Introduction
Statins are among the best-studied drugs for the primary and secondary prevention of atherosclerosis, and particularly
of coronary heart disease. Their tolerability is
generally very good. Their lipid-lowering effect is species
and dose dependent, and the maximum lowering of the
LDL cholesterol level can be up to 55%. The lowering of
the LDL cholesterol is curvilinear, and each doubling of
the dose leads to a 6% reduction of the LDL cholesterol
(rule of six). This rule also applies to the side effects,
which most often involve the liver enzymes and the musculature.
Raised liver values are found in 0.52.0% of the
patients, and the incidence of myopathy is 0.11.0%.
Higher incidences occur under combined therapies with
other drugs. Rhabdomyolysis has been observed in 0.01
0.1% of the patients treated [1, 2]. These side effects and
other unwanted effects such as headache and gastrointestinal
symptoms sometimes lead to intolerance of statins
or to intolerability when the dose is increased.
The facts that the target LDL cholesterol values cannot
always be reached with statin monotherapy, that particular patients do not tolerate statins and that combinations
with fibrates increase the risk of myopathy has led to the
search for new lipid-lowering substances.
Ezetimibe is an interesting new lipid-lowering substance
with a new mechanism of action and up till now
good tolerability.
Pharmacology
Ezetimibe was discovered by Schering-Plough, as the
first selective intestinal cholesterol absorption inhibitor
. There is evidence that it blocks the specific cholesterol
receptors in the small intestine, but these findings still
have to be confirmed. Mainly active in this respect is the
glucuronidised substance, ezetimibe, which is recirculated
in the enterohepatic circulation and inhibits the
absorption of both endogenous and exogenous cholesterol.
It is calculated that the endogenous cholesterol synthesis
amounts to about 800 mg/day, while the diet provides
approximately a further 400 mg of exogenous cholesterol.
Normally, about 800 of these 1,200 mg of cholesterol per day are re-absorbed in the ileum (enterohepatic circulation).
Under ezetimibe treatment, the excretion of cholesterol
in the faeces is increased by about 400 mg per day.
Dose-effect studies have shown that ezetimibe exerted
its maximum lipid-lowering effect in trial subjects even at
the dose of 10 mg; the effect was independent of the time
of day that the drug was taken (once-daily dosage).
Ezetimibe showed no interaction with the metabolism
of simvastatin; in combination with gemfibrozil, increases
in the gemfibrozil concentration were observed in
some trial subjects. Impaired renal function has no influence
on the pharmacokinetics of ezetimibe.
Clinical Studies of Monotherapy and Combined
Therapy with Statins
The first investigations carried out were comparative
studies versus placebo in patients with mild hypercholesterolaemia, in which it was shown that the LDL cholesterol
was lowered on average by 17.4%, while HDL cholesterol
increased by 2.6% in comparison with the placebo
group and the triglyceride level decreased by 7.7%.
Under the combination of simvastatin 10 mg with ezetimibe
10 mg, the lowering of the LDL cholesterol was the
same (44%) as that obtained with 80 mg of simvastatin
alone. Also, the lowering of the LDL cholesterol
obtained with 10 mg of atorvastatin in combination with
10 mg of ezetimibe was similar to that obtained with
80 mg of atorvastatin alone (53 and 54%, respectively). It therefore seems that even with low doses of statins,
pronounced effects of ezetimibe are to be observed, and
that with high levels of HMG-CoA reductase inhibition,
the effect of ezetimibe is relatively more pronounced. The
increase in HDL cholesterol obtained with combinations
with various different statins was 13% in comparison
with statin monotherapy, while with the addition of ezetimibe,
the lowering of the triglyceride level was 79%
more pronounced. An add-on study in almost 1,000
patients using various statins showed that ezetimibe lowered
the LDL cholesterol by 21% on average, while the
HDL cholesterol increased by 2% and the triglyceride level
was lowered by an additional 11%.
Side Effects
The incidence of side effects was as high under the combination
of ezetimibe with statins as with statins alone.
Ezetimibe should be used with caution or not at all in
children under the age of 10 years, during pregnancy and
in patients with moderate to severe impairment of liver
function.
Clinical Indications of Ezetimibe
Ezetimibe is indicated particularly in co-administration
with statins in severe cases of hypercholesterolaemia,
especially familial hypercholesterolaemia (heterozygous
LDL receptor defect).
A further therapeutic indication is in patients who do
not tolerate statins or who tolerate them only in small
doses. In any case, the attempt should be made to combine
low doses of statins with ezetimibe.
Rare Indications
Individual observations in homozygous familial hypercholesterolaemia,
a rare genetic disease which is caused
by the total absence of LDL receptors and which can
already cause severe manifestations of atherosclerosis in
children, have shown that ezetimibe is apparently also
effective in this condition.
Also, in homozygous sitosterolaemia, a lowering of the
sitosterol and campesterol levels with ezetimibe has been
observed in isolated cases.
Conclusions
Ezetimibe is an interesting new cholesterol-lowering
drug; its synergistic effect with statins makes it particularly
attractive. Unlike cholestyramine, ezetimibe is a systemically
metabolised drug; however, its safety cannot be
evaluated conclusively on the basis of the data that are
available at the present time. Also, there are no long-term
studies or cases available with hard end points (cardiovascular
morbidity, mortality). For these reasons, ezetimibe
is at present not a first-line drug in the treatment of
hypercholesterolaemia.
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