Muscle damage is an uncommon, but important, adverse reaction to HMG CoA reductase inhibitors ('statins').1Patients may experience a range of musculoskeletal symptoms varying from mild aching to severe pain, usually in proximal muscle groups. Muscle stiffness and weakness also occur to a varying degree. The concentration of creatine kinase (CK) in the blood is usually increased.

Mild symptoms, (myalgia) are usually associated with minimal elevation of CK concentrations (3-10 times upper limit of normal). Myalgia occurs in 2-7% of patients treated with statins in randomised clinical trials, but the incidence is similar in placebo-treated patients.

In myopathy, CK concentrations are more than 10 times the upper limit of normal, with or without symptoms. Myopathy occurs in 0.1-0.2% of clinical trials, at a slightly greater rate than in placebo-treated patients.1

The most serious type of muscle damage, rhabdomyolysis, occurs only rarely but is important to recognise as it may be fatal.1Rhabdomyolysis is associated with CK concentrations more than 40 times the upper limit of normal. The patient often has severe muscle pain, stiffness and weakness, with constitutional symptoms of fever and malaise. Their urine may be dark and of small volume, because of myoglobinuria and impaired renal function.

Stopping the drug is the only specific treatment for muscle damage. The symptoms usually resolve rapidly (within a few days to weeks) after withdrawal of statin therapy.

The mechanism of muscle damage is unknown at this stage. Risk factors include high blood concentrations of statins, increasing age, multi system disease, hypothyroidism, acute illness, major surgery, low body weight and female gender. Drugs that affect the cytochrome P450 system can increase the concentrations of statins that are metabolised by this enzyme system (all statins but pravastatin).2Combination therapy with nicotinic acid and gemfibrozil can also result in muscle damage.

The combination of gemfibrozil and cerivastatin was largely responsible for about 100 deaths from complications of rhabdomyolysis. This led to the withdrawal of cerivastatin from world markets in 2001, and increased the attention given to statin-associated muscle damage.3Gemfibrozil inhibits a recently reported pathway of hepatic glucuronidation, which appears to be involved in the metabolism of most statins, particularly cerivastatin.4

Recently, histologically-confirmed muscle damage has been found in four patients with normal CK concentrations.5Muscle damage was suspected because of weakness and/or severe myalgia, which responded to statin withdrawal and recurred on statin rechallenge. The histochemical changes observed on muscle biopsy suggested a defect in mitochondrial respiratory chain function. These histological changes resolved three months after statin withdrawal in the three patients who had repeat biopsies. As none of the four patients had high concentrations of statins in their blood, they may have had some kind of increased susceptibility to muscle damage with statin therapy. This finding extends previous observations made in Australia.6

The prevalence of muscle damage in patients with normal CK concentrations is unknown. The disorder must be seriously considered in any patient taking a statin who complains of muscle aches and pains and/or weakness in spite of normal CK concentrations. A trial of statin withdrawal should be considered.

A plan to manage myopathy in patients on statin therapy has been outlined in the USA.3Baseline renal, thyroid and hepatic function tests and CK concentrations are recommended before starting statin therapy. Muscle symptoms should be assessed after 6-12 weeks and at each follow-up visit. If muscle symptoms occur the CK should be measured. This advice was published before the finding that muscle damage can occur with a normal CK concentration, so the recommendations regarding statin withdrawal may be too conservative.

Controlled trials have shown that statins improve overall mortality and the incidence of all forms of cardiovascular disease in patients at increased risk of these diseases. Muscle damage must be placed in the context of the recognised benefits of statin therapy. Clinicians should be aware of the need for vigilance in the monitoring of symptoms. Patients should be advised to report any symptoms at the earliest stage in order to prevent the rare, but more serious, muscle complications of statin therapy.

In many cases (perhaps the majority), muscle symptoms will prove to be unrelated to statin therapy. In others, elevated CK concentrations may be the result of exercise or minor muscle damage from trauma. Statin withdrawal and rechallenge may also be subject to a pronounced placebo effect. There is also the potential to further reduce compliance if patients were to believe that any muscle ache or pain they experience may be related to statin therapy. These considerations suggest that the management of statin muscle damage will not be straightforward until there is a specific diagnostic test available.

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References

  1. Hamilton-Craig I. Statin-associated myopathy. Med J Aust 2001;175:486-9.
  2. Martin J, Fay M. Cytochrome P450 drug interactions: are they clinically relevant? Aust Prescr 2001;24:10-2.
  3. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40:567-72.
  4. Prueksaritanont T, Subramanian R, Fang X, Ma B, Qiu Y, Lin JH, et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos 2002;30:505-12.
  5. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002;137:581-5.
  6. England JD, Walsh JC, Stewart P, Boyd I, Rohan A, Halmagyi GM. Mitochondrial myopathy developing on treatment with the HMG CoA reductase inhibitors - simvastatin and pravastatin. Aust N Z J Med 1995;25:374-5.