004; 24:490-497.

Lipid Profile During Treatment with Torcetrapib vs Placebo for 14 days

*P < 0.05, †P < 0.01, ‡ P < 0.001.

†

‡

‡

‡

*

• Spherical particles of natural lipid

• Activates cholesterol mobilization

• Regression of atherosclerosis in preclinical models

• ETC-588-003 positive study results reported 2Q ’02

• ETC-588-004 study initiated in 2Q ’02; complete in 1Q ’03

• Target indication: acute coronary syndromes

• Spherical particles of natural lipid

• Activates cholesterol mobilization

• Regression of atherosclerosis in preclinical models

• ETC-588-003 positive study results reported 2Q ’02

• ETC-588-004 study initiated in 2Q ’02; complete in 1Q ’03

• Target indication: acute coronary syndromes

ETC-588:m LUV (large Unilamellar Vessicles) Enhancer of Reverse Lipid Transport

Mechanism of Action Mechanism of Action

Atherosclerotic lesion

Cholesterol-poorETC-588

Cholesterol-enrichedETC-588

LiverHDL

Unesterified cholesterol =

ETC-588: LUV

ETC-216: AIM (ApoA-I Milano): Variant of ApoA-I, the Major HDL Protein

• Carriers are protected against vascular disease

• AIM enhances the RLT pathway–HDL transports excess cholesterol from arteries to the liver for removal–Anti-atherosclerotic effects in preclinical models including rapid plaque stabilization

• Phase I complete; Phase II enrollment continuing

• Target indication: acute coronary syndromes

• Carriers are protected against vascular disease

• AIM enhances the RLT pathway–HDL transports excess cholesterol from arteries to the liver for removal–Anti-atherosclerotic effects in preclinical models including rapid plaque stabilization

• Phase I complete; Phase II enrollment continuing

• Target indication: acute coronary syndromes

Study Design: Double-blind, randomized, placebo-controlled multicenter pilot trial comparing the effect of intravenous recombinant Apo A-IMilano/phospholipid complexes (ETC-216) or placebo on coronary atheroma burden as measured by intravascular ultrasound (IVUS)

Intervention: 123 patients screened, 59 randomized, and 47 completed protocol; in ratio of 1:2:2, patients received 5 weekly infusions of placebo or ETC-216 at 15 mg/kg or 45 mg/kg; atheroma burden was measured by IVUS at baseline and end of 5 weeks

Results: Mean percent atheroma volume decreased by 1.06% in combined ETC-216 group (P = 0.02); absolute reduction in atheroma volume in combined ETC-216 groups was –14.1 mm3, or 4.2% decrease from baseline (P < 0.001).

Effect of Recombinant Apo A-IMilano on Coronary

Atherosclerosis in Patients with Acute Coronary Syndrome

Nissen SE et al. JAMA. 2003;290:2292–2300.

MeanMean

-1.4-1.2-1.0-0.8-0.6-0.4-0.20.00.20.4

Ch

an

ge f

rom

Bas e

line,

%Effect of Recombinant Apo A-IMilano (ETC-216) on Change

in Percent Atheroma Volume

**PP = 0.03. = 0.03.

0.140.14

Nissen SE et al. JAMA. 2003;290:2292–2300.

MedianMedian

––1.291.29

––0.730.73

––1.061.06

0.030.03

––1.141.14 **

––0.340.34

––0.810.81††

PlaceboPlacebo 15 mg/kg15 mg/kg 45 mg/kg45 mg/kg CombineCombinedd††PP = 0.02 (1° end point). = 0.02 (1° end point).

How Much of the “Atheroma Volume” Can Be Mobilized?

Necrotic Core(15%–25%)

CholesterolClefts

(5%–10%)

Macrophage(10%–20%)

Potential Potential for Lipid for Lipid

MobilizationMobilization

Potential Potential for Lipid for Lipid

MobilizationMobilization

Modified from Virmani R et al. Arterioscler Thromb Vasc Biol. 2000; 20:1262-1275.

Small changes in percent atheroma volume (-1.06%) may translate into large changes in the plaque lipid content

Before Any Journey

It’s Good To Know Where You’re Going Or What Your Goals Are

Who Should We Treat ?

Isolated decrease in HDL-C in

– Patients with CHD or risk equivalent

– 1st Degree relatives with similar lipid profile and early onset of CHD

Treatment

Meet LDL-C goals 1st

If LDL-C goal is met but TG > 200 mg/dL meetNon HDL-C goals 1st

If HDL-C still is low despite treatment of above– Nicotinic Acid (preferred)– Genfibrozil (If statin needed pravastatin preferred)

If decreased HDL-C is only associated with Increased TG start monotherapy with– Fibrate– Nicotinic Acid

Treatment

If decreased HDL-C is the only dyslipidemia– A) Nicotinic acid will increase it by 30 %– B) Genfibrozil will increase it by 10 %– C) A + B will increase it by 45 %– D) Statins will increase it by 5 % (Simvastatin >

Atorvastatin)

A,B,C: J Am Coll Ardiol 2000;35:640

D: Am J Cardiol 2000;86:221

Summary HDL metabolism is complex

HDL-C and ApoA-I levels are determined by both production and catabolic rates

Rates of reverse cholesterol transport cannot be determined solely by steady-state levels of HDL-C and ApoA-I

Effect of genetic defects or interventions that alter HDL metabolism on atherosclerosis depends on specific metabolic effects on HDL

Genes and proteins involved in HDL metabolism are potential targets for development of novel therapeutic strategies for atherosclerosis

“Good news, Mr. Dewlap. While your cholesterol hasremained the same, the research findings have changed.”

Superior doctors prevent the disease.Mediocre doctors treat the disease before evident.Inferior doctors treat the full blown disease.

— Huang Dee: Nai-Ching (2600 BC; first Chinese medical text).

Interventional CardiologistInterventional Cardiologist

INTERVENTIONAL INTERVENTIONAL LIPIDOLOGIST LIPIDOLOGIST

WWW.LIPID.ORGWWW.LIPID.ORG

Lipid free

VA-HIT trialVA-HIT trial The VA-HIT trial included 2531 with CHD who had an LDL-The VA-HIT trial included 2531 with CHD who had an LDL-

cholesterol ( 140 mg/dL or 3.6 mmol/L), an HDL-cholesterol ( 40 cholesterol ( 140 mg/dL or 3.6 mmol/L), an HDL-cholesterol ( 40 mg/dL or 1.0 mmol/L), and triglycerides 300 mg/dL (3.4 mmol/L); mg/dL or 1.0 mmol/L), and triglycerides 300 mg/dL (3.4 mmol/L);

the patients were randomly assigned to treatment with the patients were randomly assigned to treatment with gemfibrozilgemfibrozil or placebo [or placebo [7878].].

At one year, the following differences were noted in the At one year, the following differences were noted in the gemfibrozil group:gemfibrozil group:• The mean HDL-cholesterol level was 6 percent higher (34 versus 32 mg/dL for The mean HDL-cholesterol level was 6 percent higher (34 versus 32 mg/dL for

placebo [0.9 versus 0.8 mmol/L])placebo [0.9 versus 0.8 mmol/L])• The mean total cholesterol was 4 percent lower (170 versus 177 mg/dL [4.4 The mean total cholesterol was 4 percent lower (170 versus 177 mg/dL [4.4

versus 4.6 mmol/L])versus 4.6 mmol/L])• The mean triglyceride concentration was 31 percent lower (115 versus 166 The mean triglyceride concentration was 31 percent lower (115 versus 166

mg/dL [1.3 versus 1.6 mmol/L])mg/dL [1.3 versus 1.6 mmol/L]) At five years, the combined primary end point of cardiac death At five years, the combined primary end point of cardiac death

and nonfatal myocardial infarction occurred less often in the and nonfatal myocardial infarction occurred less often in the gemfibrozilgemfibrozil treated group (17.3 versus 21.7 percent for placebo). treated group (17.3 versus 21.7 percent for placebo).

The reduction in nonfatal myocardial infarction and CHD death The reduction in nonfatal myocardial infarction and CHD death was strongly correlated with the serum HDL-cholesterol was strongly correlated with the serum HDL-cholesterol concentration achieved with concentration achieved with gemfibrozilgemfibrozil therapy, but was therapy, but was independent of changes in LDL-cholesterol or triglycerides].independent of changes in LDL-cholesterol or triglycerides].

  

Muscle Complaints with StatinsMuscle Complaints with Statins

Myalgia with/without CK elevationsMyalgia with/without CK elevations Asymptomatic CK elevations <10 X NLAsymptomatic CK elevations <10 X NL Myositis: CK >10 X NL – exercise?Myositis: CK >10 X NL – exercise? Rhabdomyolysis +/- renal dysfunctionRhabdomyolysis +/- renal dysfunction Persistent myalgia after stopping drugPersistent myalgia after stopping drug

CK, creatine kinase; NL, normal.

Management of Statin-Related Management of Statin-Related Muscle Complaints: PreventionMuscle Complaints: Prevention

Lowest statin dose possible except ACS Lowest statin dose possible except ACS and CADand CAD

Avoid concomitant therapy with Avoid concomitant therapy with gemfibrozilgemfibrozil

Warn patients—muscle pain, weakness, Warn patients—muscle pain, weakness, urine discolorationurine discoloration

Don’t ignore complaintsDon’t ignore complaints Discontinue statins presurgery + extreme Discontinue statins presurgery + extreme

exertionexertion??????????ACS, acute coronary syndrome.

Liver DysfunctionLiver Dysfunction

Occurs often in 1st 3 months of Occurs often in 1st 3 months of treatmenttreatment

Look for other causesLook for other causes Ignore GGTP values aloneIgnore GGTP values alone More often with high TG and fatty More often with high TG and fatty

liver????liver???? Continue drug unless LFTs > 2–3 X Continue drug unless LFTs > 2–3 X

NL or symptomsNL or symptoms

GGTP, gamma-glutamyl transpeptidase.