C H A P T E R 4 7
Lipid-lowering agents
743
■■
HMG-CoA reductase inhibitors, or statins, block
the enzyme HMG-CoA reductase, resulting in lower
serum cholesterol levels, a resultant breakdown of
LDLs and a slight increase in HDLs.
■■
Individuals receiving HMG-CoA reductase inhibitors
should avoid pregnancy because of serious fetal
adverse effects; should take the drug in the evening to
mimic the normal patterns of lipid formation; should
have liver function monitored regularly; and should
be instructed to report any sudden muscle pain,
especially if accompanied by fever.
C
holesterol absorption
inhibitors
The first of a new class of drugs to lower cholesterol
levels was approved in 2003—ezetimibe (
Ezetrol
). Cur-
rently there is controversy about cholesterol-lowering
drugs, specifically ezetimibe, because of the ENHANCE
study (full title of the study: Effect of Combination
Ezetimibe and High-Dose Simvastatin vs Simvastatin
Alone on the Atherosclerotic Process in Subjects With
Heterozygous Familial Hypercholesterolaemia). This
study, released in January 2008, looked at the actual
post-marketing benefits of antihyperlipidaemic therapy.
The study failed to find any positive benefit from the
addition of ezetimibe to a statin. This finding called into
question the whole class of cholesterol-lowering drugs
and the benefits or lack of benefits associated with this
therapy (Box 47.7). Further studies are needed.
KEY POINTS
Therapeutic actions and indications
Ezetimibe works in the brush border of the small intes-
tine to decrease the absorption of dietary cholesterol
from the small intestine. As a result, less dietary cho-
lesterol is delivered to the liver, and the liver increases
the clearance of cholesterol from the serum to make
up for the drop in dietary cholesterol, causing the total
serum cholesterol level to drop. See Table 47.3 for usual
indications.
Pharmacokinetics
Ezetimibe is absorbed well after oral administration,
reaching peak levels in 4 to 6 hours. It is metabolised
in the liver and the small intestine, with a half-life of
22 hours. Excretion is through faeces and urine. It is not
known whether the drug crosses the placenta or enters
breast milk.
Contraindications and cautions
Ezetimibe is contraindicated in people with an allergy
to any component of the drug
to avoid hypersensitivity
reactions
. If it is used in combination with a statin, it
should not be used during pregnancy or breastfeeding
or with severe liver disease
because of the known effects
of statins, including possible liver problems and renal
failure.
The drug should be used with caution as mono-
therapy during pregnancy or breastfeeding
because the
effects on the fetus or neonate are not known
and with
elderly people or individuals with liver disease
because
of the potential for adverse reactions.
The ENHANCE Study
Modifying the risk factors established through the
Framingham Study remains the key to the prevention
of CAD. If, statistically, risk factors can be reduced, the
chances of a cardiovascular event will be smaller.The
actual process of atheroma development and vessel
occlusion remains elusive, and the role of cholesterol
and lipids in the actual process is not clearly understood.
Lowering the cholesterol and lipid levels, although putting
the person into a statistically lower risk group, does not
seem to really offer much protection against cardiovascular
events in people who have not already experienced an
event. Watching the television ads or reading magazine ads
for the lipid-lowering drugs, you will notice a disclaimer
that states that “these drugs have not been proven to
reduce your risk of heart disease or heart attack”.
When the ENHANCE study was published in 2008,
showing that the use of ezetimibe and simvastatin did
not slow the progression of atheromas, the action of
other lipid-reducing drugs was called into question.The
data on the effectiveness of atorvastatin claims a 36%
reduction in cardiac events. Based on these data, this
means that in a large study, 3% of the people receiving
no drugs suffered a cardiac event, whereas only 2% of
the people taking atorvastatin suffered a cardiovascular
event.This translates into one less heart attack in every
100 people over a 3-year period.The other 99 people
taking the drug had no measurable benefit from the drug.
The number needed to treat to show effectiveness is very
high. Other lipid-lowering drugs show similar or even
worse statistics. Should our heathcare focus so heavily,
then, on lowering cholesterol and lipid levels?Those
who feel that it should argue that with large numbers
of people using these drugs, the number of people who
are saved from a cardiovascular event is actually higher.
Those who are now questioning it wonder whether the
cost and adverse effects associated with the drugs are
justified for benefiting such a small percentage of people.
At the moment, this seems to be the best we have to offer
people, but as more research is done on the process of
CAD, standards may change.
The evidence
BOX 47.7
