Interpretation and Management of Abnormal Concentrations of High Density Lipoprotein-Cholesterol (HDL-C)

1
Interpretation and Management of Abnormal
Concentrations of High Density Lipoprotein-Cholest
erol (HDL-C)

• Jorge Mera, MD
• Presbyterian Hospital of Dallas
• October 11, 2005

2
Interpretation and Management of Abnormal
Concentrations of HDL-C

• HDL-C as a risk factor for CHD
• Atherogenesis
• HDL Metabolism
• Causes of abnormal HDL-C levels
• Treatment
• Mechanisms of used agents
• Novel targets for treatment
• Treatment with available tools

3
Risk Factors for CHD

• Modifiable
• Dyslipidemia
• Raised LDL-C
• Raised TGs
• Low HDL-C
• Smoking
• Hypertension
• Diabetes mellitus
• Obesity
• Dietary factors
• Thrombogenic factors
• Sedentary lifestyle

• Nonmodifiable
• Age
• Sex
• Family history of premature CHD

Wood DJ et al. Atherosclerosis. 1998140199-270.
4
Dyslipidemia Definition

• Elevation above the 90th percentile of the
  general population of
• Total cholesterol
• LDL-cholesterol
• Triglicyride
• Apo-B
• Lp(a)
• Concentrations below the the 10th Percentile of
  the general population of
• HDL cholesterol
• Apo A-1
• The above mentioned disorders can be Primary or
  Secondary to some underlying disease

5
What is the Relation Between HDL-C and Coronary
Heart Disease (CHD)

• Primary reductions in HDL-C are common in
  patients with premature CHD
• Low HDL levels are more common in patients with a
  first myocardial infarction (MI) than in age
  matched controls without CHD (19 vs 4 )1
• In the Beza fibrate Infarction Prevention Study
  52 of patients with CHD and with normal LDL-C
  cholesterol had low HDL-C (below 35mg/dL)

Genest,JJ et al, J Am Coll Cariol 199219792
6
What is the Relation Between HDL-C and Coronary
Heart Disease (CHD)

• The Incidence of CHD events in a normal
  population appears to be inversely related to the
  serum HDL-C concentration
• Data from the Framingham Heart Study showed that
  the risk for MI increases by 25 for every 5
  mg/dL decrement in serum HDL-C below median
  values for men and women
• HDL-C Levels are also predictive of Coronary
  events in patient with known CHD, specially in
  the subgroup with LDL-C lt 125mg dL. (LIPID and
  CARE trials)
• Concentrations of HDL-C gt 75 mg/dL are associated
  with longevity and relative freedom from CHD

7
Framingham Heart Study Risk of CAD in Men Aged
5070 by LDL-C and HDL-C Levels
Castelli W. Can J Cardiol. 19884(suppl A)5A-10A.
8
CHD Risk According to HDL-C Levels Framingham
Study
4.0
4.0
3.0
CHD Risk Ratio
2.0
2.0
1.0
1.0
0
65
25
45
HDL-C (mg/dL)
Kannel WB. Am J Cardiol. 1983529B12B.
9
Major Risk Factors (Excluding LDL-C) That Modify
LDL-C Goals

• Cigarette smoking
• Hypertension (BP ?140/90 mmHg or on
  antihypertensive medication)
• Low HDL-C (lt40 mg/dL)
• Family history of premature CHD
• CHD in male first degree relative lt55 years
• CHD in female first degree relative lt65 years
• Age (men ?45 years women ?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.
10
HDL AS CAD RISK FACTOR

• NCEP ATP III recognizes that any serum HDL
  level lt 40 mg/dL constitutes an independent risk
  factor for CAD, and therapeutic effort should be
  made to raise HDL above this threshold.

CAD, coronary artery disease.
11
Framingham CHD Risk Assessment in Men
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. 20012852486-2497.
12
Framingham CHD Risk Assessment in Women
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. 20012852486-2497.
13
Oxidized Low-Density LipoproteinA Potent
Atherogen
Bloodstream
Endothelium






O2-
Oxidized LDL
LDL
Scavenger Receptor
Lipoxygenase
Macrophage
Smooth Muscle Cells
LDL, low-density lipoprotein.

Courtesy of P Libby.
14
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 2001995-1009.
15
Endothelial Cell Adhesion Molecules
Vascular Lumen
Bound Monocyte
Circulating Monocyte
Transmigration
Endothelium
ICAM 1 VCAM 1
ICAM 1 VCAM 1
MCP-1 Gradient
Subendothelial Space
Sphingomyelin
Increase ICAM-1/VCAM-1

TNF - a
Sphingomyelinase
Activate NF-kB
Ceramide
HDL3 inhibits
Sphingosine 1-P
Sphingosine
Sphingosine Kinase
HDL, high-density lipoprotein MCP, monocyte
chemotactic protein VCAM, vascular adhesion
molecule. Xia P et al. Biol Chem.
199927433143-33147.
16
Metabolism of ApoA-Containing Lipoproteins
B
B
C-III
C-II
B
HL
HL

LPL
B

LPL
LDL 2
B
C-II
LDL 1
LPL
C-III
LDL 3
E
E
IDL
VLDL
C-II
LDL 4
B
B
B
Chol
Chol
Chol
E
CETP
Chol
VLDL
B
B
CETP
Oxidation
LDL 5
Liver
TG
LDLr
CD36
TG
SR-BI
SR-A
Macrophage
Cholesterol
A-I
A-I
A-I
Pool
A-I
LCAT
LCAT
A-I
ABCA1
Chol
A-II
Nascent
HDL
Degradation
HDL 3
HDL 2
Arterial Wall
Adapted from B Brewer.
17
Non-HDL-C
B
C-III
C-II
B
HL
HL

LPL
B

LPL
B
C-II
LDL 1
LPL
C-III
LDL 3
E
E
IDL
VLDL
C-II
LDL 4
B
B
B
Chol
Chol
Chol
E
CETP
Chol
VLDL
B
B
CETP
Oxidation
LDL 5
Liver
TG
LDLr
CD36
TG
SR-BI
SR-A
Macrophage
Cholesterol
A-I
A-I
A-I
Pool
A-I
LCAT
LCAT
A-I
ABCA1
Chol
A-II
Nascent
HDL
Degradation
HDL 3
HDL 2
Arterial Wall
Adapted from B Brewer.
18
Reverse Cholesterol Transport
Tóth PP. Am J Cardiol. 2005. In press.
19
Structure of HDL Particle
A-I
A-I
CE TG
A-II
A-I, A-II, apolipoprotein A-I, A-II CE,
cholesteryl ester TG, triglycerides.
20
Production of HDL-C by Liver and Intestine
Liver
Intestine
A-I
A-I
A-II
HDL
HDL
21
HDL Metabolism and Reverse Cholesterol Transport
Bile
A-I
A-I
FC
CE
CE
LCAT
FC
FC
CE
ABC1
Nascent HDL
SR-BI
Macrophage
Mature HDL
Liver
ABC1, ATP-binding cassette protein 1 FC, free
cholesterol LCAT, lecithin-cholesterol
acyltransferase SR-BI, scavenger receptor class
BI.
22
Role of CETP in HDL Metabolism
Bile
Macrophage
Mature HDL
Nascent HDL
A-I
A-I
FC
CE
CE
LCAT
FC
FC
CE
ABC1
SR-BI
SRA
CETP
Liver
LDLR
Oxidation
CE
B
VLDL/LDL
CETP, cholesteryl ester transfer protein LDL,
low-density lipoprotein LDLR, low-density
lipoprotein receptor VLDL, very-low-density
lipoprotein.
23
Role of HL and LPL in HDL Metabolism
Endothelium
B
C-II
TG
LPL
B
CM/VLDL
A-I
Phospholipids and apolipoproteins
CMR/IDL
PL
CE TG
A-I
HDL2
HL
PL
CE
Kidney
HDL3
CM, chylomicron CMR, chylomicron remnant HDL,
high-density lipoprotein HL, hepatic lipase
IDL, intermediate-density lipoprotein LPL,
lipoprotein lipase PL, phospholipase.
24
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25
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

26
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

27
HDL Metabolism in LCAT Deficiency
A-I
Nascent HDL
A-I
CE
LCAT
FC
FC
ABC1
Macrophage
Rapid catabolism
28
HDL Metabolism in Tangier Disease
Nascent HDL
A-I
A-I
CE
LCAT
FC
FC
ABC1
Macrophage
Rapid catabolism
29
Tangiers Disease

• Orange Tonsils
• Hepatomegaly
• Neuropathy
• Low or absent HDL-C

30
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

31
Secondary Causes of Low HDL-C

• Smoking
• Obesity (visceral fat)
• Very-low-fat diet
• Hypertriglyceridemia
• Drugs
• Beta blockers
• Androgenic steroids
• Androgenic progestins

32
Primary (Genetic) Causes of High HDL-C

• CETP
• CETP deficiency
• HL
• HL deficiency
• Unknown genetic etiology
• Familial hyperalphalipoproteinemia

33
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

34
HDL Metabolism in CETP Deficiency
HDL
Delayed catabolism
A-I
A-I
LCAT
CE
FC
FC
CE
ABC1
Nascent HDL
Macrophage
CETP
B
VLDL/LDL
35
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

36
Secondary Causes of Increased HDL-C

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

37
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

38
TREATMENT OPTIONS
39
Drug Effects on HDL Niacin
B
C-II
TG
NIACIN
LPL
CM/VLDL
Intestine
B
LDLR
CMR/IDL
NIACIN
A-I
A-I

CE
LCAT
FC
FC
CE
ABC1
Liver
Nascent HDL
HL
Macrophage
Mature HDL
Inhibits uptake of ApoA-I but not CE. .
Arterioscler Thromb Vasc Biol. 19991910511059
40
Side Effects of RR Niacin

• Flushing, itching
• Hepatitis
• Glucose intolerance
• Gout
• Peptic ulcer activation

RR, rapid-release.
41
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.
42
Drug Effects on HDL Fibrates
B
FIBRATES
C-II
TG
LPL
CM/VLDL
B
Intestine
LDLR
CMR/IDL
A-I
FIBRATES
A-I
LCAT
FC
CE
ABC1
Liver
Nascent HDL
HL
Mature HDL
Fenofibrate Clofibrate, Gemfibrozil
43
Drug Effects on HDL Statins
B
C-II
TG
LPL
CM/VLDL
B
Intestine
LDLR
STATINS
CMR/IDL
A-I
A-I
STATINS
LCAT
FC
CE
ABC1
Liver
Nascent HDL
?
HL
Mature HDL
STATINS
44
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.
45

• Novel HDL Raising Therapies
• ABCAI activators
• PPAR-alpha agonists
• Apo AI gene therapy
• CETP inhibitors
• Apo AI mimetics

46
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

47
Peroxisome Proliferator Activated Receptors
PPARa
RXR
PPARg
RXR
Primary Tissue Liver, muscle Adipose, muscle
Ligands Fatty acids Fibrates Fatty acids TZDs
Function Lipid metabolism (fat burning) Lipid metabolism Glucose homeostasis (fat storage)
Function Regulation of genes involved in lipid metabolism Regulation of genes involved in lipid metabolism
RXR, retinoid X receptor TZDs,
thiazolidinediones.
48
Effects of PPAR-a 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

49
CETP A Potential Therapeutic Target for
thePrevention of Cardiovascular Disease
Role of CETP in Lipoprotein Metabolism
50
CETP

• Lowers HDL-C
• Increases LDL-C
• Small dense LDL

Pharmacologic inhibition of CETP increases HDL-C
and lowers LDL-C
51
CETP
Apo E
VLDL
or Chylomicron Remnant
Cholesteryl Ester
Apo B
CETP
Apo AI
TG
HDL
52
Age-Adjusted 6-Year CHD/CVD Rates for Elderly
Japanese American Men With/Without CETP Mutations
CETP Mutation
18 15 12 9 6 3 0
absent present
171/1713
5/76
31/509
CHD Incidence (rate/1000 person-years)
2/42
HDL-C lt60 mg/dL
HDL-C ?60 mg/dL
Number of CHD events/men at risk. Significantly
lower risk compared to men with HDL-C lt60 mg/dL
and without a CETP mutation (P lt 0.05).
Curb JD et al. J Lipid Res. 200445948-953.
53
Torcetrapib Mechanism of Action Summary

• Enhances CETPs affinity for lipoproteins
• Does not block lipid binding to CETP
• Binds to CETP with 11 stoichiometry
• Creates a CETP/lipoprotein complex that inhibits
  lipid transfer
• Blocks CETPs 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

54
Torcetrapib Dose-Dependent CETP Inhibition, HDL
Raising and LDL Lowering in Healthy Individuals
Lipid Profile During Treatment with Torcetrapib
vs Placebo for 14 days





P lt 0.05, P lt 0.01, P lt 0.001.
Adapted from Clark RW et al. Arterioscler Thromb
Vasc Biol. 2004 24490-497.
55
ETC-588m LUV (large Unilamellar Vessicles)
Enhancer of Reverse Lipid Transport

• 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

56
ETC-588 LUV
Mechanism of Action
Atherosclerotic lesion
57
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

58
Effect of Recombinant Apo A-IMilano on Coronary
Atherosclerosis in Patients with Acute Coronary
Syndrome

• 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 122, 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 lt 0.001).

Nissen SE et al. JAMA. 200329022922300.
59
Effect of Recombinant Apo A-IMilano (ETC-216) on
Change in Percent Atheroma Volume
Mean
Median
Change from Baseline,
0.14
0.03
0.34
0.73
0.81
1.06
1.14
1.29
Placebo
15 mg/kg
45 mg/kg
Combined
P 0.03.
P 0.02 (1 end point).
Nissen SE et al. JAMA. 200329022922300.
60
How Much of the Atheroma Volume Can Be
Mobilized?
Small changes in percent atheroma volume (-1.06)
may translate into large changes in the plaque
lipid content
Necrotic Core (1525)
CholesterolClefts (510)
Potential for Lipid Mobilization
Macrophage (1020)
Modified from Virmani R et al. Arterioscler
Thromb Vasc Biol. 2000 201262-1275.
61
Before Any Journey

• Its Good To Know Where Youre Going Or What Your
  Goals Are

62
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

63
Treatment

• Meet LDL-C goals 1st
• If LDL-C goal is met but TG gt 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

64
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 gt
  Atorvastatin)

A,B,C J Am Coll Ardiol 200035640 D Am
J Cardiol 200086221
65
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

66
Good news, Mr. Dewlap. While your cholesterol
has remained the same, the research findings have
changed.
67
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).
68
Interventional Cardiologist
69
Lipid free
INTERVENTIONAL LIPIDOLOGIST WWW.LIPID.ORG
70
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71
VA-HIT trial

• 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 mg/dL or 1.0 mmol/L), and
  triglycerides 300 mg/dL (3.4 mmol/L)
• the patients were randomly assigned to treatment
  with gemfibrozil or placebo 78.
• At one year, the following differences were
  noted in the gemfibrozil group
• The mean HDL-cholesterol level was 6 percent
  higher (34 versus 32 mg/dL for placebo 0.9
  versus 0.8 mmol/L)
• The mean total cholesterol was 4 percent lower
  (170 versus 177 mg/dL 4.4 versus 4.6 mmol/L)
• The mean triglyceride concentration was 31
  percent lower (115 versus 166 mg/dL 1.3 versus
  1.6 mmol/L)
• At five years, the combined primary end point of
  cardiac death and nonfatal myocardial infarction
  occurred less often in the gemfibrozil treated
  group (17.3 versus 21.7 percent for placebo).
• The reduction in nonfatal myocardial infarction
  and CHD death was strongly correlated with the
  serum HDL-cholesterol concentration achieved with
  gemfibrozil therapy, but was independent of
  changes in LDL-cholesterol or triglycerides.
•  

72
Muscle Complaints with Statins

• Myalgia with/without CK elevations
• Asymptomatic CK elevations lt10 X NL
• Myositis CK gt10 X NL exercise?
• Rhabdomyolysis /- renal dysfunction
• Persistent myalgia after stopping drug

CK, creatine kinase NL, normal.
73
Management of Statin-Related Muscle Complaints
Prevention

• Lowest statin dose possible except ACS and CAD
• Avoid concomitant therapy with gemfibrozil
• Warn patientsmuscle pain, weakness, urine
  discoloration
• Dont ignore complaints
• Discontinue statins presurgery extreme
  exertion?????

ACS, acute coronary syndrome.
74
Liver Dysfunction

• Occurs often in 1st 3 months of treatment
• Look for other causes
• Ignore GGTP values alone
• More often with high TG and fatty liver????
• Continue drug unless LFTs gt 23 X NL or symptoms

GGTP, gamma-glutamyl transpeptidase.