Investigating myalgia in patients taking statins

Statins are among the most widely prescribed medicines in New Zealand; in 2013, approximately 500 000 patients were dispensed a prescription for either simvastatin or atorvastatin.¹ Alongside lifestyle modification, statins are the mainstay of lipid management. New Zealand and international guidelines recommend statins for the primary prevention of cardiovascular disease - see: “Guidelines for initiating statins”.^{2, 3, 4} Numerous trials have confirmed that statin treatment is effective in the secondary prevention of cardiovascular events caused by atherosclerosis. Among patients with heart disease who take statins for five years, the number needed to treat (NNT) to prevent one non-fatal myocardial infarction is 39, and the NNT to prevent one death is 83.⁵

Before a patient begins taking statin treatment it is important that causes of dyslipidaemia are considered and managed appropriately, e.g. high saturated fat diet, excessive alcohol consumption, hypothyroidism, diabetes, liver disease, nephrotic syndrome and corticosteroid treatment.⁴

Monitoring lipid profile in patients taking statins

It is recommended that once a patient is initiated on statin treatment that their lipid profile should be monitored every three to six months, until their levels are stable, and then no more than once a year.⁴ Measuring lipid levels more frequently may produce misleading results as day-to-day variation can be greater than trends over time.⁴

Low-density lipoprotein bound cholesterol (LDL-C) levels are widely used as an indicator of lipid management in patients taking statins.⁶ When given at comparable doses the ability of the various statins to reduce LDL-C is similar.⁷ There is no specific target LDL-C in patients with a five-year cardiovascular risk less than 20%; the aim is to achieve a moderate reduction in LDL-C.⁴ The intensity of statin treatment is dependent on the patient’s cardiovascular risk. A greater reduction in LDL-C from baseline should be expected in patients with a cardiovascular risk greater than 20%.²

Monitoring statin safety is not routinely required

Statins are generally considered a safe class of medicine, however, adverse effects are sometimes reported. These adverse effects can be grouped into the “Five Ms”:⁸

1. Muscle symptoms, e.g. myalgia and/or weakness
2. Medicine interactions
3. Major organ effects, e.g. hepatic and renal effects
4. Metabolism, i.e. risk of type 2 diabetes
5. Memory, i.e. cognitive adverse effects

Most guidelines suggest taking a baseline measurement of liver function (alanine aminotransferase – ALT) before initiating statin treatment. However, to avoid unnecessary testing, it is suggested by many New Zealand experts that this approach be limited to patients in whom there is reason to suspect liver dysfunction.

Baseline testing of muscle enzymes (creatine kinase) prior to statin treatment is unnecessary, unless there is a specific reason to do so, e.g. the patient has risk factors (See: Investigating Myalgia).

Once treatment has started, monitoring of ALT or creatine kinase is unnecessary unless clinically indicated, i.e. the patient is symptomatic or has specific risk factors.

Hepatotoxicity with statins

Hepatotoxicity due to statin treatment is highly unusual. Rarely, hepatitis and jaundice are reported in patients taking statins.⁹ New Zealand guidelines state that the risk of hepatotoxicity due to statin treatment appears negligible,⁶ and routine monitoring of liver function is considered unnecessary.^{2, 6}

United States guidelines recommend that a baseline ALT test be performed in patients prior to initiating statin treatment.² United Kingdom guidelines also recommend measuring liver enzyme levels within three months of starting statin treatment and at 12 months.³ However, ALT testing is unlikely to provide useful information unless there is reason to suspect that the patient has liver dysfunction. Elevations in transaminase levels are typically seen in less than 3% of patients taking statins and are not significantly different from rates among patients taking placebo.⁸ Furthermore, these elevations often return to normal without patients needing to stop taking statins.⁸

If an ALT test is requested in a patient with suspected liver dysfunction, a markedly elevated level would be considered a risk factor for adverse effects of statins, and the risk versus benefits of statin treatment should be revisited; statins should be used with caution in patients with an ALT greater than three times the upper limit of normal.⁹ If the patient does decide to begin statin treatment, a lower dose may be appropriate.⁸ Patients with non-alcoholic fatty liver disease will typically display a mild to moderate increase in ALT.¹⁰ Atorvastatin has been found to reduce aminotransferase levels in patients with fatty liver disease. Mildly abnormal LFTs in a patient with non-alcoholic fatty liver disease should not be considered a contraindication for statin treatment.¹⁰

It is reasonable to monitor hepatic function in patients taking statins with suspected liver dysfunction and an elevated baseline ALT level, or in patients who develop symptoms suggestive of hepatotoxicity, e.g. unexplained fatigue or weakness, loss of appetite, abdominal pain, dark-coloured urine, or yellowing of the skin or sclera.²

Best Practice Tip: If a liver function test is requested in the context of statin treatment, request an ALT test only, rather than “LFTs”. Further testing of liver function can be performed by the laboratory on the same blood sample if necessary, within a limited time period. Also consider customising your PMS so when requesting investigations, individual liver function tests can be selected rather than “LFTs”.

Myalgia is a potential adverse effect of statin treatment

Myalgia, with or without muscle weakness, is the most common adverse effect associated with statin use, and is reported to occur in up to 10% of people prescribed statins.¹¹ Statins are not necessarily the cause of myalgia in all of these people, however, as myalgia is frequently reported in the general population and can have many aetiologies.

Myalgia may be described as a muscular ache, heaviness, stiffness or cramping sensation; tendon pain and nocturnal leg cramps may also occur.¹² Muscle weakness can also occur without discomfort and may be noticed by patients as an inability to open jars, difficulty snapping their fingers or difficulty getting out of a chair.¹² Statin-associated myalgia is characterised by the symmetrical involvement of large and proximal muscle groups, in particular the legs.¹³ Symptoms typically begin within six months of initiating the statin.¹³

When myalgia is associated with muscle inflammation, this is referred to as myositis. Myositis is usually accompanied by an elevation in serum creatine kinase.¹² Rhabdomyolysis occurs when the inflammation is associated with muscle fibre break-down, releasing myoglobin into the bloodstream.¹³ The distinction between myositis and rhabdomyolysis is not always clear, however, a broadly accepted criteria for rhabdomyolysis is serum creatine kinase levels more than ten times the upper limit of normal, with evidence of myoglobinaemia.^{8, 11, 13} Other definitions of rhabdomyolysis include elevations of creatine kinase greater than 40 times the upper limit of normal, and increased creatine kinase in association with renal failure.¹⁴

Elevations of creatine kinase are not necessarily diagnostic of a pathological process. Transient elevations can occur in healthy people, e.g. following vigorous exercise. Serious complications of muscle cell damage are more likely to occur in patients with risk factors, such as co-morbid illness, dehydration or pre-existing renal impairment. These complications include acute kidney injury (AKI) and widespread vascular coagulation.¹² Death due to rhabdomyolysis in patients taking statins is extremely rare; more than eight thousand patients would need to take a statin for at least 40 years for one extra death to occur.¹⁵

A recent study assessing the Effect of Statins On Skeletal Muscle Function and Performance (STOMP) involved giving high dose atorvastatin (80 mg), daily, to over 200 healthy females with no history of statin use, for six months.¹⁶ It was found that the average creatine kinase level in females taking a statin increased by 20.8 U/L, compared to placebo.¹⁶ The normal creatine kinase range is 30 – 180 U/L for females and 60 – 220 U/L for males.¹⁷ Nineteen patients taking atorvastatin reported myalgia, compared to ten taking placebo, but there was no noticeable difference in terms of muscle strength, e.g. hand-grip, elbow flexor and knee extensor strength.¹⁶ A lower incidence of myalgia is reported in clinical trials than is experienced by patients taking statins in clinical practice possibly due to the exclusion from studies of patients with a history of muscle symptoms, or risk factors for the development of myalgia.⁸

The pathophysiology of statin-associated myalgia

Multiple mechanisms are thought to contribute to the development of statin-associated myalgia, and no one mechanism fully explains muscle symptoms associated with statin use:¹²

• Cholesterol plays an important role in maintaining cell membrane function. Disruptions to cholesterol synthesis may affect membrane ion channels and thereby modify muscle membrane excitability. This effect has been observed in some animal models. However, inhibitors of squalene synthase (involved in the final step in cholesterol synthesis) also lower cholesterol, but do not cause muscle damage.
• Mevalonate is a precursor of co-enzyme Q10 (CoQ10 or ubiquinine), as well as being a precursor of cholesterol, and is also an important antioxidant involved in the electron transport chain in mitochondria. Reductions in CoQ10 have been suggested to interfere with cellular respiration and result in muscle toxicity. However, muscle CoQ10 levels do not correlate well with histological changes.¹¹ There is insufficient evidence to recommend the routine administration of CoQ10 for the prevention of statin-associated myalgia.¹⁸
• Statins may cause a reduction in other synthetic precursors of cholesterol, which have functional roles in cellular protein physiology
• Programmed cell death (apoptosis) in skeletal muscle may be triggered by statins
• Statins have been shown to decrease muscle strength by altering the movement of calcium within animal muscle cells

Risk factors for statin-associated myalgia

Myalgia is more likely to be experienced in patients taking statins, if they have additional risk factors (Table 1). For example: frail, elderly females; people with co-morbidities such as chronic kidney disease and diabetes; people taking high doses of statins or medicines which interact with statins; and people with a genetic pre-disposition.¹³

Medicine interactions

The risk of patients experiencing myalgia when taking statins metabolised by the cytochrome P-450 (CYP) 3A4 system, e.g. simvastatin and to a lesser extent atorvastatin, is increased if they are taking other medicines that also interact with the CYP 3A4 system, e.g. macrolide antibiotics.¹⁹ A study investigating over 3000 cases of statin-associated rhabdomyolysis found that in more than half of cases, patients were also taking medicines known to affect statin metabolism.¹⁹

It may be necessary to temporarily stop simvastatin if patients are required to take the following medicines:²⁰

• Erythromycin and clarithromycin
• Azole antifungals, e.g. itraconazole, posaconazole and voriconazole
• Protease inhibitors, e.g. ritonavir, telaprevir, boceprevir
• Gemfibrozil
• Ciclosporin
• Danazol

Atorvastatin should also be avoided, if possible, in patients taking any of the above medicines, but if the combination is required then it should be used with caution and the patient advised to report any muscle symptoms.²⁰ There have been case reports of rhabdomyolysis occurring in patients taking simvastatin and azithromycin or roxithromycin, however, no clinically significant interactions are known to occur between these antibiotics and atorvastatin.²⁰

New Zealand guidelines recommend a maximum daily dose of simvastatin of 20 mg for patients taking amiodarone, verapamil, diltiazem, nicotinic acid > 1 g/day, and amlodipine.^{4, 9} The dose of simvastatin should be limited to 10 mg/day if given with bezafibrate.⁹ Dose reductions of simvastatin should be considered for patients taking systemic fusidic acid or terbinafine, or colchicine if the patient has renal impairment.⁴ Atorvastatin should be used with caution in patients taking these medicines and the patient advised to report any muscle symptoms.²⁰

Pravastatin is mainly cleared by the kidneys and is a fully subsidised alternative statin for patients taking medicines that may interfere with the CYP enzyme system. The combination of pravastatin with fibrates is associated with an increased risk of muscle damage.²¹

Rosuvastatin is largely metabolised by another enzyme system (OATp1B1) and therefore has fewer and different interactions than statins metabolised by the CYP 3A4 system.⁸

For further information see: “Simvastatin and atorvastatin: beware of potential CYP3A4 interactions when prescribing other medicines”, BPJ 60 (Apr, 2014).

Table 1: Risk factors for statin-associated myalgia, adapted from Ahmad 2014¹³

Monitoring and investigating mylagia in patients taking statins

Laboratory monitoring for evidence of muscle damage is not routinely recommended for asymptomatic patients on a stable dose of statins for the treatment of hypercholesterolaemia.²

Before starting statin treatment

Serum creatine kinase levels should not be routinely measured in patients prior to statin treatment, unless there are risk factors for statin-associated myalgia present (see below).² This is because an elevated creatine kinase level in patients without muscle symptoms does not necessarily predict the development of myalgia.²⁴ Creatine kinase levels up to ten times higher than normal levels have been reported to occur in patients taking statins without symptoms of myalgia.¹²

Before initiating statin treatment patients should be asked about their history of muscle symptoms, such as muscle weakness or fatigue, aching or pain, tenderness, cramps or stiffness, including frequency and duration.² The possible adverse effects of statin treatment should be discussed with patients and they should be instructed to report any unexplained muscle symptoms.

For patients who have an increased risk of developing statin-associated mylagia, it is reasonable to take a baseline serum creatine kinase measurement before initiating statin treatment, or alternatively, to have a lower threshold for measuring serum creatine kinase once statin treatment has begun. This includes patients with:²

• A personal or family history of statin intolerance
• A personal or family history of muscle disease
• Concurrent medicines that may increase the risk of myalgia
• Risk factors for statin-associated muscle damage, e.g. renal or hepatic impairment

Best Practice Tip: If testing is required, “serum creatine kinase” should be specifically requested on the form along with a note that the purpose of testing is the investigation of myalgia.

Monitoring patients during treatment

Creatine kinase levels should not be routinely monitored in asymptomatic patients taking statins.²

If creatine kinase levels are requested, e.g. in patients with risk factors for myalgia, and the patient is asymptomatic, but levels are markedly elevated, withdrawal and rechallenge of statin treatment may be appropriate to determine if the increase is associated with the statin.

If the patient is symptomatic, and creatine kinase levels are found to be elevated, investigate as below.

Investigating myalgia in patients taking statins

Myalgia is commonly reported in clinical trials by patients taking either statins or placebo, therefore it is important to avoid the unnecessary discontinuation of treatment.⁸

Differential diagnosis of myalgia

The characteristics of the patient’s pain may help determine the degree of clinical suspicion for statin-associated myalgia:

• Myalgia associated with physical activity is likely to be self-limiting
• Acute onset myalgia with upper respiratory tract symptoms suggests viral infection
• Myalgia with swelling or localised warmth suggests localised inflammation or infection
• Myalgia in a patient with poor sleep quality and stress is suggestive of fibromyalgia syndrome, a common cause of myalgia (see: “Fibromyalgia syndrome: a constellation of symptoms”)
• Muscle pain and stiffness in the morning suggests polymyalgia rheumatica (see below)
• Slow onset myalgia with long-term symptoms is more suggestive of a chronic condition such as hypothyroidism, hypercalcaemia or severe vitamin D deficiency

Consider the possibility of other causes for the patient’s symptoms and investigate as appropriate.² In patients who have a consistent history of muscle symptoms prior to starting their statin treatment, it is more likely that the cause of their myalgia is not associated with statin use. Polymyalgia rheumatica should be suspected in patients aged over 60 years who report shoulder and pelvic girdle pain and stiffness in the morning that improves later in the day.²⁵ An elevated C-reactive protein (CRP) makes a diagnosis of polymyalgia rheumatica more likely.²⁵ An elevated serum calcium level is suggestive of hyperparathyroidism.

For further information see: “Polymyalgia rheumatica: Look before you leap”, BPJ 53 (Jun, 2013).

Ask the patient about their adherence to the statin regimen, e.g. have they recently started taking higher doses, and the use of other medicines that may influence statin metabolism. If an obvious cause of the patient’s symptoms has not been identified then statin treatment should be withdrawn for at least two weeks while the patient’s condition is evaluated further.¹³ Recording the patient’s subjective baseline score, e.g. muscle pain, on a one to ten scale, before statin treatment is withdrawn, can be a useful way of comparing muscle symptoms over time if a statin rechallenge is tried (see below).

Request a serum creatine kinase test to investigate possible muscle damage and serum creatinine to assess kidney function. However, a normal creatine kinase test does not necessarily exclude the possibility of statin-induced myalgia as biopsy-proven statin-associated muscle damage, in conjunction with muscle weakness, can occur in some patients with normal creatine kinase levels.¹³ A symptom-based approach is therefore useful, supported by laboratory test results:⁴

• For patients with muscle pain, but no rise in creatine kinase, a reduction in statin dose or discontinuation of treatment may be required; monitoring of creatine kinase is not necessary.
• For patients with creatine kinase levels between three and ten times the normal level a reduction in statin dose, or discontinuation of treatment is appropriate; the patient’s symptoms and creatine kinase levels should be regularly monitored if treatment is continued, e.g. weekly.
• For patients with creatine kinase levels greater than ten times the upper limit of normal, statins should be discontinued immediately

Confirming statins as the cause of myalgia

A rechallenge of the same statin at the original, or lower dose, can be used to indicate if the statin was the cause of the patient’s symptoms.² Although the sensitivity and specificity of withdrawal and rechallenge is unknown, the STOMP trial found that 4.6% of people receiving placebo experienced myalgia during a controlled withdrawal and rechallenge.¹⁶

If a causal relationship is found between the patient’s symptoms and statin treatment then the original statin should be discontinued.¹³ At this point discuss the benefit versus risks of continued statin treatment with the patient. The adverse effects of statin treatment may outweigh the potential benefit of a reduction in cardiovascular risk provided by treatment, e.g. in frail older people. If statin treatment is reintroduced, a low dose of another statin, e.g. pravastatin, can be trialled.² Most of the LDL-C lowering benefit of statins occurs at lower doses.² The statin dose can be titrated upwards, if appropriate. Alternate day, or even twice weekly, dosing regimens have also been trialled in patients experiencing adverse effects of statin treatment.¹²

The importance of diet, exercise and avoidance of smoking should be reiterated before considering offering patients alternative lipid-lowering medicines.² Expert opinion is that high-risk patients who are intolerant to statin treatment, may benefit from non-statin lipid-lowering medicines, e.g. gemfibrozil or nicotinic acid (see New Zealand Formulary for dosing details).² High-risk patients include those with any of the following:²

• Atherosclerotic cardiovascular disease
• Diabetes and age 40 – 75 years
• LDL-C ≥ 5.0 mmol/L and an elevated cardiovascular risk

Investigating patients with unresolved symptoms or persistently elevated creatine kinase

If the patient’s symptoms or creatine kinase results have not resolved two months after the withdrawal of statin treatment then an alternative diagnosis should be reconsidered, although statin-associated symptoms may take up to three months to resolve completely.^{2, 13} Review the likelihood of conditions previously ruled-out and consider the possibility of fibromyalgia.