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Hyperlipidemia
Yasar Kucukardali
Associated Professor
Yeditepe University
Department of Internel Medicine
Objectives

To learn correct management of
hyperlipidemia

Review NCEP ATP III Guidelines

Discuss laboratory monitoring
Relation between plasma cholesterol concentration and six-year coronary
heart disease risk in 361,662 men (ages 35 to 57) screened during the
MRFIT study.
There is a continuous, positive, graded correlation between the plasma
cholesterol concentration and coronary risk.
Data from Stamler, J, Wentworth, D, Neaton, JD, JAMA 1986; 256:2823.
http://www.youtube.com/watch?v=
Vlhgzrjn4Jc
Cholesterol
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Essential component of the cell membrane
Precursor molecule from which steroid
hormones, bile salts, and vitamin D are
synthesized
Derived from
the diet
synthesized within
the body,mainly in the liver.
Dietary sources of Cholesterol
Type of Fat
Main Source
Effect on
Cholesterol levels
Monounsaturated
Olives, olive oil, canola oil, peanut oil,
cashews, almonds, peanuts and most
other nuts; avocados
Lowers LDL, Raises
HDL
Polyunsaturated
Corn, soybean, safflower and cottonseed
oil; fish
Lowers LDL, Raises
HDL
Saturated
Whole milk, butter, cheese, and ice cream;
red meat; chocolate; coconuts, coconut
milk, coconut oil , egg yolks, chicken skin
Raises both LDL and
HDL
Trans
Most margarines; vegetable shortening;
partially hydrogenated vegetable oil; deepfried chips; many fast foods; most
commercial baked goods
Raises LDL

Cholesterol circulates as a component
of lipoproteins
The principal plasma lipoproteins
chylomicrons (CMs)
very low density lipoproteins (VLDL)
low-density lipoproteins (LDL)
high-density lipoproteins (HDL)

The principal fat in the diet is the
triglycerides (TG), which are absorbed
in the intestine

The lipoproteins are transported in
combination with apoproteins (apo), like
apo-A, apo-B, and apo-C
Apolipoproteins
Apolipoproteins are proteins that bind to fats
(lipids)
 Apolipoprotein synthesis in the intestine is
regulated principally by the fat content of the
diet.
 There are six major classes of apolipoproteins
and several sub-classes:
A (apo A-I, apo A-II, apo A-IV, and apo A-V)
B (apo B48 and apo B100)
C (apo C-I, apo C-II, apo C-III, and apo C-IV)
D
E
H

The story of lipids

Chylomicrons transport fats
from the intestinal mucosa to
the liver

In the liver, the chylomicrons
release triglycerides and some
cholesterol and become lowdensity 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.
The story of lipids (cont.)

When oxidized LDL cholesterol
gets high, atheroma formation in
the walls of arteries occurs,
which causes atherosclerosis.

HDL cholesterol is able to go and
remove cholesterol from the
atheroma.

Atherogenic cholesterol → LDL,
VLDL, IDL
Clasification
Hyperlipidemias are classified as primary or secondary
Primary hyperlipidemia have been classified into
5 major groups according to plasma lipoprotein patterns
Causes of Sec. Hyperlipidemia
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Diet
Hypothyroidism
Nephrotic syndrome
Anorexia nervosa
Obstructive liver disease
Obesity
Diabetes mellitus
Pregnancy
Acute hepatitis
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AIDS (protease inhibitors)
Pancreatitis
Hematopoietic diseases
(myeloma, Waldenstrom's
macroglobulinemia, cryoglobulinemia,
hemochromatosis
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Systemic lupus
erythematousus
drugs like estrogens,
corticosteroids, and retinoids
Genetic primary hyperlipidemias
Symptoms of Hyperlipidemia
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Hyperlipidemia usually has no noticeable
symptoms and tends to be discovered during
routine examination or evaluation for
atherosclerotic cardiovascular disease.
Deposits of cholesterol (known as xanthomas)
may form under the skin
Individuals with hypertriglyceridemia may
develop numerous pimple-like lesions across
their body. **
Extremely high levels of triglycerides may also
result in pancreatitis, a severe inflammation of
the pancreas that may be life-threatening.
Dermatologic Markers of Lipid Derangement
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Abnormalities of lipid metabolism may favor lipid
deposition in the skin and present as xanthomas
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Xanthelasma palpebrarum is the commonest type
of cutaneous xanthoma
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The major lipid stored in xanthomas is esterified
cholesterol
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However, only about half of the patients with
xanthelasma are hyperlipidemic

The most frequent hyperlipidemia associated with
xanthelasma is type IIa

Isolated xanthelasmata are often treated with
destructive modalities, like trichloroacetic acid,
electrocautery, surgical excision, carbon dioxide
laser, pulsed dye laser, and erbium:YAG laser
Disorders of lipid storage
Individuals with hypertriglyceridemia may
develop numerous pimple-like lesions across their body
NCEP Guidelines

The NCEP Adult Treatment
Panel (ATP) first published
guidelines for managing
hypercholesterolemia in 1988
(ATP I)
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Revised them in 1993 (ATP 2)
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The latest NCEP report (ATP
III) has been published in
2001.
managing hypercholesterolemia
The first step is to determine lipoprotein levels after a 9- to 12-hour fast
 Next, coronary heart disease (CHD) risk equivalents and major risk
factors should be established.
CHD risk equivalents include
clinical CHD
symptomatic carotid artery disease
peripheral arterial disease
abdominal aortic aneurysm
diabetes

Major risk factors (exclusive of LDL cholesterol)
cigarette smoking
hypertension
low HDL cholesterol (<40 mg/dL)
family history of premature CHD men<55years, women<65 years
age (men >45 years; women >55 years)

CHD risk equivalents and risk factors are then used to determine the
risk category of the patient

Coronary Equivalents

Risk Factors
Abdominal Aortic Aneurysm
Hypertension
Peripheral Artery Disease
HDL <40 mg/dl
(>60 mg/dl “negative” risk
factor)
Renal Artery Stenosis
Carotid Artery Stenosis
Cerebral Vascular Disease
Diabetes Mellitus
Family history of premature
CAD (male <55 female
<65)
Male >45, Women >55
Cigarette Smoking
Framingham Ten Year Risk
Men
Women
Framingham Ten Year Risk
0
Framingham Ten Year Risk
0
3
0
Non-Smoker
Framingham Ten Year Risk
0
3
0
1
HDL = 43
Framingham Ten Year Risk
0
3
0
1
0
4
SBP = 119, untreated
Framingham Ten Year Risk
0
3
0
1
0
4
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
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Two different Recommendations
 Adult Treatment Panel (ATP III) of the National
Cholesterol Education Program (NCEP)
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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
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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.
Screening may be appropriate in older people who have never
been screened, although screening a second or third time is less
important in older people because lipid levels are less likely to
increase after age 65.
Total cholesterol

A desirable total cholesterol level is usually
less than 200 mg/dL (5.17 mmol/L)
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A total cholesterol level of 200 to 239 mg/dL
is borderline high,
Value greater than or equal to 240 mg/dL is
high
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However, most decisions about treatment are
made based upon the level of LDL or HDL
cholesterol, rather than the level of total
cholesterol
HDL cholesterol

Elevated levels of HDL cholesterol actually
lower the risk of heart disease

A very high HDL (greater than or equal to 60
mg/dL ) is considered a negative risk factor
for CHD (removes one risk factor)

Treatment is sometimes recommended for
people with low levels of HDL cholesterol
(<40 mg/dL ), particularly if they already have
heart disease
Triglycerides
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High triglyceride levels are also associated
with an increased risk of CHD. Triglyceride
levels are divided as follows:
Normal - less than 150 mg/dL (1.69 mmol/L)
Borderline high - 150 to 199 mg/dL
High - 200 to 499 mg/dL
Very high - greater than 500 mg/dL
Triglycerides should be measured after
fasting for 12 to 14 hours.
NCEP/ATP III – 9 Steps
Step 1: Obtain, complete & fasting lipids.
 Interpret: LDL < 100mg/dl
optimal
LDL 100-129 near optimal
LDL 130-159 borderline high
LDL 160-189 high
LDL >190
very high
(mg/dl x 0.0259mmol/l = SI units)

NCEP/ATP III
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Step 2: Identify if patient has CAD or
equivalent (PAD, DM, AAA, Carotid)

Step 3: Risk factor assessment (HTN,
FHx, Tob, Age & Sex, HDL<40 or >60)

Step 4: If 2 or more risk factors; do
Framingham 10-yr risk assessment.
NCEP/ATP III – Step 5
NCEP/ATP III – Step 6
Therapeutic lifestyle changes (TLC)
TLC are considered first-line therapy in the
management of high cholesterol
 A 3-month trial of TLC should precede the
use of drug therapy
The essential features of TLC
(a) reduced intake of saturated fats [less than
7% of total calories] and cholesterol [less
than 200 mg/d]
(b) therapeutic options for enhancing LDL
lowering - such as plant stanols/sterols [2
g/d] and increased soluble fiber [10-25 g/d;
(c) weight reduction
(d) increased physical activity

According to ATP III, the most cost-effective
approach to prevention of CHD
diet modification
exercise
weight control
cessation of smoking
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Cigarette smoking, leads to elevated
triglycerides and low HDL levels
Smoking cessation should receive prime
emphasis in the clinical strategy to reduce
CHD risk.
While moderate intakes of alcohol in middleaged and older adults may reduce risk for
CHD, high intakes of alcohol produce
multiple adverse effects.
Persons who do not drink should not be
encouraged to initiate regular alcohol
consumption.
Physical activity as a component of TLC
includes enough moderate exercise to
expend at least 200 kcal per day.
Traditional foods and herbal therapies
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Dietary advice has a small but significant role to
play in normalizing abnormal serum lipids and
reductions 3% to 6% are to be expected
Replacement of saturated fats by unsaturated
fats
It is not clear whether polyunsaturated or
monounsaturated fats are most cardioprotective
Rapeseed oil, which is rich in omega-3 fats, is
especially useful
Soluble fiber (in oats, pectin, psyllium, guar gum)
results in a significant but very modest lipidlowering effect
Unrealistic (47g per day) intake of purified soy
protein will lower total cholesterol levels by about
0.6 mmol L
Stanol esters and plant sterols reduce cholesterol
in those on an average diet, but may lack efficacy
in those already on a low fat diet
NCEP/ATP III – Step 7

Add drug therapy simultaneously to TLC in
patients with CHD or equivalent. Add drugs after
3 months if TLC not effective in other risk
categories.
The NCEP recommends
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The use of statins as first-line therapy
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BASA's LDL-lowering effects may be enhanced
in combination with other cholesterol-lowering
medications, particularly statins.
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Nicotinic acid is recommended for high-risk
patients with low levels of LDL cholesterol, high
triglycerides, and low HDL cholesterol - a triad
known as atherogenic dyslipidemia.
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Fibrates are primarily used for persons with very
high triglycerides to reduce risk for acute
pancreatitis and for those with
dysbetalipoproteinemia.
Drug treatment/ Statins

The statins are competitive
inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
reductase, the rate-limiting
enzyme

Inhibition of HMG-CoA reductase
leads to a decrease in intrahepatic
cholesterol concentration ,leading
to an increase in receptormediated LDL catabolism.

Statins decrease serum
triglycerides.
Statin-induced increased LDLreceptor activity also leads to the
enhanced removal of the TG-rich
lipoproteins VLDL and IDL.
Similarly, increased activity of LDL
receptor leads to enhanced uptake
of CM remnants, thereby
increasing postprandial TG
clearance.
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Drug treatment/
Bile-acid sequestrating agents (BASA)
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BASA are anion exchange resins, BASA bind the bile acids, thus
impeding their reabsorption and significantly increasing their fecal
excretion.
In response, the liver steps up the synthesis of bile acids from
cholesterol. This leads to the depletion of intrahepatic cholesterol,
which causes increased expression of LDL receptors. Hepatic LDL
uptake is thereby raised, and the net result is a decrease in LDL.
BASA promote apo-A1 synthesis by an unknown mechanism and
tend to raise HDL levels.
Three BASA are currently available . Their use has been hindered
by inconvenient dosing and by unpleasant side effects (e.g.,
constipation).
BASA nonspecifically bind anions and interfere with absorption of
a number of drugs which are anionic at intestinal pH (statins,
fenofibrate, corticosteroids, diuretics, tricyclic antidepressants,
nonsteroidal anti-inflammatory drugs, thyroxine, and digoxin).
As BASA tend to raise triglycerides, they are contraindicated in
patients with hypertriglyceridemia (>400 mg/dL).
Drug treatment/ Nicotinic
acid (NA)
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Plasma FFA are immediate precursors of hepatic
and subsequently plasma triglycerides transported
in VLDL.
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NA is immediately taken up by adipose tissue via a
specific high-affinity G-protein-coupled receptor. It
then inhibits lipolysis in adipose tissue, resulting in
a decrease in plasma FFA
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NA, in a dose-dependent way, lowers triglyceriderich VLDL and cholesterol-rich LDL.
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NA is the most potent HDL-raising drug. But the
unpleasant side effect of flushing precludes many
patients from taking this drug.
Fibric acid
derivatives (fibrates)
Drug treatment
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The lipid-modifying effects of fibrates are largely mediated by
their ability to activate peroxisome proliferator-activated
receptors (PPARs).
PPARa controls a number of genes involved in lipid metabolism,
including those encoding for apo-CIII, apo-AI, and apo-AII.
Fibrates reduce triglycerides through PPARa-mediated reduced
expression of apo-CIII, which serves as an inhibitor of lipolytic
processing and receptor-mediated clearance. This leads to
increased LPL synthesis and enhanced clearance of
triglyceride-rich lipoproteins.
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Fibrate-mediated increases in HDL are due to PPARa
stimulation of apo-AI and apo-AII expression.
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Three fibric acid derivatives are currently available Fibrates are
primarily used for lowering elevated triglycerides because the
LDL cholesterol-lowering effects of fibrates are generally only
10% or less in persons with hypercholesterolemia.
Other therapeutic targets in lipid
metabolism
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Ezetimibe blocks uptake of cholesterol into jejunal
enterocytes, hence selectively blocking dietary and
biliary cholesterol absorption from the gut. It acts by
decreasing the intestinal cholesterol supply to the
liver, lowering hepatic cholesterol levels and thus
inducing LDL receptor expression. Unlike the bileacid sequestrants, it does not interfere with absorption
of fat-soluble drugs. Moreover, ezetimibe does not
increase serum TG.
Squalene synthase (SS) is the first enzyme in the
hepatic cholesterol biosynthetic pathway which
produces a metabolite (lanosterol) committed to
cholesterol synthesis. The result of inhibition of SS is
analogous to that of HMG-CoA reductase. Induction
of LDL receptors occurs, leading to a decrease in
circulating LDL. Thus SS inhibitors act similar to
statins, albeit at a different and a more specificlevel.
Lipid-lowering agents
Hypertriglyceridemia
DRUG
Gemfibrozil
Fenofibrate
Niacin
Statins
Bile Acid Resins
Ezetimibe
Expected % Decrease
40-60
30-50
10-50
3-37
0-increase
5-6
NCEP/ATP III – Step 8
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Identify Metabolic Syndrome:
(3 of 5)
SBP>130, FBS>110, TG>150,
HDL<40 in men and <50 in
Aggressively:
 Treat underlying causes of
overweight and physical
inactivity.
 Treat HTN, use ASA for CHD
patients
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NCEP/ATP III – Step 9
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Treat elevated TG (>150mg/dl)
First lower LDL; if TG still >200 consider
adding/increasing drug therapy
 But, if TG >500mg/dl, first lower triglycerides
to prevent pancreatitis. When they are <500
then return to LDL lowering
 Treat HDL <40 after lowering LDL.
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Thank you for your attention