page182
risk of Muscle Effects, below. Patients with heterozygous
familial hypercholesterolaemia who have contra-indica-
tions
to,
or
are intolerant
of,
statins
should receive
ezetimibe.
The combination of
a statin and ezetimibe
can be considered if
a statin alone fails
to provide
adequate control (or if intolerance limits dose titration),
and when a switch to an alternative statin is being
considered.
Patients for
whom statins and ezetimibe
are inappropriate,
should be referred to a specialist for
the consideration of treatment with a bile acid seques-
trant,
nicotinic acid, or a fibrate.
The prescribing of drug therapy in homozygous familial
hypercholesterolaemia should be undertaken in a spe-
cialist centre.
Statins
The
statins
(atorvastatin,
fluvastatin,
pravastatin,
rosuvastatin,
and simvastatin)
competitively inhibit
3-hydroxy-3-methylglutaryl
coenzyme A (HMG CoA)
reductase, an enzyme involved in cholesterol synthesis,
especially in the liver.
Statins are more effective than
other lipid-regulating drugs at lowering LDL-cholesterol
concentration but
they
are
less
effective
than the
fibrates
in reducing triglyceride concentration.
How-
ever,
statins reduce cardiovascular disease events and
total
mortality irrespective of
the initial
cholesterol
concentration.
Statins should be considered for all
patients,
including
the elderly,
with symptomatic cardiovascular
disease
such as those with coronary heart
disease (including
history of angina or acute myocardial infarction), occlu-
sive arterial
disease (including peripheral
vascular dis-
ease,
non-haemorrhagic stroke,
or transient ischaemic
attacks).
In patients with diabetes mellitus, the risk of developing
cardiovascular
disease depends on the duration and
complications of
diabetes,
age,
and concomitant
risk
factors.
Statin therapy should be considered for
all
patients over 40 years with diabetes mellitus (type 1
and 2).
In younger
patients with diabetes,
treatment
with a statin should be considered if
there is target-
organ damage,
poor glycaemic control
(HbA
1c
greater
than 9%),
low HDL-cholesterol
and raised triglyceride
concentration,
hypertension,
or a family history of pre-
mature cardiovascular disease.
Statins are also used for the prevention of cardiovascu-
lar disease events in asymptomatic individuals who are
at
increased risk (see p.
161).
Statin treatment
should
also be considered if the total cholesterol concentration
to HDL-cholesterol ratio exceeds 6.
Cautions
Hypothyroidism should be managed ade-
quately before starting treatment
with a statin (see
p.
161).
Statins should be used with caution in those
with a history of
liver disease or with a high alcohol
intake—see also Hepatic impairment,
below.
There is
little information available on a rational
approach to
liver-function monitoring;
however,
a NICE guideline
1
suggests that liver enzymes should be measured before
treatment,
and repeated within 3 months and at
12
months of starting treatment,
unless indicated at other
times by signs or symptoms suggestive of
hepatotoxi-
city.
Those with serum transaminases that
are raised,
but
less than 3 times the upper limit of
the reference
range,
should not
be routinely excluded from statin
therapy.
Those
with serum transaminases
of
more
than 3 times the upper
limit
of
the reference range
should discontinue statin therapy.
Statins
should be
used with caution in those with risk factors for myo-
pathy or rhabdomyolysis; patients should be advised to
report
unexplained muscle pain (see Muscle Effects
below).
Statins should be avoided in acute porphyria
(section 9.8.2)
but
rosuvastatin is thought
to be safe.
Interactions: Appendix 1 (statins).
Hepatic impairment
Statins should be used with
caution in those with a history of
liver
disease and
avoided in active liver disease or when there are unex-
plained persistent elevations in serum transaminases.
Pregnancy
Statins should be avoided in pregnancy as
congenital
anomalies
have
been reported and
the
decreased
synthesis
of
cholesterol
possibly
affects
fetal
development.
Adequate contraception is required
during treatment and for 1 month afterwards.
Breast-feeding
The manufacturers of
atorvastatin,
fluvastatin,
rosuvastatin,
and simvastatin advise avoid-
ing use in mothers who are breast-feeding as there is no
information available. The manufacturers of pravastatin
advise against use in breast-feeding mothers as a small
amount of drug is present in breast milk.
Side-effects
The statins can cause various muscular
side-effects, including myositis, which can lead to rhab-
domyolysis.
Muscular effects are rare but often signifi-
cant
(see Muscle Effects
below).
Statins
can cause
gastro-intestinal disturbances, and very rarely pancreat-
itis. They can also cause altered liver function tests, and
rarely hepatitis and jaundice;
hepatic failure has been
reported very rarely.
Other
side-effects include sleep
disturbance,
headache,
dizziness,
depression,
paraes-
thesia,
asthenia,
peripheral
neuropathy,
amnesia,
fati-
gue,
sexual
dysfunction,
thrombocytopenia,
arthralgia,
visual
disturbance,
alopecia,
and hypersensitivity reac-
tions (including rash, pruritus, urticaria, and very rarely
lupus erythematosus-like reactions). In very rare cases,
statins can cause interstitial
lung disease;
if
patients
develop symptoms
such
as
dyspnoea,
cough,
and
weight loss,
they should seek medical attention.
Muscle effects
Myalgia, myositis, myopathy and rarely rhab-
domyolysis have been reported with the statins; if myopathy is
suspected and creatine kinase is markedly elevated (more than
5 times upper limit of normal),
or muscular symptoms are
severe, treatment should be discontinued; in patients at
increased risk of muscle effects, a statin should not be started if
creatine kinase is elevated. Patients at increased risk of myo-
pathy include those with a personal or family history of
muscular disorders, previous history of muscular toxicity, those
with a high alcohol intake, renal impairment,
hypothyroidism,
women, and the elderly. There is also an increased incidence of
myopathy if a statin is given at a high dose or given with a
fibrate, with lipid-lowering doses of nicotinic acid, or with drugs
that increase the plasma-statin concentration,
such as ciclos-
porin; close monitoring of liver function and, if symptomatic, of
creatine kinase is required in patients receiving these drugs.
Rhabdomyolysis with acute renal impairment secondary to
myoglobinuria has also been reported.
Counselling
Advise patient to report promptly unex-
plained muscle pain,
tenderness,
or weakness.
1.
NICE clinical
guideline 67 (May 2008).
Lipid Modifica-
tion—Cardiovascular risk assessment and the modification
of blood lipids for the primary and secondary prevention of
cardiovascular disease
162
2.12 Lipid-regulating drugs
BNF 61
2
Cardiovascular system