|
Ezetimibe is in a new class of lipid-lowering compounds (cholesterol absorption
inhibitor) - it selectively inhibits the intestinal absorption of cholesterol
and related plant sterols. Some features of this agent are described:
- ezetimibe localizes at the brush border of the small intestine and inhibits
the absorption of cholesterol and thus results in reduced delivery of intestinal
cholesterol to the liver. Ezetimibe does not increase bile acid secretion (like
bile acid sequestrants) and does not inhibit synthesis of cholesterol by the liver
(as do statins)
- unlike bile acid sequestrants and orlistat, ezetimibe
selectively inhibits absorption of both dietary and biliary cholesterol without
interfering with absorption of fatty acids and fat-soluble vitamins
- the
Niemann-Pick C1 like 1 protein (NPC1L1) appears to play a critical role in the
intestinal absorption. The complete insensitivity of NPC1L1-null mice to the ezetimibe
suggests that NPC1L1 or an associated protein may be the molecular target of this
drug (1)
- ezetimibe undergoes glucuronidation in the intestinal
wall and is delivered back to the intestinal site of action via enterohepatic
circulation. Glucuronidation appears to increase residence time in the intestine,
minimising systemic exposure
- ezetimibe is not metabolised by the cytochrome
P450 system and therefore does not interact with drugs that are metabolised by
this system
- as monotherapy ezetimibe treatment resulted in LDL-cholesterol
reductions, beyond those achieved with diet alone (2):
- a pooled analysis
of two phase II studies
- a total of 432 patients were included in this
pooled analysis, 243 in study A and 189 in study B
- The 5- and 10-mg doses
of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively
(P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol
(hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction
in plasma TG levels was observed (P = NS)
- combination
therapy with a statin
- there is evidence that combination therapy with
10mg ezetimibe plus 10 mg simvastatin led to a reduction LDL-cholesterol levels
by an additional 17% compared with treatment with simvastatin 10mg alone (3) (note
that generally the doubling of a statin dose only results in an additional 6%
lowering of LDL-cholesterol (4))
- in the NICE review (5), the Assessment
Group conducted a meta-analysis of the five studies identified (6 to 8 weeks in
duration) and reported the mean percentage change in lipid profiles from the time
ezetimibe was added to the statin, expressed as a proportion of post-statin cholesterol
- results showed that the addition of ezetimibe to statin therapy reduced
LDL cholesterol concentrations by 23.2% (95% CI, 24.3 to 22.1) more than statin
therapy alone
Notes: - NICE
have issued guidance on the use of ezetimibe (5).
- summary points from
the guidance:
- ezetimibe monotherapy is recommended as an option for the
treatment of adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia
who would otherwise be initiated on statin therapy but who are unable to do so
because of contraindications to initial statin therapy
- ezetimibe monotherapy
is recommended as an option for the treatment of adults with primary (heterozygous-familial
or non-familial) hypercholesterolaemia who are intolerant to statin therapy
- ezetimibe,
coadministered with initial statin therapy, is recommended as an option for the
treatment of adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia
who have been initiated on statin therapy when:
- serum total or low-density
lipoprotein (LDL) cholesterol concentration is not appropriately controlled either
after appropriate dose titration of initial statin therapy or because dose titration
is limited by intolerance to the initial statin therapy and
- consideration
is being given to changing from initial statin therapy to an alternative statin
- when
the decision has been made to treat with ezetimibe coadministered with a statin,
ezetimibe should be prescribed on the basis of lowest acquisition cost
- for
the purposes of this guidance, appropriate control of cholesterol concentrations
should be based on individualised risk assessment in accordance with national
guidance on the management of cardiovascular disease for the relevant populations
- for
the purposes of this guidance, intolerance to initial statin therapy should be
defined as the presence of clinically significant adverse effects from statin
therapy that are considered to represent an unacceptable risk to the patient or
that may result in compliance with therapy being compromised. Adverse effects
include evidence of new-onset muscle pain (often associated with levels of muscle
enzymes in the blood indicative of muscle damage), significant gastrointestinal
disturbance or alterations of liver function tests
- a
MeReC extra has reviewed the use of ezetimibe and has stated (6):
- ezetimibe
is licensed for use in primary (heterozygous-familial and non-familial) hypercholesterolaemia
i.e. patients with high (undefined) cholesterol concentrations not due to an underlying
cause
- clinical trial data has shown that ezetimibe reduces cholesterol
levels, but there are no published outcome studies which examine whether it reduces
morbidity or mortality outcomes, such as heart attacks or cardiovascular deaths
-
ezetimibe is not licensed for the primary or secondary prevention of cardiovascular
events
- results from the ENHANCE study have shown no benefit for the combination
of ezetimibe 10mg plus simvastatin 80mg compared with simvastatin 80mg alone on
carotid artery intima media thickness
The summary of product
characteristics should be consulted before prescribing this drug. Reference:
|
