Cholesterol

CHOLESTEROL IS A LIPID, OR FAT-LIKE SUBSTANCE,
made by animal cells. The role of an elevated blood
cholesterol in causing a blockage to arteries by atherosclerosis
and a subsequent myocardial infarction was a
controversial issue from 1900 to 1994. Advice to patients
during those 90 years was often half-hearted. Until recently
we were not able to put the blame firmly on cholesterol
and convince physicians and patients worldwide to
aggressively lower serum cholesterol levels. The key piece
of scientific evidence proving that lowering elevated blood
cholesterol in humans prevents fatal or nonfatal heart
attacks was missing.

I. THE MAGNITUDE OF THE PROBLEM
If cholesterol is the major cause of atheroma that obstructs
the flow of blood in arteries of the heart and brain,
significant morbidity and mortality from cardiovascular
disease would be prevented by the aggressive lowering of
total serum cholesterol and low-density lipoprotein (LDL)
cholesterol. The complete occlusion of a coronary artery or
cerebral artery is virtually always caused by a combination
of atheromatous obstruction of the artery and subsequent
rupture of the plaque of atheroma with thrombus
formation on the ruptured material. Thus, the term
atherothrombosis (see the chapter, Atherosclerosis/Atherothrombosis).
Atherothrombotic cardiovascular disease causes more
than 14 million deaths per year worldwide in a population
of about 6 billion people. This is expected to increase to
more than 25 million deaths by the year 2020 in a
population of about 7.4 billion people. It is estimated
that worldwide interventions could prevent more than
one million deaths annually. The prevention of atheroma
is obviously more important to world health than
the expensive production of so-called left ventricular assist
devices, which are a bridge to heart transplantation.

CAUSES OF HYPERCHOLESTEROLEMIA
A. Familial Hypercholesterolemia
This is a primary genetic abnormality. In very rare cases,
marked elevation of cholesterol (800–1500 mg/dl) is caused
by a genetic defect. A receptor on the surface of cells (LDL
receptors) removes LDL cholesterol from the blood. In
this disorder there is decreased production or function of
the LDL receptor. This autosomal disorder may involve
abnormalities in the synthesis, transport, or clustering of
the LDL receptor.

Homozygous familial hypercholesterolemia fortunately
is rare and occurs in approximately one per million
individuals in the United States. These patients have no
functioning LDL receptors and have markedly elevated
LDL cholesterol as high as 1200 mg/dl (31 mmol/L)
and extensive coronary and peripheral atherosclerosis.
Acute MI may occur within the first one to two years of
childhood.

Heterozygotes have a reduction of 50% of the circulating
LDL receptors and may have serum cholesterol
levels in the range of 300–800 mg/dl and manifest coronary
artery atherothrombosis, peripheral vascular disease,
or atheromatous obstruction to the abdominal aorta in
the third or fourth decade. Racial differences may determine
the number of LDL receptors, and thus the ability
to remove LDL cholesterol gradually from the bloodstream
is affected.

Familial combined hyperlipidemia is a common condition
that occurs in more than 1% of the North American
population. This disorder may cause elevation of total
cholesterol or triglycerides or both.

B. Polygenic Hypercholesterolemia
In this condition there is a genetic predisposition and
dietary factors. In susceptible individuals with a decreased
number of LDL receptors, high saturated fat and
cholesterol intake causes substantial elevation of serum
cholesterol with levels in range of 260–320 mg/dl
(6.5–8.3 mmol/L). Approximately 3% of the population
in the United States appears to be affected. Although
elevation in total cholesterol is less severe than in heterozygous
familial hypercholesterolemia, the elevation of total
and LDL cholesterol increases risk for coronary artery
disease and drug therapy with statins is advisable.
C. Other Causes for Hypercholesterolemia
Type 2 diabetes occurs in approximately 7% of the North
American population and nearly all of these individuals
have some form of dyslipidemia. Their serum cholesterol is
usually in the range of 240–290 mg/dl (6.2–7.5 mmol/L).
Hypothyroidism is a relatively common condition that
decreases the metabolism with increases in serum cholesterol
in the range of 240–320 mg/dl.

Renal disease can also affect cholesterol levels. A form of
glomerulonephritis causes marked loss of protein in the
urine, diffuse edema, and hypercholesterolemia. Biliary
cirrhosis with its prolonged obstructive jaundice causes
marked elevation in serum cholesterol. Other causes include
pancreatitis, monoclonal gammopathy, and porphyria.

IV. TYPES OF CHOLESTEROL
Cholesterol is a member of a class of naturally occurring
compounds called sterols. It is an essential part of the
fatty sheath that insulates nerves and the outer membrane
of all animal cells, and is a component of chemicals that
include steroids (cortisone) and sex hormones such as
androgens and estrogens. Cholesterol acts as a precursor
of bile acids and occurs in high concentrations in the
brain, nerves, and adrenal glands; cholesterol concentration
is greater than 3 g per 100 g in the brain. Body cells
satisfy their cholesterol requirements for maintenance
and growth by intracellular synthesis of cholesterol and
the receptor-mediated uptake from the external medium
of cholesterol-rich LDL particles.

Dietary cholesterol is absorbed from the jejunum in
an unesterified form. Within the small intestine cholesterol
is esterified with fatty acids and incorporated into the
triglyceride core of chylomicrons that are secreted into
the intestinal lymphatics and reach the blood circulation.
Within the bloodstream chylomicrons are converted
into remnant particles through the action of lipoprotein
lipase. Triglycerides are liberated and virtually all the cholesterol
particles are carried to the liver via the portal vein.
Less than half the cholesterol in the diet is absorbed. It is
interesting that after many years intensive drug research,
ezetimibe, the newest agent, has been shown to localize in
the distal and at the brush border cells of the small intestine
and inhibit cholesterol absorption. This drug is,
therefore, an important addition to our therapeutic armamentarium
because it can be combined safety with the
powerful acting statins that interfere with the manufacture
of cholesterol in the liver.

The human body and contains approximately 1 g of
cholesterol per kilogram body weight. About 1 g of cholesterol
is lost from the body by the conversion to bile
acids and steroid hormones. This loss is balanced by endogenous
synthesis from saturated fats and fecal excretion of
unabsorbed dietary cholesterol.

Some of the cholesterol in blood is derived from the
food you eat, but the major part, greater than 70%, is
manufactured in the liver, mainly from saturated fats.
Thus, if we had no cholesterol in the diet, the liver would
manufacture more cholesterol to compensate. Some excess
cholesterol is excreted in the bile. Cholesterol is present
only in foods of animal origin, in particular, eggs, milk,
butter, cheese and meats, and a very high concentration
is present in gland meats, such as liver, brain, kidney,
heart, and sweetbreads. Plant-based foods such as potatoes,
wheat, rice, vegetables, fruits, grains, and beans contain no
cholesterol.

In order to understand the changes that may be required
in your diet, it is important to learn the difference
between the types of cholesterol: total cholesterol, LDL
cholesterol, and HDL cholesterol. Individuals should
become familiar with the different types of fats in foods
such as triglycerides, saturated fats, monounsaturated fats,
and polyunsaturated fats.

A. Total Cholesterol
Cholesterol is a fat (lipid) that is insoluble in water. It is
absorbed by the intestine or released from the liver into
the bloodstream. Cholesterol does not circulate freely in
solution but is attached to a protein carrier, forming a
molecule called a lipoprotein. Lipoproteins vary in size
and density; the smaller the size, the higher the density.
Cholesterol may be transported in a low-density lipoprotein;
thus the term ‘‘low-density lipoprotein (LDL) cholesterol.’’
There is also a high-density lipoprotein (HDL)
cholesterol (see the chapter Dyslipidemia).

When a doctor states that your cholesterol is 250 mg
(6.5 mmol), he is giving you the total amount of cholesterol
in your blood, which includes LDL and HDL
cholesterol. The total figure is not broken down unless
specifically requested by the doctor. The values given in
milligrams are the amount in each 100 ml of blood or
number of millimoles in one liter of blood.

B. Low-Density Lipoprotein (Bad) Cholesterol
The low-density lipoprotein is small and contains most of
the cholesterol that is transported to cells. About 75%
of the blood cholesterol is carried as LDL cholesterol.
The LDL cholesterol particle is the one responsible for
atheroma formation and progression. The higher the level
of LDL cholesterol in the blood, the greater the risk of
coronary heart disease; thus the term ‘‘bad’’ cholesterol.
Oxidation of LDL cholesterol is believed to be an
important process in the formation and progression of
atheroma. It appears that oxidative modification of LDL
causes an increase in foam cell formation and increased
rates of LDL accumulation within developing atheromatous
plaques. In addition, oxidized LDL appears to have
direct cytotoxic effects on the endothelium of arteries at
the site of injury.

Oxidative stress causes oxidation of LDL cholesterol.
Oxidative stress results from the production of reactive
oxygen species, superoxide anion, and hydrogen peroxide
molecules that cause oxidative damage and trigger intracellular
signaling cascades. The constituents of the atheroma
plaque produce and use reactive oxygen species. LDL
cholesterol reduction appears to reduce the production of
deleterious reactive oxygen species.

This author believes that it is unlikely that LDL particles
cause direct injury to normal healthy endothelium,
because the same blood level of LDL cholesterol is present
in veins that virtually never develop atheroma except
when they are exposed to high blood pressure, such as in
severe pulmonary hypertension. It is more likely that shear
stress caused by turbulence of blood at particular focal
points in arteries, particularly at branching areas, and
other factors cause endothelial injury; LDL particles then
just partake in the orchestration of accelerated atheromatous
plaque growth. Increased blood pressure appears
to promote atherogenesis through the mechanical effects
of pulsatile blood flow (see the chapter Atherosclerosis/
Atheroma).

A plasma level of LDL cholesterol greater than
160 mg/dl is associated with a high risk for coronary
artery disease events in susceptible individuals and levels
less than 100 mg/dl confer a low risk. When an individual
is documented as having very-high-risk LDL cholesterol
levels (>200 mg/dl) associated with premature coronary
artery disease, all available first-degree relatives should be
tested.

C. High-Density Lipoprotein (Good)
Cholesterol
Much interest has been focused on HDL cholesterol,
so-called because it is very small in size and very high in
density. HDL cholesterol is believed to carry cholesterol
away from body cells such as the lining of arteries helping
to keep the artery wall clean; thus the term ‘‘good’’
cholesterol.

As discussed earlier most heart attacks occur in individuals
with total cholesterol levels between 210 and 240
mg/dl (5.5 and 6.2 mmol/L), and more than 50% of adult
Americans have cholesterol levels in this range. In these
individuals with borderline high blood cholesterol, a low
level of HDL cholesterol further increases the risk for
coronary artery disease. Figure 1 shows the incidence of
coronary heart disease in four years by HDL cholesterol
and total plasma cholesterol level for men and women
older than 49 and free of cardiovascular disease.

The HDL system comprises a variety of small lipoproteins
smaller than LDL, but both HDL and LDL
particles contain mostly cholesteryl ester. Virtually all HDL
particles contain apoA-1 as their major apolipoprotein and
the particles vary a little in size; the largest particles is HDL
2 and the predominant smaller particle HDL 3.

1. Metabolism
The many steps involved in HDL metabolism are not
fully understood. Small HDL 3 particles accumulate cholesteryl
ester and expand to HDL 2; an important step is
further transformation by interaction with cholesteryl ester
transfer protein (CETP). At each step of the HDL metabolic
cycle some apoA-1 is lost. High levels of CETP turn
up the cycle at a high rate and this diminishes the total
pool size of HDL that is manifested as a lowered HDL
cholesterol level.

It appears that CETP is an important enzyme involved
in HDL biology. Inhibiting this key enzyme that modulates
HDL can raise HDL levels. Vaccines and cardioactive
agents that may increase HDL levels significantly are being
investigated, and there is great hope that major increases in
HDL cholesterol would cause significant protection from
atherothrombosis and its serious impact on morbidity and
mortality worldwide.

2. Effect on Atherosclerosis
Several epidemiologic studies indicate an inverse relationship
between HDL cholesterol levels and risk for coronary
artery disease (see Fig. 1). A low HDL cholesterol level
greater than 35 mg/dl (0.9 mmol/L) has been designated as
a major risk factor for coronary artery disease. It is stated
that every 1% increase in HDL cholesterol decreases coronary
artery disease risk by about 2%, and each 1% reduction
in total cholesterol should produce a 2% reduction in
coronary artery disease risk. In Finland where HDL blood
cholesterol levels are among the highest in the world, the
cardiovascular death rate is the highest of all European
countries (see the chapter Heart Attacks).

Some scientists suggest that HDL promotes reverse
cholesterol transport, that is, the removal of cholesterol
from tissues including removal of unesterified cholesterol
in atheromatous plaques so that it can be transported to
the liver and excreted. But proof is required. Most important,
HDL is believed to prevent LDL from oxidation
and aggregation and thus protect against formation and
progression of atheroma. This important area requires
further intensive investigation for clarification.

3. Variability of HDL Levels
About 25% of blood cholesterol is carried as HDL
cholesterol. People with high levels of HDL cholesterol,
greater than 60 mg (1.6 mmol), appear to live longer and
have less coronary artery disease. People with levels less
than 31 mg (0.8 mmol) have an increased risk of coronary
artery disease. It is not clear why some people should have
high values and others very low. It appears that about half
of the variation in HDL levels in the general population is
explained by genetic factors. Fortunately not all individuals
with low HDL levels get heart attacks.

Nongenetic factors that are known to be associated with
low levels of HDL are diabetes, obesity, smoking, and lack
of exercise.

Most females and males prior to puberty have about the
same cholesterol levels. Boys, however, at puberty have
about a 20% drop in HDL and a rise in LDL cholesterol.
The decrease in HDL cholesterol may be due to an
increase in androgens. In men the HDL level stays fairly
constant up to age 55, then starts to rise between 55–65.
It is possible that this rise might be due to a decrease
of androgens, which occurs during the male climacteric
period. In women there is a gradual rise in HDL cholesterol
from age 25 onward. Women are believed to be
protected until post menopause by this increase in HDL
and by their hormonal status. Why women are protected
from coronary heart disease until menopause and yet not
protected from strokes is not easily explained, especially if
atherosclerosis is the basis of both diseases.
There is a relationship between HDL cholesterol
levels and population groups, foods, alcohol, exercise,
and drugs.

D. Very-Low-Density Lipoprotein
The very-low-density lipoprotein (VLDL) is very large and
low in density. It transports triglycerides, which are used
mainly as a fuel; for example, in exercising muscle. The
evidence linking elevated blood triglyceride levels with
coronary heart disease is very weak and unclear. Thus, an
elevated blood triglyceride level alone is not of importance.
Weight reduction or cessation of alcohol intake always
causes a marked reduction in triglyceride levels but does
not alter LDL cholesterol levels.

V. BLOOD TESTS
A. Total Cholesterol
What is a normal blood cholesterol, and when does the
level produce a risk of coronary heart disease? Blood
cholesterol is not necessarily very high, that is, greater than
265 mg (6.9 mmol), in those who have heart attacks. In
fact, most heart attacks occur in individuals with blood
cholesterol around the average of 220–250 mg (5.7–6.5
mmol). In the LIPID study described above, only 3806
men with a blood cholesterol greater than 265 mg could be
found from a screening of 480,000. The remainder had
cholesterol levels of less than 265 mg and most likely in the
range of 200 to 250 mg.

Between 1970 and 1989, laboratories in North America
reported a normal cholesterol as between 150 (3.9 mmol)
and 250 (6.5 mmol). But it is now established that
individuals with so-called normal cholesterol in the range
of 220–250 are at increased risk, and heart attacks are
common in individuals with such levels. A blood cholesterol
of 220–250 mg (5.7–6.5 mmol) is considered high
by world standards. Most doctors now talk about an
optimal safe total cholesterol level of less than 190 mg/dl
(4.9 mmol/l) or LDL less than 120 mg (3 mmol). Heart
attacks are uncommon in individuals with a cholesterol
level less than 160 mg (4.2 mmol).

If we treat patients with a cholesterol level greater
than 250 mg (6.5 mmol), we will be excluding more than
80% of the population who are at high risk for coronary
heart disease. To reiterate, most heart attacks in North
America occur in people with blood cholesterol between
220 and 260 mg. Individuals with a blood cholesterol
less than 180 mg (4.7 mmol) obviously deal with
cholesterol by their own natural process. They are among
the fortunate; no dietary modification is necessary, and
blood cholesterol only needs to be rechecked about every
five years.

The blood cholesterol measurement gives the total
blood cholesterol, that is, LDL cholesterol plus HDL
cholesterol. Food eaten within hours does not have an
immediate effect on total blood cholesterol and HDL
cholesterol measurements, so fasting is not necessary for
this test. Triglyceride level is not an independent risk
factor and therefore widespread screening for elevated
triglycerides is not warranted. It is also an expensive
investigation. If your doctor thinks that triglyceride determination
is necessary, you must fast for 14 h before
blood is taken. Blood tests for glucose, diabetes, and
triglycerides are the only tests for which it is necessary to
fast for 12–14 h before the test.

B. Blood LDL Cholesterol Levels
Determination of LDL cholesterol is not done routinely,
because it is a difficult, time-consuming, and expensive
technique. It must be done fasting because it is
calculated by a formula that requires a triglyceride blood
level, which must be done after fasting 12 hours. The
formula for calculating the blood LDL cholesterol level
is as follows:
LDL cholesterol
¼ total cholesterol  HDL cholesterol
 ðtriglyceride divided by 5Þ
¼ mg=dl; for the value in mmol=L divide by 2
This formula does not apply if the triglycerides exceed 250
mg/dl.

In individuals age 15–75 optimal LDL cholesterol levels
are less than 115 mg/dl (3 mmol/L). In North America,
the UK, and Europe the vast majority of individuals
have an LDL cholesterol in the range of 130–200 mg/dl
(3.4–5.2 mmol/L). In patients with coronary heart disease,
the level of LDL is of paramount importance and should
be maintained at less than 100 mg/dl (2.6 mmol).

C. HDL Cholesterol Blood Level
Blood testing for HDL cholesterol levels can be done in the
nonfasting state. Levels less than 35 mg/dl (0.9 mmol/L)
are considered low and less than 27 mg/dl (0.7 mmol/L) is
considered unacceptably low. Levels greater than 54 mg/dl
(1.4 mmol/L) are considered optimal.

CORONARY ARTERY DISEASE RISK
A. Based on LDL Cholesterol
A high LDL cholesterol level is considered the most
important major risk factor for coronary artery disease.
The relationship between LDL cholesterol and coronary
artery disease risk is continuous over a broad range of
blood levels from low to high (110 mg/dl to greater than
190 mg/dl) and LDL cholesterol is the primary target of
therapy.

Patients with established coronary artery disease are
considered to have a 10-year risk greater than 20%. It is
expected that more than 20% of such individuals will
develop a recurrent coronary artery disease event within 10
years. In these individuals LDL cholesterol levels greater
than 130 mg/dl greatly increase the risk. Most national
guidelines state that in patients with proven coronary
artery disease or CAD risk equivalent, particularly
diabetes, drug treatment is strongly indicated to maintain
the level to less than 100 mg/dl (2.6 mmol/L).

Individuals without coronary artery disease or evidence
of cardiovascular disease should be assigned a risk based on
the following:
1. Their levels of LDL cholesterol: risk is increased if the
LDL-C is >190 mg/dl, and the goal should be <130
mg/dl (3.5 mmol/L)
2. Presence of diabetes risk score of >20 with a goal LDL
<100 mg/dl
3. Age
4. Family history of premature coronary heart disease
5. HDL cholesterol level
6. Smoking
7. The presence or absence of hypertension

DIETS AND CHOLESTEROL
A. Saturated Fats and Cholesterol
All animal fat is saturated and solid at normal room
temperatures. The degree of hydrogenation of a fat
determines how solid and saturated it is. Saturated fats
are broken down in the body and increase blood cholesterol.
Therefore, the most effective dietary method of
lowering blood cholesterol is to reduce intake of saturated
fats. High-cholesterol foods are few, therefore, we do not
use the term low-cholesterol diet.

Vegetable fats are unsaturated and almost all are liquid
at room temperatures. There are three vegetable oils that
should be avoided: coconut, palm, and peanut. Coconut
oil contains a high amount of saturated fat and is used
for cooking in several countries. It is also used in North
America in nondairy cream substitutes, for example,
coffee cream. Palm oil contains significant amounts of
saturated fat, and peanut oil, though mainly unsaturated,
has certain fatty acids that produce plaques of atheroma
in animals. The only vegetable that contains a little
saturated fat is the avocado; therefore, low-cholesterol,
low-fat diets often recommend that you avoid avocados.
You will note from Table 1, however, that although a large
avocado contains a significant amount of fat, only a little
of it is saturated, and no cholesterol is present. Therefore,
one avocado a week is an excellent food, especially if a
high potassium intake is required.

B. Polyunsaturates and Linolenic Acid
The replacement of some saturated fats in the diet by
polyunsaturated, monounsaturated, and other unsaturated
fats found in abundance in vegetable oil reduces blood
LDL cholesterol. The saturated and polyunsaturated fat
contents of commonly used foods are given in Table 1.
Oils recommended for the preparation of meals include
canola, olive, and soybean because they contain alphalinolenic
acid, very low cholesterol levels, and a minimum
of saturated fat. For example, ‘‘cholesterol-free’’ canola oil
contains 6% saturates and will produce a small amount
of cholesterol in the body. Not all vegetable oils claim to
be cholesterol free but contain significant saturated fats.
Because vegetable margarines contain a small amount of
saturated fat and hydrogenation remains controversial,
they should be used in moderation. Some products may have palm or
coconut oil added to enhance hardening; these two oils are
not recommended. Olive oil is recommended
for salads, but olive oil margarines may contain palm oil
to enhance hardening so read labels carefully. Some margarines
claim that they contain no cholesterol and are
nonhydrogenated yet they contain palm oil.

It is important to note that many recipes developed for
weight reduction diets tend to cut out carbohydrate foods
in order to decrease weight and may even introduce foods
that increase blood clotting and cholesterol. Therefore,
be careful in choosing ‘‘popular’’ weight reduction diets.
Consult Table 4 and the instructions given in the chapter
on Heart Attacks.

C. Nuts and Cholesterol and Risk
Most nuts contain no cholesterol and very little saturated
fats, but the exceptions include coconut and Brazil nuts
which have high saturated fat content and their products
should be avoided (see Table 4). Cashew nuts and peanuts
have significant saturated fats, and although they contain
an adequate amount of monounsaturated and polyunsaturated
fatty acids, they are not recommended and should
be used sparingly. Additionally, it appears that peanuts
may have atherogenic potential. Nuts that contain little
saturated fat and a high amount of monounsaturated fats
include almonds, walnuts, and hazelnuts and their intake
is highly recommended.

D. General Advice on Diets
Diets to reduce atherosclerosis or heart attacks must be
tailored to meet the needs of the individual, because each
family has different eating habits. Special recipes and diet
sheets may be misleading and difficult to follow for a
lifetime and individuals should consult Table 4, or similar
information.

It is recommended that the general population use foods
that contain a low amount of saturated fat and cholesterol
and make an effort to increase intake of polyunsaturated
and monounsaturated fat, linolenic acid, and foods that
have a favorable effect on blood clotting (see the chapter
Blood Clots). Reduction in the intake of cholesterol
alone is not sufficient because saturated fat is converted
into cholesterol in the body; therefore, reduction in
saturated fat intake is essential. Most important, the
intake of trans fat must be curtailed.

The recommendation made by the American Heart
Association is as follows:
Total fat intake should be reduced from the average
40% of calories to 30%. Polyunsaturated fat should
provide up to 10% of calories and the polyunsaturated
fat to saturated fat (P/S) ratio should be about 1:1.
Carbohydrate intake should be increased from an
average of about 45%–55% to maintain average
body weight, and protein intake should remain at
about 12–14%.
Scotland has not shared, however, in the slight decline
in mortality that has been experienced in Australia,
Belgium, Canada, Finland, Norway, and the United
States. Scotland has moved up in the world league of
coronary deaths to second for men, and Northern Ireland
has moved to third for men and second for women. In the
UK, fat intake has remained the same for the past 30 years
at about 40% of food energy and even increased between
1974 and 1982 to 41% of food energy. The Department
of Health and Social Security made the following
recommendations to physicians and the general public in
the UK:

Reduce the total fat intake to 35% of food energy with
saturated fats making up no more than 11%. Increase
the polyunsaturated to saturated ratio from the present
0.27 to about 0.45. The intake of polyunsaturated
acids presently at 5% of food energy should reach 7%,
which is less than the American and World Health
Organization’s suggestion of 10%.

The UK panel claims that the effects on the population
of a P/S ratio of 1.0 and beyond are unknown. Individuals
who are considered to have a high risk of developing
coronary heart disease are advised to cut fats to 30% of
food energy, with saturated fats contributing no more
than 10%, i.e., identical to the recommendation in the
United States. Thus there is consensus on both sides of the
Atlantic.

A Mediterranean style diet that contains an abundance
of linolenic acids is strongly recommended by the author;
see the chapter Diets and Heart Disease.
The reduction in dietary saturated fat intake as well
as the cessation of smoking by many individuals has provided
a decline in the incidence of coronary heart disease
mortality.

CHOLESTEROL-LOWERING DRUGS
A. HMC-CoA Reductase Inhibitors (Statins)
The statins, atorvastatin, fluvastatin, lovastatin, pravastatin,
and simvastatin, are cholesterol-lowering agents
that are effective and have few side effects. They cause a
20–40% reduction in total, or LDL, cholesterol. They may
cause a small, 1–6%, increase in HDL cholesterol, but
this effect is variable. Clinical trials have shown that these
agents decrease LDL cholesterol levels and reduce the risk
of heart attack and death from heart attacks. The newest
agent, rosuvastatin, is even more powerful than Lipitor
in reducing LDL levels to goal. Randomized clinical trials
that document the effectiveness of these agents are given
the chapter Dyslipidemia.

Mild side effects from statins include headaches, muscle
aches, and pain in the upper abdomen without gastritis,
ulcers, or bleeding. An increase in the liver enzymes may
be detected on blood test, but the risk subsides when the
drug is discontinued. Caution: Do not take with niacin
or fibrates such as gemfibrozil or fenofibrate. Statins are
contraindicated in pregnancy.

1. Atorvastatin
Supplied: Tablets: 10, 20, 40, 60 mg.
Dosage: 10–40 mg once daily; the author’s maximum
dose is 60 mg daily. The 80 mg dose is rarely required and
more adverse effects may occur at the maximal dose of
the drug.
2. Fluvastatin
Supplied: Capsules: 20 mg.
Dosage: 20–40 mg after the evening meal or bedtime.
3. Lovastatin
Supplied: Tablets: 10, 20, 40 mg.
Dosage: 10–40 mg after the evening meal.
4. Pravastatin
Supplied: Tablets: 10, 20, 40 mg.
Dosage: 10–40 mg after the evening meal or bedtime.

5. Rosuvastatin
Supplied: Tablets: 10, 20, 40 mg.
Dosage: 10 mg once daily is more effective in lowering
LDL cholesterol than 40 mg of Lipitor or simvastatin.
It causes a better increase in HDL cholesterol. The author’s
maximum suggested dose is 20 mg daily.
6. Simvastatin
Supplied: Tablets: 5, 10, 20 40, 60 mg.
Dosage: 10–40 mg after the evening meal.
B. Cholesterol Absorption Inhibitors
1. Ezetimibe
Supplied: Tablets 10 mg.
Dosage: 10 mg once daily. This drug has a low side
effect profile and can be combined with a statin.

Resins

1. Cholestyramine
Supplied: Powder in packets or in cans with a scoop.
Dosage: 12–24 g daily in liquid a half hour before to a
half hour after meals. Start with 4 g (one scoop) twice daily
for one week, then 4 g three times daily for one month,
and if necessary, thereafter increase to 8 g three times daily.
Cholestyramine and colestipol are not absorbed from
the gut and act by binding bile salts in the intestine. This
action causes the liver to increase the conversion of
cholesterol to bile acids, which are excreted in the bile.
Cholestyramine has no serious side effects. Constipation,
nausea, bloating, gas, and abdominal cramps may
occur. High doses taken for several years can cause poor
absorption of certain vitamins. It may interfere with the
absorption of digoxin and blood thinners (anticoagulants).
The recent introduction of ezetimibe as an effective drug
will render bile acid resins such as cholestyramine and
colestipol obsolete.

Fibrates
1. Gemfibrozil
Supplied: Capsules: 300 mg.
Dosage: 300 mg taken about a half hour before the
morning and the evening meal for one to two weeks, then
300 mg twice daily.
Gemfibrozil is the first fibrate to be introduced in the
seventies since the discontinuation of clofibrate in the
late sixties. This drug causes a 5–10% reduction in serum
cholesterol, 30% reduction in triglycerides, and a 5–10 %
increase in HDL cholesterol. Side effects include stomach
pain and bloating in less than 5% of patients. Gallstones
may occur.

In the VA-HIT study gemfibrozil caused a 31% decrease
in triglycerides, but only a 6% increase in HDL cholesterol
compared with placebo. This negligible increase in HDL is
claimed to have caused a beneficial reduction in cardiac
events. There was no reduction in all cause mortality or in
total cardiac mortality; there was a small, 22% reduction
in total cardiac death and nonfatal myocardial infarction
(MI) (P<0.05), a low level of significance. Virtually all of
the benefit was due to reduction in nonfatal MIs; a result
similar to that observed for vitamin E in the CHAOS
study.

2. Fenofibrate
Supplied; Tablets 100, 160 mg.
Dosage: 100–200 mg once daily with the main meal,
maximum 100 mg in renal dysfunction.
3. Bezafibrate
Supplied: Tablets 200 mg.
Dosage: Mono formulation once daily in the evening.
E. Niacin (Nicotinic Acid)
This drug is not often used because of prominent side
effects, which include flushing, itching, nausea, abdominal
pain, diarrhea, jaundice, gout, palpitations, and increased
blood sugar in diabetics. This drug should not be used if
you have low blood pressure or have had a heart attack,
heart failure, liver disease, a stomach ulcer, or diabetes. It is
not advisable to combine niacin with statins because severe
damage to muscles and the kidneys may occur.

Combination Therapy
The combination of simvastatin and ezetimibe has been
shown in a clinical trial to be more effective than simvastatin
alone. The combination caused LDL cholesterol
reductions of 44–57% and HDL cholesterol increases of
8%–11%. Ezetimibe 10 mg plus simvastatin 10 mg and
simvastatin 80 mg alone each caused a 44% reduction
in LDL cholesterol. The combination was well tolerated
with the safety profile similar to those of simvastatin and
of placebo.

The combination of rosuvastatin and ezetimibe is
advisable for severe hypercholesterolemia. This is the
most powerful combination available for the reduction
of elevated LDL cholesterol and is a welcome addition to
the clinician’s armamentarium. Caution is required, however,
because liver dysfunction or rhabdomyolysis may be
precipitated at high doses of any statin, particularly if drug
interaction occurs.

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