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REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
48
VOLUME 12 NUMBER 2 • NOVEMBER 2015
Side effects of statins
Nikash Ramsunder
Correspondence to: Nikash Ramsunder
Department of Internal Medicine, University of Stellenbosch, Stellenbosch
e-mail:
nikashramsunder@gmail.comS Afr J Diabetes Vasc Dis
2015;
12
: 48–50
Introduction
The 3-hydroxy 3-methylglutaryl CoA (HMG CoA) reductase
inhibitors, also known as statins, were first discovered in 1971
by a Japanese biochemist from the fungus
Penicillium citrinum
.
Lovastatin was the first statin introduced on the market in 1987.
Statins are a widely used group of cholesterol-lowering agents
that act by inhibiting the enzyme HMG CoA reductase, which
catalyses the rate-limiting step in the biosynthesis of cholesterol.
1
They are currently the largest-selling class of pharmaceutical
compounds of all time, with six different statins currently available
in most parts of the world. With sales in excess of $22 billion per
annum, these drugs are taken by hundreds of millions of people
around the world to prevent vascular disease.
However these drugs are not without their side effects and it is
the purpose of this review to examine some of these side effects.
This article will divide these side effects into adverse and beneficial
effects.
Adverse effects
By far the most negative side effects of statins are their effects on
the muscles, which include myalgia, myositis and rhabdomyolysis,
and on the liver, which range from mild asymptomatic transaminitis
to severe liver toxicity or damage.
2
The risk of myositis and rhabdomyolysis was highlighted by the
removal of cerivastatin from circulation worldwide in 2001 because
of 100 deaths due to rhabdomyolysis. The FDA reported the risk to
be at 3.16 per million prescriptions of cerivastatin.
3
However, apart
from cerivastatin, serious muscle problems are relatively uncommon
with other statins.
Large clinical trials have reported the rate of non-specific muscle
or joint aches and pains at around 5%, which was found to be
similar in comparator placebo groups.
4
It should be considered,
however, that there might be under-reporting of these common
muscle aches and pains due to exclusion of patients or their
unwillingness to participate in clinical trials by people with known
prior intolerance to statins.
2
Serious muscle problems have been shown to be uncommon
in trials conducted thus far, as demonstrated by an analysis of 44
completed trials with 9 416 patients. Only one patient had a creatine
kinase level (CK) greater than 10 times the upper limit of normal,
0.4% of patients discontinued the drug due to muscle aches and
pains, and none of the patients had rhabdomyolysis.
5
In another study that included 83 858 patients from several
large statin trials where patients were randomly assigned to a statin
or placebo, 49 cases of myositis and seven cases of rhabdomyolysis
were reported in the statin group compared to 44 and five cases
in the placebo group, respectively.
6
The Anglo-Scandinavian
Cardiac Outcomes Trial (ASCOT), which was a large, multicentre,
randomised, controlled trial, revealed that only one of 5 168
patients treated with a statin had rhabdomyolysis.
7
The Heart Protection study, where more than 20 000 patients
were recruited, showed that more than 33%had muscle complaints
such as pain and weakness. Elevated CK levels of more than four
times the upper limit of normal were found in only seven of 10 267
patients in the statin-treated patients and one in the placebo group
of 10 269 patients.
8,9
Myopathies can also be divided into toxic myopathies, in which
the exact mechanism is unknown, and immune myopathies,
which are inflammatory (polymyositis and dermatomyositis) and
non-inflammatory (necrotising myopathy without significant
inflammation).
10
It must be noted that immune myopathies
secondary to statin use are a rare phenomenon.
11
The exact cause of myopathy remains elusive but seems to be
multifactorial. An increased risk of myopathy is associated with
factors such as being female, elderly (> 80 years), having a small
body frame, with disease of other organ systems, particularly
involving the liver and kidney, recent major surgery, excessive
physical activity and the consumption of large quantities of grape
juice.
12
The statins also carry a potential risk for adverse liver events,
with severe liver disease, cholestatic hepatotoxicity, autoimmune
hepatitis, fulminant hepatitis and cirrhosis also a potential problem,
but these are exceedingly rare.
2,13,14
Hepatotoxicity is defined as an
elevation in aspartate transaminase (AST) and alanine transaminase
(ALT) levels to more than three times the upper limit of normal.
15
Large, randomised trials have provided much data regarding the
prevalence of liver toxicity and the degree of severity.
8
The Heart
Protection Study showed no significant excess in ALT or AST levels,
with nine statin patients and four placebo patients having persistent
transaminase elevations of more than three times the upper limit
of normal.
9
There were also no significant differences between statin-treated
patients and the placebo group in other large-scale trials such as
the Long-term Intervention with Pravastatin in Ischemic Disease
(LIPID) trial,
16
and the West Of Scotland COronary Prevention Study
(WOSCOPS).
17
Acute Liver failure did not occur in any of the above
trials and minor elevations in liver enzymes resolved spontaneously
with continued treatment.
15
However if an increase in liver enzymes
more than three times the upper limit of normal persisted, then
discontinuation of therapy was recommended.
The evaluation of a large number of patients has shown that
marked elevations in liver enzymes are rare. They potentially occur
when other co-morbidities are present, including pre-existing
disease, and when the highest dose of statin is used, as well as
with drug interactions.
18,19
Other recorded side effects include cognitive decline, peripheral
neuropathy, diabetes, insomnia, tendinitis, arthralgia, arthritis,
cataracts and haemorrhagic stroke.
20-22
However these side effects
are exceedingly rare.
Beneficial effects
Along with the adverse side effects, there are several beneficial
effects that are provided by the statins. These are the cardiovascular