to talk about the therapy which is now available
for them. In fact, it’s only in the last
20 years that we have really had effective
therapy... pharmacological therapy and I am
going to show you some information about that
in a moment.
Let’s just talk a little bit more about
the different components of hyperlipidemia.
Here’s the evil enemy. You will notice the little
cartoon, the little devil with the tail? So,
low density lipoprotein cholesterol is the
one that gets itself into the wall of the
artery, sets off an inflammatory reaction
that eventually leads to atherosclerosis,
which is progressive. The lesions continue
to enlarge, they become often fragile and
friable. They can even crack and open and
a blood clot can form leading to a heart attack
or a stroke depending upon whether the broken
artery with the blood clot is in the heart
or whether it’s in the arteries leading
to the brain.
And again, we are going to go into this in
much more detail in the lecture on… on coronary
artery disease and atherosclerosis. In any
case, this is often referred to as the bad
cholesterol. The number that we like to see
is in milligrams percent. In the United States,
it… the number we usually like to see it
below 100 and ideally, somewhere down around
60 to 70 milligram percent or milligram per
Even that number is actually elevated compared
to what people living in a state of nature
might have. It’s been measured - LDL cholesterol,
that is, has been measured in patients who
live in the highlands of New Guinea or the
headwaters of the Amazon. There they have
a very healthy diet because it’s a tropical
area, lots of fruits and vegetables and fish
and so forth, but these people do not eat
a western diet. They have LDL cholesterols
that are only 20 to 30 milligrams percent.
So, you can see that all of us living here
with a western lifestyle actually have at
least moderately elevated LDL cholesterol.
High density lipoprotein works in the opposite
direction. You will see it has little angel
wings here. High density lipoprotein helps
to remove cholesterol from the arterial wall.
In pharmacology, there have been great attempt
to come up with a drug to increase HDL and
work against the atherosclerotic process.
Unfortunately, so far, that research has not
been successful. A number of agents have been
tried, they did indeed increase the HDL level,
but in fact, they did not decrease the heart attack
rate and in some instances, actually were
associated with a worse outcome than in
the placebo group. So, we are still searching
for a way to raise HDL cholesterol safely.
The only way to raise it safely and to retard
the development of atherosclerosis is number
one, with regular exercise and number two,
with modest use of alcohol. For example, a
glass or two of wine per day.
Now, what we do in cardiovascular pharmacology,
as I pointed out in the first lecture, is
we look to large clinical trials in which
an agent is compared to placebo. The trials
are conducted in a double-blind fashion so
that neither the doctors who are administering
the drugs nor the patients know whether the
patient is getting the placebo or whether
they are getting the drug that’s being tested.
The drugs that were tested and shown to be
very, very effective in these, what I call
gold standard clinical trials - the double-blind
clinical trials were the drugs known as Statins.
And they have become widely, they... used
throughout the world. They are now one of
the most widely used drugs throughout the
world. Why? Because they very effectively
lower LDL cholesterol and they very modestly
elevate HDL cholesterol. So, you can see they
really work in the perfect direction. They
lower the bad cholesterol and they increase
the good cholesterol a little bit, but their
major effect is in lowering LDL cholesterol.
By the way, they have some other pharmacological
actions - they are also anti-oxidant that is
they reduce so called ‘rust’ in the…
in the cells of the body and in the arterial
cells so that they decrease injury to those
arterial cells. And by the way, there’s
a lot of research going on in this area in
basic science and in clinical science trying
to come up with new drugs to reduce this oxidation,
this rusting, if you will, of our bodies.
So far, we don’t have any drugs that are
really effective long term, but it’s an
area of intense investigation.
Now, Statins also decrease inflammation, and
as I am going to point out to you in this
talk and also later on when we talk in more
in depth about atherosclerosis, the atherosclerotic
process begins with oxidation and also injury
and inflammation within the vessel wall. And
if there were ways to retard that, we might
markedly decrease the atherosclerosis. So
far, the best thing we have going forth are
the Statin drugs.
How do the Statin drugs work? The Statin drugs
work in the liver. And the way they work in
the liver is that they are able to block the
production of cholesterol within the liver
cell. They block an enzyme called HMA co-enzyme
reductase and what this does inside the liver
cell, is it slows the production of cholesterol
in the liver cell. When the liver cell looks
around and says, “Hey, I don’t see enough
cholesterol, I am going to put some more
LDL receptors up on my surface and pull some
out of the blood stream.” And when they
do that, of course, the level of LDL cholesterol
in the blood goes down and that decreases,
as you will see in a moment on the slide,
markedly the risk for heart attacks and strokes.
There are fortunately very few side effects
from Statins. They are very, very well tolerated.
Which is good because that means we can give
them to large number of people without having
too many very unpleasant adverse events, as
they are called in the pharmacology literature.
In the lay term, we call them side effects.
There is an occasional patient that has significant
liver injury from that and obviously, can’t
continue to take the drug and a fair number
of people have occasional muscle cramps or
muscle aches, but rarely there is also serious
muscle damage and consequently, those people
can’t take it. But, we are talking about
one or two people in many thousands. Many
thousands can take the drug without major
side effects and it is very, very effective
at lowering LDL cholesterol.
What we see in this slide is increases or
decreases in events with changes in either
Statins or placebo therapy. And what you can
see is in the lines that are moved to the
right, that’s a decrease in events and the
one that’s on the left, is actually at the
zero point. In other words, nothing has changed.
That’s non-cardiovascular events and you
can see, they are unaffected by Statins.
Everything else, major coronary events, that’s
heart attacks and severe angina, strokes and
cardiovascular deaths and so forth, all lie
to the right and are markedly decreased by
30 to 40%. That’s a huge decrease in cardiovascular
events with Statin therapy. All of this data
is from the double-blind randomized controlled
gold standard trials that we mentioned before
in the area of evidence based medicine. That
is, do we really have hard data that says
that these drugs work when they are tested
in that manner?
Here we see, actually, this is a composite
graph from a number of the Statin trials and
what you can see is, as LDL cholesterol on
the bottom axis goes up, moving from left
to right, you can see that the number of events
also goes, the relative risk for... for coronary
heart disease, CHD, goes up as well. And conversely,
as you move to the left on the bottom line,
in other words, the LDL gets lower, you can
see that there is a marked drop in the number
of cardiovascular coronary heart disease events.
So, this is actually data brought together.
It’s a composite from many of the Statin
trials. Essentially every Statin trial showed
the same thing, that is a marked reduction
in coronary artery disease events such as
heart attack, myocardial infarction and strokes.
Here we see all of the drugs that have been
approved, both in the United States by the
Food and Drug Administration and in Europe
by the European Licensing Agencies for the
reduction of LDL cholesterol. In other words,
all of the Statin drugs that are currently
available in local pharmacies, basically throughout
The first drug, rosuvastatin at the top, is
the most powerful and is given in lower doses.
The ones below that are less powerful and
therefore, are given in higher doses, but
you can achieve the same effect regardless
of which agent you use as long as you use
enough of it.
Other agents that are commonly used are atorvastatin,
simvastatin and pravastatin. So, the commonly
used ones then are rosuvastatin, atorvastatin,
simvastatin and pravastatin.
Now, other drugs can be used to treat increased
cholesterol or hyperlipidemia. Unfortunately,
none of them is anywhere near as effective
as the Statin drugs. But they have some use
in certain individuals who can’t tolerate
Statins and sometimes, they have been used
in addition to Statins. But unfortunately,
the most recent trial data doesn’t show
that they add very much. The Statins are really
the basis for most of the lowering of LDL
cholesterol and for lowering of the coronary
heart disease and stroke events. But, these
other agents - high dose niacin, fibrates,
one can even use a drug that… that grabs
bile as it comes into the bowel. Bile is made
from cholesterol, so it then passes out in
the feces and that also lowers the… the
LDL level. But, each of these is a minor league
player, as we say in English using the baseball
term, as opposed to the major league player
which are the Statin drugs.