Transcript Interpretation and Management of Abnormal Concentrations of High Density Lipoprotein-Cholesterol (HDL-C) Jorge Mera, MD Presbyterian Hospital of Dallas October 11, 2005

Interpretation and Management of
Abnormal Concentrations of High
Density Lipoprotein-Cholesterol
(HDL-C)
Jorge Mera, MD
Presbyterian Hospital of Dallas
October 11, 2005
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
Risk Factors for CHD

Modifiable
• Dyslipidemia
• Nonmodifiable
– Age

Raised LDL-C
– Sex

Raised TGs
– Family history of premature CHD

Low HDL-C
• Smoking
• Hypertension
• Diabetes mellitus
• Obesity
• Dietary factors
• Thrombogenic factors
• Sedentary lifestyle
Wood DJ et al. Atherosclerosis. 1998;140:199-270.
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
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 1992;19:792
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 < 125mg dL. (LIPID and CARE trials)
• Concentrations of HDL-C > 75 mg/dL are associated with
longevity 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
CHD Risk Ratio
4.0
3.0
2.0
2.0
1.0
1.0
0
25 45 65
HDL-C (mg/dL)
Kannel WB. Am J Cardiol. 1983;52:9B–12B.
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 (<40 mg/dL)*

Family history of premature CHD
• CHD in male first degree relative <55 years
• CHD in female first degree relative <65 years

Age (men 45 years; women 55 years)
60 mg/dL counts as a “negative” risk factor; its presence
removes 1 risk factor from the total count.
*HDL-C
HDL-C, high-density lipoprotein cholesterol.
HDL AS CAD RISK FACTOR
NCEP ATP III recognizes that
any serum HDL level < 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.
Framingham CHD Risk
Assessment in Men
Step 1: Age
Years
Points
20-34
-9
35-39
-4
40-44
0
45-49
3
50-54
6
55-59
8
60-64
10
65-69
11
70-74
12
75-79
13
Step 4: Systolic Blood Pressure
SBP
Points
mm Hg
Utreated
Treated
<120
0
0
120-129
0
1
130-139
1
2
140-159
1
2
>160
2
3
Step 5: Smoking Status
Nonsmoker
Smoker
20-39
0
8
Points at Age
40-49
50-59
60-69
0
0
0
5
3
1
Step 2: Total Cholesterol
TC
Points
(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
0
200-239
7
5
3
1
0
240-279
9
6
4
2
1
>280
11
8
5
3
1
Step 3: HDL-C
HDL-C
(mg/dL)
Points
>60
-1
50-59
0
40-49
1
<40
2
Step 6: Adding Up The Points
Category:
Points
Age
Total-C
HDL-C
SBP
Smoking status
Point Total:
70-79
0
1
Step 7: CHD Risk
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%
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.
Framingham CHD Risk
Assessment in Women
Step 1: Age
Years
Points
20-34
-7
35-39
-3
40-44
0
45-49
3
50-54
6
55-59
8
60-64
10
65-69
12
70-74
14
75-79
16
Step 4: Systolic Blood Pressure
SBP
Points
mm Hg
Utreated
Treated
<120
0
0
120-129
1
3
130-139
2
4
140-159
3
5
>160
4
6
Step 5: Smoking Status
20-39
0
9
Points at Age
40-49
50-59
60-69
0
0
0
7
4
2
Nonsmoker
Smoker
Step 2: Total Cholesterol
TC
Points
(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
1
200-239
8
6
4
2
1
240-279
11
8
5
3
2
>280
13
10
7
4
2
Step 3: HDL-C
HDL-C
(mg/dL)
Points
>60
-1
50-59
0
40-49
1
<40
2
Step 6: Adding Up The Points
Category:
Points
Age
Total-C
HDL-C
SBP
Smoking status
Point Total:
70-79
0
1
Step 7: CHD Risk
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%
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.
Oxidized Low-Density Lipoprotein:
A Potent Atherogen
Bloodstream
Endothelium
*
O2 Lipoxygenase
*
Scavenger
Receptor
Macrophage
Smooth Muscle Cells
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.
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
HDL3 inhibits
Sphingosine 1-P
Ceramide
Sphingosine
Sphingosine Kinase
HDL, high-density lipoprotein; MCP, monocyte chemotactic protein;
VCAM, vascular adhesion molecule.
Xia P et al. Biol Chem. 1999;274:33143-33147.
Metabolism of ApoA-Containing Lipoproteins
HL
HL
LPL
LPL
B
LDL 2
LPL
LDL 1
E
E
LDL 3
IDL
VLDL
B
Chol
E
CETP
VLDL
Liver
LDLr
Chol
Chol
Chol
B
CETP
Oxidation
LDL 5
TG
CD36
TG
SR-BI
Macrophage
A-I
A-I
LCAT
LCAT
Degradation
Adapted from B Brewer.
B
LDL 4
HDL 2
HDL 3
A-I
Nascent
HDL
A-I
Chol
SR-A
Cholesterol
Pool
ABCA1
Arterial Wall
Non-HDL-C
HL
HL
LPL
LPL
B
LPL
LDL 1
E
E
LDL 3
IDL
VLDL
B
Chol
E
CETP
VLDL
Liver
LDLr
Chol
Chol
Chol
B
CETP
Oxidation
LDL 5
TG
CD36
TG
SR-BI
Macrophage
A-I
A-I
LCAT
LCAT
Degradation
Adapted from B Brewer.
B
LDL 4
HDL 2
HDL 3
A-I
Nascent
HDL
A-I
Chol
SR-A
Cholesterol
Pool
ABCA1
Arterial Wall
Reverse Cholesterol Transport
Tóth PP. Am J Cardiol. 2005. In press.
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.
Production of HDL-C by Liver and
Intestine
Liver
Intestine
A-I
A-I
A-II
HDL
HDL
HDL Metabolism and
Reverse Cholesterol Transport
Bile
A-I
FC
CE
SR-BI
Liver
CE
Mature
HDL
A-I
LCAT
CE
FC
ABC1
Nascent
Macrophage
HDL
FC
ABC1, ATP-binding cassette protein 1; FC, free cholesterol; LCAT, lecithin-cholesterol
acyltransferase; SR-BI, scavenger receptor class BI.
Role of CETP in HDL Metabolism
Bile
FC
Mature HDL
A-I
CE
SR-BI
Liver
LDLR
CE
Nascent HDL
A-I
LCAT
CETP
CE
FC
Macrophage
FC
ABC1
SRA
B
VLDL/LDL
CETP, cholesteryl ester transfer protein; LDL, low-density lipoprotein; LDLR, lowdensity lipoprotein receptor; VLDL, very-low-density lipoprotein.
CE
Role of HL and LPL in HDL Metabolism
Endothelium
B
TG
LPL
B
CMR/IDL
CM/VLDL
A-I
PL CE
A-I
TG
HL
C-II
HDL2
PL
CE
HDL3
Kidney
CM, chylomicron; CMR, chylomicron remnant; HDL, high-density lipoprotein; HL, hepatic
lipase; IDL, intermediate-density lipoprotein; LPL, lipoprotein lipase; PL, phospholipase.
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
Nascent HDL
A-I
LCAT
FC
ABC1
FC
CE
Macrophage
Rapid
catabolism
HDL Metabolism in Tangier Disease
A-I
Nascent HDL
A-I
LCAT
FC
Rapid
catabolism
FC
CE
ABC1
Macrophage
Tangiers Disease




Orange Tonsils
Hepatomegaly
Neuropathy
Low or absent
HDL-C
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
HDL
Delayed A-I
catabolism
CE
LCAT
CETP
B
VLDL/LDL
A-I
FC
Nascent
HDL
FC
ABC1
CE
Macrophage
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 Metabolism
Potential 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
B
TG
C-II
LPL
CM/VLDL
Intestine
B
LDLR
CMR/IDL
A-I
*
Liver
A-I
LCAT
CE
HL
Mature HDL
*Inhibits uptake of ApoA-I but not CE.
Arterioscler Thromb Vasc Biol. 1999;19:1051–1059
.
FC
Nascent
HDL
CE
ABC1
FC
Macrophage
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
B
TG
+
C-II
LPL
FIBRATES
CM/VLDL
B
Intestine
LDLR
+
A-I
FIBRATES
LCAT
Liver
CMR/IDL
CE
Mature HDL
HL
A-I
FC
Nascent
HDL
Fenofibrate Clofibrate, Gemfibrozil
CE
ABC1
FC
Macrophage
Drug Effects on HDL: Statins
B
C-II
LPL
TG
CM/VLDL
+
Intestine
B
LDLR
A-I
+
STATINS
STATINS
A-I
LCAT
Liver
CE
Mature HDL
HL
?
FC
Nascent
HDL
STATINS
CMR/IDL
CE
ABC1
FC
Macrophage
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
PPARa RXR
Primary
Tissue
PPARg RXR
Liver, muscle
Adipose, muscle
Fatty acids
Fatty acids
Fibrates
TZDs
Ligands
Lipid metabolism
Lipid metabolism
Function
(“fat burning”)
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 Disease
Role 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
Apo E
VLDL
or Chylomicron Remnant
Cholesteryl Ester
Apo AI
HDL
Apo B
CETP
TG
Age-Adjusted 6-Year CHD/CVD Rates for Elderly Japanese
CHD Incidence (rate/1000 person-years)
American Men With/Without CETP Mutations
18
CETP Mutation:
171/1713*
absent
present
15
12
5/76
9
31/509†
2/42
6
3
0
HDL-C <60 mg/dL
HDL-C 60 mg/dL
*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).
Curb JD et al. J Lipid Res. 2004;45:948953.
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
Torcetrapib: Dose-Dependent CETP Inhibition, HDL
Raising and LDL Lowering in Healthy Individuals
Lipid Profile During Treatment with Torcetrapib vs Placebo for 14 days
80
% Change
60
40
HDL-C
LDL-C
TG
‡
‡
‡
20
†
0
*
-20
-40
0
10
30
60
Torcetrapib (mg)
*P < 0.05, †P < 0.01, ‡ P < 0.001.
Adapted from Clark RW et al. Arterioscler Thromb Vasc Biol. 2004; 24:490-497.
120
ETC-588:m 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
ETC-588: LUV
Mechanism of Action
Unesterified cholesterol =
Liver
HDL
Cholesterol-poor
ETC-588
Cholesterol-enriched
ETC-588
Atherosclerotic lesion
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
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 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).
Nissen SE et al. JAMA. 2003;290:2292–2300.
Effect of Recombinant Apo A-IMilano (ETC-216) on Change
in Percent Atheroma Volume
Mean
0.4
0.2
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
Median
0.14
0.03
–0.34
–0.73
–0.81
†
–1.29
–1.06
Placebo
15
*P = 0.03. mg/kg
Nissen SE et al. JAMA. 2003;290:2292–2300.
–1.14
*
45
Combine
mg/kg
†P =
0.02 (1° endd point).
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
(15%–25%)
Potential
for Lipid
Mobilization
Cholesterol
Clefts
(5%–10%)
Macrophage
(10%–20%)
Modified from Virmani R et al. Arterioscler Thromb Vasc Biol. 2000; 20:1262-1275.
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 meet
Non 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 has
remained 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 Cardiologist
Lipid free
INTERVENTIONAL
LIPIDOLOGIST
WWW.LIPID.ORG
VA-HIT trial
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The VA-HIT trial included 2531 with CHD who had an LDLcholesterol ( 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:
•
•
•
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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].
Muscle Complaints with Statins

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
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Myalgia with/without CK elevations
Asymptomatic CK elevations <10 X NL
Myositis: CK >10 X NL – exercise?
Rhabdomyolysis +/- renal dysfunction
Persistent myalgia after stopping drug
CK, creatine kinase; NL, normal.
Management of Statin-Related
Muscle Complaints: Prevention
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Lowest statin dose possible except ACS
and CAD
Avoid concomitant therapy with
gemfibrozil
Warn patients—muscle pain, weakness,
urine discoloration
Don’t ignore complaints
Discontinue statins presurgery +
ACS, acute coronary syndrome.
extreme
exertion?????
Liver Dysfunction
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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 > 2–3 X
NL or symptoms
GGTP, gamma-glutamyl transpeptidase.