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.