Transcript Primary hyperlipidemias

Dr Shreetal Rajan , Senior Resident,
Cardiology,MCH,Calicut
Primary hyperlipidemias
 Classification of hyperlipidemias
 Overview on lipid metabolism
 Primary hyperlipidemias
 Management
Terminology
Hyperlipidemia
Dyslipidemia
 Concentration of lipid in
 Dyslipidemia –
the blood exceeds the
upper range of normal in a
12 hr fasting blood sample
 Includes both
hypercholesterolemia and
hypertriglyceridemia
derangement in blood
lipid concentration or
composition
 Almost always due to
hyperlipidemia
 Dyslipidemia – major role
in atherosclerosis and CAD
Lipoprotein structure
 hydrophobic core
 triglyceride and/or
 cholesterol ester
 surface coat
 phospholipid monolayer
 interspersed free cholesterol
and apolipoproteins
The lipoprotein fractions
 Chylomicrons
 Very Low density
lipoproteins (VLDL)
 Intermediate density
Lipoproteins (IDL)
 Low density
Lipoproteins (LDL)
 High density
Lipoproteins (HDL)
Apolipoprotein classes
Lipoproteins – physiological functions
 absorption of
- dietary cholesterol
- long-chain fatty acids
- fat-soluble vitamins
 transport of
- triglycerides
- cholesterol
- fat-soluble vitamins
- from the liver to peripheral tissues
 transport of cholesterol
- from peripheral tissues to the liver
Apolipoproteins - functions
 proteins associated with lipoproteins.
 lipoprotein assembly and function.
 activate enzymes in lipoprotein metabolism.
 ligands for cell surface receptors.
The story of lipids – the normal
physiology
 Chylomicrons transport fats from the intestinal
mucosa to the liver
 In the liver, the chylomicrons release triglycerides
and some cholesterol and become low-density
lipoproteins (LDL).
 LDL then carries fat and cholesterol to the body’s
cells.
 High-density lipoproteins (HDL) carry fat and
cholesterol back to the liver for excretion.
Why study of lipoproteins and
apolipoproteins are important?
 Atherosclerosis and dyslipoproteinemias have a very
close association
 All the cardiovascular risk models advocate lipoprotein
studies in risk stratification and prognostication
 Recently, non – HDL fraction, apo B , ratio of apo B to
apo A 1, number and size of small, dense LDL particles
are all emerging as risk markers for CAD.
 Subendothelial retention of LDL -initiating factor for
atherosclerotic plaque formation
Attributable Risk Factors
for a First Myocardial Infarction
PAR (%)
INTERHEART Study
100
90
80
60
40
50
36
20
0
33
14
Smoking
12
Fruits/ Exercise
Veg
18
7
Alcohol
Hypertension
20
10
Diabetes Abdominal Psychoobesity
social
Lipids
All 9 risk
factors
Lifestyle factors
n=15,152 patients and 14,820 controls in 52 countries
MI=Myocardial infarction, PAR=Population
attributable risk (adjusted for all risk factors)
Source: Yusuf S et al. Lancet. 2004;364:937-952
Classification - hyperlipidemia
 Primary
 Secondary
defect in genes and /or enzymes involved in
lipoprotein metabolism
1st case report of Familial hypercholesterolemia
 In 1938 Carl Mu¨ller, a Norwegian clinician, described FH
as an “inborn error of metabolism” that produces high
blood cholesterol and myocardial infarctions (heart
attacks) in young people
Primary hyperlipidemia –
Fredrickson classification
Alternative classification
I . Primary
 Primary Disorders of Elevated ApoB -Containing
Lipoproteins
 Inherited Causes of Low Levels of ApoB -Containing
Lipoproteins
 Genetic Disorders of HDL Metabolism
 MiscellaneousElevated Plasma Levels of Lipoprotein(a)
Elevated small dense LDL particles
II . Secondary forms of hyperlipidemia
Primary Disorders of Elevated
Apo B -Containing Lipoproteins
 Lipid disorders
associated with elevated
LDL and normal
triglycerides
 Lipid disorders
associated with elevated
triglycerides
Lipid disorders associated with elevated LDL
and normal triglycerides
1.
2.
3.
4.
5.
6.
Familial Hypercholesterolemia (FH)
Familial Defective ApoB-100 (FDB)
Autosomal Dominant Hypercholesterolemia Due to
Mutations in Pcsk9 (ADH-Pcsk9 or ADH3)
Autosomal Recessive Hypercholesterolemia (ARH)
Sitosterolemia
Polygenic Hypercholesterolemia
Familial hypercholesterolemia
 Autosomal codominant
disorder
 Elevated plasma levels of
LDL-C
 Triglyceride level-normal
 Premature coronary
atherosclerosis
Pathophysiology
 Defect in LDL receptor
 Homozygous and
heterozygous
 Receptor negative : < 2%
LDL receptor activity
 Receptor defective: 225% receptor activity
Familial hypercholesterolemia
 tendon xanthomas –hands, wrists, elbows, knees, heels
or buttocks
 Total cholesterol levels > 500 mg/Dl
 Accelerated atherosclerosis – begins in aortic root and
extends into coronary ostia
 Receptor negative-untreated patients don’t survive
beyond 2nd decade
 Receptor defective- better prognosis
Familial Defective Apob-100 (FDB)
 Dominantly inherited disorder
 Elevated plasma LDL levels with normal triglycerides, tendon
xanthomas, increased incidence of premature ASCVD
 mutations in the LDL receptor–binding domain of apoB-100
LDL binds the receptor with reduced affinity -> removed from
the circulation at a reduced rate
 Clinically identical to heterozygous FH but have lower plasma
levels of LDL
Autosomal Dominant
Hypercholesterolemia - physiology
 AD disorder ; gain-of-function mutations in PCSK9
 PCSK9 is a secreted protein that binds to the LDL receptor
causing its degradation
 LDL is internalized along with the receptor after binding
 In the low pH of the endosome LDL dissociates from the
receptor and the receptor returns to the cell surface
 The LDL is delivered to the lysosome
Autosomal Dominant
Hypercholesterolemia- pathology
 When PCSK9 binds to the receptor, the complex is internalized
and the receptor is redirected to the lysosome rather than to the
cell surface
 The missense mutations enhance the activity of PCSK9
 The number of hepatic LDL receptors is reduced
 indistinguishable clinically from patients with FH
Autosomal Recessive
Hypercholesterolemia (ARH)
 LDL Receptor Adaptor Protein (LDLRAP) is involved in LDL
receptor–mediated endocytosis in the liver.
 In the absence of LDLRAP, lipoprotein-receptor complex fails to
be internalized
 Hypercholesterolemia, tendon xanthomas, premature CAD
 Hyperlipidemia responds partially to treatment with HMG-CoA
reductase inhibitors
 Usually require LDL apheresis to lower plasma LDL-C
Sitosterolemia
 Autosomal recessive disease
 severe hypercholesterolemia, tendon xanthomas, premature
ASCVD (Atherosclerotic CardioVascular Disease)
 mutations in either of two members of the ATP-binding cassette
(ABC) half transporter family, ABCG5 and ABCG8
 genes are expressed in enterocytes and hepatocytes
Sitosterolemia
 intestinal
absorption
sterols
increased
is
of
and
biliary excretion of the sterols
is reduced
 increased plasma and tissue
levels of both plant sterols
and cholesterol
 Dysmorphic red blood cells
and megathrombocytes
 hemolysis
distinctive
clinical feature of this disease
 respond
to reductions in
dietary cholesterol content
 do not respond to statins.
 Bile acid sequestrants and
cholesterol
absorption
inhibitors - effective
Polygenic Hypercholesterolemia
 Elevated LDL with a normal plasma level of triglyceride in the
absence of secondary causes of hypercholesterolemia
 Plasma LDL levels are generally not as elevated as they are in
other primary hypercholesterolemias
 Family studies to differentiate polygenic hypercholesterolemia
from single-gene disorders
Lipid Disorders Associated with
Elevated Triglycerides
1.
2.
3.
4.
5.
6.
7.
Familial Chylomicronemia Syndrome (Type I
Hyperlipoproteinemia; Lipoprotein Lipase and
ApoC-II Deficiency)
Familial Dysbetalipoproteinemia (Type III
Hyperlipoproteinemia)
Apo A-V Deficiency
GPIHBP1 Deficiency
Hepatic Lipase Deficiency
Familial Hypertriglyceridemia (FHTG)
Familial Combined Hyperlipidemia (FCHL)
Familial Chylomicronemia
Syndrome
 LPL (Lipoprotein Lipase) is required for the hydrolysis of
triglycerides in chylomicrons and VLDLs
 apoC-II is a cofactor for LPL
 Genetic deficiency or inactivity of LPL or apo C II results in
impaired lipolysis and elevations in plasma chylomicrons
 The fasting plasma is turbid
 Very high triglyceride levels
Familial Chylomicronemia
Syndrome
 Present in childhood with features suggestive of acute pancreatitis
 Lipemia retinalis
 Eruptive xanthomas
 Hepatosplenomegaly
 Premature CHD not a feature
Familial Chylomicronemia
Syndrome- diagnosis
 IV heparin injection - endothelial-bound LPL is released
 LPL activity is profoundly reduced in both LPL and apo C-II
deficiency
 normalizes after the addition of normal plasma (providing a
source of apoC-II)
Familial Chylomicronemia
Syndrome
 dietary fat restriction with fat-soluble vitamin supplementation
 medium-chain triglycerides
 Fish oils
 Fresh frozen plasma – source of apo C
 Plasmapheresis in pregnancy
HYPERTRIGLYCERIDEMIA
- OTHER CAUSES
APO A V DEFICIENCY
 Apo A-V required for the
association of VLDL and
chylomicrons with LPL
 Deficiency presents as
hyperchylomicronemia
GPIHBP1 Deficiency
 LPL is attached to a protein
on the endothelial surface of
capillaries called GPIHBP1
 mutations that interfere with
GPIHBP1 synthesis or folding
cause severe
hypertriglyceridemia
Hepatic Lipase Deficiency
 autosomal recessive disorder
 elevated plasma levels of cholesterol and triglycerides (mixed
hyperlipidemia) due to the accumulation of circulating lipoprotein
remnants
 association of this genetic defect with ASCVD is not clearly known
 Lipid-lowering therapy with statins along with other drugs
Familial Dysbetalipoproteinemia –
FDBL (Type III
Hyperlipoproteinemia)
 mixed hyperlipidemia; due to genetic variations in apoE
 Patients homozygous for the E2 allele (the E2/E2 genotype)
comprise the most common subset of patients with FDBL
 precipitating factors usually present
 hyperlipidemia,
xanthomas,
peripheral vascular disease
premature
coronary
disease,
Familial Dysbetalipoproteinemia
(Type III Hyperlipoproteinemia)
 The disease seldom presents in women before menopause
 Two distinctive types of xanthomas- tuberoeruptive and palmar
 Broad beta band on electrophoresis
 Premature CHD
 Dramatic response to weight reduction and dietary changes; statins
 Treatment of other metabolic conditions
Familial Hypertriglyceridemia
(FHTG)
 The diagnosis of FHTG is suggested by the triad of
 Elevated levels of plasma triglycerides (250–1000 mg/dL)
 Normal or only mildly increased cholesterol levels (<250 mg/dL)
 Reduced plasma levels of HDL-C
 Plasma LDL-C levels are generally not increased and are often
reduced due to defective metabolism of the triglyceride-rich
particles
Familial Hypertriglyceridemia
(FHTG)
 type IV and type V of
Fredrickson classification
 autosomal dominant disorder of
 secondary causes of
hypertriglyceridemia to be
ruled out
unknown etiology
 VLDL is elevated
 Precipitating factors
 not associated with increased risk
of ASCVD
 Monitor pancreatitis
Familial Combined Hyperlipidemia
(FCHL)
 autosomal dominant
 one of three phenotypes
 Elevated
plasma levels of
LDL-C
 Elevated
plasma levels of
triglycerides due to elevation
in VLDL
 Elevated
plasma levels of
both LDL-C and triglyceride
 classical feature of FCHL -
lipoprotein profile can switch
among
these
three
phenotypes in the same
individual over time
 Associated
with
metabolic risk factors
 Family
other
history
of
hyperlipidemia
and/or
premature CHD
Familial Combined Hyperlipidemia
(FCHL)
 significantly elevated plasma levels of apoB
(Hyperapobetalipoproteinemia)
 Increased small, dense LDL particles are characteristic of this
syndrome
 Overproduction of VLDL by liver – cause not known
Inherited Causes of Low Levels of
Apo B Containing Lipoproteins
Familial Hypobetalipoproteinemia (FHB)
 MOST COMMON INHERITED FORM OF
HYPOCHOLESTEROLEMIA
 low total cholesterol and LDL-C due to mutations in
apoB
 LDL levels < 80 mg%
 Protection from CHD
 Parents have abnormal lipid fractions
Pcsk9 Deficiency
 Loss of function mutations
 PCSK9 normally promotes the degradation of the LDL
receptor
 Absence cause increased activity of LDL receptor and
low LDL levels ( 40% reduction)
 Protection from CHD increases as plasma LDL levels
decrease
Abetalipoproteinemia
 autosomal recessive
disease
 loss-of-function
mutations in the gene
encoding microsomal
triglyceride transfer
protein (MTP)
 transfers lipids to nascent
chylomicrons and VLDLs
in the intestine and liver
 Parents have normal lipid
levels
 diarrhea and failure to
thrive
 Neurologic
manifestations
 Pigmented
retinopathydefective
absorption and transport
of fat soluble vitamins –
vitamin E
 low-fat, high-caloric,
vitamin-enriched diet
Genetic Disorders of HDL Metabolism
 Inherited causes of low levels of HDL-C
1.
2.
3.
4.

1.
2.
Gene Deletions in the Apo A V-AI-CIII-AIV Locus
and Coding Mutations in ApoA-I
Tangier Disease (ABCA1 Deficiency)
LCAT Deficiency
Primary Hypoalphalipoproteinemia
Inherited causes of high levels of HDL-C
CETP Deficiency
Familial Hyperalphalipoproteinemia
Gene Deletions in the ApoAV-AI-CIII-AIV
Locus and Coding Mutations in ApoA-I
 Absence of mature HDL
 Free cholesterol increase in HDL and in tissues
 corneal opacities and planar xanthomas
 Premature CHD
Tangier Disease (ABCA1
Deficiency)
 autosomal recessive
 ABCA1, a cellular transporter that facilitates efflux of
unesterified cholesterol and phospholipids from cells
to apoA-I
 extremely low circulating plasma levels of HDL-C (<5
mg/dL) and apoA-I (<5 mg/dL).
 hepatosplenomegaly , pathognomonic enlarged
grayish yellow or orange tonsils, mononeuritis
multiplex
 Premature CHD not so common – because LDL levels
also low
LCAT Deficiency
 Autosomal recessive
 defective formation of mature HDL
2 types – complete and partial
Progressive corneal opacification
Low levels of HDL
COMPLETE FORM – hemolytic anemia, progressive
renal insufficiency and ESRD
PREMATURE CHD not seen
Primary Hypoalphalipoproteinemia
(isolated low HDL Syndrome)
 defined as a plasma HDL-C level below the tenth
percentile in the setting of relatively normal
cholesterol and triglyceride level
 no apparent secondary causes of low plasma HDL-C
 no clinical signs of LCAT deficiency or Tangier
disease.
 Premature CHD not a consistent feature
Inherited causes of high levels
of HDL-C
CETP DEFICIENCY
 Loss-of-function mutations
 CETP facilitates transfer of cholesteryl esters from
HDL to apoB-containing lipoproteins
 CETP deficiency results in an increase in the
cholesteryl ester content of HDL,decreased clearance
of HDL and a reduction in plasma levels of LDL-C
 The relationship of CETP deficiency to ASCVD
remains unresolved
Inherited causes of high levels
of HDL-C
Hyperalphalipoproteinemia
 defined as a plasma HDL-C level above the ninetieth
percentile
 mutations in endothelial lipase
 Relation to reduced CHD risk and increased longevity
not consistent
Secondary forms of
lipoproteinemia
ManagementWhat are the
recommendations?
Checking lipids
 Nonfasting lipid panel

measures HDL and total cholesterol
 Fasting lipid panel


Measures HDL, total cholesterol and triglycerides
LDL cholesterol is calculated:

LDL cholesterol = total cholesterol – (HDL + triglycerides/5)
When to check lipid panel
 Two different Recommendations
 Adult Treatment Panel (ATP III) of the National Cholesterol
Education Program (NCEP)


Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile
consisting of total cholesterol, LDL, HDL and triglycerides
Repeat testing every 5 years for acceptable values
 United States Preventative Services Task Force



Women aged 45 years and older, and men ages 35 years and older undergo
screening with a total and HDL cholesterol every 5 years.
If total cholesterol > 200 or HDL <40, then a fasting panel should be obtained
Cholesterol screening should begin at 20 years in patients with a history of
multiple cardiovascular risk factors, diabetes, or family history of either
elevated cholesteral levels or premature cardiovascular disease.
Goals for Lipids
 LDL
 HDL
 < 100 →Optimal
 < 40 → Low
 100-129 → Near optimal
 ≥ 60 → High
 130-159 → Borderline
 160-189→ High
 ≥ 190 → Very High
 Total Cholesterol
 < 200 → Desirable
 200-239 → Borderline
 ≥240 → High
 Serum Triglycerides
 < 150 → normal
 150-199 → Borderline
 200-499 → High
 ≥ 500 → Very High
Determining Cholesterol Goal
 JNC 7 Risk Factors





Cigarette smoking
Hypertension (BP ≥140/90 or on anti-hypertensives)
Low HDL cholesterol (< 40 mg/dL)
Family History of premature coronary heart disease
(CHD) (CHD in first-degree male relative <55 or CHD in firstdegree female relative < 65)
Age (men ≥ 45, women ≥ 55)
ATP III LDL-C Goals and
Cut-points for Drug Therapy
Risk Category
Consider
Drug Therapy
LDL-C Goal
Initiate TLC
High risk:
CHD or CHD risk equivalents
(10-year risk >20%)
<100 mg/dL
(optional goal:
<70)
100 mg/dL
>100 mg/dL
(<100 mg/dL: consider
drug options)
Moderately high risk:
2+ risk factors*
(10-year risk 10% to 20%)
<130 mg/dL
(optional goal:
<100)
130 mg/dL
>130 mg/dL
(100-129 mg/dL: consider
drug options)
Moderate risk:
2+ risk factors*
(10 year risk <10%)
<130 mg/dL
130 mg/dL
>160 mg/dL
Lower risk:
0-1 risk factor*
<160 mg/dL
160 mg/dL
>190 mg/dL
(160-189 mg/dL: LDL-C
lowering drug optional)
*Risk factors for CHD include: cigarette smoking, hypertension (blood pressure >140/90 mmHg or on
antihypertensive medication, HDL-C <40 mg/dl (>60 mg/dl is a negative risk factor), family history of
premature CHD, age >45 years in men or >55 years in women
ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low
density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes
Source: Grundy S et al. Circulation 2004;110:227-239
ATP III Classification of Other Lipoprotein Levels
Total Cholesterol
Level (mg/dl)
Classification
HDL-Cholesterol
Level (mg/dl)
Classification
<200
Desirable
>40
Minimum goal*
200-239
Borderline High
40-50
Desired goal*
>240
High
>50
High
Triglyceride
Level (mg/dl)
Classification
<150
Normal
150-199
Borderline High
200-499
High
>500
Very High
*These goals apply to men. For women, the minimum goal is >50 mg/dL
HDL=High density lipoprotein
Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-2497
TREATMENT
 Lifestyle changes- diet, exercise and yoga
mediterranean diet
 Drugs
 New therapies
LDL apheresis, monoclonal antibodies,Apo A –I
mimetics
Drug therapies available
Class
Drug(s)
3-Hydroxy-3-Methylglutaryl Coenzyme A (HMGCoA) reductase inhibitors [Statins]
Atorvastatin
Fluvastatin
Lovastatin
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin
Bile acid sequestrants
Cholestyramine
Colesevelam
Colestipol
Cholesterol absorption inhibitor
Ezetimibe
Nicotinic acid
Niacin
Dietary Adjuncts
Soluble fiber
Soy protein
Stanol esters
Newer therapies
CETP inhibitors, APO A analogues, monoclonal
antibodies
Ezetimibe Evidence:
Efficacy at Reducing LDL-C
892 patients with primary hypercholesterolemia randomized to ezetimibe
(10 mg) or placebo for 12 weeks
LDL-C
HDL-C
Triglycerides
+5.7
+5
Mean % change from
baseline to week 12
0
+1.3
+0.4
–1.6
–5
–5.7
–10
Placebo
–15
–16.9*
Ezetimibe 10 mg
–20
*p<0.01 compared to placebo
HDL-C=High density lipoprotein cholesterol,
LDL-C=Low density lipoprotein cholesterol
Source: Dujovne CA et al. Am J Cardiol 2002;90:1092-1097
Bile Acid Sequestrant Evidence:
Primary Prevention
Lipid Research Clinics-Coronary Primary Prevention Trial
(LRC-CPPT)
3,806 men with primary hypercholesterolemia randomized to cholestyramine
(24 grams) or placebo for 7.4 years
19% RRR
Rate of MI or CHD
death (%)
9
8.6
7.0
6
3
0
P<0.05
Placebo
Cholestyramine
A bile acid sequestrant provides benefit in those with high cholesterol levels
CHD=Coronary heart disease, MI=Myocardial infarction,
RRR=Relative risk reduction
Source: The LRC-CPPT Investigators. JAMA 1984;251:351-364
CHD Risk According to HDL-C Level
Framingham Study
4.0
4.0
CHD risk ratio
3.0
2.0
2.0
1.0
1.0
0
65
25
45
HDL-C (mg/dL)
CHD=Coronary heart disease, HDLC=High-density lipoprotein cholesterol
Source: Kannel WB. Am J Cardiol 1983;52:9B–12B
Nicotinic Acid Evidence:
Secondary Prevention
HDL-Atherosclerosis Treatment Study (HATS)
160 men with CAD, low HDL-C, and normal LDL-C randomized to simvastatin (1020 mg) + niacin (1000 mg bid), simvastatin (10-20 mg) + niacin (1000 mg bid) +
antioxidants, antioxidants, or placebo for 3 years
*
**
**
Placebo (n=34)
Niacin/Simvastatin (n=33)
Placebo + Vitamins (n=39)
Niacin/Simvastatin + Vitamins (n=40)
A statin plus niacin provides benefit to men with CAD and low HDL-C levels
*Includes cardiovascular death, MI, stroke, or need for coronary revascularization
**p<0.01, but low absolute event rates
CAD=Coronary artery disease, HDL-C=High density lipoprotein
cholesterol, LDL-C=Low density lipoprotein cholesterol
Source: Brown BG et al. NEJM 2001;345:1583-1592
Nicotinic Acid Evidence:
Secondary Prevention
Atherothrombosis Intervention in Metabolic Syndrome with
Low HDL/High Triglycerides: Impact of Global Health
Outcomes (AIM-HIGH) Trial
Primary outcome (%)**
3414 patients with established CV disease randomized to niacin (up to 2000
mg/day) or placebo on a background of statin therapy for a mean of 3 years*
16.4%
20
Combination Therapy
Monotherapy
16.2%
10
HR 1.02, p=0.79
0
0
1
2
3
4
Time (years)
Niacin provides no benefit to those with CV disease and low HDL-C levels
*The study was stopped prematurely
**Composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for ACS,
or symptom-driven coronary/cerebral revascularization
CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol
Source: AIM-HIGH Investigators. NEJM 2011;365:2255-2267
Cholesterol Ester Transfer Protein Evidence:
Secondary Prevention
Investigation of Lipid Level Management to Understand its
Impact in Atherosclerotic Events (ILLUMINATE) Trial
P=0.001
9
6
3
6.2
5.0
All-cause
mortality (%)
Primary end point** (%)
15,067 patients at high CV risk randomized to torcetrapib (60 mg/day) plus
atorvastatin versus atorvastation alone for a median of 1.5 years*
3
0
Atorvastatin
Atorvastatin and
Torcetrapib
P=0.006
2
1.2
1
0
0.8
Atorvastatin
Atorvastatin and
Torcetrapib
The CETP inhibitor, torcetrapib, is associated with increased CV risk
*The trial was stopped prematurely
**Composite of death from coronary heart disease, nonfatal myocardial
infarction, stroke, or hospitalization for unstable angina
CETP=Cholesterol ester transfer protein, CV=Cardiovascular
Source: Barter PJ et al. NEJM 2007;357:2109-2122
Cholesterol Ester Transfer Protein Evidence:
Secondary Prevention
Dal-OUTCOMES Trial
15,871 patients with a recent ACS randomized to dalcetrapib (600 mg/day)
or placebo for a median of 2.6 years
Primary end point** (%)
P=0.52
9
8.3
8.0
6
3
0
Placebo
Dalcetrapib
The CETP inhibitor, dalcetrapib, is associated with no CV benefit
*The trial was stopped prematurely
**Composite of death from coronary heart disease, nonfatal myocardial infarction,
ischemic stroke, unstable angina, or cardiac arrest with resuscitation
ACS=Acute coronary syndrome, CETP=Cholesterol ester
transfer protein, CV=Cardiovascular
Source: Barter PJ et al. NEJM 2007;357:2109-2122
Fibrate Evidence:
Effect on Lipid Parameters
180 patients with type IIa or IIb hyperlipidemia randomized to fenofibrate
(100 mg three times daily) or placebo for 24 weeks
50
Type IIa hyperlipidemia
Type IIb hyperlipidemia
40
Mean % change from baseline
30
20
10
0
+11*
LDL
-30
-40
-50
TG
HDL
-10
-20
+15*
LDL
-6*
TG
HDL
-20*
-38*
-45*
*p<0.01
HDL=High density lipoprotein, LDL=Low density
lipoprotein, TG=Triglyceride
Source: Knopp RH et al. Am J Med 1987;83:50-9
Omega-3 Fatty Acids Evidence:
Primary and Secondary Prevention
Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS)
18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a
statin or a statin alone for 5 years
Years
Omega-3 fatty acids provide CV benefit, particularly in secondary prevention
*Composite of cardiac death, myocardial infarction, angina, PCI, or CABG
CV=Cardiovascular, EPA=Eicosapentaenoic acid
Source: Yokoyama M et al. Lancet 2007;369:1090-1098
Dietary Adjuncts Evidence:
Efficacy at Reducing LDL-C
Therapy
Dose (g/day)
Effect
Dietary soluble fiber
5-10 (psyllium)
 LDL-C 10-15%
Soy protein
20-30
 LDL-C 5-7%
Stanol esters
1.5-2
 LDL-C 15-20%
LDL-C=Low density lipoprotein cholesterol
Sources:
Kwiterovich Jr PO. Pediatrics 1995;96:1005-1009
Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214
Miettinen TA et al. Ann Med 2004;36:126-134
Effect of Pharmacotherapy
on Lipid Parameters
Therapy
TC
LDL-C
HDL-C
TG
Patient
tolerability
Statins*
- 19-37%
- 25-50%
+ 4-12%
- 14-29%
Good
- 13%
- 18%
+ 1%
- 9%
Good
Bile acid
sequestrants
- 7-10%
- 10-18%
+ 3%
Neutral or
Poor
Nicotinic acid
- 10-20%
- 10-20%
+ 14-35%
- 30-70%
Reasonable
to Poor
- 19%
- 4-21%
+ 11-13%
- 30%
Good
Ezetimibe
Fibrates
*Daily dose of 40mg of each drug, excluding rosuvastatin
HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein
cholesterol, TC=Total cholesterol, TG=Triglyceride
SUMMARY
 The role of lipoproteins
 Diet , exercise , yoga
increasing day by day
 Watch out for the
dyslipidemic triadincreased TG,
decreased HDL and
increase in small
dense LDL
 Primary
hyperlipidemias are
not so uncommon
- mediterranean
 Hypolipidemic agents
used according to the
lipid goal to be achieved
 Watch for adverse effects
 Newer treatments- LDL
apheresis/apo A
analogues
Editorial : A System for Phenotyping Hyperlipoproteinemia
DONALD S. FREDRICKSON and ROBERT S. LEES
CIRCULATION: 1965;31:321-327
Primary Hyperlipoproteinemias Caused
by Known Single Gene Mutations