Zahida Bashir

ABSTRACT

Statins are the mainstay of treatment of lipid disorders that are characterized by
elevations in low-density lipoprotein cholesterol (LDL-C). Inhibition of the synthesis of
mevalonate, leading to depletion of its metabolites, such as cholesterol, isoprenoids,
and ubiquinone (coenzyme Q10). Observational studies estimate that statin users
develop statin-related muscle side effects ranging from mild myalgia to more severe
muscle symptoms with significant CPK elevations. There are multiple risk factors for
statin-induced myopathy that are both patient-related (age, genetics, co-morbidities)
and drug-related. Management options for statin-intolerant patients include statin
switching, especially to low-dose, non-daily doses of long-acting statins, such as
rosuvastatin and atorvastatin, and other non-statin lipid-lowering agents such as
Cholesterol Absorption Inhibitor (Ezetimibe) and possibly red yeast rice. In
conclusion, statin-induced myopathy is a significant clinical problem that contributes
considerably to statin therapy discontinuation. However, there exist multiple and
effective management options for statin intolerant patients.
KEY WORDS
Myopathy disorders characterized by a primary structural or functional impairment of skeletal
muscle.
Rhabdomyolysis is a serious syndrome due to a direct or indirect muscle injury. It results from the death
of muscle fibers and release of their contents into the bloodstream.
Mevalonate pathway or HMG-CoA reductase pathway (3-hydroxy-3-methyl-glutaryl-
coenzyme) is metabolic pathway in eukaryotes and bacteria. It produces two
five-carbon building blocks called isopentenyl pyrophosphate (IPP), to
make isoprenoids, such as cholesterol, vitamin K, Coenzyme Q10.
Coenzyme Q10 makes the heart's muscle cells more efficient at producing and using energy
Statins are a class of prescription drugs designed to lower high cholesterol. Side effects such are
Muscle pain, nausea and diarrhea, liver and kidney damage & type 2 diabetes. Statins also lower your
body’s levels of coenzyme Q10.

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BACKGROUND
One study reported 5150 cases of minor muscle pain per 100,000 patient years, 97
cases of myopathy and 4.4 cases of rhabdomyolysis. 24The PRIMO study, which
included 8,000 patients receiving high-dose statin therapy for hyperlipidaemia, found
that muscular symptoms were reported in 10.5% of the subjects. Estimates suggest
around 1.5 million people per year worldwide will experience myotoxicity related to
statin use. In one large, population based study of patients from general practices
between 1991 and 1997, the mean incidence of myopathy in patients taking statins
was 1.2 per 10 000 person years. In another large study that examined
rhabdomyolysis in a hospital population, the average incidence per 10 000 person
years for monotherapy with simvastatin was 0.44. A recent European study
estimated that 20% of patients with coronary heart disease do not use statins.
Statins however, 10 -- 12% of patients develop muscle related adverse effects.

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INTRODUCTION
Statins are the mainstay of treatment of lipid disorders that are characterized by
elevations in low-density lipoprotein cholesterol (LDL-C). Inhibition of the synthesis of
mevalonate, leading to depletion of its metabolites, such as cholesterol, isoprenoids,
and ubiquinone (coenzyme Q10). Despite reducing clinical cardiovascular end
points by 30%. and having a positive benefit risk ratio, statins are underutilized.
Understanding statin-induced myopathy is important given the large and expanding
numbers of patients eligible for statin therapy and the fact that myalgia is one of the
most frequent causes of discontinuation of therapy. The purpose of this review article
is to provide an updated review of the epidemiology, clinical features, risk factors and
mechanisms of statin-induced myopathy. It also provides an updated, evidence-
based management algorithm for managing patients with statin myopathy.
Simvastatin, the most lipophilic one, was most likely to be associated with muscular
adverse effects. Risk factors for statin induced myopathy include a history of muscle
symptoms or elevated CK, hypothyroidism, female sex, older age, renal and hepatic
insufficiency, diabetes, excessive alcohol consumption, and concomitant use of
medications that increase the serum concentration of statins. In Clinical
Presentation The most common symptoms displayed with statin-associated
myopathies include fatigue, flulike symptoms, and nocturnal cramping. Other
symptoms may include unintentional weight loss, tachycardia, nausea, and brown
urine from myoglobin breakdown. Main Adverse effects Muscle pain, Studies of
statins indicate that people taking statins develop muscle pain at the same rate as
people taking placebo. But up to 29 percent of the people who start taking statins
report muscle pain and many discontinue statins because of it. Many of these people
do well when they are switched to a different variety of statin. Other Side effects are
Liver damage, Increase blood sugar etc.
Management of statin-associated muscle symptoms:

 Ensure that there is an indication for statin use and that the patient is fully
aware of the expected benefit in cardiovascular disease risk reduction that
can be achieved with this treatment
 Ensure that there are no contraindications to statin use
 Counsel patients regarding the risk of ‘side effects’ and the high probability
that these can be dealt with successfully
 Emphasize dietary and other lifestyle measures
 Use statin-based strategies preferentially notwithstanding the presence of
statin-attributed muscle-related symptoms
 If re-challenge does not work; use a low or intermittent dosing preferably of a
different (potent or efficacious) statin
 Use non-statin therapies as adjuncts as needed to achieve
 low-density lipoprotein cholesterol goal

Pharmacists can help manage patients who take statins to ensure early identification
of drug interactions or pharmacokinetic changes that might influence serum drug
levels.

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CASE

Mr KM is a fairly active 69-year-old. He has regularly presented his repeat

prescription for atenolol 50 mg daily, aspirin 75 mg daily and simvastatin 40 mg daily
to the same community pharmacy for several years. Last month diltiazem SR 60 mg
twice daily was added, as he had been getting increasing angina symptoms. He asks
for a topical product to treat neck pain, which has developed in the last few days
which he puts down to a ‘frozen shoulder’.
Questions
 Could this be an ADR and why did it develop now?
 Is it appropriate to change to another statin?
 What actions should the pharmacist take?

DISCUSSION

Neck pain, ‘frozen shoulder’ are typical of the muscular pain which is induced by
statins. The onset varies from a few weeks to over 2 years after starting treatment,
the incidence is dose-related and the severity ranges from mild aches to severe pain,
causing reduced mobility. Older people, who may have reduced renal function or
liver function, are at greater risk of statin-induced myopathy.
Diltiazem can inhibit the metabolism of simvastatin due to its actions on cytochrome
P450 isoenzyme CYP3A4, thereby increasing the risk of myopathy. Statin-induced
myopathy ranges from mild myopathies, to rare cases of potentially life-threatening
rhabdomyolysis, in which muscle cell walls are disrupted and the contents leak into
the systemic circulation. Muscle pain in patients taking statins should, therefore,
always be taken seriously.
The problem is associated with all drugs in the class. Although simvastatin’s are the
most widely prescribed, are both lipophilic and metabolised by cytochrome P450 3A4
and, therefore, may be most likely to cause muscle pain, there is no reliable
comparative data on different statins.
Creatinine kinase (CK) levels should have been measured before initiating statin
therapy, a CK level should be measured now, plus liver function tests and the
patient encouraged to report the ADR via the Yellow Card Scheme. It may be
appropriate to discontinue or reduce the dose of the simvastatin, depending on the
result of the CK level and the severity of the symptoms. The problem may not
resolve immediately on discontinuation. Grapefruit juice can increase blood levels of
simvastatin and high alcohol intake increases the risk of myopathy, so the
pharmacist should also warn Mr KL about avoiding these.

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REFERENCES

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